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COMMITTEE OF EXPERTS ON THE CLASSIFICATION OF MEDICINES AS REGARDS THEIR SUPPLY (CD-P-PH/PHO)

Report classification/justification of

- Medicines belonging to the ATC group M01 (Antiinflammatory and antirheumatic products)

Table of Contents

Page

INTRODUCTION 6

DISCLAIMER 8

GLOSSARY OF TERMS USED IN THIS DOCUMENT 9

ACTIVE SUBSTANCES

Phenylbutazone (ATC: M01AA01) 11

Mofebutazone (ATC: M01AA02) 17

Oxyphenbutazone (ATC: M01AA03) 18

Clofezone (ATC: M01AA05) 19

Kebuzone (ATC: M01AA06) 20

Indometacin (ATC: M01AB01) 21

Sulindac (ATC: M01AB02) 25

Tolmetin (ATC: M01AB03) 30

Zomepirac (ATC: M01AB04) 33

Diclofenac (ATC: M01AB05) 34

Alclofenac (ATC: M01AB06) 39

Bumadizone (ATC: M01AB07) 40

Etodolac (ATC: M01AB08) 41

Lonazolac (ATC: M01AB09) 45

Fentiazac (ATC: M01AB10) 46

Acemetacin (ATC: M01AB11) 48

Difenpiramide (ATC: M01AB12) 53

Oxametacin (ATC: M01AB13) 54

Proglumetacin (ATC: M01AB14) 55

Ketorolac (ATC: M01AB15) 57

Aceclofenac (ATC: M01AB16) 63

Bufexamac (ATC: M01AB17) 67

2 , Combinations (ATC: M01AB51) 68

Diclofenac, Combinations (ATC: M01AB55) 69

Piroxicam (ATC: M01AC01) 73

Tenoxicam (ATC: M01AC02) 77

Droxicam (ATC: M01AC04) 82

Lornoxicam (ATC: M01AC05) 83

Meloxicam (ATC: M01AC06) 87

Meloxicam, Combinations (ATC: M01AC56) 91

Ibuprofen (ATC: M01AE01) 92

Naproxen (ATC: M01AE02) 98

Ketoprofen (ATC: M01AE03) 104

Fenoprofen (ATC: M01AE04) 109

Fenbufen (ATC: M01AE05) 112

Benoxaprofen (ATC: M01AE06) 113

Suprofen (ATC: M01AE07) 114

Pirprofen (ATC: M01AE08) 115

Flurbiprofen (ATC: M01AE09) 116

Indoprofen (ATC: M01AE10) 120

Tiaprofenic Acid (ATC: M01AE11) 121

Oxaprozin (ATC: M01AE12) 125

Ibuproxam (ATC: M01AE13) 128

Dexibuprofen (ATC: M01AE14) 129

Flunoxaprofen (ATC: M01AE15) 134

Alminoprofen (ATC: M01AE16) 135

Dexketoprofen (ATC: M01AE17) 136

Naproxcinod (ATC: M01AE18) 140

Ibuprofen, Combinations (ATC: M01AE51) 141

Naproxen and (ATC: M01AE52) 146

Ketoprofen, Combinations (ATC: M01AE53) 153

Naproxen and (ATC: M01AE56) 157

3 (ATC: M01AG01) 158

Tolfenamic Acid (ATC: M01AG02) 164

Flufenamic Acid (ATC: M01AG03) 169

Meclofenamic Acid (ATC: M01AG04) 170

Celecoxib (ATC: M01AH01) 171

Rofecoxib (ATC: M01AH02) 178

Valdecoxib (ATC: M01AH03) 179

Parecoxib (ATC: M01AH04) 180

Etoricoxib (ATC: M01AH05) 187

Lumiracoxib (ATC: M01AH06) 195

Polmacoxib (ATC: M01AH07) 197

Nabumetone (ATC: M01AX01) 198

Niflumic acid (ATC: M01AX02) 201

Azapropazone (ATC: M01AX04) 204

Glucosamine (ATC: M01AX05) 205

Benzydamine (ATC: M01AX07) 207

Glucosaminoglycan Polysulfate (ATC: M01AX12) 208

Proquazone (ATC: M01AX13) 209

Orgotein (ATC: M01AX14) 210

Nimesulide (ATC: M01AX17) 211

Feprazone (ATC: M01AX18) 214

Diacerein (ATC: M01AX21) 215

Morniflumate (ATC: M01AX22) 218

Tenidap (ATC: M01AX23) 221

Oxaceprol (ATC: M01AX24) 222

Chondroitin (ATC: M01AX25) 224

Avocado and Soyabean Oil, Unsaponifiables (ATC: M01AX26) 226

Feprazone, Combinations (ATC: M01AX68) 228

Phenylbutazone and (ATC: M01BA01) 229

Dipyrocetyl and Corticosteroids (ATC: M01BA02) 231

4 Acetylsalicylic Acid and Corticosteroids (ATC: M01BA03) 232

Other Antiinflammatory/Antirheumatic Agents in Combination with Other Drugs (ATC: M01BX) 233

Oxycinchophen (ATC: M01CA03) 235

Sodium Aurothiomalate (ATC: M01CB01) 236

Sodium Aurotiosulfate (ATC: M01CB02) 240

Auranofin (ATC: M01CB03) 241

Aurothioglucose (ATC: M01CB04) 245

Aurotioprol (ATC: M01CB05) 246

Penicillamine (M01CC01) 247

Bucillamine (ATC: M01CC02) 254

Other specific Antirheumatic Agents (ATC: M01CX) 255

LIST OF AUTHORS 256

5 INTRODUCTION

The availability of medicines with or without a medical prescription has implications on patient safety, accessibility of medicines to patients and responsible management of health care expenditure.

The decision on prescription status and related supply conditions is a core competency of national health authorities. The conditions of the supply of medicines vary considerably in Council of Europe member states, due to the fact that the provisions are differently interpreted and implemented by the member states, and that important additional classification criteria are not harmonised.

The Committee of Experts on the Classification of Medicines as regards their Supply (CD-P- PH/PHO)1 is co-ordinated by the European Directorate for the Quality of Medicines and HealthCare (EDQM, Council of Europe) and its working programme is based on Committee of Ministers Resolution CM/Res(2018)1 on the classification of medicines as regards their supply2.

In its work, the CD-P-PH/PHO focuses on public health promotion and uses scientific approaches, taking account of the national assessments of direct and indirect risks which may occur under normal treatment conditions and under medical surveillance, as well as from foreseeable misuse or abuse of medicines.

The CD-P-PH/PHO issues twice a year recommendations to health authorities of Council of Europe member states (EU and non-EU member states) on the classification of medicines and establishes good classification practices.

The recommendations are also useful for pharmaceutical manufacturers and commercial operators of mail-order trade in medicines where such trade is legal.

A pioneer in this field, Council of Europe bodies have been concerned since 1961 with issues relating to the classification of medicines into prescription and non-prescription medicines and have inspired relevant EU legislation.

The classification criteria set out in the Council of Europe resolutions have been supplanted by Directives 92/26/CEE and 2001/83/EC (art. 70-75). Directive 2001/83/EC refers to the Council of Europe in its Whereas 32: “It is therefore appropriate, as an initial step, to harmonise the basic principles applicable to the classification for the supply of medicinal products in the Community or in the Member State concerned, while taking as a starting point the principles already established on this subject by the Council of Europe”3.

It is important to note that:

- The CD-P-PH/PHO does not issue recommendations on the classification of particular medicines, but on active substances used in a medicine for a specific therapeutic purpose.

- In its work, the CD-P-PH/PHO uses the Anatomical Therapeutic Chemical (ATC) classification maintained by the WHO Collaborating Centre for Drug Statistics Methodology4 to identify active substances or combinations of active substances.

- The CD-P-PH/PHO does not give advice relating to pending marketing authorisation procedures.

1 http://go.edqm.eu/PHO

2 http://go.edqm.eu/CMRes20181

3 https://goo.gl/at4RZo

4 https://goo.gl/KvqKir

6 The CD-P-PH/PHO supervises a database (i.e. Melclass1), hosted by the EDQM, which stores the recommendations that the Committee of Experts issues twice a year to health authorities of the Council of Europe member states which are parties to the Convention on the Elaboration of a European Pharmacopoeia, as well as national information about the classification status and supply conditions of medicines in these member states. The information is publicly available. Recommendations about 2300 medicines are published in the Melclass database.

Providing a platform for dialogue and consensus building on the supply conditions of medicines in Europe as facilitated by Council of Europe Committee of Ministers Resolution CM/Res(2018)1, the CD-P-PH/PHO promotes patient safety and, where appropriate, access to medicines without a prescription across Europe, which helps to foster public health and to responsibly manage healthcare resources.

1 https://melclass.edqm.eu/

7 DISCLAIMER

This document is published for information only.

The reports included in this document have no legal status and no binding character.

They reflect the debates and conclusions of the reviews of scientific classifications of medicines that took place at the 62nd and 63rd meetings of the CD-P-PH/PHO (May and November 2017, respectively). The document was reviewed and endorsed by the CD-P-PH/PHO at its 64th meeting (April 2018).

The reviews carried out do not commit the parent authorities of the experts nor the Council of Europe/EDQM.

8 GLOSSARY OF TERMS USED IN THIS DOCUMENT

ACE Angiotensin-converting ALT aminotransferase ARF Acute renal failure ASA Acetylsalicylic acid AST Aspartate aminotransferase ATC Anatomical Therapeutic Chemical classification 1 AUC Area under curve CABG Coronary artery bypass grafting CBC CgA Chromogranin A CHMP Committee for Medicinal Products for Human Use Coordination Group for Mutual Recognition and Decentralised CMDh Procedures - Human CNS Central nervous system COX CYP Cytochromes EE Ethinyl EMA European Medicines Agency FDA Food and Drug Administration GI Gastrointestinal HMA Heads of Medicines Agencies HRT Hormone replacement therapy IM Intramuscular INR International normalised ratio IV Intravenous LDH Lactate dehydrogenase MI MS Maximal strength MDD Maximal daily dose MQP Maximal quantity per pack MRI Mutual recognition information NO Naproxen-based NSAID Non-steroidal antiinflammatory drug OA OTC Over-the-counter (medicine supplied without prescription) PDR Physicians’ Desk Reference PIL Patient information leaflet POM Prescription only medicine PPI Proton pump inhibitors PRAC Risk Assessment Committee RA Rheumatoid SGOT Serum glutamic oxaloacetic transaminase SGPT Serum glutamic pyruvic transaminase SLE Systemic lupus erythematosus SmPC Summary of product characteristics

Classification used throughout this document

Following the stipulations of Resolution CM/Res(2018)1, the lists of active substances classified according to the conditions of supply of the medicines which contain them are drawn up with reference to all the risks, direct or indirect, which they may represent to human health whether they are used in accordance with the product information leaflet or not.

The differentiation into two prescription lists (List I and List II) applies only to the countries which classify prescription medicines into two categories based on whether the prescription can be renewed or not.

1 WHO Collaborating Centre for Drug Statistics Methodology - https://goo.gl/KvqKir

9 1. Active substances in medicines subject to prescription

List I: the supply of a medicine containing one of the substances in this list should not be renewed without the prescriber having so specified. This classification should apply to active substances of medicines indicated for conditions calling for short-term treatment and/or for which continuous medical supervision is necessary, either because of potential undesirable effects or to check the of treatment; or active substances of medicines administered for diagnostic purposes; or active substances with a new pharmacological .

List II: the supply of a medicine containing one of the substances in this list can be renewed. This classification should apply to active substances in medicines indicated for conditions for which the patient may continue the regular or intermittent treatment without new medical advice, and for which well-known undesirable effects do not call for frequent clinical examination.

Exemptions from Lists I and II under certain circumstances: depending on the conditions of use of the medicine, active substances contained in prescription medicines may also be contained in medicines classified under the same ATC code but which are not subject to prescription.

Under certain circumstances, exemptions from the prescription requirement may be set out in the Melclass database:

- in respect of a low dosage or concentration of the active substances and/or the therapeutic indications of medicines in which they are contained;

- according to the route of administration and the composition of the medicine;

- according to the total amount of the medicine per container.

2. List of active substances in medicines not subject to prescription: active substances in medicines which are not classified as subject to prescription in Lists I or II.

10 1. THERAPEUTIC PROFILE

1.1 Active ingredient: Phenylbutazone

1.2 ATC code: M01AA01

1.3 Therapeutic indications: oral: . Phenylbutazone should only be used where other therapies have been found unsuitable.

1.4 Posology and duration of treatment: oral: undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms. When long-term treatment is unavoidable, special precautions should be taken and the dosage should be adjusted to the needs of each patient taking account of the patient’s age and general condition.

Phenylbutazone tablets should be swallowed whole with a meal together with liquid. Patients with sensitive stomachs should be given sodium-free at the same time.

Adults: for the initial 48 hours 400-600 mg daily in divided doses. Thereafter, reduce to the minimum amount necessary, usually 200-300 mg daily in divided doses.

Elderly: the elderly are at increased risk of the serious consequences of adverse reactions. If a non- steroidal antiinflammatory drug (NSAID) is considered necessary, the lowest effective dose should be used and for the shortest possible duration. The patient should be monitored regularly for gastrointestinal (GI) during NSAID therapy.

Children: not recommended for children under 14 years.

1.5 Pharmaceutical forms: tablets: 100 mg, 200 mg; rectal suppositories: 200 mg.

Topical formulations (e.g. ointment) are included under ATC code M02AA01.

1.6 Contraindications: hypersensitivity to phenylbutazone or to any of the excipients. Patients who have shown hypersensitivity reactions or asthmatic patients in whom attacks of asthma, urticaria, angioedema or acute rhinitis are precipitated by NSAIDs, including acetylsalicylic acid and ibuprofen, or by other drugs with synthetase inhibiting activity.

Active or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding). History of gastrointestinal bleeding or perforation related to previous NSAID therapy. Use with other NSAIDs including COX-2 selective inhibitors. Patients with symptoms or a history of inflammatory bowel disease with or without ulceration as these conditions may be exacerbated.

Blood dyscrasias and/or haemorrhagic diathesis.

Severe , hepatic, renal or pulmonary insufficiency, oedema or where there is danger of cardiac decompensation.

Last trimester of (premature closure of ductus arteriosus).

Thyroid disease.

Sjögrens’ syndrome.

1.7 Relevant warnings: phenylbutazone should be used only under close medical supervision.

Minimising undesirable effects: in all patients: undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms. Elderly patients are generally more prone to adverse reactions, especially gastrointestinal bleeding and perforation which may be fatal. Particular caution should be exercised.

11 Blood dyscrasias: blood dyscrasias may occur suddenly after a small dose or insidiously after prolonged therapy, particularly in the elderly. If treatment is expected to continue for more than one week, blood counts should be monitored before and regularly during therapy. If significant changes occur, e.g. decrease in leucocyte and/or counts or in the haematocrit, phenylbutazone should be withdrawn. Therapy should also be stopped if symptoms suggestive of a dyscrasia arise (e.g. bruising, fever, sore throat, rash, mouth ulceration) and patients should be advised of this. Granulocytopaenia or aplastic anaemia has to be excluded in patients with before treatment with phenylbutazone is started, as stomatitis might indicate a pre-existing haematological abnormality of this type.

Gastrointestinal bleeding, ulceration and perforation: serious gastrointestinal reactions such as bleeding, ulceration and perforation, which can be fatal, have been reported with NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious GI events. The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation, and in the elderly. These patients should commence treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients and also for patients requiring concomitant low-dose or other drugs likely to increase gastrointestinal risk. Patients with a history of GI , particularly the elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment. Although minor upper gastrointestinal reactions such as dyspepsia are common, usually developing early in therapy, physicians should watch for ulceration and bleeding in patients treated with NSAIDs, even in the absence of previous symptoms. If any of the symptoms or signs suggestive of gastrointestinal toxicity occur, phenylbutazone should be discontinued immediately. Caution should be advised in patients receiving concomitant which could increase the risk of gastrotoxicity or bleeding, such as corticosteroids, such as , selective serotonin reuptake inhibitors or antiplatelet agents such as aspirin. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients. When GI bleeding or ulceration occurs in patients receiving phenylbutazone, the treatment should be withdrawn. NSAIDs should be given with care to patients with a history of GI disease (, Crohn’s disease) as these conditions may be exacerbated. The use of phenylbutazone with concomitant NSAIDs including COX-2 selective inhibitors should be avoided.

Respiratory disorders: NSAIDs inhibit prostaglandin synthetase activity and can precipitate acute attacks of bronchospasm in patients suffering from, or with a previous history of, bronchial asthma. Caution is required when administering phenylbutazone to these patients.

Cardiovascular and cerebrovascular effects: appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy. and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long-term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or ). There are insufficient data to exclude such a risk for phenylbutazone. Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease should only be treated with phenylbutazone after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

Cardiovascular, renal and hepatic impairment: NSAIDs cause dose-dependent reduction in prostaglandin formation, can cause oedema and fluid/sodium retention and may precipitate renal failure. Patients at greatest risk are those with impaired renal function, cardiac impairment, dysfunction, those taking and the elderly. Renal function should be monitored in these patients. Severe hepatic reactions including jaundice and hepatitis have been reported with phenylbutazone. If abnormal liver tests persist or worsen, or clinical consistent with liver disease develop, the drug should be discontinued.

Dermatological: serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens- Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely in association with NSAIDs. Patients appear to be at highest risk for these reactions early in the course of therapy: the onset of the reaction occurring in most cases within the first month of treatment. Phenylbutazone should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of

12 hypersensitivity.

Monitoring - blood tests: if phenylbutazone is given for more than one week, liver function tests, function tests and blood counts should be performed periodically. If significant changes occur, the drug should be withdrawn.

Connective tissue disorders/SLE: patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders may be at increased risk of aseptic meningitis.

Impaired female fertility: the use of phenylbutazone may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of phenylbutazone should be considered.

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): Gastrointestinal: gastrointestinal disorders are the most commonly observed adverse events. Peptic ulcers, perforation or GI bleeding, sometimes fatal, particularly in the elderly, may occur. , , diarrhoea, flatulence, constipation, dyspepsia, abdominal , melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn’s disease have been reported. Less frequently, gastritis has been observed. Isolated cases of pancreatitis, oesophagitis, oesophageal ulcer, benign stricture of the oesophagus and small bowel obstruction have also been reported.

Hypersensitivity: hypersensitivity reactions have been reported following treatment with NSAIDs. These may consist of (a) non-specific allergic reactions and (b) respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea or (c) associated skin disorders including rashes of various types, pruritus, urticaria, purpura, angioedema and more rarely exfoliative and bullous dermatoses (including Stevens-Johnson syndrome, epidermal necrolysis and erythema multiforme). Isolated cases of serum sickness, lymphadenopathy, vasculitis, systemic lupus erythematosus-like syndrome, eosinophilic pulmonary infiltrates and fever have also been reported.

Cardiovascular and cerebrovascular: oedema, hypertension and cardiac failure, have been reported in association with NSAID treatment. Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long-term treatment) may be associated with an increased risk of arterial thrombotic events (for example myocardial infarction or stroke). Rare: congestive heart failure, pulmonary oedema. Isolated cases: hypertension, myocarditis, pericarditis.

Body as a whole: Frequent: oedema, /sodium retention.

Endocrine system: Occasional: goitre, lowering of plasma thyroid hormone concentration. Isolated cases: hypothyroidism.

Neurological and special senses: visual disturbances, optic , , paraesthesia, reports of aseptic meningitis (especially in patients with existing autoimmune disorders, such as systemic lupus erythematosus, mixed connective tissue disease) with symptoms such as stiff neck, , nausea, vomiting, fever or disorientation, depression, confusion, hallucinations, tinnitus, vertigo, dizziness, malaise and drowsiness. Isolated cases: , excitation, blurred vision, retinal haemorrhage, hearing loss.

Haematological: Rare: anaemia due to occult gastrointestinal blood loss, haemolytic anaemia, thrombocytopenia, neutropenia, , leucopenia, pancytopenia, marrow depression, aplastic anaemia.

Hepatic: Rare: increase in serum transaminases, hepatitis and jaundice. Isolated cases: fulminant hepatitis. Frequency unknown: abnormal liver function.

Renal: Rare: impaired renal function, acute renal failure, haematuria, proteinuria. Isolated cases: acute tubular necrosis, acute interstitial nephritis, nephrotic syndrome, glomerulonephritis, papillary necrosis, ureteral obstruction with uric acid crystal formation. Frequency unknown: in various

13 forms.

Respiratory tract: Isolated cases: exacerbation of bronchial asthma and of an “acute pulmonary syndrome” – marked by dyspnoea, fever, shadows in radiographs of the lungs and sometimes also by – have been reported. Although a causal relationship with the latter has not been proven, the drug should be withdrawn at the first signs of this potentially serious syndrome for the treatment of which corticosteroids and supportive cardiotherapy may be necessary.

Dermatological: Very rare: bullous reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis. Frequency unknown: photosensitivity.

Others: occasional stomatitis. Rare: salivary gland enlargement, dry mouth.

2.2 Indirect risks (incorrect use): overdosage: symptoms: gastrointestinal: nausea, vomiting, epigastric pain, rarely diarrhoea, gastrointestinal bleeding, peptic ulceration.

Central nervous system (CNS): tinnitus and deafness, headache, dizziness, drowsiness, disorientation, excitation, fainting, hyperventilation and sweating, agitation, , occasionally convulsions.

Haematological: anaemia, leucopenia, thrombocytopenia, hypoprothrombinaemia.

Cardiac: (occasionally hypertension), , cardiac .

Pulmonary: adult respiratory distress syndrome, cyanosis.

Acid-base/Electrolyte: metabolic acidosis and respiratory alkalosis, hyperglycaemia, hypocalcaemia.

Hepatic: including elevated transaminases, jaundice and hepatic necrosis which may be delayed.

Renal: renal toxicity, acute renal failure, urinary retention. Urine may be discoloured red due to a metabolite.

Effects in severe poisoning may last for days or even weeks. Therapeutic measures: for adults ingesting >1 g, gastric lavage followed by 50 g activated charcoal is recommended within one hour of ingestion. For adults ingesting <1 g, activated charcoal should be considered within one hour of ingestion. For children ingesting >100 mg, 10-15 g of activated charcoal is recommended. Observation for 36 hours may be required due to the delayed effects. Care should be symptomatic and supportive. Frequent or prolonged convulsions should be treated with intravenous . Check and correct urine and electrolytes, pH, blood gases. Maintain good urine output. Monitor hepatic and renal function. Treat hypotension with fluids, taking care not to overhydrate (oedema secondary to renal failure may occur). Cardiac monitoring is required in symptomatic patients. In severe cases charcoal haemoperfusion may be considered.

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions

Country Classification Additional information Routes of administration/ MS MDD MQP Indications (AT) Not authorised (BE) Not authorised (CH) Not authorised Czech Republic (CZ) Not authorised Comment: risk/benefit (DE) POM evaluation ongoing Estonia (EE) Not authorised

14 Spain (ES) Not authorised Finland (FI) Not authorised France (FR) Not authorised Croatia (HR) Not authorised Hungary (HU) Not authorised Ireland (IE) Withdrawn 1982 Italy (IT) Not authorised Lithuania (LT) Not authorised Latvia (LV) Not authorised Macedonia (MK) Not authorised

Netherlands (NL) POM Rectal suppository

Poland (PL) POM Adults only, no longer 250 mg 500 mg 1250 mg than 5 days, contraindicated <14 years Portugal (PT) Not authorised Romania (RO) List II 750 mg 750 mg 2500 mg Serbia (RS) Not authorised (UK) POM Hospital use only

Melclass database1: List I

Available data indicate that phenylbutazone is not authorised in Austria, Belgium, Croatia, Czech Republic, Estonia, Finland, France, Hungary, Ireland, Italy, Latvia, Lithuania, Macedonia, Portugal, Serbia, Spain or Switzerland (October 2016).

In Germany there is ongoing risk/benefit review at a national level.

No data are available from other member states.

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: phenylbutazone is an NSAID with , and antiinflammatory properties. It is associated with toxicity, including blood dyscrasias, and therefore its systemic use in some countries is restricted to the treatment of rheumatic conditions where other treatments have failed. In many countries, systemic formulations are no longer authorised. Phenylbutazone is indicated for adults. It is not indicated for children under 14 years. Phenylbutazone is subject to prescription in the member states where it is authorised.

The current Melclass supply status is List I. This is considered appropriate given that phenylbutazone is not generally indicated for first-line use in rheumatic conditions and given the significant toxicity.

In conclusion, the current classification is List I. No change in the classification is proposed.

3.2.2 Paediatric use: not indicated for children under 14 years.

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

Medicines and Healthcare products Regulatory Agency (MHRA) (UK): SmPC 100 mg Tablets – Available at: https://goo.gl/xuUjhi

1 Melclass database - Available at: http://www.edqm.eu/melclass/ (NB: this is the CD-P-PH/PHO’s recommendation at the moment of the compilation of the evidence-based review)

15 MHRA SmPC Phenylbutazone 200 mg Tablets – Available at: https://goo.gl/27Ki9S

16 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AA02

1.3 Therapeutic indications: -

1.4 Posology and duration of treatment: -

1.5 Pharmaceutical forms: -

1.6 Contraindications: -

1.7 Relevant warnings: -

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): -

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, no medicines containing this active substance are authorised in member states).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, no medicines containing this active substance are authorised in member states: Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References: -

17 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AA03

1.3 Therapeutic indications: -

1.4 Posology and duration of treatment: -

1.5 Pharmaceutical forms: -

1.6 Contraindications: -

1.7 Relevant warnings: -

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): -

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, no medicines containing this active substance are authorised in member states).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, no medicines containing this active substance are authorised in member states: Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References: -

18 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AA05

1.3 Therapeutic indications: -

1.4 Posology and duration of treatment: -

1.5 Pharmaceutical forms: -

1.6 Contraindications: -

1.7 Relevant warnings: -

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): -

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, no medicines containing this active substance are authorised in member states).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, no medicines containing this active substance are authorised in member states: Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References: -

19 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AA06

1.3 Therapeutic indications: -

1.4 Posology and duration of treatment: -

1.5 Pharmaceutical forms: -

1.6 Contraindications: -

1.7 Relevant warnings: -

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): -

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, no medicines containing this active substance are authorised in member states).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, no medicines containing this active substance are authorised in member states: Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References: -

20 1. THERAPEUTIC PROFILE

1.1 Active ingredient: Indometacin

1.2 ATC code: M01AB01

1.3 Therapeutic indications: indicated for the active stages of , osteoarthritis, ankylosing spondylitis, acute musculoskeletal disorders, degenerative joint disease of the hip, low-back pain and acute gouty arthritis. Also indicated in , pain and oedema following orthopaedic procedures and for the treatment of pain and associated symptoms of primary dysmenorrhoea.

1.4 Posology and duration of treatment: capsules: in chronic conditions, starting therapy with a low dosage, increasing this gradually as necessary and continuing a trial of therapy for an adequate period (in some cases, up to one month) will give the best results with a minimum of unwanted reactions. The recommended oral dosage range is 50 mg to 200 mg daily in divided doses. Paediatric dosage not established. Dosage in dysmenorrhoea: up to 75 mg a day, starting with onset of cramps or bleeding and continuing for as long as the symptoms usually last. Dosage in acute gouty arthritis: 150 mg to 200 mg daily in divided doses until all symptoms and signs subside.

Suppositories: the usual adult dosage is one suppository to be inserted into the rectum once or twice a day. One should be used at bedtime and if another is necessary it should be used in the morning.

1.5 Pharmaceutical forms: capsules: 25 mg, 50 mg and 75 mg; suppositories: 100 mg.

1.6 Contraindications: history of peptic ulcer or active peptic ulcer; recurrent history of gastrointestinal lesions; in patients who have nasal polyps associated with angioneurotic oedema, who show sensitivity to indometacin or who have experienced acute asthmatic attacks, urticaria or rhinitis as a result of therapy with aspirin or other NSAIDs. Indometacin should not be used during pregnancy or lactation.

1.7 Relevant warnings: safety for use in children has not been established.

Headache, sometimes accompanied by dizziness and light-headedness, may occur, usually early in treatment. Starting therapy with a low dosage and increasing it gradually will usually minimise the incidence of headache. These symptoms frequently disappear on continuing therapy or reducing the dosage, but if headache persists despite dosage reduction, indometacin should be withdrawn. Patients should be warned that they may experience dizziness and, if they do, should not drive a car or undertake potentially dangerous activities needing alertness.

Indometacin should be used cautiously in patients with a history of bronchial asthma and in patients with psychiatric disorders, or Parkinsonism, as indometacin may tend to aggravate these disorders.

NSAIDs should only be given with care to patients with a history of gastrointestinal disease.

Gastrointestinal disturbances may be minimised by giving indometacin orally with food or an antacid. They usually disappear on reducing the dosage; if not, the risks of continuing therapy should be weighed against the possible benefits. If gastrointestinal bleeding does occur, indometacin should immediately be discontinued.

Single or multiple ulcerations, including perforation and haemorrhage of the oesophagus, stomach, duodenum or small or large intestine, have been reported to occur with indometacin. Fatalities have been reported in some instances. Rarely, intestinal ulceration has been associated with stenosis and obstruction. Gastrointestinal bleeding without obvious ulcer formation and perforation of pre-existing sigmoid lesions (diverticulum, carcinoma, etc.) has occurred.

Increased abdominal pain in ulcerative colitis patients or the development of ulcerative colitis and regional ileitis have been reported to occur rarely.

Fluid retention and peripheral oedema have been observed in some patients taking indometacin. Indometacin should therefore be used with caution in patients with cardiac dysfunction, hypertension or other conditions predisposing to fluid retention.

21 Indometacin may mask the signs and symptoms of . Indometacin should be used with caution in patients with existing but controlled infection.

In patients with rheumatoid arthritis, eye changes may occur which may be related to the underlying disease or to the therapy. Therefore, in chronic rheumatoid disease, ophthalmological examinations at periodic intervals are recommended. Discontinue therapy if eye changes are observed.

Patients should be periodically observed to allow early detection of any unwanted effects on peripheral blood (anaemia), liver function or gastrointestinal tract.

Indometacin can inhibit platelet aggregation. This effect usually disappears within 24 hours of discontinuing indometacin. Bleeding time is prolonged (but within normal range) in normal adults. Because this effect may be exaggerated in patients with underlying haemostatic defects, indometacin should be used cautiously in patients with coagulation defects.

As with other NSAIDs, there have been reports of acute interstitial nephritis with haematuria, proteinuria and occasionally nephrotic syndrome in patients receiving long-term administration of indometacin.

In patients with reduced renal blood flow where renal play a major role in maintaining renal perfusion, administration of a non-steroidal antiinflammatory agent may precipitate overt renal decompensation.

Patients at greatest risk of this reaction are those with renal or hepatic dysfunction, diabetes mellitus, advanced age, extracellular volume depletion, congestive heart failure, or concomitant use of any nephrotoxic drug. An NSAID should be given with caution and renal function should be monitored in any patient who may have reduced renal reserve. Discontinuation of non-steroidal antiinflammatory therapy is usually followed by recovery to the pretreatment state.

Increases in plasma concentration, including hyperkalaemia, have been reported, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninaemic-hypoaldosteronism state.

Since indometacin is eliminated primarily by the kidneys, patients with significantly impaired renal function should be closely monitored; a lower daily dosage should be used to avoid excessive drug accumulation.

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): CNS reactions: headaches, dizziness, light-headedness, depression, vertigo and fatigue (including malaise and listlessness). Reactions reported infrequently include mental confusion, anxiety, syncope, drowsiness, convulsions, coma, peripheral neuropathy, muscle weakness, involuntary muscle movements, , psychiatric disturbances such as hallucinations and depersonalisation; and rarely, paraesthesia, dysarthria, aggravation of epilepsy and Parkinsonism. These are often transient and disappear frequently with continued treatment or with reduced dosage. However, occasionally, severe reactions require stopping therapy.

Gastrointestinal: the more frequent reactions are nausea, , vomiting, epigastric distress, abdominal pain, constipation and diarrhoea. Others which may develop are ulceration - single or multiple - of oesophagus, stomach, duodenum or small or large intestine (including perforation and haemorrhage with a few fatalities having been reported), gastrointestinal tract bleeding without obvious ulcer formation and increased abdominal pain when used in patients with pre-existing ulcerative colitis. Reactions occurring infrequently are stomatitis, gastritis, flatulence, bleeding from the sigmoid colon - occult or from a diverticulum - and perforation of pre-existing sigmoid lesions (diverticula, carcinoma). Rarely, intestinal strictures (diaphragms) and intestinal ulceration followed by stenosis and obstruction have been reported. With suppositories, tenesmus and irritation of the rectal mucosa have occasionally been reported. Other gastrointestinal side effects which may or may not be caused by indometacin include: ulcerative colitis and regional ileitis.

Hepatic: rarely, hepatitis and jaundice (some fatalities reported).

22 Cardiovascular/Renal: oedema, increased blood pressure, tachycardia, chest pain, , palpitation, hypotension, congestive heart failure, blood elevation and haematuria (all infrequent).

Dermatological/Hypersensitivity: pruritus, urticaria, angioneurotic oedema, angiitis, erythema nodosum, skin rash and photosensitivity, exfoliative dermatitis, Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, loss of hair, rapid fall in blood pressure resembling a shock-like state, acute anaphylaxis, acute respiratory distress including sudden dyspnoea, dyspnoea, asthma and pulmonary oedema (all infrequent). Bronchospasm may be precipitated in patients suffering from, or with a history of, bronchial asthma or allergic disease.

Haematological: infrequently, blood dyscrasias may occur, including leucopenia, petechiae or ecchymosis, purpura, aplastic and haemolytic anaemia, agranulocytosis, bone-marrow depression, disseminated intravascular coagulation and particularly thrombocytopenia. Because some patients may develop anaemia secondary to obvious or occult gastrointestinal bleeding, appropriate blood determinations are recommended.

Ocular: infrequently, blurred vision, diplopia and orbital and peri-orbital pain. Corneal deposits and retinal disturbances, including those of the macula, have been reported in patients with rheumatoid arthritis on prolonged therapy, but similar changes may also be expected in patients with rheumatoid arthritis who have not received indometacin.

Aural: tinnitus, hearing disturbances (rarely deafness).

Genito-urinary: proteinuria, nephrotic syndrome, interstitial nephritis and renal insufficiency including renal failure (all rare).

Miscellaneous: vaginal bleeding, hyperglycaemia, glycosuria, hyperkalaemia, flushing and sweating, epistaxis, breast changes including enlargement and tenderness, gynaecomastia and ulcerative stomatitis (all rare).

Laboratory tests: borderline elevations of one or more liver tests may occur and significant elevations of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) have been seen in less than 1% of patients receiving therapy with NSAIDs in controlled clinical trials. If abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop or if systemic manifestations such as rash or eosinophilia occur, indometacin should be stopped. False-negative results in the suppression test in patients being treated with indometacin have been reported. Thus, results of this test should be used with caution in these patients.

2.2 Indirect risks (incorrect use): the following symptoms may be observed following overdosage: nausea, vomiting, intense headache, dizziness, mental confusion, disorientation or lethargy. There have been reports of paraesthesia, numbness and convulsions. Treatment is symptomatic and supportive. The stomach should be emptied as quickly as possible if the ingestion is recent and correction of severe electrolyte abnormalities may need to be considered. If vomiting has not occurred spontaneously, the patient should be induced to vomit with . If the patient is unable to vomit, gastric lavage should be performed. Once the stomach has been emptied, 25 or 50 g of activated charcoal may be given. Depending on the condition of the patient, close medical observation and nursing care may be required. The patient should be followed for several days because gastrointestinal ulceration and haemorrhage have been reported as adverse reactions of indometacin. Use of may be helpful. The plasma elimination of indometacin is biphasic with a terminal half-life phase of between 2.6 and 11.2 hours.

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions:

23

Country Classification Additional information Routes of administration/ MS MDD MQP Indication Armenia (AM) POM Oral use Exemptions: Exemptions: Exemptions: BE POM + Exemption Exemptions: oral use 100 mg 200 mg 900 mg CH List II EE POM ES POM FI POM FR List I DE POM + Exemption Exemptions: oral use IE Not authorised IT List II Oral and rectal forms LT POM LV POM MK POM Oral and rectal forms NL POM PL POM PT POM Oral and rectal forms RO List II RS Not authorised

Melclass database1: List II + Exemption (exemptions: oral use)

No data available from other member states.

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: List I

Criteria: medical supervision required

Note: indometacin is a POM in the majority of the member states.

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

SmPC available in the following databases of medicines: Portugal and United Kingdom Portugal (PT): http://www.infarmed.pt/infomed/pesquisa.php United Kingdom (UK): http://www.mhra.gov.uk/spc-pil/index.htm

1 Melclass database - Available at: http://www.edqm.eu/melclass/ (NB: this is the CD-P-PH/PHO’s recommendation at the moment of the compilation of the evidence-based review)

24 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AB02

1.3 Therapeutic indications: indicated in osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, acute gouty arthritis and peri-articular disorders such as , tendinitis and tenosynovitis.

1.4 Posology and duration of treatment: the dosage should be taken twice a day and adjusted to the severity of the disease. The usual dosage is 200 mg twice daily. However, the dosage may be lowered depending on the response. Doses above 400 mg/day are not recommended. In the treatment of acute gouty arthritis, therapy for seven days is usually adequate. In peri-articular disorders, treatment should be limited to seven to ten days.

1.5 Pharmaceutical forms: tablets: 100 mg and 200 mg.

1.6 Contraindications: hypersensitivity to any component of this product. The use of sulindac is contraindicated in severe heart failure, severe renal failure and in patients with hepatic insufficiency. Poor liver function may alter the blood levels of circulating metabolites of sulindac. Sulindac should not be used in patients in whom acute asthmatic attacks, urticaria, rhinitis or angioedema have been precipitated by ibuprofen, aspirin or other non-steroidal antiinflammatory agents. The drug should not be administered to patients with active gastrointestinal bleeding or a history of gastrointestinal bleeding or perforation related to previous NSAID therapy. The use of sulindac should be avoided in patients with active or previous peptic ulcer or haemorrhage (two or more distinct episodes of proven ulceration or bleeding). Since paediatric indications and dosage have not yet been established, sulindac should not be given to children. Use of sulindac is contraindicated during the last trimester of pregnancy.

1.7 Relevant warnings: undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms. Caution should be advised in patients receiving concomitant medications which could increase the risk of gastrotoxicity or bleeding, such as corticosteroids, anticoagulants such as warfarin, selective serotonin reuptake inhibitors or antiplatelet agents such as aspirin. The use of sulindac with concomitant NSAIDs, including COX-2 inhibitors, should be avoided. The elderly have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation which may be fatal. Sulindac has less effect on platelet function and bleeding time than aspirin; however, since sulindac is an inhibitor of platelet function, patients who may be adversely affected should be carefully observed when sulindac is administered. Sulindac should be used with caution in patients having a history of gastrointestinal haemorrhage, ulcers, ulcerative colitis or Crohn’s disease. Gastrointestinal bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious GI events. Patients should report experiencing any of these effects, particularly the elderly, and the treatment should be withdrawn. Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding). In patients with a history of and in the elderly, NSAIDs should be given only after other forms of treatment have been considered. The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation and in the elderly. These patients should commence treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients and also for patients requiring concomitant low-dose aspirin or other drugs likely to increase gastrointestinal risk. Caution is required if administered to patients suffering from, or with a previous history of, bronchial asthma since NSAIDs have been reported to precipitate bronchospasm in some patients.

Hypersensitivity syndrome: a potentially life-threatening, apparent hypersensitivity syndrome has been reported. In cases where the syndrome is suspected, therapy should be discontinued immediately and not recontinued. This syndrome may include constitutional symptoms (fever, chills, diaphoresis, flushing), cutaneous findings (rash or other dermatological reactions), conjunctivitis, involvement of major organs (changes in liver function tests, hepatic failure, jaundice, pancreatitis, pneumonitis with or without pleural effusion, leucopenia, leucocytosis, eosinophilia, disseminated intravascular coagulation, anaemia and renal impairment, including renal failure) and other less specific findings (adenitis,

25 , arthritis, , fatigue, malaise, hypotension, chest pain, tachycardia).

Infections: NSAIDs, including sulindac, may mask the usual signs and symptoms of infection; therefore, the physician must be continually on the alert for this and should use the drug with extra care in the presence of existing infection.

Because of reports of adverse eye findings with agents of this class it is recommended that patients who develop eye complaints during treatment with sulindac have ophthalmological evaluations. Peripheral oedema has been observed in some patients taking sulindac; therefore, as with other drugs in this class, sulindac should be used with caution in patients with compromised cardiac function, hypertension or other conditions predisposed to fluid retention. Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy. Clinical trial and epidemiological data suggest that use of some NSAIDS (particularly at high doses and in long-term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). There are insufficient data to exclude such a risk for sulindac. Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease should only be treated with sulindac after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking). A patient with signs and/or symptoms suggesting liver dysfunction, or in whom an abnormal liver-function test has occurred, should be evaluated for evidence of a more severe hepatic reaction while on therapy. Significant elevations of AST and ALT (three times higher than normal) were seen in less than 1% of patients in controlled clinical trials. Cases of hepatitis, jaundice or both, with or without fever, may occur within the first three months of therapy. In some patients, the findings are consistent with those of cholestatic hepatitis. Fever or other evidence of hypersensitivity, including abnormalities in one or more liver-function tests and skin reactions, have occurred during therapy. Some fatalities have occurred. Whenever a patient develops unexplained fever, rash, other dermatological reactions or constitutional symptoms, sulindac should be permanently stopped and liver function investigated. Fever and abnormal liver function are reversible.

Renal effects: as with other NSAIDs, there have been reports of acute interstitial nephritis with haematuria, proteinuria and, occasionally, nephrotic syndrome in patients receiving sulindac. In patients with reduced renal blood flow where renal prostaglandins play a major role in maintaining renal perfusion, administration of a non-steroidal antiinflammatory agent may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with renal or hepatic dysfunction, diabetes mellitus, advanced age, extracellular volume depletion, congestive heart failure, sepsis or concomitant use of any nephrotoxic drug. NSAIDs should be given with caution and renal function should be monitored in any patient who may have reduced renal reserve. Discontinuation of non- steroidal antiinflammatory therapy is usually followed by recovery to the pretreatment state. Since sulindac is eliminated primarily by the kidneys, patients with significantly impaired renal function should be closely monitored; a lower daily dosage should be used to avoid excessive drug accumulation. Sulindac metabolites have been reported rarely as the major, or a minor, component in renal stones in association with other calculus components. Sulindac should be used with caution in patients with a history of renal lithiasis and they should be kept well hydrated while receiving sulindac. In patients with renal functional impairment, since the major route of of the drug is via the kidney, the dosage may need to be reduced. Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs. Patients appear to be at highest risk for these reactions early in the course of therapy: the onset of the reaction occurring in the majority of cases within the first month of treatment. Sulindac should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity. The use of sulindac may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of sulindac should be considered. In patients with SLE and mixed connective tissue disorders there may be an increased risk of aseptic meningitis.

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): sulindac is generally well tolerated. Those side effects

26 experienced are usually mild and may often respond to a reduction in dosage.

Side effects reported frequently

Gastrointestinal: the most frequent types of side effects occurring with sulindac are gastrointestinal; these include gastrointestinal pain, dyspepsia, nausea with or without vomiting, diarrhoea, constipation, flatulence, anorexia and gastrointestinal cramps. Dermatological: rash, pruritus.

Central nervous system: dizziness, headache, nervousness.

Special senses: tinnitus.

Miscellaneous: oedema.

Side effects reported less frequently

Gastrointestinal: stomatitis, gastritis or gastroenteritis. Peptic ulcer, exacerbation of colitis and Crohn’s disease have been reported, as well as gastrointestinal bleeding and gastrointestinal perforations, sometimes fatal, particularly in the elderly. Pancreatitis, ageusia, glossitis, intestinal strictures (diaphragms) haematemesis, melaena, nausea. It has also been reported that a probable sulindac metabolite has been found in biliary sludge in patients with symptoms of cholecystitis who underwent a cholecystectomy.

Hepatic: liver-function-test abnormalities, jaundice sometimes with fever, cholestasis, hepatitis, hepatic failure.

Dermatological: purpura, sore or dry mucous membranes, alopecia, photosensitivity, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis.

Cardiovascular: congestive heart failure, especially in patients with marginal cardiac function; palpitation, hypertension.

Oedema, hypertension and cardiac failure have been reported in association with clinical trials and epidemiological data suggest that use of some NSAIDS (particularly at high doses and in long-term treatment) may be associated with an increased risk of arterial thrombotic events (for example myocardial infarction or stroke).

Haematological: thrombocytopenia, ecchymosis, purpura, leucopenia, agranulocytosis, neutropenia, bone-marrow depression including aplastic anaemia, haemolytic anaemia, increased in patients on oral anticoagulants.

Renal/Genito-urinary: urine discoloration, dysuria, vaginal bleeding, haematuria, proteinuria, crystalluria, renal impairment including renal failure, interstitial nephritis, nephrotic syndrome.

Nervous system: hallucinations, malaise, fatigue, drowsiness, vertigo, , insomnia, sweating, asthenia, paraesthesia, convulsions, syncope, depression, confusion, psychic disturbances including acute , aseptic meningitis (especially in patients with systemic lupus erythematosus (SLE) and, mixed connective tissue disease) with symptoms such as stiff neck, headache, nausea, vomiting, fever and disorientation

Metabolic: hyperkalaemia.

Musculoskeletal: muscle weakness.

Special senses: visual disturbances including blurred vision, optic neuritis, decreased hearing, metallic or bitter .

Respiratory: epistaxis.

Hypersensitivity: hypersensitivity reactions have been reported following treatment with NSAIDs. These

27 may consist of (a) non-specific allergic reactions and anaphylaxis, (b) respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea or (c) assorted skin disorders, including rashes of various types, pruritus, urticaria, purpura, angioedema and, more rarely, exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme), hypersensitivity vasculitis, hypersensitivity syndrome.

Causal relationship unknown: other reactions have been reported in clinical trials or since the drug was marketed, but occurred under circumstances where a causal relationship could not be established. However, in these rarely reported events, that possibility cannot be excluded. Therefore, these observations are listed to serve as alerting information to physicians. Cardiovascular: arrhythmia; metabolic: hyperglycaemia; nervous system: neuritis; special senses: disturbances of the retina and its vasculature; miscellaneous: gynaecomastia; rarely, occurrences of fulminant necrotising fasciitis, particularly in association with Group A β-haemolytic streptococcus, have been described in persons treated with non-steroidal antiinflammatory agents, sometimes with fatal outcome

2.2 Indirect risks (incorrect use): cases of overdosage have been reported and, rarely, fatalities have occurred. The following signs and symptoms may be observed following overdosage: headache, nausea, vomiting, epigastric pain, gastrointestinal pain and bleeding; rarely, diarrhoea, disorientation, excitation, stupor, coma, drowsiness, dizziness, tinnitus, fainting; occasionally convulsions, diminished urine output and hypotension. In isolated cases patients have received up to 600 mg a day without adverse consequences being reported. In cases of significant poisoning acute renal failure and liver damage are possible. Within one hour of ingestion of a potentially toxic amount, activated charcoal should be considered. Alternatively, in adults, gastric lavage may be considered within one hour of ingestion of a potentially life-threatening overdose. Good urine output should be ensured. Renal and liver function should be closely monitored. Patients should be observed for at least eight hours after ingestion of doses exceeding 600 mg. Frequent or prolonged convulsions should be treated with intravenous diazepam. Other measures may be indicated by the patient's clinical condition. Animal studies show that absorption is decreased by the prompt administration of activated charcoal and excretion is enhanced by alkalinisation of the urine. The readiness of sulindac and its metabolites to dialyse is unknown at present, but because they are highly bound to plasma proteins, dialysis is not likely to be effective. The mean half-life of sulindac is 7.8 hours while the mean half-life of the active sulphide metabolite is 16.4 hours.

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions:

Country Classification Additional information Routes of administration/ MS MDD MQP Indication AM Not authorised BE Not authorised CH Not authorised DE Not authorised EE Not authorised ES Not authorised FI List I FR Not authorised IE Not authorised IT Not authorised LT Not authorised LV Not authorised MK Not authorised PL Not authorised PT Not authorised RO Not authorised RS Not authorised

28 Melclass database1: List II

No data available from other member states.

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: Not to classify

Criteria: sulindac is not authorised in at least 3 member states.

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

MHRA (UK) – available at: http://www.mhra.gov.uk/spc-pil/index.htm

1 Melclass database - Available at: http://www.edqm.eu/melclass/ (NB: this is the CD-P-PH/PHO’s recommendation at the moment of the compilation of the evidence-based review)

29 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AB03

1.3 Therapeutic indications: osteoarthritis, rheumatoid arthritis

1.4 Posology and duration of treatment: initial: 400 mg orally three times a day for 1 to 2 weeks. Maintenance: 200 to 600 mg orally three times a day, maximum 1800 mg/day.

1.5 Pharmaceutical forms: tablets and capsules for oral use.

1.6 Contraindications: asthma, urticaria or allergic-type reaction following aspirin or other NSAID administration. Hypersensitivity to tolmetin. Treatment of perioperative pain in the setting of coronary artery bypass grafting (CABG) surgery.

1.7 Relevant warnings: cardiovascular thrombotic events, myocardial infarction, stroke and fatalities have been reported. Risk may increase with duration of use, cardiovascular disease, risk factors for cardiovascular disease or treatment of perioperative pain in the setting of CABG surgery (unapproved use); monitoring recommended.

Gastrointestinal adverse events (e.g. ulceration, bleeding or perforation of stomach or intestines, potentially fatal) may occur without warning. Risk increased in patients with prior history of peptic ulcer disease or gastrointestinal bleeding, elderly, those with poor general health status, smoking, longer duration of therapy and with concomitant use of oral corticosteroids, anticoagulants and . Monitoring recommended; discontinuation may be necessary.

Concomitant use: not recommended with aspirin.

Dermatological: skin reactions, including potentially fatal events of exfoliative dermatitis, Stevens- Johnson syndrome and toxic epidermal necrolysis, may occur without warning; discontinue use at first sign of skin rash or any other sign of hypersensitivity.

Haematological: anaemia may occur; monitoring recommended with long-term use. Prolonged bleeding time may occur due to platelet aggregation inhibition. Risk is increased in coagulation disorders or concomitant anticoagulants; monitoring recommended.

Hepatic: hepatic reactions, including notable elevation of liver , jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, sometimes fatal, have been reported. Monitoring recommended; discontinue use if signs of liver disease or systemic manifestations occur.

Immunological: anaphylactoid reactions may occur. Avoid use in patients with aspirin triad.

Renal: renal papillary necrosis and other renal injury (e.g. acute interstitial nephritis with haematuria, proteinuria and nephritic syndrome) may occur with long-term use. Risk increased in patients with renal impairment, heart failure, liver dysfunction, concurrent use of angiotensin-converting enzyme (ACE) inhibitors and diuretics, and the elderly. Monitoring recommended, discontinuation may be required. Avoid use in advanced renal disease. If use is required, monitoring recommended.

Reproductive: avoid use during late pregnancy; premature closure of the ductus arteriosus may occur.

Respiratory: use with caution in pre-existing asthma; potentially fatal bronchospasm may occur due to cross-reactivity in aspirin-sensitive patients.

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): Common: gastrointestinal: abdominal pain (3% to 9%), diarrhoea (3% to 9%), flatulence (3% to 9%), indigestion (3% to 9%), nausea (11%), vomiting (3% to

30 9%).

Serious:

Cardiovascular: hypertension (3% to 9%), myocardial infarction.

Dermatological: erythema multiforme (less than 1%), scaling eczema, Stevens-Johnson syndrome, toxic epidermal necrolysis (less than 1%).

Gastrointestinal: gastrointestinal haemorrhage (up to 4%), gastrointestinal perforation (1% to 4%), gastrointestinal ulcer (1% to 4%), inflammatory disorder of digestive tract (1% to 4%).

Haematological: anaemia (less than 1%), blood coagulation disorder, thrombotic tendency observations.

Hepatic: hepatitis, increased liver function test results (up to 15%), jaundice, .

Immunological: anaphylactoid reaction (less than 1%).

Neurological: cerebrovascular accident.

Renal: acute renal failure.

Respiratory: bronchospasm, aspirin-sensitive patients.

2.2 Indirect risks (incorrect use): no information available

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions:

Country Classification Additional information Routes of administration/ MS MDD MQP Indication AM Not authorised BE Not authorised CH Not authorised DE Not authorised EE Not authorised ES Not authorised FI Not authorised FR Not authorised IE Not authorised IT Not authorised LT Not authorised LV Not authorised MK Not authorised NL Not authorised PL Not authorised PT Not authorised RO Not authorised RS Not authorised

Melclass database1: List II

No data available from other member states.

1 Melclass database - Available at: http://www.edqm.eu/melclass/ (NB: this is the CD-P-PH/PHO’s recommendation at the moment of the compilation of the evidence-based review)

31 3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: Not to classify

Criteria: tolmetin is not authorised in at least 3 member states.

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

MHRA (UK) – available at: http://www.mhra.gov.uk/spc-pil/index.htm

32 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AB04

Zomepirac sodium, a pyrrole- derivative related to tolmetin, is an NSAID drug. It was withdrawn from the market following reports of serious hypersensitivity reactions, including bronchospasm and anaphylactic shock.

1.3 Therapeutic indications: -

1.4 Posology and duration of treatment: -

1.5 Pharmaceutical forms: -

1.6 Contraindications: -

1.7 Relevant warnings: -

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): -

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, no medicines containing this active substance are authorised in member states).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, no medicines containing this active substance are authorised in member states: Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References: -

33 1. THERAPEUTIC PROFILE

1.1 Active ingredient: Diclofenac

1.2 ATC code: M01AB05

1.3 Therapeutic indications: 12.5 mg (OTC): relief of painful states, such as headaches, toothaches, menstrual , rheumatic and muscular pains and joint pains. Relief of the symptoms of the flu and colds. Reduction of fever.

25 mg, 50 mg, 75 mg (POM): relief of all grades of pain and inflammation in a wide range of conditions. Treatment of inflammatory and degenerative forms of rheumatism: rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, spondylarthritis and psoriatic arthropathy. Acute attacks of . Post-traumatic and post-operative pain, inflammation and swelling, e.g. following dental or orthopaedic surgery. Painful and/or inflammatory conditions in gynaecology, e.g. primary dysmenorrhoea or adnexitis and associated menorrhagia. As an adjuvant in severe painful inflammatory of the ear, nose or throat, e.g. pharyngotonsillitis, otitis.

25 mg/ml, 75 mg/ml Solution for (POM): : treatment of exacerbation of inflammatory and degenerative forms of rheumatism, rheumatoid arthritis and osteoarthritis, renal colic and biliary colic, acute attacks of gout, acute trauma and fractures, post traumatic and post-operative pain, inflammation and swelling. Intravenous infusion: for treatment or prevention of post-operative pain in the hospital setting.

1.4 Posology and duration of treatment: 12.5 mg (OTC): adults and children over 14 years: initially two tablets, followed by 1 or 2 tablets every 4 to 6 hours, as required. Do not take more than 6 tablets (75 mg) for every 24 hours.

25 mg, 50 mg, 75 mg (POM): adults: 75-150 mg daily in two or three divided doses. The recommended maximum daily dose is 150 mg. This may be administered using a combination of dosage forms, e.g. tablets and suppositories. Children and adolescents: children aged 1 year or over and adolescents should be given 0.5 to 2 mg/kg body weight daily, in 2 to 3 divided doses, depending on the severity of the disorder. For the treatment of juvenile rheumatoid arthritis, the daily dosage can be raised to a maximum of 3 mg/kg daily, given in divided doses. The maximum daily dose of 150 mg should not be exceeded. Because of their dosage strength, diclofenac 50 mg gastro-resistant tablets are not recommended for use in children and adolescents below 14 years of age; diclofenac 25 mg gastro-resistant tablets could be used in these patients.

25 mg/ml, 75 mg/ml Solution for Injection (POM): for intravenous infusion or intramuscular use only. Intravenous use: diclofenac should not be administered by intravenous bolus injection. Immediately before starting an intravenous infusion, diclofenac solution for injection must be diluted. Two alternative dosage regimens of diclofenac solution for injection are recommended. For the treatment of moderate to severe post-operative pain, 75 mg should be infused continuously over a period of 30 minutes to 2 hours. If necessary, treatment may be repeated after 4-6 hours, but the dose should not exceed 150 mg within any period of 24 hours. For the prevention of post- operative pain, a loading dose of 25 mg to 50 mg should be infused after surgery over 15 minutes to 1 hour, followed by a continuous infusion of about 5 mg/hour up to a maximum daily dose of 150 mg.

Intramuscular use: recommended dosage schedule: the following directions for intramuscular injection must be followed in order to avoid damage to a nerve or other tissue at the injection site. One ampoule once (or in severe cases twice) daily intramuscularly by deep intragluteal injection into the upper outer quadrant. If two injections daily are required, it is advised the alternative buttock be used for the second injection. Alternatively, one ampoule of 75 mg can be combined with other pharmaceutical forms of diclofenac (e.g. tablets, suppositories) up to a maximum daily dose of 150 mg.

1.5 Pharmaceutical forms: tablets: 12.5 mg, 25 mg, 50 mg and 75 mg; solution for injection: 25 mg/ml, 75 mg/ml.

34 1.6 Contraindications: known hypersensitivity to the active substance; active gastric or intestinal ulcer, bleeding or perforation; history of gastrointestinal bleeding or perforation related to previous NSAID therapy; active or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding); last trimester of pregnancy; hepatic failure; chronic kidney disease grade 5 (GFR <15); like other NSAIDs, diclofenac is also contraindicated in patients in whom attacks of asthma, urticaria or acute rhinitis are precipitated by acetylsalicylic acid or other NSAID drugs with prostandin-synthetase inhibiting activity; established congestive heart failure (NYHA II-IV), ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease.

1.7 Relevant warnings: gastrointestinal effects: gastrointestinal bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs, including diclofenac, and may occur at any time during treatment, with or without warning symptoms or a previous history of serious gastrointestinal events. They generally have more serious consequences in the elderly. If gastrointestinal bleeding or ulceration occurs in patients receiving diclofenac, the medicinal product should be withdrawn. As with all NSAIDs, close medical surveillance is imperative and particular caution should be exercised when prescribing diclofenac in patients with symptoms indicative of gastrointestinal disorders or with a history suggestive of gastric or intestinal ulceration, bleeding or perforation in patients with ulcerative colitis or Crohn’s disease and in patients suffering from impaired hepatic function. The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation. The elderly have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation which may be fatal. To reduce the risk of GI toxicity in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation, and in the elderly, the treatment should be initiated and maintained on the lowest effective dose. Combination therapy with protective agents (e.g. proton pump inhibitors or misoprostol) should be considered for these patients and also for patients requiring concomitant use of medicinal products containing low-dose acetylsalicylic acid/aspirin or other medicinal products likely to increase gastrointestinal risk. Patients with a history of GI toxicity, particularly the elderly, should report any unusual abdominal symptoms (especially GI bleeding), particularly in the initial stages of treatment. Caution is recommended in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, antiplatelet agents such as aspirin or selective serotonin reuptake inhibitors. Close medical surveillance and caution should also be exercised in patients with ulcerative colitis or Crohn’s disease, as their condition may be exacerbated.

Hepatic effects: close medical surveillance is required when prescribing diclofenac to patients with impaired hepatic function, as their condition may be exacerbated. As with other NSAIDs, values of one or more liver enzymes may increase. During prolonged treatment with diclofenac, regular monitoring of hepatic function is indicated as a precautionary measure. If abnormal liver function tests persist or worsen, if clinical signs or symptoms consistent with liver disease develop or if other manifestations occur (e.g. eosinophilia, rash, etc.), diclofenac should be discontinued. Hepatitis may occur with diclofenac without prodromal symptoms. Caution is called for when using diclofenac in patients with hepatic , since it may trigger an attack.

Renal effects: as fluid retention and oedema have been reported in association with NSAID therapy, including diclofenac, particular caution is called for in patients with impaired cardiac or renal function, history of hypertension, the elderly, patients receiving concomitant treatment with diuretics or medicinal products that can significantly impact renal function and in those patients with substantial extracellular volume depletion from any cause, e.g. before or after major surgery. Monitoring of renal function is recommended as a precautionary measure when using diclofenac in such cases. Discontinuation of therapy is usually followed by recovery to the pretreatment state.

Skin Effects: serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens- Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs, including diclofenac. Patients appear to be at highest risk of these reactions early in the course of therapy, the onset of the reaction occurring in the majority of cases within the first month of treatment. Diclofenac should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.

As with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, can also

35 occur in rare cases with diclofenac without earlier exposure to the drug.

Cardiovascular and cerebrovascular effects: appropriate monitoring and advice are required for patients with a history of hypertension and/or congestive heart failure (NYHA-1) as fluid retention and oedema have been reported in association with NSAID therapy. Clinical trial epidemiological data suggest that the use of diclofenac, particularly at high dose (150 mg daily) and in long-term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). Patients with congestive heart failure (NYHA-1) and patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking) should only be treated with diclofenac after careful consideration. As the cardiovascular risks of diclofenac may increase with dose and duration of exposure, the shortest duration possible and the lowest effective daily dose should be used. The patient’s need for symptomatic relief and response to therapy should be re-evaluated periodically. Patients should remain alert for the signs and symptoms of serious arteriothrombotic events (e.g. chest pain, shortness of breath, weakness, slurring of speech), which can occur without warning. Patients should be instructed to see a physician immediately in case of such an event.

Haematological effects: during prolonged treatment with diclofenac, as with other NSAIDs, monitoring of the blood count is recommended. Like other NSAIDs, diclofenac may temporarily inhibit platelet aggregation. Patients with defects of haemostasis should be carefully monitored.

Pre-existing asthma: in patients with asthma, seasonal , swelling of the nasal mucosa (i.e. nasal polyps), chronic obstructive pulmonary diseases or chronic infections of the respiratory tract (especially if linked to allergic rhinitis-like symptoms), reactions to NSAIDs like asthma exacerbations (so-called intolerance to /analgesic asthma syndrome), Quincke’s oedema or urticaria are more frequent than in other patients. Therefore, special precaution is recommended in such patients (readiness for emergency). This is also applicable for patients who are allergic to other substances, e.g. with skin reactions, pruritus or urticaria.

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): Blood and lymphatic disorders: Very rare: thrombocytopenia, leukopenia, anaemia (including haemolytic and aplastic anaemia), agranulocytosis.

Immune system disorders: Rare: hypersensitivity reactions such as asthma, systemic anaphylactic and anaphylactoid reactions (including hypotension and shock). Very rare: angioedema (including face oedema).

Psychiatric disorders: Very rare: disorientation, depression, insomnia, nightmares, irritability, psychotic disorder.

Nervous system disorders: Common: headache, dizziness. Rare: somnolence. Very rare: paraesthesia, memory impairment, convulsion, anxiety, tremor, aseptic meningitis, dysgeusia, cerebrovascular accident.

Eye disorders: Very rare: visual impairment (vision blurred, diplopia).

Ear and labyrinth disorders: Common: vertigo. Very rare: tinnitus, hearing impaired.

Cardiac disorders: Uncommon: myocardial infarction, cardiac failure, palpitations, chest pain.

Vascular disorders: Very rare: hypertension, vasculitis

Respiratory, thoracic and mediastinal disorders: Rare: asthma/bronchospasm (including dyspnoea). Very rare: pneumonitis.

Gastrointestinal tract disorders: Common: nausea, vomiting, diarrhoea, dyspepsia, abdominal pain, flatulence, decreased appetite. Rare: gastritis, gastrointestinal haemorrhage, haematemesis, melaena, diarrhoea, haemorrhagic, gastric or intestinal ulcer (with or without bleeding or

36 perforation). Very rare: colitis (including haemorrhagic colitis and exacerbation of ulcerative colitis or Crohn’s disease), constipation, stomatitis (including ulcerative stomatitis), glossitis, oesophageal disorder, diaphragm-like intestinal strictures, pancreatitis. Not known: ischaemic colitis.

Hepatobiliary disorders: Common: transaminases increased. Rare: hepatitis, with or without jaundice, liver disorder. Very rare: hepatitis fulminant, hepatic necrosis, hepatic failure.

Skin and subcutaneous tissue disorders: Common: rash. Rare: urticaria. Very rare: dermatitis bullous, eczema, erythema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), dermatitis exfoliative, alopecia, photosensitivity reaction, purpura, including allergic purpura, Henoch-Schönlein purpura, pruritus.

Renal and urinary disorders: Very rare: acute renal failure, haematuria, proteinuria, nephritic syndrome, tubulointerstitial nephritis, renal papillary necrosis.

General disorders and administration site conditions: Rare: oedema.

2.2 Indirect risks (incorrect use): overdosage: symptoms: there is no typical clinical picture resulting from diclofenac overdosage. Overdosage can cause symptoms such as vomiting, gastrointestinal haemorrhage, diarrhoea, dizziness, tinnitus or convulsions. In the event of significant poisoning, acute renal failure and liver damage are possible.

Therapeutic measures: management of acute poisoning with NSAIDs, including diclofenac, consists essentially of supportive measures and symptomatic treatment. Supportive measures and symptomatic treatment should be given for complications such as hypotension, renal failure, convulsions, gastrointestinal disorder and respiratory depression. Special measures such as forced diuresis, dialysis or haemoperfusion are probably unlikely to be helpful in accelerating the elimination of NSAIDs, including diclofenac, because of their high protein binding rate and extensive . Activated charcoal may be considered after ingestion of a potentially toxic overdose, and gastric decontamination (e.g. vomiting, gastric lavage) after ingestion of a potentially life-threatening overdose.

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions:

Country Classification Additional information Routes of administration/ MS MDD MQP Indications AM POM BE POM 50 mg 200 mg List II: 100 List II: 150 mg mg Exemptions: oral CH List II + Exemption use Exemptions: 75 Exemptions: mg 25 mg Exemptions: oral Exemptions: Exemptions: 75 DE POM + Exemption use 25 mg mg Exemptions: oral Exemptions: Exemptions: EE POM + Exemption use 12.5 mg 125 mg ES POM FI POM FR List II IE List II Exemptions: oral Exemptions: Exemptions: 75 IT List II + Exemption use 25 mg mg Exemptions: oral Exemptions: Exemptions: LT POM + Exemption use 12.5 mg 125 mg Exemptions: oral Exemptions: LV POM + Exemption use 12.5 mg

37

Patch: 140 mg MK POM 100 mg 200 mg 4 g Exemptions: oral Exemptions: Exemptions: NL POM + Exemption use 12.5 mg 300 mg Exemptions: oral Exemptions: Exemptions: 75 Exemptions: PL POM + Exemption use 25 mg mg 500 mg Exemptions: oral Exemptions: Exemptions: PT POM + Exemption use 12.5 mg 500 mg RO List II 150 mg 150 mg 4500 mg POM (solution for RS injection - for hospital use 100 mg 150 mg 2250 mg only)

Melclass database1: List II + Exemption (exemptions: oral use)

No data available from other member states.

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: List II

Criteria: Not first-line treatment for fever and pain. Safety concerns around cardiovascular risks (European Medicines Agency’s (EMA) Pharmacovigilance Risk Assessment Committee (PRAC): Safety Advice for Diclofenac: https://goo.gl/MjikEE)

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

SmPC available in the following databases of medicines: Portugal and United Kingdom: PT: http://www.infarmed.pt/infomed/pesquisa.php UK: http://www.mhra.gov.uk/spc-pil/index.htm

EMA’s PRAC: https://goo.gl/MjikEE

1 Melclass database - Available at: http://www.edqm.eu/melclass/ (NB: this is the CD-P-PH/PHO’s recommendation at the moment of the compilation of the evidence-based review)

38 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AB06

1.3 Therapeutic indications: treatment of rheumatoid arthritis and ankylosing spondylitis.

1.4 Posology and duration of treatment: alclofenac 2 to 4 grams orally daily (in divided doses) has been effective in the treatment of rheumatoid arthritis. Single nightly doses of 1.5 gram have been somewhat effective in relieving rheumatoid morning stiffness. Doses of 1 gram three or four times daily have been effective in treating ankylosing spondylitis in limited studies.

1.5 Pharmaceutical forms: -

1.6 Contraindications: hypersensitivity to alclofenac; rhinitis; urticaria/angioedema; asthma or allergic reactions to aspirin or other antiinflammatory agents.

1.7 Relevant warnings: history of coagulation defects; history of liver dysfunction; hypertension or cardiac conditions aggravated by fluid retention and oedema; previous history of gastrointestinal disease or ulceration; previous hypersensitivity to or salts may increase the risk of developing skin rash during alclofenac therapy; renal dysfunction.

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): Cardiovascular: vasculitis. Dermatological: rash. Gastrointestinal: constipation, diarrhoea, gastrointestinal haemorrhage, indigestion, loss of appetite, nausea, ulcer of mouth, vomiting. Haematological: leukopenia. Immunological: anaphylactoid reaction. Neurological: dizziness, headache. Aural: tinnitus. Renal: papillary necrosis, renal failure. Other: angioedema, fatigue.

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, no medicines containing this active substance are authorised in member states).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, no medicines containing this active substance are authorised in member states: Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References: -

39 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AB07

1.3 Therapeutic indications: -

1.4 Posology and duration of treatment: -

1.5 Pharmaceutical forms: -

1.6 Contraindications: -

1.7 Relevant warnings: -

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): -

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

Bumadizone is an NSAID that is metabolised to phenylbutazone and oxyphenbutazone. Use has been limited by the risk of agranulocytosis and other haematological adverse effects.

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, no medicines containing this active substance are authorised in member states).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, no medicines containing this active substance are authorised in member states: Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References: -

40 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AB08

1.3 Therapeutic indications: degenerative articular disease (osteoarthrosis), rheumatoid arthritis, ankylosing spondylitis, acute gout crisis, extra-articular rheumatism, tendinitis, fibrositis, mild to moderately severe pain (following dental surgery, post-operative, post-traumatic, etc.).

1.4 Posology and duration of treatment: usual adult dose 1-2 hard capsules daily in two divided doses or as a single daily dose.

1.5 Pharmaceutical forms: tablets and capsules: 200 mg, 300 mg, 600 mg.

1.6 Contraindications: etodolac is contraindicated in the following patient groups: previous history of hypersensitivity to etodolac or to any of the excipients; active or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding). In general, NSAIDs are contraindicated in patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, angioedema or urticaria) in response to ibuprofen, aspirin or other NSAIDs and those with a history of gastrointestinal bleeding or perforation related to previous NSAID therapy. Etodolac should not be used in patients with severe heart failure, hepatic failure or renal failure or during the last trimester of pregnancy.

1.7 Relevant warnings: undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms. The use of etodolac with concomitant NSAIDs, including COX-2 selective inhibitors, should be avoided.

Respiratory disorders: caution is required if etodolac is administered to patients suffering from, or with a previous history of, bronchial asthma since NSAIDs have been reported to cause bronchospasm in such patients.

Cardiovascular, renal and hepatic impairment: the administration of an NSAID may cause a dose- dependent reduction in prostaglandin formation and precipitate renal failure. Patients at greatest risk of this reaction are those with impaired renal function, cardiac impairment, liver dysfunction, those taking diuretics and the elderly. The dose should be low and renal function should be monitored in these patients. Etodolac should be used with caution in patients with fluid retention, hypertension or heart failure. Hepatic and renal function, and haematological parameters of patients on long-term use of etodolac should be regularly reviewed.

Platelets: although NSAIDs do not have the same direct effects on as aspirin, all such drugs which inhibit the biosynthesis of prostaglandins may interfere with platelet function. Patients who may be adversely affected due to inhibition of platelet function should be carefully observed.

Elderly: no dosage adjustment is generally necessary in the elderly. However, caution should be exercised in treating the elderly, and when individualising their dosage, extra care should be taken while increasing the dose. The elderly have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation which may be fatal.

Paediatric population: safety and efficacy in children have not been established and therefore etodolac is not recommended in children.

Cardiovascular and cerebrovascular effects: appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy.

Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long-term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). There are insufficient data to exclude such a risk for etodolac.

41 Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease should only be treated with etodolac after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

Gastrointestinal bleeding, ulceration and perforation: GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious GI events. The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer – particularly if complicated with haemorrhage or perforation – and in the elderly. These patients should commence treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients and also for patients requiring concomitant low-dose aspirin or other drugs likely to increase gastrointestinal risk. Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment. Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin reuptake inhibitors or antiplatelet agents such as aspirin. When GI bleeding or ulceration occurs in patients receiving etodolac, the treatment should be withdrawn. NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn’s disease) as these conditions may be exacerbated.

SLE and mixed connective tissue disease: in patients with SLE and mixed connective tissue disorders there may be an increased risk of aseptic meningitis.

Dermatological: serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens- Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs. Patients appear to be at highest risk for these reactions early in the course of therapy: the onset of the reaction occurring in the majority of cases within the first month of treatment. Etodolac should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.

Impaired female fertility: the use of etodolac may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of etodolac should be considered.

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): the most commonly-observed adverse events are gastrointestinal in nature.

Blood and lymphatic system disorders: thrombocytopenia, neutropenia, agranulocytosis, aplastic anaemia and haemolytic anaemia.

Immune system disorders: hypersensitivity reactions have been reported following treatment with NSAIDs. These may consist of non-specific allergic reactions and anaphylaxis, anaphylactoid reaction respiratory tract reactivity (comprising asthma, aggravated asthma, bronchospasm or dyspnoea) or assorted skin disorders including rashes of various types, pruritus, urticaria, purpura, angioedema and, more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).

Nervous system disorders: depression, headaches, dizziness, insomnia, confusion, hallucinations, disorientation, paraesthesia, tremor, weakness, nervousness and drowsiness, reports of aseptic meningitis (especially in patients with existing autoimmune disorders, such as systemic lupus erythematosus, mixed connective tissue disease), with symptoms such as stiff neck, headache, nausea, vomiting.

Eye disorders: visual disturbances (abnormal vision), optic neuritis.

42 Ear and labyrinth disorders: tinnitus, vertigo.

Cardiac disorders: oedema, hypertension, palpitation and cardiac failure have been reported in association with NSAID treatment.

Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long-term treatment) may be associated with an increased risk of arterial thrombotic events (for example myocardial infarction or stroke).

Vascular disorders: vasculitis.

Gastrointestinal disorders: peptic ulcers, perforation or GI bleeding, sometimes fatal, particularly in the elderly, may occur. Nausea, vomiting, diarrhoea, dyspepsia, epigastric pain, ulcerative stomatitis, abdominal pain, constipation, flatulence, haematemesis, melaena, gastrointestinal ulceration, indigestion, heartburn, rectal bleeding. Exacerbation of colitis and Crohn’s disease has been reported following administration. Less frequently, gastritis has been observed. Pancreatitis has been reported very rarely.

Hepatobiliary disorders: abnormal liver function (bilirubinuria) hepatitis and jaundice.

Skin and subcutaneous tissue disorders: bullous reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis (very rare), photosensitivity.

Renal and urinary disorders: dysuria, urinary frequency (<1%), nephrotoxicity in various forms, including interstitial nephritis, nephritic syndrome and renal failure.

General disorders: malaise, fatigue, asthenia, chills, fever.

2.2 Indirect risks (incorrect use): overdosage: symptoms include headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, rarely diarrhoea, disorientation, excitation, coma, drowsiness, dizziness, tinnitus, fainting, occasional convulsions. In cases of significant poisoning acute renal failure and liver damage are possible.

Therapeutic measures: patients should be treated symptomatically as required. Within one hour of ingestion of a potentially toxic amount, activated charcoal should be considered. Alternatively, in adults, gastric lavage should be considered within one hour of ingestion of a potentially life-threatening overdose. Good urine output should be ensured. Renal and liver function should be closely monitored. Patients should be observed for at least four hours after ingestion of potentially toxic amounts. Frequent or prolonged convulsions should be treated with intravenous diazepam. Other measures may be indicated by the patient's clinical conditions.

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions:

Country Classification Additional information Routes of administration/ MS MDD MQP Indication AM Not authorised BE Not authorised CH List II DE Not authorised EE Not authorised ES Not authorised FI POM FR List II IE Not authorised IT Not authorised LT POM

43 LV Not authorised MK POM NL Not authorised PL Not authorised PT POM RO Not authorised RS POM

Melclass database1: List II

No data available from other member states.

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: List II

Criteria: regular medical follow-up required.

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

SmPC available in the following databases of medicines: Portugal and United Kingdom: PT: http://www.infarmed.pt/infomed/pesquisa.php UK: http://www.mhra.gov.uk/spc-pil/index.htm

1 Melclass database - Available at: http://www.edqm.eu/melclass/ (NB: this is the CD-P-PH/PHO’s recommendation at the moment of the compilation of the evidence-based review)

44 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AB09

1.3 Therapeutic indications: -

1.4 Posology and duration of treatment: -

1.5 Pharmaceutical forms: -

1.6 Contraindications: -

1.7 Relevant warnings: -

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): -

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

Lonazolac calcium is an NSAID. It has been given orally and rectally in the treatment of pain, inflammation and musculoskeletal and joint disorders.

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, no medicines containing this active substance are authorised in member states).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, no medicines containing this active substance are authorised in member states: Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References: -

45 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AB10

1.3 Therapeutic indications: oral route: for symptomatic relief of upper respiratory tract, genitourinary and osteoarticular inflammation and pain of various aetiologies, adult oral dosage of fentiazac is 200 to 400 mg daily in 2 divided doses. For minor pain, a single 100 to 200 mg dose is effective. As with other NSAIDs, a 2- to 3-week initial period on recommended dosage may be needed to maximise symptomatic relief, after which dosage should be reduced to the lowest possible effective level.

Rectal route: the adult dosage of fentiazac suppositories is 212 mg once or twice daily.

Topical application route: fentiazac 5% cream has been applied topically 2 to 3 times daily for treatment of acute musculoskeletal disorders and soft tissue injuries.

Dosage in geriatric patients: since geriatric patients are reportedly at increased risk for potentially severe nephrotoxicity and gastrointestinal toxicity of NSAIDs, dosage reduction of fentiazac should be considered in the elderly.

1.4 Posology and duration of treatment: -

1.5 Pharmaceutical forms: -

1.6 Contraindications: hypersensitivity to fentiazac, acetylsalicylic acid or any other NSAID; active gastric and duodenal ulcer; active gastrointestinal bleeding; concurrent long-term therapy.

1.7 Relevant warnings: upper gastrointestinal tract disease, haemorrhagic disorders, renal or hepatic impairment, compromised cardiac function. The possibility that antipyretic and antiinflammatory effects of the drug may mask the usual signs of even serious infections should be taken into account. Fentiazac cannot replace in the treatment of bacterial infections with inflammation.

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): -

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, no medicines containing this active substance are authorised in member states).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, no medicines containing this active substance are authorised in member states: Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

46 4. REFERENCES/COMMENTS

4.1 References: -

47 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AB11

1.3 Therapeutic indications: rheumatoid arthritis, osteoarthritis, and post-operative pain and inflammation.

1.4 Posology and duration of treatment: one capsule (60 mg) 2 or 3 times a day. One prolonged- release capsule (90 mg) 2 times a day.

1.5 Pharmaceutical forms: capsules: 60 mg; prolonged-release capsules: 90 mg.

1.6 Contraindications: hypersensitivity to the active substance, indometacin; active or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding); in patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, angioedema or urticaria) in response to ibuprofen, aspirin or other NSAIDs; severe heart failure, hepatic failure and renal failure; during the last trimester of pregnancy; history of gastrointestinal bleeding or perforation related to previous NSAID therapy; nasal polyps associated with angioneurotic oedema; blood formation disorder of unclear aetiology; children and adolescents.

1.7 Relevant warnings: elderly: the elderly have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation which may be fatal.

Respiratory disorders: caution is required if administered to patients suffering from, or with a previous history of, bronchial asthma since NSAIDs have been reported to precipitate bronchospasm in such patients. Patients who suffer from asthma, hay fever, swollen nasal mucosae or chronic respiratory disease are at particular risk of hypersensitivity reactions.

Cardiovascular, renal and hepatic impairment: the administration of an NSAID may cause a dose- dependent reduction in prostaglandin formation and precipitate renal failure. Patients at greatest risk of this reaction are those with impaired renal function, cardiac impairment, liver dysfunction, those taking diuretics and the elderly. Renal function should be monitored in these patients. An increase in the parameters of liver and kidney function tests has been observed in some patients being treated with acemetacin. Under long-term treatment, monitoring of liver and kidney function is strongly recommended.

Cardiovascular and cerebrovascular effects: appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy. Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long-term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). There are insufficient data to exclude such a risk for acemetacin. Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease should only be treated with acemetacin after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

Gastrointestinal bleeding, ulceration and perforation: GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious GI events. Inhibition of platelet aggregation may occur. The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation, and in the elderly. These patients should commence treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients and also for patients requiring concomitant low-dose aspirin or other drugs likely to increase gastrointestinal risk.

48 Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment. Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin reuptake inhibitors or antiplatelet agents such as aspirin. When GI bleeding or ulceration occurs in patients receiving acemetacin, the treatment should be withdrawn. In patients with an increased haemorrhagic tendency, platelet aggregation may be affected and the tendency to bleed may be increased. Under long-term treatment haemogram and blood coagulation monitoring is strongly recommended. NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn’s disease) as these conditions may be exacerbated.

SLE and mixed connective tissue disease: in patients with SLE and mixed connective tissue disorders there may be an increased risk of aseptic meningitis.

Dermatological: serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs. Patients appear to be at highest risk for these reactions early in the course of therapy: the onset of the reaction occurring in the majority of cases within the first month of treatment. Acemetacin should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.

Impaired female fertility: the use of acemetacin may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of acemetacin should be considered.

Eye disorders: eye changes may occur in chronic rheumatoid disease and patients should receive periodic ophthalmological examinations; therapy should be discontinued if changes occur.

Neurological: aggravation of psychiatric disorders, epilepsy or Parkinsonism may occur.

Other: signs and symptoms of infection may be masked.

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): the most commonly observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or gastrointestinal bleeding, sometimes fatal, particularly in the elderly, may occur: nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease have been reported following administration. Less frequently, gastritis has been observed. Pancreatitis has been reported very rarely. In particular the risk for the occurrence of gastrointestinal bleeding depends on the dose range and the duration of treatment.

Hypersensitivity: hypersensitivity reactions have been reported following treatment with NSAIDs. These may consist of a) non-specific allergic reactions and anaphylaxis, b) respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea and c) assorted skin disorders, including rashes of various types, pruritus, urticaria, purpura, angioedema and, more rarely, exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).

Cardiovascular and cerebrovascular: oedema, hypertension and cardiac failure have been reported in association with NSAID treatment. Clinical trials and epidemiological data suggest that use of some NSAIDs (especially when used at high doses and in long-term treatment) may be associated with a small increase in the risk for arterial thrombotic events (for example myocardial infarction or stroke).

Infections and infestations: in very rare cases, exacerbation of inflammation caused by infection (e.g. development of necrotising fasciitis) has been described in a temporal relationship with the systemic use of non-steroidal antiinflammatory agents. This may be associated with the mechanism of action of NSAIDs. Therefore, the patient should contact a doctor if any symptoms of

49 the infection recur or become worse under treatment with acemetacin. The doctor shall check whether an anti-infective/ therapy should be indicated.

Blood and the lymphatic system disorders: Very rare: anaemia caused by occult blood loss from the gastrointestinal tract, haemolytic anaemia, pancytopenia (anaemia including aplastic anaemia, leucopenia, agranulocytosis, thrombocytopenia). The initial symptoms may include: fever, sore throat, superficial lesions in the mouth, flu-like symptoms, severe tiredness, epistaxis and subcutaneous haemorrhage. In these cases, use of the medicinal product must be discontinued immediately and a doctor must be consulted. Any self- with analgesic agents and/or shall not happen. In case of long-term treatment, the blood count should be checked at regular intervals. An influence on thrombocyte aggregation, as well as increased haemorrhagic diathesis, is possible.

Immune system disorders: Common: hypersensitivity reactions, such as skin rashes and pruritus. Uncommon: urticaria. Very rare: severe general hypersensitivity reactions. These may manifest in the form of: oedema of the face and the eyelids, swollen tongue, internal laryngeal oedema with stenosis of the airways (angioneurotic oedema), respiratory distress that may to an asthma attack, aggravated asthma, tachycardia, blood pressure decrease leading to life-threatening shock. Should the patient experience any of these phenomena (which may occur as early as upon the first use of this medicinal product), medical assistance will be required. Very rare: -related vasculitis and pneumonitis.

Endocrine disorders: Very rare: hyperglycaemia and glucosuria.

Metabolism and disorders: Rare: hyperkalaemia

Psychiatric disorders: Common: agitation. Rare: irritability, confusion. Very rare: mental disorders, disorientation, anxiety, nightmares, tremor, psychosis, hallucination, depression and transitory loss of consciousness that may lead to coma. Treatment with acemetacin may intensify the symptoms of preexisting psychiatric diseases.

Nervous system disorders: Common: central nervous disorders such as headache, sleepiness/fatigue, dizziness, malaise and drowsiness. Very rare: sensibility disorders, muscular asthenia, hyperhidrosis, dysgeusia, impaired memory, sleep disorders, , reports of aseptic meningitis (especially in patients with existing autoimmune disorders, such as systemic lupus erythematosus, mixed connective tissue disease) with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation. Administration of acemetacin may intensify the symptoms of epilepsy and Parkinson's disease. Frequency not known: optic neuritis, paraesthesia.

Eye disorders: Uncommon: in the course of long-term treatment with indometacin, the main metabolite of acemetacin, pigment degeneration of the retina and corneal opacity have been reported. Blurred or double vision may be a typical symptom.

Ear and labyrinth disorders: Very rare: tinnitus and transitory hearing impairment.

Cardiac disorders: Very rare: palpitations, angina pectoris, cardiac failure

Vascular disorders: Very rare: hypertension. Frequency not known: circulatory collapse

Gastrointestinal disorders: Very common: gastrointestinal disorders such as nausea, vomiting, abdominal pain, diarrhoea and minor haemorrhage from the gastrointestinal tract which, in exceptional cases, can cause anaemia. Common: dyspepsia, flatulence, abdominal cramps, loss of appetite and gastrointestinal ulcers (sometimes accompanied by bleeding and perforation). Uncommon: blood can appear in vomit, faeces or diarrhoea. Very rare: stomatitis, inflammation of the tongue, lesions on the oesophagus, complaints in the lower abdomen (e.g. non-specific, bleeding inflammation of the colon) exacerbation of Crohn's disease or ulcerative colitis and constipation have been reported. Formation of intestinal diaphragm-like strictures and pancreatitis have been observed. The patient shall be instructed to discontinue the medicinal product and to consult a doctor immediately in case of any severe abdominal pain and/or the occurrence of melaena or haematemesis.

50 Hepatobiliary disorders: Common: hepatic enzyme increased. Uncommon: hepatic damage (toxic hepatitis with or without icterus), cholestasis. Very rare: taking a fulminant course without prodromal symptoms. The patient’s liver values should therefore be monitored at regular intervals.

Skin and subcutaneous tissue disorders: Uncommon: alopecia. Very rare: eczema, enanthema, erythema, photosensitivity reaction, minor and extensive cutaneous bleeding, exfoliative dermatitis and rash with bullous eruption, which may also take a grave course such as Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome).

Renal and urinary disorders: Uncommon: development of oedema (e.g. peripheral oedema) in particular in patients with hypertension and/or impaired renal function. Very rare: micturition disorders, increase in blood urea, acute renal insufficiency, proteinuria, haematuria or renal damage (interstitial nephritis, nephrotic syndrome, papillary necrosis). Therefore, the patient's renal function should be checked at regular intervals.

Reproductive system and breast disorders: very rare: vaginal haemorrhage.

2.2 Indirect risks (incorrect use): overdosage: symptoms: headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, rarely diarrhoea, disorientation, excitation, coma, drowsiness, dizziness, tinnitus, fainting, occasionally convulsions. In cases of significant poisoning acute renal failure and liver damage are possible.

Therapeutic measures: patients should be treated symptomatically as required. Within one hour of ingestion of a potentially toxic amount, activated charcoal should be considered. Alternatively, in adults, gastric lavage should be considered within one hour of ingestion of a potentially life- threatening overdose. Good urine output should be ensured. Renal and liver function should be closely monitored. Patients should be observed for at least four hours after ingestion of potentially toxic amounts. Frequent or prolonged convulsions should be treated with intravenous diazepam. Other measures may be indicated by the patient’s clinical condition.

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions:

Country Classification Additional information Routes of administration/ MS MDD MQP Indications AM Not authorised BE Not authorised CH List II DE POM ES Not authorised FI Not authorised FR Not authorised IE Not authorised IT Not authorised LT Not authorised LV Not authorised MK Not authorised NL Not authorised PL POM PT POM RO List II RS POM

Melclass database1: List I

1 Melclass database - Available at: http://www.edqm.eu/melclass/ (NB: this is the CD-P-PH/PHO’s recommendation at the moment of the compilation of the evidence-based review)

51 No data available from other member states.

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: List I

Criteria: medical supervision required

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

SmPC available in the following databases of medicines: Portugal and United Kingdom: PT: http://www.infarmed.pt/infomed/pesquisa.php UK: http://www.mhra.gov.uk/spc-pil/index.htm

52 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AB12

Difenpiramide is an NSAID that has been used in musculoskeletal, joint and soft-tissue disorders.

1.3 Therapeutic indications: -

1.4 Posology and duration of treatment: -

1.5 Pharmaceutical forms: -

1.6 Contraindications: -

1.7 Relevant warnings: -

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): -

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, no medicines containing this active substance are authorised in member states).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, no medicines containing this active substance are authorised in member states: Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References: -

53 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC Code: M01AB13

Oxametacin, an indometacin derivative, is an NSAID that has been used in painful and inflammatory conditions.

1.3 Therapeutic indications: -

1.4 Posology and duration of treatment: -

1.5 Pharmaceutical forms: -

1.6 Contraindications: -

1.7 Relevant warnings: -

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): -

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, no medicines containing this active substance are authorised in member states).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, no medicines containing this active substance are authorised in member states: Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References: -

54 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AB14

1.3 Therapeutic indications: rheumatoid arthritis, inflammatory stages of arthrosis whatever location, lumbago, sciatica, radiculitis, acute rheumatism, gout, extra-articular rheumatic (tendinitis, bursitis, synovitis, tenosynovitis, periarthropaty, torticollis, neuralgia and neuritis, fibromyositis), inflammation in trauma of the , ligaments, muscles and joints (muscle distensions, bruises, luxation, sprains, fractures, post-surgery arthropathy, orthopaedic surgery), local degenerative forms of rheumatism, such as osteoarthritis of peripheral joints and spine.

1.4 Posology and duration of treatment: usually 2 tablets/day. In clinical situations whose inflammatory activity justifies it: initial treatment of 3 tablets/day followed by a maintenance dose of 2 tablets/day.

1.5 Pharmaceutical forms: tablets: 300 mg.

1.6 Contraindications: severe renal failure; severe hepatic failure; severe heart failure; history of recurrent gastric or duodenal ulcer or active gastric or duodenal ulcer; patients in whom NSAIDs induce asthma; pregnancy and lactation; gastrointestinal bleeding, cerebrovascular bleeding or other active bleeding.

1.7 Relevant warnings: bowel inflammatory disease (ulcerative colitis, Crohn’s disease), concomitant use with medicines which may increase risk of ulceration or bleeding such as oral low- dose acetylsalicylic acid, corticosteroids, anticoagulants (such as warfarin), selective serotonin reuptake inhibitors or antiplatelet agents such as acetylsalicylic acid. Concomitant use with other NSAIDs, including COX-2 selective inhibitors. Severe cutaneous reactions including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis (stop treatment at first signs of skin rash, mucosal lesions or any other sign of hypersensitivity). Small increased risk of arterial thrombotic events (for example myocardial infarction or stroke) particularly at high doses and in long-term treatment. Caution in patients with uncontrolled hypertension and/or congestive heart failure (liquid retention and oedema have been reported), established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease. Before initiating longer-term treatment of patients with risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking). Elderly (increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation). Proglumetacin may mask signs of infection. Neurotoxic symptoms in patients with renal failure or central nervous system conditions, if used above recommended dosage. Patients exposed to prolonged treatment should be submitted to renal, hepatic and haematological monitoring.

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): nausea, dyspepsia, vomiting, abdominal pain, diarrhoea, constipation, cardiac failure, peptic ulcer, drilling, gastrointestinal bleeding, Crohn's disease (exacerbation), foot-and-mouth disease, Stevens-Johnson syndrome, epidermal necrolysis, hypertension, gastritis.

2.2 Indirect risks (incorrect use): in case of massive ingestion, the symptomatology may include drowsiness, confusion, vomiting, paresthesias, oedema, aggressive behaviour and convulsions. Gastric lavage should be performed and the patient kept under surveillance for several days. Consider the possibility of ulceration or digestive haemorrhage. The administration of antacids may be useful to minimise the effects in the medium term.

2.3 Recent cases at European level: -

55 3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions:

Country Classification Additional information Routes of administration/ MS MDD MQP Indication AM Not authorised BE POM CH Not authorised DE Not authorised EE Not authorised ES Not authorise FI Not authorised FR Not authorised IE Not authorised IT List II LT Not authorised LV Not authorised NL Not authorised PL Not authorised PT POM RO Not authorised RS Not authorised

Melclass database1: List II

No data available from other member states.

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: List II

Criteria: indicated for long-term treatment under medical supervision.

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

National Authority of Medicines and Health Products (INFARMED) (PT) – available at: http://www.infarmed.pt/infomed/pesquisa.php

1 Melclass database - Available at: http://www.edqm.eu/melclass/ (NB: this is the CD-P-PH/PHO’s recommendation at the moment of the compilation of the evidence-based review)

56 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AB15

1.3 Therapeutic indications: short-term management of moderate to severe acute post-operative pain. Treatment should only be initiated in hospitals. The maximum duration of treatment is two days.

1.4 Posology and duration of treatment: for administration by intramuscular or bolus intravenous injection. Bolus intravenous doses should be given over no less than 15 seconds. Ketorolac should not be used for epidural or spinal administration. The time to onset of analgesic effect following both intravenous (IV) and intramuscular (IM) administration is approximately 30 minutes, with maximum analgesia occurring within one to two hours. The median duration of analgesia is generally four to six hours. Dosage should be adjusted according to the severity of the pain and the patient response. The administration of continuous multiple daily doses of ketorolac intramuscularly or intravenously should not exceed two days because adverse events may increase with prolonged usage. There has been limited experience with dosing for longer periods since the vast majority of patients have transferred to oral medication or no longer require analgesic therapy after this time. The recommended initial dose of ketorolac injection is 10 mg, followed by 10 to 30 mg every four to six hours as required. In the initial post-operative period, ketorolac may be given as often as every two hours if needed. The lowest effective dose should be given. A total daily dose of 90 mg for non-elderly and 60 mg for the elderly, renally impaired patients and patients less than 50 kg should not be exceeded. The maximum duration of treatment should not exceed two days. Reduce dosage in patients under 50 kg.

1.5 Pharmaceutical forms: solution for injection: 10 mg/ml and 30 mg/ml.

1.6 Contraindications: ketorolac is contraindicated in patients with previously demonstrated hypersensitivity to ketorolac or other NSAIDs and patients in whom aspirin or other prostaglandin synthesis inhibitors induce allergic reactions (severe anaphylactic-like reactions have been observed in such patients). Such reactions have included asthma, rhinitis, angioedema and urticaria. Ketorolac is also contraindicated in those with a history of asthma and children under 16 years of age; in patients with active or a history of gastrointestinal bleeding or perforation related to previous NSAID therapy; active or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding); in patients with severe heart failure, hepatic failure and renal failure; in patients taking anticoagulants such as warfarin.

1.7 Relevant warnings: epidemiological evidence suggests that ketorolac may be associated with a high risk of serious gastrointestinal toxicity, relative to some other NSAIDs, especially when used outside the licensed indications and/or for prolonged periods. Physicians should be aware that in some patients pain relief may not occur until upwards of 30 minutes after IV or IM administration. The use of ketorolac with concomitant NSAIDs, including COX-2 selective inhibitors, should be avoided. Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms.

Gastrointestinal ulceration, bleeding and perforation: GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs, including ketorolac therapy, at any time during treatment, with or without warning symptoms or a previous history of serious GI events. In a non-randomised, in- hospital post-marketing surveillance study, increased rates of clinically serious GI bleeding were seen in patients <65 years of age who received an average daily dose of >90 mg ketorolac IM as compared to those patients receiving parenteral .

The elderly have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation, which may be fatal. Debilitated patients seem to tolerate ulceration or bleeding less well than others. Most of the fatal gastrointestinal events associated with NSAIDs occurred in the elderly and/or debilitated patients. The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, including ketorolac IV, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation, and in the elderly. The risk of clinically serious gastrointestinal bleeding is dose dependent. These patients should commence treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors)

57 should be considered for these patients and also for patients requiring concomitant low-dose aspirin or other drugs likely to increase gastrointestinal risk. This age-related risk of gastrointestinal bleeding and perforation is common to all NSAIDs. Compared to young adults, the elderly have an increased plasma half-life and reduced plasma clearance of ketorolac. A longer dosing interval is advisable.

NSAIDs should be given with care to patients with a history of inflammatory bowel disease, (ulcerative colitis and Crohn’s disease) as these conditions may be exacerbated. Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment. When GI bleeding or ulceration occurs in patients receiving ketorolac IV, treatment should be withdrawn.

Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, selective serotonin reuptake inhibitors or antiplatelet agents such as aspirin.

As with other NSAIDs the incidence and severity of gastrointestinal complications may increase with increasing dose and duration of treatment with ketorolac IV. The risk of clinically serious gastrointestinal bleeding is dose-dependent. This is particularly true in elderly patients who receive an average daily dose greater than 60 mg/day of Ketorolac IV. A history of peptic ulcer disease increases the possibility of developing serious gastrointestinal complications during Ketorolac therapy.

Haematological effects: patients with coagulation disorders should not receive ketorolac. Patients on anticoagulation therapy may be at increased risk of bleeding if given ketorolac concurrently. The concomitant use of ketorolac and prophylactic low-dose (2500-5000 units 12-hourly) and dextrans has not been studied extensively and may also be associated with an increased risk of bleeding. Patients already on anticoagulants or who require low-dose heparin should not receive ketorolac. Patients who are receiving other drug therapy that interferes with haemostasis should be carefully observed if ketorolac is administered. In controlled clinical studies, the incidence of clinically significant postoperative bleeding was less than 1%. Ketorolac inhibits platelet aggregation and prolongs bleeding time. In patients with normal bleeding function, bleeding times were raised, but not outside the normal range of two to eleven minutes. Unlike the prolonged effects from aspirin, platelet function returns to normal within 24 to 48 hours after ketorolac is discontinued. In post-marketing experience, postoperative wound haemorrhage has been reported in association with the peri-operative use of ketorolac for injection IM/IV. Therefore, ketorolac should not be used in patients who have had operations with a high risk of haemorrhage or incomplete haemostasis. Caution should be used where strict haemostasis is critical, e.g. in cosmetic or day-case surgery, resection of the prostate or tonsillectomy. Haematomas and other signs of wound haemorrhage and epistaxis have been reported with the use of ketorolac. Physicians should be aware of the pharmacological similarity of ketorolac to other NSAIDs that inhibit cyclooxygenase and the risk of bleeding, particularly in the elderly.

Skin reactions: serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens- Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs. Patients appear to be at highest risk for these reactions early in the course of therapy: the onset of the reactions occurring in the majority of cases within the first month of treatment. Ketorolac should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.

SLE and mixed connective tissue disease: in patients with SLE and mixed connective tissue disorders there may be an increased risk of aseptic meningitis.

Sodium/fluid retention in cardiovascular conditions and peripheral oedema: caution is required in patients with a history of hypertension and/or heart failure as fluid retention and oedema have been reported in association with NSAID therapy. Fluid retention, hypertension and peripheral oedema have been observed in some patients taking NSAIDs, including ketorolac, and it should therefore be used with caution in patients with cardiac decompensation, hypertension or similar conditions.

Cardiovascular and cerebrovascular effects: appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy. Clinical trial and epidemiological data suggest that use of coxibs and some NSAIDs (particularly at high doses) may be associated with a

58 small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). Although ketorolac has not been shown to increase thrombotic events such as myocardial infarction, there are insufficient data to exclude such a risk for ketorolac. Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease should only be treated with ketorolac after careful consideration. Similar consideration should be made before initiating treatment of patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus and smoking).

Cardiovascular, renal and hepatic impairment: caution should be observed in patients with conditions leading to a reduction in blood volume and/or renal blood flow, where renal prostaglandins have a supportive role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in renal prostaglandin formation and may precipitate overt renal failure. Patients at greatest risk of this reaction are those who are volume depleted because of blood loss or severe dehydration, patients with impaired renal function, heart failure, liver dysfunction, the elderly and those taking diuretics. Renal function should be monitored in these patients. Discontinuation of NSAID therapy is typically followed by recovery to the pretreatment state. Inadequate fluid/blood replacement during surgery, leading to hypovolaemia, may lead to renal dysfunction which could be exacerbated when ketorolac is administered. Therefore, volume depletion should be corrected and close monitoring of serum urea and creatinine and urine output is recommended until the patient is normovolaemic. In patients on renal dialysis, ketorolac clearance was reduced to approximately half the normal rate and terminal half-life increased approximately three-fold.

Renal effects: as with other NSAIDs, ketorolac should be used with caution in patients with impaired renal function or a history of kidney disease because it is a potent inhibitor of prostaglandin synthesis. Caution should be observed as renal toxicity has been seen with ketorolac and other NSAIDs in patients with conditions leading to a reduction in blood volume and/or renal blood flow where renal prostaglandins have a supportive role in the maintenance of renal perfusion. In these patients administration of ketorolac or other NSAIDs may cause a dose-dependent reduction in renal prostaglandin formation and may precipitate overt renal decompensation or failure. Patients at greatest risk of this reaction are those with impaired renal function, hypovolaemia, heart failure, liver dysfunction, those taking diuretics and the elderly. Discontinuation of ketorolac or other non-steroidal antiinflammatory therapy is usually followed by recovery to the pretreatment state. As with other drugs that inhibit prostaglandin synthesis, elevations of serum urea, creatinine and potassium have been reported with ketorolac and may occur after one dose. Patients with impaired renal function: since ketorolac trometamol and its metabolites are excreted primarily by the kidney, patients with moderate to severe impairment of renal function (serum creatinine greater than 160 micromol/l) should not receive it. Patients with lesser renal impairment should receive a reduced dose of ketorolac (not exceeding 60 mg/day IM or IV) and their renal status should be closely monitored.

Use in patients with impaired liver function: patients with impaired hepatic function from cirrhosis do not have any clinically important changes in ketorolac clearance or terminal half-life. Borderline elevations of one or more liver function tests may occur. These abnormalities may be transient, may remain unchanged or may progress with continued therapy. Meaningful elevations (greater than 3 times normal) of serum glutamate pyruvate transaminase or serum glutamate oxaloacetate transaminase occurred in controlled clinical trials in less than 1% of patients. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur, ketorolac should be discontinued.

Anaphylactic (anaphylactoid) reactions (including, but not limited to, anaphylaxis, bronchospasm, flushing, rash, hypotension, laryngeal oedema and angioedema) may occur in patients with or without a history of hypersensitivity to aspirin, other NSAIDs or ketorolac IV. These may also occur in individuals with a history of angioedema, bronchospastic reactivity (e.g. asthma) and nasal polyps. Anaphylactoid reactions, like anaphylaxis, may have a fatal outcome. Therefore, ketorolac should be used with caution in patients with a history of asthma and in patients with the complete or partial syndrome of nasal polyps, angioedema and bronchospasm.

Precautions related to fertility: the use of ketorolac, as with any drug known to inhibit cyclooxygenase/prostaglandin synthesis, may impair fertility and is not recommended in women attempting to conceive. In women who have difficulty conceiving or are undergoing investigation of fertility, withdrawal of ketorolac should be considered.

59 Caution is advised when is administered concurrently since some prostaglandin synthesis-inhibiting drugs have been reported to reduce the clearance of methotrexate and thus possibly enhance its toxicity.

Paediatric use: ketorolac tablets are not recommended for use in children. Ketorolac given parenterally is not recommended in children younger than 2 years of age.

Drug abuse and dependence: ketorolac is devoid of addictive potential. No withdrawal symptoms have been observed following abrupt discontinuation of ketorolac IV.

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): the following undesirable effects may occur in patients receiving ketorolac (frequencies of reported events are not known, because they were reported voluntarily from a population of uncertain size):

Gastrointestinal disorders: the most commonly observed adverse events are gastrointestinal in nature. Peptic ulcers, ulcers, perforation or GI bleeding, sometimes fatal, particularly in the elderly, may occur. Nausea, dyspepsia, abdominal pain/discomfort, haematemesis, stomatitis, dry mouth, oesophagitis, diarrhoea, eructation, constipation, flatulence, fullness, melaena, gastrointestinal ulceration, rectal bleeding, ulcerative stomatitis, vomiting, pancreatitis, exacerbation of colitis and Crohn's disease have been reported following administration. Less frequently, gastritis has been observed.

Blood and lymphatic system disorders: thrombocytopenia, purpura, neutropenia, agranulocytosis, aplastic anaemia, haemolytic anaemia.

Immune system disorders: anaphylaxis and anaphylactoid reactions which may have a fatal outcome, hypersensitivity reactions such as bronchospasm flushing, rash, hypotension, laryngeal oedema. These may also occur in individuals with a history of angioedema, bronchospastic reactivity (e.g. asthma and nasal polyps).

Infection: aseptic meningitis (especially in patients with existing autoimmune disorders, such as systemic lupus erythematosus, mixed connective tissue disease), with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation.

Metabolic and nutrition disorders: anorexia, hyponatraemia, hyperkalaemia.

Psychiatric disorders: abnormal thinking, depression, euphoria, insomnia, anxiety, nervousness, psychotic reactions, abnormal dreams, hallucinations, inability to concentrate, drowsiness, confusion, stimulation.

Nervous system disorders: dizziness, headache, paraesthesia, convulsions, abnormal taste, hyperkinesia.

Eye disorders: optic neuritis, abnormal vision, visual disturbances.

Ear disorders: hearing loss, tinnitus, vertigo.

Renal and urinary disorders: increased urinary frequency, oliguria, acute renal failure, haemolytic uraemic syndrome, flank pain (with or without haematuria +- azotaemia), interstitial nephritis, urinary retention, nephrotic syndrome. As with other drugs that inhibit renal prostaglandin synthesis signs of renal impairment, such as, but not limited to, elevations of creatinine and potassium can occur after one dose of ketorolac.

Cardiac disorders: bradycardia, palpitations, cardiac failure.

Vascular disorders: flushing, pallor, hypertension, oedema, hypotension, postoperative wound haemorrhage, haematoma.

60 Clinical trial and epidemiological data suggest that use of coxibs and some NSAIDs (particularly at high doses) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). Although ketorolac has not shown to increase thrombotic events, such as myocardial infarction, there are insufficient data to exclude such a risk with ketorolac.

Reproductive system and breast disorders: female infertility.

Respiratory, thoracic and mediastinal disorders: dyspnoea, asthma, pulmonary oedema, epistaxis.

Hepatobiliary disorders: hepatitis, cholestatic jaundice and liver failure.

Skin and subcutaneous tissue disorders: pruritus, urticaria, purpura, angioedema, exfoliative dermatitis, maculopapular rash, sweating, bullous reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis (very rare). Additionally erythema multiforme and skin photosensitivity have been observed.

Musculoskeletal and connective tissue disorders: myalgia, functional disorders.

General disorders and administration site conditions: excessive thirst, asthenia, weight gain, fever, injection site reactions and pain, chest pain, malaise, fatigue.

Investigations: bleeding time prolonged, serum urea increased and creatinine increased, abnormal liver function, laboratory abnormalities.

2.2 Indirect risks (incorrect use): overdosage: symptoms and signs: single overdoses of ketorolac have been variously associated with abdominal pain, nausea, vomiting, hyperventilation, peptic ulcers and/or erosive gastritis and renal dysfunction, which have resolved after discontinuation of dosing. Gastrointestinal bleeding may occur. Hypertension, acute renal failure, respiratory depression and coma may occur after the ingestion of NSAIDs but are rare. Headache, epigastric pain, disorientation, excitation, drowsiness, dizziness, tinnitus and fainting have also been observed. Rare cases of diarrhoea and occasional convulsions have been reported. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs and may occur following an overdose.

Treatment: patients should be managed by symptomatic and supportive care following NSAID overdose. There are no specific . Dialysis does not significantly clear ketorolac from the blood stream. Within one hour of ingestion of a potentially toxic amount, activated charcoal should be considered. Alternatively, in adults, gastric lavage should be considered within one hour of ingestion of a potentially life-threatening overdose. Good urine output should be ensured. Renal and liver function should be closely monitored. Patients should be observed for at least four hours after ingestion of potentially toxic amounts. Frequent or prolonged convulsions should be treated with intravenous diazepam. Other measures may be indicated by the patient's clinical condition.

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions:

Country Classification Additional information Routes of administration/ MS MDD MQP Indication AM POM BE POM CH List II DE Not authorised ES POM FI POM FR Not authorised IE Not authorised IT List I (renewal of

61 prescription forbidden) LT POM LV POM MK Not authorised NL Not authorised PL Not authorised POM (solution for PT injection: hospital use only) RO List II POM (solution for RS injection - for hospital use only)

Melclass database1: List II

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: List I

Criteria: short-term treatment to be carried out under medical supervision.

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

SmPC available in the following databases of medicines: Portugal and United Kingdom PT: http://www.infarmed.pt/infomed/pesquisa.php UK: http://www.mhra.gov.uk/spc-pil/index.htm

1 Melclass database - Available at: http://www.edqm.eu/melclass/ (NB: this is the CD-P-PH/PHO’s recommendation at the moment of the compilation of the evidence-based review)

62 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AB16

1.3 Therapeutic indications: treatment of inflammatory and degenerative forms of rheumatism: osteoarthrosis, periarthritis, rheumatoid arthritis, ankylosing spondylitis. Analgesic treatment of extra- articular rheumatism, such as lumbago, sciatica and bursitis, and painful conditions (trauma, orthopaedic, surgery). Treatment of painful and inflammatory conditions, such as tendinitis, tenosynovitis, sprains, luxations, periarthritis, distensions, lumbago and torticollis.

1.4 Posology and duration of treatment: the recommended dose is 200 mg daily, taken as two separate 100 mg doses, one in the morning and one in the evening.

1.5 Pharmaceutical forms: tablets: 100 mg.

1.6 Contraindications: hypersensitivity to aceclofenac or to any of the excipients; active or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding); in patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, angioedema or urticaria) in response to ibuprofen, aspirin or other NSAIDs; severe heart failure, hepatic failure and renal failure; history of gastrointestinal bleeding or perforation related to previous NSAID therapy. Aceclofenac should not be prescribed during pregnancy, especially during the last trimester of pregnancy, unless there are compelling reasons for doing so. The lowest effective dosage should be used.

1.7 Relevant warnings: undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms.

The use of aceclofenac with concomitant NSAIDs, including COX-2 selective inhibitors, should be avoided.

Elderly: the elderly have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation, which may be fatal.

Respiratory disorders: caution is required if administered to patients suffering from, or with a previous history of, bronchial asthma since NSAIDs have been reported to precipitate bronchospasm in such patients.

Cardiovascular and renal impairment: the administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and precipitate renal failure. Patients at greatest risk of this reaction are those with impaired renal function, cardiac impairment, liver dysfunction, those taking diuretics and the elderly. Renal function should be monitored in these patients. The importance of prostaglandins in maintaining renal blood flow should be taken into account in patients with impaired cardiac or renal function, those being treated with diuretics or recovering from major surgery. Effects on renal function are usually reversible on withdrawal of aceclofenac.

Hepatic impairment: if abnormal liver function tests persist or worsen, clinical signs or symptoms consistent with liver disease develop or if other manifestations occur (eosinophilia, rash), aceclofenac should be discontinued. Close medical surveillance is necessary in patients suffering from mild to moderate impairment of hepatic function. Hepatitis may occur without prodromal symptoms. Use of aceclofenac in patients with hepatic porphyria may trigger an attack.

Cardiovascular and cerebrovascular effects: appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy.

Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long-term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). There are insufficient data to exclude such a risk for

63 aceclofenac. Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease should only be treated with aceclofenac after careful consideration. Similar consideration should be made before initiating longer- term treatment of patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

Gastrointestinal bleeding, ulceration and perforation: GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs. Such reactions can occur at any time during treatment, with or without warning symptoms or a previous history of serious GI events. Close medical surveillance is imperative in patients with symptoms indicative of gastrointestinal disorders, with a history suggestive of gastrointestinal ulceration, with ulcerative colitis or with Crohn's disease, bleeding diathesis or haematological abnormalities, as these conditions may be exacerbated. The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation, and in the elderly. These patients should commence treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients and also for patients requiring concomitant low-dose aspirin or other drugs likely to increase gastrointestinal risk. Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment. Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin reuptake inhibitors or antiplatelet agents such as aspirin. When GI bleeding or ulceration occurs in patients receiving aceclofenac, the treatment should be withdrawn. NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn’s disease) as these conditions may be exacerbated.

SLE and mixed connective tissue disease: in patients with SLE and mixed connective tissue disorders there may be an increased risk of aseptic meningitis.

Dermatological: serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens- Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs. Patients appear to be at highest risk for these reactions early in the course of therapy: the onset of the reaction occurring in the majority of cases within the first month of treatment. Aceclofenac should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.

Impaired female fertility: the use of aceclofenac may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of aceclofenac should be considered.

Hypersensitivity reactions: as with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, can also occur without earlier exposure to the drug.

Haematological: aceclofenac may reversibly inhibit platelet aggregation.

Long-term treatment: all patients who are receiving NSAIDs should be monitored as a precautionary measure e.g. renal failure, hepatic function (elevation of liver enzymes may occur) and blood counts.

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): Gastrointestinal: the most commonly-observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or GI bleeding, sometimes fatal, particularly in the elderly, may occur. Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative, stomatitis, exacerbation of colitis and Crohn’s disease have been reported following administration. Less frequently, gastritis has been observed. Pancreatitis has been reported very rarely.

Hypersensitivity: hypersensitivity reactions have been reported following treatment with NSAIDs. These may consist of (a) non-specific allergic reactions and anaphylaxis, (b) respiratory tract reactivity

64 comprising asthma, aggravated asthma, bronchospasm or dyspnoea and (c) assorted skin disorders, including rashes of various types, pruritus, urticaria, purpura, angioedema and, more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).

Cardiovascular: oedema, hypertension and cardiac failure have been reported in association with NSAID treatment.

Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long-term treatment) may be associated with an increased risk of arterial thrombotic events (for example myocardial infarction or stroke).

Renal: nephrotoxicity in various forms, including interstitial nephritis, nephritic syndrome and renal failure.

Hepatic: abnormal liver function, hepatitis and jaundice.

Neurological and special senses: visual disturbances, optic neuritis, headaches, paraesthesia, reports of aseptic meningitis (especially in patients with existing autoimmune disorders, such as systemic lupus erythematosus, mixed connective tissue disease), with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation, depression, confusion, hallucinations, tinnitus, vertigo, dizziness, malaise, fatigue and drowsiness.

Haematological: thrombocytopenia, neutropenia, agranulocytosis, aplastic anaemia and haemolytic anaemia.

Dermatological: bullous reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis (very rare). Photosensitivity.

2.2 Indirect risks (incorrect use): overdosage: symptoms: headache, nausea, vomiting, epigastric pain, gastrointestinal irritation, gastrointestinal bleeding, rarely diarrhoea, disorientation, excitation, coma, drowsiness, dizziness, tinnitus, hypotension, respiratory depression, fainting and occasionally convulsions. In cases of significant poisoning acute renal failure and liver damage are possible.

Therapeutic measures: patients should be treated symptomatically as required. Within one hour of ingestion of a potentially toxic amount, activated charcoal should be considered. Alternatively, in adults, gastric lavage should be considered within one hour of ingestion of a potentially life-threatening overdose. Specific therapies such as dialysis or haemoperfusion are probably of no help in eliminating NSAIDs due to their high rate of protein binding and extensive metabolism. Good urine output should be ensured. Renal and liver function should be closely monitored. Patients should be observed for at least four hours after ingestion of potentially toxic amounts. In cases of frequent or prolonged convulsions, patients should be treated with intravenous diazepam. Other measures may be indicated by the patient's clinical condition. Management of acute poisoning with NSAIDs essentially consists of supportive and symptomatic measures.

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions:

Country Classification Additional information Routes of administration/ MS MDD MQP Indication AM POM BE POM CH Not authorised DE POM ES POM FI Not authorised FR List II

65 IE List II IT List II Oral use LT POM LV POM MK Not authorised NL POM PL POM PT POM RO List II RS POM

Melclass database1: List II

No data available from other member states.

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: List II

Criteria: long-term treatment.

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

SmPC available in the following databases of medicines: Portugal and United Kingdom PT: http://www.infarmed.pt/infomed/pesquisa.php UK: http://www.mhra.gov.uk/spc-pil/index.htm

1 Melclass database - Available at: http://www.edqm.eu/melclass/ (NB: this is the CD-P-PH/PHO’s recommendation at the moment of the compilation of the evidence-based review)

66 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AB17

1.3 Therapeutic indications: -

1.4 Posology and duration of treatment: -

1.5 Pharmaceutical forms: -

1.6 Contraindications: -

1.7 Relevant warnings: -

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): -

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, no medicines containing this active substance are authorised in member states).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, no medicines containing this active substance are authorised in member states: Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References: -

67 1. THERAPEUTIC PROFILE

1.1 Active ingredient: Indometacin, Combinations

1.2 ATC code: M01AB51

1.3 Therapeutic indications: -

1.4 Posology and duration of treatment: -

1.5 Pharmaceutical forms: -

1.6 Contraindications: -

1.7 Relevant warnings: -

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): -

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, no medicines containing indometacin in combination with other active substances are authorised in member states).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, no medicines containing indometacin in combination with other active substances are authorised in member states: Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References: -

68 1. THERAPEUTIC PROFILE

1.1 Active ingredient: Diclofenac, Combinations

1.2 ATC code: M01AB55

1.3 Therapeutic indications: available combination product: diclofenac/misoprostol, indicated for patients who require the NSAID diclofenac together with misoprostol. This medication is indicated for the symptomatic treatment of osteoarthritis and rheumatoid arthritis. The misoprostol component is indicated for patients with a special need for the prophylaxis of NSAID-induced gastric and duodenal ulceration.

1.4 Posology and duration of treatment: one tablet to be taken with food, two or three times daily. Tablets should be swallowed whole, not chewed.

1.5 Pharmaceutical forms: modified-release tablets: diclofenac 50 mg/misoprostol 200 micrograms; diclofenac 75 mg/misoprostol 200 micrograms.

1.6 Contraindications: patients with active peptic ulcer/haemorrhage or perforation or who have active GI bleeding or other active e.g. cerebrovascular bleedings; pregnant women and women planning a pregnancy; patients with a known hypersensitivity to diclofenac, aspirin, other NSAIDs, misoprostol, other prostaglandins or any other ingredient in the product; patients in whom attacks of asthma, urticaria or acute rhinitis are precipitated by aspirin or other non-steroidal antiinflammatory agents; treatment of peri-operative pain in the setting of CABG surgery; patients with severe renal and hepatic failure; patients with established congestive heart failure (NYHA II-IV), ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease.

1.7 Relevant warnings: the use of diclofenac/misoprostol with concomitant NSAIDs, including COX-2 inhibitors, should be avoided.

Use in premenopausal women: diclofenac/misoprostol should not be used in premenopausal women unless they use effective contraception and have been advised of the risks of taking the product if pregnant.

Precautions: undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms.

Renal/Cardiac/Hepatic: in patients with renal, cardiac or hepatic impairment and in the elderly, caution is required since the use of NSAIDs may result in deterioration of renal function. Diclofenac/misoprostol should be used only in exceptional circumstances and with close clinical monitoring in the following conditions: advanced cardiac failure, advanced , advanced liver disease, severe dehydration. Diclofenac metabolites are eliminated primarily by the kidneys. The extent to which the metabolites may accumulate in patients with renal failure has not been studied. As with other NSAIDs, metabolites of which are excreted by the kidney, patients with significantly impaired renal function should be more closely monitored. In rare cases, NSAIDs, including diclofenac/misoprostol, may cause interstitial nephritis, glomerulitis, papillary necrosis and nephrotic syndrome. NSAIDs inhibit the synthesis of renal prostaglandin which plays a supportive role in the maintenance of renal perfusion in patients whose renal blood flow and blood volume are decreased. In these patients, administration of an NSAID may precipitate overt renal decompensation, which is typically followed by recovery to pretreatment state upon discontinuation of NSAID therapy. Patients at greatest risk of such a reaction are those with congestive heart failure, liver cirrhosis, nephrotic syndrome and overt renal disease. Such patients should be carefully monitored while receiving NSAID therapy. Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy. As with all NSAIDS, diclofenac/misoprostol can lead to the onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of cardiovascular events. NSAIDs, including diclofenac/misoprostol, should be used with caution in patients with hypertension. Blood pressure should be monitored closely during the initiation of therapy with diclofenac/misoprostol and throughout the course of therapy. Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease should

69 only be treated with diclofenac after careful consideration. Patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking) should only be treated with diclofenac after careful consideration. As the cardiovascular risks of diclofenac may increase with dose and duration of exposure, the shortest duration possible and the lowest effective daily dose may be used. The patient’s need for symptomatic relief and response to therapy should be re-evaluated periodically. Clinical trial and epidemiological data suggest that use of diclofenac, particularly at high dose (150 mg daily) and in long-term treatment may be associated with a small increased risk of serious arterial thrombotic events (for example myocardial infarction or stroke). Physicians and patients should remain alert for the development of such events, even in the absence of previous cardiovascular symptoms. Patients should be informed about the signs and/or symptoms of serious cardiovascular toxicity and the steps to take if they occur.

Blood system/Gastrointestinal: NSAIDs, including diclofenac/misoprostol, can cause serious GI adverse events including inflammation, bleeding, ulceration and perforation of the stomach, small intestine or large intestine, which can be fatal. When GI bleeding or ulceration occurs in patients receiving diclofenac/misoprostol, the treatment should be withdrawn. These events can occur at any time during treatment, with or without warning symptoms or in patients with a previous history of serious GI events. Patients most at risk of developing these types of GI complications with NSAIDs are those treated at higher doses, the elderly, patients with cardiovascular disease, patients using concomitant aspirin or patients with a prior history of, or active, gastrointestinal disease, such as ulceration, GI bleeding or inflammatory conditions. Patients most at risk of developing these types of GI complications with NSAIDs are those treated at higher doses, the elderly, patients with cardiovascular disease, patients using concomitant aspirin or patients with a prior history of, or active, gastrointestinal disease, such as ulceration, GI bleeding or inflammatory conditions. Therefore, diclofenac/misoprostol should be used with caution in these patients and treatment commenced at the lowest dose available. Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment. Caution should be advised in patients receiving concomitant medicines which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin reuptake inhibitors or antiplatelet agents such as aspirin. Diclofenac/misoprostol, in common with other NSAIDs, may decrease platelet aggregation and prolong bleeding time. Extra supervision is recommended in haematopoietic disorders or in conditions with defective coagulation or in patients with a history of cerebrovascular bleeding. Caution is required in patients suffering from ulcerative colitis or Crohn's Disease as these conditions may be exacerbated. Care should be taken in elderly patients and in patients treated with corticosteroids, other NSAIDs or anticoagulants.

Skin Reactions: serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens- Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs, including diclofenac/misoprostol. Patients appear to be at highest risk for these events early in the course of therapy, the onset of the event occurring in the majority of cases within the first month of treatment. Diclofenac/misoprostol should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.

Hypersensitivity: NSAIDs may precipitate bronchospasm in patients suffering from, or with a history of, bronchial asthma or allergic disease.

Long-term treatment: all patients who are receiving long-term treatment with NSAIDs should be monitored as a precautionary measure (e.g. renal, hepatic function and blood counts). During long-term, high-dose treatment with analgesic/antiinflammatory drugs, headaches can occur which must not be treated with higher doses of the medicinal product.

Diclofenac/misoprostol may mask fever and thus an underlying infection.

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): Infections and infestations: aseptic meningitis.

Blood and lymphatic system disorders: thrombocytopaenia, aplastic anaemia, agranulocytosis, haemolytic anaemia, leucopenia.

70 Immune system disorders: anaphylactic reaction, hypersensitivity.

Metabolism and nutrition disorders: anorexia.

Psychiatric disorders: insomnia, psychotic reaction, disorientation, depression, anxiety, nightmares, mood change, irritability.

Nervous system disorders: headache, dizziness, convulsions, memory disturbance, drowsiness, tremor, taste disturbance, paraesthesia.

Eye disorders: visual disturbances, blurred vision.

Ear and labyrinth disorders: tinnitus.

Cardiac disorders: cardiac failure, palpitations.

Vascular disorders: shock, hypertension, hypotension, vasculitis.

Respiratory, thoracic and mediastinal disorders: asthma, pneumonitis, dyspnoea.

GI disorders: abdominal pain, diarrhoea, nausea, dyspepsia, gastritis, vomiting, flatulence, eructation, constipation, peptic ulcer, stomatitis, GI perforation, GI bleeding, melaena, haematemesis, colitis, Crohn's disease, oesophageal disorder, mouth ulceration, glossitis, tongue oedema, dry mouth.

Hepatobiliary disorders: alanine aminotransferase increased, hepatitis, jaundice, fulminant hepatitis, aspartate aminotransferase increased, blood bilirubin increased.

Skin and subcutaneous tissue disorders: erythema multiforme, rash, pruritus, purpura, urticaria, angioedema, toxic epidermal necrolysis, Stevens-Johnson syndrome, dermatitis exfoliative, dermatitis bullous, Henoch-Schönlein purpura, mucocutaneous rash, rash vesicular, photosensitivity reaction, alopecia, urticaria.

Renal and urinary disorder: renal failure, acute renal failure, renal papillary necrosis, nephritis interstitial, nephrotic syndrome, proteinuria, haematuria.

Pregnancy, puerperium and perinatal conditions: intra-uterine , uterine rupture, incomplete abortion, premature baby, anaphylactoid syndrome of pregnancy, retained placenta or membranes, uterine contractions abnormal.

Reproductive system and breast disorders: menorrhagia, metrorrhagia, vaginal haemorrhage, postmenopausal haemorrhage, uterine haemorrhage.

Congenital, familial and genetic disorders: birth defects.

General disorders and administration site conditions: oedema, chest pain, face oedema, fatigue, pyrexia, chills, inflammation.

Investigations: blood alkaline phosphatase increased, decreased haemoglobin.

Injury, poisoning and procedural complications: uterine perforation.

2.2 Indirect risks (incorrect use): the toxic dose of diclofenac/misoprostol has not been determined and there is no experience of overdosage. Intensification of the pharmacological effects may occur with overdosage. Management of acute poisoning with NSAIDs essentially consists of supportive and symptomatic measures. It is reasonable to take measures to reduce absorption of any recently consumed drug by forced emesis, gastric lavage or activated charcoal.

2.3 Recent cases at European level: -

71 3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions:

Country Classification Additional information Routes of administration/ MS MDD MQP Indication AM POM BE Not authorised CH List II DE POM ES POM FI POM List I (combination with FR misoprostol which is List I) IE List I IT List II LT POM LV POM POM (infusion solution that MK can be administered in health facilities only) NL POM PL POM PT POM RO List II RS Not authorised

Melclass database1: -

No data available from other member states.

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: List I

Criteria: medical supervision required.

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

SmPC available in the following databases of medicines: Portugal and United Kingdom PT: http://www.infarmed.pt/infomed/pesquisa.php UK: http://www.mhra.gov.uk/spc-pil/index.htm

1 Melclass database - Available at: http://www.edqm.eu/melclass/ (NB: this is the CD-P-PH/PHO’s recommendation at the moment of the compilation of the evidence-based review)

72 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AC01

1.3 Therapeutic indications: symptomatic relief of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis.

1.4 Posology and duration of treatment: capsules and tablets for oral use: to be taken preferably with or after food. The prescription of piroxicam should be initiated by physicians with experience in the diagnostic evaluation and treatment of patients with inflammatory or degenerative rheumatic diseases. The maximum recommended daily dose is 20 mg. The benefit and tolerability of treatment should be reviewed within 14 days. Considering the increased risk of gastrointestinal complications when using piroxicam, there may be a need for combination therapy with gastroprotective agents (e.g. misoprostol or proton pump inhibitors), in particular for elderly patients.

Adults: initially 20 mg given as a single daily dose. The majority of patients may be maintained on 20 mg a day; a relatively small group of patients may be maintained on 10 mg daily.

Children: not recommended for children under 12 years of age.

Elderly: there are no specific modifications required in the elderly, except where hepatic, renal or cardiac function is impaired, in which case dosage should be individually assessed. The elderly are at increased risk of the serious consequences of adverse reactions. If an NSAID is considered necessary, the lowest effective dose should be used and for the shortest possible duration. The patient should be monitored regularly for GI bleeding during NSAID therapy.

1.5 Pharmaceutical forms: capsules for oral use 10 mg and 20 mg; tablets 20 mg; injections for parenteral use.

1.6 Contraindications: history of previous serious allergic drug reaction of any type, especially cutaneous reactions such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis; patients with active peptic ulcer, inflammatory gastrointestinal disorder or gastrointestinal bleeding, history of gastrointestinal ulceration, bleeding or perforation, patient history of gastrointestinal disorders that predispose to bleeding disorders such as ulcerative colitis, Crohn's disease, gastrointestinal or diverticulitis; concomitant use with other NSAIDs, including COX-2 selective NSAIDs and aspirin at analgesic doses; concomitant use with anticoagulants (piroxicam should not therefore be administered to patients in whom aspirin and other NSAIDs induce the symptoms of angioneurotic oedema, asthma, rhinitis, nasal polyps or urticarial); patients with severe heart failure.

1.7 Relevant warnings: cardiovascular and cerebrovascular effects: appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy. Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long-term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). Careful consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

Cardiovascular, renal and hepatic impairment: the administration of an NSAID may cause a dose- dependent reduction in prostaglandin formation and precipitate renal failure. Due to the renal excretion of piroxicam, patients with severely impaired renal function should be closely monitored.

Elderly: the elderly have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation, which may be fatal.

Respiratory disorders: caution is required if administered to patients suffering from or with a previous history of bronchial asthma.

73 Ocular effects: due to reports of adverse eye findings with NSAIDs, it is recommended that patients who develop visual complaints during treatment with piroxicam have ophthalmic evaluation.

Gastrointestinal bleeding, ulceration and perforation: piroxicam can cause serious gastrointestinal events including bleeding, ulceration and perforation of the stomach, small intestine or large intestine, which can be fatal. Evidence from observational studies suggests that piroxicam may be associated with a high risk of serious gastrointestinal toxicity, relative to other NSAIDs. The risk for developing serious GI complications increases with age. Age over 70 years is associated with a high risk of complications. Administration to patients older than 80 years should be avoided. When GI bleeding or ulceration occurs in patients receiving piroxicam the treatment should be withdrawn. Patients taking concomitant oral corticosteroids, selective serotonin reuptake inhibitors or antiplatelet agents such as low-dose aspirin are at increased risk of serious GI complications. Patients and physicians should remain alert for signs and symptoms of GI ulceration and/or bleeding during piroxicam treatment.

SLE and mixed connective tissue disease: in patients with SLE and mixed connective tissue disorders there may be an increased risk of aseptic meningitis.

Skin reactions: evidence from observational studies suggests that piroxicam may be associated with a higher risk of serious skin reactions than other NSAIDs. Life-threatening cutaneous reactions Stevens- Johnson syndrome and toxic epidermal necrolysis have been reported with the use of piroxicam. If symptoms or signs of Stevens-Johnson syndrome or toxic epidermal necrolysis are present, piroxicam treatment should be discontinued.

Impaired female fertility: the use of piroxicam is not recommended in women attempting to conceive (in particular, in women who have difficulties conceiving or who are undergoing investigation of infertility).

Interaction with other medicinal products and other forms of interaction: oral piroxicam has been reported to potentiate the anticoagulant effect of dicoumarol because of its effect on platelets. It can cause sodium, potassium and fluid retention and may interfere with the natriuretic action of agents and thus aggravate or precipitate heart failure.

2. LIST DIRECT/INDIRECTRISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): gastrointestinal symptoms are the most commonly encountered side effects. These adverse reactions include stomatitis, anorexia, epigastric distress, gastritis, nausea, vomiting, constipation, abdominal discomfort, flatulence, diarrhoea, abdominal pain and indigestion. Rare cases of pancreatitis have been reported. Peptic ulceration, perforation and gastrointestinal bleeding (including haematemesis and melaena), in rare cases fatal, have been reported with piroxicam.

Central nervous system: dizziness, headache, somnolence, insomnia, depression, nervousness, hallucinations, mood alterations, dream abnormalities, mental confusion, paraesthesiae and vertigo have been reported rarely.

Dermal hypersensitivity: rash and pruritus, onycholysis and alopecia, photo-allergic reactions, toxic epidermal necrolysis (Lyell's disease), Stevens-Johnson syndrome and vesiculobullous reactions.

Hypersensitivity reactions: hypersensitivity reactions such as anaphylaxis, bronchospasm, urticaria/angioneurotic oedema, vasculitis and serum sickness.

Renal function: interstitial nephritis, nephrotic syndrome, renal failure and renal papillary necrosis.

Haematological: anaemia has been reported. Thrombocytopenia and non-thrombocytopenic purpura (Henoch-Schönlein), leucopenia and eosinophilia have been reported. Cases of aplastic anaemia, haemolytic anaemia and epistaxis have rarely been reported.

Liver function: severe hepatic reactions, including jaundice and cases of fatal hepatitis have been reported.

74 The following have been reported rarely: palpitations and dyspnoea, anecdotal cases of positive antinuclear antibodies, anecdotal cases of hearing abnormalities, metabolic abnormalities such as hypoglycaemia, hyperglycaemia, weight increase or decrease. Swollen eyes, blurred vision and eye irritations have been reported.

2.2 Indirect risks (incorrect use): in the event of overdosage with piroxicam, supportive and symptomatic therapy is indicated. Studies indicate that administration of activated charcoal may result in reduced reabsorption of piroxicam thus reducing the total amount of active drug available.

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC code) and supply conditions:

Country Classification Additional information Route of administration/ MS MDD MQP Indication AM POM Oral use 20 mg 200 mg BE POM Oral use 20 mg CH List II Oral use 20 mg 600 mg Exemptions: oral DE POM + Exemption use EE POM ES POM FR List I IE List II Oral and parenteral IT List II 20 mg 20mg 600mg use LT POM 20 mg 20 mg 400 mg MK POM 20 mg 20 mg 400 mg NL POM PL POM 20 mg 20 mg 4000 mg PT POM RO List II 20 mg 20 mg 600 mg

Melclass database1: List I(1) + Exemption (exemptions: oral use)

No data available from other member states.

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: List I

Criteria: Medical supervision required: risk of systemic adverse effects, in particular the side effects on GI system (most commonly encountered side effects). Hypersensitivity reactions.

Note: classification status of piroxicam in most member states is POM.

3.2.2 Paediatric use: piroxicam for oral use is not recommended for children under 12 years of age.

3.2.3 Social dimension: due to lack of health literacy of the population it is possible that in some countries NSAID abuse may occur, in particular if the medicine can be supplied without prescription.

1 Melclass database - Available at: http://www.edqm.eu/melclass/ (NB: this is the CD-P-PH/PHO’s recommendation at the moment of the compilation of the evidence-based review)

75 4. REFERENCES/COMMENTS

4.1 References:

Physicians’ Desk Reference (PDR) – available at: http://www.pdr.net/drug-summary

Electronic Medicines Compendium (eMC) - available at: http://www.medicines.org.uk/emc/

MHRA (UK) – available at: http://www.mhra.gov.uk

Macedonian Agency for Medicine and Medical Products – available at: http://www.malmed.gov.mk

76 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AC02

1.3 Therapeutic indications: tenoxicam is indicated for the relief of pain and inflammation in osteoarthritis and rheumatoid arthritis. It is also indicated for the short-term management of acute musculoskeletal disorders including strains, sprains and other soft-tissue injuries. Intravenous and intramuscular tenoxicam is also available for these indications in those patients considered unable to take oral tenoxicam.

1.4 Posology and duration of treatment: for oral administration. To be taken preferably with or after food. Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms.

Adults: a single daily dose of 20 mg tenoxicam should be taken at the same time each day. Tablets are for oral administration with water or other fluid. Higher doses should be avoided as they do not usually achieve significantly greater therapeutic effect but may be associated with a higher risk of adverse events. In acute musculoskeletal disorders treatment should not normally be required for more than 7 days, but in severe cases it may be continued up to a maximum of 14 days.

Elderly: the elderly are at increased risk of the serious consequences of adverse reactions. They are also more likely to be receiving concomitant medication or to have impaired hepatic, renal or cardiovascular function. If an NSAID is considered necessary the lowest effective dose should be used and for the shortest possible duration. The patient should be monitored regularly for GI bleeding during NSAID therapy.

Children: there are insufficient data to make a recommendation for administration of tenoxicam to children.

1.5 Pharmaceutical forms: oral use: tablets: 20 mg; parenteral use: IV, IM.

1.6 Contraindications: active or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding); history of gastrointestinal bleeding (melaena, haematemesis), perforation related to previous NSAID therapy or severe gastritis; hypersensitivity to tenoxicam or to any of the excipients; severe renal, hepatic or heart failure; last trimester of pregnancy. In general, NSAIDs are contraindicated in patients who have previously shown hypersensitivity reactions (induced symptoms of asthma, rhinitis, angioedema or urticaria) in response to salicylates, ibuprofen, aspirin or other NSAIDs.

1.7 Relevant warnings: gastrointestinal bleeding, ulceration and perforation: patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment. Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin reuptake inhibitors or antiplatelet agents such as aspirin. When GI bleeding or ulceration occurs in patients receiving tenoxicam, the treatment should be withdrawn. NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease) as these conditions may be exacerbated.

SLE and mixed connective tissue disease: in patients with SLE and mixed connective tissue disorders there may be an increased risk of aseptic meningitis.

Dermatological: serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens- Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs. Patients should be advised of the signs and symptoms and monitored closely for skin reactions.

Cardiovascular, renal and hepatic impairment: in rare cases, NSAIDs may cause interstitial nephritis, glomerulonephritis, papillary necrosis and nephrotic syndrome. Such agents inhibit the synthesis of

77 renal prostaglandin which plays a supportive role in the maintenance of renal perfusion in patients whose renal blood flow and blood volume are decreased. Patients at greatest risk of such a reaction are those with pre-existing renal disease (including diabetics with impaired renal function), nephrotic syndrome, volume depletion, hepatic disease, congestive cardiac failure, patients receiving concomitant therapy with diuretics or potentially nephrotoxic drugs and the elderly. Such patients should have their renal, hepatic and cardiac functions carefully monitored. The dose should be kept as low as possible in patients with renal, hepatic or cardiac impairment.

Respiratory disorders: caution is required if administered to patients suffering from, or with a previous history of, bronchial asthma since tenoxicam has been reported to cause bronchospasm in such patients.

Elderly: the elderly have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation, which may be fatal. Debilitated patients seem to tolerate ulceration or bleeding less well than others. Most of the fatal gastrointestinal events associated with NSAIDs occurred in the elderly and/or debilitated patients. Particular care should be taken to regularly monitor elderly patients to detect possible interactions with concomitant therapy and to review renal, hepatic and cardiovascular function which may be potentially influenced by NSAIDs.

Ocular effects: adverse eye findings have been reported with NSAIDs; therefore, it is recommended that patients who develop visual disturbances during treatment with tenoxicam have ophthalmic evaluation.

Cardiovascular and cerebrovascular effects: appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy. Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long-term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). There are insufficient data to exclude such a risk for tenoxicam. Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease should only be treated with tenoxicam after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

Impaired female fertility: the use of tenoxicam, as with any drug known to inhibit cyclooxygenase/prostaglandin synthesis, may impair fertility and is not recommended in women attempting to conceive. In women who have difficulty conceiving or are undergoing investigation of infertility, withdrawal of tenoxicam should be considered.

Pregnancy: inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. If tenoxicam is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible. During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to: cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension); renal dysfunction, which may progress to renal failure with oligohydramnios. At the end of pregnancy, all prostaglandin synthesis inhibitors may expose the mother and the neonate to: a possible prolongation of bleeding time, an anti-aggregating effect which may occur even at low doses and inhibition of uterine contractions resulting in delayed or prolonged labour. Consequently, tenoxicam is contraindicated during the third trimester of pregnancy.

Lactation: in the limited studies available so far, NSAIDs can appear in breast in very low concentrations. NSAIDs should, if possible, be avoided when . Based on findings from single dose administration, a very small amount (mean value less than 0.3% of the dose) of tenoxicam passes into breast milk. There is no evidence of adverse reactions in breastfed infants of mothers taking tenoxicam. Nevertheless, infants should be weaned or the drug discontinued.

2. LIST DIRECT/INDIRECTRISKS (SAFETY PROFILE)

78 2.1 Direct risks (pharmacovigilance): Blood and lymphatic disorders: Frequency not known: agranulocytosis, anaemia, aplastic anaemia, haemolytic anaemia, leucopenia, thrombocytopenia, non- thrombocytopenic purpura, eosinophilia.

Immune system disorders: Frequency not known: hypersensitivity reactions such as asthma, anaphylactic reactions, angioedema.

Metabolism and nutrition disorders: Common: anorexia. Rare: metabolic abnormalities (including: hyperglycaemia, weight increased/decreased).

Psychiatric disorders: Rare: sleep disorder (e.g. insomnia), depression, nervousness, dream abnormalities. Frequency not known: confusional state, hallucinations.

Nervous system disorders: Common: dizziness, headache. Frequency not known: somnolence, paraesthesia.

Eye disorders: Frequency not known: visual disturbances (such as visual impairment and vision blurred), swollen eyes, eye irritation.

Ear and labyrinth disorders: Rare: vertigo. Frequency not known: tinnitus.

Cardiac disorders: Rare: palpitations. Frequency not known: cardiac failure. The possibility of precipitating congestive cardiac failure in elderly patients or those with compromised cardiac function should therefore be borne in mind.

Vascular disorders: Rare: thrombotic events (e.g. myocardial infarction or stroke) (clinical trial and epidemiological data suggest that use of selective COX-2 inhibitors and some NSAIDs (particularly at high doses and in long-term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke)). Frequency not known: vasculitis, hypertension.

Respiratory, thoracic and mediastinal disorders: Rare: bronchospasm, aggravated asthma, dyspnoea. Frequency not known: epistaxis.

Gastrointestinal disorders: Very Common: gastric, epigastric and abdominal pain and discomfort, dyspepsia, nausea, vomiting, flatulence, constipation, diarrhoea, indigestion, epigastric distress, stomatitis. Common: gastrointestinal haemorrhage, gastrointestinal perforation, gastrointestinal ulcers, peptic ulcer, sometimes fatal, particularly in the elderly, haematemesis, melaena, constipation, diarrhoea, mouth ulceration, gastritis, dry mouth, exacerbation of colitis and Crohn's disease. Very rare: pancreatitis.

Hepatobiliary disorders: Uncommon: increased hepatic enzymes. Frequency not known: hepatitis, jaundice.

Skin and subcutaneous tissue disorders: Uncommon: pruritus, erythema, exanthema, rash, urticarial; Rare: vesiculobullous reactions. Very rare: severe cutaneous adverse reactions: Stevens-Johnson syndrome, toxic epidermal necrolysis. Frequency not known: photosensitivity reaction. Nail disorders, photosensitivity reaction and alopecia have been reported rarely following treatment with NSAIDs.

Renal and urinary disorders: Uncommon: increased blood urea or creatinine. Frequency not known: nephrotoxicity (e.g. renal failure, interstitial nephritis, nephrotic syndrome, increased blood urea or creatinine).

Reproductive system and breast disorders: isolated cases of female infertility have been reported with drugs known to inhibit cyclooxygenase/prostaglandin synthesis, including tenoxicam.

General disorders and administration site conditions: Uncommon: fatigue, oedema. Frequency not known: malaise.

79 2.2 Indirect risks (incorrect use): overdosage: symptoms: in general, symptoms of NSAID overdosage usually include nausea, vomiting, epigastric pain, rarely diarrhoea, gastrointestinal bleeding, tinnitus, headache, blurred vision and dizziness. There have been isolated reports of more serious toxicity after ingestion of substantial quantities; they include seizures, excitation, drowsiness, hypotension, apnoea, coma electrolyte imbalance and renal failure. Exacerbation of asthma is a possible effect.

Management: patients should be treated symptomatically as required. In case of overdosage, discontinuation of the drug and the administration of activated charcoal, gastric lavage, antacids and proton-pump inhibitors may be indicated. Within one hour of ingestion of a potentially toxic amount, activated charcoal should be considered. There are no specific antidotes. The benefit of gastric decontamination is uncertain. Dialysis does not significantly clear NSAIDs from the blood stream. Good urine output should be ensured – maintain adequate hydration. Renal and liver function should be closely monitored. Patients should be observed for at least four hours after ingestion of potentially toxic amounts. Frequent or prolonged convulsions should be treated with intravenous diazepam. Other measures may be indicated by the patient's clinical condition.

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC code) and supply conditions:

Country Classification Additional information Route of administration/ MS MDD MQP Indication AM POM Oral use 20 mg 20 mg 20 mg 20 mg (40 mg for CH List II Oral use 20 mg 2 days in cases of 600 mg acute gout) ES POM FR List I IT List II Oral use 20 mg 20 mg 400 mg PL POM RO List II Oral use 20 mg 20 mg 400 mg

Melclass database1: List II

No data available from other member states.

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: List I

Criteria: Risk of systemic adverse effects, in particular GI disorders which are very common. Medical supervision required.

Note: classification status of tenoxicam in the majority of the member states is POM.

3.2.2 Paediatric use: there are insufficient data to make a recommendation for the administration of tenoxicam to children.

3.2.3 Social dimension: -

1 Melclass database - Available at: http://www.edqm.eu/melclass/ (NB: this is the CD-P-PH/PHO’s recommendation at the moment of the compilation of the evidence-based review)

80 4. REFERENCES/COMMENTS

4.1 References:

PDR – available at: http://www.pdr.net/drug-summary eMC - available at: http://www.medicines.org.uk/emc/

MHRA (UK) – available at: http://www.mhra.gov.uk

Macedonian Agency for Medicine and Medical Products – available at: http://www.malmed.gov.mk

81 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AC04

1.3 Therapeutic indications: droxicam is an NSAID of the class. It is a pro-drug of piroxicam, used for the relief of pain and inflammation in musculoskeletal disorders such as rheumatoid arthritis and osteoarthritis. The pharmacological activity spectrum of droxicam is similar to that of piroxicam, combined with a far better gastric tolerance and a safety index 10-fold that of piroxicam. Droxicam was conceived as a piroxicam pro-drug with two essential characteristics: greatly improved gastrointestinal tolerance together with maintenance of pharmacological activity.

1.4 Posology and duration of treatment: -

1.5 Pharmaceutical forms: -

1.6 Contraindications: -

1.7 Relevant warnings: -

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): -

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, no medicines containing this active substance are authorised in member states).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, no medicines containing this active substance are authorised in member states: Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

Martínez L, Sánchez J. Pharmacokinetic profile of droxicam. Eur J Rheumatol Inflamm. 1991; 11(4):10- 14.

Esteve J, Farri AJ, Roser R. Pharmacological profile of droxicam. General : The Vascular System. 1988; 19(1): 49-54

82 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AC05

1.3 Therapeutic indications: short-term relief of acute mild to moderate pain.

1.4 Posology and duration of treatment: tablets, for oral use: should be taken with a sufficient quantity of liquid. For all patients the appropriate dosing regimen should be based upon individual response to treatment. Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms.

Acute pain: 8-16 mg lornoxicam given in doses of 8 mg. An initial dose of 16 mg followed by 8 mg 12 hours later can be given on the first treatment day. After the first treatment day the maximum recommended daily dose is 16 mg.

Children and adolescents: lornoxicam is not recommended for use in children and adolescents under 18 because of a lack of data on safety and efficacy.

Elderly: no special dosage modification is required for elderly patients aged over 65 unless renal or hepatic function is impaired. Lornoxicam should be administered with precaution as GI adverse effects are less well tolerated in this group.

Renal impairment: reduction of dose frequency of lornoxicam to once daily in patients suffering from renal impairment is recommended.

Hepatic impairment: reduction of dose frequency of lornoxicam to once daily in patients suffering from hepatic impairment is recommended.

1.5 Pharmaceutical forms: film-coated tablets: 4 mg and 8 mg; parenteral forms: 8 mg/2 ml.

1.6 Contraindications: hypersensitivity to lornoxicam; thrombocytopenia; hypersensitivity (symptoms like asthma, rhinitis, angioedema or urticaria) to other NSAIDs including acetylsalicylic acid; severe heart failure; gastrointestinal bleeding, cerebrovascular bleeding or other bleeding disorders; history of gastrointestinal bleeding or perforation related to previous NSAID therapy; active or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding); severe hepatic impairment; severe renal impairment (serum creatinine >700 µmol/l); third trimester of pregnancy.

1.7 Relevant warnings: Pregnancy: it should not be used during pregnancy in the first and second trimesters and delivery, as no clinical data on exposed are available. There are no adequate data from the use of lornoxicam in pregnant women. Studies in animals have shown reproductive toxicity. Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation after use of a prostaglandin synthesis inhibitor in early pregnancy. The risk is believed to increase with dose and duration of therapy. In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation loss and embryo-foetal lethality. During the first and second trimester of pregnancy, prostaglandin synthesis inhibitors should not be given unless clearly necessary. Prostaglandin synthesis inhibitors administered during the third trimester of pregnancy may expose the foetus to cardiopulmonary toxicity (premature closure of the ductus arteriosus and pulmonary hypertension) and renal dysfunction which may lead to renal failure and hence a reduced quantity of amniotic fluid. At the end of pregnancy, prostaglandin synthesis inhibitors may expose the mother and the foetus to increased bleeding time and inhibition of uterine contractions, which may delay or prolong the labour. Therefore, the use of lornoxicam is contraindicated during the third trimester of pregnancy.

Breastfeeding: there are no data on the excretion of lornoxicam in human breast milk. Lornoxicam is excreted in milk of lactating rats in relatively high concentrations. Therefore lornoxicam should not be used in breastfeeding women.

83 2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance):

Infections and infestations: Rare: pharyngitis.

Blood and lymphatic system disorders: Rare: anaemia, thrombocytopenia, leukopenia, prolonged bleeding time. Very rare: ecchymosis. NSAIDs have been reported to cause potentially severe haematological disorders like neutropenia, agranulocytosis, aplastic anaemia and haemolytic anaemia as class effects.

Immune system disorders: Rare: hypersensitivity, anaphylactoid reaction and anaphylaxis.

Metabolism and nutrition disorders: Uncommon: anorexia, weight changes.

Psychiatric disorders: Uncommon: insomnia, depression. Rare: confusion, nervousness, agitation.

Nervous system disorders: Common: mild and transient headache, dizziness. Rare: somnolence, paraesthesia, dysgeusia, tremor, . Very rare: aseptic meningitis in patients with SLE and mixed connective tissue disorder.

Eye disorders: Uncommon: conjunctivitis. Rare: visual disturbances.

Ear and labyrinth disorders: Uncommon: vertigo, tinnitus.

Cardiac disorders: Uncommon: palpitations, tachycardia, oedema, cardiac failure.

Vascular disorders: Uncommon: flushing, oedema. Rare: hypertension, hot flush, haemorrhage, haematoma.

Respiratory, thoracic and mediastinal disorders: Uncommon: rhinitis. Rare: dyspnoea, cough, bronchospasm.

Gastrointestinal disorders: Common: nausea, abdominal pain, dyspepsia, diarrhoea, vomiting. Uncommon: constipation, flatulence, eructation, dry mouth, gastritis, gastric ulcer, abdominal pain upper, duodenal ulcer, mouth ulceration. Rare: melaena, haematemesis, stomatitis, oesophagitis, gastro-oesophageal reflux, dysphagia, aphthous stomatitis, glossitis, perforated peptic ulcer, gastrointestinal haemorrhage.

Hepatobiliary disorders: Uncommon: increase in liver function tests. Very rare: hepatotoxicity resulting in e.g. hepatic failure, hepatitis, jaundice and cholestasis.

Skin and subcutaneous tissue disorders: Uncommon: rash, pruritus, hyperhidrosis, rash erythematous, urticaria and angioedema, alopecia. Rare: dermatitis and eczema, purpura. Very rare: oedema and bullous reactions, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders: Uncommon: arthralgia. Rare: bone pain, muscle spasms, myalgia.

Renal and urinary disorders: Rare: nocturia, micturition disorders, increase in blood urea and creatinine levels. Very rare: lornoxicam may precipitate acute renal failure in patients with pre-existing renal impairment, who are dependent on renal prostaglandins for maintenance of renal blood flow. Nephrotoxicity in various forms, including nephritis and nephrotic syndrome, has been associated with NSAIDs.

General disorders and administration site conditions: Uncommon: malaise, face oedema. Rare: asthenia.

2.2 Indirect risks (incorrect use): there is no experience of overdose to permit definition of the consequence of an overdose or to suggest specific management. It can be expected that after an

84 overdose with lornoxicam, the following symptoms could be seen: nausea, vomiting, cerebral symptoms (dizziness, disturbances in vision). Severe symptoms are ascending to coma and cramps, liver and kidney damage and possibly coagulation disorders. In the case of a real or suspected overdose, the medicinal product should be withdrawn. Due to its short half-life, lornoxicam is rapidly excreted. Lornoxicam is not dialysable. No specific is known to date. The usual emergency measures including gastric lavage should be considered. Based on principles, administering activated charcoal only immediately after the intake of lornoxicam can lead to diminished absorption of the preparation. Gastrointestinal disorders can for example be treated with a or .

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC code) and supply conditions:

Country Classification Additional information Route of administration/ MS MDD MQP Indication Tablets 8 mg; Tablets 16 mg; Tablets 80 mg; AM POM powder lyophilised powder lyophilised powder lyophilised for injection 8 mg for injection 16 mg for injection 40 mg CH List II 8 mg 16 mg 100 × 8 mg DE POM EE POM ES POM FR List I 32 mg (first day) 16 IT List II 8 mg 240 mg mg (second day) LT POM LV POM 8 mg 16 mg 400 mg PL POM 8 mg 24 mg 800 mg PT POM RO List II 16 mg 16 mg 800 mg POM (powder and solvent RS for solution for injection - 8 mg 16 mg 160 mg for hospital use only

Melclass database1: List II

No data available from other member states.

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable): Proposed recommendation: List I

Criteria: Risk of adverse reactions in particular GI disorders. Short-term treatment. Medical supervision required.

Note: in the majority of member states, the classification status of lornoxicam is POM.

3.2.2 Paediatric use: lornoxicam is not recommended for use in children and adolescents below age 18 (lack of data on safety and efficacy).

3.2.3 Social dimension: -

1 Melclass database - Available at: http://www.edqm.eu/melclass/ (NB: this is the CD-P-PH/PHO’s recommendation at the moment of the compilation of the evidence-based review)

85 4. REFERENCES/COMMENTS

4.1 References:

PDR – available at: http://www.pdr.net/drug-summary eMC - available at: http://www.medicines.org.uk/emc/

MHRA (UK) – available at: http://www.mhra.gov.uk

Macedonian Agency for Medicine and Medical Products – available at: http://www.malmed.gov.mk

86 1. THERAPEUTIC PROFILE

1.1 Active ingredient: Meloxicam

1.2 ATC code: M01AC06

1.3 Therapeutic indications: short-term symptomatic treatment of exacerbations of osteoarthrosis. Long-term symptomatic treatment of rheumatoid arthritis or ankylosing spondylitis.

1.4 Posology and duration of treatment: capsules and tablets for oral use: the total dose should be taken as a single dose with water or another liquid, with or after food.

The maximum recommended daily dose is 20 mg.

Exacerbations of osteoarthrosis: 7.5 mg once daily. If necessary, in the absence of improvement, the dose may be increased to 15 mg once daily.

Rheumatoid arthritis, ankylosing spondylitis: 15 mg once daily. According to the therapeutic response the dose may be reduced to 7.5 mg once daily.

Special populations: elderly patients and patients with increased risks for adverse reactions: the recommended dose for long-term treatment of rheumatoid arthritis and ankylosing spondylitis in elderly patients is 7.5 mg/day. Patients with increased risk for adverse reactions should start treatment with 7.5 mg/day. Renal impairment: in dialysis patients with severe renal failure, the dose should not exceed 7.5 mg/day. No dose reduction is required in patients with mild to moderate renal impairment. Hepatic impairment: no dose reduction is required in patients with mild to moderate hepatic impairment. Children and adolescents: meloxicam should not be used in children and adolescents aged under 16 years.

1.5 Pharmaceutical forms: capsules for oral use: 10 mg, 20 mg; tablets: 7.5 mg and 15 mg; forms for parenteral use.

1.6 Contraindications: hypersensitivity to meloxicam or to one of the excipients or hypersensitivity to substances with a similar action, e.g. NSAIDs, acetylsalicylic acid; third trimester of pregnancy and lactation; children and adolescents aged under 16 years. Not be given to patients who have developed signs of asthma, nasal polyps, angioneurotic oedema or urticaria following the administration of acetylsalicylic acid or other NSAIDs. History of gastrointestinal bleeding or perforation related to previous NSAID therapy; active or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding); severely impaired liver function; non-dialysed severe renal failure; gastrointestinal bleeding, history of cerebrovascular bleeding or other bleeding disorders; severe heart failure.

1.7 Relevant warnings: the recommended maximum daily dose should not be exceeded in cases of insufficient therapeutic effect, nor should an additional NSAID be added to the therapy because this may increase the toxicity while therapeutic advantage has not been proven. The use of meloxicam with concomitant NSAIDs, including COX-2 selective inhibitors, should be avoided. Meloxicam is not appropriate for the treatment of patients requiring relief from acute pain. In the absence of improvement after several days, the clinical benefit of the treatment should be reassessed. Any history of oesophagitis, gastritis and/or peptic ulcer must be sought in order to ensure their total cure before starting treatment with meloxicam. Attention should routinely be paid to the possible onset of a recurrence in patients treated with meloxicam and with a past history of this type.

Pregnancy: data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation and gastroschisis after the use of a prostaglandin synthesis inhibitor in early pregnancy. The risk is believed to increase with dose and duration of therapy. During the first and second trimesters of pregnancy, meloxicam should not be given unless clearly necessary. If meloxicam is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible.

87 2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance):

Blood and lymphatic system disorders: Uncommon: anaemia. Rare: blood count abnormal (including differential white cell count), leukopenia thrombocytopenia. Very rare cases of agranulocytosis have been reported

Immune system disorders: Uncommon: allergic reactions other than anaphylactic or anaphylactoid reactions.

Psychiatric disorders: Rare: mood altered, nightmares.

Nervous system disorders: Common: headache. Uncommon: dizziness, somnolence.

Eye disorders: Rare: visual disturbances including blurred vision; conjunctivitis.

Ear and labyrinth disorders: Uncommon: vertigo. Rare: tinnitus.

Cardiac disorders: Rare: palpitations. Cardiac failure has been reported in association with NSAID treatment.

Vascular disorders: Uncommon: blood pressure increased, flushing.

Respiratory, thoracic and mediastinal disorders: Rare: asthma in individuals allergic to acetylsalicylic acid or other NSAIDs.

Gastrointestinal disorders: Very common: dyspepsia, nausea, vomiting, abdominal pain, constipation, flatulence, diarrhoea. Uncommon: occult or macroscopic gastrointestinal haemorrhage, stomatitis, gastritis, eructation. Rare: colitis, gastroduodenal ulcer, oesophagitis. Very rare: gastrointestinal perforation. Gastrointestinal haemorrhage, ulceration or perforation may sometimes be severe and potentially fatal, especially in the elderly.

Hepatobiliary disorders: Uncommon: liver function disorder (e.g. raised transaminases or bilirubin). Very rare: hepatitis.

Skin and subcutaneous tissue disorders: Uncommon: angioedema, pruritus, rash. Rare: severe cutaneous adverse reactions: Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported; urticaria. Very rare: dermatitis bullous, erythema multiforme.

Renal and urinary disorders: Uncommon: sodium and water retention, hyperkalaemia, renal function test abnormal (increased serum creatinine and/or serum urea). Very rare: acute renal failure in particular in patients with risk factors.

2.2 Indirect risks (incorrect use): overdosage: symptoms following acute NSAID overdose are usually limited to lethargy, drowsiness, nausea, vomiting and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Severe poisoning may result in hypertension, acute renal failure, hepatic dysfunction, respiratory depression, coma, convulsions, cardiovascular collapse and cardiac arrest. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs and may occur following an overdose.

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC code) and supply conditions:

88 Country Classification Additional information Route of administration/ MS MDD MQP Indication Tablets 75 and Tablets 7.5 and 15 Oral and parenteral 150 mg; injection AM POM mg; injection 10 15 mg use 45 mg, 75 mg, mg/ml 150 mg BE POM Oral use 15 mg CH List II Oral use 7.5 mg 15 mg 375 mg DE POM EE POM ES POM FI POM FR List I Prescription - IE renewable Oral and parenteral 15 mg oral use IT List II use and intramuscular 15 mg 450 mg (tablets) use LV POM LT POM Oral use 15 mg 15 mg MK POM Oral use 15 mg 15 mg 300 mg NL POM Oral use Exemptions: oral Exemptions: 7.5 Exemptions: Exemptions: 225 PL POM + Exemption use mg 7.5 mg mg PT POM RO List II 15 mg 15 mg 300 mg POM (solution for RS injection - for hospital 15 mg 15 mg 450 mg use only)

Melclass database1: List II

No data available from other member states.

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: List I

Criteria: Risk of systemic adverse effects, in particular GI adverse events which are very common. Medical supervision required.

Note: classification status of meloxicam in the majority of member states is POM (there is one exemption only, i.e. Poland where meloxicam 7.5 mg is classified as OTC).

3.2.2 Paediatric use: meloxicam should not be used in children and adolescents under 16 years of age.

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

PDR – available at: http://www.pdr.net/drug-summary eMC - available at: http://www.medicines.org.uk/emc/

1 Melclass database - Available at: http://www.edqm.eu/melclass/ (NB: this is the CD-P-PH/PHO’s recommendation at the moment of the compilation of the evidence-based review)

89 MHRA (UK) – available at: http://www.mhra.gov.uk

Macedonian Agency for Medicine and Medical Products – available at: http://www.malmed.gov.mk

90 1. THERAPEUTIC PROFILE

1.1 Active ingredient: Meloxicam, combinations

1.2 ATC code: M01AC56

1.3 Therapeutic indications: meloxicam combinations can be used for providing symptomatic relief or treatment of pain, in an algesic and/or hyperalgesic state, with or without fever, in particular that associated with inflammation, trauma, osteoarthritis, rheumatoid arthritis, non-inflammatory myalgia or dysmenorrhoea.

1.4 Posology and duration of treatment: -

1.5 Pharmaceutical forms: -

1.6 Contraindications: -

1.7 Relevant warnings: -

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): -

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, no medicines containing meloxicam in combination with other active substances are authorised in member states).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, no medicines containing meloxicam in combination with other active substances are authorised in member states: Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References: -

91 1. THERAPEUTIC PROFILE

1.1 Active ingredient: Ibuprofen

1.2 ATC code: M01AE01

1.3 Therapeutic indications: orodispersible tablets (100 mg): reduction of fever and relief of mild to moderate pain, such as cold and flu symptoms, toothache, headache, sprains and strains and to ease the pain of sore throats and earache.

Oral suspension (100 mg/5 ml): reduction of fever and relief of mild to moderate pain, such as cold and flu symptoms, teething pain, headache, sprains and strains and to ease the pain of sore throats and earache.

Tablets (400 mg): as an antiinflammatory, analgesic and antipyretic for short-term management of mild to moderate pain such as is associated with headache, dental pain, fever, period pain, muscular strain, backache and for the management of the symptoms of head colds and influenza.

Tablets (600 mg): rheumatic conditions such as arthritic diseases (e.g. rheumatoid arthritis including juvenile rheumatoid arthritis), degenerative arthritic conditions (e.g. osteoarthritis), non-articular rheumatic conditions, other muscular and joint disorders and soft tissue injuries.

Suppositories (150 mg): for the symptomatic treatment of mild to moderate pain and fever in children of 3 years or older and with body weight of at least 15 kg.

Suppositories (60 mg): age 3 months to 2 years: reduction of fever and relief of mild to moderate pain, such as teething pain, toothache, headache, sprains and strains and to ease the pain of sore throats and earache. Relief of pain and fever associated with colds and influenza.

1.4 Posology and duration of treatment:

Tablets (400 mg): for oral administration and short-term use only. Adults and children over 12 years: initial dose is one tablet and subsequently, if necessary, one every four hours with a maximum of 3 tablets in a 24-hour period i.e. a maximum dose of 1200 mg in a 24-hour period. Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms. If the medicinal product is required for more than 3 days or if the symptoms worsen, the patient should consult a doctor. If in adolescents this medicinal product is required for more than 3 days, or if symptoms worsen, a doctor should be consulted. Not suitable for children under 12 years of age without medical advice.

Tablets (600 mg): rheumatic diseases:

Adults: the usual dose is 400-600 mg 3 times a day. Maintenance doses of 600-1200 mg daily may be effective in some patients. In acute and severe conditions the dose may be increased to a maximum of 2400 mg in 3 or 4 divided doses.

Adolescents over 12 years of age (>40 kg): the recommended dose is 20 mg/kg to a maximum of 40 mg/kg body weight daily in 3 to 4 divided doses. There are other dosage forms which may be more suitable to attain the required posology in this age and body weight group.

Elderly: NSAIDs should be used with particular caution in elderly patients who are more prone to adverse events and are at increased risk of potentially fatal gastrointestinal haemorrhage, ulceration or perforation. If treatment is considered necessary, the lowest dose for the shortest duration necessary to control symptoms should be used. Treatment should be reviewed at regular intervals and discontinued if no benefit is seen or intolerance occurs.

Impaired renal function: in patients with mild or moderate reduction of renal function, the dose should be kept as low as possible for the shortest duration necessary to control symptoms and renal function monitored.

92 Impaired liver function: in patients with mild or moderate reduction of liver function the dose should be kept as low as possible for the shortest duration necessary to control symptoms and renal function monitored.

1.5 Pharmaceutical forms: orodispersible tablets100 mg; oral suspension 100 mg/5 ml; tablets 400 mg and 600 mg; suppositories 60 mg and 150 mg.

1.6 Contraindications: previous hypersensitivity reactions (e.g. asthma, rhinitis, urticaria or angioedema) in response to acetylsalicylic acid or other NSAIDs; history of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy; active or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding); severe hepatic or severe renal insufficiency; severe heart failure (NYHA Class IV) or coronary heart disease; last trimester of pregnancy; significant dehydration (caused by vomiting, diarrhoea or insufficient fluid intake); cerebrovascular or other active bleeding; dyshaematopoiesis of unknown origin.

1.7 Relevant warnings: gastrointestinal bleeding, ulceration and perforation: GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious GI events. The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation, and in the elderly. These patients should commence treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients and also for patients requiring concomitant low-dose acetylsalicylic acid or other medicinal products likely to increase gastrointestinal risk. Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment. Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin or heparin, selective serotonin reuptake inhibitors or antiplatelet agents such as acetylsalicylic acid.

Cardiovascular and cerebrovascular effects: appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention, hypertension and oedema have been reported in association with NSAID therapy. Clinical studies suggest that use of ibuprofen, particularly at a high dose (2400 mg/day) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). Overall, epidemiological studies do not suggest that low-dose ibuprofen (e.g. 1200 mg/day) is associated with an increased risk of arterial thrombotic events. Patients with uncontrolled hypertension, congestive heart failure (NYHA II-III), established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease should only be treated with ibuprofen after careful consideration and high doses (2400 mg/day) should be avoided. Careful consideration should also be exercised before initiating long-term treatment of patients with risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking), particularly if high doses of ibuprofen (2400 mg/day) are required.

As with other NSAIDs, the prolonged administration of ibuprofen to animals has resulted in renal papillary necrosis and other pathological renal changes. In humans, there have been reports of acute interstitial nephritis with haematuria, proteinuria and occasionally nephrotic syndrome. Cases of renal toxicity have also been observed in patients in whom prostaglandins play a compensatory role in the maintenance of renal perfusion. In these patients, administration of NSAIDs may cause a dose- dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of suffering this reaction are those with renal dysfunction, heart failure, hepatic dysfunction, those taking diuretics and ACE inhibitors and the elderly. Discontinuation of NSAID treatment is generally followed by recovery to the pretreatment state.

SLE and mixed connective tissue disease: in patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders there may be an increased risk of aseptic meningitis (symptoms of aseptic meningitis, such as stiff neck, headache, nausea, vomiting, fever and disorientation have been observed. Aseptic meningitis has been observed on rare occasions in patients on ibuprofen therapy. Although it is probably more likely to occur in patients with systemic lupus erythematosus and related connective tissue diseases, it has been reported in patients who do not have an underlying chronic disease).

93 Other precautions: bronchospasm, urticaria or angioedema may be precipitated in patients suffering from or with a previous history of bronchial asthma, chronic rhinitis, sinusitis, nasal polyps, adenoids or allergic diseases. Ibuprofen may mask the signs or symptoms of an infection (fever, pain and swelling). During the long-term, high-dose use of analgesics headaches may occur which should not be treated with elevated doses of the medicinal product. In general the habitual intake of analgesics, particularly the combined use of different analgesic substances, may cause permanent renal damage and a risk of renal failure (analgesics nephropathy). Ibuprofen may temporarily inhibit platelet aggregation and prolong the bleeding time. Therefore, patients with coagulation defects or on anticoagulant therapy should be observed carefully. In cases of long-term treatment with ibuprofen a periodical monitoring of hepatic and renal function as well as the blood count is necessary, especially in high-risk patients. Consumption of alcohol should be avoided since it may intensify side effects of NSAIDs, especially if affecting the gastrointestinal tract or the central nervous system. Patients on ibuprofen should report to their doctor signs or symptoms of gastrointestinal ulceration or bleeding, blurred vision or other eye symptoms, skin rash, weight gain or oedema.

Paediatric population: there is a risk of renal impairment in dehydrated children and adolescents.

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): Cardiac disorders: palpitations, heart failure, myocardial infarction, acute pulmonary oedema, oedema.

Blood and lymphatic system disorders: haematopoietic disorders (anaemia, leucopenia, thrombocytopenia, pancytopenia, agranulocytosis). The first symptoms or signs may include: fever, sore throat, surface mouth ulcers, flu-like symptoms, severe fatigue, nasal and skin bleeding, neutropenia.

Nervous system disorders: headache, somnolence, vertigo, fatigue, agitation, dizziness, insomnia, irritability, optic neuritis, paraesthesia, aseptic meningitis.

Eye disorders: visual disturbances.

Gastrointestinal disorders: gastrointestinal disorders, such as heartburn, dyspepsia, abdominal pain and nausea, vomiting, flatulence, diarrhoea, constipation, gastrointestinal ulcers, sometimes with bleeding and perforation, occult blood loss which may lead to anaemia, melaena, haematemesis, ulcerative stomatitis, colitis, exacerbation of inflammatory bowel disease, complications of colonic diverticula (perforation, fistula).

Renal and urinary disorders: development of oedema especially in patients with arterial hypertension or renal insufficiency, nephrotic syndrome, interstitial nephritis which can be associated with renal failure, renal papillary necrosis in long-term use.

Skin and subcutaneous tissue disorders: severe forms of skin reactions (erythema multiforme, exfoliative dermatitis, bullous reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis, alopecia, necrotising fasciitis).

Vascular disorder: hypertension.

Immune system disorders: hypersensitivity reactions such as urticaria, pruritus, purpura and exanthema as well as asthma attacks (sometimes with hypotension), lupus erythematosus syndrome.

Hepatobiliary disorders: liver dysfunction, liver damage, especially in long-term use, liver failure, acute hepatitis, jaundice.

Psychiatric disorders: depression, confusion, hallucinations, anxiety.

2.2 Indirect risks (incorrect use): overdosage: symptoms: most patients who have ingested clinically important amounts of NSAIDs will develop no more than nausea, vomiting, epigastric pain or, more rarely, diarrhoea. Tinnitus, headache, dizziness, vertigo and gastrointestinal bleeding may also occur. In more serious poisoning, toxicity is seen in the central nervous system, manifesting as drowsiness,

94 occasionally excitation and disorientation or coma. Occasionally patients develop convulsions. Children may also develop myoclonic cramps. In serious poisoning metabolic acidosis may occur and the prothrombin time/INR may be prolonged, probably due to the actions of circulating clotting factors. Acute renal failure, liver damage, hypotension, respiratory depression and cyanosis may occur. Exacerbation of asthma is possible in asthmatics.

Management: treatment should be symptomatic and supportive and include the maintenance of a clear airway and monitoring of cardiac and vital signs until stable. Gastric emptying or oral administration of activated charcoal is indicated if the patient presents within one hour of the ingestion of more than 400 mg/kg of body weight. If ibuprofen has already been absorbed, alkaline substances should be administered to promote the excretion of the acid ibuprofen in the urine. If frequent or prolonged, convulsions should be treated with intravenous diazepam or . Other measures may be indicated by the patient’s clinical condition. Bronchodilators should be given for asthma. No specific antidote is available. Renal and liver function should be closely monitored. Patients should be observed for at least four hours after ingestion of potentially toxic amounts.

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions:

Country Classification Additional information Route of administration/ MS MDD MQP Indications Exemptions: AM POM + Exemption Exemptions: oral use 400 mg Exemptions: symptomatic treatment of mild to moderate pain (i.e. headache, toothache, Exemptions: Exemptions: AT List II + Exemption n.a. menstrual cramps) 400 mg 1200 mg and for the symptomatic treatment of pain and fever in common colds Exemptions: pain, fever, inflammation; Exemptions: Exemptions: BE POM + Exemption no limits POM: also chronic 400 mg 1200 mg inflammatory diseases Exemptions: Exemptions: CH II + Exemption Exemptions: oral use Exemptions: 4 g 400 mg 1200 mg DE POM + Exemption Exemptions: oral use Exemptions: FR List II + Exemption Exemptions: oral use Exemptions: 4 g 400 mg Exemptions: Exemptions: Exemptions: 8.0 HR List I + Exemption 400 mg 1200 mg g Exemptions: internal: rheumatic and muscular pain, backache, neuralgia, migraine, headache, Exemptions: Exemptions: IE List II +Exemption Exemptions: 10 g dental pain, 400 mg 1200 mg dysmenorrhoea, feverishness, symptoms of colds and influenza. Exemptions: Exemptions: 400 mg 2400 mg

IT List II + Exemption Exemptions: oral use List II: vials List II: no 40 0mg/3 ml more than (parenteral 2500 mg use)

95 Ibuprofen is indicated for treatment of rheumatoid arthritis (including juvenile rheumatoid arthritis or Still's disease), ankylosing spondylitis, osteoarthritis and other non-rheumatoid (seronegative) arthropathies; MK OTC 400 mg 4000 mg treatment of non- articular rheumatic conditions, periarticular conditions such as frozen shoulder (capsulitis), bursitis, tendonitis, tenosynovitis and low back pain; soft tissue injuries such as sprains and strains Short-term OTC indication: treatment of Exemptions: Exemptions: PL POM + Exemption Exemptions: 24 g acute pain mild to 400 mg 1200 mg moderate and/or fever Exemptions: Exemptions: Exemptions: PT POM + Exemption Exemptions: oral use 600 mg 1200 mg 36 000 mg Exemptions: this medicinal product is suitable for adults for the relief of mild to moderate pain such Exemptions: Exemptions: RO POM + Exemption as headache, 200 mg 2400 mg muscular pain, period pain/dysmenorrhoea, dental pain, feverishness Exemptions: relief of Exemptions: Exemptions: Exemptions: RS POM + Exemption mild to moderate pain 400 mg 1200 mg 9600 mg GSL: for the treatment of rheumatic or muscular pain, backache, neuralgia, migraine, headache, dental pain, dysmenorrhoea, feverishness, symptoms of colds 200 mg and influenza; 3.2 g (GSL) and UK OTC (P and GSL) (GSL); 400 1200 mg rheumatic and 12.8 g (P) mg (P) muscular pain, pain of non-serious arthritic conditions, backache, neuralgia, migraine, headache, dental pain, dysmenorrhoea, feverishness, symptoms of colds and influenza.

Melclass database1: -

No data available from other member states.

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

1 Melclass database - Available at: http://www.edqm.eu/melclass/ (NB: this is the CD-P-PH/PHO’s recommendation at the moment of the compilation of the evidence-based review)

96 Proposed recommendation: List II + Exemption

Exemptions: Route of Administration: oral use MS: 400 mg MDD: 1200 mg No longer than 5 days

Criteria: Well-known safety profile. Continuous medical supervision not required.

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

MHRA (UK) – available at: http://www.mhra.gov.uk/spc-pil/index.htm

Martindale: The Complete Drug Reference – 38th Edition

Romanian Agency for Medicine and Medical Products (ANM) – available at: http://www.anm.ro

97 1. THERAPEUTIC PROFILE

1.1 Active ingredient: Naproxen

1.2 ATC code: M01AE02

1.3 Therapeutic indications: adults: naproxen is used in the treatment of rheumatoid arthritis, osteoarthrosis (degenerative arthritis), ankylosing spondylitis, acute gout and acute inflammatory musculoskeletal disorders.

Children: naproxen is effective in the treatment of juvenile rheumatoid arthritis in children over 5 years of age.

1.4 Posology and duration of treatment:

Adult dosage: a) Rheumatoid arthritis, osteoarthritis, ankylosing spondylitis: 500 mg to 1 g/day taken in 2 doses at 12 hour intervals. b) For severe night-time pain and/or morning stiffness, in patients being switched to naproxen from a high dose of another NSAID or in osteoarthrosis where pain is the predominant symptom: loading dose of 750 mg to 1 g/day during the acute phase. c) Acute gout: initial dose of 750 mg at once then 250 mg every 6-8 hours until the attack has passed. d) Acute inflammatory musculoskeletal disorders: 500 mg initially, followed by 250 mg in 6-8 hour intervals as needed. Maximum daily dose is 1250 mg.

Paediatric population: for juvenile rheumatoid arthritis: a dose of 10 mg/kg body weight daily in two divided doses taken in children over 5 years of age. Naproxen is not recommended for use in any other indication in children under 16 years of age.

Use in the elderly: the elderly are at increased risk of the serious consequences of adverse reactions. If an NSAID is considered necessary, the lowest effective dose should be used and for the shortest possible duration as older people are more prone to adverse events. The patient should be monitored regularly for GI bleeding during NSAID therapy. Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. The implication of this finding for naproxen dosing is unknown.

Dosage in patients with renal/hepatic impairment: a reduction in dosage may be necessary if there is impaired renal function.

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms.

1.5 Pharmaceutical forms: tablets for oral use: 220 mg, 275 mg and 550 mg.

1.6 Contraindications: active or history of recurrent peptic ulceration/haemorrhage (two or more distinct episodes of proven ulceration or bleeding); in patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, angioedema or urticaria) in response to ibuprofen, aspirin or other NSAIDs; severe hepatic, renal and cardiac failure; a history of gastrointestinal bleeding or perforation related to previous NSAID therapy; during the last trimester of pregnancy.

1.7 Relevant warnings: Respiratory disorders: bronchospasm may be precipitated in patients with, or with a history of, bronchial asthma or allergic disease.

Use in patients with impaired renal function: naproxen is eliminated to a large extent (95%) by urinary excretion via glomerular filtration; it should be used with great caution in patients with significantly impaired renal function and the monitoring of serum creatinine and/or creatinine clearance is advised in these patients. Naproxen should not be used chronically in patients having baseline creatinine clearance less than 30 ml/minute. Haemodialysis does not decrease the plasma concentration of naproxen because of the high degree of protein binding. Certain patients, specifically those where renal blood flow is compromised, such as in extracellular volume depletion, cirrhosis of the liver, sodium

98 restriction, congestive heart failure and pre-existing renal disease, should have renal function assessed before and during naproxen therapy. Some elderly patients, in whom impaired renal function may be expected, could also fall within this category. A reduction in the daily dosage should be considered to avoid the possibility of excessive accumulation of naproxen metabolites in these patients.

Use in patients with impaired liver function: chronic alcoholic liver disease and probably other forms of cirrhosis reduce the total plasma concentration of naproxen but the plasma concentration of unbound naproxen is increased, so caution is advised when high doses are required. The implication of this finding for naproxen dosing is unknown but it is prudent to use the lowest effective dose.

Gastrointestinal bleeding, ulceration and perforation: although gastro-resistant NSAIDs cause less gastric irritation, GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious GI events. The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation, and in the elderly. These patients should commence treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients and also for patients requiring concomitant low-dose aspirin or other drugs likely to increase gastrointestinal risk. NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn’s disease) as these conditions may be exacerbated. Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment. Caution should be advised in patients receiving concomitant medications which could increase the risk of gastrotoxicity or bleeding, such as corticosteroids, anticoagulants such as warfarin or antiplatelet agents such as aspirin. When GI bleeding or ulceration occurs in patients receiving naproxen, the treatment should be withdrawn.

Renal failure linked to reduced prostaglandin production: the administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and precipitate renal failure. Patients at greatest risk of this reaction are those with impaired renal function, cardiac impairment, liver dysfunction (especially in the case of long-term treatment), those taking diuretics, angiotensin-converting enzyme inhibitors, angiotensin-II antagonists and the elderly. Care must also be taken to ensure adequate diuresis.

SLE and mixed connective tissue disease: in patients with SLE and mixed connective tissue disorders there may be an increased risk of aseptic meningitis.

Female fertility: the use of naproxen may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of naproxen should be considered.

Dermatological: serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens- Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs. Patients appear to be at highest risk for these reactions early in the course of therapy: the onset of the reaction occurring in the majority of cases within the first month of treatment. Naproxen should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.

Anaphylactic (anaphylactoid) reactions: hypersensitivity reactions may occur in susceptible individuals. Anaphylactic (anaphylactoid) reactions may occur both in patients with and without a history of hypersensitivity or exposure to aspirin, other NSAIDs or naproxen-containing products. They may also occur in individuals with a history of angioedema, bronchospastic reactivity (e.g. asthma), rhinitis and nasal polyps. Anaphylactoid reactions, like anaphylaxis, may have a fatal outcome.

Haematological: naproxen, in common with other NSAIDs, decreases platelet aggregation and prolongs bleeding time. This effect should be kept in mind when bleeding times are determined. Patients receiving anticoagulant therapy and patients who have coagulation disorders should be carefully monitored if prescribed naproxen.

99 Steroids: if steroid dosage is reduced or eliminated during therapy, the steroid dosage should be reduced slowly and the patients must be observed closely for any evidence of adverse effects, including adrenal insufficiency and exacerbation of symptoms of arthritis.

Ocular effects: studies have not shown changes in the eye attributable to naproxen administration. In rare cases, adverse ocular disorders including papillitis, retrobulbar optic neuritis and papilledema, have been reported in users of NSAIDs, including naproxen, although a cause-and-effect relationship cannot be established; accordingly, patients who develop visual disturbances during treatment with naproxen- containing products should have an ophthalmological examination.

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): Blood and lymphatic disorders: thrombocytopenia, neutropenia, granulocytopaenia (including agranulocytosis, aplastic anaemia and haemolytic anaemia) may occur rarely.

Immune system disorders: hypersensitivity reactions have been reported following treatment with NSAIDs. These may consist of (a) non-specific allergic reactions and anaphylactic reactions to naproxen and naproxen sodium formulations (eosinophilic pneumonia may occur rarely), (b) respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea or (c) assorted skin disorders, including rashes of various types, pruritis, urticaria, purpura, angioedema and, more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).

Metabolic and nutrition disorders: hyperkalaemia.

Nervous system disorders: visual disturbances, optic neuritis, paraesthesia, headaches, hearing impairment, pancreatitis, alveolitis. Reports of induction or exacerbation of colitis and aseptic meningitis (especially in patients with existing autoimmune disorders, such as systemic lupus erythematosus, mixed connective tissue disease), with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation, depression, confusion, hallucinations, tinnitus, vertigo, malaise, fatigue dizziness, nervousness, insomnia, inability to concentrate, cognitive dysfunction and drowsiness.

Eye disorders: visual disturbances, corneal opacity, papillitis and papilloedema.

Ear and labyrinth disorders: tinnitus, hearing disturbances including impairment and vertigo.

Cardiovascular: oedema, palpitations, cardiac failure and congestive heart failure have been reported in association with NSAID treatment.

Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long-term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke).

Vascular disorder: hypertension, vasculitis.

Respiratory, thoracic and mediastinal disorder: dyspnoea, asthma, eosinophilic pneumonitis and pulmonary oedema.

Gastrointestinal: the most commonly observed adverse events are gastrointestinal in nature: heartburn, nausea, anorexia, constipation, vomiting, epigastric distress, dyspepsia. More serious reactions which may occur are peptic ulcers (sometimes with haemorrhage and perforation) or GI bleeding, sometimes fatal, particularly in the elderly. Abdominal pain, melaena, haematemesis, flatulence, ulcerative stomatitis, non-peptic gastrointestinal ulceration, perforation and obstruction of the upper and lower gastrointestinal tract, diarrhoea, exacerbation of colitis and Crohn’s disease and oesophagitis have been reported following administration. Less frequently, gastritis has been observed. Pancreatitis has been reported very rarely.

Hepatobiliary disorders: jaundice, fatal hepatitis and abnormal liver function tests.

100 Skin and subcutaneous tissue disorders: skin rashes including fixed drug eruption, itching (pruritus), urticaria, ecchymoses, purpura, sweating. Alopecia, erythema multiforme and bullous reactions (including Stevens-Johnson syndrome, erythema nodosum, lichen planus, pustular reaction, SLE, epidermal necrolysis and toxic epidermal necrolysis) have been reported very rarely. Photosensitivity reactions (including cases in which the skin resembles porphyria cutanea tarda, ‘pseudoporphyria’) or epidermolysis bullosa-like reactions may occur rarely. If skin fragility, blistering or other symptoms suggestive of pseudoporphyria occur, treatment should be discontinued and the patient monitored.

Musculoskeletal and connective tissue disorders: myalgia and muscle weakness.

Renal and urinary disorders: nephrotoxicity in various forms, including glomerular nephritis, interstitial nephritis, nephrotic syndrome, haematuria, raised serum creatinine, renal papillary necrosis and renal failure.

Reproductive system and breast disorders: impaired female fertility.

2.2 Indirect risks (incorrect use): overdosage: symptoms: significant overdosage of the drug may be characterised by drowsiness, dizziness, heartburn, epigastric pain, indigestion, nausea, transient alterations in liver function, hypoprothrombinaemia, renal dysfunction, metabolic acidosis, apnoea, disorientation or vomiting. A few patients have experienced seizures, but it is not known whether these were naproxen-related or not. It is not known what dose of the drug would be life-threatening. Gastrointestinal bleeding may occur. Hypertension, acute renal failure, respiratory depression and coma may occur after the ingestion of NSAIDs but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs and may occur following an overdose.

Management: patients should be managed by symptomatic and supportive care following NSAID overdose. There are no specific antidotes. Prevention of further absorption (e.g. activated charcoal) may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose. Forced diuresis, alkalinisation of urine, haemodialysis or haemoperfusion may not be useful due to high protein binding. Good urine output should be ensured. Renal and liver function should be closely monitored. Patients should be observed for at least four hours after ingestion of potentially toxic amounts. Frequent or prolonged convulsions should be treated with intravenous diazepam. However, haemodialysis may still be appropriate in a patient with renal failure who has taken naproxen.

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions:

Country Classification Additional information Route of administration/ MS MDD MQP Indication Juvenile rheumatoid arthritis. Treatment of rheumatoid arthritis, osteoarthritis AM POM (degenerative arthritis), 500 mg 1000 mg 14 000 mg ankylosing spondylitis, acute gout, acute musculoskeletal disorders and dysmenorrhoea. Exemptions: symptomatic treatment of mild to moderate pain (i.e. Exemptions: 200 Exemptions: 600 AT List II + Exemption n.a. headache, toothache, mg mg menstrual cramps) and pain in common colds Exemptions: short-term Exemptions: 220 Exemptions: 660 BE POM + Exemption treatment of fever and Exemptions: 8.8 g mg mg pain CH List II + Exemption Exemptions: 200 Exemptions: 600 Exemptions: 2.4 g

101 mg mg

DE POM + Exemption Exemptions: oral use FR List II Exemptions: indications: treatment of rheumatoid arthritis, osteoarthritis (degenerative arthritis), Exemptions: 275 Exemptions: 825 HR List I + Exemption Exemptions: 4.4.g ankylosing spondylitis, mg mg acute gout, acute musculoskeletal disorders and dysmenorrhoea Prescription IE renewable (List II) Exemptions: 275 Exemptions: 1100 IT List II + Exemption mg mg Exemptions: treatment of rheumatoid arthritis, osteoarthrosis (degenerative arthritis), Exemptions: 550 Exemptions: 1100 Exemptions: 5500 MK POM + Exemption ankylosing spondylitis, mg mg mg acute gout, acute musculoskeletal disorders and dysmenorrhoea. Exemptions: acute pain Exemptions: 220 Exemptions: 660 PL POM + Exemption mild to moderate and/or Exemptions: 6.6 g mg mg fever, PT POM + Exemption Exemptions: oral use POM: 500 mg POM: 1000 mg POM: 30 g Naproxen is used in the treatment of rheumatoid arthritis, osteoarthrosis (degenerative arthritis), RO List II ankylosing spondylitis, 550 mg 1100 mg 27 500 mg acute gout and acute inflammatory musculoskeletal disorders. Exemptions: relief of mild to moderate pain including headache, dental pain, rheumatic and muscular Exemptions: 275 Exemptions: 825 Exemptions: 2750 RS POM + Exemption pain, back pain, mg mg mg dysmenorrhoea, feverishness and for the relief of the symptoms of cold and influenza. Exemptions: treatment of primary dysmenorrhoea in Exemptions: 250 Exemptions: 750 UK POM + Exemption - women aged between 15 mg mg and 50 years

Melclass database1: -

No data available from other member states.

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: List II + Exemption

Exemptions: Oral use MS: 275 mg MDD: 825 mg No longer than 5 days Adults and children >12 years

1 Melclass database - Available at: http://www.edqm.eu/melclass/ (NB: this is the CD-P-PH/PHO’s recommendation at the moment of the compilation of the evidence-based review)

102 Criteria: Known safety profile. Continuous medical supervision not required.

3.2.2 Paediatric use: for juvenile rheumatoid arthritis: a dose of 10 mg/kg body weight daily in two divided doses taken in children over 5 years of age. Naproxen is not recommended for use in any other indication in children under 16 years of age.

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

MHRA (UK) – available at: http://www.mhra.gov.uk/spc-pil/index.htm

Martindale: The Complete Drug Reference – 38th Edition

ANM (RO) – available at: http://www.anm.ro

103 1. THERAPEUTIC PROFILE

1.1 Active ingredient: Ketoprofen

1.2 ATC code: M01AE03

1.3 Therapeutic indications: recommended for the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and other musculoskeletal conditions including bursitis, capsulitis, synovitis, tendinitis, fibrositis and low back pain. It is also useful to relieve the pain of sciatica, acute gout and dysmenorrhoea.

1.4 Posology and duration of treatment: one 200 mg ketoprofen to be taken orally once daily with a little food. The maximum daily dose is 200 mg. The balance of risks and benefits should be carefully considered before commencing treatment with 200 mg daily; higher doses are not recommended.

Elderly: the elderly are at increased risk of serious adverse reactions from NSAIDs. If an NSAID is considered necessary, it is generally advisable in the elderly to begin ketoprofen therapy at the lower end of the dose range and to maintain such patients on the lowest effective dosage. The patient should be monitored for GI bleeding during NSAID therapy.

Patients with impaired hepatic function: these patients should be carefully monitored and kept at the minimal effective daily dosage.

1.5 Pharmaceutical forms: oral forms: tablets: 100 mg, 150 mg, 200 mg.

1.6 Contraindications: in patients who have a history of hypersensitivity reactions such as bronchospasm, asthma attacks, rhinitis, angioedema, urticaria or other allergic-type reactions to ketoprofen, any other ingredients in the product, acetylsalicylic acid (ASA) or other NSAIDs; severe heart failure; active or a history of, peptic ulcer/haemorrhage, ulceration or perforation; a history of gastrointestinal bleeding or perforation related to NSAID therapy; haemorrhagic diathesis; severe hepatic insufficiency; severe renal insufficiency; third trimester of pregnancy.

1.7 Relevant warnings: Respiratory disorders: some patients with a history of bronchial asthma or allergic disease may suffer bronchospasm, particularly those with a history of allergy to ketoprofen and related compounds.

Cardiovascular, renal and hepatic impairment: at the start of treatment, renal function must be carefully monitored in patients with heart impairment, heart failure, liver dysfunction, cirrhosis and nephrosis, in patients receiving diuretic therapy and in patients with chronic renal impairment, particularly if the patient is elderly. In these patients, administration of ketoprofen may induce a reduction in renal blood flow caused by prostaglandin inhibition and lead to renal decomposition. NSAIDs have also been reported to cause nephrotoxicity in various forms and this can lead to interstitial nephritis, nephrotic syndrome and renal failure.

In patients with abnormal liver function tests or with a history of liver disease, transaminase levels should be evaluated periodically, particularly during long-term therapy. Rare cases of jaundice and hepatitis have been described with ketoprofen.

Cardiovascular and cerebrovascular effects: appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy. Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease should only be treated with ketoprofen after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

Gastrointestinal bleeding, ulceration and perforation: GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious GI events.

104 Some epidemiological evidence suggests that ketoprofen may be associated with a high risk of serious gastrointestinal toxicity, relative to some other NSAIDs, especially at high doses. The risk of GI bleeding, ulceration or perforation is higher with increasing NSAlD doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation, and in the elderly. These patients should commence treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients and also for patients requiring concomitant low-dose aspirin or other drugs likely to increase gastrointestinal risk. NSAIDs should only be given with care to patients with a history of gastrointestinal disease (e.g. ulcerative colitis, Crohn's disease) as these conditions may be exacerbated. Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding), particularly in the initial stages of treatment.

SLE and mixed connective tissue disease: in patients with systemic lupus erythematosus and mixed connective tissue disorders, there may be an increased risk of aseptic meningitis.

Female fertility: the use of ketoprofen, as with other NSAIDs, may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulty conceiving or who are undergoing investigation of infertility, withdrawal of ketoprofen should be considered.

Skin reactions: serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens- Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs. Patients appear to be at highest risk of these reactions early in the course of therapy, the onset of the reaction occurring in the majority of cases within the first month of treatment. Treatment should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.

Infectious disease: as with other NSAIDs, in the presence of an infectious disease, it should be noted that the antiinflammatory, analgesic and antipyretic properties of ketoprofen may mask the usual signs of infection progression such as fever.

Visual disturbances: if visual disturbances such as blurred vision occur treatment should be discontinued.

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): the following adverse reactions have been reported with ketoprofen in adults:

Blood and lymphatic system disorders: Rare: haemorrhagic anaemia. Not known: agranulocytosis, thrombocytopenia, failure, haemolytic anaemia, leucopenia.

Immune system disorders: Not known: anaphylactic reactions (including shock).

Psychiatric disorders: Not known: depression, hallucinations, confusion, mood altered.

Nervous system disorders: Uncommon: headache, dizziness, somnolence. Rare: paraesthesia. Not known: aseptic meningitis, convulsions, dysgeusia, vertigo.

Eye disorders: Rare: vision blurred.

Ear and labyrinth disorders: Rare: tinnitus.

Cardiac disorders: Not known: heart failure.

Vascular disorders: Not known: hypertension, vasodilatation, vasculitis (including leukocytoclastic vasculitis).

Respiratory, thoracic and mediastinal disorders: Rare: asthma. Not known: bronchospasm (particularly in patients with known hypersensitivity to ASA and other NSAIDs), rhinitis.

105 Gastrointestinal disorders: Common: dyspepsia, nausea, abdominal pain, vomiting; uncommon: constipation, diarrhoea, flatulence, gastritis; rare: stomatitis, peptic ulcer. Not known: exacerbation of colitis and Crohn’s disease, gastrointestinal haemorrhage and perforation, pancreatitis.

Hepatobiliary disorders: Rare: hepatitis, transaminases increased, elevated serum bilirubin due to hepatitis disorders.

Skin and subcutaneous disorders: Uncommon: rash, pruritis. Not known: photosensitivity reaction, alopecia, urticaria, angioedema, bullous eruption including Stevens-Johnson syndrome and toxic epidermal necrolysis, acute generalised exanthematous pustulosis.

Renal and urinary disorders: Not known: renal failure acute, tubulointerstitial nephritis, nephritic syndrome, renal function tests abnormal.

General disorders and administration site conditions: Uncommon: oedema. Not known: fatigue.

Metabolism and nutritional disorders: Unknown: hyponatraemia, hyperkalaemia.

Investigations: Rare: weight increased.

2.2 Indirect risks (incorrect use): cases of overdose have been reported with doses up to 2.5 g of ketoprofen. In most instances, the symptoms observed have been benign and limited to lethargy, drowsiness, nausea, vomiting and epigastric pain. There are no specific antidotes to ketoprofen overdosages. In cases of suspected massive overdosages, a gastric lavage is recommended and symptomatic and supportive treatment should be instituted to compensate for dehydration, to monitor urinary excretion and to correct acidosis, if present. If renal failure is present, haemodialysis may be useful to remove circulating medicinal product.

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions:

Country Classification Additional information Route of administration/ Indications MS MDD MQP Rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, acute articular and peri-articular disorders, (bursitis, capsulitis, synovitis, tendinitis), cervical spondylitis, low back pain (strain, POM 150 mg 200 mg 4500 mg AM lumbago, sciatica, fibrositis), painful musculoskeletal conditions, acute gout, dysmenorrhoea and control of pain and inflammation following orthopaedic surgery. Acute and chronic arthritis, Bechterew’s disease, arthroses and AT List II spondylarthroses, painful inflammations 100 mg 200 mg n.a. after injuries or surgeries, , soft tissue rheumatism BE POM Pain, inflammatory diseases 200 mg 200 mg no limit CH Not authorised DE POM FR List II Rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, acute articular and peri-articular disorders, (bursitis, List I 100 mg 200 mg 4.5 g HR capsulitis, synovitis, tendinitis), cervical spondylitis, low back pain (strain, lumbago, sciatica, fibrositis), painful

106 musculoskeletal conditions, acute gout, dysmenorrhoea and control of pain and inflammation following orthopaedic surgery. Prescription

IE renewable (II) Exemptions: 25 Exemptions: 750 mg Exemptions: 75 mg List II + mg IT Exemptions: oral use Exemption List II: 320 mg List II: 1280 mg (oral) and 160 List II: 320 mg

mg (parenteral) Treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, acute articular and peri-articular disorders, (bursitis, capsulitis, synovitis, tendinitis), cervical spondylitis, low back MK POM 200 mg 200 mg 4000 mg pain (strain, lumbago, sciatica, fibrositis), painful musculoskeletal conditions, acute gout, dysmenorrhoea and control of pain and inflammation following orthopaedic surgery. Exemptions: oral use; short-term POM + Exemptions: 50 PL treatment of mild to moderate pain; Exemption mg adults and children >16 years PT POM 200 mg 200 mg 6000 mg Recommended in the management of rheumatoid arthritis, osteoarthritis, List II 150 mg 200 mg 4500 mg RO ankylosing spondylitis, acute articular and peri-articular disorders. Symptomatic treatment of inflammatory, degenerative and metabolic rheumatic POM 100 mg RS conditions and for relief of acute and chronic pain. UK POM 200 mg

Melclass database1: -

No data available from other member states.

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: List II + Exemption

Exemptions: Oral use MS: 50 mg MDD: 150 mg No longer than 5 days Adults and children >16 years

Criteria: Known safety profile. Continuous medical supervision not required.

3.2.2 Paediatric use: the safety and effectiveness of ketoprofen capsules have not been established.

3.2.3 Social dimension:

4. REFERENCES/COMMENTS

1 Melclass database - Available at: http://www.edqm.eu/melclass/ (NB: this is the CD-P-PH/PHO’s recommendation at the moment of the compilation of the evidence-based review)

107 4.1 References:

MHRA (UK) – available at: http://www.mhra.gov.uk/spc-pil/index.htm

Martindale: The Complete Drug Reference – 38th Edition

ANM (RO) – available at: http://www.anm.ro

108 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AE04

1.3 Therapeutic indications: treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis. Relief of mild to moderate pain.

1.4 Posology and duration of treatment: for oral administration to adults only and not recommended for administration to children. Dosage: 300-600 mg three or four times per day. To be taken preferably with or after food. The maximum daily dose should not exceed 3 g. If fenoprofen is administered with meals the total amount absorbed is not affected although peak blood levels are delayed and diminished.

Elderly: there is no difference in the metabolism or of fenoprofen in the elderly. The elderly are at increased risk of the serious consequences of adverse reactions. If an NSAID is considered necessary, the lowest effective dose should be used and for the shortest possible duration. The patient should be monitored regularly for GI bleeding during NSAID therapy.

1.5 Pharmaceutical forms: oral form: tablets: 300 mg.

1.6 Contraindications: active or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding); history of upper gastrointestinal bleeding or perforation related to previous NSAID therapy; patients in whom aspirin, ibuprofen and other NSAIDs induce any hypersensitivity reaction such as asthma, rhinitis, angioedema or urticaria, because cross-sensitivity to these drugs occurs in a high proportion of patients; patients with a history of significantly impaired renal function, severe hepatic or severe heart/cardiac failure; during the last trimester of pregnancy.

1.7 Relevant warnings: respiratory disorders: caution is required if administered to patients suffering from, or with a previous history of, bronchial asthma since NSAIDs have been reported to precipitate bronchospasm in such patients.

Cardiovascular and cerebrovascular effects: appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy.

Liver function: some patients have developed elevation of serum transaminase, LDH and alkaline phosphatase and it is recommended that fenoprofen be discontinued if any significant liver abnormalities occur. Borderline elevations of one or more liver function tests may occur in up to 15% of patients. Severe hepatic reactions, including jaundice and cases of fatal hepatitis, have been reported. Patients in whom an abnormal liver test has occurred should be evaluated for evidence of more severe hepatic reactions. During long-term therapy, liver function tests should be monitored periodically. If fenoprofen is used in the presence of impaired liver function, it must be done under strict observation.

Gastrointestinal bleeding, ulceration and perforation: GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious GI events. Minor upper gastrointestinal problems, such as dyspepsia, are common, usually developing early in therapy. The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation, and in the elderly. These patients should commence treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant low-dose aspirin or other drugs likely to increase gastrointestinal risk. Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment. Caution should be advised in patients receiving concomitant medications which could increase the risk of gastrotoxicity, ulceration or bleeding, such as oral corticosteroids, or anticoagulants such as warfarin, selective serotonin reuptake inhibitors or antiplatelet agents such as aspirin. When GI bleeding or ulceration occurs in patients receiving fenoprofen, the treatment should be withdrawn. NSAIDs should be given with care to patients

109 with a history of gastrointestinal disease (ulcerative colitis, Crohn’s disease) as these conditions may be exacerbated.

SLE and mixed connective tissue disease: in patients with SLE and mixed connective tissue disorders, there may be an increased risk of aseptic meningitis.

Impaired female fertility: the use of fenoprofen may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of fenoprofen should be considered.

Dermatological: serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens- Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs. Patients appear to be at highest risk for these reactions early in the course of therapy: the onset of reaction occurring in the majority of cases within the first month of treatment. Fenoprofen should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity. Patients with initial low haemoglobin values who are receiving long-term therapy with fenoprofen should have a haemoglobin determination at reasonable intervals. Studies to date have not shown changes in the eyes attributable to the administration of fenoprofen. However, adverse ocular effects have been observed with other antiinflammatory drugs, so eye examinations should be performed if visual disturbances occur in patients taking fenoprofen. Since the safety of fenoprofen has not been established in patients with impaired hearing, these patients should have periodic tests of auditory function during chronic therapy. Fenoprofen decreases platelet aggregation and may prolong bleeding time.

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): GI: the most commonly observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or GI bleeding, sometimes fatal, particularly in the elderly, may occur. Nausea, dry mouth, metallic taste, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, pancreatitis, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn’s disease have been reported following administration. Less frequently, gastritis has been observed.

Hypersensitivity: hypersensitivity reactions have been reported following treatment with NSAIDs. They may consist of (a) non-specific allergic reactions and anaphylaxis, (b) respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea or (c) assorted skin disorders, including rashes of various types, pruritus, urticaria, purpura, angioedema and more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).

Cardiovascular and cerebrovascular: palpitations, tachycardia, atrial fibrillation, pulmonary oedema, hypertension, cardiac failure, ECG changes and supraventricular tachycardia have been reported in association with NSAID treatment. Clinical trial and epidemiological data suggest that the use of some NSAIDs (particularly at high doses and in long-term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke).

Renal (reported less commonly): nephrotoxicity in various forms, including interstitial nephritis, nephrotic syndrome, papillary necrosis and renal failure. Episodes of dysuria, cystitis and haematuria, oliguria, azotaemia and anuria have occurred.

Hepatic (reported less commonly): abnormal liver function, hepatitis and jaundice. Increases in alkaline phosphatase, lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) have been observed.

Neurological and special senses (reported less commonly): visual disturbances, optic neuritis, amblyopia, diplopia, headaches, paraesthesia, reports of aseptic meningitis (especially in patients with existing autoimmune disorders, such as systemic lupus erythematosus, mixed connective tissue disease), with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation, depression, confusion, hallucinations, tinnitus, hearing decrease, vertigo, dizziness, nervousness,

110 malaise, fatigue, drowsiness, burning tongue, breast pain, personality change, lymphadenopathy, mastodynia, fever, upper respiratory infection and nasopharyngitis have been reported.

Haematological (reported less commonly): thrombocytopenia, neutropenia, agranulocytosis, aplastic anaemia and haemolytic anaemia.

Dermatological (reported less commonly): photosensitivity, pruritus, rash, urticaria, anaphylaxis, Stevens-Johnson syndrome, angioneurotic oedema, increased sweating, exfoliative dermatitis; toxic epidermal necrolysis and alopecia have been reported.

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, medicines containing this active substance are authorised only in the UK (classification: POM)).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, medicines containing this active substance are authorised only in the UK: Not to classify

Criteria: see above

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

MHRA (UK) – available at: http://www.mhra.gov.uk/spc-pil/index.htm

Martindale: The Complete Drug Reference – 38th Edition

111 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AE05

1.3 Therapeutic indications: fenbufen is an NSAID used primarily to treat inflammation in osteoarthritis, ankylosing spondylitis and tendinitis. It can also be used to relieve backaches, sprains and fractures. Fenbufen acts by preventing cyclooxygenase from producing prostaglandins which can cause inflammation. It is an arylpropionic acid derivative.

1.4 Posology and duration of treatment: -

1.5 Pharmaceutical forms: -

1.6 Contraindications: -

1.7 Relevant warnings: -

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): -

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, medicines containing this active substance are authorised only in the UK (classification: POM)).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, medicines containing this active substance are authorised only in the UK: Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

Martindale: The Complete Drug Reference – 38th Edition

PDR – available at: http://www.pdr.net/drug-summary

112 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AE06

1.3 Therapeutic indications: -

1.4 Posology and duration of treatment: -

1.5 Pharmaceutical forms: -

1.6 Contraindications: -

1.7 Relevant warnings: -

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): -

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, no medicines containing this active substance are authorised in member states).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, no medicines containing this active substance are authorised in member states: Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References: -

113 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AE07

1.3 Therapeutic indications: -

1.4 Posology and duration of treatment: -

1.5 Pharmaceutical forms: -

1.6 Contraindications: -

1.7 Relevant warnings: -

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): -

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, no medicines containing this active substance are authorised in member states).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, no medicines containing this active substance are authorised in member states: Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References: -

114 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AE08

1.3 Therapeutic indications: -

1.4 Posology and duration of treatment: -

1.5 Pharmaceutical forms: -

1.6 Contraindications: -

1.7 Relevant warnings: -

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): -

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, no medicines containing this active substance are authorised in member states).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, no medicines containing this active substance are authorised in member states: Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References: -

115 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AE09

1.3 Therapeutic indications: POM: treatment of rheumatoid disease, osteoarthritis, ankylosing spondylitis, musculoskeletal disorders and trauma such as periarthritis, frozen shoulder, bursitis, tendinitis, tenosynovitis, low back pain, sprains and strains.

Non-prescription: short-term symptomatic relief of sore throat in adults and children over the age of 12 years. Flurbiprofen is limited, in adults and children from 15 years old, to long-term symptomatic treatment of chronic inflammatory rheumatism (including rheumatoid arthritis, ankylosing spondylitis or related syndromes, such as Fiessinger-Leroy-Reiter syndrome and ) and some painful and disabling arthrosis. Short-term symptomatic treatment of acute attacks of abarticular rheumatism (such as scapulohumeral periarthritis, tendinitis, bursitis), arthrosis, back pain, radiculalgia, dysmenorrhea after etiological research.

1.4 Posology and duration of treatment: rheumatic conditions: treatment of attack: 1 tablet (100 mg) 3 times a day or 300 mg/day; maintenance treatment: 1 tablet (100 mg) 1 to 2 times daily, i.e. 100 to 200 mg/day; dysmenorrhoea: 1 tablet (100 mg) 2 to 3 times a day, i.e. 200 to 300 mg/day from the beginning of the pain until the disappearance of the symptoms.

1.5 Pharmaceutical forms: oral forms: 50 mg, 100 mg and 200 mg.

1.6 Contraindications: after 24 weeks of amenorrhea (5 months pregnant); history of allergy or asthma triggered by taking this drug or other closely related substances such as other NSAIDs, acetylsalicylic acid; history of bleeding or digestive perforation during previous NSAID treatment; progressive peptic ulcer, history of peptic ulcer or recurrent haemorrhage (2 or more distinct episodes of haemorrhage or ulceration); severe hepatocellular insufficiency; severe renal insufficiency; severe heart failure; children under 15 years old. Generally not recommended in combination with oral anticoagulants, other NSAIDs (including high-dose salicylates), (parenteral route).

1.7 Relevant warnings: Gastrointestinal effects: gastrointestinal bleeding, ulceration or perforation, sometimes fatal, has been reported with all NSAIDs at any time during treatment, without necessarily warning signs or a history of adverse effects. The risk of haemorrhage, ulceration or gastrointestinal perforation increases with the dose used in patients with a history of ulcer disease, particularly in cases of haemorrhage or perforation complication in the elderly subject. In these patients, treatment should be started at the lowest dose possible. Protective mucosal therapy (e.g. misoprostol or proton pump inhibitor) should be considered for these patients, as for patients requiring low-dose acetylsalicylic acid therapy or other drugs that may increase gastrointestinal risk. Patients with a gastrointestinal history, especially elderly patients, should report any unusual abdominal symptoms (especially gastrointestinal bleeding), particularly at the beginning of treatment. Special attention should be paid to patients receiving associated therapies that may increase the risk of ulceration or bleeding, such as oral corticosteroids, oral anticoagulants such as warfarin, selective serotonin reuptake inhibitors and antiplatelet agents such as acetylsalicylic acid. If bleeding or ulceration occurs in a patient receiving flurbiprofen, treatment should be discontinued. NSAIDs should be administered with caution and under close supervision in patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease) due to a risk of aggravation of the condition.

Hydro-sodium retention: fluid-sodium retention with possibility of oedema, hypertension or hypertension aggravation, worsening of heart failure. Clinical monitoring is necessary from the beginning of treatment in case of hypertension or heart failure. A decrease in the effect of antihypertensives is possible.

Hyperkalaemia: hyperkalaemia exacerbated by diabetes or concomitant treatment with hyperkalaemic drugs. Regular monitoring of serum potassium should be performed under these circumstances.

Cardiovascular and cerebrovascular effects: adequate monitoring and recommendations are required in patients with a history of hypertension and/or mild to moderate heart failure, with reports of water- sodium retention and oedema associated with NSAID therapy. Clinical studies and epidemiological data

116 suggest that the use of certain NSAIDs (especially when used at high doses and over a long period of time) may be associated with a small increase in the risk of arterial thrombotic events (e.g. infarction myocardium or stroke). There is currently insufficient data to rule out this increased risk for flurbiprofen. Patients with uncontrolled hypertension, congestive heart failure, ischemic heart disease, peripheral arterial disease and/or with a history of stroke (including transient ischemic attack) should be treated with flurbiprofen only after a careful evaluation of the benefit/risk ratio. Similar attention should be paid to initiating long-term treatment in patients with risk factors for cardiovascular disease (such as hypertension, hyperlipidaemia, diabetes or smoking).

Functional renal insufficiency: by inhibiting the vasodilator action of renal prostaglandins, NSAIDs are likely to cause functional renal failure by decreasing glomerular filtration. This is dose dependent. At the beginning of treatment or after an increase in dosage, monitoring of diuresis and renal function is recommended in patients with the following risk factors: elderly subjects; associated medicines such as ACE inhibitors, sartans, diuretics; hypovolemia, whatever the cause; heart failure; chronic renal failure, nephrotic syndrome, Lupus nephropathy; decompensated liver cirrhosis.

Patients with uncontrolled hypertension, congestive heart failure, ischemic heart disease, peripheral arterial disease and/or with a history of stroke (including transient ischemic attack) should be treated with flurbiprofen only after a careful evaluation of the benefit/risk ratio. Similar attention should be paid to initiating long-term treatment in patients with risk factors for cardiovascular disease (such as hypertension, hyperlipidaemia, diabetes or smoking).

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): Gastrointestinal effects: the most commonly observed side effects are gastrointestinal in nature. Peptic ulcers, perforations or gastrointestinal bleeding, sometimes fatal, may occur, especially in the elderly. Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, ulcerative stomatitis, abdominal pain, melaena, hematemesis, exacerbation of recto-colitis or Crohn's disease have been reported following administration of NSAIDs. Less frequently, gastritis has been observed.

Cardiovascular effects: oedema, hypertension and heart failure have been reported in combination with NSAID therapy. Rarely reported: elevation of blood pressure, tachycardia, chest pain, arrhythmia, palpitations, hypotension and congestive heart failure.

Hypersensitivity reactions: General: anaphylactic reaction, angioedema.

Respiratory: the onset of asthma attack may be observed in some subjects, particularly those allergic to aspirin and other NSAIDs.

Skin reactions: Very rarely bullous reactions (including Stevens-Johnson syndrome and Lyell's syndrome) have been observed. Also reported: rash, urticaria and worsening of chronic urticaria, pruritus, purpura. Cases of photosensitisation have been exceptionally reported.

Renal and urinary disorders: toxic nephropathy in various forms, including interstitial nephritis, nephrotic syndrome and renal failure.

Effects on the central nervous system: dizziness, headache.

Other adverse reactions: hydrosodium retention, hyperkalaemia. Rarely: sight disorders, increased transaminases. Exceptionally: agranulocytosis, haemolytic anaemia, thrombocytopenia.

2.2 Indirect risks (incorrect use): overdosage: symptoms: headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, rarely diarrhoea, disorientation, excitation, coma, drowsiness, dizziness, tinnitus, fainting and occasionally convulsions. In cases of significant poisoning, acute renal failure and liver damage are possible.

117 Therapeutic measures: patients should be treated symptomatically as required. Within one hour of ingestion of a potentially toxic amount, activated charcoal should be considered. Alternatively, in adults, gastric lavage should be considered within one hour of ingestion of a potentially life-threatening overdose. Good urine output should be ensured. Renal and liver function should be closely monitored. Patients should be observed for at least four hours after ingestion of potentially toxic amounts. Frequent or prolonged convulsions should be treated with intravenous diazepam. Other measures may be indicated by the patient’s clinical condition.

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions:

Country Classification Additional information Route of administration/ MS MDD MQP Indication AM Not auth. AT Not auth. BE Not auth. CH List II DE OTC FR List II IE Not auth. IT List II 100 mg 400 mg 3000 mg LT Not auth. Treatment of rheumatoid disease, osteoarthritis, ankylosing spondylitis, musculoskeletal disorders and trauma such as periarthritis, frozen shoulder, bursitis, tendinitis, tenosynovitis, low MK POM 100 mg 300 mg 3000 mg back pain, sprains and strains. Flurbiprofen is also indicated for its analgesic effect in the relief of mild to moderate pain in conditions such as dental pain, post-operative pain, dysmenorrhoea and migraine. PL Not auth. PT POM 100 mg 300 mg 6000 mg RO Not auth. For the treatment of rheumatoid disease, osteoarthritis, ankylosing spondylitis, musculoskeletal disorders and RS POM 100 mg trauma such as periarthritis, frozen shoulder, bursitis, tendinitis, tenosynovitis, low back pain, sprains and strains. POM - the treatment of rheumatoid disease, osteoarthritis, ankylosing spondylitis, musculoskeletal Exemptions: disorders and trauma such as UK POM + Exemptions 9.75 mg periarthritis, frozen shoulder, lozenge bursitis, tendinitis, tenosynovitis, low back pain, sprains and strains

118 Exemptions: short-term symptomatic relief of sore throat in adults and children over the age of 12 years.

Melclass database1: List I

No data available from other member states.

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: List II

Criteria: medical supervision required.

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

MHRA (UK) – available at: http://www.mhra.gov.uk/spc-pil/index.htm

Martindale: The Complete Drug Reference – 38th Edition

National Agency for the Safety of Medicine and Health Products (ANSM) (FR) – available at: http://agence-prd.ansm.sante.fr/php/ecodex/index.php

PDR – available at: http://www.pdr.net/drug-summary

ANM (RO) – available at: http://www.anm.ro

1 Melclass database - Available at: http://www.edqm.eu/melclass/ (NB: this is the CD-P-PH/PHO’s recommendation at the moment of the compilation of the evidence-based review)

119 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

Indoprofen is an NSAID. It is a monocarboxylic acid that is in which one of the at position 2 is substituted by a 4-(1-oxo-1,3-dihydroisoindol-2-yl)phenyl group. Initially used as an antiinflammatory and analgesic, it was withdrawn from the market because it caused severe gastrointestinal bleeding.

1.2 ATC code: M01AE10

1.3 Therapeutic indications: -

1.4 Posology and duration of treatment: -

1.5 Pharmaceutical forms: -

1.6 Contraindications: -

1.7 Relevant warnings: -

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): -

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, no medicines containing this active substance are authorised in member states).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, no medicines containing this active substance are authorised in member states: Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

Martindale: The Complete Drug Reference – 38th Edition

PDR – available at: http://www.pdr.net/drug-summary

120 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AE11

1.3 Therapeutic indications: rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, low back pain, musculoskeletal disorders (such as fibrositis, capsulitis, epicondylitis and other soft-tissue inflammatory conditions), sprains and strains, post-operative inflammation and pain and other soft tissue injuries.

1.4 Posology and duration of treatment: adults: 600 mg daily in divided doses (300 mg twice a day; alternatively 200 mg three times a day).

Elderly: as for adults. NSAIDs should be used with particular caution in older patients who are at increased risk of the serious consequences of adverse reactions. In cases of renal, cardiac or hepatic impairment, the dosage should be kept as low as possible. It is suggested that in such cases, the dosage be reduced to 200 mg twice daily. If an NSAID is considered necessary, elderly patients should receive the lowest effective dose for the shortest possible duration and be monitored regularly for gastrointestinal bleeding following initiation of NSAID therapy.

Children: there are insufficient data to recommend use in children.

1.5 Pharmaceutical forms: oral form: tablets: 300 mg.

1.6 Contraindications: active or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding); history of gastrointestinal bleeding or perforation related to previous NSAID therapy; active bladder or prostatic disease or symptoms; history of recurrent urinary tract disorders; hypersensitivity to tiaprofenic acid or to any of the excipients; patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, angioedema or urticaria) in response to ibuprofen, aspirin or other NSAIDs; last trimester of pregnancy; severe heart failure, hepatic failure and renal failure.

1.7 Relevant warnings: tiaprofenic acid should be used with caution in patients with chronic renal insufficiency (particularly careful monitoring of renal function is required), patients with arterial hypertension and/or heart failure, elderly subjects as they have an increased frequency of adverse reactions to NSAIDs, particularly gastrointestinal bleeding and perforation, which may be fatal, and patients with a history of hepatic insufficiency.

Respiratory disorders: caution is required if administered to patients suffering from, or with a previous history of, bronchial asthma since NSAIDs have been reported to precipitate bronchospasm in such patients. Tiaprofenic acid may cause sodium and water retention with oedema. At the start of therapy, urine volume and renal function should be carefully monitored in patients with a history of hypertension, cardiac insufficiency, liver cirrhosis or nephrotic syndrome, and in patients on diuretics.

Urinary symptoms and cystitis have been reported with tiaprofenic acid and other NSAIDs. Tiaprofenic acid appears to have a greater propensity than other NSAIDs to generate reports of cystitis, which may become severe if the treatment is continued after the onset of urinary symptoms. Nonrecognition has led to extensive investigations and even surgical intervention in some patients. If urinary symptoms such as frequency, urgency, dysuria, nocturia or haematuria occur, tiaprofenic acid should be stopped immediately and urinalysis and urine culture performed; complete recovery is the rule. Before starting treatment with tiaprofenic acid, the patient should be asked to inform his/her physician of any urinary symptom, even if the physician is familiar with these symptoms from the patient's medical history. Patients should be warned about the onset of urinary symptoms which may suggest cystitis and are advised to stop taking the drug and seek medical advice if these occur.

Gastrointestinal bleeding, ulceration and perforation: GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious GI events. The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer (particularly if complicated with haemorrhage or perforation) and in the elderly. These patients should commence treatment on the

121 lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients and also for patients requiring concomitant low-dose aspirin or other drugs likely to increase gastrointestinal risk.

Dermatological: serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens- Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDSs. Patients appear to be at highest risk of these reactions early in the course of therapy, the onset of the reaction occurring in the majority of cases within the first month of treatment. Tiaprofenic acid should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.

Impaired female fertility: the use of tiaprofenic acid may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of tiaprofenic acid should be considered.

There is a risk of cross-sensitivity among aspirin and NSAIDs, including the group to which tiaprofenic acid belongs. These pseudo-allergic reactions may include rash, urticaria and angioedema or more potentially severe manifestations (e.g. laryngeal oedema, bronchoconstriction and shock). The risk of pseudo-allergic reactions is greater in patients with recurrent rhino-sinusitis, nasal polyposis or chronic urticaria. Asthmatic patients are particularly at risk of dangerous reactions. Therefore tiaprofenic acid must not be administered to patients with a history of asthma. As NSAIDs can interfere with platelet function, they should be used with caution in patients with intracranial haemorrhage and bleeding diathesis.

Cardiovascular, renal and hepatic impairment: the administration of an NSAID may cause a dose- dependent reduction in prostaglandin formation and precipitate renal failure. Patients at greatest risk of this reaction are those with impaired renal function, cardiac impairment, liver dysfunction, those taking diuretics and the elderly. Renal function should be monitored in these patients.

Cardiovascular and cerebrovascular effects: appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy. Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long-term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). There are insufficient data to exclude such a risk for tiaprofenic acid. Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease should only be treated with tiaprofenic acid after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

SLE and mixed connective tissue disease: in patients with SLE and mixed connective tissue disorders there may be an increased risk of aseptic meningitis.

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): Nervous system disorders: optic neuritis.

Eye disorders: visual disturbances.

Musculoskeletal and connective tissue disorders: paraesthesia.

Psychiatric disorders: depression, confusion, hallucinations.

General disorders and administration site conditions: fatigue, malaise.

Blood and lymphatic system disorders: neutropenia, agranulocytosis, aplastic anaemia, haemolytic anaemia.

122 Nervous disorders: reports of aseptic meningitis (especially in patients with existing autoimmune disorders, such as systemic lupus erythematosus, mixed connective tissue disease), with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation.

Vascular and cardiac disorders: oedema, hypertension and cardiac failure have been reported in association with NSAID treatment.

Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long-term treatment) may be associated with an increased risk of arterial thrombotic events (for example myocardial infarction or stroke).

2.2 Indirect risks (incorrect use): overdosage: symptoms include headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, rarely diarrhoea, disorientation, excitation, coma, drowsiness, dizziness, tinnitus, fainting, occasionally convulsions. In cases of significant poisoning acute renal failure and liver damage are possible.

Therapeutic measures: patients should be treated symptomatically as required. Within one hour of ingestion of a potentially toxic amount, activated charcoal should be considered. Alternatively, in adults, gastric lavage should be considered within one hour of ingestion of a potentially life-threatening overdose. Good urine output should be ensured. Renal and liver function should be closely monitored. Patients should be observed for at least four hours after ingestion of potentially toxic amounts. Frequent or prolonged convulsions should be treated with intravenous diazepam. Other measures may be indicated by the patient's clinical condition.

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions:

Country Classification Additional information Route of administration/ MS MDD MQP Indications AM Not auth. AT Not auth. BE Not auth. CH Not auth. DE POM FR List II HR Not auth. IE Not auth. IT List II 300 mg 600 mg 9000 mg LT Not auth. MK Not auth. PL Not auth. PT Not auth. RO Not auth. For the treatment of rheumatoid disease, osteoarthritis, ankylosing spondylitis, musculoskeletal RS POM disorders and trauma such as 300 mg

fibrositis, capsulitis, epicondilitis, low back pain, sprains and strains, postoperative pain. Rheumatoid arthritis, UK POM 300 mg osteoarthritis, ankylosing

123 spondylitis, low back pain, musculoskeletal disorders such as fibrositis, capsulitis, epicondylitis and other soft-tissue inflammatory conditions, sprains and strains, post-operative inflammation and pain and other soft tissue injuries.

Melclass database1: -

No data available from other member states.

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: List II

Criteria: medical supervision required.

3.2.2 Paediatric use: children: there are insufficient data to recommend use in children.

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

MHRA (UK) – available at: http://www.mhra.gov.uk/spc-pil/index.htm

Martindale: The Complete Drug Reference – 38th Edition

ANSM (FR) – available at: http://agence-prd.ansm.sante.fr/php/ecodex/index.php

PDR – available at: http://www.pdr.net/drug-summary

1 Melclass database - Available at: http://www.edqm.eu/melclass/ (NB: this is the CD-P-PH/PHO’s recommendation at the moment of the compilation of the evidence-based review)

124 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AE12

1.3 Therapeutic indications: short or long-term treatment of the inflammatory and pain symptoms associated with osteoarticular diseases.

1.4 Posology and duration of treatment: osteoarthritis: 1 to 2 tablets, depending on the severity of the symptoms. Inflammation of muscles, tendons and ligaments: 2 tablets daily, in a single dose. Inflammation of the joints (rheumatoid arthritis) and inflammation of the joints of the spine (patients with Bechterew’s disease): 2 tablets a day. It is sometimes necessary to administer 3 tablets to obtain an optimal result. In this case, 2 tablets in the morning and 1 tablet in the evening are recommended.

Dosage in case of renal failure: patients on haemodialysis and those with moderate to severe renal impairment should take 1 tablet a day.

1.5 Pharmaceutical forms: oral form: tablets: 600 mg.

1.6 Contraindications: in patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, angioedema or urticaria) in response to ibuprofen, aspirin or other NSAIDs; history of gastrointestinal bleeding or perforation related to previous NSAID therapy; severe heart failure, hepatic failure and renal failure; breastfeeding period; children and adolescents under 16 years old.

1.7 Relevant warnings: Gastrointestinal bleeding, ulceration and perforation: GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious GI events. The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation, and in the elderly. These patients should commence treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients and also for patients requiring concomitant low-dose aspirin or other drugs likely to increase gastrointestinal risk.

Dermatological: serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens- Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs. Patients appear to be at highest risk of these reactions early in the course of therapy, the onset of the reaction occurring in the majority of cases within the first month of treatment. Oxaprozin should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.

Impaired female fertility: the use of oxaprozin may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of oxaprozin should be considered.

As NSAIDs can interfere with platelet function, they should be used with caution in patients with intracranial haemorrhage and bleeding diathesis.

Cardiovascular, renal and hepatic impairment: the administration of an NSAID may cause a dose- dependent reduction in prostaglandin formation and precipitate renal failure. Patients at greatest risk of this reaction are those with impaired renal function, cardiac impairment, liver dysfunction, those taking diuretics and the elderly. Renal function should be monitored in these patients.

Cardiovascular and cerebrovascular effects: appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy. Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long-term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). There are insufficient data to exclude such a risk for oxaprozin. Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease

125 and/or cerebrovascular disease should only be treated with oxaprozin after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): Nervous system disorders: optic neuritis.

Eye disorders: visual disturbances.

Musculoskeletal and connective tissue disorders: paraesthesia.

Psychiatric disorders: depression, confusion, hallucinations.

General disorders and administration site conditions: fatigue, malaise.

Blood and lymphatic system disorders: neutropenia, agranulocytosis, aplastic anaemia, haemolytic anaemia.

Nervous disorders: reports of aseptic meningitis (especially in patients with existing autoimmune disorders, such as systemic lupus erythematosus, mixed connective tissue disease), with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation.

Vascular and cardiac disorders: oedema, hypertension and cardiac failure have been reported in association with NSAID treatment.

Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long-term treatment) may be associated with an increased risk of arterial thrombotic events (for example myocardial infarction or stroke).

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, medicines containing this active substance are authorised only in Belgium (classification: POM) and Italy (classification: List II)).

Melclass database1: -

No data available from other member states.

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, medicines containing this active substance are authorised only in Belgium and Italy: Not to classify

Criteria: see above.

3.2.2 Paediatric use:

1 Available at: https://melclass.edqm.eu/ (NB: this is the CD-P-PH/PHO’s recommendation at the moment of the compilation of the evidence-based review)

126 3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

MHRA (UK) – available at: http://www.mhra.gov.uk/spc-pil/index.htm

Martindale: The Complete Drug Reference – 38th Edition

127 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AE13

1.3 Therapeutic indications: -

1.4 Posology and duration of treatment: -

1.5 Pharmaceutical forms: -

1.6 Contraindications: -

1.7 Relevant warnings: -

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): -

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, no medicines containing this active substance are authorised in member states).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, no medicines containing this active substance are authorised in member states: Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References: -

128 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AE14

1.3 Therapeutic indications: symptomatic treatment for the relief of pain and inflammation associated with osteoarthritis. Acute symptomatic treatment of pain during menstrual bleeding (primary dysmenorrhoea). Symptomatic treatment of mild to moderate pain, such as muscular-skeletal pain or dental pain.

1.4 Posology and duration of treatment: the dosage should be adjusted to the severity of the disorder and the complaints of the patient. Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms. The maximum single dose is 400 mg, the maximum daily dose is 1200 mg dexibuprofen. For individual dosage, film-coated tablets with 300 and 400 mg dexibuprofen are available.

Osteoarthritis: the recommended dose is 600 to 900 mg dexibuprofen daily, divided in up to three single doses, for example 400 mg twice a day or 300 mg two to three times a day. The dose may be increased up to 1200 mg dexibuprofen per day in patients with acute conditions or exacerbations.

Dysmenorrhoea: the recommended dose is 600 to 900 mg dexibuprofen daily, divided in up to three single doses, for example 400 mg twice a day or 300 mg two to three times a day.

Mild to moderate pain: the recommended dose is 600 mg dexibuprofen daily, divided in up to three single doses. If clearly needed in patients with acute pain conditions (e.g. in surgical extraction of teeth) the dose may be transiently increased up to 1200 mg dexibuprofen per day.

Children and adolescents: dexibuprofen has not been studied in children and adolescents (<18 years): safety and efficacy have not been established and therefore it is not recommended in these age groups.

Elderly: no special dosage modifications are required in the elderly. However, individual dose reduction and assessment has to be considered due to increased susceptibility to GI adverse reactions in the elderly.

Hepatic dysfunction: patients with mild to moderate hepatic dysfunction should start therapy at reduced doses and be closely monitored.

Renal dysfunction: the initial dose should be reduced in patients with mild to moderate impaired renal function.

1.5 Pharmaceutical forms: oral forms: tablets: 200 mg, 300 mg and 400 mg.

1.6 Contraindications: in whom substances with a similar action (e.g. acetylsalicylic acid or other NSAIDs) precipitate attacks of asthma, bronchospasm or acute rhinitis, or cause nasal polyps, urticaria or angioneurotic oedema; in patients with a history of gastrointestinal bleeding or perforation related to previous NSAID therapy; with active or a history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding); with cerebrovascular bleeding or other active bleedings; with active Crohn’s disease or active ulcerative colitis; with severe heart failure; with severe renal dysfunction (GFR <30 ml/min); with severely impaired hepatic function; from the beginning of 6th month of pregnancy.

1.7 Relevant warnings: Gastrointestinal risks: the elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation, which may be fatal. Gastrointestinal bleeding, ulceration and perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious GI events. The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID dose, in patients with a history of ulcers, particularly if complicated with haemorrhage or perforation, alcoholism and in the elderly. These patients should commence treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be

129 considered for these patients and also for patients requiring concomitant low-dose acetylsalicylic acid or other drugs likely to increase gastrointestinal risk. Patients with a history of GI toxicity, particularly when elderly, should report any abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment. Caution should be advised in patients receiving concomitant medication which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin reuptake inhibitors or antiplatelet agents such as acetylsalicylic acid. When GI bleeding or ulceration occurs in patients receiving dexibuprofen, the treatment should be withdrawn. NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn’s disease) as their condition may be exacerbated.

Hypersensitivity: as with other NSAIDs, allergic reactions, including anaphylactic/anaphylactoid reactions, can also occur without earlier exposure to the drug. Caution is required in patients suffering from, or with a previous history of, bronchial asthma since NSAIDs can cause bronchospasm in such patients.

Cardiovascular and cerebrovascular effects: appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy. Clinical trial and epidemiological data suggest that use of ibuprofen, particularly at a high dose (2400 mg daily) and in long-term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). Overall, epidemiological studies do not suggest that low-dose ibuprofen (e.g. ≤ 1200 mg daily) is associated with an increased risk of myocardial infarction. There are insufficient data to exclude such a risk for dexibuprofen. Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease should only be treated with dexibuprofen after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

Renal and hepatic effects: caution is required in patients suffering hepatic and renal disease; the risk of fluid retention, oedema and deterioration in renal function must be taken into account. If used in these patients, the dose of dexibuprofen should be kept as low as possible and renal function should be regularly monitored. As with other NSAIDs, dexibuprofen can be associated with adverse effects on the renal system, which can lead to glomerular nephritis, interstitial nephritis, renal papillary necrosis, nephrotic syndrome and acute renal failure. As with all NSAIDs, dexibuprofen can increase plasma urea nitrogen and creatinine. As with other NSAIDs, dexibuprofen can cause transient small increases in some liver parameters and also significant increases in serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT). In case of a relevant increase in such parameters, therapy must be discontinued.

Reactions of the skin: serious skin reactions, some of them fatal, including dermatitis exfoliative, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs. Patients appear to be at highest risk of these reactions early in the course of therapy, the onset of the reaction occurring in the majority of cases within the first month of treatment. Dexibuprofen should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.

Coagulation: in common with other NSAIDs dexibuprofen may reversibly inhibit platelet aggregation and function and prolong bleeding time. Caution should be exercised in patients with haemorrhagic diathesis and other coagulation disorders and when dexibuprofen is given concurrently with oral anticoagulants.

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance):

Immune system disorders: Uncommon: purpura (including allergic purpura), angioedema. Rare: anaphylactic reaction.

Psychiatric disorders: Uncommon: anxiety. Rare: psychotic reaction, depression, irritability.

130 Nervous system disorders: Common: drowsiness, headache, dizziness, vertigo. Uncommon: insomnia, restlessness. Rare: disorientation, confusion, agitation. Very rare: aseptic meningitis (see immune system disorders).

Eye disorders: Uncommon: visual disturbances. Rare: reversible toxic amblyopia.

Ear and labyrinth disorders: Uncommon: tinnitus. Rare: impaired hearing.

Gastrointestinal disorders: Very common: dyspepsia, abdominal pain. Common: diarrhoea, nausea, vomiting. Uncommon: gastrointestinal ulcers and bleeding, gastritis, ulcerative stomatitis, melaena. Rare: gastrointestinal perforation, flatulence, constipation, oesophagitis, oesophageal strictures, exacerbation of diverticular disease, unspecific haemorrhagic colitis, ulcerative colitis or Crohn’s disease. If gastrointestinal blood loss occurs, this may cause anaemia and haematemesis.

Skin and subcutaneous tissue disorders: Common: rash. Uncommon: urticaria, pruritus. Very rare: erythema multiforme, epidermal necrolysis, systemic lupus erythematosus, alopecia, photosensitivity reactions, bullous reactions including Stevens-Johnson-Syndrome, acute toxic epidermal necrolysis (Lyell-Syndrome) and allergic vasculitis.

Respiratory, thoracic and mediastinal disorders: Uncommon: rhinitis, bronchospasm.

Renal and urinary disorder: Very rare: interstitial nephritis, nephrotic syndrome or renal failure.

Hepatobiliary disorders: Rare: abnormal liver function, hepatitis and jaundice.

General disorders: Common: fatigue, fluid retention: patients with hypertension or renal impairment seem to be predisposed.

2.2 Indirect risks (incorrect use): overdose: dexibuprofen has a low acute toxicity and patients have survived after single doses as high as 54 g of ibuprofen (equivalent to approximately 27 g of dexibuprofen). Most overdoses have been asymptomatic. There is a risk of symptoms at doses >80 - 100 mg/kg ibuprofen. The onset of symptoms usually occurs within 4 hours. Mild symptoms are most common, including abdominal pain, nausea, vomiting, lethargy, drowsiness, headache, nystagmus, tinnitus and ataxia. Rarely, moderate or severe symptoms include gastrointestinal bleeding, hypotension, hypothermia, metabolic acidosis, seizures, impaired kidney function, coma, adult respiratory distress syndrome and transient episodes of apnoea (in very young children following large ingestions). Treatment is symptomatic and there is no specific antidote. Amounts not likely to produce symptoms (less than 50 mg/kg dexibuprofen) may be diluted with water to minimise gastrointestinal upset. In case of ingestion of a significant amount, activated charcoal should be administered. Emptying of the stomach by emesis may only be considered if the procedure can be undertaken within 60 minutes of ingestion. Gastric lavage should not be considered unless a patient has ingested a potentially life-threatening amount of the drug and the procedure can be undertaken within 60 minutes of ingestion. Forced diuresis, haemodialysis or haemoperfusion are unlikely to be of assistance because dexibuprofen is strongly bound to plasma proteins.

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions:

Country Classification Additional information Route of administration/ MS MDD MQP Indications AM Not auth. Exemptions: symptomatic treatment of mild to Exemptions: Exemptions: AT List II + Exemption n.a. moderate pain (i.e. 200 mg 600 mg headache, toothache,

131 menstrual cramps) and pain in common colds and rheumatoid arthritis and osteoarthritis BE Not auth. CH List II DE POM FR Not auth. HR Not auth. IE Not auth. IT List II 400 mg 1200 mg 9000 mg LT Not auth. MK Not auth. Exemptions: acute pain Exemptions: Exemptions: Exemptions: PL POM + Exemption mild to moderate, adults 200 mg 1200 mg 12 g only, short-term use PT POM 400 mg 1200 mg 40 000 mg RO Not auth. RS Not auth. Pain and inflammation associated with osteoarthritis and other UK POM musculoskeletal disorders; 400 mg mild to moderate pain and inflammation including dental pain.

Melclass database1: -

No data available from other member states.

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: List II + Exemption

Exemptions: Route of Administration: oral use MS: 200 mg MDD: 600 mg No longer than 5 days Adults only

Criteria: Known safety profile. Continuous medical supervision not required.

3.2.2 Paediatric use: dexibuprofen has not been studied in children and adolescents (<18 years): safety and efficacy have not been established and therefore it is not recommended in these age groups.

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

1 Melclass database - Available at: http://www.edqm.eu/melclass/ (NB: this is the CD-P-PH/PHO’s recommendation at the moment of the compilation of the evidence-based review)

132 MHRA (UK) – available at: http://www.mhra.gov.uk/spc-pil/index.htm

Martindale: The Complete Drug Reference – 38th Edition

133 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AE15

1.3 Therapeutic indications: -

1.4 Posology and duration of treatment: -

1.5 Pharmaceutical forms: -

1.6 Contraindications: -

1.7 Relevant warnings: -

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): -

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, no medicines containing this active substance are authorised in member states).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, no medicines containing this active substance are authorised in member states: Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References: -

134 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AE16

1.3 Therapeutic indications: -

1.4 Posology and duration of treatment: -

1.5 Pharmaceutical forms: -

1.6 Contraindications: -

1.7 Relevant warnings: -

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): -

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, medicines containing this active substance are authorised only in France (classification: List II)).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, medicines containing this active substance are authorised only in France: Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References: -

135 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AE17

1.3 Therapeutic indications: oral administration: short-term symptomatic treatment of mild to moderate acute pain, such as acute muscular pain or joint pain, painful periods (dysmenorrhoea).

Injection: symptomatic treatment of acute pain of moderate to severe intensity, when oral administration is not appropriate, such as post-operative pain, renal colic and low back pain.

1.4 Posology and duration of treatment: adults: according to the nature and severity of pain, the recommended dosage is generally 12.5 mg every 4-6 hours or 25 mg every 8 hours. The total daily dose should not exceed 75 mg. Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms. Dexketoprofen tablets are not intended for long-term use and the treatment must be limited to the symptomatic period.

Dexketoprofen has not been studied in children and adolescents. Therefore the safety and efficacy in children and adolescents have not been established and the product should not be used in children and adolescents.

Older people: in elderly patients it is recommended to start the therapy at the lower end of the dosage range (50 mg total daily dose). The dosage may be increased to that recommended for the general population only after good general tolerance has been ascertained.

Hepatic dysfunction: patients with mild to moderate hepatic dysfunction should start therapy at reduced doses (50 mg total daily dose) and be closely monitored. Dexketoprofen tablets should not be used in patients with severe hepatic dysfunction.

Renal dysfunction: the initial dosage should be reduced to 50 mg total daily dose in patients with mildly impaired renal function (creatinine clearance 60 - 89 ml/min). Dexketoprofen should not be used in patients with moderate to severe renal dysfunction (creatinine clearance ≤59 ml/min).

1.5 Pharmaceutical forms: oral form: tablets: 25 mg; parenteral form: injection: 50 mg/ml.

1.6 Contraindications: patients in whom substances with a similar action (e.g. acetylsalicylic acid or other NSAIDs) precipitate attacks of asthma, bronchospasm or acute rhinitis, or cause nasal polyps, urticaria or angioneurotic oedema; in patients with known photoallergic or phototoxic reactions during treatment with ketoprofen or ; patients with history of gastrointestinal bleeding or perforation related to previous NSAID therapy; patients with active peptic ulcer/gastrointestinal haemorrhage or any history of gastrointestinal bleeding, ulceration or perforation; patients with chronic dyspepsia; patients who have other active bleedings or bleeding disorders; patients with Crohn’s disease or ulcerative colitis; patients with severe heart failure; patients with moderate to severe renal dysfunction (creatinine clearance ≤59 ml/min); patients with severely impaired hepatic function (Child-Pugh score 10-15); patients with haemorrhagic diathesis and other coagulation disorders; patients with severe dehydration (caused by vomiting, diarrhoea or insufficient fluid intake); during the third trimester of pregnancy and lactation period.

1.7 Relevant warnings: Gastrointestinal safety: gastrointestinal bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious gastrointestinal events. When gastrointestinal bleeding or ulceration occurs in patients receiving dexketoprofen, the treatment should be withdrawn. The risk of gastrointestinal bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation, and in older people. The elderly have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation, which may be fatal. These patients should commence treatment on the lowest dose available. As with all NSAIDs, any history of oesophagitis, gastritis and/or peptic ulcer must be sought in order to ensure their total cure before starting treatment with dexketoprofen trometamol. Patients with gastrointestinal symptoms or history of gastrointestinal disease

136 should be monitored for digestive disturbances, especially gastrointestinal bleeding. NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn’s disease) as their condition may be exacerbated. Patients with a history of gastrointestinal toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially gastrointestinal bleeding) particularly in the initial stages of treatment.

Renal safety: caution should be exercised in patients with impaired renal function. In these patients, the use of NSAIDs may result in deterioration of renal function, fluid retention and oedema. Caution is also required in patients receiving diuretic therapy or those who could develop hypovolaemia as there is an increased risk of nephrotoxicity. Adequate fluid intake should be ensured during treatment to prevent dehydration and possibly associated increased renal toxicity. As with all NSAIDs, it can increase plasma urea nitrogen and creatinine. As with other inhibitors of prostaglandin synthesis, it can be associated with adverse effects on the renal system which can lead to glomerular nephritis, interstitial nephritis, renal papillary necrosis, nephrotic syndrome and acute renal failure. Older patients are more likely to be suffering from impaired renal function.

Liver safety: caution should be exercised in patients with impaired hepatic function. As with other NSAIDs, it can cause transient small increases in some liver parameters and also significant increases in SGOT and SGPT. In case of a relevant increase in such parameters, therapy must be discontinued. Older patients are more likely to be suffering from impaired hepatic function.

Cardiovascular and cerebrovascular safety: appropriate monitoring and advice are required for patients with history of hypertension and/or mild to moderate heart failure. Special caution should be exercised in patients with a history of cardiac disease, in particular those with previous episodes of heart failure as there is an increased risk of triggering heart failure, since fluid retention and oedema have been reported in association with NSAID therapy. Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long-term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). There are insufficient data to exclude such a risk for dexketoprofen trometamol. Consequently, patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease should only be treated with dexketoprofen trometamol after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

Skin reactions: serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens- Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs. Patients appear to be at highest risk of these reactions early in the course of therapy, the onset of the reaction occurring in the majority of cases within the first month of treatment. Dexketoprofen should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): Gastrointestinal: the most commonly-observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or gastrointestinal bleeding, sometimes fatal, particularly in the elderly, may occur. Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn’s disease have been frequently observed. Less frequently, gastritis has been observed.

Oedema, hypertension and cardiac failure have been reported in association with NSAID treatment. As with other NSAIDs the following undesirable effects may appear: aseptic meningitis, which might predominantly occur in patients with systemic lupus erythematosus or mixed connective tissue disease; haematological reactions (purpura, aplastic and haemolytic anaemia, and rarely agranulocytosis and medullar hypoplasia). Bullous reactions including Stevens-Johnson syndrome and toxic epidermal- necrolysis are very rare. Use of some NSAIDs (particularly at high doses and in long-term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke).

137 2.2 Indirect risks (incorrect use): overdosage: the symptomatology following overdose is not known. Similar medicinal products have produced gastrointestinal (vomiting, anorexia, abdominal pain) and neurological (somnolence, vertigo, disorientation, headache) disorders. In case of accidental or excessive intake, immediately institute symptomatic therapy according to the patient's clinical condition. Activated charcoal should be administered if more than 5 mg/kg has been ingested by an adult or a child within an hour. Dexketoprofen trometamol may be removed by dialysis.

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions:

Country Classification Additional information Route of administration/ MS MDD MQP Indications Exemptions: oral administration. It is used for short-term symptomatic treatment of mild to moderate acute pain, such as acute muscular pain or joint pain, painful periods (dysmenorrhoea), Exemptions: Exemptions: AM POM + Exemption toothache. 25 mg 75 mg

POM: injection: symptomatic treatment of acute pain of moderate to severe intensity, when oral administration is not appropriate, such as post- operative pain, renal colic and low back pain. Symptomatic treatment of mild to moderate pain (i.e. AT List II 25 mg 75 mg n.a. headache, toothache, menstrual cramps) Symptomatic treatment of light to moderate pain, BE POM 25 mg 75 mg 12.5 g such as myalgia, bone pain, toothache CH List II FR List II For the symptomatic relief POM (List II: mild to moderate pain tablets/granules for (granules, tablets). For HR 25 mg 75 mg 500 mg oral solution; List I: the symptomatic relief solution for injection) moderate to severe pain (solution for injection). POM (List I: parenteral IE use; List II: oral use) Exemptions: 25 mg Exemptions: Exemptions: IT List II + Exemption Exemptions: oral use List II: 50 75 mg 250 mg mg/ml injection Exemptions: Exemptions: LT POM + Exemption Exemptions: oral use 25 mg 75 mg Symptomatic treatment of pain of mild to moderate intensity, such as MK POM 25 mg 1250 mg musculoskeletal pain, dysmenorrhoea dental pain.

138 Exemptions: mild to Exemptions: Exemptions: Exemptions: PL POM + Exemption moderate pain for short- 25 mg 75 mg 7.5 g term use, adults only PT POM 400 mg 1200 mg 40 000 mg Symptomatic treatment of pain of mild to moderate intensity, such as RO List II 25 mg 75 mg 1250 mg musculoskeletal pain, dysmenorrhoea, dental pain. Relief of mild to moderate pain including RS POM musculoskeletal pain, 25 mg

dysmenorrhoea and dental pain UK POM

Melclass database1: -

No data available from other member states.

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: List II + Exemption

Exemptions: Route of Administration: oral use MS: 25 mg MDD: 75 mg No longer than 5 days

Criteria: Well-known safety profile. Continuous medical supervision not required.

3.2.2 Paediatric use: dexketoprofen has not been studied in children and adolescents. Therefore the safety and efficacy in children and adolescents have not been established and the product should not be used in children and adolescents.

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

MHRA (UK) – available at: http://www.mhra.gov.uk/spc-pil/index.htm

Martindale: The Complete Drug Reference – 38th Edition

ANSM (FR) – available at: http://agence-prd.ansm.sante.fr/php/ecodex/index.php

PDR – available at: http://www.pdr.net/drug-summary

ANM (RO) – available at: http://www.anm.ro

1 Available at: https://melclass.edqm.eu/ (NB: this is the CD-P-PH/PHO’s recommendation at the moment of the compilation of the evidence-based review)

139 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

Naproxcinod is a naproxen-based nitric oxide (NO)-donating antiinflammatory drug belonging to the cyclooxygenase (COX)-inhibiting NO donors (CINODs) class. Naproxcinod is a COX-inhibiting compound that has both analgesic and antiinflammatory effects and was originally developed for the treatment of osteoarthritis.

1.2 ATC code: M01AE18

1.3 Therapeutic indications: -

1.4 Posology and duration of treatment: -

1.5 Pharmaceutical forms: -

1.6 Contraindications: -

1.7 Relevant warnings: -

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): -

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, no medicines containing this active substance are authorised in member states).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, no medicines containing this active substance are authorised in member states: Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

PDR – available at: http://www.pdr.net/drug-summary

140 1. THERAPEUTIC PROFILE

1.1 Active ingredient: Ibuprofen, Combinations

1.2 ATC code: M01AE51

1.3 Therapeutic indications: ibuprofen and : this medicine is indicated in patients older than 12 years of age for the short-term treatment of acute moderate pain which is not considered to be relieved by other analgesics (e.g. , ibuprofen or aspirin) alone, such as: rheumatic and muscular pain, backache, neuralgia, migraine, headache, dental pain, dysmenorrhoea.

Ibuprofen and paracetamol: for the temporary relief of mild to moderate pain associated with migraine, headache, backache, period pain, dental pain, rheumatic and muscular pain, pain of non-serious arthritis, cold and flu symptoms, sore throat and fever. This product is especially suitable for pain which requires stronger analgesia than ibuprofen or paracetamol alone.

Ibuprofen and hydrochloride: symptomatic treatment of mild to moderate pain or fever and nasal congestion related to colds and influenza in adults and adolescents older than 12 years of age.

1.4 Posology and duration of treatment: ibuprofen and codeine: for oral administration and short- term use only. Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms. Recommended dosage: adults over 18 years: one or two tablets every four to six hours. Do not take more than 6 tablets in 24 hours. Leave at least four hours between doses. Children aged 12 years to 18 years: the recommended dose is one or two tablets every 6 hours when necessary up to a maximum of 6 tablets in 24 hours. Children under 12 years: this medicine should not be used in children below the age of 12 years because of the risk of toxicity due to the variable and unpredictable metabolism of codeine to .

Ibuprofen and paracetamol: if the one tablet dose does not control symptoms, a maximum of two tablets may be taken up to three times a day. Leave at least six hours between doses. Do not take more than six tablets (3000 mg Paracetamol, 1200 mg Ibuprofen) in any 24-hour period.

Ibuprofen and phenylephrine hydrochloride: for short-term use only. Two tablets every 8 hours. Leave at least 4 hours between doses and do not exceed six tablets in any 24-hour period. Adults, the elderly and adolescents over 12 years: undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms. Adults: the patient should consult a doctor if symptoms persist or worsen, or if the medicinal product is required for more than 5 days. Paediatric population: adolescents over 12 years: if this medicinal product is required for more than 3 days or if symptoms worsen a doctor should be consulted. Children: not to be given to children under 12 years.

1.5 Pharmaceutical forms: oral forms: available combination products: ibuprofen 200 mg + codeine 12.8 mg; ibuprofen 200 mg + paracetamol 325 mg and 500 mg; ibuprofen 200 mg + phenylephrine hydrochloride 5 mg.

1.6 Contraindications: ibuprofen and codeine: contraindicated in patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, angioedema or urticaria) in response to aspirin or other NSAIDs; patients with active or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding); patients with history of upper gastrointestinal bleeding or perforation related to previous NSAID therapy; patients with severe hepatic failure, renal failure or heart failure (NYHA Class IV); last trimester of pregnancy; patients with respiratory depression, chronic constipation; all paediatric patients (0-18 years of age) who undergo tonsillectomy and/or adenoidectomy for obstructive sleep apnoea syndrome due to an increased risk of developing serious and life-threatening adverse reactions; women during breastfeeding.

Ibuprofen and paracetamol: contraindicated in patients with a history of or an existing gastrointestinal ulceration/perforation or bleeding, including that associated with NSAIDs; patients with defects in coagulation; patients with severe hepatic failure, severe renal failure or severe heart failure (NYHA Class IV); last trimester of pregnancy due to risk of premature closure of the foetal ductus arteriosus

141 with possible pulmonary hypertension; concomitant use with other NSAID-containing products, including COX-2 specific inhibitors and doses of acetylsalicylic acid above 75 mg daily: increased risk of adverse reactions; concomitant use with other paracetamol-containing products: increased risk of serious adverse effects.

Ibuprofen and phenylephrine hydrochloride: contraindicated in severe heart failure (NYHA Class IV); renal failure or hepatic failure; in the case of concomitant NSAIDs including COX-2 specific inhibitors; hyperthyroidism; patients currently receiving or within two weeks of stopping therapy with monoamine oxidase inhibitors.

1.7 Relevant warnings: Ibuprofen: see evidence-based review Ibuprofen (pages 92-97).

Paracetamol: care is advised in the administration of paracetamol to patients with severe renal or severe hepatic impairment. The hazards of overdose are greater in those with non-cirrhotic alcoholic liver disease. Patients should be advised to consult their doctor if their headaches become persistent. Patients should be advised not to take other paracetamol-containing products concurrently. In addition, patients should be advised that paracetamol may cause severe skin reactions. If a skin reaction such as skin reddening, blisters, or rash occurs, they should stop use and seek medical assistance right away.

Codeine: codeine should be used with caution in those with hypotension and/or hypothyroidism. The tablets should be used with caution in patients with raised intracranial pressure or head injury. The effects of CNS (including alcohol) may be potentiated by codeine. Codeine is a narcotic analgesic. No more than the stated dose of this medicine should be taken. Prolonged regular use, except under medical supervision, may lead to physical and (addiction) and result in withdrawal symptoms, such as restlessness and irritability once the drug is stopped. It is important to consult a doctor if a patient experiences the need to use this product all the time. General symptoms of opioid toxicity include confusion, somnolence, shallow breathing, small pupils, nausea, vomiting, constipation and lack of appetite. In severe cases this may include symptoms of circulatory and respiratory depression, which may be life threatening and very rarely fatal. Children with compromised respiratory function: codeine is not recommended for use in children in whom respiratory function might be compromised including neuromuscular disorders, severe cardiac or respiratory conditions, upper respiratory or lung infections, multiple trauma or extensive surgical procedures. These factors may worsen symptoms of morphine toxicity.

Phenylephrine hydrochloride: it should be used with caution in patients with occlusive vascular disease including Raynaud’s phenomenon. Although has virtually no pressor effects in patients with normal blood pressure, phenylephrine hydrochloride should be used with caution in patients taking antihypertensive agents including adrenergic neurone blockers and beta blockers, other sympathomimetic agents, such as decongestants, appetite suppressants and -like psycho-stimulants. The effects of a single dose on the blood pressure of these patients should be observed before recommending repeated or unsupervised treatment. If hallucinations, restlessness or sleep disturbances are experienced whilst taking the product, use of the product should be discontinued.

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): Ibuprofen: see evidence-based review Ibuprofen (pages 92-97).

Paracetamol: clinical trials with combination products containing ibuprofen and paracetamol have not indicated any other side effects other than those for paracetamol alone or ibuprofen alone. With reference to paracetamol, its adverse effects are rare. Very rare cases of serious skin reactions have been reported. There have been reports of blood dyscrasias including thrombocytopenia purpura, methaemoglobenaemia and agranulocytosis, but these were not necessarily causality related to paracetamol.

Codeine: side effects include constipation, respiratory depression, cough suppression, nausea and drowsiness. Regular prolonged use of codeine is known to lead to addiction and symptoms of restlessness and irritability may result when treatment is then stopped. Prolonged use of a pain killer for headaches can make them worse.

142 Phenylephrine: should be used with care in patients with cardiovascular disease, diabetes mellitus, closed-angle , prostatic enlargement and hypertension. Paediatric population: there is a risk of renal impairment in dehydrated adolescents.

2.2 Indirect risks (incorrect use): ibuprofen and codeine: overdosage: in children ingestion of more than 400 mg/kg of ibuprofen may cause symptoms; in adults the dose response effect is less clear cut. The half-life in overdose is 1.5-3 hours. Most patients who have ingested clinically important amounts of NSAIDs will develop no more than nausea, vomiting, epigastric pain or, more rarely, diarrhoea. Tinnitus, headache and gastrointestinal bleeding are also possible. In more serious poisoning, toxicity is seen in the central nervous system, manifesting as drowsiness, occasionally excitation and disorientation or coma. Occasionally patients develop convulsions. In serious poisoning metabolic acidosis may occur and the prothrombin time/INR may be prolonged, probably due to interference with the actions of circulating clotting factors. Acute renal failure and liver damage may occur. Exacerbation of asthma is possible in asthmatics.

Management should be symptomatic and supportive and include the maintenance of a clear airway and monitoring of cardiac and vital signs until stable. Consider oral administration of activated charcoal if the patient presents within 1 hour of ingestion of a potentially toxic amount. If frequent or prolonged, convulsions should be treated with intravenous diazepam or lorazepam. Give bronchodilators for asthma.

Symptoms of overdose with codeine: nausea and vomiting are prominent features. Respiratory depression, excitability, convulsions, hypotension and loss of consciousness may occur with large codeine overdose. The stomach should be emptied. If severe CNS depression has occurred, artificial respiration, oxygen and parenteral may be needed. Imbalance in electrolyte levels should be considered.

Ibuprofen and paracetamol: Ibuprofen: overdosage: see evidence-based review Ibuprofen (pages 92- 97).

Paracetamol: overdosage: liver injury and even failure can occur following paracetamol overdose. Symptoms of paracetamol overdose in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal pain. Liver damage may become apparent 12 to 48 hours after ingestion. Abnormalities of metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may proceed to encephalopathy, coma and death. Acute renal failure with acute tubular necrosis may develop in the absence of severe liver damage. Cardiac arrhythmias have been reported. Liver damage is possible in adults who have taken 10 g or more of paracetamol, due to excess quantities of a toxic metabolite.

Management: prompt treatment is essential in the management of paracetamol overdose even when there are no obvious symptoms, because of the risks of liver injury, which presents after some hours or even days delay. Medical treatment is advised, without delay in any patient who has ingested 7.5 g or more of paracetamol in the preceding 4 hours. Management should be in accordance with established treatment guidelines. Treatment with activated charcoal should be considered if the overdose has been taken within 1 hour. Plasma paracetamol concentration should be measured at 4 hours or later after ingestion (earlier concentrations are unreliable). Treatment with N- may be used up to 24 hours after ingestion of paracetamol; however, the maximum protective effect is obtained up to 8 hours post ingestion. If required the patient should be given intravenous-N-acetylcysteine, in line with the established dosage schedule. If vomiting is not a problem, oral may be a suitable alternative for remote areas, outside hospital. Management of patients who present with serious hepatic dysfunction beyond 24 hours from ingestion should be discussed with a poisons information centre or a liver unit.

Ibuprofen and phenylephrine hydrochloride: overdosage: may result in nervousness, agitation, anxiety, irritability, restlessness, dizziness, tremor, vertigo, insomnia, nausea, abdominal pain, vomiting, epigastric pain, diarrhoea, bradycardia, palpitation, tachycardia, tinnitus, headache and gastrointestinal bleeding. Hyperkalaemia, metabolic acidosis, hypertension or hypotension are also possible signs of overdose. Toxicity may manifest as drowsiness, excitation, disorientation or coma. The patient may develop convulsions. Hepatic function may be abnormal. Metabolic acidosis may occur and the prothrombin time/INR may be prolonged. Acute renal failure and liver damage may occur. In asthmatics, exacerbation of asthma is possible.

143 Management: due to the rapid absorption of the two active ingredients from the gastrointestinal tract, emetics and gastric lavage must be instituted within four hours of overdosage to be effective. Charcoal is effective only if given within one hour. Cardiac status should be monitored and the serum electrolytes measured. If there are signs of cardiac toxicity, may be administered intravenously. A slow infusion of a dilute solution of potassium chloride should be initiated in the event of a drop in the serum potassium level. Despite hypokalaemia, the patient is unlikely to be potassium depleted, therefore overload must be avoided. Continued monitoring of the serum potassium is advisable for several hours after administration of the . For or convulsions, intravenous administration of diazepam is indicated.

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions:

Country Classification Additional information Route of administration/ MS MDD MQP Indications AM OTC Short-term treatment of mild to AT OTC moderate pain in adults BE Not auth. CH Not auth. POM + DE Exemptions: oral use Exemption FR Not auth. For the symptomatic relief mild to moderate pain or fever and HR OTC nasal congestion associated with flu and colds in adults and adolescents over 12 years. Exemptions: Exemptions: List II + Exemptions : 400 mg IE Exemptions: oral use 1200 mg 10 g Exemption ibuprofen ibuprofen ibuprofen Exemptions: Exemptions: List II + Exemptions: 200 mg IT Exemptions: oral use 1200 mg 12 000 mg Exemption ibuprofen ibuprofen ibuprofen LT OTC For temporary relief of pain associated with: headache, migraine, backache, period MK OTC pain, dental pain, muscular pain, cold and flu symptoms, sore throat and fever. Exemptions: 1) short-term relief of the symptoms of nasal Exemptions: available obstruction and sinus blockage, combination products: accompanied by headache and fever in the course of common 1) ibuprofen 400 mg + cold or flu; 2) symptomatic pseudoephedrine 60 mg treatment of pain mild to moderate or fever and nasal 2) ibuprofen 200 mg + POM + congestion associated with the phenylephrine PL Exemption common cold and influenza; 3) hydrochloride 5 mg; symptomatic treatment of acute pain, mild to moderate in adults, 3) ibuprofen 200 mg + when the treatment with other codeine phosphate 12.8 analgesics such as ibuprofen or mg; paracetamol is ineffective; 4) acute pain mild to moderate, 4) ibuprofen 200 mg + when ibuprofen or paracetamol paracetamol 500 mg alone are not sufficient PT Not auth.

144 For the short-term treatment of acute moderate pain, rheumatic and muscular pain, backache, neuralgia, migraine, headache, dental pain or for the relief of RO OTC symptoms of cold and flu with associated congestion, including aches and pains, headache, fever, sore throat, blocked nose and sinuses. For the temporary relief of mild to moderate pain associated with headache, backache, period pain, dental pain, post- Available combination traumatic pain, postoperative product: ibuprofen 200 RS OTC pain, cold and flu symptoms, mg + paracetamol 325 sore throat and fever. This mg product is especially suitable for pain which requires stronger analgesia than ibuprofen or paracetamol alone. UK OTC (P)

Melclass database1: -

No data available from other member states.

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: List II + Exemption

Exemptions: Route of Administration: oral use MS: 400 mg MDD: 1200 mg No longer than 5 days

Criteria: Known safety profile of the active ingredients. Continuous medical supervision not required.

3.2.2 Paediatric use: ibuprofen and phenylephrine hydrochloride: adolescents over 12 years: if this medicinal product is required for more than 3 days, or if symptoms worsen, a doctor should be consulted. Children: not to be given to children under 12 years.

Phenylephrine: risk of renal impairment in dehydrated adolescents.

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

MHRA (UK) – available at: http://www.mhra.gov.uk/spc-pil/index.htm

Martindale: The Complete Drug Reference – 38th Edition

1 Available at: https://melclass.edqm.eu/ (NB: this is the CD-P-PH/PHO’s recommendation at the moment of the compilation of the evidence-based review)

145 1. THERAPEUTIC PROFILE

1.1 Active ingredient: Naproxen and Esomeprazole

1.2 ATC code: M01AE52

1.3 Therapeutic indications: in adults for the symptomatic treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis, in patients who are at risk for developing NSAID-associated gastric and/or duodenal ulcers and where treatment with lower doses of naproxen or of other NSAIDs is not considered sufficient.

1.4 Posology and duration of treatment: the recommended dose is 1 tablet (500 mg/20 mg) twice daily. Undesirable effects of naproxen may be minimised by using the lowest effective dose for the shortest duration possible. In patients not treated with an NSAID previously, a lower daily dose of naproxen or of another NSAID should be considered. For this purpose non-fixed combination products are available. When a total daily dose of 1000 mg naproxen (500 mg twice daily) is not considered appropriate, alternative treatment with a lower strength of naproxen or of other NSAIDs as non-fixed combinations should be utilised. Treatment should be continued to achieve individual treatment goals, reviewed at regular intervals and discontinued if no benefit or if worsening is seen. Due to the delayed release of naproxen from the enteric-coated formulation (3-5 hours), naproxen and esomeprazole is not intended for rapid relief of acute pain conditions (such as dental pain). However, flares of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis may be treated with naproxen and esomeprazole.

Renal impairment: in patients with mild to moderate renal impairment naproxen and esomeprazole should be used cautiously and renal function should be monitored closely. A reduction in the total daily naproxen dose should be considered. When a total daily dose of 1000 mg naproxen (500 mg twice daily) is not considered appropriate, alternative treatment with a lower strength of naproxen or of other NSAIDs as non-fixed combinations should be utilised and, in addition, the need for continuation of the gastroprotective treatment should be re-evaluated. Naproxen and esomeprazole is contraindicated in patients with severe renal impairment (creatinine clearance <30 ml/minute) because accumulation of naproxen metabolites has been seen in patients with severe renal failure and in those on dialysis.

Hepatic impairment: in patients with mild to moderate hepatic impairment, the drug should be used cautiously and hepatic function should be monitored closely. A reduction in the total daily naproxen dose should be considered. When a total daily dose of 1000 mg naproxen (500 mg twice daily) is not considered appropriate, alternative treatment with a lower strength of naproxen or of other NSAIDs as non-fixed combinations should be utilised and, in addition, the need for continuation of the gastroprotective treatment should be re-evaluated. It is contraindicated in patients with severe hepatic impairment.

Elderly (>65 years): older people are at an increased risk of the serious consequences of adverse reactions. When a total daily dose of 1000 mg naproxen (500 mg twice daily) is not considered appropriate (e.g. in older people with impaired renal function or low body weight), alternative treatment with a lower strength of naproxen or of other NSAIDs as non-fixed combinations should be utilised and, in addition, the need for continuation of the gastroprotective treatment should be re-evaluated.

Paediatric population: the safety and efficacy of this combination in children aged 0 to 18 years has not been established.

1.5 Pharmaceutical forms: oral forms: tablets: 500 mg naproxen and 20 mg esomeprazole.

1.6 Contraindications: history of asthma, urticaria or allergic-type reactions induced by administration of acetylsalicylic acid or other NSAIDs; third trimester of pregnancy; severe hepatic impairment (e.g. Child-Pugh C); severe heart failure; severe renal impairment; active peptic ulceration; gastrointestinal bleeding, cerebrovascular bleeding or other bleeding disorders.

1.7 Relevant warnings: to prevent overtreatment, the prescriber should assess at clinically meaningful intervals, based on the individual risks and depending on the characteristics and the severity of the treated underlying disease, whether sufficient pain control is possible with lower doses of NSAIDs as non-fixed combinations. When a total daily dose of 1000 mg naproxen (500 mg twice daily) is not

146 considered appropriate, alternative treatment with a lower strength of naproxen or of other NSAIDs as non-fixed combinations should be utilised and, in addition, the need for continuation of the gastro protective treatment should be re-evaluated. Risk-factors to developing NSAID-related gastrointestinal complications include increased age, concomitant use of anticoagulants, corticosteroids or other NSAIDs (including low-dose acetylsalicylic acid), debilitating cardiovascular disease, Helicobacter pylori infection and a history of gastric and/or duodenal ulcers and upper gastrointestinal bleeding. In patients with the following conditions, naproxen should only be used after a rigorous benefit-risk ratio: inducible porphyries, systemic lupus erythematosus and mixed connective tissue disease, as rare cases of aseptic meningitis have been described in these patients. Patients on long-term treatment (particularly those treated for more than a year) should be kept under regular surveillance.

Elderly: naproxen: older people have an increased frequency of adverse reactions especially gastrointestinal bleeding and perforation, which may be fatal. Esomeprazole decreases the incidence of ulcers in older people.

Gastrointestinal effects: naproxen: GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious GI events. The risk of GI bleeding, ulceration or perforation with NSAIDs is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation, and in older people. These patients should begin treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors (PPIs)) should be considered for these patients and also for patients requiring concomitant low-dose acetylsalicylic acid or other drugs likely to increase gastrointestinal risk. Esomeprazole is a PPI. Patients with a history of GI toxicity, particularly older people, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment. Caution should be advised in patients receiving NSAIDs with concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin reuptake inhibitors or antiplatelet agents such as acetylsalicylic acid. When GI bleeding or ulceration occurs in patients the treatment should be withdrawn. NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn’s disease) as these conditions may be exacerbated.

Cardiovascular and cerebrovascular effects: naproxen: appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy. Clinical trial and epidemiological data suggest that use of coxibs and some NSAIDs (particularly at high doses and in long-term treatment) may be associated with a small increased risk of arterial thrombotic events (e.g. myocardial infarction or stroke). Although data suggest that the use of naproxen (1000 mg daily) may be associated with a lower risk, some risk cannot be excluded. Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease should only be treated with naproxen after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

Renal effects: naproxen: long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, hypovolemia, heart failure, liver dysfunction, salt depletion, those taking diuretics, angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor antagonists and older people. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. As naproxen and its metabolites are eliminated to a large extent (95%) by urinary excretion via glomerular filtration, it should be used with great caution in patients with impaired renal function and the monitoring of serum creatinine and/or creatinine clearance is advised in these patients. Naproxen and esomeprazole is contraindicated in patients having a baseline creatinine clearance of less than 30 ml/minute. Haemodialysis does not decrease the plasma concentration of naproxen because of the high degree of protein binding. Certain patients, specifically those whose renal blood flow is compromised, because of extracellular volume depletion, cirrhosis of the liver, sodium restriction, congestive heart failure or pre-existing renal disease, should have renal function assessed before and during naproxen and esomeprazole therapy. Some older patients in whom impaired renal function may be expected, as

147 well as patients using diuretics, ACE-inhibitors or angiotensin II receptor antagonists also fall within this category. A reduction in daily dosage should be considered to avoid the possibility of excessive accumulation of naproxen metabolites in these patients.

Hepatic effects: borderline elevations of one or more liver tests may occur in patients taking NSAIDs. Hepatic abnormalities may be the result of hypersensitivity rather than direct toxicity. Rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes, have been reported.

Hepatorenal syndrome: the use of NSAIDs may be associated with acute renal failure in patients with severe hepatocirrhosis. These patients frequently also have concomitant coagulopathy related to inadequate synthesis of clotting factors. Antiplatelet effects associated with naproxen could further increase the risk of severe bleeding in these patients.

Haematological effects: naproxen: patients who have coagulation disorders or are receiving drug therapy that interferes with haemostasis should be carefully observed if naproxen-containing products are administered. Patients at high risk of bleeding and those on full anticoagulation therapy (e.g. dicoumarol derivatives) may be at increased risk of bleeding if given naproxen-containing products concurrently. Naproxen decreases platelet aggregation and prolongs bleeding time. This effect should be kept in mind when bleeding times are determined. When active and clinically significant bleeding from any source occurs in patients, the treatment should be withdrawn.

Eye effects: naproxen: because of adverse eye findings in animal studies with NSAIDs, it is recommended that an ophthalmic examination be carried out if any change or disturbance in vision occurs.

Dermatological effects: naproxen: serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs. Patients appear to be at highest risk of these reactions early in the course of therapy, the onset of the reaction occurring within the first month of treatment in the majority of cases.

Anaphylactic (anaphylactoid) reactions: naproxen: hypersensitivity reactions may occur in susceptible individuals. Anaphylactic (anaphylactoid) reactions may occur both in patients with and without a history of hypersensitivity or exposure to acetylsalicylic acid, other NSAIDs or naproxen-containing products. They may also occur in individuals with a history of angioedema, bronchospastic reactivity (e.g. asthma), rhinitis and nasal polyps.

Pre-existing asthma: naproxen: the use of acetylsalicylic acid in patients with acetylsalicylic acid- sensitive asthma has been associated with severe bronchospasm, which can be fatal. Since cross reactivity, including bronchospasm, between acetylsalicylic acid and other NSAIDs has been reported in such acetylsalicylic acid-sensitive patients, this medication should not be administered to patients with this form of acetylsalicylic acid sensitivity and should be used with caution in patients with pre-existing asthma.

Inflammation: naproxen: the antipyretic and antiinflammatory activities of naproxen may reduce fever and other signs of inflammation, thereby diminishing their utility as diagnostic signs.

Female fertility: the use of this medication, as with any drug known to inhibit cyclooxygenase/prostaglandin synthesis, may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of the drug should be considered.

GI effect: esomeprazole: in the presence of any alarm symptom (e.g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis or melaena) and when gastric ulcer is suspected or present, malignancy should be excluded as treatment with esomeprazole may alleviate symptoms and delay diagnosis. Treatment with PPIs may lead to slightly increased risk of gastrointestinal infections, such as Salmonella and Campylobacter. Esomeprazole, as with all acid-blocking medicines, might reduce the absorption of B12 () due to hypo- or achlorhydria. This should be

148 considered in patients with reduced body stores or risk factors of reduced absorption on long-term therapy.

Dermatological effects: esomeprazole: PPIs are associated with very infrequent cases of subacute cutaneous lupus erythematosus (SCLE). If lesions occur, especially in sun-exposed areas of the skin and if accompanied by arthralgia, the patient should seek medical help promptly and the health care professional should consider stopping drug treatment.

Esomeprazole is a CYP2C19 inhibitor. When starting or ending treatment with esomeprazole, the potential for interactions with drugs metabolised by CYP2C19 should be considered. An interaction is observed between and esomeprazole. The clinical relevance of this interaction is uncertain.

Hypomagnesaemia: severe hypomagnesaemia has been reported in patients treated with PPIs like esomeprazole for at least three months and in most cases for a year. Serious manifestations of hypomagnesaemia, such as fatigue, tetany, delirium, convulsions, dizziness and ventricular arrhythmia, can occur but they may begin insidiously and be overlooked. In most affected patients, hypomagnesaemia improved after replacement and discontinuation of the PPI. For patients expected to be on prolonged treatment or who take PPIs with or drugs that may cause hypomagnesaemia (e.g. diuretics), healthcare professionals should consider measuring magnesium levels before starting PPI treatment and periodically during treatment.

Bone fracture: PPIs, especially if used in high doses and over long durations (>1 year), may modestly increase the risk of hip, wrist and spine fracture, predominantly in older people or in the presence of other recognised risk factors. Observational studies suggest that PPIs may increase the overall risk of fracture by 10-40%. Some of this increase may be due to other risk factors. Patients at risk of osteoporosis should receive care according to current clinical guidelines and they should have an adequate intake of and calcium.

Interference with laboratory tests: increased chromogranin A (CgA) levels may interfere with investigations for neuroendocrine tumours. To avoid this interference, this combination treatment should be stopped for at least 5 days before CgA measurement. If CgA and gastrin levels have not returned to reference range after initial measurement, measurements should be repeated 14 days after cessation of PPI treatment.

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): blood and lymphatic system disorders: neutropenia, thrombocytopenia, granulocytopaenia including agranulocytosis, eosinophilia, leucopenia, aplastic anaemia and haemolytic anaemia.

Immune system disorders: hypersensitivity reactions have been reported following treatment with NSAIDs in patients with or without a history of previous hypersensitivity reactions to NSAIDs. These may consist of non-specific allergic reactions and anaphylaxis, respiratory tract reactivity (comprising asthma, aggravated asthma, bronchospasm or dyspnoea), assorted skin disorders (including rashes of various types, pruritus, urticaria, purpura, angioedema) and more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).

Metabolism and nutrition disorders: hyperkalaemia.

Psychiatric disorders: insomnia, dream abnormalities, depression, confusion and hallucinations.

Nervous system disorders: convulsions, dizziness, headache, lightheadedness, drowsiness, paraesthesia, retrobulbar optic neuritis, inability to concentrate and cognitive dysfunction have been reported. Aseptic meningitis (especially in patients with existing autoimmune disorders, such as systemic lupus erythematosus, mixed connective tissue disease), with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation.

Eye disorders: visual disturbances, corneal opacity, papillitis and papilloedema.

149 Ear and labyrinth disorders: tinnitus, hearing disturbances including impairment and vertigo.

Cardiac disorders: oedema, palpitations, cardiac failure and congestive heart failure have been reported with NSAID treatment. Clinical trial and epidemiological data suggest that use of coxibs and some NSAIDs (particularly at high doses and in long-term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke).

Vascular disorders: hypertension, vasculitis.

Respiratory, thoracic and mediastinal disorders: dyspnoea, asthma, eosinophilic pneumonitis and pulmonary oedema.

Gastrointestinal disorders: the most commonly observed adverse reactions are gastrointestinal in nature: heartburn, nausea, vomiting, constipation, diarrhoea, flatulence, dyspepsia, abdominal discomfort and epigastric distress. More serious reactions which may occur are gastrointestinal bleeding (which is sometimes fatal, particularly in the elderly), inflammation, ulceration, perforation and obstruction of the upper and lower gastrointestinal tract, melaena, haematemesis, stomatitis, exacerbation of ulcerative colitis and Crohn’s disease, oesophagitis, gastritis and pancreatitis.

Hepatobiliary disorders: jaundice, fatal hepatitis and abnormal liver function tests.

Skin and subcutaneous tissue disorders: skin rashes including fixed drug eruption, itching (pruritis), urticaria, ecchymoses, purpura, sweating. Alopecia, erythema multiforme, Stevens-Johnson syndrome, erythema nodosum, lichen planus, pustular reaction, SLE, epidermal necrolysis, very rarely toxic epidermal necrolysis and photosensitivity reactions (including cases in which the skin resembles porphyria cutanea tarda, "pseudoporphyria") or epidermolysis bullosa-like reactions may occur rarely. If skin fragility, blistering or other symptoms suggestive of pseudoporphyria occur, treatment should be discontinued and the patient monitored.

Musculoskeletal and connective tissue disorders: myalgia, muscle weakness.

Renal and urinary disorders: including but not limited to glomerular nephritis, interstitial nephritis, nephrotic syndrome, haematuria, raised serum creatinine, renal papillary necrosis and renal failure.

Reproductive system and breast disorders: female infertility.

General disorders and administration site conditions: thirst, pyrexia, fatigue and malaise.

2.2 Indirect risks (incorrect use): there is no clinical data on overdose with this medication. Any effects of an overdose with this medication would be expected to primarily reflect the effects of an overdose with naproxen.

Symptoms: related to naproxen overdose: significant naproxen overdosage may be characterised by lethargy, dizziness, drowsiness, epigastric pain, abdominal discomfort, heartburn, indigestion, nausea, transient alterations in liver function, hypoprothrombinaemia, renal dysfunction, metabolic acidosis, apnoea, disorientation or vomiting. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs and may occur following an overdose. A few patients have experienced convulsions, but it is not clear whether or not these were drug-related. It is not known what dose of the drug would be life-threatening.

Related to esomeprazole overdose: the symptoms described in connection with deliberate esomeprazole overdose (limited experience of doses in excess of 240 mg/day) are transient. Single doses of 80 mg esomeprazole were uneventful.

Management: related to naproxen: patients should be managed by symptomatic and supportive care following an NSAID overdose, particularly with respect to GI effects and renal damage. There are no specific antidotes. Haemodialysis does not decrease the plasma concentration of naproxen because of the high degree of protein binding. Emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with

150 symptoms or following a large overdose. Forced diuresis, alkalinisation of urine or haemoperfusion may not be useful due to high protein binding.

Related to esomeprazole: no specific antidote is known. Esomeprazole is extensively plasma protein bound and is therefore not readily dialysable. As in any case of overdose, treatment should be symptomatic and general supportive measures should be utilised.

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions:

Country Classification Additional information Route of administration/ MS MDD MQP Indications AM Not auth. Symptomatic treatment of arthroses, rheumatoid 500 mg + 20 1000 mg + 40 AT List II arthritis and spondylitis in n.a. mg mg adults with the risk of gastric ulcers BE Not auth. CH List II DE POM FR Not auth. HR Not auth. IE List II 500 mg + 20 1000 mg + 40 15 000 mg + 600 IT List II mg mg mg LT POM MK Not auth. PL Not auth. 500 mg + 20 1000 mg + 40 30 000 mg + PT POM mg mg 1200 mg Indicated in adults for the symptomatic treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis, in patients who are at risk for developing 1000 mg + 40 30 000 mg + RO List I NSAID-associated gastric mg 1200 mg and/or duodenal ulcers and where treatment with lower doses of naproxen or of other NSAIDs is not considered sufficient. RS Not auth. Indicated in adults for the symptomatic treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis, in patients who are at risk for developing 500 mg + 20 UK POM 60 units NSAID-associated gastric mg and/or duodenal ulcers and where treatment with lower doses of naproxen or of other NSAIDs is not considered sufficient.

151 Melclass database1: -

No data available from other member states.

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: List II

Criteria: combination product which requires regular medical supervision.

3.2.2 Paediatric use: the safety and efficacy of this combination in children aged 0 to 18 years has not been established.

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

MHRA (UK) – available at: http://www.mhra.gov.uk/spc-pil/index.htm

Martindale: The Complete Drug Reference – 38th Edition

ANM (RO) – available at: http://www.anm.ro

1 Melclass database - Available at: http://www.edqm.eu/melclass/ (NB: this is the CD-P-PH/PHO’s recommendation at the moment of the compilation of the evidence-based review)

152 1. THERAPEUTIC PROFILE

1.1 Active ingredient: Ketoprofen, Combinations

1.2 ATC code: M01AE53

1.3 Therapeutic indications: symptomatic treatment of rheumatoid arthritis, ankylosing spondylitis and osteoarthritis in patients with a previous history or who are at risk of developing NSAID-associated gastric ulcers or duodenal ulcers.

1.4 Posology and duration of treatment: the dose is one capsule daily.

1.5 Pharmaceutical forms: oral form: capsules: 100 mg ketoprofen and 20 mg ; 200 mg ketoprofen and 20 mg omeprazole.

1.6 Contraindications: previous hypersensitivity reactions (e.g. asthma, urticaria, angioedema or rhinitis) in response to ibuprofen, aspirin or other NAISDs; severe hepatic, renal and cardiac failure; during the last trimester of pregnancy; active or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding); history of GI bleeding or perforation related to previous NSAID therapy; established congestive heart failure (NYHA II-IV), ischemic heart disease, peripheral arterial disease and/or cerebrovascular disease. Omeprazole, like other PPIs, must not be used concomitantly with .

1.7 Relevant warnings: ketoprofen: SLE and mixed connective tissue disease: in patients with SLE and mixed connective tissue disorders there may be an increased risk of aseptic meningitis.

Dermatological: serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens- Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs. Patients appear to be at highest risk for these reactions early in the course of therapy: the onset of the reaction occurring in the majority of cases within the first month of treatment.

Gastrointestinal bleeding, ulceration and perforation: GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious GI events. The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation, and in the elderly. These patients should commence treatment on the lowest dose available. Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment. Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin reuptake inhibitors or antiplatelet agents such as aspirin.

Cardiovascular and cerebrovascular effects: appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy.

The administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and precipitate renal failure. Patients at greatest risk of this reaction are those with impaired renal function, cardiac impairment, liver dysfunction, those taking diuretics and the elderly. Renal function should be monitored in these patients.

Respiratory disorders: in patients with asthma, seasonal allergic rhinitis, swelling of the nasal mucosa (i.e. nasal polyps), chronic obstructive pulmonary diseases or chronic infections of the respiratory tract (especially if linked to allergic rhinitis-like symptoms), reactions to NSAIDs like asthma exacerbations (so-called intolerance to analgesics/analgesic asthma), Quincke's oedema or urticaria are more frequent than in other patients.

Omeprazole: in the presence of any alarm symptom (e.g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis or melaena) and when gastric ulcer is suspected or present, malignancy should be excluded as treatment may alleviate symptoms and delay diagnosis. Co-

153 administration of with PPIs is not recommended. If the combination of atazanavir with a PPI is judged unavoidable, close clinical monitoring (e.g. virus load) is recommended in combination with an increase in the dose of atazanavir to 400 mg with 100 mg ; omeprazole dose should not exceed 20 mg. Omeprazole, as with all acid-blocking medicines, may reduce the absorption of vitamin B12 (cyanocobalamin) due to hypo- or achlorhydria. This should be considered in patients with reduced body stores or risk factors for reduced vitamin B12 absorption on long-term therapy. Omeprazole is a CYP2C19 inhibitor. When starting or ending treatment with omeprazole, the potential for interactions with drugs metabolised by CYP2C19 should be considered. An interaction is observed between clopidogrel and omeprazole. The clinical relevance of this interaction is uncertain. As a precaution, concomitant use of omeprazole and clopidogrel should be discouraged. Severe hypomagnesaemia has been reported in patients treated with PPIs like omeprazole for at least three months, and in most cases, for a year. Serious manifestations of hypomagnesaemia, such as fatigue, tetany, delirium, convulsions, dizziness and ventricular arrhythmia, can occur but they may begin insidiously and be overlooked. In most affected patients, hypomagnesaemia improved after magnesium replacement and discontinuation of the PPI. For patients expected to be on prolonged treatment or who take PPIs with digoxin or drugs that may cause hypomagnesaemia (e.g. diuretics), healthcare professionals should consider measuring magnesium levels before starting PPI treatment and periodically during treatment. PPIs, especially if used in high doses and over long durations (>1 year), may modestly increase the risk of hip, wrist and spine fracture, predominantly in the elderly or in the presence of other recognised risk factors. Observational studies suggest that PPIs may increase the overall risk of fracture by 10-40%. Some of this increase may be due to other risk factors. Patients at risk of osteoporosis should receive care according to current clinical guidelines and they should have an adequate intake of vitamin D and calcium.

Subacute cutaneous lupus erythematosus (SCLE): PPIs are associated with very infrequent cases of SCLE. If lesions occur, especially in sun-exposed areas of the skin and if accompanied by arthralgia, the patient should seek medical help promptly and the health care professional should consider stopping treatment. Treatment with PPIs may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter. As in all long-term treatments, especially when exceeding a treatment period of 1 year, patients should be kept under regular surveillance.

Interference with laboratory tests: increased CgA levels may interfere with investigations for neuroendocrine tumours. To avoid this interference, omeprazole treatment should be stopped for at least 5 days before CgA measurement. If CgA and gastrin levels have not returned to reference range after initial measurement, measurements should be repeated 14 days after cessation of PPI.

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): Blood and lymphatic system disorders: agranulocytosis, pancytopenia.

Metabolism and nutrition disorders: hyponatraemia, hypomagnesaemia.

Psychiatric disorders: agitation, confusion, depression, aggression, hallucinations, insomnia.

Eye disorders: blurred vision.

Gastrointestinal disorders: abdominal pain, constipation, diarrhoea, flatulence, nausea/vomiting, fundic gland polyps (benign), dry mouth, stomatitis, gastrointestinal candidiasis, microscopic colitis.

Hepatobiliary disorders: increased liver enzymes, hepatic failure, encephalopathy in patients with pre- existing liver disease, hepatitis with or without jaundice.

Skin and subcutaneous tissue disorders: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), dermatitis, pruritus, rash, urticaria.

2.2 Indirect risks (incorrect use): overdosage: ketoprofen: in adults and adolescents the following main symptoms of overdose have been observed: headache, dizziness, somnolence, nausea, vomiting,

154 diarrhoea and abdominal pain. In the case of severe intoxication, hypotension, respiratory depression and GI haemorrhage have been reported.

Omeprazole: there have been rare reports of overdose with omeprazole exceeding 2400 mg in a single oral dose. Symptoms such as nausea, vomiting, dizziness, abdominal pain, headache, apathy, depression and confusion have been reported. However, they were transient and without serious consequences and no specific treatment was necessary.

Treatment: ketoprofen: the patient should be immediately hospitalised and symptomatic and supportive care should be carried out. Due to the slow release characteristics of the medicine, ketoprofen will continue to be absorbed up to 16 hours after intake. Gastric lavage can be performed or can be administered to reduce the absorption of ketoprofen. There is no specific antidote.

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions:

Country Classification Additional information Route of administration/ MS MDD MQP Indications Symptomatic treatment of rheumatoid arthritis, ankylosing spondylitis and osteoarthritis in patients with a AM POM 200 mg 200 mg 6000 mg previous history or who are at risk of developing NSAID- associated gastric ulcers or duodenal ulcers. AT Not auth. BE Not auth. CH Not auth. CZ Not auth. DE Not auth. ES Not auth. FI Not auth. FR List II HR Not auth. IE Not auth. IT Not auth. LT Not auth. LV Not auth. MK Not auth. NL Not auth. PL Not auth. PT POM RO Not auth. RS Not auth. SL Not auth.

155 SE Not auth. Patients requiring ketoprofen for osteoarthritis, rheumatoid arthritis and ankylosing UK POM spondylitis, who are 100 mg + 20 mg at risk of NSAID- associated duodenal or gastric ulcer or gastroduodenal erosions

Melclass database1: -

No data available from other member states.

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: List II

Criteria: regular medical supervision required.

3.2.2 Paediatric use: not recommended for use in children, due to lack of data on safety and efficacy.

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

MHRA (UK) – available at: http://www.mhra.gov.uk/spc-pil/index.htm

Martindale: The Complete Drug Reference – 38th Edition

ANSM (FR) – available at: http://agence-prd.ansm.sante.fr/php/ecodex/index.php

PDR – available at: http://www.pdr.net/drug-summary

ANM (RO) – available at: http://www.anm.ro

1 Melclass database - Available at: http://www.edqm.eu/melclass/ (NB: this is the CD-P-PH/PHO’s recommendation at the moment of the compilation of the evidence-based review)

156 1. THERAPEUTIC PROFILE

1.1 Active ingredient: Naproxen and Misoprostol

1.2 ATC code: M01AE56

1.3 Therapeutic indications: -

1.4 Posology and duration of treatment: -

1.5 Pharmaceutical forms: -

1.6 Contraindications: -

1.7 Relevant warnings: -

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): -

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, medicines containing these active substances are authorised only in the UK (classification: POM)).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, medicines containing these active substances are authorised only in the UK: Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References: -

157 1. THERAPEUTIC PROFILE

1.1 Active ingredient: Mefenamic Acid

1.2 ATC code: M01AG01

1.3 Therapeutic indications: antiinflammatory analgesic used for the symptomatic relief of rheumatoid arthritis (including Still's disease), osteoarthritis, pain (including muscular, traumatic and dental pain, headaches of most aetiology, post-operative and post-partum pain), pyrexia in children, primary dysmenorrhoea, menorrhagia due to dysfunctional causes and presence of an intrauterine device (when other pelvic pathology has been ruled out).

1.4 Posology and duration of treatment: adults: 2 capsules (500 mg) three times daily. In menorrhagia to be administered on the first day of excessive bleeding and continued according to the judgment of the physician. In dysmenorrhoea to be administered at the onset of menstrual pain and continued according to the judgment of the physician.

Elderly (over 65 years): as for adults. Whilst no pharmacokinetic or clinical studies specific to the elderly have been undertaken with mefenamic acid, it has been used at normal dosage in trials which included many elderly patients.

Children: it is recommended that children under 12 years of age should be given mefenamic acid suspension (50 mg/5 ml).

1.5 Pharmaceutical forms: tablets and capsules: 250 and 500 mg.

1.6 Contraindications: hypersensitivity to mefenamic acid or any of the other ingredients; inflammatory bowel disease; history of gastrointestinal bleeding or perforation related to previous NSAID therapy; active or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding); severe heart failure; hepatic failure; renal failure. Because the potential exists for cross-sensitivity to aspirin, ibuprofen or other NSAIDs, mefenamic acid must not be given to patients who have previously shown hypersensitivity reaction (e.g. asthma, bronchospasm, rhinitis, angioedema or urticaria) to these medicines; during the last trimester of pregnancy; treatment of pain after CABG surgery.

1.7 Relevant warnings: the elderly are at increased risk of the serious consequences of adverse reactions. If an NSAID is considered necessary, the lowest effective dose should be used and for the shortest possible duration. The patient should be monitored regularly for GI bleeding during NSAID therapy. Mefenamic acid should be used with caution in elderly patients suffering from dehydration and renal disease. Non-oliguric renal failure and proctocolitis have been reported mainly in elderly patients who have not discontinued mefenamic acid after the development of diarrhoea.

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms. Patients on prolonged therapy should be kept under regular surveillance with particular attention to liver dysfunction, rash, blood dyscrasias or development of diarrhoea. Appearance of any of these symptoms should be regarded as an indication to stop therapy immediately. Use with concomitant NSAIDs, including COX-2 specific inhibitors: prolonged use of any type of painkiller for headaches can make them worse. If this situation is experienced or suspected, medical advice should be obtained and treatment should be discontinued. The diagnosis of 'medication overuse headache' should be suspected in patients who have frequent or daily headaches despite (or because of) the regular use of headache medications.

Precaution should be taken in patients suffering from dehydration and renal disease, particularly the elderly.

158 Elderly: the elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation, which may be fatal.

Respiratory disorders: caution is required if administered to patients suffering from, or with a previous history of, bronchial asthma since NSAIDs have been reported to precipitate bronchospasm in such patients.

Cardiovascular, renal and hepatic impairment: the administration of an NSAID may cause a dose- dependent reduction in prostaglandin formation and precipitate renal failure. Patients at greatest risk of this reaction are those with impaired renal function, cardiac impairment, liver dysfunction, those taking diuretics and the elderly. Renal function should be monitored in these patients.

Cardiovascular and cerebrovascular effects: appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy.

Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long-term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). There are insufficient data to exclude such a risk for mefenamic acid.

Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease should only be treated with mefenamic acid after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking). As NSAIDs can interfere with platelet function, they should be used with caution in patients with intracranial haemorrhage and bleeding diathesis.

Gastrointestinal bleeding, ulceration and perforation: GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious GI events. Smoking and alcohol use are added risk factors. The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation, and in the elderly. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for patients at risk of GI bleeding, such as the elderly, and also for patients requiring concomitant low-dose aspirin or other drugs likely to increase gastrointestinal risk. Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding), particularly in the initial stages of treatment. Caution should be advised in patients receiving concomitant medications which could increase the risk of gastrotoxicity or bleeding such as corticosteroids, anticoagulants such as warfarin, selective serotonin reuptake inhibitors or antiplatelet agents such as aspirin. When GI bleeding or ulceration occurs in patients receiving mefenamic acid the treatment should be withdrawn.

SLE and mixed connective tissue disease: in patients with systemic lupus erythematosus and mixed connective tissue disorders there may be an increased risk of aseptic meningitis.

Skin reactions: serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens- Johnson syndrome and toxic epidermal necrolysis, have been reported in association with NSAID use. Patients appear to be at highest risk of these reactions early in the course of therapy, the onset of the reaction occurring in the majority of cases within the first month of treatment. Mefenamic acid should be stopped at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.

Female fertility: the use of mefenamic acid may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of mefenamic acid should be considered. In dysmenorrhoea and menorrhagia lack of response should alert the physician to investigate other causes.

159 Epilepsy: caution should be exercised when treating patients suffering from epilepsy. In patients who are known or suspected to be poor CYP2C9 metabolisers based on previous history/experience with other CYP2C9 substrates, mefenamic acid should be administered with caution as they may have abnormally high plasma levels due to reduced metabolic clearance.

Interaction with other medicinal products and other forms of interaction: concurrent therapy with other drugs may necessitate a modification in dosage.

Anticoagulants: NSAIDs may enhance the effects of anticoagulants, such as warfarin. Concurrent administration of mefenamic acid with oral anticoagulant drugs requires careful prothrombin time monitoring. It is considered unsafe to take NSAIDs in combination with warfarin or heparin unless under direct medical supervision.

Lithium: because of the potential for a reduction in renal clearance and the elevation of plasma lithium levels, patients should be observed carefully for signs of .

The following interactions have been reported with NSAIDs but have not necessarily been associated with mefenamic acid:

Other analgesics including COX-2 selective inhibitors: avoid concomitant use of two or more NSAIDs (including aspirin) as this may increase the risk of adverse effects.

Antidepressants: selective serotonin reuptake inhibitors: increased risk of gastrointestinal bleeding.

Antihypertensives and diuretics: a reduction in antihypertensive and diuretic effects has been observed. Diuretics can increase the nephrotoxicity of NSAIDs.

ACE inhibitors and angiotensin-II-receptor antagonists: a reduction in antihypertensive effect and an increased risk of renal impairment especially in elderly patients. Patients should be adequately hydrated and the renal function assessed in the beginning and during concomitant therapy.

Aminoglycosides: reduction in renal function in susceptible individuals, decreased elimination of aminoglycosides and increased plasma concentrations.

Antiplatelet agents: increased risk of gastrointestinal ulceration or bleeding.

Acetylsalicylic acid: experimental data implies that mefenamic acid interferes with the antiplatelet effect of low-dose aspirin when given concomitantly and thus may interfere with aspirin's prophylactic treatment of cardiovascular disease. However, the limitations of this experimental data and the uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm conclusions can be made for regular mefenamic acid use.

Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce glomerular filtration rate and increase plasma cardiac glycoside levels.

Cyclosporin: the risk of nephrotoxicity of cyclosporin may be increased with NSAIDs.

Corticosteroids: concomitant use may increase the risk of gastrointestinal ulceration or bleeding.

Oral hypoglycaemic agents: inhibition of metabolism of drugs, prolonged half-life and increased risk of hypoglycaemia.

Methotrexate: elimination of the drug can be reduced, resulting in increased plasma levels.

Mifepristone: NSAIDs should not be taken for 8-12 days after administration, NSAIDs can reduce the effects of mifepristone.

Probenecid: reduction in metabolism and elimination of NSAIDs and metabolites.

160 Quinolone antibiotics: animal data indicates that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions.

Tacrolimus: possible increased risk of nephrotoxicity when NSAIDS are given with .

Zidovudine: increased risk of haematological toxicity when NSAIDs are given with . There is evidence of an increased risk of haemarthroses and haematoma in HIV(+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.

Pregnancy: congenital abnormalities have been reported in association with NSAID administration in man; however, these are low in frequency and do not appear to follow any discernible pattern. In view of the known effects of NSAIDs on the foetal cardiovascular system (risk of closure of the ductus arteriosus), use in the last trimester of pregnancy is contraindicated. The onset of labour may be delayed and the duration increased with an increased bleeding tendency in both mother and child. NSAIDs should not be used during the first two trimesters of pregnancy or labour unless the potential benefit to the patient outweighs the potential risk to the foetus.

Lactation: trace amounts of mefenamic acid may be present in breast milk and transmitted to the nursing infant. Therefore, mefenamic acid should not be taken by nursing mothers.

2.1 Direct risks (pharmacovigilance): the most frequently reported side effects associated with mefenamic acid involve the gastrointestinal tract. Diarrhoea occasionally occurs following the use of mefenamic acid. Although this may occur soon after starting treatment, it may also occur after several months of continuous use. The diarrhoea has been investigated in some patients who have continued this drug in spite of its continued presence. These patients were found to have associated proctocolitis. If diarrhoea does develop the drug should be withdrawn immediately and the patient should not receive mefenamic acid again.

Frequencies are not known for the following adverse reactions:

Blood and lymphatic system disorders: haemolytic anaemia, anaemia, hypoplasia bone marrow, haematocrit decreased, thrombocytopenic purpura, temporary lowering of the count (leukopenia) with a risk of infection, sepsis and disseminated intravascular coagulation. Agranulocytosis, aplastic anaemia, eosinophilia, neutropenia, pancytopenia, thrombocytopenia.

Immune system disorders: hypersensitivity reactions have been reported following treatment with NSAIDs. These may consist of non-specific allergic reactions and anaphylaxis, respiratory tract reactivity (comprising asthma, aggravated asthma, bronchospasm or dyspnoea), assorted skin disorders (including rashes of various types, pruritus, urticaria, purpura, angioedema) and more rarely exfoliative or bullous dermatoses (including epidermal necrolysis and erythema multiforme).

Metabolism and nutritional disorders: glucose intolerance in diabetic patients, hyponatraemia.

Psychiatric disorders: confusion, depression, hallucinations, nervousness.

Nervous system disorders: optic neuritis, headaches, paraesthesia, dizziness, drowsiness, reports of aseptic meningitis (especially in patients with existing autoimmune disorders, such as systemic lupus erythematosus, mixed connective tissue disease), with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation Blurred vision, convulsions, insomnia.

Eye disorders: eye irritation, reversible loss of colour vision, visual disturbances.

Ear and labyrinth disorders: ear pain, tinnitus, vertigo.

Cardiac/Vascular disorders: oedema, hypertension and cardiac failure have been reported in association with NSAID treatment. Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long-term treatment) may be associated with an increased risk of arterial thrombotic events (for example myocardial infarction or stroke). Palpitations. Hypotension.

161 Respiratory, thoracic and mediastinal disorders: asthma, dyspnoea.

Gastrointestinal disorders: the most commonly observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or GI bleeding, sometimes fatal, particularly in the elderly, may occur. Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease have been reported following administration. Less frequently, gastritis has been observed. Elderly or debilitated patients seem to tolerate gastrointestinal ulceration or bleeding less well than other individuals and most spontaneous reports of fatal GI events are in this population. Anorexia, colitis, enterocolitis, gastric ulceration with or without haemorrhage, pancreatitis, steatorrhea.

Hepatobiliary disorders: borderline elevations of one or more liver function tests, cholestatic jaundice mild hepatotoxicity, hepatitis, hepatorenal syndrome.

Skin and subcutaneous tissue disorders: angioedema, laryngeal oedema, erythema multiforme, face oedema, bullous reactions (including Lyell's syndrome (toxic epidermal necrolysis) and Stevens-Johnson syndrome), perspiration, rash, photosensitivity reaction, pruritus and urticaria.

Renal and urinary disorders: allergic glomerulonephritis, acute interstitial nephritis, dysuria, haematuria, nephrotic syndrome, non-oliguric renal failure (particularly in dehydration), proteinuria, renal failure including renal papillary necrosis.

General disorders: fatigue, malaise, multi-organ failure, pyrexia.

Investigations: a positive reaction in certain tests for bile in the urine of patients receiving mefenamic acid has been demonstrated to be due to the presence of the drug and its metabolites and not to the presence of bile.

2.2 Indirect risks (incorrect use): it is important that the recommended dose is not exceeded and the regime adhered to since some reports have involved daily dosages under 3 g. Symptoms of overdosage include headache, nausea, vomiting epigastric pain, gastrointestinal bleeding; rarely diarrhoea, disorientation, excitation, coma, drowsiness, tinnitus, fainting; occasionally convulsions (mefenamic acid has a tendency to induce tonic-clonic (grand mal) convulsions in overdose). In cases of significant poisoning acute renal failure and liver damage are possible.

Therapeutic measures: patients should be treated symptomatically as required. Within one hour of ingestion of a potentially toxic amount activated charcoal should be considered. Alternatively, in adults gastric lavage should be considered within one hour of ingestion of a potentially life- threatening overdose. Good urine output should be ensured. Renal and liver function should be closely monitored. Patients should be observed for at least four hours after ingestion of potentially toxic amounts. Frequent or prolonged convulsions should be treated with intravenous diazepam. Other measures may be indicated by the patient's clinical condition. Haemodialysis is of little value since mefenamic acid and its metabolites are firmly bound to plasma proteins.

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

Mefenamic acid is absorbed from the gastrointestinal tract. Peak plasma concentrations occur about 2 to 4 hours after ingestion. The plasma elimination half-life is reported to be 2 to 4 hours. Mefenamic acid is extensively bound to plasma proteins. It is distributed into breast milk. Mefenamic acid is metabolised by the isoenzyme CYP2C9 to 3-hydroxymethyl mefenamic acid which may then be oxidised to 3-carboxymefenamic acid. Over 50% of a dose may be recovered in the urine, as unchanged drug or conjugates of mefenamic acid and its metabolites. Mefenamic acid, an derivative, is an NSAID, although its antiinflammatory properties are considered to be minor. It is used in mild to moderate pain including headache, dental pain, postoperative and postpartum pain and dysmenorrhoea, in musculoskeletal and joint disorders such as osteoarthritis and rheumatoid arthritis and in menorrhagia.

162 3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC code) and supply conditions:

Country Classification Additional information Route of Administration/ MS MDD MQP Indications AT List II BE Not authorised CH List II DE Not authorised FR Not authorised HU List II HR Not authorised IT Not authorised IE List II LT Not authorised MK Not authorised PT POM PL POM RO List II RS Not authorised UK POM

Melclass database1: -

No data available from other member states.

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: List II

Criteria: In cases of prolonged use, systematic evaluation is needed. Adverse events possible.

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

Martindale: The Complete Drug Reference – 36th Edition

EMC - available at: https://www.medicines.org.uk/

1 Melclass database - Available at: http://www.edqm.eu/melclass/ (NB: this is the CD-P-PH/PHO’s recommendation at the moment of the compilation of the evidence-based review)

163 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AG01

1.3 Therapeutic indications: acute migraine attacks.

1.4 Posology and duration of treatment: migraine - acute attacks: adults: 200 mg when the first symptoms of migraine appear. The treatment can be repeated once after 1-2 hours if a satisfactory response is not obtained.

Children: paediatric dosage regimen has not yet been established.

Elderly: the elderly are at increased risk of the serious consequences of adverse reactions. If an NSAID is considered necessary, the lowest effective dose should be used and for the shortest possible duration. The patient should be monitored regularly for GI bleeding during NSAID therapy.

1.5 Pharmaceutical forms: tablets 200 mg.

1.6 Contraindications: hypersensitivity to tolfenamic acid or to any of the excipients; active or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding); in patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, angioedema or urticaria) in response to ibuprofen, aspirin or other NSAIDs; severe heart failure, hepatic failure and renal failure; during the last trimester of pregnancy; history of gastrointestinal bleeding or perforation related to previous NSAID therapy.

1.7 Relevant warnings: in all patients: undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms. The use of this product with concomitant NSAIDs, including COX-2 selective inhibitors, should be avoided.

Elderly: the elderly have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation which may be fatal.

Respiratory disorders: caution is required if administered to patients suffering from, or with a previous history of, bronchial asthma since NSAIDs have been reported to precipitate bronchospasm in such patients.

Cardiovascular, renal and hepatic impairment: the administration of an NSAID may cause a dose- dependent reduction in prostaglandin formation and precipitate renal failure. Patients at greatest risk of this reaction are those with impaired renal function, cardiac impairment, liver dysfunction, those taking diuretics and the elderly. Renal function should be monitored in these patients.

Cardiovascular and cerebrovascular effects: appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy. Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long-term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). There are insufficient data to exclude such a risk for tolfenamic acid. Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease should only be treated with tolfenamic acid after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular disease (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

Gastrointestinal bleeding, ulceration and perforation: GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious GI events. The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation, and in the elderly. These patients should commence

164 treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients and also for patients requiring concomitant low-dose aspirin or other drugs likely to increase gastrointestinal risk. Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment. Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin reuptake inhibitors or antiplatelet agents such as aspirin. When GI bleeding or ulceration occurs in patients receiving tolfenamic acid, the treatment should be withdrawn. NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease) as these conditions may be exacerbated.

SLE and mixed connective tissue disease: in patients with systemic lupus erythematosus and mixed connective tissue disorders there may be an increased risk of aseptic meningitis.

Dermatological: serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs. Patients appear to be at highest risk for these reactions early in the course of therapy, the onset of the reaction occurring in the majority of cases within the first month of treatment. This product should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.

Impaired female fertility: the use of tolfenamic acid may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of tolfenamic acid should be considered.

Interaction with other medicinal products and other forms of interaction: other analgesics, including COX-2 selective inhibitors: avoid concomitant use of two or more NSAIDs (including aspirin) as this may increase the risk of adverse effects.

Antihypertensives: reduced antihypertensive effect.

Diuretics: reduced diuretic effect. Diuretics can increase the risk of nephrotoxicity of NSAIDs.

Cardiac glycosides: NSAIDs may exacerbate cardiac failure, reduce glomerular filtration rate and increase plasma glycoside levels.

Lithium: the effect of lithium may be increased due to decreased elimination.

Methotrexate: decreased elimination of methotrexate.

Cyclosporin: increased risk of nephrotoxicity.

Mifepristone: NSAIDs should not be used for 8-12 days after mifepristone administration as they can reduce the effect of mifepristone.

Corticosteroids: increased risk of gastrointestinal ulceration or bleeding.

Anticoagulants: NSAIDs may enhance the effects of anticoagulants such as warfarin. In patients treated with anticoagulants, close monitoring of blood coagulation is recommended.

Quinolone antibiotics: animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions.

Antiplatelet agents and selective serotonin reuptake inhibitors: increased risk of GI bleeding.

Tacrolimus: possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.

165 Zidovudine: increased risk of haematological toxicity when NSAIDs are given with zidovudine. There is evidence of an increased risk of haemarthroses and haematoma in HIV(+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.

Pregnancy: inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for cardiovascular malformation was increased from less than 1%, up to approximately 1.5%. The risk is believed to increase with dose and duration of therapy. In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation loss and embryo-foetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period. During the first and second trimester of pregnancy, tolfenamic acid should not be given unless clearly necessary. If tolfenamic acid is used by a woman attempting to conceive or during the first and second trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible. During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to: cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension); renal dysfunction, which may progress to renal failure with oligohydramnios in the mother and the neonate, and at the end of the pregnancy, to possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses and inhibition of uterine contractions resulting in delayed or prolonged labour. Consequently, tolfenamic acid is contraindicated during the third trimester of pregnancy.

Lactation: in limited studies so far available, NSAIDs can appear in breast milk in very low concentrations. NSAIDs should, if possible, be avoided when breastfeeding.

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): GI: the most commonly-observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or GI bleeding, sometimes fatal, particularly in the elderly, may occur. Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's have been reported following administration. Less frequently, gastritis has been observed. Pancreatitis has been reported very rarely.

Hypersensitivity: hypersensitivity reactions have been reported following treatment with NSAIDs. These may consist of non-specific allergic reactions and anaphylaxis, respiratory tract reactivity (comprising asthma, aggravated asthma, bronchospasm or dyspnoea), assorted skin disorders (including rashes of various types, pruritus, urticaria, purpura, angioedema) and, more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme).

Cardiovascular and cerebrovascular: oedema, hypertension and cardiac failure have been reported in association with NSAID treatment. Clinical trial and epidemiological data suggest that use of some NSAIDs (particularly at high doses and in long-term treatment) may be associated with an increased risk of arterial thrombotic events (for example myocardial infarction or stroke).

Other adverse reactions reported less commonly include:

Renal: nephrotoxicity in various forms, including interstitial nephritis, nephrotic syndrome and renal failure. Harmless dysuria in the form of smarting during urination may occur occasionally, most commonly in males. The occurrence is correlated with the concentration of a metabolite and is most probably due to a local irritating effect on the urethra. Increased consumption of liquid or reduction of the dose diminishes the risk of smarting. The urine may, due to coloured metabolites, become a little more lemon coloured.

Hepatic: abnormal liver function, hepatitis and jaundice.

166 Neurological and special senses: visual disturbances, optic neuritis, headaches, paraesthesia, reports of aseptic meningitis (especially in patients with existing autoimmune disorders, such as systemic lupus erythematosus, mixed connective tissue disease) with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation, depression, confusion, hallucinations, tinnitus, vertigo, tremor, euphoria, dizziness, malaise, fatigue and drowsiness.

Haematological: thrombocytopenia, neutropenia, agranulocytosis, aplastic anaemia and haemolytic anaemia.

Dermatological: bullous reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis (very rare). Photosensitivity.

2.2 Indirect risks (incorrect use): overdosage: symptoms: headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding; rarely diarrhoea, disorientation, excitation, coma, drowsiness, dizziness, tinnitus, fainting; occasionally convulsions. In cases of significant poisoning acute renal failure and liver damage are possible.

Therapeutic measures: patients should be treated symptomatically as required. Within one hour of ingestion of a potentially toxic amount, activated charcoal should be considered. Alternatively, in adults, gastric lavage should be considered within one hour of ingestion of a potentially life- threatening overdose. Good urine output should be ensured. Renal and liver function should be closely monitored. Patients should be observed for at least four hours after ingestion of potentially toxic amounts. Frequent or prolonged convulsions should be treated with intravenous diazepam. Other measures may be indicated by the patient's clinical condition.

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

Tolfenamic acid is readily absorbed from the gastrointestinal tract. Peak plasma concentrations are reached about 60 to 90 minutes after an oral dose. Tolfenamic acid is about 99% bound to plasma proteins. The plasma half-life is about 2 hours. Tolfenamic acid is metabolised in the liver; the metabolites and unchanged drug are conjugated with . About 90% of an ingested dose is excreted in the urine and the remainder in the faeces. Tolfenamic acid is distributed into breast milk. Uses and Administration: tolfenamic acid, an anthranilic acid derivative related to mefenamic acid, is an NSAID. In the treatment of acute attacks of migraine tolfenamic acid is given in a usual dose of 200 mg by mouth when the first symptoms appear; if a satisfactory response is not obtained this dose may be repeated once after 1 to 2 hours. Tolfenamic acid has also been given for the relief of mild to moderate pain in disorders such as dysmenorrhoea, rheumatoid arthritis or osteoarthritis in doses of 100 to 200 mg three times daily.

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC code) and supply conditions:

Country Classification Additional information Route of Administration/ MS MDD MQP Indications AM Not authorised AT Not authorised BE Not authorised CH Not authorised CZ Not authorised DE Not authorised FI POM FR Not authorised HU Not authorised HR Not authorised IT Not authorised IE Not authorised LT Not authorised LV Not authorised

167 MK Not authorised PT Not authorised PL OTC Acute migraine attacks 200 mg 400 mg 800 mg RO Not authorised RS Not authorised SE Not authorised UK POM

Melclass database1: -

No data available from other member states.

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: List II

Criteria: Self-diagnosis possible. Need to be used at the beginning of migraine attack.

3.2.2 Paediatric use: no paediatric data available.

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

Martindale: The Complete Drug Reference – 36th Edition

EMC - available at: https://www.medicines.org.uk/

1 Melclass database - Available at: http://www.edqm.eu/melclass/ (NB: this is the CD-P-PH/PHO’s recommendation at the moment of the compilation of the evidence-based review)

168 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AG03

1.3 Therapeutic indications: flufenamic acid is mainly used in topical preparations in a concentration of 3 or 3.5% for the relief of pain and inflammation associated with musculoskeletal, joint and soft-tissue disorders. It has also been given by mouth.

1.4 Posology and duration of treatment: -

1.5 Pharmaceutical forms: -

1.6 Contraindications: -

1.7 Relevant warnings: -

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): -

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

Flufenamic acid has been associated with acute attacks of porphyria (and is considered unsafe in porphyric patients) and with acute proctocolitis after oral use.

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, no medicines containing this active substance are authorised in member states).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, no medicines containing this active substance are authorised in member states: Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

Martindale: The Complete Drug Reference – 36th Edition

169 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AG04

1.3 Therapeutic indications: -

1.4 Posology and duration of treatment: -

1.5 Pharmaceutical forms: -

1.6 Contraindications: -

1.7 Relevant warnings: -

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): -

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

Meclofenamic acid, an anthranilic acid derivative similar to mefenamic acid, is an NSAID. It is given orally as the sodium salt in musculoskeletal and joint disorders such as osteoarthritis and rheumatoid arthritis, in mild to moderate pain and in dysmenorrhoea and menorrhagia. Meclofenamic acid has been given orally and as a rectal suppository and is also used in veterinary medicine. At the moment there are no marketed products in Europe.

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, no medicines containing this active substance are authorised in member states).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, no medicines containing this active substance are authorised in member states: Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

Martindale: The Complete Drug Reference – 36th Edition

Drugs@FDA: FDA approved medicines - available at: https://www.accessdata.fda.gov/scripts/cder/daf/

170 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AH01

1.3 Therapeutic indications: in adults for symptomatic relief in the treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis.

Note: the decision to prescribe a selective COX-2 inhibitor should be based on an assessment of the individual patient's overall risks.

1.4 Posology and duration of treatment: as the cardiovascular risks of celecoxib may increase with dose and duration of exposure, the shortest duration possible and the lowest effective daily dose should be used. The patient's need for symptomatic relief and response to therapy should be re-evaluated periodically, especially in patients with osteoarthritis.

Osteoarthritis: the usual recommended daily dose is 200 mg taken once daily or in two divided doses. In some patients, with insufficient relief from symptoms, an increased dose of 200 mg twice daily may increase efficacy. In the absence of an increase in therapeutic benefit after two weeks, other therapeutic options should be considered.

Rheumatoid arthritis: the initial recommended daily dose is 200 mg taken in two divided doses. The dose may, if needed, later be increased to 200 mg twice daily. In the absence of an increase in therapeutic benefit after two weeks, other therapeutic options should be considered.

Ankylosing spondylitis: the recommended daily dose is 200 mg taken once daily or in two divided doses. In a few patients, with insufficient relief from symptoms, an increased dose of 400 mg once daily or in two divided doses may increase efficacy. In the absence of an increase in therapeutic benefit after two weeks, other therapeutic options should be considered.

The maximum recommended daily dose is 400 mg for all indications.

Elderly (>65 years): as in younger adults, 200 mg/day should be used initially. The dose may, if needed, later be increased to 200 mg twice daily. Particular caution should be exercised in elderly patients with a body weight less than 50 kg.

Paediatric population: celecoxib is not indicated for use in children in Europe.

Poor CYP2C9 metabolisers: patients who are known or suspected to be poor CYP2C9 metabolisers based on genotyping or previous history/experience with other CYP2C9 substrates should be administered celecoxib with caution as the risk of dose-dependent adverse effects is increased. Consider reducing the dose to half the lowest recommended dose.

Hepatic impairment: treatment should be initiated at half the recommended dose in patients with established moderate liver impairment with a serum albumin of 25-35 g/l. Experience in such patients is limited to cirrhotic patients.

Renal impairment: experience with celecoxib in patients with mild or moderate renal impairment is limited; therefore, such patients should be treated with caution.

1.5 Pharmaceutical forms: oral form: capsules: 100 and 200 mg.

1.6 Contraindications: hypersensitivity to the active substance or to any of the excipients and known hypersensitivity to sulphonamides; active peptic ulceration or GI bleeding; patients who have experienced asthma, acute rhinitis, nasal polyps, angioneurotic oedema, urticaria or other allergic-type reactions after taking acetylsalicylic acid (aspirin) or other NSAIDs, including COX-2 inhibitors; in pregnancy and in women of childbearing potential unless using an effective method of contraception (celecoxib has been shown to cause malformations in the two animal species studied. The potential for human risk in pregnancy is unknown, but cannot be excluded);

171 breastfeeding; severe hepatic dysfunction (serum albumin <25 g/l or Child-Pugh score ≥10); patients with estimated creatinine clearance <30 ml/min; inflammatory bowel disease; congestive heart failure (NYHA II-IV); established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease.

1.7 Relevant warnings: GI effects: upper and lower gastrointestinal complications (perforations, ulcers or bleedings, some of them resulting in fatal outcome, have occurred in patients treated with celecoxib. Caution is advised with treatment of patients most at risk of developing a gastrointestinal complication with NSAIDs: the elderly, patients using any other NSAID or acetylsalicylic acid concomitantly, glucocorticoids, patients using alcohol or patients with a prior history of gastrointestinal disease, such as ulceration and GI bleeding. There is a further increase in the risk of gastrointestinal adverse effects for celecoxib (gastrointestinal ulceration or other gastrointestinal complications), when celecoxib is taken concomitantly with acetylsalicylic acid (even at low doses). A significant difference in GI safety between selective COX-2 inhibitors + acetylsalicylic acid vs. NSAIDs + acetylsalicylic acid has not been demonstrated in long-term clinical trials.

Concomitant NSAID use: the concomitant use of celecoxib and non-aspirin NSAIDs should be avoided.

Cardiovascular effects: an increased number of serious cardiovascular events, mainly myocardial infarction, has been found in a long-term placebo-controlled study in subjects with sporadic adenomatous polyps treated with celecoxib at doses of 200 mg BID and 400 mg BID compared to placebo. As the cardiovascular risks of celecoxib may increase with dose and duration of exposure, the shortest duration possible and the lowest effective daily dose should be used. The patient's need for symptomatic relief and response to therapy should be re-evaluated periodically, especially in patients with osteoarthritis. Patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking) should only be treated with celecoxib after careful consideration. COX-2 selective inhibitors are not a substitute for acetylsalicylic acid for prophylaxis of cardiovascular thromboembolic diseases because of their lack of antiplatelet effects. Therefore, antiplatelet therapies should not be discontinued.

Fluid retention and oedema: as with other drugs known to inhibit prostaglandin synthesis, fluid retention and oedema have been observed in patients taking celecoxib. Therefore, celecoxib should be used with caution in patients with history of cardiac failure, left ventricular dysfunction or hypertension and in patients with pre-existing oedema for any other reason, since prostaglandin inhibition may result in deterioration of renal function and fluid retention. Caution is also required in patients taking diuretic treatment or otherwise at risk of hypovolaemia.

Hypertension: as with all NSAIDS, celecoxib can lead to the onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of cardiovascular events. Therefore, blood pressure should be monitored closely during the initiation of therapy with celecoxib and throughout the course of therapy.

Hepatic and renal effects: compromised renal or hepatic function and especially cardiac dysfunction are more likely in the elderly and therefore medically appropriate supervision should be maintained. NSAIDs, including celecoxib, may cause renal toxicity. Clinical trials with celecoxib have shown renal effects similar to those observed with comparator NSAIDs. Patients at greatest risk for renal toxicity are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics, ACE-inhibitors and angiotensin II receptor antagonists and the elderly. Such patients should be carefully monitored while receiving treatment with celecoxib. Some cases of severe hepatic reactions, including fulminant hepatitis (some with fatal outcome), liver necrosis and hepatic failure (some with fatal outcome or requiring liver transplant), have been reported with celecoxib. Among the cases that reported time to onset, most of the severe adverse hepatic events developed within one month after initiation of celecoxib treatment. If during treatment patients deteriorate in any of the organ system functions described above, appropriate measures should be taken and discontinuation of celecoxib therapy should be considered.

CYP2D6 inhibition: celecoxib inhibits CYP2D6. Although it is not a strong inhibitor of this enzyme, a dose reduction may be necessary for individually dose-titrated drugs that are metabolised by CYP2D6.

172 Poor CYP2C9 metabolisers: patients known to be poor CYP2C9 metabolisers should be treated with caution.

Skin and systemic hypersensitivity reactions: serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely in association with the use of celecoxib. Patients appear to be at highest risk for these reactions early in the course of therapy, the onset of the reaction occurring in the majority of cases within the first month of treatment. Serious hypersensitivity reactions (including anaphylaxis, angioedema and drug rash with eosinophilia and systemic symptoms, or hypersensitivity syndrome), have been reported in patients receiving celecoxib. Patients with a history of sulphonamide allergy or any drug allergy may be at greater risk of serious skin reactions or hypersensitivity reactions. Celecoxib should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.

General: celecoxib may mask fever and other signs of inflammation.

Interaction with other medicinal products and other forms of interaction:

Use with oral anticoagulants: in patients on concurrent therapy with warfarin, serious bleeding events, some of them fatal, have been reported. Increased prothrombin time with concurrent therapy has been reported. Therefore, this should be closely monitored in patients receiving warfarin/-type oral anticoagulants, particularly when therapy with celecoxib is initiated or celecoxib dose is changed. Concomitant use of anticoagulants with NSAIDS may increase the risk of bleeding. Caution should be exercised when combining celecoxib with warfarin or other oral anticoagulants, including novel anticoagulants (e.g. , and ). Bleeding events in association with increases in prothrombin time have been reported, predominantly in the elderly, in patients receiving celecoxib concurrently with warfarin, some of them fatal.

Antihypertensives: NSAIDs may reduce the effect of antihypertensive medicinal products, including ACE-inhibitors, angiotensin II receptor antagonists, diuretics and beta-blockers. The risk of acute renal insufficiency, which is usually reversible, may be increased in some patients with compromised renal function (e.g. dehydrated patients, patients on diuretics or elderly patients) when ACE inhibitors, angiotensin II receptor antagonists and/or diuretics are combined with NSAIDs, including celecoxib. Therefore, the combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy and periodically thereafter. In a 28-day clinical study in patients with -controlled Stage I and II hypertension, administration of celecoxib 200 mg twice a day resulted in no clinically significant increases, when compared to placebo treatment, in mean daily systolic or diastolic blood pressure as determined using 24-hour ambulatory blood pressure monitoring. Among patients treated with celecoxib 200 mg twice a day, 48% were considered unresponsive to lisinopril at the final clinic visit (defined as either cuff diastolic blood pressure >90 mmHg or cuff diastolic blood pressure increased >10% compared to baseline), compared to 27% of patients treated with placebo; this difference was statistically significant.

Cyclosporin and tacrolimus: co-administration of NSAIDs and cyclosporin or tacrolimus may increase the nephrotoxic effects of these drugs. Renal function should be monitored when celecoxib and any of these drugs are combined.

Acetylsalicylic acid: celecoxib can be used with low-dose acetylsalicylic acid but is not a substitute for acetylsalicylic acid for cardiovascular prophylaxis. In the submitted studies, as with other NSAIDs, an increased risk of gastrointestinal ulceration or other gastrointestinal complications compared to use of celecoxib alone was shown for concomitant administration of low-dose acetylsalicylic acid.

CYP2D6 inhibition: celecoxib is an inhibitor of CYP2D6. The plasma concentrations of drugs that are substrates of this enzyme may be increased when celecoxib is used concomitantly. Examples of drugs which are metabolised by CYP2D6 are ( and selective serotonin reuptake inhibitors), neuroleptics and antiarrhythmic drugs. The dose of individually dose-titrated

173 CYP2D6 substrates may need to be reduced when treatment with celecoxib is initiated or increased if treatment with celecoxib is terminated. Concomitant administration of celecoxib 200 mg twice daily resulted in 2.6-fold and 1.5-fold increases in plasma concentrations of and (CYP2D6 substrates), respectively. These increases are due to inhibition of CYP2D6 substrate metabolism by celecoxib.

CYP2C19 inhibition: in vitro studies have shown some potential for celecoxib to inhibit CYP2C19- catalysed metabolism. The clinical significance of this in vitro finding is unknown. Examples of drugs which are metabolised by CYP2C19 are diazepam, and .

Methotrexate: in patients with rheumatoid arthritis celecoxib had no statistically significant effect on the pharmacokinetics (plasma or renal clearance) of methotrexate (in rheumatologic doses). However, adequate monitoring for methotrexate-related toxicity should be considered when combining these two drugs.

Lithium: in healthy subjects, co-administration of celecoxib 200 mg twice daily with 450 mg twice daily of lithium resulted in a mean increase in Cmax of 16% and in AUC of 18% of lithium. Therefore, patients on lithium treatment should be closely monitored when celecoxib is introduced or withdrawn.

Oral contraceptives: in an interaction study, celecoxib had no clinically relevant effects on the pharmacokinetics of oral contraceptives (1 mg / 35 micrograms ethinyl estradiol).

Glibenclamide/: celecoxib does not affect the pharmacokinetics of tolbutamide (CYP2C9 substrate) or to a clinically relevant extent.

Poor CYP2C9 metabolisers: in individuals who are poor CYP2C9 metabolisers and demonstrate increased systemic exposure to celecoxib, concomitant treatment with CYP2C9 inhibitors such as could result in further increases in celecoxib exposure. Such combinations should be avoided in known poor CYP2C9 metabolisers.

CYP2C9 inhibitors and inducers: since celecoxib is predominantly metabolised by CYP2C9 it should be used at half the recommended dose in patients receiving fluconazole. Concomitant use of a 200 mg single dose of celecoxib and 200 mg once daily of fluconazole, a potent CYP2C9 inhibitor, resulted in a mean increase in celecoxib Cmax of 60% and in AUC of 130%. Concomitant use of inducers of CYP2C9, such as , and , may reduce plasma concentrations of celecoxib.

Ketoconazole and antacids: neither nor antacids have been observed to affect the pharmacokinetics of celecoxib.

Paediatric population: interaction studies have only been performed in adults.

Pregnancy: studies in animals (rats and rabbits) have shown reproductive toxicity, including malformations. Inhibition of prostaglandin synthesis might adversely affect pregnancy. Data from epidemiological studies suggest an increased risk of spontaneous abortion after use of prostaglandin synthesis inhibitors in early pregnancy. The potential for human risk in pregnancy is unknown, but cannot be excluded. Celecoxib, as with other drugs inhibiting prostaglandin synthesis, may cause uterine inertia and premature closure of the ductus arteriosus during the last trimester. Celecoxib is contraindicated in pregnancy and in women who can become pregnant. If a woman becomes pregnant during treatment, celecoxib should be discontinued.

Breastfeeding: celecoxib is excreted in the milk of lactating rats at concentrations similar to those in plasma. Administration of celecoxib to a limited number of lactating women has shown a very low transfer of celecoxib into breast milk. Women who take celecoxib should not breastfeed.

Fertility: based on the mechanism of action, the use of NSAIDs, including celecoxib, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women.

174 2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): Infections and infestations: Common: sinusitis, upper respiratory tract infection, pharyngitis, urinary tract infection.

Blood and lymphatic system disorders: Uncommon: anaemia. Rare: leukopenia, thrombocytopaenia. Very rare: pancytopenia.

Immune system disorders: Common: hypersensitivity. Very rare: anaphylactic shock, anaphylactic reaction.

Metabolism and nutrition disorders: Uncommon: hyperkalaemia.

Psychiatric disorders: Common: insomnia. Uncommon: anxiety, depression, fatigue. Rare: confusional state, hallucinations.

Nervous system disorders: Common: dizziness, hypertonia, headache. Uncommon: cerebral infarction, paraesthesia, somnolence. Rare: ataxia, dysgeusia. Very rare: haemorrhage intracranial (including fatal intracranial haemorrhage), aseptic meningitis, epilepsy (including aggravated epilepsy), ageusia, anosmia.

Eye disorders: Uncommon: vision blurred, conjunctivitis. Rare: eye haemorrhage. Very rare: retinal artery occlusion, retinal occlusion.

Ear and labyrinth disorders: Uncommon: tinnitus, hypoacusis.

Cardiac disorders: Common: myocardial infarction. Uncommon: cardiac failure, palpitations, tachycardia. Rare: arrhythmia.

Vascular disorders: Very common: hypertension (including aggravated hypertension). Rare: pulmonary embolism, flushing. Very rare: vasculitis

Respiratory, thoracic and mediastinal disorders: Common: rhinitis, cough, dyspnoea. Uncommon: bronchospasm. Rare: pneumonitis

GI disorders: Common: nausea, abdominal pain, diarrhoea, dyspepsia, flatulence, vomiting, dysphagia. Uncommon: constipation, gastritis, stomatitis, gastrointestinal inflammation (including aggravation of gastrointestinal inflammation), eructation. Rare: gastrointestinal haemorrhage, duodenal ulcer, gastric ulcer, oesophageal ulcer, intestinal ulcer, large intestinal ulcer, intestinal perforation, oesophagitis, melaena, pancreatitis, colitis.

Hepatobiliary disorders: Uncommon: hepatic function abnormal, hepatic enzyme increased (including increased SGOT and SGPT). Rare: hepatitis. Very rare: hepatic failure (sometimes fatal or requiring liver transplant), fulminant hepatitis (some with fatal outcome), hepatic necrosis, cholestasis, cholestatic hepatitis, jaundice.

Skin and subcutaneous tissue disorders: Common: rash, pruritus (includes pruritus generalised). Uncommon: urticaria, ecchymosis. Rare: angioedema, alopecia, photosensitivity. Very rare: dermatitis exfoliative, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, acute generalised exanthematous pustulosis, dermatitis bullous.

Musculoskeletal and connective tissue disorders: Common: arthralgia. Uncommon: muscle spasms (leg cramps). Very rare: myositis.

Renal and urinary disorders: Uncommon: blood creatinine increased, blood urea increased. Rare: renal failure acute, hyponatraemia. Very rare: tubulointerstitial nephritis, nephrotic syndrome, glomerulonephritis minimal lesion.

175 Reproductive system and breast disorders: Rare: menstrual disorder. Frequency not known: infertility female (female fertility decreased).

General disorders and administrative site conditions: Common: influenza-like illness, peripheral oedema /fluid retention. Uncommon: face oedema, chest pain.

Injury, poisoning and procedural complications: Common: injury (accidental injury).

2.2 Indirect risks (incorrect use): there is no clinical experience of overdose. Single doses up to 1200 mg and multiple doses up to 1200 mg twice daily have been administered to healthy subjects for nine days without clinically significant adverse effects. In the event of suspected overdose, appropriate supportive medical care should be provided, e.g. by eliminating the gastric contents, clinical supervision and, if necessary, the institution of symptomatic treatment. Dialysis is unlikely to be an efficient method of drug removal due to high protein binding.

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

Celecoxib is an oral NSAID that has analgesic, antiinflammatory and antipyretic activity. It is a selective COX-2 inhibitor which is believed to inhibit prostaglandin synthesis within the clinical dose range of 200-400mg daily. No statistically significant inhibition of COX-1 at this dose range was observed in healthy volunteers. Celecoxib was observed to show reduced incidence of colonic tumour activity in animal models. Celecoxib is available as 100 mg and 200 mg hard capsules for oral use. There is no paediatric formulation. Celecoxib received first regulatory approval on 31 December 1998 in the (USA) and is currently approved in 135 countries and marketed in 125 countries. Celecoxib was developed and approved for the following indications: relief of the signs and symptoms of osteoarthritis or rheumatoid arthritis, treatment of primary dysmenorrhea and management of the signs and symptoms of ankylosing spondylitis. In some markets, celecoxib is also indicated for the management of acute pain in adults and relief of the signs and symptoms of juvenile idiopathic arthritis in patients 2 years and older.

Note: celecoxib is not indicated for use in children in the European Union.

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC code) and supply conditions:

Country Classification Additional information Route of Administration/ Indications MS MDD MQP AM POM AT List I BE POM CH List II CZ POM DE POM FR List I HR List I HU POM IE List II IT POM LT POM LV POM MK POM PT POM PL POM RO List I RS POM UK POM

Melclass database1: -

1 Melclass database - Available at: http://www.edqm.eu/melclass/ (NB: this is the CD-P-PH/PHO’s recommendation at the moment of the compilation of the evidence-based review)

176 No data available from other member states.

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: List I

Criteria: Serious adverse effects possible. Need for systematic evaluation of the patient.

3.2.2 Paediatric use: celecoxib is not indicated for use in children in countries of the European Union.

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

EMC - available at: https://www.medicines.org.uk/

Public Assessment Report for paediatric studies submitted in accordance with Article 46 of Regulation (EC) No1901/2006, as amended Celebra/Celebrex/Solexa/Aclarex/Artilog/Celecoxib (celecoxib) MT/W/0010/pdWS/001 – available at: https://goo.gl/KqxYMo

177 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AH02

1.3 Therapeutic indications: -

1.4 Posology and duration of treatment: -

1.5 Pharmaceutical forms: -

1.6 Contraindications: -

1.7 Relevant warnings: -

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): -

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

Rofecoxib is an NSAID reported to be a selective inhibitor of COX-2. It was given by mouth for symptomatic relief in the treatment of osteoarthritis and rheumatoid arthritis, and in the management of acute pain, dysmenorrhoea and migraine. It was withdrawn worldwide after reports of cardiovascular adverse effects.

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, no medicines containing this active substance are authorised in member states).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, no medicines containing this active substance are authorised in member states (withdrawn): Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

Martindale: The Complete Drug Reference – 36th Edition

178 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AH03

1.3 Therapeutic indications: -

1.4 Posology and duration of treatment: -

1.5 Pharmaceutical forms: -

1.6 Contraindications: -

1.7 Relevant warnings: -

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): -

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

Valdecoxib is an NSAID reported to be a selective inhibitor of COX-2. It was given by mouth in the treatment of osteoarthritis and rheumatoid arthritis and for the pain of dysmenorrhoea. The risk of serious skin reactions associated with valdecoxib, in addition to its cardiovascular adverse effects, prompted its general withdrawal worldwide in April 2005.

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, no medicines containing this active substance are authorised in member states).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, no medicines containing this active substance are authorised in member states (withdrawn): Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

Martindale: The Complete Drug Reference – 36th Edition

European Medicines Agency public statement on the suspension of the marketing authorisation for bextra (valdecoxib) in the European Union27/10/2005 (doc. ref.: EMEA/136288/2008) – available at: https://goo.gl/8PPrcd

179 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AH04

1.3 Therapeutic indications: for the short-term treatment of postoperative pain in adults. The decision to prescribe a selective COX-2 inhibitor should be based on an assessment of the individual patient's overall risks.

1.4 Posology and duration of treatment: the recommended dose is 40 mg administered IV or IM, followed every 6 to 12 hours by 20 mg or 40 mg as required, not to exceed 80 mg/day. As the cardiovascular risk of COX-2-specific inhibitors may increase with dose and duration of exposure, the shortest duration possible and the lowest effective daily dose should be used. There is limited clinical experience with parecoxib treatment beyond three days.

Concomitant use with opioid analgesics: opioid analgesics can be used concurrently with parecoxib, dosing as described in the paragraph above. In all clinical assessments parecoxib was administered at a fixed time interval whereas the opioids were administered on an as-needed basis.

Elderly: no dose adjustment is generally necessary in elderly patients (≥65 years). However, for elderly patients weighing less than 50 kg, treatment should be initiated with half the usual recommended dose of parecoxib and the maximum daily dose reduced to 40 mg.

Hepatic impairment: there is no clinical experience in patients with severe hepatic impairment (Child-Pugh score ≥10); therefore, its use is contraindicated in these patients. No dosage adjustment is generally necessary in patients with mild hepatic impairment (Child-Pugh score 5-6). Parecoxib should be introduced with caution and at half the usual recommended dose in patients with moderate hepatic impairment (Child-Pugh score 7-9) and the maximum daily dose should be reduced to 40 mg.

Renal impairment: in patients with severe renal impairment (creatinine clearance <30 ml/min) or patients who may be predisposed to fluid retention, parecoxib should be initiated at the lowest recommended dose (20 mg) and the patient's kidney function should be closely monitored. On the basis of pharmacokinetics, no dose adjustment is necessary in patients with mild to moderate renal impairment (creatinine clearance of 30-80 ml/min).

Paediatric population: the safety and efficacy of parecoxib in children under 18 years old have not been established. No data are available. Therefore, parecoxib is not recommended in these patients.

Method of administration: the IV bolus injection may be given rapidly and directly into a vein or into an existing IV line. The IM injection should be given slowly and deeply into the muscle.

1.5 Pharmaceutical forms: powder for solution for injection (40 mg).

1.6 Contraindications: hypersensitivity to the active substance or to any of the excipients; history of previous serious allergic drug reaction of any type, especially cutaneous reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme or patients with known hypersensitivity to sulfonamides; active peptic ulceration or GI bleeding; patients who have experienced bronchospasm, acute rhinitis, nasal polyps, angioneurotic oedema, urticaria or other allergic-type reactions after taking acetylsalicylic acid or NSAIDs, including COX-2 inhibitors; third trimester of pregnancy and breast-feeding; severe hepatic impairment (serum albumin <25 g/l or Child-Pugh score ≥10); inflammatory bowel disease; congestive heart failure (NYHA II-IV); treatment of post-operative pain following coronary artery bypass graft (CABG) surgery; established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease.

1.7 Relevant warnings: parecoxib has been studied in dental, orthopaedic, gynaecologic (principally hysterectomy) and CABG surgery. There is little experience in other types of surgery,

180 for example gastrointestinal or urological surgery. Modes of administration other than IV or IM (e.g. intra-articular, intrathecal) have not been studied and should not be used.

Because of the possibility for increased adverse reactions at higher doses of parecoxib, other COX-2 inhibitors and NSAIDs, patients treated with parecoxib should be reviewed following dose increase and, in the absence of an increase in efficacy, other therapeutic options should be considered.

If, during treatment, patients deteriorate in any of the organ system functions described below, appropriate measures should be taken and discontinuation of parecoxib therapy should be considered.

Cardiovascular: COX-2 inhibitors have been associated with increased risk of cardiovascular and thrombotic adverse events when taken long-term. The exact magnitude of the risk associated with a single dose has not been determined, nor has the exact duration of therapy associated with increased risk. Patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking) should only be treated with parecoxib after careful consideration. Appropriate measures should be taken and discontinuation of parecoxib therapy should be considered if there is clinical evidence of deterioration in the condition of specific clinical symptoms in these patients. Parecoxib has not been studied in cardiovascular revascularisation procedures other than CABG procedures. Studies in types of surgery other than CABG procedures included patients with the American Society of Anaesthesiology Physical Status Class-III only.

Acetylsalicylic acid and other NSAIDs: COX-2 inhibitors are not a substitute for acetylsalicylic acid for prophylaxis of cardiovascular thromboembolic diseases because of their lack of antiplatelet effects. Therefore, antiplatelet therapies should not be discontinued.

Caution should be exercised when co-administering parecoxib with warfarin and other oral anticoagulants.

The concomitant use of parecoxib with other non-acetylsalicylic acid NSAIDs should be avoided.

Parecoxib may mask fever and other signs of inflammation. In isolated cases, an aggravation of soft tissue infections has been described in connection with the use of NSAIDs and in nonclinical studies with parecoxib). Caution should be exercised with respect to monitoring the incision for signs of infection in surgical patients receiving parecoxib.

Gastrointestinal: upper GI complications, some of them resulting in fatal outcome, have occurred in patients treated with parecoxib. Caution is advised in the treatment of patients most at risk of developing a gastrointestinal complication with NSAIDs: the elderly, patients using any other NSAID or acetylsalicylic acid concomitantly, glucocorticoids, selective serotonin reuptake inhibitors, patients ingesting alcohol or patients with a prior history of gastrointestinal disease, such as ulceration and GI bleeding. There is further increase in the risk of gastrointestinal adverse effects gastrointestinal ulceration or other gastrointestinal complications), when parecoxib is taken concomitantly with acetylsalicylic acid (even at low doses).

Skin reactions: serious skin reactions, including erythema multiforme, exfoliative dermatitis and Stevens-Johnson syndrome (some of them fatal) have been reported through post-marketing surveillance in patients receiving parecoxib. Additionally, fatal reports of toxic epidermal necrolysis have been reported in patients receiving valdecoxib (the active metabolite of parecoxib) and cannot be ruled out for parecoxib. Patients appear to be at highest risk for these reactions early in the course of therapy, the onset of the reaction occurring in the majority of cases within the first month of treatment. Appropriate measures should be taken by physicians to monitor for any serious skin reactions with therapy, e.g. additional patient consultations. Patients should be advised to immediately report any emergent skin condition to their physician. Parecoxib should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity. Serious skin reactions are known to occur with NSAIDs including COX-2 selective inhibitors as well as other medicinal products. However, the reported rate of serious skin events appears to be greater for valdecoxib (the active metabolite of parecoxib) compared to other COX-2 selective inhibitors. Patients with a history of allergy may be at greater risk of skin

181 reactions. Patients without a history of sulfonamide allergy may also be at risk for serious skin reactions.

Hypersensitivity: hypersensitivity reactions (anaphylaxis and angioedema) have been reported with valdecoxib and parecoxib. Some of these reactions have occurred in patients with a history of allergic-type reactions to sulfonamides Parecoxib should be discontinued at the first sign of hypersensitivity. Cases of severe hypotension shortly following parecoxib administration have been reported. Some of these cases have occurred without other signs of anaphylaxis. The physician should be prepared to treat severe hypotension.

Fluid retention, oedema, renal: as with other medicinal products known to inhibit prostaglandin synthesis, fluid retention and oedema have been observed in some patients taking parecoxib. Therefore, parecoxib should be used with caution in patients with compromised cardiac function, preexisting oedema or other conditions predisposing to, or worsened by, fluid retention including those taking diuretic treatment or otherwise at risk of hypovolemia. If there is clinical evidence of deterioration in the condition of these patients, appropriate measures, including discontinuation of parecoxib, should be taken. Acute renal failure has been reported in patients receiving parecoxib. Since prostaglandin synthesis inhibition may result in deterioration of renal function and fluid retention, caution should be observed when administering parecoxib in patients with impaired renal function or hypertension, or in patients with compromised cardiac or hepatic function or other conditions predisposing to fluid retention. Caution should be used when initiating treatment with parecoxib in patients with dehydration. In this case, it is advisable to rehydrate patients first and then start therapy with parecoxib.

Hypertension: as with all NSAIDs, parecoxib can lead to the onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of cardiovascular events. Parecoxib should be used with caution in patients with hypertension. Blood pressure should be monitored closely during the initiation of therapy with parecoxib and throughout the course of therapy. If blood pressure rises significantly, alternative treatment should be considered.

Hepatic impairment: parecoxib should be used with caution in patients with moderate hepatic impairment (Child-Pugh score 7-9).

Use with oral anticoagulants: the concomitant use of NSAIDs with oral anticoagulants increases the risk of bleeding. Oral anticoagulants include warfarin/coumarin-type and novel oral anticoagulants (e.g. apixaban, dabigatran and rivaroxaban).

Interaction with other medicinal products and other forms of interaction: anticoagulant therapy should be monitored, particularly during the first few days after initiating parecoxib therapy in patients receiving warfarin or other anticoagulants, since these patients have an increased risk of bleeding complications. Therefore, patients receiving oral anticoagulants should be closely monitored for their prothrombin time INR, particularly in the first few days when therapy with parecoxib is initiated or the dose of parecoxib is changed. Parecoxib had no effect on acetylsalicylic acid-mediated inhibition of platelet aggregation or bleeding times. Clinical trials indicate that parecoxib can be given with low-dose acetylsalicylic acid (≤325 mg). In the submitted studies, as with other NSAIDs, an increased risk of gastrointestinal ulceration or other gastrointestinal complications compared to use of parecoxib alone was shown for concomitant administration of low-dose acetylsalicylic acid. Co-administration of parecoxib and heparin did not affect the of heparin (activated partial thromboplastin time) compared to heparin alone. Inhibition of prostaglandins by NSAIDs, including COX-2 inhibitors, may diminish the effect of ACE inhibitors, angiotensin II antagonists, beta-blockers and diuretics. This interaction should be given consideration in patients receiving parecoxib concomitantly with these medicines.

In patients who are elderly, volume-depleted (including those on diuretic therapy) or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors or angiotensin-II antagonists may result in further deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Therefore, the concomitant administration of these drugs should be done with caution. Patients should be

182 adequately hydrated and the need to monitor the renal function should be assessed at the beginning of the concomitant treatment and periodically thereafter.

Co-administration of NSAIDs and cyclosporin or tacrolimus has been suggested to increase the nephrotoxic effects of cyclosporin and tacrolimus because of NSAID effects on renal prostaglandins. Renal function should be monitored when parecoxib and any of these medicinal products are co-administered.

Parecoxib may be co-administered with opioid analgesics. In clinical trials, the daily requirement for PRN opioids was significantly reduced when coadministered with parecoxib.

Parecoxib is rapidly hydrolysed to the active metabolite valdecoxib. In humans, studies demonstrated that valdecoxib metabolism is predominantly mediated via CYP3A4 and 2C9 isozymes. Plasma exposure (AUC and Cmax) to valdecoxib was increased (62% and 19%, respectively) when co-administered with fluconazole (predominantly a CYP2C9 inhibitor), indicating that the dose of parecoxib should be reduced in those patients who are receiving fluconazole therapy. Plasma exposure (AUC and Cmax) to valdecoxib was increased (38% and 24%, respectively) when co-administered with ketoconazole (CYP3A4 inhibitor); however, a dosage adjustment should not generally be necessary for patients receiving ketoconazole. The effect of enzyme induction has not been studied. The metabolism of valdecoxib may increase when co- administered with enzyme inducers such as rifampicin, , carbamazepine or dexamethasone.

Treatment with valdecoxib (40 mg twice daily for 7 days) produced a 3-fold increase in plasma concentrations of dextromethorphan (CYP2D6 substrate). Therefore, caution should be observed when co-administering parecoxib and medicinal products that are predominantly metabolised by CYP2D6 and which have narrow therapeutic margins (e.g. , , metoprolol). Plasma exposure of omeprazole (CYP2C19 substrate) 40 mg once daily was increased by 46% following administration of valdecoxib 40 mg twice daily for 7 days, while the plasma exposure to valdecoxib was unaffected. These results indicate that although valdecoxib is not metabolised by CYP2C19, it may be an inhibitor of this isoenzyme. Therefore, caution should be observed when administering parecoxib with medicinal products known to be substrates of CYP2C19 (e.g. phenytoin, diazepam or imipramine).

In two pharmacokinetic interaction studies in rheumatoid arthritis patients receiving a stable weekly methotrexate dose (5-20 mg/week, as a single oral or intramuscular dose), orally administered valdecoxib (10 mg twice daily or 40 mg twice daily) had little or no effect on the steady-state plasma concentrations of methotrexate. However caution is advised when methotrexate is administered concurrently with NSAIDs, because NSAID administration may result in increased plasma levels of methotrexate. Adequate monitoring of methotrexate-related toxicity should be considered when co-administering parecoxib and methotrexate.

Co-administration of valdecoxib and lithium produced significant decreases in lithium serum clearance (25%) and renal clearance (30%) with a 34% higher serum exposure compared to lithium alone. Lithium serum concentration should be monitored closely when initiating or changing parecoxib therapy in patients receiving lithium.

Co-administration of valdecoxib with glibenclamide (CYP3A4 substrate) did not affect either the pharmacokinetics (exposure) or the pharmacodynamics (blood glucose and levels) of glibenclamide.

Injectable anaesthetics: co-administration of IV parecoxib 40 mg with (CYP2C9 substrate) or (CYP3A4 substrate) did not affect either the pharmacokinetics (metabolism and exposure) or the pharmacodynamics (EEG effects, psychomotor tests and waking from ) of IV propofol or IV midazolam. Additionally, co-administration of valdecoxib had no clinically significant effect on the hepatic or intestinal CYP3A4-mediated metabolism of orally administered midazolam. Administration of IV parecoxib 40 mg had no significant effect on the pharmacokinetics of either IV or IV (CYP3A4 substrates).

183 Inhalation anaesthetics: no formal interaction studies have been done. In surgery studies in which parecoxib was administered pre-operatively, no evidence of pharmacodynamic interaction was observed in patients receiving parecoxib and the inhalation anaesthetic agents and .

Pregnancy: parecoxib is suspected to cause serious birth defects when administered during the last trimester of pregnancy because, as with other medicinal products known to inhibit prostaglandin, it may cause premature closure of the ductus arteriosus or uterine inertia. NSAID use during the second or third trimester of pregnancy may cause foetal renal dysfunction which may result in reduction of amniotic fluid volume or oligohydramnios in severe cases. Such effects may occur shortly after treatment initiation and are usually reversible. Pregnant women on NSAIDs should be closely monitored for amniotic fluid volume. Parecoxib is contraindicated in the third trimester of pregnancy. There are no adequate data from the use of parecoxib in pregnant women or during labour. However, inhibition of prostaglandin synthesis might adversely affect pregnancy. Data from epidemiological studies suggest an increased risk of miscarriage after use of prostaglandin synthesis inhibitors in early pregnancy. In animals, administration of prostaglandin synthesis inhibitors, including parecoxib, has been shown to result in increased pre- and post- implantation loss and embryo-foetal lethality. During the first and second trimester of pregnancy, parecoxib should not be given unless clearly necessary.

Breastfeeding: administration of a single dose of parecoxib to lactating women following caesarean section resulted in the transfer of a relatively small amount of parecoxib and its active metabolite valdecoxib into human milk, and this resulted in a low relative dose for the infant (approximately 1% of the weight-adjusted maternal dose). Parecoxib must not be administered to women who breastfeed.

Fertility: the use of parecoxib, as with any medicinal product known to inhibit cyclooxygenase/prostaglandin synthesis, is not recommended in women attempting to conceive. Based on the mechanism of action, the use of NSAIDs may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of NSAIDs, including parecoxib, should be considered.

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): the most common adverse reaction for parecoxib is nausea. The most serious reactions occur uncommonly to rarely and include cardiovascular events such as myocardial infarction and severe hypotension, as well as hypersensitivity events such as anaphylaxis, angioedema and severe skin reactions. Following coronary artery bypass graft surgery, patients administered parecoxib have a higher risk of adverse reactions such as cardiovascular/thromboembolic events (including myocardial infarction, stroke/TIA, pulmonary embolus and deep vein thrombosis), deep surgical infections and sternal wound healing complications.

The following adverse reactions were reported for patients who received parecoxib (N = 5402) in 28 placebo-controlled clinical trials. Reports from post-marketing experience have been listed as “frequency not known” because the respective frequencies cannot be estimated from the available data. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Infections and infestations: Common: pharyngitis, alveolar osteitis (dry socket). Uncommon: abnormal sternal serous wound drainage, wound infection.

Blood and lymphatic system disorders: Common: anaemia postoperative. Uncommon thrombocytopenia.

Immune System Disorders: Rare: anaphylactoid reaction.

184 Metabolism and nutrition disorders: Common: hypokalaemia. Uncommon: hyperglycaemia, anorexia.

Psychiatric disorders: Common: agitation, insomnia.

Nervous system disorders: Common: hypoaesthesia, dizziness. Uncommon: cerebrovascular disorder.

Ear and labyrinth disorders: Uncommon: ear pain.

Cardiac disorders: Uncommon: myocardial infarction, bradycardia. Not known: circulatory collapse, congestive heart failure, tachycardia.

Vascular disorders: Common: hypertension, hypotension. Uncommon: hypertension (aggravated), orthostatic hypotension.

Respiratory, thoracic and mediastinal disorders: Common: respiratory insufficiency. Uncommon: pulmonary embolism. Not known: dyspnoea.

Gastrointestinal disorders: Very common: nausea. Common: abdominal pain, vomiting, constipation, dyspepsia, flatulence. Uncommon: gastroduodenal ulceration, gastro-oesophageal reflux disease, dry mouth, gastrointestinal sounds abnormal. Rare: pancreatitis, oesophagitis, oedema mouth (perioral swelling).

Skin and subcutaneous tissue disorders: Common: pruritus, hyperhidrosis. Uncommon: ecchymosis, rash, urticaria. Unknown: Stevens-Johnson syndrome, erythema multiforme, exfoliative dermatitis.

Musculoskeletal and connective tissue disorders: Common: back pain. Uncommon: arthralgia.

Renal and urinary disorders: Common: oliguria. Rare: renal failure. Not known: acute renal failure.

General disorders and administration site conditions: Common: peripheral oedema. Uncommon: asthenia, injection site pain, injection site reaction. Not known: hypersensitivity reactions including anaphylaxis and angioedema.

Investigations: Common: blood creatinine increased. Uncommon: blood phosphokinase increased, blood lactate dehydrogenase increased, serum glutamic oxaloacetic transaminase increased, serum glutamic pyruvic transaminase increased, blood urea nitrogen increased.

Injury, poisoning and procedural complications: Uncommon: post procedural complication (skin).

Description of selected adverse reactions: in post-marketing experience, toxic epidermal necrolysis has been reported in association with the use of valdecoxib and cannot be ruled out for parecoxib. In addition, the following rare, serious adverse reactions have been reported in association with the use of NSAIDs and cannot be ruled out for parecoxib: bronchospasm and hepatitis.

2.2 Indirect risks (incorrect use): reporting of overdose with parecoxib has been associated with adverse reactions which have also been described with recommended doses of parecoxib. In case of overdose, patients should be managed by symptomatic and supportive care. Valdecoxib is not removed by haemodialysis. Diuresis or alkalisation of urine may not be useful due to high protein binding of valdecoxib.

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC code) and supply conditions:

185

Country Classification Additional information Route of Administration/ MS MDD MQP Indications AM Not authorised AT List I BE POM CH Not authorised DE POM FR Not authorised HR Not authorised IT POM IE List I MK Not authorised NL Not authorised PT POM PL POM RO List I RS Not authorised UK POM

Melclass database1: -

No data available from other member states

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: List I

Criteria: Parenteral form. Treatment should be started after individual patient’s benefit/risk evaluation. Short-term use (3 days) only. Serious adverse events possible.

3.2.2 Paediatric use: No data, not recommended for children.

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

EMC - available at: https://www.medicines.org.uk/

1 Melclass database - Available at: http://www.edqm.eu/melclass/ (NB: this is the CD-P-PH/PHO’s recommendation at the moment of the compilation of the evidence-based review)

186 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AH05

1.3 Therapeutic indications: etoricoxib is indicated in adults and adolescents 16 years of age and older for the symptomatic relief of osteoarthritis (OA), rheumatoid arthritis (RA), ankylosing spondylitis and the pain and signs of inflammation associated with acute gouty arthritis. Etoricoxib is indicated in adults and adolescents 16 years of age and older for the short-term treatment of moderate pain associated with dental surgery.

The decision to prescribe a selective COX-2 inhibitor should be based on an assessment of the individual patient's overall risks.

1.4 Posology and duration of treatment: as the cardiovascular risks of etoricoxib may increase with dose and duration of exposure, the shortest duration possible and the lowest effective daily dose should be used. The patient's need for symptomatic relief and response to therapy should be re-evaluated periodically, especially in patients with osteoarthritis.

Osteoarthritis: the recommended dose is 30 mg once daily. In some patients with insufficient relief from symptoms, an increased dose of 60 mg once daily may increase efficacy. In the absence of an increase in therapeutic benefit, other therapeutic options should be considered.

Rheumatoid arthritis: the recommended dose is 60 mg once daily. In some patients with insufficient relief from symptoms, an increased dose of 90 mg once daily may increase efficacy. Once the patient is clinically stabilised, down-titration to a 60 mg once daily dose may be appropriate. In the absence of an increase in therapeutic benefit, other therapeutic options should be considered.

Ankylosing spondylitis: the recommended dose is 60 mg once daily. In some patients with insufficient relief from symptoms, an increased dose of 90 mg once daily may increase efficacy. Once the patient is clinically stabilised, down-titration to a 60 mg once daily dose may be appropriate. In the absence of an increase in therapeutic benefit, other therapeutic options should be considered.

Acute pain conditions: for acute pain conditions, etoricoxib should be used only for the acute symptomatic period.

Acute gouty arthritis: the recommended dose is 120 mg once daily. In clinical trials for acute gouty arthritis, etoricoxib was given for 8 days.

Postoperative dental surgery pain: the recommended dose is 90 mg once daily, limited to a maximum of 3 days. Some patients may require other postoperative analgesia in addition to etoricoxib during the 3-day treatment period.

Elderly patients: no dosage adjustment is necessary for elderly patients. As with other drugs, caution should be exercised in elderly patients.

Patients with hepatic impairment: regardless of indication, in patients with mild hepatic dysfunction (Child-Pugh score 5-6) a dose of 60 mg once daily should not be exceeded. In patients with moderate hepatic dysfunction (Child-Pugh score 7-9), regardless of indication, the dose of 30 mg once daily should not be exceeded. Clinical experience is limited particularly in patients with moderate hepatic dysfunction and caution is advised. There is no clinical experience in patients with severe hepatic dysfunction (Child-Pugh score ≥10); therefore, its use is contraindicated in these patients.

Patients with renal impairment: no dosage adjustment is necessary for patients with creatinine clearance ≥30 ml/min. The use of etoricoxib in patients with creatinine clearance <30 ml/min is contraindicated.

187 Paediatric population: etoricoxib is contraindicated in children and adolescents under 16 years of age.

Method of administration: etoricoxib is administered orally and may be taken with or without food. The onset of the effect of the medicinal product may be faster when etoricoxib is administered without food. This should be considered when rapid symptomatic relief is needed.

1.5 Pharmaceutical forms: oral: film-coated tablets 30 mg, 60 mg, 90 mg and 120 mg.

1.6 Contraindications: hypersensitivity to the active substance or to any of the excipients; active peptic ulceration or GI bleeding; patients who, after taking acetylsalicylic acid or NSAIDs, including COX-2 inhibitors, experience bronchospasm, acute rhinitis, nasal polyps, angioneurotic oedema, urticaria or allergic-type reactions; pregnancy and lactation; severe hepatic dysfunction (serum albumin <25 g/l or Child-Pugh score ≥10); estimated renal creatinine clearance <30 ml/min; children and adolescents under 16 years of age; inflammatory bowel disease; congestive heart failure (NYHA II-IV); patients with hypertension whose blood pressure is persistently elevated above 140/90 mmHg and has not been adequately controlled; established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease.

1.7 Relevant warnings: Gastrointestinal effects: upper gastrointestinal complications, some of them resulting in fatal outcome, have occurred in patients treated with etoricoxib. Caution is advised with treatment of patients most at risk of developing a gastrointestinal complication with NSAIDs: the elderly, patients using any other NSAID or acetylsalicylic acid concomitantly or patients with a prior history of gastrointestinal disease, such as ulceration and GI bleeding. There is a further increase in the risk of gastrointestinal adverse effects (gastrointestinal ulceration or other gastrointestinal complications) when etoricoxib is taken concomitantly with acetylsalicylic acid (even at low doses). A significant difference in GI safety between selective COX-2 inhibitors + acetylsalicylic acid vs. NSAIDs + acetylsalicylic acid has not been demonstrated in long-term clinical trials.

Cardiovascular effects: clinical trials suggest that the selective COX-2 inhibitor class of drugs may be associated with a risk of thrombotic events (especially myocardial infarction (MI) and stroke), relative to placebo and some NSAIDs. As the cardiovascular risks of etoricoxib may increase with dose and duration of exposure, the shortest duration possible and the lowest effective daily dose should be used. The patient's need for symptomatic relief and response to therapy should be re- evaluated periodically, especially in patients with osteoarthritis. Patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking) should only be treated with etoricoxib after careful consideration. COX-2 selective inhibitors are not a substitute for acetylsalicylic acid for prophylaxis of cardiovascular thromboembolic diseases because of their lack of antiplatelet effect. Therefore antiplatelet therapies should not be discontinued.

Renal effects: renal prostaglandins may play a compensatory role in the maintenance of renal perfusion. Therefore, under conditions of compromised renal perfusion, administration of etoricoxib may cause a reduction in prostaglandin formation and, secondarily, in renal blood flow, and thereby impair renal function. Patients at greatest risk of this response are those with pre-existing significantly impaired renal function, uncompensated heart failure or cirrhosis. Monitoring of renal function in such patients should be considered.

Fluid retention, oedema and hypertension: as with other medicinal products known to inhibit prostaglandin synthesis, fluid retention, oedema and hypertension have been observed in patients taking etoricoxib. All NSAIDs, including etoricoxib, can be associated with new onset or recurrent congestive heart failure. Caution should be exercised in patients with a history of cardiac failure, left ventricular dysfunction or hypertension and in patients with pre-existing oedema for any other reason. If there is clinical evidence of deterioration in the condition of these patients, appropriate measures, including discontinuation of etoricoxib, should be taken. Etoricoxib may be associated with more frequent and severe hypertension than some other NSAIDs and selective COX-2 inhibitors, particularly at high doses. Therefore, hypertension should be controlled before treatment with etoricoxib and special attention should be paid to blood pressure monitoring during treatment with etoricoxib. Blood pressure should be monitored within two weeks after initiation of treatment

188 and periodically thereafter. If blood pressure rises significantly, alternative treatment should be considered.

Hepatic effects: elevations of alanine aminotransferase and/or aspartate aminotransferase (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials treated for up to one year with etoricoxib 30, 60 and 90 mg daily. Any patients with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver function test has occurred, should be monitored. If signs of hepatic insufficiency occur, or if persistently abnormal liver function tests (three times the upper limit of normal) are detected, etoricoxib should be discontinued.

General: if during treatment, patients deteriorate in any of the organ system functions described above, appropriate measures should be taken and discontinuation of etoricoxib therapy should be considered.

Medically appropriate supervision should be maintained when using etoricoxib in the elderly and in patients with renal, hepatic or cardiac dysfunction.

Caution should be used when initiating treatment with etoricoxib in patients with dehydration. It is advisable to rehydrate patients prior to starting therapy with etoricoxib.

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs and some selective COX-2 inhibitors during post-marketing surveillance. Patients appear to be at highest risk for these reactions early in the course of therapy with the onset of the reaction occurring in the majority of cases within the first month of treatment. Serious hypersensitivity reactions (such as anaphylaxis and angioedema) have been reported in patients receiving etoricoxib. Some selective COX-2 inhibitors have been associated with an increased risk of skin reactions in patients with a history of any drug allergy. Etoricoxib should be discontinued at the first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity.

Etoricoxib may mask fever and other signs of inflammation.

Caution should be exercised when co-administering etoricoxib with warfarin or other oral anticoagulants.

The use of etoricoxib, as with any medicinal product known to inhibit cyclooxygenase/prostaglandin synthesis, is not recommended in women attempting to conceive.

Interaction with other medicinal products and other forms of interaction: oral anticoagulants: in subjects stabilised on chronic warfarin therapy, the administration of etoricoxib 120 mg daily was associated with an approximate 13% increase in prothrombin time International Normalised Ratio (INR). Therefore, patients receiving oral anticoagulants should be closely monitored for their prothrombin time INR, particularly in the first few days when therapy with etoricoxib is initiated or the dose of etoricoxib is changed.

Diuretics, ACE inhibitors and angiotensin II antagonists: NSAIDs may reduce the effect of diuretics and other antihypertensive drugs. In some patients with compromised renal function (e.g. dehydrated patients or elderly patients with compromised renal function) the co-administration of an ACE inhibitor or angiotensin II antagonist and agents that inhibit cyclooxygenase may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. These interactions should be considered in patients taking etoricoxib concomitantly with ACE inhibitors or angiotensin II antagonists. Therefore, the combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy and periodically thereafter.

Acetylsalicylic acid: in a study in healthy subjects, at steady state, etoricoxib 120 mg once daily had no effect on the antiplatelet activity of acetylsalicylic acid (81 mg once daily). Etoricoxib can be used concomitantly with acetylsalicylic acid at doses used for cardiovascular prophylaxis (low-dose

189 acetylsalicylic acid). However, concomitant administration of low-dose acetylsalicylic acid with etoricoxib may result in an increased rate of GI ulceration or other complications compared to use of etoricoxib alone. Concomitant administration of etoricoxib with doses of acetylsalicylic acid above those for cardiovascular prophylaxis or with other NSAIDs is not recommended.

Ciclosporin and tacrolimus: although this interaction has not been studied with etoricoxib, co- administration of or tacrolimus with any NSAID may increase the nephrotoxic effect of ciclosporin or tacrolimus. Renal function should be monitored when etoricoxib and either of these drugs is used in combination.

Lithium: NSAIDs decrease lithium renal excretion and therefore increase lithium plasma levels. If necessary, monitor blood lithium closely and adjust the lithium dosage while the combination is being taken and when the NSAID is withdrawn.

Methotrexate: two studies investigated the effects of etoricoxib 60, 90 or 120 mg administered once daily for seven days in patients receiving once-weekly methotrexate doses of 7.5 to 20 mg for rheumatoid arthritis. Etoricoxib at 60 and 90 mg had no effect on methotrexate plasma concentrations or renal clearance. In one study, etoricoxib 120 mg had no effect, but in the other study, etoricoxib 120 mg increased methotrexate plasma concentrations by 28% and reduced renal clearance of methotrexate by 13%. Adequate monitoring for methotrexate-related toxicity is recommended when etoricoxib and methotrexate are administered concomitantly.

Oral contraceptives: etoricoxib 60 mg given concomitantly with an oral contraceptive containing 35 micrograms ethinyl estradiol (EE) and 0.5 to 1 mg norethindrone for 21 days increased the steady state AUC0-24hr of EE by 37%. Etoricoxib 120 mg given with the same oral contraceptive concomitantly or separated by 12 hours, increased the steady state AUC0-24hr of EE by 50 to 60%. This increase in EE concentration should be considered when selecting an oral contraceptive for use with etoricoxib. An increase in EE exposure can increase the incidence of adverse events associated with oral contraceptives (e.g. venous thromboembolic events in women at risk).

Hormone replacement therapy (HRT): administration of etoricoxib 120 mg with hormone replacement therapy consisting of conjugated oestrogens (0.625 mg etoricoxib) for 28 days, increased the mean steady state AUC0-24hr of unconjugated oestrone (41%), (76%) and 17- β-estradiol (22%). The effect of the recommended chronic doses of etoricoxib (30, 60 and 90 mg) has not been studied. The effects of etoricoxib 120 mg on the exposure (AUC0-24hr) to these oestrogenic components of etoricoxib were less than half of those observed when etoricoxib was administered alone and the dose was increased from 0.625 to 1.25 mg. The clinical significance of these increases is unknown and higher doses of etoricoxib were not studied in combination with etoricoxib. These increases in estrogenic concentration should be taken into consideration when selecting post-menopausal for use with etoricoxib because the increase in oestrogen exposure might increase the risk of adverse events associated with HRT.

Prednisone/: in drug-interaction studies, etoricoxib did not have clinically important effects on the pharmacokinetics of /prednisolone.

Digoxin: etoricoxib 120 mg administered once daily for 10 days to healthy volunteers did not alter the steady-state plasma AUC0-24hr or renal elimination of digoxin. There was an increase in digoxin Cmax (approximately 33%). This increase is not generally important for most patients. However, patients at high risk of should be monitored for this when etoricoxib and digoxin are administered concomitantly.

Effect of etoricoxib on drugs metabolised by : etoricoxib is an inhibitor of human activity and has been shown to increase the serum concentrations of ethinyl estradiol. While knowledge about effects of multiple sulfotransferases is presently limited and the clinical consequences for many drugs are still being examined, it may be prudent to exercise care when administering etoricoxib concurrently with other drugs primarily metabolised by human sulfotransferases (e.g. oral and ).

Effect of etoricoxib on drugs metabolised by cytochromes (CYP) isoenzymes: based on in vitro studies, etoricoxib is not expected to inhibit CYPs 1A2, 2C9, 2C19, 2D6, 2E1 or 3A4. In a study in

190 healthy subjects, daily administration of etoricoxib 120 mg did not alter hepatic CYP3A4 activity as assessed by the breath test.

Effects of other drugs on the pharmacokinetics of etoricoxib: the main pathway of etoricoxib metabolism is dependent on CYP enzymes. CYP3A4 appears to contribute to the metabolism of etoricoxib in vivo. In vitro studies indicate that CYP2D6, CYP2C9, CYP1A2 and CYP2C19 can also catalyse the main metabolic pathway, but their quantitative roles have not been studied in vivo.

Ketoconazole: a potent inhibitor of CYP3A4, ketoconazole dosed at 400 mg once a day for 11 days to healthy volunteers did not have any clinically important effect on the single-dose pharmacokinetics of 60 mg etoricoxib (43% increase in area under the curve (AUC)).

Voriconazole and : co-administration of either oral or topical miconazole oral gel (both strong CYP3A4 inhibitors) with etoricoxib caused a slight increase in exposure to etoricoxib, but is not considered clinically meaningful based on published data.

Rifampicin: co-administration of etoricoxib with rifampicin, a potent inducer of CYP enzymes, produced a 65% decrease in etoricoxib plasma concentrations. This interaction may result in recurrence of symptoms when etoricoxib is co-administered with rifampicin. While this information may suggest an increase in dose, doses of etoricoxib greater than those listed for each indication have not been studied in combination with rifampicin and are therefore not recommended.

Antacids: antacids do not affect the pharmacokinetics of etoricoxib to a clinically relevant extent.

Pregnancy: no clinical data on exposed pregnancies are available for etoricoxib. Studies in animals have shown reproductive toxicity. The potential for human risk in pregnancy is unknown. Etoricoxib, as with other medicinal products inhibiting prostaglandin synthesis, may cause uterine inertia and premature closure of the ductus arteriosus during the last trimester. Etoricoxib is contraindicated in pregnancy. If a woman becomes pregnant during treatment, etoricoxib must be discontinued.

Breastfeeding: it is not known whether etoricoxib is excreted in human milk. Etoricoxib is excreted in the milk of lactating rats. Women who use etoricoxib must not breastfeed

Fertility: the use of etoricoxib, as with any drug substance known to inhibit COX-2, is not recommended in women attempting to conceive.

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): in clinical trials, etoricoxib was evaluated for safety in 9295 individuals, including 6757 patients with OA, RA, chronic low back pain or ankylosing spondylitis (approximately 600 patients with OA or RA were treated for one year or longer). In clinical studies, the undesirable effects profile was similar in patients with OA or RA treated with etoricoxib for one year or longer. In a clinical study for acute gouty arthritis, patients were treated with etoricoxib 120 mg once daily for eight days. The adverse experience profile in this study was generally similar to that reported in the combined OA, RA and chronic low back pain studies. In a cardiovascular safety outcomes programme of pooled data from three active comparator controlled trials, 17 412 patients with OA or RA were treated with etoricoxib (60 mg or 90 mg) for a mean duration of approximately 18 months. In clinical studies for acute postoperative dental pain following surgery including 614 patients treated with etoricoxib (90 mg or 120 mg), the adverse experience profile in these studies was generally similar to that reported in the combined OA, RA and chronic low back pain studies. The following undesirable effects were reported at an incidence greater than placebo in clinical trials in patients with OA, RA, chronic low back pain or ankylosing spondylitis treated with etoricoxib 30 mg, 60 mg or 90 mg up to the recommended dose for up to 12 weeks, in MEDAL Programme studies for up to 3.5 years, in short-term acute pain studies for up to 7 days or in post-marketing experience:

System Organ Class Adverse Reactions Frequency Category* alveolar osteitis Common Infections and infestations gastroenteritis, upper respiratory infection, Uncommon urinary tract infection

191 anaemia (primarily associated with Blood and lymphatic system disorders gastrointestinal bleeding), leukopenia, Uncommon thrombocytopenia hypersensitivity‡ ß Uncommon Immune system disorders angioedema/anaphylactic/anaphylactoid Rare reactions including shock‡ oedema/fluid retention Common Metabolism and nutrition disorders appetite increase or decrease, weight gain Uncommon anxiety, depression, mental acuity decreased, Uncommon Psychiatric disorders hallucinations‡ confusion‡, restlessness‡ Rare dizziness, headache Common Nervous system disorders dysgeusia, insomnia, Uncommon paraesthesia/hypaesthesia, somnolence Eye disorders blurred vision, conjunctivitis Uncommon Ear and labyrinth disorders tinnitus, vertigo Uncommon palpitations, arrhythmia‡ Common ‡ Cardiac disorders atrial fibrillation, tachycardia , congestive heart failure, non-specific electrocardiogram changes, Uncommon angina pectoris‡, myocardial infarction§ hypertension Common Vascular disorders flushing, cerebrovascular accident§, transient Uncommon ischaemic attack, hypertensive crisis‡, vasculitis‡ bronchospasm‡ Common Respiratory, thoracic and mediastinal disorders cough, dyspnoea, epistaxis Uncommon abdominal pain Very common Constipation, flatulence, gastritis, heartburn/acid reflux, diarrhoea, dyspepsia/epigastric Common discomfort, nausea, vomiting, oesophagitis, oral Gastrointestinal disorders ulcer abdominal distention, bowel movement pattern change, dry mouth, gastroduodenal ulcer, peptic Uncommon ulcers including gastrointestinal perforation and bleeding, irritable bowel syndrome, pancreatitis‡ alanine aminotransferase increased, aspartate Common aminotransferase increased Hepatobiliary disorders hepatitis‡ Rare hepatic failure‡, jaundice‡ Rare† ecchymosis Common facial oedema, pruritus, rash, erythema‡, Uncommon Skin and subcutaneous tissue disorders urticaria‡ Stevens-Johnson syndrome‡, toxic epidermal Rare† necrolysis‡, fixed drug eruption‡ Musculoskeletal and connective tissue muscular cramp/spasm, musculoskeletal Uncommon disorders pain/stiffness proteinuria, serum creatinine increased, renal Renal and urinary disorders Uncommon failure/renal insufficiency‡ General disorders and administration site asthenia/fatigue, flu-like disease Common conditions chest pain Uncommon blood urea nitrogen increased, creatine phosphokinase increased, hyperkalaemia, uric Uncommon Investigations acid increased blood sodium decreased Rare *Frequency category: defined for each adverse experience by the incidence reported in the clinical trials database: Very Common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1000 to <1/100), Rare (≥1/10 000 to <1/1000), Very Rare (<1/10 000).

‡ This adverse reaction was identified through post-marketing surveillance. Its reported frequency has been estimated based upon the highest frequency observed across clinical trial data pooled by indication and approved dose.

†The frequency category of “Rare” was defined per the SmPC guidance (rev. 2, Sept 2009) on the basis of an estimated upper bound of the 95% confidence interval for 0 events given the number of subjects treated with this medication in the analysis of the Phase III data pooled by dose and indication (n = 15 470).

192

ß Hypersensitivity includes the terms "allergy", "drug allergy", "drug hypersensitivity", "hypersensitivity", "hypersensitivity not otherwise specified", "hypersensitivity reaction" and "nonspecific allergy".

§Based on analyses of long-term placebo and active controlled clinical trials, selective COX-2 inhibitors have been associated with an increased risk of serious thrombotic arterial events, including myocardial infarction and stroke. The absolute risk increase for such events is unlikely to exceed 1% per year based on existing data (uncommon).

The following serious undesirable effects have been reported in association with the use of NSAIDs and cannot be ruled out for etoricoxib: nephrotoxicity, including interstitial nephritis and nephrotic syndrome.

2.2 Indirect risks (incorrect use): in clinical studies, administration of single doses of etoricoxib up to 500 mg and multiple doses up to 150 mg/day for 21 days did not result in significant toxicity. There have been reports of acute overdosage with etoricoxib, although adverse experiences were not reported in the majority of cases. The most frequently observed adverse experiences were consistent with the safety profile for etoricoxib (e.g. gastrointestinal events, cardiorenal events). In the event of overdose, it is reasonable to employ the usual supportive measures, e.g. remove unabsorbed material from the GI tract, employ clinical monitoring and institute supportive therapy, if required. Etoricoxib is not dialysable by haemodialysis; it is not known whether etoricoxib is dialysable by peritoneal dialysis.

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC code) and supply conditions:

Country Classification Additional information Route of Administration/ MS MDD MQP Indications AM POM AT List I BE POM CH List II DE POM FR List I HR List I IE List II IT POM MK POM PL POM PT POM RO List I RS POM UK POM

Melclass database1: POM

No data available from other member states.

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: List I

Criteria: Treatment should be started after individual patient’s benefit/risk evaluation. Short-term use (3 to 8 days) only.

1 Melclass database - Available at: http://www.edqm.eu/melclass/ (NB: this is the CD-P-PH/PHO’s recommendation at the moment of the compilation of the evidence-based review)

193 Serious adverse events possible.

3.2.2 Paediatric use: etoricoxib is contraindicated in children <16 years old.

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

EMC - available at: https://www.medicines.org.uk/

194 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AH06

1.3 Therapeutic indications: -

1.4 Posology and duration of treatment: -

1.5 Pharmaceutical forms: -

1.6 Contraindications: -

1.7 Relevant warnings: -

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): -

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

Lumiracoxib is an NSAID reported to be a selective inhibitor of COX-2. It was withdrawn in many countries after reports of hepatotoxicity. Lumiracoxib has been used in the treatment of osteoarthritis of the knee and hip in an oral dose of 100 mg once daily. Higher doses of up to 400 mg daily have also been used, but may be associated with an increased risk of hepatotoxicity.

The liver safety of lumiracoxib has been monitored continuously since its launch in 2005. In August 2007, the SmPC was updated with contraindications for patients with potential liver problems and advice to doctors that they should frequently monitor patients treated with lumiracoxib for liver reactions. Several spontaneous reports of serious liver problems have been received since then, which have increased the concerns regarding hepatic safety for lumiracoxib. In addition, the EMA’s Committee for Medicinal Products for Human Use (CHMP) considered that the proposed measures to reduce the risk of liver reactions could not ensure adequate patient safety and could not be considered realistic given the approved clinical indication. Consequently, the CHMP recommended the withdrawal of the marketing authorisations (2007).

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, no medicines containing this active substance are authorised in member states).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, no medicines containing this active substance are authorised in member states (withdrawn): Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

195 4.1 References:

Martindale: The Complete Drug Reference – 36th Edition

Press release - European Medicines Agency recommends withdrawal of the marketing authorisations for lumiracoxib-containing medicines (doc. ref. EMEA/CHMP/579301/2007) – available at: https://goo.gl/VTwHCU

196 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AH07

1.3 Therapeutic indications: -

1.4 Posology and duration of treatment: -

1.5 Pharmaceutical forms: -

1.6 Contraindications: -

1.7 Relevant warnings: -

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): -

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, no medicines containing this active substance are authorised in member states).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, no medicines containing this active substance are authorised in member states: Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References: -

197 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AX01

1.3 Therapeutic indications: for use in osteoarthritis and rheumatoid arthritis requiring antiinflammatory and analgesic treatment.

1.4 Posology and duration of treatment: the usual starting dose is 1 g/day taken as a single daily dose at bedtime. For severe or persistent symptoms, or during acute exacerbations, an additional 500 mg - 1 g may be given as a morning dose.

Elderly: the recommended daily dose of 1 g should not be exceeded in this age group and in some cases 500 mg may give satisfactory relief.

The lowest dose possible should be used and patients should be monitored for GI bleeding for 4 weeks following initiation of therapy with nabumetone.

1.5 Pharmaceutical forms: tablets: 500 mg.

1.6 Contraindications: patients who have experienced asthma, urticaria or allergic-type reactions after taking acetylsalicylic acid or other NSAIDs; patients with severe hepatic failure; patients with a history of gastrointestinal bleeding or perforation related to previous NSAIDs therapy; patients with active or history of recurrent, peptic ulcer/haemorrhage; third trimester of pregnancy and in nursing mothers; patients with severe heart failure and patients with current cerebrovascular or other haemorrhage.

1.7 Relevant warnings: not recommended for children as there is no clinical data. Undesirable effects may be minimised by using the minimum effective dose for the shortest duration necessary to control symptoms. The elderly have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation, which may be fatal. GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious GI events. Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy. Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs. The use of nabumetone may impair female fertility and is not recommended in women attempting to conceive. NSAIDs may mask the signs or symptoms of an infection (fever, pain and swelling). Cases of blurred vision or reduced visual activity have been reported with NSAID use, including nabumetone.

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): the most commonly observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or GI bleeding, sometimes fatal, particularly in the elderly, may occur. Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease have been reported following administration. Less frequently, gastritis has been observed.

Other adverse events are:

Blood and lymphatic system disorders: thrombocytopenia, anaemia (incl. aplastic anaemia and haemolytic anaemia).

Immune system disorders: anaphylaxis, anaphylactoid reaction.

Psychiatric disorders: confusion, nervousness, insomnia, hallucinations.

Nervous system disorders: somnolence, dizziness, headache, paraesthesia, aseptic meningitis

198 (especially in patients with existing autoimmune disorders such as systemic lupus erythematosus, mixed connective tissue disease, with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation).

Eye disorders: abnormal vision, eye disorder.

Ear and labyrinth disorders: tinnitus, ear disorder.

Vascular disorders: increases in blood pressure.

Respiratory, thoracic and mediastinal disorders: dyspnoea, respiratory disorder, epistaxis, interstitial pneumonitis.

Hepatobiliary disorders: hepatic failure, jaundice.

Skin and subcutaneous tissue disorders: rash, pruritus, photosensitivity, urticaria, sweating, bullous reactions including toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, angioedema, pseudoporphyria, alopecia.

Musculoskeletal and connective tissue disorders: myopathy.

Renal and urinary disorders: urinary tract disorder, renal failure, nephrotic syndrome.

Reproductive system and breast disorders: menorrhagia.

General disorders and administration site conditions: oedema, asthenia, fatigue.

Investigations: elevated liver function tests.

2.2 Indirect risks (incorrect use): there is no information about overdose. Symptoms may include nausea, vomiting, epigastric pain, GI bleeding, rarely diarrhoea, disorientation, excitation, coma, drowsiness, dizziness and occasionally convulsions. In cases of significant poisoning, acute renal failure and liver damage are possible. There is no specific antidote and the active metabolite 6-MNA is not dialysable. Accidental overdose should be treated with gastric lavage followed by activated charcoal and appropriate supportive therapy.

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions:

Country Classification Additional information Route of Administration/ MS MDD MQP Indications AM Not authorised AT Not authorised BE POM CH Not authorised DE POM FR List I HR Not authorised IE List II Osteoarthritis, rheumatoid IT List II 1000 mg 2000 mg 30 000 mg arthritis MK Not authorised Osteoarthritis, rheumatoid PL POM 500 mg 2 g 30 g arthritis – adults only PT POM 500 mg 2000 mg 60 000 mg RO Not authorised RS Not authorised

199 Melclass database1: List II

No data available from other member states.

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: List II

Criteria: active substance of medicines indicated for conditions for which the patient may continue regular or intermittent treatment without new medical advice, and for which well-known undesirable effects do not call for frequent clinical examination.

Note: nabumetone is classified as POM in most member states.

3.2.2 Paediatric use: not recommended for children as there is no clinical data.

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

Martindale: The Complete Drug Reference – 38th Edition

MHRA (UK) – available at: http://www.mhra.gov.uk

1 Melclass database - Available at: http://www.edqm.eu/melclass/ (NB: this is the CD-P-PH/PHO’s recommendation at the moment of the compilation of the evidence-based review)

200 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AX02

1.3 Therapeutic indications: long-term symptomatic treatment of chronic inflammatory rheumatism, including rheumatoid arthritis, painful and disabling arthritis. Short-term symptomatic treatment of acute outbreaks of arthroses, articular rheumatism such as tendonitis, bursitis. Symptomatic treatment of pain associated with inflammation in otolaryngological and stomatological procedures. Traumatic conditions (e.g. fractures, distortions, soft tissue injuries, joint pain). Gynaecology: pelvic inflammation, primary dysmenorrhoea, insertion and removal of an intrauterine contraceptive device.

1.4 Posology and duration of treatment: capsule: 250 mg three or four times daily; up to 1500 mg daily has been used in severe disorders. Suppositories: 500 mg two times daily.

1.5 Pharmaceutical forms: capsules: 250 mg; suppositories: 500 mg (adults) and 285 mg (children).

1.6 Contraindications: patients who have experienced asthma, urticaria or allergic-type reactions after taking acetylsalicylic acid or other NSAIDs; patients with severe hepatic failure; patients with a history of gastrointestinal bleeding or perforation related to previous NSAID therapy; patients with active or history of recurrent, peptic ulcer/haemorrhage; patients with severe heart failure and patients with current cerebrovascular or other haemorrhage; children under 12 years (capsules).

1.7 Relevant warnings: undesirable effects may be minimised by using the minimum effective dose for the shortest duration necessary to control symptoms. The elderly have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding and perforation, which may be fatal. GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious GI events. Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy. Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens- Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs.

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): the most commonly observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or GI bleeding, sometimes fatal, particularly in the elderly, may occur. Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease have been reported following administration. Less frequently, gastritis has been observed.

Other adverse events are:

Cardiovascular disorders: elevated blood pressure, tachycardia, chest pain, arrhythmia, palpitations, hypotension, congestive heart failure, oedema, hypertension and heart failure have also been reported in combination with NSAID therapy.

Hypersensitivity reactions: photosensitivity.

Respiratory disorders: asthma attacks have been reported in some people who are allergic to aspirin and other NSAIDs.

General disorders: general malaise-type symptoms with hypotension, anaphylactic shock.

Skin and subcutaneous tissue disorders: very rarely bullous reactions (including Stevens-Johnson syndrome and Lyell's syndrome) have been observed. Also reported were: rash, urticaria and aggravation of chronic urticaria, pruritus, purpura.

201 Effect on the central nervous system: dizziness.

Renal disorders: acute renal failure, interstitial nephritis, nephrotic syndromes.

Investigations: abnormal liver tests and thrombocytopenia.

2.2 Indirect risks (incorrect use): overdosage: the symptomatology of acute overdose with niflumic acid is usually benign. Signs of digestive irritation are most commonly observed. Other disorders observed are somnolence (5% of cases) and headache. In a patient who had ingested 7.5 g of niflumic acid, acute, reversible glomerulonephritis occurred. Accidental overdose should be treated with gastric lavage followed by activated charcoal and appropriate supportive therapy.

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions:

Country Classification Additional information Route of Administration/ MS MDD MQP Indications AM Not authorised AT Not authorised BE Not authorised CH Not authorised CZ Not authorised DE Not authorised ES POM FR List II HR Not authorised IE Not authorised IT List II 250 mg 1000 mg 7500 mg LT Not authorised LV Not authorised MK Not authorised NL Not authorised PL Not authorised PT Not authorised RO Not authorised SE Not authorised SI Not authorised RS Not authorised

Melclass database1: List II

No data available from other member states.

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: List II

Criteria: active substance of medicines indicated for conditions for which the patient may continue regular or intermittent treatment without new medical advice, and for which well-known undesirable effects do not call for frequent clinical examination.

3.2.2 Paediatric use: not for children under 12 years (capsules). Not for children under 6 months

1 Melclass database - Available at: http://www.edqm.eu/melclass/ (NB: this is the CD-P-PH/PHO’s recommendation at the moment of the compilation of the evidence-based review)

202 (suppositories).

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

Martindale: The Complete Drug Reference – 38th Edition

ANSM (FR) – available at: http://agence-prd.ansm.sante.fr/php/ecodex/index.php

Italian Medicines Agency (AIFA) – available at: https://farmaci.agenziafarmaco.gov.it/bancadatifarmaci/farmaco?farmaco=022824

Spanish Agency for Medicines and Health Products (AEMPS) – available at: https://www.aemps.gob.es/cima/fichasTecnicas.do?metodo=buscar

National Institute of Pharmacy and Nutrition (HU) – available at: http://www.ogyei.gov.hu/drug_database/

203 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AX04

1.3 Therapeutic indications: azapropazone is an NSAID, structurally related to phenylbutazone, which has uricosuric properties. Because azapropazone appears to be associated with a higher incidence of adverse effects than with some other NSAIDs, its use was restricted to the treatment of rheumatoid arthritis, ankylosing spondylitis and acute gout in patients for whom other NSAIDs have been ineffective.

1.4 Posology and duration of treatment: -

1.5 Pharmaceutical forms: -

1.6 Contraindications: -

1.7 Relevant warnings: -

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): -

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, no medicines containing this active substance are authorised in member states).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, no medicines containing this active substance are authorised in member states: Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References: -

204 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AX05

1.3 Therapeutic indications: relief of symptoms in mild to moderate osteoarthritis of the knee. Glucosamine has been given for its supposed chondroprotective action in musculoskeletal and joint disorders, including osteoarthritis.

1.4 Posology and duration of treatment: 1500 mg/day. Relief of symptoms (especially pain relief) may not be experienced until after several weeks of treatment and in some cases even longer. If no relief of symptoms is experienced after 2-3 months, continued treatment with glucosamine should be re- evaluated.

1.5 Pharmaceutical forms: tablets: 500 mg, 750 mg and 1500 mg; capsules: 750 mg; powder for oral solution: 750 mg and 1500 mg.

1.6 Contraindications: patients who are allergic to shellfish as the active ingredient is obtained from shellfish.

1.7 Relevant warnings: the presence of other joint disease, which would require alternative treatment, should be excluded.

In patients with impaired glucose tolerance, monitoring of the blood glucose levels and, where relevant, insulin requirements is recommended before starting treatment and periodically during treatment.

In patients with a known risk factor for cardiovascular disease, monitoring of the blood levels is recommended since hypercholesterolemia has been observed in a few patients treated with glucosamine.

A report on exacerbated asthma symptoms triggered after initiation of glucosamine therapy has been described (symptoms resolved after withdrawal of glucosamine). Asthmatic patients starting on glucosamine should therefore be aware of potential worsening of asthma symptoms.

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): the most common adverse reactions associated with treatment with glucosamine are nausea, abdominal pain, indigestion, constipation and diarrhoea. In addition, headache, tiredness, rash, itching and flushing have been reported. The reported adverse reactions are usually mild and transitory.

2.2 Indirect risks (incorrect use): overdosage: signs and symptoms of accidental or intentional overdose with glucosamine might include headache, dizziness, disorientation, arthralgia, nausea, vomiting, diarrhoea or constipation. In case of overdose, treatment with glucosamine should be discontinued and standard supportive measures should be adopted as required.

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions:

Country Classification Additional information Route of Administration/ MS MDD MQP Indications AM POM Symptoms of osteoarthritis 1500 mg 1500 mg 45 g AT List II Symptom relief of mild to 1500 mg 1500 mg n.a.

205 moderate arthroses of knee joint Relief of symptoms in mild BE OTC to moderate osteoarthritis of 1178 mg 1178 mg the knee CH Not authorised DE OTC Oral use FR OTC Oral use 1500 mg 1500 mg 45 g Symptomatic therapy of mild to moderate HR OTC degenerative knee joint disease OTC (some prescription, Relief of symptoms in mild IE renewable products to moderate osteoarthritis of 1500 mg 1500 mg authorised) the knee IT List II Arthroses 1500 mg 1500 mg 30 g MK OTC Exemptions: oral use; Exemptions: Exemptions: Exemptions: PL POM + Exemption treatment of mild knee 750 mg 1500 mg 45 g arthritis PT POM 1500 mg 1500 mg 90 g Relief of symptoms in mild RO List I to moderate osteoarthritis of 625 mg 1250 mg 112.5 g the knee Symptomatic treatment of RS OTC 1500 mg 1500 mg 30 g osteoarthritis

Melclass database1: List II + Exemption (exemptions: oral use; MS: 1500 mg; MDD: 1500 mg)

No data available from other member states.

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: List II + Exemption

Exemptions: Route of Administration: oral use MS: 1500 mg MDD: 1500 mg

Criteria: active substance of medicines indicated for conditions for which the patient may continue regular or intermittent treatment without new medical advice, and for which well-known undesirable effects do not call for frequent clinical examination.

3.2.2 Paediatric use: not for children under 18 years.

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

Martindale: The Complete Drug Reference – 38th Edition

MHRA (UK) – available at: http://www.mhra.gov.uk

ALIMS (RS) – available at: http://www.alims.gov.rs/eng/medicinal-products/search-for-human- medicines/

1 Melclass database - Available at: http://www.edqm.eu/melclass/ (NB: this is the CD-P-PH/PHO’s recommendation at the moment of the compilation of the evidence-based review)

206 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AX07

1.3 Therapeutic indications: -

1.4 Posology and duration of treatment: -

1.5 Pharmaceutical forms: -

1.6 Contraindications: -

1.7 Relevant warnings: -

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): -

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, no medicines containing this active substance are authorised in member states).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, no medicines containing this active substance are authorised in member states: Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References: -

207 1. THERAPEUTIC PROFILE

1.1 Active ingredient: Glucosaminoglycan Polysulfate

1.2 ATC code: M01AX12

1.3 Therapeutic indications: -

1.4 Posology and duration of treatment: -

1.5 Pharmaceutical forms: -

1.6 Contraindications: -

1.7 Relevant warnings: -

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): -

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, no medicines containing this active substance are authorised in member states).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, no medicines containing this active substance are authorised in member states: Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References: -

208 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AX13

1.3 Therapeutic indications: proquazone is an NSAID that has been used orally and rectally in musculoskeletal and joint disorders.

1.4 Posology and duration of treatment: -

1.5 Pharmaceutical forms: -

1.6 Contraindications: -

1.7 Relevant warnings: -

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): -

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, no medicines containing this active substance are authorised in member states).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, no medicines containing this active substance are authorised in member states: Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References: -

209 1. THERAPEUTIC PROFILE

1.1 Active ingredient: Orgotein

1.2 ATC code: M01AX14

1.3 Therapeutic indications: -

1.4 Posology and duration of treatment: -

1.5 Pharmaceutical forms: -

1.6 Contraindications: -

1.7 Relevant warnings: -

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): -

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, no medicines containing this active substance are authorised in member states).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, no medicines containing this active substance are authorised in member states: Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References: -

210 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AX17

1.3 Therapeutic indications: treatment of acute pain and primary dysmenorrhoea. Nimesulide should only be prescribed as second-line treatment. The decision to prescribe nimesulide should be based on assessment of the individual patient’s overall risks.

The EMA’s CHMP concluded that the benefits of nimesulide used systemically continue to outweigh its risks, but that its use should be restricted to the treatment of acute pain and primary dysmenorrhoea. It issued a recommendation that it should no longer be used for the treatment of painful osteoarthritis.

1.4 Posology and duration of treatment: adults and children over 12 years: 100 mg, two times daily. Maximal duration of treatment: 15 days. It has also been given rectally in a dose of 200 mg twice daily.

1.5 Pharmaceutical forms: tablets and granules for oral suspension: 100 mg and 400 mg; orodispersible tablets: 100 mg; suppositories: 100 mg and 200 mg.

1.6 Contraindications: history of hypersensitivity reactions (e.g. bronchospasm, rhinitis, urticaria) in response to acetylsalicylic acid or other NSAIDs; history of hepatotoxic reactions to nimesulide; concomitant exposure to other potentially hepatotoxic substances; alcoholism, drug addiction; active gastric or duodenal ulcer, a history of recurrent ulceration or gastrointestinal bleeding, cerebrovascular bleeding or other active bleeding or bleeding disorders; severe coagulation disorders; severe heart failure; severe renal impairment; hepatic impairment; patients with fever and/or flu-like symptoms; children under 12 years; third trimester of pregnancy and breastfeeding.

1.7 Relevant warnings: the risk of undesirable effects may be reduced by using nimesulide for the shortest possible duration. Treatment should be discontinued if no benefit is seen. Rarely nimesulide has been reported to be associated with serious hepatic reactions, including very rare fatal cases. Patients who experience symptoms compatible with hepatic injury during treatment with nimesulide (e.g. anorexia, nausea, vomiting, abdominal pain, fatigue, dark urine) or patients who develop abnormal liver function tests should have treatment discontinued. These patients should not be rechallenged with nimesulide. Liver damage, in most cases reversible, has been reported following short exposure to the drug. Gastrointestinal bleeding or ulceration/perforation can occur at any time during treatment with or without warning symptoms or a previous history of gastrointestinal events. If gastrointestinal bleeding or ulceration occurs, nimesulide should be discontinued. Nimesulide should be used with caution in patients with gastrointestinal disorders, including history of peptic ulceration, history of gastrointestinal haemorrhage, ulcerative colitis or Crohn’s disease. In patients with renal or cardiac impairment, caution is required since the use of nimesulide may result in deterioration of renal function. In the event of deterioration, treatment should be discontinued. As nimesulide can interfere with platelet function, it should be used with caution in patients with bleeding diathesis. The use of nimesulide may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of nimesulide should be considered.

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): most common adverse reactions are gastrointestinal disorders (diarrhoea, nausea, vomiting, constipation, flatulence, gastritis).

The following adverse effects are also reported:

Blood disorders: Rare: anaemia, eosinophilia. Very rare: thrombocytopenia, pancytopenia, purpura.

Immune system disorders: Rare: hypersensitivity. Very rare: anaphylaxis.

Metabolism and nutrition disorders: Rare: hyperkalaemia.

211 Psychiatric disorders: Rare: anxiety, nervousness, nightmare.

Nervous system disorders: Uncommon: dizziness. Very rare: headache, somnolence, encephalopathy (Reye’s syndrome).

Eye disorders: Rare: vision blurred. Very rare: visual disturbance.

Ear and labyrinth disorders: Very rare: vertigo.

Cardiac disorders: Rare: tachycardia.

Vascular disorders: Uncommon: hypertension. Rare: haemorrhage, blood pressure fluctuation, hot flushes.

Respiratory disorders: Uncommon: dyspnoea. Very rare: asthma, bronchospasm.

Hepatobiliary disorders: Very rare: hepatitis, fulminant hepatitis (including fatal cases), jaundice, cholestasis.

Skin and subcutaneous tissue disorders: Uncommon: pruritus, rash, sweating increased. Rare: erythema, dermatitis. Very rare: urticaria, angioneurotic oedema, face oedema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Renal and urinary disorders: Rare: dysuria, haematuria, urinary retention. Very rare: renal failure, oliguria, interstitial nephritis.

General disorders: Uncommon: oedema. Rare: malaise, asthenia. Very rare: hypothermia.

Investigations: Common: hepatic enzymes increased.

2.2 Indirect risks (incorrect use): overdosage: symptoms following acute NSAID overdoses are usually limited to lethargy, drowsiness, nausea, vomiting and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs and may occur following an overdose.

Management: patients should be managed by symptomatic and supportive care following an NSAID overdose. There are no specific antidotes. No information is available regarding the removal of nimesulide by haemodialysis, but based on its high degree of plasma protein binding (up to 97.5%) dialysis is unlikely to be useful in overdose. Emesis and/or activated charcoal (60 to 100 g in adults) and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose. Forced diuresis, alkalinisation of urine, haemodialysis or haemoperfusion may not be useful due to high protein binding. Renal and hepatic function should be monitored.

2.3 Recent cases at European level: CHMP referral – available at: https://goo.gl/t2Wn3

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions:

Country Classification Additional information Route of Administration/ MS MDD MQP Indications Treatment of acute pain, symptomatic AM POM 100 mg 200 mg 3000 mg treatment of painful osteoarthritis,

212 primary dysmenorrhoea AT Not authorised BE Not authorised CH List II DE Not authorised FR List I HR Not authorised IE Not authorised IT List I Moderate pain 100 mg 200 mg 3000 mg Treatment of acute pain, MK POM 100 mg 2000 mg primary dysmenorrhoea PL POM 100 mg 200 mg PT POM 100 mg 200 mg 3000 mg Acute pain and RO List I 100 mg 200 mg 3000 mg dysmenorrhoea RS POM 100 mg

Melclass database1: List I(1)

No data available from other member states.

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: List I

Criteria: Short-term treatment (maximal duration of treatment is 15 days) Individual risk-benefit assessment needed Serious adverse effects possible

3.2.2 Paediatric use: not for children under 12 years.

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

Martindale: The Complete Drug Reference – 38th Edition

MHRA (UK) – available at: http://www.mhra.gov.uk

ALIMS (RS) – available at: http://www.alims.gov.rs/eng/medicinal-products/search-for-human- medicines/

CHMP referral – available at: https://goo.gl/t2Wn3

1 Melclass database - Available at: http://www.edqm.eu/melclass/ (NB: this is the CD-P-PH/PHO’s recommendation at the moment of the compilation of the evidence-based review)

213 1. THERAPEUTIC PROFILE

1.1 Active ingredient: Feprazone

1.2 ATC code: M01AX18

1.3 Therapeutic indications: feprazone, a phenylbutazone derivative, is an NSAID. It has been given orally in the treatment of mild to moderate pain, fever and inflammation associated with musculoskeletal and joint disorders.

1.4 Posology and duration of treatment: -

1.5 Pharmaceutical forms: -

1.6 Contraindications: -

1.7 Relevant warnings: -

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): -

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, no medicines containing this active substance are authorised in member states).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, no medicines containing this active substance are authorised in member states: Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References: -

214 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AX21

1.3 Therapeutic indications: treatment of symptoms in patients with osteoarthritis of the hip or knee, with delayed effect. Treatment with diacerein is not recommended in patients with rapidly progressive hip osteoarthritis, as they may have a weaker response to diacerein.

1.4 Posology and duration of treatment: as some patients may experience loose stools or diarrhoea, the recommended starting dose is 50 mg once daily with the evening meal for the first 2 to 4 weeks of treatment, after which the recommended daily dose is 50 mg twice daily. The treatment should be taken with food, one dose with breakfast and the other with evening meal.

1.5 Pharmaceutical forms: capsules: 50 mg.

1.6 Contraindications: inflammatory bowel disease (ulcerative colitis, Crohn's disease); intestinal obstruction or pseudoobstruction; abdominal pain of unclear origin; current and/or history of liver disease.

1.7 Relevant warnings: intake of diacerein frequently to diarrhoea that can consequently lead to dehydration and hypokalaemia. Patients should be advised to stop diacerein treatment in cases of diarrhoea and contact their physician to discuss treatment alternatives. Caution should be exercised in patients receiving diuretics because dehydration and hypokalaemia may occur. Particular caution should also be exercised in cases of hypokalaemia in patients treated with cardiac glycosides (, digoxin). Elevated serum hepatic enzyme levels and symptomatic acute hepatic injury have been reported with diacerein in the post-marketing phase. Before treatment with diacerein is initiated, the patient should be questioned about possible comorbid conditions and past or concurrent liver disease and screened for major causes of active hepatic disease. A diagnosis of liver disease is a contraindication to diacerein use. Signs of hepatic injury should be monitored and caution should be exercised when diacerein is used concomitantly with other medicinal products associated with hepatic injury. Patients should be advised to limit their alcohol intake while taking diacerein. Treatment with diacerein should be stopped if elevation of hepatic enzymes or suspected signs or symptoms of liver damage are detected. Patients should be advised about the signs and symptoms of hepatotoxicity and must be advised to immediately contact their physician in cases of the appearance of symptoms suggestive of liver damage.

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): GI: diarrhoea, abdominal pain (very common), frequent bowel movements, flatulence (common). As a rule, these effects abate with continuing treatment. In some cases, diarrhoea was severe with complications such as dehydration and disorders of fluid and electrolyte balance.

Hepatobiliary disorders: cases of elevated hepatic enzymes in serum (uncommon). Cases of acute liver injury, including elevated serum hepatic enzymes and cases of hepatitis have been reported in the post- marketing phase with diacerein. Most of these occurred during the first months of treatment. Patients should be monitored for signs and symptoms of hepatic injury.

Skin and subcutaneous tissue disorders: pruritus, rash, eczema (common).

2.2 Indirect risks (incorrect use): accidental or intentional use of high doses of diacerein may cause diarrhoea. There is no specific antidote. The treatment is symptomatic and focuses primarily on restoration of electrolyte and fluid balance. No case of overdose has been reported.

2.3 Recent cases at European level: -

215 3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions:

Country Classification Additional information Route of Administration/ MS MDD MQP Indications AM Not authorised Symptomatic treatment of AT List II arthroses of hips or knees BE Not authorised CH Not authorised CZ POM FI Not authorised ES POM FR List I HR Not authorised IE Not authorised LT Not authorised LV Not authorised MK Not authorised NL Not authorised PL Not authorised PT POM RO Not authorised SE Not authorised SI Not authorised RS Not authorised

Melclass database1: List I

No data available from other member states.

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: List I

Criteria: the above recommendation is based on the review of the benefits and risks of diacerein conducted by the EMA’s Pharmacovigilance and Risk Assessment Committee (PRAC) following concerns raised by the French National Agency for the Safety of Medicine and Health Products (ANSM) about diacerein’s gastrointestinal and liver effects. Based on available data, the use of diacerein is to be limited to treating symptoms of osteoarthritis affecting the hip or knee. Treatment should only be started by physicians experienced in treating osteoarthritis.

3.2.2 Paediatric use: not for children under 18 years.

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

EMA - Diacerein-containing medicines for oral administration - available at: https://goo.gl/m94u8n

ANSM (FR) – available at: http://agence-prd.ansm.sante.fr/php/ecodex/index.php

1 Melclass database - Available at: http://www.edqm.eu/melclass/ (NB: this is the CD-P-PH/PHO’s recommendation at the moment of the compilation of the evidence-based review)

216 Martindale: The Complete Drug Reference – 38th Edition

217 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AX22

1.3 Therapeutic indications: morniflumate, the morpholinoethyl of niflumic acid, is an NSAID. It has been used in inflammatory conditions. Long-term symptomatic treatment of chronic inflammatory rheumatism, including rheumatoid arthritis, painful and disabling arthritis. Short-term symptomatic treatment of acute outbreaks of arthroses, articular rheumatism such as tendonitis and bursitis. Symptomatic treatment of pain associated with inflammation in otolaryngological and stomatological procedures.

1.4 Posology and duration of treatment: 700 mg given twice daily orally or rectally as suppositories.

1.5 Pharmaceutical forms: suppositories: 400 mg and 700 mg; tablets: 350 mg and 700 mg; granules for oral suspension: 350 mg.

1.6 Contraindications: patients who have experienced asthma, urticaria or allergic-type reactions after taking acetylsalicylic acid or other NSAIDs; patients with severe hepatic failure; patients with a history of gastrointestinal bleeding or perforation related to previous NSAID therapy; patients with active or history of recurrent, peptic ulcer/haemorrhage; patients with severe heart failure and patients with current cerebrovascular or other haemorrhage; children under 12 years (capsules).

1.7 Relevant warnings: GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious GI events. Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy. Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs.

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): the most commonly observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or GI bleeding, sometimes fatal, particularly in the elderly, may occur. Nausea, vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melaena, haematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn's disease have been reported following administration. Less frequently, gastritis has been observed.

Other adverse events include:

Cardiovascular disorders: elevated blood pressure, tachycardia, chest pain, arrhythmia, palpitations, hypotension, congestive heart failure, oedema, hypertension and heart failure have also been reported in combination with NSAID therapy.

Hypersensitivity reactions: photosensitivity.

Respiratory disorders: asthma attacks have been reported in some people who are allergic to aspirin and other NSAIDs.

General disorders: general malaise-type symptoms with hypotension, anaphylactic shock.

Skin and subcutaneous tissue disorders: very rarely bullous reactions (including Stevens-Johnson syndrome and Lyell's syndrome) have been observed. Also reported were: rash, urticaria and aggravation of chronic urticaria, pruritus, purpura.

Effect on the central nervous system: dizziness.

218 Renal disorders: acute renal failure, interstitial nephritis, nephrotic syndromes.

Investigations: abnormal liver tests and thrombocytopenia.

2.2 Indirect risks (incorrect use): overdosage: the symptomatology of acute overdose with niflumic acid is usually benign. Signs of digestive irritation are most commonly observed. Other disorders observed are somnolence (5% of cases) and headache. In a patient who had ingested 7.5 g of niflumic acid, acute, reversible glomerulonephritis occurred. Accidental overdose should be treated with gastric lavage followed by activated charcoal and appropriate supportive therapy.

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions:

Country Classification Additional information Route of Administration/ MS MDD MQP Indications AM Not authorised AT Not authorised BE Not authorised CH Not authorised CZ Not authorised DE Not authorised FI Not authorised ES Not authorised FR List II HR Not authorised IE Not authorised IT List II LT Not authorised LV Not authorised NL Not authorised PL Not authorised PT Not authorised RO Not authorised SE Not authorised SI Not authorised RS Not authorised

Melclass database1: -

No data available from other member states.

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: Not to classify

Criteria: medicines containing morniflumate as the active substance have not been authorised in at least three member states.

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

1 Melclass database - Available at: http://www.edqm.eu/melclass/ (NB: this is the CD-P-PH/PHO’s recommendation at the moment of the compilation of the evidence-based review)

219 4. REFERENCES/COMMENTS

4.1 References:

ANSM (FR) – available at: http://agence-prd.ansm.sante.fr/php/ecodex/index.php

Martindale: The Complete Drug Reference – 38th Edition

220 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AX23

1.3 Therapeutic indications: tenidap is an NSAID that also acts as a modulator. It has been studied in the treatment of rheumatoid arthritis and osteoarthritis but development for these indications was abandoned because of concern over its potential effect on bone .

1.4 Posology and duration of treatment: -

1.5 Pharmaceutical forms: -

1.6 Contraindications: -

1.7 Relevant warnings: -

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): -

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, no medicines containing this active substance are authorised in member states).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, no medicines containing this active substance are authorised in member states: Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References: -

221 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01AX24

1.3 Therapeutic indications: symptomatic treatment of osteoarthritis of knee and hip.

1.4 Posology and duration of treatment: 200 mg three times daily. In severe cases 400 mg three times daily. Continuous use for longer than three weeks is not recommended.

1.5 Pharmaceutical forms: tablets: 200 mg.

1.6 Contraindications: severe heart disorders; severe renal impairment; children under 18 years.

1.7 Relevant warnings: -

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): Common: nausea, gastric pain, diarrhoea. Uncommon: red and itchy skin, exanthema. Very rare: , arthralgia, vasculitis, urticaria, angioedema, allergic eosinophilia.

2.2 Indirect risks (incorrect use): overdosage: oxaceprol has a very low toxicity. Intoxication has not reported so far. There is no specific antidote.

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions:

Country Classification Additional information Route of Administration/ MS MDD MQP Indications AM Not authorised AT Not authorised BE Not authorised CH Not authorised CZ Not authorised DE Not authorised FI Not authorised ES Not authorised FR Not authorised Symptomatic therapy of HR List I degenerative knee joint 200 mg 1200 mg 20 g disease IE Not authorised IT Not authorised LT Not authorised LV Not authorised PL Not authorised PT Not authorised Adjuvant in RO List II 200 mg 600 mg 20 000 mg osteoarthritis SE Not authorised SI Not authorised RS POM 200 mg

222 Melclass database1: List II

No data available from other member states.

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: List I

Criteria: short-term treatment (up to 3 weeks).

3.2.2 Paediatric use: not for children under 18 years.

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

ALIMS (RS) – available at: http://www.alims.gov.rs/eng/medicinal-products/search-for-human- medicines/

Martindale: The Complete Drug Reference – 38th Edition

1 Melclass database - Available at: http://www.edqm.eu/melclass/ (NB: this is the CD-P-PH/PHO’s recommendation at the moment of the compilation of the evidence-based review)

223 1. THERAPEUTIC PROFILE

1.1 Active ingredient: Sulfate

1.2 ATC code: M01AX25

1.3 Therapeutic indications: symptomatic treatment of osteoarthritis.

1.4 Posology and duration of treatment: 800 mg/day as a single dose for at least 3 months. For symptoms of severe inflammation, the recommend starting dose is 1200 mg/day as a single or divided dose for 4-6 weeks, followed by 800 mg for up to 3 months. Therapy comprises repeatable courses of treatment; each course comprises at least 3 months intake, followed by a 2 month treatment-free interval.

1.5 Pharmaceutical forms: capsules: 250 mg, 400 mg and 500 mg; tablets: 800 mg; granules for oral solution: 800 mg.

1.6 Contraindications: -

1.7 Relevant warnings: heart and/or kidney failure: on very rare occasions such patients have experienced cases of oedema and/or water retention. This can be attributed to the osmotic effect of .

Liver failure: there is no experience available on the use of chondroitin sulfate by patients suffering from liver failure. Therefore, it is not recommended for use in this group.

No effect at platelet level has been observed within the recommended dose rates.

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): GI disorders: Rare: epigastralgia, nausea, diarrhoea.

Skin and subcutaneous tissue disorders: Rare: erythema, rash, rash maculopapular. Very rare: urticaria, eczema, pruritus, allergic reaction.

General disorders and administration site conditions: Very rare: oedema.

2.2 Indirect risks (incorrect use): overdosage: during post-marketing surveillance, one case of intentional overdose to commit was observed. After a dose of 64 g, the patient did not experience any adverse reactions and laboratory data showed electrolyte values in the normal range.

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions:

Country Classification Additional information Route of Administration/ MS MDD MQP Indications AM POM Osteoarthritis 500 mg 1000 mg 30 000 mg supportive treatment AT List II 800 mg 800 mg n.a. of arthroses BE Not authorised CH List II Exemptions: CZ POM + Exemption Exemptions: oral use 400 mg DE Not authorised FI POM

224 ES Not authorised FR OTC HR Not authorised IE List II IT POM Knee arthrosis 400mg 2400mg 8000mg LT Not authorised LV Not authorised MK Not authorised PL POM PT POM 500 mg 1500 mg 30 000 mg Treatment of RO List II 500 mg 1000 mg 30 000 mg osteoarthritis SE Not authorised SI Not authorised RS Not authorised

Melclass database1: List II

No data available from other member states.

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: List II

Criteria: long-term treatment. This active substance is contained in medicines indicated for conditions for which the patient may continue regular or intermittent treatment without new medical advice and for which well-known undesirable effects do not call for frequent clinical examination.

Note: in most member states chondroitin sulfate is classified as POM (List II).

3.2.2 Paediatric use: not recommended for children under 18 years.

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

Health Products Regulatory Authority (HPRA) (IE) – available at: https://goo.gl/xBv7m6

Martindale: The Complete Drug Reference – 38th Edition

1 Melclass database - Available at: http://www.edqm.eu/melclass/ (NB: this is the CD-P-PH/PHO’s recommendation at the moment of the compilation of the evidence-based review)

225 1. THERAPEUTIC PROFILE

1.1 Active ingredient: Avocado and Soyabean Oil, Unsaponifiables

1.2 ATC code: M01AX26

1.3 Therapeutic indications: rheumatology: symptomatic slow-acting treatment of osteoarthritis of the hip and knee. Dentistry: adjuvant therapy of periodontitis.

1.4 Posology and duration of treatment: avocado oil 100 mg + soyabean oil 200 mg, once daily. Duration of treatment: rheumatology: between 3 and 6 months, at least 3 months; dentistry: between 5 weeks and 3 months, at least 5 weeks.

1.5 Pharmaceutical forms: capsules 50 mg, 100 mg and 200 mg.

1.6 Contraindications: -

1.7 Relevant warnings: not for children under 18 years.

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): Common: lipid regurgitation. Rare: hypersensitivity reactions. Very rare: hepatobiliary disorders, increased level of transaminases, alkaline phosphatases, bilirubin and gamma GT. Unknown frequency: diarrhoea and epigastralgia

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions:

Country Classification Additional information Route of Administration/ MS MDD MQP Indications AM Not authorised AT Not authorised BE Not authorised CH Not authorised CZ POM DE Not authorised FI Not authorised ES Not authorised FR OTC HR Not authorised IE Not authorised IT Not authorised LT Not authorised LV Not authorised MK Not authorised NL Not authorised 100 mg 100 mg Mild osteoarthritis; 3 avocado oil + avocado oil + PL OTC - 6 months; adults 200 mg soya 200 mg soya only bean oil bean oil PT Not authorised RO Not authorised SE Not authorised SI Not authorised RS OTC Rheumatology: 100 mg 100 mg 1500 mg

226 symptomatic slow- avocado oil + avocado oil + avocado oil + acting treatment of 200 mg soya 200 mg soya 3000 mg soya osteoarthritis of the bean oil bean oil bean oil hip and knee. Dentistry: adjuvant therapy of periodontitis.

Not for children under 18

Melclass database1: -

No data available from other member states.

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: OTC

Criteria: Low general toxicity; low risk of serious and non-serious adverse reactions. Interactions with other medicines are not reported. Low risk of incorrect use.

3.2.2 Paediatric use: not for children under 18 years.

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

ALIMS (RS) – available at: http://www.alims.gov.rs/eng/medicinal-products/search-for-human- medicines/

Martindale: The Complete Drug Reference – 38th Edition

ANSM (FR) – available at: http://agence-prd.ansm.sante.fr/php/ecodex/index.php

1 Melclass database - Available at: http://www.edqm.eu/melclass/ (NB: this is the CD-P-PH/PHO’s recommendation at the moment of the compilation of the evidence-based review)

227 1. THERAPEUTIC PROFILE

1.1 Active ingredient: Feprazone, Combinations

1.2 ATC code: M01AX68

1.3 Therapeutic indications: combination of feprazone, paracetamol and was used in treatment of cough and cold symptoms. Combination of bromhexine hydrochloride and feprazone was used in treatment of respiratory-tract disorders. These preparations are no longer authorised/marketed.

1.4 Posology and duration of treatment: -

1.5 Pharmaceutical forms: -

1.6 Contraindications: -

1.7 Relevant warnings: -

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): -

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, no medicines containing this active substance are authorised in member states).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, no medicines containing this active substance are authorised in member states: Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References: -

228 1. THERAPEUTIC PROFILE

1.1 Active ingredient: Phenylbutazone and Corticosteroids

1.2 ATC code: M01BA01

1.3 Therapeutic indications: available combination product (Hungary): phenylbutazone (100 mg) + prednisolone (20 mg). Main therapeutic indications: ankylosing spondylitis, seronegative spondyloarthritis, acute gout attack, inflammatory arthrosis (when other less-toxic NSAIDs are ineffective), rheumatoid arthritis (acute phase).

1.4 Posology and duration of treatment: adults: individual dose adjustment should be established. When determining dosage, the total content of phenylbutazone should be taken into account. Average adult dose: 1 tablet 3-4 times a day for up to 14 days. Exceptionally, a dose of 600 mg phenylbutazone per day (6 tablets) may be given on the first 2 days.

Children: the safety of this medicinal product has not been studied in children; therefore, it should not be administered to children.

Elderly (>65 years): side effects of phenylbutazone are more common in elderly patients; therefore, this medication should be given with caution to patients >65 years of age.

1.5 Pharmaceutical forms: tablets: phenylbutazone (100 mg) + prednisolone (20 mg).

1.6 Contraindications: patients with known hypersensitivity to the active substances or to any of the other ingredients contained in this medicinal product; during ; patients suffering from diabetes mellitus; patients with known sensitivity to derivatives; patients suffering from blood cell disorders (e.g. leukopenia, thrombocytopenia, anaemia); patients suffering from kidney and liver disorders; patients suffering from gastric and duodenal ulcers, gastrointestinal inflammation, severe or persistent dyspepsia; patients suffering from heart rhythm disorders, vitium cordis, congestive heart disease, hypertension; patients suffering from thyroid dysfunction; pregnancy; children.

1.7 Relevant warnings: treatment should last up to 14 days. It may be necessary to readjust the dose of oral antidiabetics and anticoagulants during treatment with phenylbutazone/prednisolone. When administered with diuretics, electrolyte levels (in particular, potassium levels) should be closely monitored. Once treatment is completed, blood count, platelet count, urine and liver function should be monitored. Phenylbutazone/prednisolone should be avoided during lactation. Patients with rare hereditary problems of intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): the following side effects have been observed: reduced resistance to infections, hypertension, glycosuria, hypokalaemia, adrenal cortical atrophy, osteoporosis, disorders of the haematopoietic system (agranulocytosis, aplastic anaemia, thrombocytopenia, leukopenia), peptic ulceration, gastrointestinal bleeding, abdominal dysfunction, gastritis, epigastric pain, fluid and salt retention, allergic reactions.

2.2 Indirect risks (incorrect use): overdose: these are the most common symptoms in the case of overdose: nausea, vomiting, abdominal pain. Rarely, the following effects may be observed: severe intoxication, kidney/liver/pulmonary and cardiac dysfunction, metabolic acidosis, cardiogenic shock, coma, convulsions. Hyperglycaemia, hypocalcaemia, cyanosis, paraesthesia, rash, sweating and dyspnoea may also occur.

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

229 3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: based on available data, Hungary is the only member state where a combination product with this INN/ATC code is authorised (classification status: POM).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

SmPC for Rheosolon – available at: https://www.ogyei.gov.hu/main_page/ (Hungarian only)

4.2 Comments:

The information reported in this review is based on the details included in the above SmPC.

Based on the data available in Melclass, Hungary seems to be the only member state where a combination product with this INN/ATC code is authorised/marketed (i.e. Rheosolon tablets containing 100 mg phenylbutazone and 20 mg prednisolone per tablet).

230 1. THERAPEUTIC PROFILE

1.1 Active ingredient: and Corticosteroids

1.2 ATC code: M01BA02

1.3 Therapeutic indications: -

1.4 Posology and duration of treatment: -

1.5 Pharmaceutical forms: -

1.6 Contraindications: -

1.7 Relevant warnings: -

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): -

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, no medicines containing dipyrocetyl in combination with corticosteroids are authorised in member states).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, no medicines containing dipyrocetyl in combination with corticosteroids are authorised in member states: Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References: -

231 1. THERAPEUTIC PROFILE

1.1 Active ingredient: Acetylsalicylic Acid and Corticosteroids

1.2 ATC code: M01BA03

1.3 Therapeutic indications: -

1.4 Posology and duration of treatment: -

1.5 Pharmaceutical forms: -

1.6 Contraindications: -

1.7 Relevant warnings: -

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): -

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, no medicines containing acetylsalicylic acid in combination with corticosteroids are authorised in member states).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, no medicines acetylsalicylic acid in combination with corticosteroids are authorised in member states: Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References: -

232 1. THERAPEUTIC PROFILE

1.1 Active ingredient: Other Antiinflammatory/Antirheumatic Agents in Combination with Other Drugs

1.2 ATC code: M01BX

1.3 Therapeutic indications: available combination product classified under this ATC code (Germany and Sweden): diclofenac (75 mg) + misoprostol (0.2 mg). This combination is covered under the evidence-based review Diclofenac, Combinations on pages 69-72.

Based on the available data, no combination products classified under this ATC code are authorised in member states.

1.4 Posology and duration of treatment: -

1.5 Pharmaceutical forms: -

1.6 Contraindications: -

1.7 Relevant warnings: -

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): -

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions:

Country Classification Additional information Route of Administration MS MDD MQP / Indications AM Not authorised AT Not authorised BE Not authorised CH Not authorised CZ Not authorised DE POM FI Not authorised ES Not authorised FR Not authorised HR Not authorised IE Not authorised IT Not authorised LT Not authorised LV Not authorised MK Not authorised NL Not authorised PL Not authorised PT Not authorised RO Not authorised SE POM SI Not authorised RS Not authorised UK Not authorised

233 Melclass database1: -

No data available from other member states.

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References: -

4.2 Comments:

It is not clear which combination products are classified under this ATC code.

1 Melclass database - Available at: http://www.edqm.eu/melclass/ (NB: this is the CD-P-PH/PHO’s recommendation at the moment of the compilation of the evidence-based review)

234 1. THERAPEUTIC PROFILE

1.1 Active ingredient: Oxycinchopen

1.2 ATC code: M01CA03

1.3 Therapeutic indications: -

1.4 Posology and duration of treatment: -

1.5 Pharmaceutical forms: -

1.6 Contraindications: -

1.7 Relevant warnings: -

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): -

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, no medicines containing this active substance are authorised in member states).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, no medicines containing this active substance are authorised in member states: Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References: -

235 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01CB01

1.3 Therapeutic indications: management of active progressive rheumatoid arthritis and progressive juvenile chronic arthritis, especially if polyarticular or seropositive. It may also be beneficial in psoriatic arthritis. Generally used as disease-modifying antirheumatic drug in patients whose symptoms are unresponsive to or inadequately controlled by NSAIDs alone.

1.4 Posology and duration of treatment: an initial test dose of 10 mg should be given in the first week followed by weekly doses of 50 mg until signs of remission occur. At this point 50 mg doses should be given at two week intervals until full remission occurs. With full remission the interval between injections should be increased progressively to three, four and then, after 18 months to 2 years, to six weeks. If after reaching a total dose of 1 g (excluding the test dose) no major improvement has occurred and the patient has not shown any signs of gold toxicity, six 100 mg injections may be administered at weekly intervals. If no sign of remission occurs after this time other forms of treatment are to be considered.

Elderly: there are no specific dosage recommendations. Elderly patients should be monitored with extra caution.

Children: progressive juvenile chronic arthritis: weekly doses of 1 mg/kg should be given but not exceeding a maximum weekly dose of 50 mg. Depending on urgency, this dose may be preceded by a smaller test dose such as 1/10 or 1/5 of the full dose for 2-3 weeks. Continue weekly doses until signs of remission appear then increase the intervals between injections to two weeks. With full remission increase the interval to three then four weeks. In the absence of signs of remission after twenty weeks consider raising the dose slightly or changing to another therapy.

Treatment should be continued for six months. A response can be expected at the 300-500 mg level. If patients respond, maintenance therapy should be continued with the dosage administered over the previous 2-4 weeks for 1-5 years.

1.5 Pharmaceutical forms: solution for intramuscular injection: 20 mg/ml and 100 mg/ml. The medication should be administered only by deep intramuscular injection followed by gentle massage of the area. The patient should remain under medical observation for a period of 30 minutes after drug administration.

1.6 Contraindications: the absolute contraindications should be positively excluded before considering gold therapy: pregnancy; patients with gross renal or hepatic disease; a history of blood dyscrasias; exfoliative dermatitis; systemic lupus erythematosus.

1.7 Relevant warnings: as with other gold preparations, reactions which resemble anaphylactoid effects have been reported. These effects may occur after any course of therapy within the first ten minutes following drug administration. If anaphylactoid effects are observed, treatment with sodium aurothiomalate should be discontinued.

Sodium aurothiomalate should be administered with extra caution in the elderly and in patients with a history of urticaria, eczema or colitis. Extra caution should also be exercised if phenylbutazone or oxyphenbutazone are administered concurrently.

Before starting treatment, and again before each injection, the urine should be tested for protein, the skin inspected for rash and a full blood count performed, including a numerical platelet count (not an estimate), and the readings plotted. Blood dyscrasias are most likely to occur when between 400 mg and 1 g of gold have been given, or between the 10th and 20th week of treatment, but can also occur with much lower doses or after only 2-4 weeks of therapy.

236 The presence of albuminuria, pruritus, rash or eosinophilia is indicative of developing toxicity. Treatment should be withheld for one or two weeks until all signs have disappeared when the course may be restarted on a test dose followed by a decreased frequency of gold injections.

A complaint of sore throat, glossitis, buccal ulceration and/or easy bruising or bleeding demands an immediate blood count, followed, if indicated, by appropriate treatment for agranulocytosis, aplastic anaemia and/or thrombocytopenia.

Every patient treated with sodium aurothiomalate should be warned to report immediately the appearance of pruritus, metallic taste, sore throat or tongue, buccal ulceration or easy bruising, purpura, epistaxis, bleeding gums, menorrhagia or diarrhoea.

Interaction with other medicinal products and other forms of interaction: concurrent gold administration may exacerbate aspirin-induced hepatic dysfunction. Caution should be exercised if phenylbutazone or oxyphenbutazone are administered concurrently. Caution is needed in patients treated concomitantly with sodium aurothiomalate and angiotensin-converting enzyme inhibitors due to an increased risk of severe anaphylactoid reaction in these patients.

Pregnancy and lactation: the safety of sodium aurothiomalate in the foetus and the newborn has not been established. Female patients receiving sodium aurothiomalate should be instructed to avoid pregnancy. Pregnant patients should not be treated with sodium aurothiomalate. Lactating mothers under treatment with sodium aurothiomalate excrete significant amounts of gold in their breast milk and should not breastfeed their infants.

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): blood dyscrasias, including thrombocytopenia, pancytopenia, agranulocytosis, aplastic anaemia, leucopenia and neutropenia, have been reported. Anaphylactic/anaphylactoid reactions have been reported, symptoms of which may include weakness, flushing, hypotension, tachycardia, dyspnoea, palpitations, abdominal pain, shock and possibly collapse. Hepatotoxicity with cholestatic jaundice is a rare complication which may occur early in the course of treatment. It subsides on withdrawing sodium aurothiomalate. A rare but severe form of enterocolitis has been described. Diffuse unilateral or bilateral very rarely occurs. This progressive condition usually responds to drug withdrawal and steroid therapy. An annual x-ray is recommended and attention should be paid to unexplained breathlessness and dry cough. Side effects may be largely avoided by the indicated careful titration of dosage. Minor reactions, usually manifesting as skin rashes and pruritus, are the most frequent and are commonly benign, but as such reactions may be the forerunners of severe gold toxicity they must never be treated lightly. Other indicators of developing toxicity could be the presence of albuminuria or an eosinophilia. Severe skin reactions that have been reported include exfoliative dermatitis and bullous eruptions. Irreversible skin pigmentation (chrysiasis) can occur in sun- exposed areas after prolonged treatment with sodium aurothiomalate. Rare reports of alopecia exist. Nephrotic syndrome has been rarely reported. Neurological manifestations of gold toxicity, including very rare cases of peripheral neuropathy, Guillain-Barré syndrome and encephalopathy, have been observed.

2.2 Indirect risks (incorrect use): minor side effects resolve spontaneously on withdrawal of sodium aurothiomalate. Symptomatic treatment of pruritus with may be helpful. Major skin lesions and serious blood dyscrasias demand hospital admission when or may be used to enhance gold excretion. Fresh blood and/or platelet transfusions, corticosteroids and androgenic steroids may be required in the management of severe blood dyscrasias.

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

237 Pharmacokinetics: sodium aurothiomalate is absorbed readily after intramuscular injection and 85 to 95% becomes bound to plasma proteins. With doses of 50 mg weekly a steady-state serum concentration of gold of about 3 to 5 micrograms/ml is reached in 5 to 8 weeks. It is widely distributed to body tissues and fluids, including , and accumulates in the body. The serum half-life of gold is about 5 to 6 days but this increases after successive doses and after a course of treatment, gold may be found in the urine for up to 1 year or more owing to its presence in deep body compartments. Sodium aurothiomalate is mainly excreted in the urine, with smaller amounts in the faeces. Gold has been detected in the foetus when sodium aurothiomalate was given to the mother. Gold is distributed into breast milk.

Reports show a wide range for the incidence of adverse effects of sodium aurothiomalate. However, authorities consider that with careful treatment about one-third of patients will experience adverse effects. It is also considered that about 5% of patients will experience severe adverse effects and that some of the effects will be fatal.

Effects such as eosinophilia, proteinuria, pruritus and rash arising during gold treatment should be allowed to resolve before therapy is continued. The manufacturer recommends that annual chest X-rays should be carried out. Sodium aurothiomalate is given by deep intramuscular injection; the area should be gently massaged and, due to the possibility of vasomotor reactions, the patient should remain recumbent for 10 minutes and kept under close observation for 30 minutes after each injection.

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC code) and supply conditions:

Country Classification Additional information Route of Administration/ MS MDD MQP Indications AM Not authorised AT Not authorised BE Not authorised CH List II CZ Not authorised DE POM ES Not authorised FI POM FR Not authorised HU Not authorised HR Not authorised IT Not authorised IE Not authorised LT Not authorised LV Not authorised MK Not authorised NL POM PT Not authorised PL Not authorised RO Not authorised SE POM SI POM RS Not authorised UK POM

Melclass database1: -

No data available from other member states

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: List I

1 Melclass database - Available at: http://www.edqm.eu/melclass/ (NB: this is the CD-P-PH/PHO’s recommendation at the moment of the compilation of the evidence-based review)

238 Criteria: Parenteral use. Adverse effects including severe suspected. Careful evaluation needed before staring treatment. Close observation during treatment needed.

3.2.2 Paediatric use: children: progressive juvenile chronic arthritis: weekly doses of 1 mg/kg should be given, not exceeding a maximum weekly dose of 50 mg.

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

MHRA (UK): SmPC of Myocrisin - available at: http://www.mhra.gov.uk

Martindale: The Complete Drug Reference – 38th Edition

239 1. THERAPEUTIC PROFILE

1.1 Active ingredient: Sodium Aurotiosulfate

1.2 ATC code ATC: M01CB02

1.3 Therapeutic indications: -

1.4 Posology and duration of treatment: -

1.5 Pharmaceutical forms: -

1.6 Contraindications: -

1.7 Relevant warnings: -

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): -

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, no medicines containing this active substance are authorised in member states).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, no medicines containing this active substance are authorised in member states: Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References: -

240 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01CB03

1.3 Therapeutic indications: auranofin is indicated in the management of adults with active classical or definite rheumatoid arthritis who have had an insufficient therapeutic response to, or are intolerant of, an adequate trial of full doses of one or more NSAIDs. Auranofin should be added to a comprehensive baseline program that includes non-drug therapies. Unlike antiinflammatory drugs, auranofin does not produce an immediate response. Therapeutic effects may be seen after three to four months of treatment, although improvement has not been seen in some patients before six months. When and bone damage has already occurred, gold cannot reverse structural damage to joints caused by previous disease. The greatest potential benefit occurs in patients with active synovitis, particularly in its early stage.

1.4 Posology and duration of treatment: the usual adult dosage of auranofin is 6 mg daily, given either as 3 mg twice daily or 6 mg once daily. Initiation of therapy at dosages exceeding 6 mg daily is not recommended because it is associated with an increased incidence of diarrhoea. If response is inadequate after six months, an increase to 9 mg (3 mg three times daily) may be tolerated. If response remains inadequate after a three-month trial of 9 mg daily, auranofin therapy should be discontinued. Safety at dosages exceeding 9 mg daily has not been studied.

Paediatric use: auranofin is not recommended for use in paediatric patients because its safety and effectiveness have not been established.

1.5 Pharmaceutical forms: capsules for oral use: 3 mg.

1.6 Contraindications: in patients with a history of any of the following gold-induced disorders: anaphylactic reactions, necrotising enterocolitis, pulmonary fibrosis, exfoliative dermatitis, bone marrow aplasia or other severe haematological disorders.

1.7 Relevant warnings: General: the safety of concomitant use of auranofin with injectable gold, , penicillamine, immunosuppressive agents (e.g. , or methotrexate) or high doses of corticosteroids has not been established. Medical problems that might affect the signs or symptoms used to detect auranofin toxicity should be under control before starting auranofin. The potential benefits of using auranofin in patients with progressive renal disease, significant hepatocellular disease, inflammatory bowel disease, skin rash or history of bone marrow depression should be weighed against 1) the potential risks of gold toxicity on organ systems previously compromised or with decreased reserve and 2) the difficulty in quickly detecting and correctly attributing the toxic effect.

The following adverse reactions have been reported with the use of gold preparations and require modification of auranofin treatment or additional monitoring:

Gastrointestinal reactions: gastrointestinal reactions reported with gold therapy include diarrhoea/loose stools, nausea, vomiting, anorexia and abdominal cramps. The most common reaction to auranofin is diarrhoea/loose stools reported in approximately 50% of patients. This is generally manageable by reducing the dosage (e.g. from 6 mg daily to 3 mg) and in only 6% of patients is it necessary to discontinue auranofin permanently. Ulcerative enterocolitis is a rare serious gold reaction. Therefore, patients with gastrointestinal symptoms should be monitored for the appearance of gastrointestinal bleeding.

Cutaneous reactions: dermatitis is the most common reaction to injectable gold therapy and the second most common reaction to auranofin. Any eruption, especially if pruritic, that develops during treatment should be considered a gold reaction until proven otherwise. Pruritus often exists before dermatitis becomes apparent and therefore should be considered to be a warning signal of a cutaneous reaction. Gold dermatitis may be aggravated by exposure to sunlight or an actinic rash may develop. The most serious form of cutaneous reaction reported with injectable gold is generalised exfoliative dermatitis.

241 Mucous membrane reactions: stomatitis, another common gold reaction, may be manifested by shallow ulcers on the buccal membranes, on the borders of the tongue and on the palate or in the pharynx. Stomatitis may occur as the only adverse reaction or with dermatitis. Sometimes diffuse glossitis or gingivitis develops. A metallic taste may precede these oral mucous membrane reactions and should be considered a warning signal.

Renal reactions: gold can produce a nephrotic syndrome or glomerulitis with proteinuria and haematuria. These renal reactions are usually relatively mild and subside completely if recognised early and treatment is discontinued. They may become severe and chronic if treatment is continued after the onset of the reaction. Therefore it is important to perform urinalyses regularly and to discontinue treatment promptly if proteinuria or haematuria develops.

Haematological reactions: blood dyscrasias, including leukopenia, granulocytopaenia, thrombocytopenia and aplastic anaemia, have all been reported as reactions to injectable gold and auranofin. These reactions may occur separately or in combination at any time during treatment. Because they have potentially serious consequences, blood dyscrasias should be constantly watched for through regular monitoring (at least monthly) of the formed elements of the blood throughout treatment.

Miscellaneous reactions: rare reactions attributed to gold include cholestatic jaundice; gold bronchitis and interstitial pneumonitis and fibrosis; peripheral neuropathy; partial or complete hair loss; fever. Patients should be advised of the possibility of toxicity from auranofin and of the signs and symptoms that they should report promptly. Women of childbearing potential should be warned of the potential risks of auranofin therapy during pregnancy.

Laboratory tests: complete blood count (CBC) with differential, platelet count, urinalysis and renal and liver function tests should be performed prior to auranofin therapy to establish a baseline and to identify any preexisting conditions. CBC with differential, platelet count and urinalysis should then be monitored at least monthly; other parameters should be monitored as appropriate.

Drug interactions: in a single-patient report, there is the suggestion that concurrent administration of auranofin and phenytoin may have increased phenytoin blood levels.

Pregnancy: use of auranofin by pregnant women is not recommended. Furthermore, women of childbearing potential should be warned of the potential risks of auranofin therapy during pregnancy. There are no adequate and well-controlled auranofin studies in pregnant women.

Nursing mothers: nursing during auranofin therapy is not recommended. Following the administration of injectable gold, gold appears in the milk of nursing women; human data on auranofin are not available.

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): the adverse reaction incidences listed below are based on observations of 1) 4784 auranofin-treated patients in clinical trials (2474 US; 2310 foreign), of whom 2729 were treated for more than one year and 573 for more than three years, and 2) post- marketing experience. The highest incidence is during the first six months of treatment; however, reactions can occur after many months of therapy. With rare exceptions, all patients were on concomitant non-steroidal antiinflammatory therapy; some of them were also taking low dosages of corticosteroids.

Reactions occurring in more than 1% of auranofin-treated patients: Gastrointestinal: loose stools or diarrhoea (47%); abdominal pain (14%); nausea with or without vomiting (10%); constipation; anorexia*; flatulence*; dyspepsia*; dysgeusia. Dermatological: rash (24%); pruritus (17%); hair loss; urticaria. Mucous membrane: stomatitis (13%); conjunctivitis*; glossitis. Haematological: anaemia; leukopenia; thrombocytopenia; eosinophilia. Renal: proteinuria*; haematuria. Hepatic: elevated liver enzymes.

242 NOTE: * reactions marked with an asterisk occurred in 3-9% of patients. The other reactions listed occurred in 1-3%.

Reactions occurring in less than 1% of auranofin-treated patients: Gastrointestinal: dysphagia; gastrointestinal bleeding†; melaena†; positive stool for occult blood†; ulcerative enterocolitis. Dermatological: angioedema. Mucous membrane: gingivitis†. Haematological: aplastic anaemia; neutropenia†; agranulocytosis; pure red cell aplasia; pancytopenia. Hepatic: jaundice. Respiratory: interstitial pneumonitis. Neurological: peripheral neuropathy. Ocular: gold deposits in the lens or cornea unassociated clinically with eye disorders or visual impairment.

NOTE: † reactions marked with a dagger occurred in 0.1-1% of patients. The other reactions listed occurred in less than 0.1%.

2.2 Indirect risks (incorrect use): the acute oral lethal dose 50% for auranofin is 310 mg/kg in adult mice and 265 mg/kg in adult rats. The minimum lethal dose in rats is 30 mg/kg. In case of acute overdosage, immediate induction of emesis or gastric lavage and appropriate supportive therapy are recommended. Auranofin overdosage experience is limited. There has been no experience with treating auranofin overdosage with modalities such as chelating agents. However, they have been used with injectable gold and may be considered for auranofin overdosage.

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

Auranofin is a gold compound with a gold content of about 29%; it has similar actions and uses to those of sodium aurothiomalate. It is given orally in active progressive rheumatoid arthritis; such oral treatment is less toxic than intramuscular gold but is also much less effective. The usual initial dose of auranofin is 6 mg daily given in two divided doses at first, then, if tolerated, as a single dose. Treatment should be continued for at least 6 months to assess the response; the dose may be increased after 6 months, if the response is inadequate, to 3 mg three times daily. If the response is still inadequate after 3 months at this dosage, then treatment should be discontinued. As for sodium aurothiomalate, urine and blood tests should be carried out before starting auranofin and monthly thereafter.

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC code) and supply conditions:

Country Classification Additional information Route of Administration/ MS MDD MQP Indications AM Not authorised AT List II BE Not authorised CH Not authorised CZ Not authorised DE POM ES Not authorised FI POM FR Not authorised HU Not authorised HR Not authorised IT Not authorised IE Not authorised LT Not authorised LV Not authorised MK Not authorised NL Not authorised

243 PT Not authorised PL Not authorised RO Not authorised SE POM SI Not authorised RS Not authorised UK Not authorised

Melclass database1: -

No data available from other member states.

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: List I

Criteria: Adverse effects including severe suspected. Careful evaluation needed before staring treatment. Close observation during treatment needed.

3.2.2 Paediatric use: auranofin is not recommended for use in paediatric patients because its safety and effectiveness have not been established.

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

SmPC of Ridaura (USA) – available at: https://www.drugs.com/pro/ridaura.html

Martindale: The Complete Drug Reference – 38th Edition

1 Melclass database - Available at: http://www.edqm.eu/melclass/ (NB: this is the CD-P-PH/PHO’s recommendation at the moment of the compilation of the evidence-based review)

244 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01CB04

1.3 Therapeutic indications: -

1.4 Posology and duration of treatment: -

1.5 Pharmaceutical forms: -

1.6 Contraindications: -

1.7 Relevant warnings: -

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): -

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

Aurothioglucose is a gold compound with a gold content of about 50%; it has similar actions and uses to those of sodium aurothiomalate. It has been used in the treatment of active rheumatoid arthritis and juvenile idiopathic arthritis. Aurothioglucose was given intramuscularly as a suspension in oil.

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, no medicines containing this active substance are authorised in member states).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, no medicines containing this active substance are authorised in member states (withdrawn): Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References: -

245 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01CB05

1.3 Therapeutic indications: -

1.4 Posology and duration of treatment: -

1.5 Pharmaceutical forms: -

1.6 Contraindications: -

1.7 Relevant warnings: -

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): -

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

According to “Martindale: The Complete Drug Reference – 36th Edition”: Aurotioprol is a gold compound with a gold content of about 50%; it has similar actions and uses to those of sodium aurothiomalate. It is given by intramuscular injection for the treatment of rheumatoid arthritis. The initial dose is 25 mg weekly, increased to 50 to 100 mg weekly, until a total dose of 1.2 to 1.5 g has been given. If improvement has occurred with no signs of toxicity, this may be followed by a dose of 50 to 100 mg intramuscularly every month.

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, no medicines containing this active substance are authorised in member states).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, no medicines containing this active substance are authorised in member states: Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

Martindale: The Complete Drug Reference – 36th Edition

246 1. THERAPEUTIC PROFILE

1.1 Active ingredient: Penicillamine

1.2 ATC code: M01CC01

1.3 Therapeutic indications: severe, active rheumatoid arthritis, including juvenile forms, Wilson's disease (hepatolenticular degeneration) in adults and children (0 to 18 years), cystinuria-dissolution and prevention of cystine stones in adults and children (0 to 18 years), in adults and children (0 to 18 years), chronic active hepatitis in adults.

1.4 Posology and duration of treatment: penicillamine should be taken on an empty stomach at least half an hour before meals or on retiring. As the smallest available tablet is 125 mg, this might not be suitable for very young children.

Rheumatoid arthritis:

Adults: a dose of 125-250 mg daily for the initial 4-week period. Increase by the same amount every 4 to 12 weeks until remission occurs. The minimum maintenance dose to achieve suppression of symptoms should be used and treatment should be discontinued if no benefit is obtained within 12 months. Improvement may not occur for some months. The usual maintenance dose is 500-750 mg daily in divided dosages. A few patients may require up to 1500 mg daily to obtain benefit. When clinical assessment shows that suppression of disease activity has been achieved, the dose should be kept at this maintenance level for six months, thereafter reducing the daily dosage by 125 to 250 mg amounts every 12 weeks may be attempted. Relapse may occur following withdrawal or when an inadequate dose level is reached, usually within three months, but most patients respond to further courses of penicillamine.

Children: the usual maintenance dose is 15 to 20 mg/kg/day. The initial dose should be lower (2.5 to 5 mg/kg/day) and increased every four weeks over a period of three to six months.

Elderly: increased toxicity unrelated to renal function occurs in the elderly. Initial dose should not exceed 125 mg daily for the first month, increasing by similar increments every four to twelve weeks until the minimum maintenance dose to suppress symptoms is reached. Daily dosage should not exceed 1000 mg.

Renal Insufficiency: penicillamine therapy should be initiated at a low dose with intervals between dose increases of at least 12 weeks. Fortnightly monitoring for toxicity is mandatory throughout treatment for rheumatoid arthritis.

Wilson's disease: penicillamine is a -chelating agent and is most effectively used in conjunction with a low-copper diet (below 1 mg copper per day). Patients must be maintained in negative copper balance and the minimum dose of penicillamine required to achieve this should be given.

Adults: 1500 to 2000 mg daily in divided doses. The optimum dose to achieve a negative copper balance (measured by analysis of 24-hour urinary copper excretion and subsequently by monitoring free copper in the serum) should be chosen. The dose may be reduced to 750-1000 mg daily when disease control is achieved as evidenced by urinary copper excretion. A dose of 2000 mg daily should not be continued for more than one year.

Children: 20 mg/kg/day in two or three divided doses, given 1 hour before meals. For older children (>12 years) the usual maintenance dose is 0.75-1 g daily.

Elderly: up to 20 mg/kg body weight daily in divided doses. The dosage should be adjusted to the minimal level necessary to achieve disease control.

Renal Insufficiency: extra precautions should be taken to monitor for adverse effects in patients with Wilson's disease and renal insufficiency.

Cystinuria: ideally establish the lowest effective dose by quantitative chromatography of urine.

247 Dissolution of cystine stones: adults: for the treatment of cystinuria or cystine stones, 1000-3000 mg daily in divided doses, adjusted to maintain urinary cystine below 200 mg/litre. Maintain adequate fluid intake of 3 litres/day to provide a urine flow of 2 ml/min.

Prevention of cystine stones:

Adults: 500 mg to 1000 mg on retiring. Fluid intake should not be less than 3 litres/day. Urine cystine levels of not more than 300 mg/l should be maintained.

Children: 20 to 30 mg/kg/day in two or three divided doses, given 1 hour prior to meals, adjusted to maintain urinary cystine levels below 200 mg/litre.

Elderly: the minimum dose which maintains urinary excretion of cystine below 200 mg/litre.

Renal insufficiency: if renal insufficiency is present at the onset of therapy, the starting dose should be lower, but it will be necessary to give sufficient penicillamine to achieve urine cystine levels of not more than 300 mg/l. The maintenance dose should be reviewed at intervals of not more than four weeks.

Lead poisoning:

Adults: daily oral dose of 1000-1500 mg in divided doses until urinary lead is stabilised at less than 0.5 mg/day.

Children: penicillamine should only be used in cases where blood lead levels are <45 mcg/dl. A total of 15-20 mg/kg/day in 2-3 doses should be used.

Elderly: 20 mg/kg body weight daily in divided doses until urinary lead is stabilised at less than 0.5 mg/day.

Chronic Active Hepatitis:

Adults: penicillamine is intended for the maintenance treatment of chronic active hepatitis. The diagnosis should be based on a history of at least three months’ duration with features of chronic aggressive hepatitis with or without cirrhosis. Treatment with penicillamine should not be commenced until the disease process has been brought under control, initially by treatment with corticosteroids. Disease control should be evidenced by biochemical analysis of liver function to include evaluation of serum bilirubin and transaminase activity. Penicillamine therapy should be commenced with 500 mg daily in divided doses, increasing gradually over three months to the maintenance dose of 1250 mg daily. Concurrently, the dosage of corticosteroids should be reduced and phased out over a three-month period. Throughout therapy, liver function tests should be carried out at suitable intervals for assessment of disease status.

Children: the safety and efficacy of penicillamine in children less than 18 years with chronic active hepatitis have not been established. No data are available.

Elderly: not recommended.

1.5 Pharmaceutical forms: tablets: 125 mg and 250 mg.

1.6 Contraindications: hypersensitivity to penicillamine or any of the ingredients. Penicillamine is contraindicated in patients with moderate or severe renal insufficiency, lupus erythematosus, a history of penicillamine induced agranulocytosis, aplastic anaemia or severe thrombocytopenia.

1.7 Relevant warnings: penicillamine should not be given with other drugs capable of causing similar serious haematological or renal adverse effects (e.g. , , , hydroxychloroquine or immunosuppressive drugs).

Patients who are allergic to penicillin may react similarly to penicillamine, but cross-sensitivity appears to be rare. Penicillamine should be used with caution in patients who have had adverse reactions to gold. Concomitant or previous treatment with gold may increase the risk of side effects with penicillamine treatment. Therefore, penicillamine should be used with caution in patients who have previously had adverse reactions to gold and concomitant treatment with gold should be avoided. Concomitant oral , digoxin or antacid therapy should not be given within 2 hours of taking penicillamine. In general, the elderly are more likely to have adverse effects.

248 Because of the potential for serious haematological and renal adverse reactions to occur at any time, full blood count and urinalysis should be performed weekly for at least the first 2 months of therapy (or after any change in dose) and should be repeated monthly thereafter. In cystinuria or Wilson's disease, longer intervals may be adequate.

Patients should be instructed to report promptly the development of signs and symptoms of granulocytopaenia and/or thrombocytopenia such as fever, chills, sore throat, easy bruising or unexplained bleeding, mouth ulcers or rashes. Laboratory tests should be repeated in this case.

Consider withdrawing therapy if platelet count falls below 120 000/mm3 or WBC below 2500/mm3, or if either parameter shows 3 successive falls within the reference range. Therapy can be reintroduced at a lower dose when the count returns to normal, but should be discontinued permanently if neutropaenia or thrombocytopenia recurs. Similarly, proteinuria and/or haematuria may be warning signs of glomerulonephritis. In some patients the proteinuria disappears with continued therapy but close observation is essential and therapy should be discontinued if there is heavy or increasing proteinuria or significant haematuria.

Care should be exercised in patients with renal insufficiency; modification of dosage may be necessary.

Especially careful monitoring is necessary in the elderly since increased toxicity has been observed in this patient population regardless of renal function.

With the exception of Wilson's disease, patient's platelet and white cell counts must be normal before commencing treatment. A low platelet or white cell count is not a contraindication to commence treatment of Wilson's disease. Treatment should be discontinued, however, if a low initial count falls further and/or excessive bruising or petechial haemorrhages occur. Liver function tests should be carried out at a frequency determined by the clinical setting (e.g. chronic active hepatitis will require more frequent monitoring.

Concomitant use of NSAIDs and other nephrotoxic drugs may increase the risk of renal damage.

Antihistamines, corticosteroids or temporary reduction of dose will control allergic phenomena occurring early, unless severe.

In the treatment of rheumatoid arthritis, response to penicillamine is often slow and the use of existing analgesics, antiinflammatories or steroids should be continued and later gradually withdrawn, subject to patient improvement.

Pyridoxine 25 mg daily may be given to patients taking penicillamine for long periods, especially if they are on a restricted diet (e.g. Wilson's disease or cystinuria) since penicillamine increases the requirement for this vitamin.

It has been suggested that doses of penicillamine should be reduced to 250 mg daily for 6 weeks prior to elective surgery because of possible effects of penicillamine on collagen and elastin (and thereby on wound healing).

Reversible loss of taste may occur. Mineral supplements to overcome this are not recommended.

Haematuria is rare but if it occurs in the absence of renal stones or other known causes, treatment should be stopped immediately.

A late rash, described as "acquired epidermolysis bullosa" and "penicillamine dermopathy", may occur after several months or years of therapy and may necessitate a reduction in dosage.

The use of disease-modifying antirheumatic drugs, including penicillamine, has been linked to the development of septic arthritis in patients with rheumatoid arthritis, although rheumatoid arthritis is a stronger predictor for the development of septic arthritis than the use of a disease-modifying antirheumatic drug.

Deterioration of the neurological symptoms of Wilson's disease (dystonia, rigidity, tremor, dysarthria) have been reported following introduction of penicillamine in patients treated for this condition. This may be a consequence of mobilisation and redistribution of copper from the liver to the brain.

249 Breast enlargement has been reported as a rare complication of penicillamine therapy in both women and men. Penicillamine has been used successfully to treat breast enlargement which does not regress on drug discontinuation.

Interaction with other medicinal products and other forms of interaction: concomitant oral iron or antacids should not be given within 2 hours of taking penicillamine as oral absorption of penicillamine may be reduced. Penicillamine should not be given concurrently with iron or other heavy metals with which it may form complexes. Concomitant digoxin should not be given within 2 hours of taking penicillamine as oral absorption of digoxin may be reduced. Concomitant use of NSAIDs and other nephrotoxic drugs may increase the risk of renal damage. Concomitant gold and penicillamine treatment is not recommended. It should not be used in patients who are receiving concurrent gold therapy, antimalarials, immunosuppressive or cytotoxic drugs, clozapine, oxyphenbutazone or phenylbutazone since these drugs have a propensity to cause similar serious haematological and/or renal adverse reactions. Co-administration with levodopa may result in elevated levodopa levels. Co-administration with may result in decreased penicillamine levels; absorption of zinc may also be reduced by penicillamine.

Pregnancy: the safety of penicillamine in pregnancy has not been established. It has been shown to be teratogenic in rats when given in doses several times higher than those administered to humans. Penicillamine should be used in pregnancy only when the expected benefits outweigh the risks of discontinuing the medication.

Wilson's disease: there have been several cases of reversible cutis laxa in infants born to mothers taking penicillamine throughout pregnancy. Although there have been no controlled studies on the use of penicillamine during pregnancy, two retrospective studies have reported the successful delivery of 43 normal infants to 28 women receiving between 500 and 2000 mg penicillamine daily. There are also anecdotal reports both of congenital abnormalities and of successful outcomes in patients who have remained on penicillamine during pregnancy. If treatment with penicillamine is to be continued following a risk-benefit analysis, consideration should be given to reducing the dose of penicillamine to the lowest effective dose.

Cystinuria: whilst normal infants have been delivered, there is one report of a severe connective tissue abnormality in the infant of a mother who received 2000 mg penicillamine daily throughout pregnancy. Whenever possible, penicillamine should be withheld during pregnancy, but if stones continue to form, the benefit of resuming treatment must be weighed against the possible risk to the foetus.

Rheumatoid arthritis or chronic active hepatitis: penicillamine should not be administered to patients who are pregnant and therapy should be stopped when pregnancy is diagnosed or suspected, unless considered to be absolutely essential by the physician.

Breastfeeding: due to the lack of data on use in breastfeeding patients and the possibility that penicillamine may be transmitted to newborns through breast milk, Penicillamine should only be used in breastfeeding patients when it is considered absolutely essential by the physician.

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): both the frequency and severity of many side effects and adverse reactions to penicillamine are found to be dose-related and vary according to the nature of the disease under treatment, hence the importance of initiating therapy at low doses and gradually increasing the quantity of drug given to optimum level. The most common side effects are thrombocytopenia and proteinuria. Thrombocytopenia occurs commonly. It may occur any time during treatment and is usually reversible. Proteinuria occurs in up to 30% of patients and is partially dose-related. Adverse reactions are ranked under headings of frequency, the most frequent first, using the following convention: Very common (>1/10), Common (1/100, <1/10), Uncommon (1/1000, <1/100), Rare (1/10,000, <1/1000), Very rare (<1/10,000), including isolated reports. Not known is used where no valid estimate of the incidence has been derived.

250 Blood and lymphatic system disorders: Common: thrombocytopenia. Not known: neutropenia8, agranulocytosis1, aplastic anaemia1, haemolytic anaemia, leucopenia.

Immune system disorders: Rare: allergic reactions including hypersensitivity.

Metabolism and nutrition disorders: Not known: anorexia2.

Psychiatric disorders: Not known: confusion2.

Nervous system disorders: Not known: loss of taste4, headache2, dizziness2.

Eye disorders: Not known: abnormal vision2.

Ear and labyrinth disorders: Rare: deafness.

Vascular disorders: Not known: pulmonary haemorrhage.

Respiratory, thoracic and mediastinal disorders: Not known: dyspnoea, pleural effusion, alveolitis, pulmonary fibrosis, bronchiolitis, pneumonitis.

GI disorders: Rare: mouth ulceration, stomatitis, glossitis. Not known: pancreatitis, nausea2, vomiting2, diarrhoea2.

Hepatobiliary disorders: Not known: cholestatic jaundice.

Skin and subcutaneous tissue disorders: Rare: alopecia, pseudoxanthoma elasticum, elastosis perforans, skin laxity. Not known: rash2, urticarial reactions3, acquired epidermolysis bullosa6, penicillamine dermopathy6, dermatomyositis, pemphigus, Stevens-Johnson syndrome, yellow nail syndrome.

Musculoskeletal, connective tissue and bone disorders: Not known: drug-induced lupus erythamatosus, , polymyositis, rheumatoid arthritis.

Renal and urinary disorders: Very common: proteinuria. Rare: haematuria5. Not known: nephrotic syndrome, glomerulonephritis, Goodpasture syndrome.

Reproductive system and breast disorders: Rare: breast enlargement7.

General disorders and administration site conditions: Not known: fever2.

1 from agranulocytosis and aplastic anaemia have occurred. 2 Nausea, anorexia, fever, rash, vomiting, diarrhoea, headaches, dizziness, abnormal vision and confusion may occur early in therapy especially when full doses are given from the start. 3 Penicillamine may cause allergic reactions such as urticaria and erythema accompanied by hyperpyrexia. Transient rashes and fever may occur early in therapy; if persistent, antihistamines or temporary withdrawal of treatment with or without a short course of steroids may be necessary. Penicillamine may be reintroduced at a lower dosage. If steroids are given, penicillamine should be reintroduced before steroid withdrawal. Urticarial reactions have been reported. 4 Reversible loss of taste may occur. Mineral supplements to overcome this are not recommended. 5 Haematuria may occur rarely, but if it occurs in the absence of renal stones or other known cause, treatment should be stopped immediately. 6 A late rash, described as "acquired epidermolysis bullosa" and "penicillamine dermopathy" may occur, after several months or years of therapy and may necessitate a reduction in dosage. 7 Breast enlargement has been reported as a rare complication of penicillamine therapy in both women and men. 8 Neutropenia may occur at any time during treatment and is usually reversible. Iron deficiency may occur in menstruating women.

2.2 Indirect risks (incorrect use): no instances of adverse reactions to an overdose of penicillamine have been recorded and no specific measures are indicated. Treatment of overdosage is symptomatic and withdrawal of the drug is necessary if serious side effects as mentioned above occur.

251 2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

Penicillamine is a chelator that aids the elimination from the body of certain heavy metal , including copper, lead and , by forming stable soluble complexes with them that are readily excreted by the kidney. It is used in the treatment of Wilson's disease (to promote the excretion of copper), in heavy metal poisoning such as lead poisoning, in cystinuria (to reduce urinary concentrations of cystine), in severe active rheumatoid arthritis and in chronic active hepatitis. Penicillamine is given orally and should be taken on an empty stomach. A low initial dose increased gradually to the minimum optimal maintenance dosage may reduce the incidence of adverse effects as well as provide closer control of the condition being treated. Adverse effects of penicillamine are frequent.

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC code) and supply conditions:

Country Classification Additional information Route of Administration/ MS MDD MQP Indications AM Not authorised AT List II BE Not authorised CH Not authorised CZ POM DE POM ES POM FI POM FR List I HU Not authorised HR Not authorised IT Not authorised IE Not authorised LT Not authorised LV Not authorised MK Not authorised NL Not authorised PT POM PL POM RO List I SE POM SI POM RS Not authorised UK POM

Melclass database1: -

No data available from other member states.

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: List I

Criteria: Self-diagnosis not possible. Frequent serious adverse reactions. Regular patient evaluation during treatment needed.

1 Melclass database - Available at: http://www.edqm.eu/melclass/ (NB: this is the CD-P-PH/PHO’s recommendation at the moment of the compilation of the evidence-based review)

252 3.2.2 Paediatric use: penicillamine is recommended in children in the treatment of severe, active rheumatoid arthritis, including juvenile forms; Wilson's disease (hepatolenticular degeneration) in children from 0 to 18 years; cystinuria-dissolution and prevention of cystine stones in children from 0 to 18 years; lead poisoning in children from 0 to 18 years.

Recommended dosage: see section 1.4 Posology and duration of treatment.

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

Martindale: The Complete Drug Reference – 36th Edition

EMC - available at: https://www.medicines.org.uk/

253 1. THERAPEUTIC PROFILE

1.1 Active ingredient:

1.2 ATC code: M01CC02

1.3 Therapeutic indications: -

1.4 Posology and duration of treatment: -

1.5 Pharmaceutical forms: -

1.6 Contraindications: -

1.7 Relevant warnings: -

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): -

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

Bucillamine is structurally related to penicillamine and is reported to be an immunomodulator. Bucillamine has been used in rheumatoid arthritis. It has been implicated in the development of skin and kidney disorders.

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, no medicines containing this active substance are authorised in member states).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, no medicines containing this active substance are authorised in member states: Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References:

Martindale: The Complete Drug Reference – 34th Edition

254 1. THERAPEUTIC PROFILE

1.1 Active ingredient: Other Specific Antirheumatic Agents

1.2 ATC code: M01CX

1.3 Therapeutic indications: -

1.4 Posology and duration of treatment: -

1.5 Pharmaceutical forms: -

1.6 Contraindications: -

1.7 Relevant warnings: -

2. LIST DIRECT/INDIRECT RISKS (SAFETY PROFILE)

2.1 Direct risks (pharmacovigilance): -

2.2 Indirect risks (incorrect use): -

2.3 Recent cases at European level: -

3. CONCLUSIONS – RECOMMENDATIONS FOR LEGAL CLASSIFICATION

3.1 Member states’ legal classification of the active ingredient for these therapeutic indications (ATC codes) and supply conditions: no data (based on the available data, no medicines containing these active substances are authorised in member states).

3.2 Social dimension of classification:

3.2.1 Conditions of supply (Indications, Administration Route, MS, MDD, MQP, as applicable):

Proposed recommendation: based on the available data, no medicines containing these active substances are authorised in member states: Not to classify

3.2.2 Paediatric use: -

3.2.3 Social dimension: -

4. REFERENCES/COMMENTS

4.1 References: -

255 LIST OF AUTHORS

Dr Elaine BRESLIN Health Products Regulatory Authority (HPRA) Kevin O'Malley House Earlsfort Centre Earlsfort Terrace DUBLIN 2 (Ireland)

Mr Marcello CHIAVONI Italian Medicines Agency (AIFA) Via del Tritone 181 00187 ROME (Italy)

Mrs Merjem HADJIHAMZA Macedonian Agency for Medicine and Medical Products Ministry of Health 50 Divizjia bb 1000 SKOPJE (“the former Yugoslav Republic of Macedonia”)

Mr Veljko JEREMIC Medicines and Medical Devices Agency of Serbia (ALIMS) 458 Vojvode Stepe Street 11221 BELGRADE (Serbia)

Dr Denisse MAZILU National Medicines Agency (ANM) 48 Av. Sanatescu Street 1 BUCHAREST (Romania)

Dr Irena MEISSNER-WANTUCH Ministry of Health UL. Akacjowa 9 05-540 ZALESIE GORNE (Poland)

Ms Sandra MONTEIRO National Authority of Medicines and Health Products (INFARMED) Parque da Saude de Lisboa Av. do Brasil 53 1749-004 LISBON (Portugal)

SECRETARIAT Biological Standardisation, Network of Official Medicines Control Laboratories (OMCL) and HealthCare Department (DBO) EDQM – Council of Europe 7 Allée Kastner, CS 30026 67081 STRASBOURG (France)

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