CMDh/223/2005 February 2014

Public Assessment Report

Scientific discussion

Dropizol 10mg/ml, Oral drops, solution (Opium Tincture, standardised)

DK/H/2691/001/DC

Date: 28-05-2020

This module reflects the scientific discussion for the approval of Dropizol. The procedure was finalised on 15 August 2017. For information on changes after this date please refer to the module ‘Update’.

I. INTRODUCTION

Based on the review of the quality, safety and efficacy data, the Member States have granted a marketing authorisation for Dropizol 10mg/ml, Oral drops, solution, from Pharmanovia A/S. Agreement between Member States was reached during a written procedure. There was no discussion in the CMDh.

The product is indicated for severe diarrhoea such as diarrhoea caused by cytostatic medication, radiation or neuroendocrine tumours when use of other anti-diarrhoea treatments have not given sufficient effect.

A comprehensive description of the indications and posology is given in the SmPC.

Dropizol, oral drops consist of standardised tincture of opium, (Ph.Eur. 8th ed.) containing morphine (0.95-1.05 %) and codeine (minimum 0.1 %). The tincture is produced from raw opium (Ph.Eur. 8th ed.) and equal volumes of ethanol (70 per cent) and water.

Opium is the dried latex from the unripe seed capsule of the opium poppy, Papaver somniferum and it has been used as an analgesic, sedative and antidiarrheal drug for thousands of years. Four naturally occurring alkaloids morphine, codeine, papaverine and thebain can be isolated from opium.

The marketing authorisation has been granted pursuant Article 10a of EU Directive 2001/83/EC. No new non-clinical nor clinical studies have been conducted.

II. QUALITY ASPECTS

II.1 Introduction Each ml of oral liquid contains 1 ml of tincture from Papaver somniferum L., succus siccum (Opium, raw) corresponding to 10 mg of morphine. 1 drop contains 50 mg opium tincture corresponding to 0.5 mg (10 mg/ml) anhydrous morphine.

Dropizol oral drops is a dark, reddish brown liquid. The oral drops are available in brown glass bottle with a white LDPE dropper and white polypropylene (PP) childproof closure in pack sizes of 1 x 10 ml, 3 x 10 ml and 10 x 10 ml. However, not all pack sizes may be marketed.

The excipients are purified water and ethanol 96% v/v.

Compliance with Good Manufacturing Practice The Member States have been assured that acceptable standards of GMP (see Directive 2003/94/EC) are in place for this product type at all sites responsible for the manufacture and assembly of this product prior to granting its national authorisation.

II.2 Drug Substance The herbal preparation and the herbal substance are described in the European Pharmacopoeia. The Active Substance Master File (ASMF) procedure is used.

Herbal substance: Opium Raw - Ph.Eur 01/2015: 0777 Herbal preparation: Opium tincture, standardised – Ph.Eur 01/2015:1841

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The control tests and specifications for drug substance (herbal preparation) product are adequately drawn up.

Nomenclature Plant name: Papaver somniferum L. (harvested from Unripe capsules of Papaver somniferum L) DER ratio: 1:10 – 1:13 Solvents: Water and 96% ethanol Other names: Laudanum Lab code: 68000355

Structure Opium tincture, standardised. Contains morphine and codeine, expressed as percentage value. It is characterised (Ph.Eur 1841) by:  Morphine (C17H19NO3): 0.95 to 1.05 percent  Codeine (C18H21NO3): minimum 0.1 percent  Ethanol: 31 to 34 percent V/V  Thebaine (2.2.29): maximum 0.3 percent  Dry residue (2.8.16): minimum 4.0 percent m/m

II.3 Medicinal Product The development of the product has been described based on long standing history of hospital productions of this product. The product is the herbal preparation Opium tincture, standardised, which is bottled into glass bottle with an appropriate dropper and closure system.

The product specifications cover in general appropriate parameters for this dosage form. All analytical methodology is based on Ph.Eur specific and general monographs. Batch analyses have been performed on 3 batches. The batch analyses results show that the finished products meet the specification proposed.

The conditions used in the stability studies are according to the ICH stability guideline. The control tests and specification for drug product are adequately drawn up.

The approved shelf life is 36 months with no special storage conditions.

III. NON-CLINICAL ASPECTS

III.1 Introduction The toxicology of morphine and codeine has been presented in brief by the Applicant. Information regarding the reproductive and developmental toxicity has been presented. Information regarding carcinogenicity and reproductive and developmental toxicity has been included in SmPC section 5.3 and 4.6 as requested.

Use of opioids may induce dependence. However, the Applicant claims that administration of Dropizol drops in the sought indication and posology have little potential for causing dependence. The risk is however mentioned in the SmPC.

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III.2 Ecotoxicity/environmental risk assessment (ERA) Since opium has been used for the treatment of diarrhoea for thousands of years, and it has been in well-established use as a medicinal product within the Community for more than 25 years. An environmental risk assessment has not been provided and is not deemed necessary as the introduction of this product will most likely not give rise to an increase in the use of Opium drops.

IV. CLINICAL ASPECTS

IV.1 Introduction Opium tincture, standardised contains morphine and codeine. Morphine and codeine are well- known active substances with established efficacy and tolerability. The dossier is based on well-established use of opium.

The MAH submitted a clinical overview for the justification of the proposed indications and posology. The clinical report refers 23 publications. The clinical overview on the clinical pharmacology, efficacy and safety is adequate.

IV.2 Pharmacokinetics After oral administration of morphine in an immediate release formulation, approximately 40 to 50 percent of the administered dose reaches the central nervous system within 30 minutes. The reason for this poor penetration is poor lipid solubility, protein binding, rapid conjugation with glucuronic acid and ionisation of the drug at physiological pH.

In the liver and gut wall, morphine is metabolised by glucuronidation to active metabolites excreted in the urine. The metabolites are morphine-6-glucuronide (M6G) and morphine-3 glucuronide (M3G). Glucuronidation is the predominant mode of metabolism, however approximately 5% of morphine is demethylated into normorphine and small amounts are metabolised to codeine and hydromorphone.

The elimination half-life of morphine is approximately 2 hours. An elimination half-life of 2.4 to 6.7 hours has been reported for M3G.

Up to 10 % of a dose of morphine may eventually be excreted as conjugates through the bile and into the faeces. The remainder is excreted in the urine as conjugates.

Somogyi et al. have investigated the pharmacokinetics of a range of opium tinctures in the management of opium withdrawal. The Tincture of Opium (TOP) in this study was a preparation of opium in alcohol differing from Dropizol oral drops, as it also contained Tincture Gential, Berberis Extract and peppermint spirit. Forty-five opium-dependent Thai subjects were recruited and thirty-two completed the study. The subjects were allocated to three dosing groups. Thirteen subjects received 10 ml (6.66 mg morphine equivalents), eight received 20 ml (13.3 morphine equivalents) and 11 subjects received 30 ml (20 mg morphine equivalents), all doses were administered twice daily. On day 5 of dosing, blood samples were taken and plasma morphine concentrations were quantified by High-Performance Liquid Chromatography (HPLC). Plasma morphine-3-glucuronide (M3G) and morphine-6- glucuronide (M6G) were quantified by Chromatographic-Mass Spectrometry (LCMS).

There was considerable inter-individual variability in plasma morphine concentrations in subjects receiving the same dose of TOP. The maximum plasma concentration of morphine was reached at 1-hour post-dosing in all dosing groups and the plasma concentration rapidly

PAR Scientific discussion 4/14 declined to a minimum at 8 hours (h) post-dosing for all three doses. The area under the plasma morphine concentration curve (AUC) from 0 to 8 h differed significantly between the three groups with the AUC for those receiving the highest dose (30 ml TOP) being higher than for those receiving 10 ml TOP (p<0.01). The mean ratios of the morphine glucuronides were found to be M3G/M6G = 7.7, M3G/morphine = 35.6 and M6G/morphine = 4.9. Pharmacokinetics in special patient populations

Elderly The pharmacokinetics of morphine has been compared in healthy elderly subjects (60 to 69 years) and young subjects (24-26 years) following intravenous injection of morphine. The study showed that although the terminal rate of disappearance from plasma was faster in the elderly group, apparent volume of distribution at steady state was about half that of the young group and plasma clearance was reduced.

Hepatic impairment The pharmacokinetics may be altered in patients with hepatic impairment, and hepatic impairment could be expected to affect elimination of morphine. The mean elimination half- life of morphine in patients with liver cirrhosis has been shown to be almost twice that of healthy subjects following administration of a modified release oral preparation of morphine.

Renal impairment Only a small amount of morphine is excreted unchanged in the urine and there are conflicting reports on morphine accumulation in patients with renal impairment. However, it does seem clear that morphine metabolites accumulate in patients with renal impairment including patients on peritoneal dialysis. The half-life of the active metabolite M6G was reported to be prolonged and its clearance reduced when given to patients with renal impairment. Opioid intoxication and prolonged opioid effect in patients with renal failure has been associated with M6G.

Children The pharmacokinetics of morphine in children are generally considered similar to those in adults. However, in neonates, clearance is generally reduced and pharmacokinetics are more variable. Elimination half-life of 6.7 and 10 hours have been reported in term and preterm infants after a single intravenous dose of morphine, with nearly 80% of the dose remaining unbound. The reduced clearance and higher morphine concentrations are probably due to reduced metabolism in neonates as well as to immature renal function. The capacity to conjugate morphine by glucuronidation is reduced in preterm infants and some premature neonates may lack the capacity entirely.

The details provided focus on the main opioid component of standardised opium tincture i.e. morphine which is considered acceptable. Details provided are brief but satisfactory and the references provided to support the PK section suffice.

Conclusion on pharmacokinetics The details provided focus on the main opioid component of standardised opium tincture i.e. morphine which is considered acceptable. Details are brief but satisfactory. The references provided to support the PK section suffice.

IV.3 Pharmacodynamics As Dropizol oral drops are only indicated for treatment of diarrhoea, the pharmacodynamic section focuses on gastrointestinal pharmacology.

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The effects of opium are mediated through opioid receptors Mu (μ), Kappa (κ) and Delta (δ), where μ receptors are found primarily in the brain stem and medial thalamus, κ receptors in the limbic and other diencephalic areas, brain stem and spinal cord, and δ receptors mainly in the brain. All three receptor types are localised in human GIT but their relative distribution varies with the GI layer and region. Opioid peptides modify the gastrointestinal (GI) function by interaction with opioid receptors on the enteric circuitries that control motility and secretion.

The μ-opioid receptor agonists inhibit gastric emptying, increases pyloric muscle tone, induce pyloric and duodenojejunal phasic pressure activity, disturb the migrating myoelectric complex, delay transit time through the small and large intestine and elevate the resting anal sphincter pressure. Opioids also attenuate the intestinal secretion of electrolytes and water and thereby facilitate the net absorption of fluid. In addition to this, the μ, κ and δ-opioid receptors contribute to opioid-inhibition of muscle activity in the intestine. The result of all these effects is constipation.

There is evidence that some GI effects of opioid receptor agonists may be mediated by opioid receptors in the brain, however experimental and clinical studies with opioid receptor agonists unable to enter the brain have shown that the GI effects of opioids arise from a peripheral site of action.

Interactions Drug-drug interactions with morphine are believed to be rare, however studies have shown that drugs inhibiting the UGT27B pathway may alter the M3G and M6G pathway. The most potent inhibitors of this pathway included drugs such as tamoxifen, diclofenac, naloxone, carbamazepine, tricyclic and heterocyclic antidepressants and benzodiazepine. However, it is uncertain if these interactions occur and they may not be clinically relevant.

CNS depressants The depressants effects of opioids are enhanced by other CNS depressants such as alcohol, anesthetics, anxiolytics, hypnotics, tricyclic antidepressants and antipsychotics.

Antibacterials Rifampicin can reduce the serum concentration of morphine. Opioid premedicants such as papaveretum have been reported to reduce serum concentrations of ciprofloxacin.

Histamine H2-antagonists Histamine H2-antagonists may enhance the effect of some opioids. One study has shown that cimetidine did not affect the disposition of morphine in healthy subjects and another study showed that pre-and postoperative intravenous cimetidine did not significantly affect morphine consumption and incidence of adverse reactions when compared with placebo. However, there has been isolated reports of possible interactions between morphine and H2- antagonists such as cimetidine and ranitidine.

A single literature article has been provided covering opioid receptors in the GIT and effects of opioids on the GIT. The article (Holtzer P. 2009) is of good quality and is focused towards constipation as an unwanted effect of opioid analgesic therapy rather than on treatment of diarrhoea with opioids. Notwithstanding this fact, the mechanisms of action of opioids in the GIT in relation to constipation and diarrhoea are satisfactorily addressed.

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IV.4 Clinical efficacy A literature search revealed no clinical studies of opium used for treatment of diarrhoea, but confirmed that tinctures of opium are widely recommended in diarrhoea treatment guidelines, and used in the treatment of diarrhoea. In general, opium is considered to be among the most effective nonspecific antidiarrheal drugs.

Chronic diarrhoea Chronic diarrhoea can be due to several conditions. If a specific cause of the diarrhoea cannot be identified, empiric treatment with simple opiate antidiarrheal may be initiated. Usually it is recommended to start treatment with less potent opiates such as loperamide and diphenoxylate and only use the more potent agents such as codeine or opium in refractory cases. The opium treatment recommended includes opium tincture standardised to morphine 4 mg/mL or morphine 10 mg/mL. The recommended dosages are doses equivalent to 1 to 2 mg morphine four times a day, titrated up to doses equivalents to 60 mg morphine four times daily if needed.

Cancer-treatment induced diarrhoea Current guidelines recommend the use of opium tincture as a second-line treatment in cases of mild to moderate chemotherapy-induced diarrhoea which has not resolved after 48 hours treatment with loperamide. The recommended doses are as follows: - Opium tincture containing the equivalent of 10 mg/mL morphine: 10-15 drops in water every 3-4 hours. - Opium tincture containing the equivalent of 0.4 mg/mL morphine: 5 mL every 3-4 hours.

Diarrhoea in patients with inflammatory bowel disease (IBD) Diarrhoea is one of the most common symptoms present in patients with IBD. When treating diarrhoea in those patients, physicians try to control the inflammatory activity by using appropriate anti-inflammatory therapies including aminosalicylates, corticosteroids, immune modifiers and biologic treatment. In addition to this, other medications such as loperamide, codeine sulphate and tincture of opium may be used to slow the motility and thus increase the absorption of fluids and nutrients.

Summary of dosage recommendations The recommended treatment of diarrhoea with opium tinctures includes tinctures of different strengths with regard to morphine equivalents. Below is a summary of the treatment recommendations.

Indication Preparation, Dosage in ml or Corresponding dose strength drops in morphine (morphine equivalent equivalent) Chronic Paregoric Not stated 1 to 2 mg morphine diarrhoea tincture of four times daily, opium titrated up to 60 mg (camphorated morphine four times opium tincture), daily as needed 0.4 mg/mL Chronic Deodorized Not stated 1 to 2 mg morphine diarrhoea tincture of four times daily, titrated up to 60 mg

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opium, 10 morphine four times mg/mL daily as needed

Cancer treatment Deodorized 10 – 15 drops in 5 – 7.5 mg* every 3-4 induced tincture of water every 3 to hours diarrhoea opium, 10 4 hours mg/mL Cancer treatment Paregoric 5 mL in water 2 mg every 3 to 4 induced tincture of every 3 to 4 hours diarrhoea opium hours (camphorated opium tincture), 0.4 mg/mL) Diarrhoea Tincture of Average dose: 6 to 15 mg opium 1% 0.6 to 15 mL Diarrhoea Paregoric Average dose: 2 mg tincture of 5 mL opium (camphorated opium tincture), 0.4 mg/mL) * The calculation is based on the assumption that 20 drops correspond to 1 mL.

Conclusion on clinical efficacy There is a distinct paucity of evidence-based efficacy studies on the use of opium for diarrhoea in the literature and what little there is, has been cited above by the Applicant. The literature articles merely guide on what is commonly available in terms of various dosage forms and strengths, and what is known to be used.

In the Bensen et al. (2004) article, it is clearly recommended to use loperamide for the treatment of cancer and following the outlined treatment guideline and only switch to other second-line agent (e.g. tincture of opium) after 48 hours of loperamide treatment. These treatment recommendations follow a consensus conference on cancer-induced diarrhoea originally published in 1998 and updated in 2004.

Schiller (2005) recommends that more potent opiates than loperamide and diphenoxylate should only be considered for the treatment of chronic diarrhoea, when these safer and better- tolerated agents fail.

Stein et al. (2010) echo the comments made by Benson et al. (2004) and provide a copy of the same treatment guideline. No new information on the efficacy of opium on diarrhoea is therefore presented.

Piertrusko (1979) comments that the antidiarrhoeal effects of opium are primarily due to the morphine content but no information is presented on efficacy or under which circumstances opium should be used. However, it is commented that narcotic-type antidiarrheal agents, aluminum salts, tricyc1ic antidepressants, high-fiber diets and cholestyramine resin may occasionally be of some benefit. In addition, some patients with inflammatory bowel disease have diarrhoea even after treatment with sulfasalazine and steroids. Judicious use of opiates

PAR Scientific discussion 8/14 and anticholinergics may provide symptomatic relief of abdominal cramps and diarrhoea in regional enteritis. Use of these drugs in ulcerative colitis should be avoided if possible since toxic megacolon may result.

In conclusion, the literature data supports a second-line use of opium for the treatment of chronic diarrhoea and cancer-induced diarrhoea where loperamide or similar have been tried for at least 48 hours and are considered insufficient. It is also clear from the presented articles that an antimotility drug such as opium must not be employed where underlying infections are the cause of the diarrhoea.

IV.5 Clinical safety The overview of safety is based on data from a clinical trial evaluating the safety of an opium tincture in healthy subjects, data available from Martindale and from current SmPCs on similar products. In addition to this, records from VigiAccessTM have been reviewed.

Clinical study investigating the safety of opium tincture in healthy subjects De Moraes et al (2008) investigated the safety of an opium tincture, Elixir Paregorico® in 28 healthy volunteers. Elixir Paregorico is a liquid extract of papaver somniferum commonly used in Brazil for the treatment of diarrhoea. The elixir contained morphine (0.05%), papaverine (0.005%), benzoic acid, camphor and aniseed essence. 3 mL of extract diluted in 30 mL of water was administered four times daily for ten days to 28 healthy subjects (14 males and 14 females) aged 18 - 50 years. The results of all haematological and biochemical tests performed pre- and post-treatment were within the normal range. There were no statistically significant differences in the results of the clinical laboratory tests performed at screening,on 5th and 10th day of treatment and at the final assessment.

The adverse reactions reported included constipation (32%), sleepiness (14.3%), moderate headache (25%), fever (3.5%) and flatulence (3.5%). According to the investigators, the constipation and sleepiness were treatment related, but the reported cases of headache, fever and flatulence may be due to other causes. No serious adverse events were reported.

Information from Martindale Martindale does not contain specific information on adverse reactions (ADRs) reported on opioids used for the treatment of diarrhoea, only data on opioid analgesics are included. The most common adverse effects of opioid analgesics are nausea, vomiting, constipation, drowsiness and confusion. Micturition may be difficult, there may be uretic and biliary spasms and the latter may be associated with alterations in liver enzyme values. Opioid analgesic may also have an anti-diuretic effect. Dry mouth, dizziness, sweating, facial flushing, headache, vertigo, bradycardia, tachycardia, palpitations, orthostatic hypotension, hyperthermia, restlessness, change of moods, decreased libido or potency, hallucinations and miosis may also occur. Contact dermatitis has been reported. Increased intracranial pressure may occur in some patients.

Following larger doses of opioids, respiratory depression and hypotension with circulating failure and deepening coma may occur. In addition to this, muscular rigidity has been reported after administration of high doses. Convulsions may occur, especially in infants and children. Death may occur from respiratory failure.

Morphine and some other opioids have a dose-related histamine-releasing effect, which may be responsible in part for reactions such as urticaria, pruritus, hypotension and flushing.

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Following larger doses of opioids, respiratory depression and hypotension with circulating failure and deepening coma may occur. In addition to this, muscular rigidity has been reported after administration of high doses. Convulsions may occur, especially in infants and children. Death may occur from respiratory failure.

Morphine and some other opioids have a dose-related histamine-releasing effect, which may be responsible in part for reactions such as urticaria, pruritus, hypotension and flushing.

Data from VigiAccessTM 187 records on adverse reactions (ADR) were retrieved in VigiAccess from 1971 to June 201519. The most serious and/or most frequently reported ADR are shown in the table below. Some reactions clearly related to parenteral administration have been excluded from the table.

Serious and/or frequently reported ADR retrieved in VigiAccess 1971- 2015 System Organ Class (Number) Adverse reactions Cardiac disorders (14) Cardiac arrhythmias (7) Heart failure (2) Gastrointestinal disorders (71) Diarrhoea (excl. infective) (11) Constipation (3) Abdominal pain (25) Abdominal upper pain (8) Nausea (7) Vomiting (17) Gastrointestinal stenosis and obstruction (3) Gastric ulcers (2) Eye disorders (6) Miosis (2) Vision disorders (2) General disorders and administration site Death and sudden death (7) conditions (44) Asthenic conditions (7) General signs and systems NEC (10) Immune system disorders (6) Hypersensitivity (2) Drug hypersensitivity (1) Anaphylactic responses (3) Investigations (12) Liver function analysis (6) Nervous system disorders (40) Coma (6) Disturbances in consciousness (17) Psychiatric disorders (33) Disturbances in thinking and perception (5) Drug abuse (6) Drug dependence (6) Renal and urinary disorders (6) Renal failure and impairment (4) Respiratory, thoracic and mediastinal Breathing abnormalities (20) disorders (29) Skin and subcutaneous tissue disorders (24) Angioedema and urticaria (4) Erythema multiforma (3) Steven-Johnson syndrome (7) Toxic epidermal necrolysis (3)

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Vascular disorders (5) Shock (1) Hypotension (1)

The information from VigiAccess is consistent with the physiological effects of opium, and the information presented in the SmPC.

Overdose Symptoms of opioid over dosage include coma, miosis and respiratory failure. Dilatation of pupils occurs as hypoxia develops9. In addition, many patients will develop pulmonary oedema.

Dependence and abuse Repeated use of opioids entails a risk of development of psychological and physical dependence. This is less of a problem with legitimate therapeutic use, but dependence may develop rapidly, if opioids are abused for their euphorbiant effects. It is believed that patients using opioids for chronic diarrhoea rarely abuses these drugs, if they are closely monitored and not predisposed to drug abuse in the first place. Therapy should be stopped gradually in patients who may have developed physical dependence to avoid withdrawal symptoms.

Contraindications Opioids are generally contraindicated in acute respiratory depression and obstructive airways diseases and in comatose patients. They are also contraindicated or should be used with great caution in patients with convulsive disorders, head injuries and conditions where the intracranial pressure is raised. Opioids should not be given to patients at risk of paralytic ileus.

Precautions In general, anti-diarrheals like opium tincture are not recommended as primary therapy in patients with acute dysentery, acute ulcerative colitis, and bacterial enterocolitis caused by invasive organisms due to the risk of increasing toxicity of a bacterial diarrhoea. Neither should they be used in patients with pseudomembranous colitis associated with the use of broad-spectrum antibiotics and they should not be used in severely ill patients such as patients with ulcerative colitis due to the risk of development of toxic megacolon.

Opioids should be used with caution or in decreased dose to patients with hyperthyroidism, adrenocortical insufficiency, asthma or decreased respiratory reserve, renal or hepatic impairment, prostatic hyperplasia, hypotension, shock, inflammatory or obstructive bowel disorders or myasthenia gravis. Opioids should be used with great caution in patients with acute alcoholism and it should be noted that Opium “NMI” oral drops contains ethanol.

Elderly or debilitated patients Dosage should be reduced in elderly or debilitated patients.

Children Opium tincture is not recommended for the treatment of acute diarrhoea in children due to its marked depressant effects on ventilation and in general antimotility drugs including opiates are not recommended for treatment of diarrhoea in children.

Pregnancy and lactation Use of opioids during labour may cause respiratory depression in the neonate. Babies born to opioid dependent mothers may suffer from withdrawal symptoms. PAR Scientific discussion 11/14

Morphine is excreted into breastmilk; however, it is considered that the effects to breast-fed infants are negligible and according to the American Academy of Pediatrics, maternal medication with morphine is usually compatible with breastfeeding.

Conclusion on clinical safety As before for efficacy, there is very little in the scientific literature documenting controlled trials where the safety of use of opium for the treatment of diarrhoea has been investigated. However, given the presented ADR listing from VigiAccess over the period 1975 to 2015, no new adverse reactions have emerged. Dosing against diarrhoea is lower than for analgesia and therefore not expected to present additional problems.

The proposed Dropizol product contains the equivalent of 10mg/ml anhydrous morphine. Each ml of solution contains 21 drops and each drop contains the equivalent of 0.5mg anhydrous morphine.

The proposed posology is 5-10 drops, 2-3 times daily where individual doses should not exceed 1 ml and the total daily dose should not exceed 6ml

This equates to 2.5-5.0 mg morphine, 2-3 times daily with individual doses not exceeding 10 mg and a total daily dose not more than 60 mg.

Only one article in the submitted documentation (Schiller) cites doses up to 60mg x 4 daily (Schiller) whereas the others are more modest with doses up to 7.5mg every 3-4 hours (equivalent to max. 60mg per day).

The proposed posology is therefore considered acceptable and justified by the presented literature.

Contra-indications, special warnings and precautions for use are in line with those in general for opioid products used for pain management though some amendments are required.

IV.6 Risk Management Plan The marketing authorisation holder has submitted a risk management plan, in accordance with the requirements of Directive 2001/83/EC as amended, describing the pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to Dropizol.

Summary table of safety concerns as approved in RMP Important identified risks  Respiratory depression  Dependence and abuse  Urinary retention  Hypersensitivity reactions  Exacerbation of central nervous system depression with CNS depressants and MAO-inhibitors (MAOIs)  Interaction with disulfiram, metronidazole PAR Scientific discussion 12/14

Important potential risks  Use in patients at risk of paralytic ileus  Toxic megacolon and intestinal perforation  Use in patients with increased intracranial pressure  Deterioration of glaucoma  Use in pregnancy and lactation  Reduced opioid effect with concomitant rifampicin

Missing information None

Summary of Safety Concerns and Planned Risk Minimisation Activities as approved in RMP Summary of safety concerns Important identified risks  Respiratory depression  Dependence and abuse  Urinary retention  Hypersensitivity reactions  Exacerbation of central nervous system depression with CNS depressants and MAO-inhibitors (MAOIs)  Interaction with disulfiram, metronidazole Important potential risks  Use in patients at risk of paralytic ileus  Toxic megacolon and intestinal perforation  Use in patients with increased intracranial pressure  Deterioration of glaucoma  Use in pregnancy and lactation  Reduced opioid effect with concomitant rifampicin Missing information None

Routine pharmacovigilance is suggested and no additional pharmacovigilance activities are proposed by the applicant, which is endorsed.

V. USER CONSULTATION

The package leaflet has been evaluated via a user consultation study in accordance with the requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC. The language used for the purpose of user testing the PIL was English. The results show that the package leaflet meets the criteria for readability as set out in the Guideline on the readability of the label and package leaflet of medicinal products for human use.

The test consisted of: a pilot test with 5 participants, followed by two rounds with 10 participants each. The questions covered the following areas sufficiently: traceability, comprehensibility and applicability.

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VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION

Dropizol 10mg/ml, Oral drops, solution has a proven chemical-pharmaceutical quality. The dossier is based on well-established use of opium. The marketing authorisation holder submitted a clinical overview for the justification of the proposed indications and posology.

The MAH presented a risk management plan summarising the safety concerns. There are no additional pharmacovigilance or risk minimisation measures.

Agreement between Member States was reached during a written procedure. There was no discussion in the CMD(h). The decentralised procedure was finalised on 15 August 2017.

The MAH presented a risk management plan summarising the safety concerns. There are no additional pharmacovigilance or risk minimisation measures.

The marketing authorisation holder shall submit the first periodic safety update report for this product within 6 months following authorisation. Subsequently, the marketing authorisation holder shall submit periodic safety update reports for this product in accordance with the requirements set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web- portal.

The date for the first renewal will be 15 August 2022.

There were no post-approval commitments made during the procedure.

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