Public Assessment Report Decentralised Procedure - · PDF filemethadone hydrochloride sugar free 1 mg/ml oral solution procedure no: uk/h/3367/001/dc uk licence no: pl 00289/1343 teva

Public Assessment Report

Decentralised Procedure

METHADONE HYDROCHLORIDE SUGAR FREE 1 MG/ML ORAL SOLUTION

Procedure No: UK/H/3367/001/DC

UK Licence No: PL 00289/1343

TEVA UK LIMITED

PAR Methadone Hydrochloride sugar Free 1 mg/ml Oral solution UK/H/3367/001/DC

2

LAY SUMMARY

On 20 April 2011, Ireland, the Netherlands and the UK agreed to grant a Marketing Authorisation to Teva UK Limited for the medicinal product Methadone Hydrochloride sugar Free 1 mg/ml Oral solution (PL 00289/1343; UK/H/3367/001/DC). After a subsequent national phase, a Marketing Authorisation was granted in the UK on 19 May 2011. The licence was granted via the Decentralised Procedure (DCP), with the UK as Reference Member State (RMS). This product is a prescription-only medicine (POM) used to treat opioid drug addiction. Methadone Hydrochloride sugar Free 1 mg/ml Oral solution contains the active ingredient methadone hydrochloride, which belongs to a group of medicines called narcotic analgesics. No new or unexpected safety concerns arose from this application and it was, therefore, judged that the benefits of taking Methadone Hydrochloride sugar Free 1 mg/ml Oral solution outweigh the risks, hence a Marketing Authorisation has been granted.


3

TABLE OF CONTENTS

Module 1: Information about initial procedure Page 4 Module 2: Summary of Product Characteristics Page 5 Module 3: Product Information Leaflets Page 12 Module 4: Labelling Page 14 Module 5: Scientific Discussion Page 19 1 Introduction 2 Quality aspects 3 Non-clinical aspects 4 Clinical aspects 5 Overall conclusions Module 6: Steps taken after initial procedure Page 26


4

Module 1

Product Name Methadone Hydrochloride sugar Free 1 mg/ml Oral solution Type of Application Generic, Article 10(1) Active Substances Methadone Hydrochloride Form Oral solution Strength 1 mg/ml MA Holder

Teva UK Limited, Brampton Road, Hampden Park Eastbourne, BN22 9AG, U K.

Reference Member State (RMS) UK Concerned Member States (CMS)

Ireland and the Netherlands.

Procedure Number UK/H/3367/001/DC Timetable Day 210 – 20 Apr 2011


5

Module 2 Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT Methadone Hydrochloride sugar Free 1 mg/ml Oral solution

2 QUALITATIVE AND QUANTITATIVE COMPOSITION One millilitre of oral solution contains 1 mg of methadone hydrochloride. Excipients One millilitre of oral solution contains 1.2 mg methyl parahydroxybenzoate, 0.3 mg propyl parahydroxybenzoate and 300 mg of maltitol liquid. For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM Oral solution Clear, green liquid

4 CLINICAL PARTICULARS 4.1 Therapeutic indications

For use in the treatment of opioid addictions (as a narcotic abstinence syndrome suppressant). Local guidance on the management of opioid addiction should be followed.

4.2 Posology and method of administration For oral administration only. Local guidance may differ from the posology described hereafter and should be followed. Methadone should preferably be prescribed in special treatment institutions in view of the great risks that such treatment involves. In cases where this is not possible, contact should be made with the nearest drugs advice centre. Addiction Adults Initially 10-20 mg per day. A supplementary dose on the same day may be considered when there is evidence of persistent opioid withdrawal provided that the person has been fully assessed by a clinician with appropriate skills and experience. The dose should be increased by 10 mg per day until there are no signs of withdrawal or intoxication. The usual dose is 60-100 mg per day. The dose is adjusted according to the degree of dependence with the aim of gradual reduction at a speed dependent on the individual person e.g. 3% per week. Elderly In the case of elderly or ill patients repeated doses should only be given with extreme caution. Children Not recommended for children.

4.3 Contraindications − Hypersensitivity to methadone or to any of the excipients − Respiratory depression − Obstructive airways disease − Raised intracranial pressure or head injury − Concurrent administration with monoamine oxidase (MAO) inhibitors or within 2 weeks of

discontinuation of treatment with them − Absence of dependence on opioid substances Use during labour is not recommended, the prolonged duration of action increases the risk of neonatal depression. This medicinal product is not suitable for paediatric use.


6

4.4 Special warnings and precautions for use Caution should be exercised in patients with hepatic dysfunction or renal dysfunction, hypothyroidism or prostatic hypertrophy. In the case of the elderly or ill patients repeated doses should only be given with extreme caution. Addiction/tolerance/dependence Methadone is a substance of addiction and is controlled under the Misuse of Drugs Act 1971 (Schedule 2). It has a long half-life and can therefore accumulate. A single dose which will relieve symptoms may, if repeated on a daily basis, lead to accumulation and possible death. Tolerance and dependence may occur as with morphine. Methadone can produce drowsiness and reduce consciousness although tolerance to these effects can occur after repeated use. Withdrawal Abrupt cessation of treatment can lead to withdrawal symptoms which, although similar to those with morphine, are less intense but more prolonged. Withdrawal of treatment should therefore be gradual. Respiratory depression Due to the slow accumulation of methadone in the tissues, respiratory depression may not be fully apparent for a week or two and may exacerbate asthma due to histamine release. Use during an asthma attack is not recommended.

Hepatic disorders Caution is required as methadone may precipitate porto-systemic encephalopathy in patients with severe liver damage. Opioids including methadone may cause troublesome constipation, which is particularly dangerous in patients with severe hepatic impairment, and measures to avoid constipation should be initiated early. Neonates/children As there is a risk of greater respiratory depression in neonates and because there are currently insufficient published data on use in children, methadone is not recommended in those under 16 years of age (see sections 4.2, 5.2). Further warnings Babies born to mothers receiving methadone may suffer withdrawal symptoms. Methadone should be used with great caution in patients with acute alcoholism, convulsive disorders and head injuries. Methadone has the potential to increase intracranial pressure especially where it is already raised. Methadone should be used with caution in patients with hypothyroidism, adrenocortical insufficiency, prostatic hyperplasia, hypotension, shock, inflammatory or obstructive bowel disorders or myasthenia gravis. Cases of QT interval prolongation and torsades de pointes have been reported during treatment with methadone, particularly at high doses (>100 mg/day). Methadone should be administered with caution to patients at risk for development of prolonged QT interval, e.g. in case of − history of cardiac conduction abnormalities, − advanced or ischaemic heart disease, − liver disease, − family history of sudden death, − electrolyte abnormalities, i.e. hypokalaemia, hypomagnesaemia − concomitant treatment with substances that have a potential for QT-prolongation, − concomitant treatment with substances which may cause electrolyte abnormalities, − concomitant treatment with cytochrome P450 CYP3A4 inhibitors (see section 4.5).


7

In patients with recognised risk factors for QT-prolongation, or in case of concomitant treatment with substances that have a potential for QT-prolongation, ECG monitoring is recommended prior to methadone treatment, with a further ECG test at dose stabilisation. ECG monitoring is recommended, in patients without recognised risk factors for QT-prolongation, before dose titration above 100 mg/day and at seven days after titration. Caution should be exercised in patients who are concurrently taking central nervous system (CNS) depressants.

Excipients This medicinal product contains parahydroxybenzoates and may cause allergic reactions (possibly delayed). This medicinal product contains maltitol liquid: patients with rare hereditary problems of fructose intolerance should not take this medicinal product.

4.5 Interaction with other medicinal products and other forms of interaction MAO inhibitors The concurrent use of MAO inhibitors is contraindicated (see section 4.3) as they may prolong and enhance the respiratory depressant effects of methadone. CNS depressants Alcohol, anaesthetics, hypnotics and sedatives, barbiturates, phenothiazines, some other major tranquillizers and tricyclic antidepressants may increase the general depressant effects of methadone when used concomitantly (see section 4.4). There are reports that antidepressants (e.g. fluvoxamine and fluoxetine) may increase serum levels of methadone. Histamine H2- antagonists Histamine H2 antagonists such as cimetidine can reduce the protein binding of methadone resulting in increased opiate action.

Rifampicin Reduced plasma levels and increased urinary excretion of methadone can occur with concurrent administration of rifampicin. Adjustment of the dose of methadone may be necessary. Anticonvulsants such as phenytoin, phenobarbital, carbamazepine and primidone Anticonvulsants induce methadone metabolism with the risk of precipitating withdrawal syndrome. Adjustment of the dose of methadone should be considered. pH of urine Substances that acidify or alkalinise the urine may have an effect on clearance of methadone as it is increased at acidic pH and decreased at alkaline pH. Opioid agonist analgesics These agents have additive CNS depression, respiratory depression and hypotension. Opioid antagonists Naloxone and naltrexone antagonises the analgesic, CNS and respiratory depressant effects of methadone and can rapidly precipitate withdrawal symptoms (see section 4.9). Similarly buprenorphine and pentazocine may precipitate withdrawal symptoms. Antiretroviral agents such as nevirapine, efavirenz, nelfinavir, ritonavir Based on the known metabolism of methadone, these agents may decrease plasma concentrations of methadone by increasing its hepatic metabolism. Methadone may increase the plasma concentration of zidovudine. Narcotic withdrawal syndrome has been reported in patients treated with some retroviral agents and methadone concomitantly. Methadone maintained patients beginning antiretroviral therapy should be monitored for evidence of withdrawal and the methadone dose should be adjusted accordingly.


8

Ciprofloxacin Concomitant use may lead to sedation, confusion and respiratory depression.

Other agents Methadone may have an effect on other substances as a consequence of reduced gastrointestinal motility. Pregnancy tests Methadone may interfere with urine testing for pregnancy. Cytochrome P450 3A4 inhibitors Methadone clearance is decreased when co-administered with substances which inhibit CYP3A4 activity, such as some anti-human immunodeficiency (HIV) agents, macrolide antibiotics, cimetidine and azole antifungal agents (since the metabolism of methadone is mediated by the CYP3A4 isoenzyme). St. John's Wort St. John's Wort may lower plasma concentrations of methadone. In patients taking agents affecting cardiac conduction, or substances which may affect electrolyte balance there is a risk of cardiac events when methadone is taken concurrently.

4.6 Fertility, pregnancy and lactation Pregnancy Limited data on the use of methadone in pregnancy in humans show no elevated risk of congenital abnormalities. Withdrawal symptoms / respiratory depression may occur in neonates of mothers who were treated with methadone chronically during pregnancy. Data from animal studies have shown reproduction toxicity (see section 5.3). It is generally advisable not to detoxify the patient, especially after the 20th week of pregnancy, but to administer maintenance treatment with methadone. The use of methadone oral solution just before and during birth is advised against because of the risk of neonatal respiratory depression.

Lactation Methadone is excreted in breast milk and the average milk/plasma ratio is 0.8. Breast-feeding may be given on doses of up to 20 mg per day. At higher doses the benefits of breast-feeding must be weighed against the possible adverse effects on the infant.

4.7 Effects on ability to drive and use machines Methadone has major influence on the ability to drive and use machines, during and after treatment, as it may cause drowsiness and reduce alertness. The time after which such activities may be safely resumed is extremely patient-dependent and must be decided by the physician.

4.8 Undesirable effects The adverse effects of methadone are generally the same as with other opioids, most commonly nausea and vomiting, which are observed in approximately 20% of the patients who undergo methadone out-patient treatment, where the medicinal control is often unsatisfactory. The most serious adverse effect of methadone is respiratory depression, which may emerge during the stabilisation phase. Apnoea, shock and cardiac arrest have occurred. Adverse reactions listed below are classified according to frequency and system organ class. These reactions are more frequently observed in non-opioid-tolerant individuals. Frequency groupings are defined according to the following convention: 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).

System organ class (MedDRA) Frequency Adverse event Blood and lymphatic system disorders Not known Reversible thrombocytopenia has been reported

in opioid-dependent patients with chronic hepatitis.

Metabolism and nutrition disorders Common Fluid retention


9

System organ class (MedDRA) Frequency Adverse event Unknown Anorexia Not known Hypokalaemia, hypomagnesaemia Common Euphoria, hallucinations Psychiatric disorders Uncommon Dysphoria, agitation, insomnia, disorientation,

reduced libido Common Sedation Nervous system disorders Uncommon Headache, syncope

Eye disorders Common Blurred vision, miosis Ear and labyrinth disorders Common Vertigo Cardiac disorders Rare Bradycardia, palpitations, cases of prolonged

QT interval and torsade de pointes have been reported, especially with high doses of methadone.

Vascular disorders Uncommon Facial flush, hypotension Respiratory, thoracic and mediastinal disorders

Uncommon Pulmonary oedema, respiratory depression

Very common Nausea, vomiting Common Constipation

Gastrointestinal disorders

Uncommon Xerostomia, glossitis Hepatobiliary disorders Uncommon Bile duct dyskinesia

Common Transient rash, sweating Skin and subcutaneous tissue disorders Uncommon Pruritus, urticaria, other rash and in very

uncommon cases bleeding urticaria Renal and urinary disorders Uncommon Urinary retention, anti-diuretic effect Reproductive system and breast disorders Uncommon Reduced potency and amenorrhoea

Common Fatigue General disorders and administration site conditions Uncommon Oedema of the lower extremities, asthenia,

oedema Investigations Common Weight increase

4.9 Overdose

Symptoms Serious overdose is characterised by respiratory depression, extreme somnolence progressing to stupor or coma, maximally constricted pupils, skeletal muscle flaccidity, cold and clammy skin and sometimes bradycardia and hypotension. In severe overdose, particularly by the intravenous route, apnoea, circulatory collapse, cardiac arrest and death may occur. Treatment A patent airway and assisted or controlled ventilation must be assured. Narcotic antagonists may be required, but it should be remembered that methadone is a long-acting depressant (36 to 48 hours), whereas antagonists act for 1 to 3 hours, so that treatment with the latter must be repeated as needed. An antagonist should not be administered, however, in the absence of clinically significant respiratory or cardiovascular depression. The administration of naloxone is advised. Oxygen, intravenous fluids, vasopressors and other supportive measures should be employed as indicated. In a person physically dependent on narcotics, administration of the usual dose of a narcotic antagonist will precipitate an acute withdrawal syndrome; use of the antagonist in such a person should be avoided if possible but if it must be used to treat serious respiratory depression it should be administered with great care.

5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs used in opioid dependence ATC code: N07B C02 Methadone is a strong opioid agonist with actions predominantly at the μ receptor. The analgesic activity of the racemate is almost entirely due to the l-isomer, which is at least 10 times more potent as an analgesic than the d-isomer. The d-isomer lacks significant respiratory depressant activity but does have anti-tussive effects. Methadone also has some agonist actions at the κ and δ opiate receptors.


10

These actions result in analgesia, depression of respiration, suppression of cough, nausea and vomiting (via an effect of the chemoreceptor trigger zone) and constipation. An effect on the nucleus of the oculomotor nerve, and perhaps on opioid receptors in the pupillary muscles, causes pupillary constriction. All these effects are reversible by naloxone with pA2 value similar to its anti-antagonism of morphine. Like many basic substances, methadone enters mast cells and releases histamine by a non-immunological mechanism. It causes a dependence syndrome of the morphine type.

5.2 Pharmacokinetic properties Absorption Methadone is one of the more lipid-soluble opioids and is well absorbed from the gastrointestinal tract, but undergoes fairly extensive first-pass metabolism. With an intramuscular dose of 10 mg, a peak plasma level of 75 µg/L is reached in one hour. With regular oral doses of 100-120 mg daily, plasma concentrations rise from trough levels of approximately 500 μg/L to a peak of about 900 μg/L in 4 hours. Marked variations in plasma levels occur in dependent persons on a stable dose of oral methadone, without any relation to symptoms. Distribution Methadone is bound to albumin and other plasma proteins and to tissue proteins (probably lipoproteins), the concentrations in the lung, liver and kidneys being much higher than in blood. The pharmacokinetics of methadone are unusual, in that there is extensive binding to tissue proteins and fairly slow transfer between some parts of this tissue reservoir and the plasma. Methadone is secreted in sweat and found in saliva and in high concentrations in gastric juice. The concentration in cord blood is about half the maternal level. Metabolism The metabolism of methadone is catalysed primarily by CYP3A4, but CYP2D6 and CYP2B6 are also involved, to a smaller extent. Metabolism is mainly N-demethylation, which produces the most important metabolites: 2-ethylidine, 1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenyl-1-pyrrolidine (EMDP), which are both inactive. Hydroxylation to methanol followed by N-demethylation to normethadol also occurs to some extent. Other metabolic reactions also occur, and at least eight other metabolites are known. Elimination The half-life after a single oral dose is 12-18 (mean 15) hours, partly reflecting distribution into tissue stores, as well as metabolic and renal clearance. With regular doses, the tissue reservoir is already partly filled and so the half-life is extended to 13-47 hours (mean 25) hours reflecting only clearance. In the first 96 hours after administration, 15-60% can be recovered from the urine, and as the dose is increased so a higher proportion of unchanged methadone is found there. Acidification of the urine can increase the renal clearance by a factor of at least three, and thus appreciably reduce the half life of elimination. Special populations There are no significant differences in the pharmacokinetics between men and women. The clearance of methadone is decreased only to some extent in the elderly (>65 years).

5.3 Preclinical safety data Methadone at high doses caused birth abnormalities in marmots, hamsters and mice, in which most reports were of exencephaly and defects in the central nervous system. Rachischisis in the cervical region was found occasionally in mice. Non-closure of the neural tube was found in chicken embryos. Methadone was not teratogenic in rats and rabbits. Also a reduced number of young was found in rats and increased mortality, growth retardation, neurological behavioural effects and reduced brain weight were found in the pups. Reduced ossification of the digits, sternum and skull was found in mice and a smaller number of fetuses per litter. No carcinogenicity studies have been carried out.

6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients

Methyl parahydroxybenzoate (E218) Propyl parahydroxybenzoate (E216) Propylene glycol (E1520)


11

Maltitol, liquid (E965) Caramel colour (E150d) Patent blue 85 (E131) Purified water

6.2 Incompatibilities

None known

6.3 Shelf life 2 years Shelf-life after first opening: 50 days

6.4 Special precautions for storage Do not freeze. Keep the bottle tightly closed.

6.5 Nature and contents of container Amber glass bottles with White/yellow plastic child-resistant tamper evident polypropylene closures Pack sizes: 30, 50, 100 or 500 ml. Not all pack sizes may be marketed.

6.6 Special precautions for disposal Any unused product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER Teva UK Limited Brampton Road Hampden Park Eastbourne BN22 9AG United Kindgom

8 MARKETING AUTHORISATION NUMBER(S) PL 00289/1343

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 19/05/2011 10 DATE OF REVISION OF THE TEXT

19/05/2011


12

Module 3


13


14

Module 4 Labelling

Carton:

Bottle label


15

Carton:

Bottle label:


16

Carton:

Bottle label:


17

Carton:


18

Bottle label:


19

Module 5

Scientific discussion during initial procedure

I INTRODUCTION Based on the review of the data on quality, safety and efficacy, the Member States considered that the application for Methadone Hydrochloride sugar Free 1 mg/ml Oral solution (PL 00289/1343; UK/H/3367/001/DC) could be approved. This application was submitted via the Decentralised Procedure (DCP), with the UK as Reference Member State (RMS), and Ireland and the Netherlands as Concerned Member States (CMS). The product is a prescription-only medicine (POM) indicated for use in the treatment of opioid addictions (as a narcotic abstinence syndrome suppressant). The application was made under Article 10(1) of Directive 2001/83/EC, as amended, claiming to be a generic medicinal product of the reference product Methadone Hydrochloride Sugar Free 1 mg/ml Oral Solution (Rosemont Pharmaceuticals Ltd, UK) which was first authorised in June 1998. Methadone is a potent opioid analgesic that acts as a competitive agonist at the μ receptor where the other effects of methadone such as respiratory depression, euphoria, reduced gut motility and physical dependence are also activated. Analgesia, euphoria and dependence as well as respiratory depression may result from effects upon a specialised μ1 receptor, distinct from the μ2 receptor mediating respiratory depression and gut motility. Methadone also acts at the κ receptor mediating spinal analgesia, miosis and sedation. The remaining opioid receptors, δ and σ, are not thought to be significantly affected by methadone. No new non-clinical studies were conducted, which is acceptable given that the application was based on being a generic medicinal product of a reference product that has been licensed for over 10 years. A single-dose, bioequivalence study was submitted to support this application, comparing the test product Methadone Hydrochloride sugar Free 1 mg/ml Oral solution (Teva UK Limited) and the reference product Methadone Hydrochloride Sugar Free 1 mg/1 ml Oral Solution (Rosemont Pharmaceuticals Limited, UK). The bioequivalence study was carried out in accordance with Good Clinical Practice (GCP). With the exception of the bioequivalence study, no new clinical studies were performed, which is acceptable given that the application was based on being a generic medicinal product of a reference product that has been in clinical use for over 10 years. The RMS has been assured that acceptable standards of Good Manufacturing Practice (GMP) are in place for this product type at all sites responsible for the manufacture, assembly and batch release of this products. The RMS and CMS considered that the application could be approved with the end of procedure (Day 210) on 20 April 2011. After a subsequent national phase, the licence was granted in the UK on 19 May 2011.


20

II. ABOUT THE PRODUCT Name of the product in the Reference Member State Methadone Hydrochloride sugar Free 1 mg/ml

Oral solution Name(s) of the active substance(s) (INN) Methadone Hydrochloride Pharmacotherapeutic classification (ATC code) Drugs used in opioid dependence (N07B C02) Pharmaceutical form and strength(s) 1 mg/ml oral solution Reference numbers for the Decentralised procedure UK/H/3367/001/DC Reference Member State (RMS) United Kingdom Concerned Member States (CMS) Ireland and the Netherlands. Marketing Authorisation Number(s) PL 00289/1343 Name and address of the authorisation holder Teva UK Limited, Brampton Road, Hampden

Park, Eastbourne, BN22 9AG, U K.


21

III SCIENTIFIC OVERVIEW AND DISCUSSION III.1 QUALITY ASPECTS S. Active substance INN: Methadone hydrochloride Chemical name: ( ±)-6-Dimethylamino-4,4-diphenylheptan-3-one hydrochloride Structure:

Molecular formula: C21H28ClNO Molecular mass: 345.9 Appearance & solubility: Methadone hydrochloride is a white or almost white crystalline

powder which is soluble in water, freely soluble in alcohol and very slightly soluble in methylene chloride.

Methadone hydrochloride is the subject of a European Pharmacopoeia monograph. All aspects of the manufacture and control of the active substance methadone hydrochloride are covered by a European Directorate for the Quality of Medicines (EDQM) Certificate of Suitability. P. Medicinal Product Other Ingredients Other ingredients consist of the pharmaceutical excipients methyl parahydroxybenzoate (E218), propyl parahydroxybenzoate (E216), propylene glycol (E1520), maltitol liquid (E965), caramel colour (E150d), Patent blue 85 (E131) and purified water All excipients comply with their respective European Pharmacopoeia monograph with the exception of the Patent blue and caramel colour which are controlled to suitable in-house specifications and are in compliance with current EEC directives concerning the use of colouring agents. Satisfactory Certificates of Analysis have been provided for all excipients. None of the excipients contain materials of animal or human origin. No genetically modified organisms (GMO) have been used in the preparation of these products. Pharmaceutical Development The objective of the development programme was to formulate a product that could be considered a generic medicinal product of the reference product Methadone Hydrochloride Sugar Free 1 mg/1 ml Oral Solution (Rosemont Pharmaceuticals Limited, UK). Details of the pharmaceutical development of the product have been supplied and are satisfactory. Comparative impurity profiles have been provided for the proposed and reference products.


22

Manufacturing Process Satisfactory batch formulae have been provided for the manufacture of the product, along with an appropriate account of the manufacturing process. The manufacturing process has been validated using pilot batches and has shown satisfactory results. The applicant has committed to performing process validation with the first three full-scale batches of the drug product. Finished Product Specification The finished product specification proposed is acceptable. Test methods have been described and have been adequately validated. Batch data have been provided and comply with the release specifications. Certificates of Analysis have been provided for all working standards used. Container-Closure System The finished product is packaged in amber glass bottles with a white/yellow child-resistant, tamper-evident polypropylene closure and is available in pack sizes of 30, 50, 100 or 500 ml. It has been stated that not all pack sizes may be marketed, however, the marketing authorisation holder has provided mock-ups for all available pack-sizes. Satisfactory specifications and Certificates of Analysis have been provided for all packaging components. All primary packaging complies with the current European regulations concerning materials in contact with food. Stability of the product Stability studies were performed in accordance with current guidelines on batches of the finished product packed in the packaging proposed for marketing. The data from these studies support a shelf-life of 2 years for the unopened product, which reduces to 50 days once opened, with the storage conditions ‘Do not freeze. Keep the bottle tightly closed’. Bioequivalence/bioavailability Satisfactory certificates of analysis have been provided for the test and reference batches used in the bioequivalence study. Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL), Labels The SmPC, PIL and labels are acceptable. A package leaflet has been submitted to the MHRA along with results of consultations with target patient groups ("user testing"), in accordance with Article 59 of Council Directive 2001/83/EC, as amended. The leaflet conforms to the requirements. The test shows that the patients/users are able to act upon the information that the leaflet contains. MAA form The MAA form is satisfactory. Expert report The quality overall summary has been written by an appropriately qualified person and is a suitable summary of the pharmaceutical dossier. Conclusion There are no objections to the approval of this product from a pharmaceutical viewpoint.


23

III.2 NON-CLINICAL ASPECTS As the pharmacodynamic, pharmacokinetic and toxicological properties of methadone are well-known, no new non-clinical studies are required and none have been provided. The applicant’s non-clinical expert report has been written by an appropriately qualified person and is satisfactory, providing an appropriate review of the products’ pharmacology and toxicology. A suitable justification has been provided for non-submission of an environmental risk assessment. As this product is intended for generic substitution with a currently marketed brand leader, i.e. no increase in environmental burden is anticipated, the justification is accepted. There are no objections to the approval of this product from a non-clinical viewpoint. III.3 CLINICAL ASPECTS Pharmacokinetics In support of this application, the marketing authorisation holder has submitted the following bioequivalence study: An open label, randomised, two-treatment, two period, two-sequence, single dose, crossover study to compare the pharmacokinetics of the test product Methadone Hydrochloride sugar Free 1 mg/ml Oral solution (Teva UK Limited) versus the reference product Methadone Hydrochloride Sugar Free 1 mg/1 ml Oral Solution (Rosemont Pharmaceuticals Limited, UK) in healthy, adult volunteers under fasted conditions. All volunteers received a single 10 mg oral dose administered as 10 ml of solution, of either the test or reference product, following an overnight fast of at least 10 hours. Blood samples were taken for the measurement of pharmacokinetic parameters at pre- and up to 144 hours post dose. The washout period between treatment periods was at least 14 days. The pharmacokinetic results for R-methadone are presented below (geometric Least Squares Mean, ratios and 90% confidence intervals):


24

Treatment AUC0-t

ng/ml/h AUC0-∞

ng/ml/h Cmax

ng/ml Test (mean) 617.1498

741.7096

15.7812

Reference (mean) 627.2358

770.2914

16.2431

*Ratio (90% CI)

97.38 (94.05-100.84%)

95.54 (91.66-99.58%)

97.24 (93.90-100.71%)

AUC0-∞ area under the plasma concentration-time curve from time zero to infinity AUC0-t area under the plasma concentration-time curve from time zero to t hours Cmax maximum plasma concentration

*ln-transformed values The 90% confidence intervals for AUC and Cmax for the test versus reference product of R-methadone are within predefined acceptance criteria specified in the Note for Guidance on the Investigation of Bioavailability and Bioequivalence (CPMP/EWP/QWP/1401/98 Rev 1). Thus, the data support the claim that the test product is bioequivalent to the reference product. Pharmacodynamics No new pharmacodynamic data were submitted and none were required for the application. Efficacy No new efficacy data were submitted and none were required for the application. Safety With the exception of the data generated during the bioequivalence study, no new safety data were submitted and none were required for the application. No new or unexpected safety issues were raised by the bioequivalence data. Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL), Labels The SmPC, PIL and labels are acceptable. The SmPC is consistent with that for the reference product. The PIL is consistent with the SmPC and in-line with current guidelines. The labelling is in-line with current guidelines. Clinical Expert Report The clinical expert report has been written by an appropriately qualified physician and is a suitable summary of the clinical aspects of the dossier. Pharmacovigilance System and Risk Management Plan The Pharmacovigilance System, as described by the applicant, fulfils the requirements and provides adequate evidence that the applicant has the services of a qualified person responsible for pharmacovigilance, and has the necessary means for the notification of any adverse reaction suspected of occurring either in the Community or in a third country. A suitable justification has been provided for not submitting a Risk Management Plan for the product. Conclusion There are no objections to the approval of the application from a clinical viewpoint.


25

IV OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT QUALITY The important quality characteristics of Methadone Hydrochloride sugar Free 1 mg/ml Oral solution are well-defined and controlled. The specifications and batch analytical results indicate consistency from batch to batch. There are no outstanding quality issues that would have a negative impact on the benefit-risk balance. NON-CLINICAL No new non-clinical data were submitted and none are required for an application of this type. The pharmacodynamic, pharmacokinetic and toxicological properties of methadone are well-known. EFFICACY With the exception of the bioequivalence study, no new data were submitted and none are required for applications of this type. Bioequivalence has been demonstrated between the applicant’s Methadone Hydrochloride sugar Free 1 mg/ml Oral solution and its respective reference product. SAFETY With the exception of the bioequivalence study, no new data were submitted and none are required for applications of this type. As the safety profile of methadone is well-known, no additional data were required. No new or unexpected safety concerns arose from the safety data from the bioequivalence study. PRODUCT LITERATURE The SmPCs, PIL and labelling are satisfactory and consistent with that for the reference product, where appropriate. BENEFIT-RISK ASSESSMENT The quality of the product is acceptable, and no new non-clinical or clinical safety concerns have been identified. The bioequivalence study supports the claim that the applicant’s product and the reference product are interchangeable. Extensive clinical experience with methadone is considered to have demonstrated the therapeutic value of the compound. The benefit-risk is, therefore, considered to be positive.


26

Module 6

STEPS TAKEN AFTER INITIAL PROCEDURE - SUMMARY

Date submitted

Application type

Scope Outcome

Documents

Public Assessment Report Decentralised Procedure - · PDF filemethadone hydrochloride sugar free 1 mg/ml oral solution procedure no: uk/h/3367/001/dc uk licence no: pl 00289/1343 teva