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Home , Acemetacin

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

< invented name > 60 mg capsules, hard

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule, hard contains 60 mg acemetacin.

Excipients with known effects: 55 mg lactose (as monohydrate) per capsule, hard 0,022 mg Azorubine (E122) per capsule, hard

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Capsule, hard

Hard gelatine capsule, size 4 (14.3 mm x 53 mm) with an ivory-coloured opaque body and a violet opaque cap.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Symptomatic treatment of pain and inflammation in

 acute arthritis (including )  chronic arthritis, particularly in (chronic polyarthritis)  (Bechterew’s Disease) and other inflammatory rheumatic spinal disorders   soft tissue inflammatory rheumatic disorders  painful inflammation and swelling due to trauma

4.2 Posology and method of administration

Posology with single and daily doses:

Acemetacin is dosed according to the severity of the disease. Adults:

The recommended dose range is between 60 and 180 mg per day divided into 1 – 3 three single doses.

Age: Single-dose: Daily dose

Adults 60 mg Acemetacin 60 - 180 mg Acemetacin

The physician should decide on the duration of treatment.

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control the symptoms (see section 4.4).

Treatment of rheumatic diseases may require intake of < invented name > over a longer period.

Acute gout:

For the treatment of acute gout a daily dose of 180 mg is recommended until symptoms subside.

Higher doses may occasionally be required for the first 24 to 48 hours. Treatment with a daily dose higher than 180 mg should only occur under the close supervision of the prescribing physician.

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.

Paediatric population: < invented name > is not recommended for use in children and adolescents due to insufficient data on safety and efficacy in this patient-group.

Method of administration

For oral use.

< invented name > should be swallowed unchewed and with a sufficient amount of liquid. < invented name > should not be taken on an empty stomach.

For patients with a sensitive stomach it is recommended to take < invented name > during a meal.

4.3 Contraindications

 hypersensitivity to the active substance, or to any of the excipients listed in section 6.1.  known reactions of bronchospasm, asthma attacks, rhinitis or urticaria in response to acetylsalicylic acid or other non-steroidal anti-inflammatory medicinal products  unexplained disturbance of hemopoiesis  active, or history of recurrent peptic ulcer/hemorrhage (at least two or more different episodes of proven ulceration or bleeding)  a history of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy  cerebrovascular or other active bleeding  severe heart failure  severe renal and hepatic failure

< invented name > is also contraindicated during the third trimester of pregnancy

4.4 Special warnings and precautions for use

Gastrointestinal safety:

The use of < invented name > in combination with other NSAIDS, including -2 selective inhibitors, should be avoided.

Undesirable effects may be minimized by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.2, and gastrointestinal and cardiovascular risks below).

Elderly

The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal (see section 4.2).

Gastrointestinal bleeding, ulceration and perforation:

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

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 (see section 4.3), and in the elderly. These patients should commence treatment on the lowest dose available. Combination therapy with protective agents (e.g. 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 (see below and 4.5).

Patients with a history of gastrointestinal toxicity, particularly the elderly, should report any unusual abdominal symptoms (especially GI bleeding), particularly in the initial stages of treatment. Caution is advised in patients receiving concomitant medications, such as oral , such as , selective serotonin-reuptake inhibitors or anti-platelet agents such as acetylsalicylic acid (see section 4.5), which could increase the risk of ulceration or bleeding.

When gastrointestinal bleeding or ulceration occurs in patients receiving < Invented Name >, the treatment should be withdrawn.

NSAIDs should be given with caution to patients with a history of gastrointestinal disease (e.g. ulcerative colitis, Crohn’s disease) as their condition may worsen (see section 4.8).

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 the use of some NSAIDs (particularly at high doses and in long term treatment) may be associated with a slightly 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).

Effects on the skin: 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 (see section 4.8). 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. < invented name > should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Renal and Hepatic Impairment: The administration of an NSAID may cause a dose dependent reduction in formation and precipitate renal failure. Patients at greatest risk of this reaction are those with impaired renal function, cardiac impairment, liver dysfunction, those taking and the elderly. Renal function should be monitored in these patients (see also section 4.3)

< invented name > should only be used after careful consideration of the risk-benefit ratio in patients  with acute porphyria  with systemic lupus erythematosus (SLE) or mixed connective tissue disease (see section 4.8)

Particular supervision by a physician is necessary in patients  with renal impairment  with hepatic impairment  immediately after major surgical intervention  with allergic rhinitis, nasal polyps or chronic obstructive pulmonary disease because of a higher risk for allergic reactions, such as acute asthma attack ( induced asthma), Quincke’s edema or urticaria  with a history of allergic reaction to other substances because of a higher risk for an allergic reaction to < invented name >

Severe allergic reactions, e.g. anaphylactic shock, are very rare. < invented name > must be discontinued at the first appearance of any sign of severe hypersensitivity. Depending on the symptoms, suitable treatment should be initiated by healthcare professionals.

< invented name > can induce transitory inhibition of thrombocyte aggregation. Patients with blood clotting disturbance should, therefore, be observed carefully.

Patients receiving long-term treatment should be regularly screened for renal and hepatic parameters and blood counts.

Particular caution is advised before surgical interventions.

Headache may occur due to long-term treatment with ; this should not be treated with higher doses of the offending substance.

In general, habitual use of analgesics, especially the combination of different analgesic substances, may lead to irreversible renal impairment with the risk of renal insufficiency (analgesic induced nephropathy).

Concomitant intake of NSAIDs and my increase the risk of acemetacin-related adverse reactions, particularly adverse reactions involving the or the central nervous system.

During long-term treatment with indometacin, the main active metabolite of acemetacin, changes to the retina of the eye (pigmentary degeneration of the retina) and corneal opacity were occasionally observed. Blurred vision may be a sign of this and requires a thorough ophthalmological examination. As these changes may also be asymptomatic, patients receiving acemetacin as long-term treatment should receive regular ophthalmological examinations and therapy should be discontinued if such changes occur.

For information relating to female fertility see section 4.6.

< invented name > contains Azorubine (E122). May cause allergic reactions. < invented name > contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

As with other NSAIDs, caution is advised when acemetacin is used concomitantly with the following active substances:

Other NSAIDs including salicylates: Concomitant intake of several non-steroidal anti-inflammatory medicinal products including cyclooxygenase-2-selective inhibitors may increase the risk of gastrointestinal ulceration and bleeding due to synergistic effects. Therefore, concomitant use of acemetacin with other NSAIDs should be avoided (see section 4.4).

Digoxin, phenytoin or : Concomitant use of < invented name > with , phenytoin or lithium may increase the plasma levels of these compounds. Monitoring of lithium serum levels is necessary.

Diuretics, ACE-inhibitors and angiotensin 2 antagonists: NSAIDs may diminish the effect of diuretics and antihypertensives. In patients with impaired renal function (e.g. dehydrated patients or elderly patients) concomitant intake of ACE inhibitors or angiotensin 2 antagonists with an active substance which inhibits cyclooxygenase may lead to further impaired renal function including potential acute renal failure (usually reversible). Therefore, this combination should be used with caution, especially in the elderly. Patients should be advised to ensure adequate fluid intake. Regular checking of renal parameters should be considered after starting combination therapy.

Concomitant intake of < invented name > and potassium-sparing diuretics may lead to hyperkalemia. Therefore, monitoring of serum potassium levels is necessary.

Glucocorticosteroids: Concomitant use of glucocorticosteroids may increase the risk of gastrointestinal ulceration or bleeding (see section 4.4).

Thrombocyte aggregation inhibitors such as acetylsalicylic acid and selective serotonin reuptake inhibitors (SSRI): Concomitant administration of thrombocyte aggregation inhibitors such as acetylsalicylic acid and SSRIs may increase the risk of gastrointestinal bleeding (see section 4.4).

Methotrexate: When taken within 24 hours before or after administration of , < invented name > may increase methotrexate blood concentration and therefore increase the toxic effects of methotrexate.

Cyclosporine: The risk of nephropathic effects of cyclosporine is increased by concomitant administration of certain NSAIDs. This effect can also not be excluded for the combination of cyclosporine and acemetacin.

Anti-coagulants: NSAIDs may enhance the effects of anti-coagulants such as warfarin (See section 4.4). Therefore, it is recommended to monitor blood coagulation status in case of concomitant therapy.

Sulfonylureas: Clinical studies have demonstrated interactions between certain NSAIDs and oral antidiabetic agents (e.g. sulfonylureas). Although such interactions have not been described for acemetacin and sulfonylureas, monitoring of blood glucose is recommended during concomitant use.

Probenecid or : Medicinal products containing probenecid or sulfinpyrazone may delay the elimination of acemetacin.

Furosemide: Furosemide accelerates the elimination of acemetacin.

Triamterene: < invented name > should not be administered together with triamterene. Cases of acute renal failure were observed following concomitant administration of triamterene during treatment with indometacin, the main metabolite of acemetacin.

Diflunisal: < invented name > should not be used concomitantly with because this may lead to an increased plasma level of indometacin, the main metabolite of acemetacin, resulting in an increase in adverse effects.

Penicillin-Antibiotics: Acemetacin may delay the elimination of penicillin antibiotics.

Concomitant intake of < invented name > and other centrally acting medicinal products or alcohol requires special caution (see section 4.4).

4.6 Fertility, pregnancy and lactation

Pregnancy:

Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or embryo/foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation and gastroschisis after use of prostaglandin synthesis inhibitors in early pregnancy. It is assumed that the risk increases with the administered dose and with the duration of the therapy.

In animals, administration of prostaglandin synthesis inhibitors has been shown to result in increased pre- and post-implantation loss and embryo-foetal lethality. In addition, increased incidence of various malformations, including cardiovascular defects, have been reported in animals given prostaglandin synthesis inhibitors during the organogenetic period.

During the first and second trimester of pregnancy, acemetacin should not be given unless clearly necessary. If acemetacin is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low as possible and the 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 oligohydroamniosis  may expose the mother and the neonate, at the end of pregnancy, to: - possible prolongation of bleeding time, an anti-aggregating effect that may occur even at very low doses - inhibition of uterine contractions resulting in delayed or prolonged labour

Therefore, acemetacin is contraindicated during the third trimester of pregnancy.

Lactation:

Small amounts of acemetacin and its metabolites are detectable in the breast milk. Treatment with < invented name > should be avoided during lactation.

Fertility:

As described for other active substances which are known to inhibit cyclooxygenase/prostaglandin synthesis, the use of < invented name > 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 < invented name > should be considered.

4.7 Effects on ability to drive and use machines

As < invented name > in high dosages may cause adverse effects on the central nervous system such as somnolence and dizziness, < invented name > may have minor influence on the ability to drive and use machines. Concomitant use of alcohol enhances these effects.

4.8 Undesirable effects

The frequencies of adverse events are ranked as follows: Very common ( 1/10); common ( 1/100 to < 1/10); uncommon ( 1/1,000 to < 1/100); rare ( 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data).

The following adverse drug effects are predominantly dose dependent and vary between individuals.

The most commonly observed adverse events are gastrointestinal in nature. Peptic ulceration, perforation or gastrointestinal bleeding may occur and are sometimes fatal, particularly in the elderly (see section 4.4). , vomiting, diarrhoea, flatulence, constipation, dyspepsia, abdominal pain, melena, hematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn’s disease (see section 4.4) have been reported following administration. Less frequently, gastritis has been observed.

The risk for gastrointestinal bleeding in particular depends on the dose administered and the duration of treatment.

Edema, 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 a small increased risk of arterial thrombotic events (e.g. myocardial infarction or stroke) (see section 4.4).

Infections and infestations Very rare: deterioration of infectious inflammation (e.g. development of necrotizing fasciitis) in temporal relation with systemic administration of NSAIDs. This effect may be related to the mode of action of NSAIDs. If during the treatment with < invented name> signs of infection appear or worsen, the patient should be advised to contact a physician immediately. It should be evaluated whether starting antiinfective/antibiotic therapy is justified.

Blood and lymphatic system disorders Very rare: hamolytic , impaired blood formation (anemia including aplastic anemia, leucopenia, agranulocytosis, thrombocytopenia). Fever, sore throat, aphthous ulcers, flu-like symptoms, abnormal fatigue, epistaxis, and ecchymosis may be first symptoms.

In these cases, the medicinal product should be discontinued immediately, and a physician should be consulted. Self-medication of the patient with analgesics and should not be performed. In case of long-term therapy, monitoring of blood parameters should be performed on a regular basis. Influence on the aggregation of thrombocytes and increased risk of bleeding is possible.

Immune system disorders Common: hypersensitivity reactions such as skin rash and itching. Uncommon: urticaria. Very rare: severe hypersensitivity reactions. This may include face and lid edema, swollen tongue, edema of the larynx with airway constriction (angioneurotic edema), dyspnea up to asthma attack, tachycardia, and fall in blood pressure up to life-threating shock. These conditions, which can occur even after the first administration, require immediate medical intervention. Very rare: allergic vasculitis and pneumonitis.

Endocrine disorders Very rare: hyperglycemia, glucosuria.

Psychiatric disorders Common: excitation. Rare: irritability. Very rare: psychological disorders, disorientation, anxiety, nightmares, trembling, psychosis, hallucinations, depression and transient unconsciousness up to coma. Not known: Enhancement of the symptoms of psychiatric conditions may occur during the treatment with < invented name >.

Nervous System disorders Common: central nervous system disturbances, such as headache, fatigue, somnolence and dizziness. Very rare: sensory disturbance, muscle weakness, hyperhidrosis, taste disturbance, impaired memory, insomnia, seizures. Not known: Deterioration of symptoms of epilepsy and Parkinson’s disease may be possible during therapy with < invented name >.

Eye disorders Uncommon: diplopia; for indometacin, the main metabolite of acemetacin, pigmentary degeneration of the retina and corneal opacity during long-term treatment were reported. Blurred vision may be a symptom of this (see section 4.4).

Ear and Labyrinth Disorders Very rare: tinnitus and transient auditory disturbances.

Cardiac disorders Very rare: palpitations, chest pain (similar to angina pectoris), heart insufficiency

Vascular disorders Very rare: hypertension.

Gastrointestinal Disorders Very common: gastrointestinal symptoms such as nausea, vomiting, abdominal pain, diarrhoea, minor gastrointestinal blood loss (may cause anemia in exceptional cases). Common: dyspepsia, flatulence, abdominal cramps, lack of appetite, gastric or intestinal ulceration (in certain circumstances with bleeding and perforation). Uncommon: hematemesis, melena or bloody diarrhoea. Very rare: stomatitis, glossitis, esophageal lesions, complaints of the lower abdomen (e.g. non-specific bleeding colitis, exacerbation of Crohn’s disease or ulcerative colitis), constipation; diaphragm-like intestinal strictures; pancreatitis.

The patient must be advised to immediately stop intake of the medicinal product and to seek medical advice in case of severe abdominal pain, melena or hematemesis.

Hepatobiliary disorders Common: increase in liver (transaminases). Uncommon: liver damage (toxic hepatitis with or without jaundice), Very rare: fulminant hepatic failure, also without prodromal symptoms).

Liver enzymes should therefore be monitored on a regular basis.

Skin and subcutaneous tissue disorders Uncommon: loss of hair. Very rare: eczema, enanthema, erythema, photosensitivity, ecchymosis and cutaneous bleeding (also caused by hypersensitivity), serious skin reactions (bullous reactions including Stevens Johnson Syndrome, Toxic Epidermal Necrolysis, exfoliative dermatitis, and Lyell’s syndrome).

Renal and urinary disorders Uncommon: edema (e.g. peripheral edema), especially in patients with hypertension or impaired renal function. Very rare: micturition disorders, increase in serum urea, acute renal failure, proteinuria, hematuria or renal damage (interstitial nephritis, nephrotic syndrome, papillary necrosis). Renal function should therefore be monitored regularly.

Reproductive system and breast disorders Very rare: vaginal bleeding.

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose a) Symptoms Symptoms of overdose include central nervous system disturbances, such as headache, dizziness, somnolence, disorientation, lethargy, decreased seizure threshold and unconsciousness up to coma. Abdominal pain, nausea, vomiting, gastrointestinal bleeding, sweating, electrolyte disturbances, hypertension, ankle edema, oliguria, hematuria, respiratory depression as well as hepatic and renal dysfunction may also occur. b) Therapeutic measures There is no specific antidote. In cases of overdose, symptomatic measures are recommended. Depending on the patient’s condition, supervision and treatment in an intensive care unit may be necessary. Measures for diminishing absorption and substitution of electrolytes are indicated.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Anti-inflammatory and antirrheumatic products, non-steroids; derivatives and related substances ATC code: M01AB11

Acemetacin belongs to the group of indoleacetic acid derivatives. Its therapeutic effects are mainly caused by the active metabolite indometacin. Acemetacin is a non-steroidal anti- inflammatory/antirrheumatic active substance. Its effect is due to the inhibition of prostaglandin synthesis as shown in common animal models of inflammation. In humans, acemetacin reduces pain, swelling and fever caused by inflammation. Furthermore, acemetacin inhibits ADP-induced platelet aggregation.

5.2 Pharmacokinetic properties

After oral administration of the enteric-coated pharmaceutical form, acemetacin is rapidly and completely absorbed. is almost 100% following multiple dosing (three times a day for up to 10 days). Acemetacin is metabolized to the active metabolite indometacin.

Detected pharmacologically inactive metabolites are: O-desmethyl-, desp-chlorbenzoyl- and O- desmethyl-des-p-chlorbenzoyl derivatives of acemetacin and indometacin as well as their glucuronide conjugates. Maximum plasma levels of about 2 mg/l acemetacin and 1.4 mg/l of the active metabolite indometacin are reached after 1-16 hours, depending on the duration of gastric transit, on average after 2-3 hours. About 50 % of the active substance is metabolised and excreted in the faeces. Approximately 40% is excreted via kidneys after hepatic metabolism to pharmacologically inactive metabolites (hydroxylation and conjugation). Binding to plasma proteins is high.

Acemetacin accumulates in areas of inflammation. After 6 days of treatment, significantly higher levels of the active substance could be detected in the synovial liquid, , muscles and bones than in the blood 6 hours after the last application.

Bioavailability

In 2009 a comparative bioavailability study on Acemtacin forte 60 mg capsules was performed in 28 subjects. In this study the following mean (SD) results were obtained in comparison to a Reference formulation over four study periods (replicate design).

Acemetacin forte 60 mg capsules Reference formulation

Treatment A1 A2 R1 R2

AUC0-t (ng /ml.h) 645.97 653.73 678.02 693.30 (208.41) (211.74) (217.00) (219.27)

Cmax (ng/ml) 238.62 257.35 321.45 339.01 (117.97) (101.19) (147.53) (222.63)

tmax (h) 4.63 4.52 4.63 (1.32) 4.70 (1.70) (0.70) (1.37)

t1/2 (h) 2.80 2.79 3.54 (6.44) 3.01 (3.62) (5.50) (4.17)

5.3 Preclinical safety data

In animal studies, subchronic and chronic toxicity of acemetacin has been observed mainly as gastrointestinal lesions (including ulceration), increased bleeding, hepatic and renal lesions as well as changes in blood count. No-effect-doses (body-weight adjusted) in rats were 1.0 mg/kg bw and in monkeys 4.5 mg/kg bw; in rats the no-effect-dose lies within the therapeutic range of humans, whereas the no-effect-dose in monkeys is higher than the human therapeutic range. In vitro and in vivo tests on mutagenicity did not reveal evidence for a mutagenic activity of acemetacin. Long-term studies in rats and mice did not indicate carcinogenic potential. Teratogenic effects have been studied in rabbits and rats. Fetal death and growth-retardation were found in doses which also cause maternal toxicity. Malformations were not observed. Gestation period and parturition were prolonged by acemetacin.. Negative influence on fertility has not been detected.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule content: Lactose monohydrate Sodium laurilsulfate Talc Magnesium stearate Silica colloidal anhydrous

Capsule Shell: Gelatine Titan dioxide (E171) Azorubine (E122) Patent blue V (E131) Iron oxide, yellow (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

5 years

6.4 Special precautions for storage

Do not store above 30°C.

6.5 Nature and contents of container

[Invented Name] is packed in blisters (PVC/PE/PVDC foil and aluminium foil). [Invented Name] is available in packs of 20, 50 and 100 capsules, hard

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7. MARKETING AUTHORISATION HOLDER

[To be completed nationally]

8. MARKETING AUTHORISATION NUMBER(S)

[To be completed nationally]

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

[To be completed nationally]

10. DATE OF REVISION OF THE TEXT

[To be completed nationally]