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Public Assessment Report

Decentralised Procedure

Entacapone 200 mg Film-Coated Tablets

Procedure No: UK/H/4846/DC

UK Licence No: PL 29831/0471

Wockhardt UK Limited

Entacapone 200 mg Film-Coated Tablets UK/H/4846/001/DC

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LAY SUMMARY On 01 March 2012, the Medicines and Healthcare products Regulatory Agency (MHRA) granted a Marketing Authorisation to Wockhardt UK Limited for the medicinal product Entacapone 200 mg Film-Coated Tablets (PL 29831/0471; UK/H/4846/001/DC). This is a prescription-only medicine (POM) used together with levodopa to treat Parkinson’s disease. Entacapone Tablets aid levodopa in relieving the symptoms of Parkinson's disease. Entacapone Tablets have no effect on relieving the symptoms of Parkinson´s disease unless taken with levodopa. The active ingredient in Entacapone 200 mg Film-Coated Tablets is entacapone, which belongs to a group of medicines called catechol-O-methyl transferase (COMT) inhibitors. No new or unexpected safety concerns arose from this application and it was therefore judged that the benefits of taking Entacapone 200 mg Film-Coated Tablets outweigh the risks and a Marketing Authorisation was granted.


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TABLE OF CONTENTS

Module 1: Information about initial procedure Page 4 Module 2: Summary of Product Characteristics Page 5 Module 3: Product Information Leaflet Page 12 Module 4: Labelling Page 13 Module 5: Scientific Discussion Page 22 1 Introduction 2 Quality aspects 3 Non-clinical aspects 4 Clinical aspects 5 Overall conclusions Module 6 Steps taken after initial procedure


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Module 1 Information about the initial procedure

Product Name Entacapone 200 mg Film-Coated Tablets Type of Application Generic, Article 10(1) Active Substance Entacapone Form Film-coated tablets Strength 200 mg MA Holder

Wockhardt UK Limited Ash Road North Wrexham LL13 9UF UK

Reference Member State (RMS) UK Concerned Member States (CMS) Germany and Malta Procedure Number UK/H/4846/001/DC Timetable Day 210 – 18 January 2012


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Module 2 Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Entacapone 200 mg Film-Coated Tablets 2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 200mg entacapone. For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet Brownish-orange, oval, biconvex film-coated tablet with “W477” engraved on one side and plain on the other side.

4 CLINICAL PARTICULARS 4.1 Therapeutic indications

Entacapone is indicated as an adjunct to standard preparations of levodopa/benserazide or levodopa/carbidopa for use in adult patients with Parkinson’s disease and end-of-dose motor fluctuations, who cannot be stabilised on those combinations.

4.2 Posology and method of administration

Entacapone should only be used in combination with levodopa/benserazide or levodopa/carbidopa. The prescribing information for these levodopa preparations is applicable to their concomitant use with entacapone. Posology One 200 mg tablet is taken with each levodopa/dopa decarboxylase inhibitor dose. The maximum recommended dose is 200 mg ten times daily, i.e. 2,000 mg of entacapone. Entacapone enhances the effects of levodopa. Hence, to reduce levodopa-related dopaminergic adverse reactions, e.g. dyskinesias, nausea, vomiting and hallucinations, it is often necessary to adjust levodopa dosage within the first days to first weeks after initiating entacapone treatment. The daily dose of levodopa should be reduced by about 10-30% by extending the dosing intervals and/or by reducing the amount of levodopa per dose, according to the clinical condition of the patient. If entacapone treatment is discontinued, it is necessary to adjust the dosing of other antiparkinsonian treatments, especially levodopa, to achieve a sufficient level of control of the parkinsonian symptoms. Entacapone increases the bioavailability of levodopa from standard levodopa/benserazide preparations slightly (5-10%) more than from standard levodopa/carbidopa preparations. Hence, patients who are taking standard levodopa/benserazide preparations may need a larger reduction of levodopa dose when entacapone is initiated. Renal impairment: Renal insufficiency does not affect the pharmacokinetics of entacapone and there is no need for dose adjustment. However, for patients who are receiving dialysis therapy, a longer dosing interval may be considered (see section 5.2). Hepatic impairment: see section 4.3. Elderly: No dosage adjustment of entacapone is required for elderly patients. Pediatric population: The safety and efficacy of Entacapone Tablets in children below age 18 have not been established. No data are available.


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Method of administration Entacapone is administered orally and simultaneously with each levodopa/carbidopa or levodopa/benserazide dose. Entacapone can be taken with or without food (see section 5.2).

4.3 Contraindications - Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. - Hepatic impairment. - Phaeochromocytoma. - Concomitant use of entacapone and non-selective monoamine oxidase (MAO-A and MAO-B)

inhibitors (e.g. phenelzine, tranylcypromine). - Concomitant use of a selective MAO-A inhibitor plus a selective MAO-B inhibitor and entacapone

(see section 4.5). - A previous history of neuroleptic malignant syndrome (NMS) and/or non-traumatic rhabdomyolysis.

4.4 Special warnings and precautions for use

Rhabdomyolysis secondary to severe dyskinesias or neuroleptic malignant syndrome (NMS) has been observed rarely in patients with Parkinson’s disease. NMS, including rhabdomyolysis and hyperthermia, is characterised by motor symptoms (rigidity, myoclonus, tremor), mental status changes (e.g. agitation, confusion, coma), hyperthermia, autonomic dysfunction (tachycardia, labile blood pressure) and elevated serum creatine phosphokinase. In individual cases, only some of these symptoms and/or findings may be evident. Neither NMS nor rhabdomyolysis have been reported in association with entacapone treatment from controlled trials in which entacapone was discontinued abruptly. Since the introduction into the market, isolated cases of NMS have been reported, especially following abrupt reduction or discontinuation of entacapone and other concomitant dopaminergic medicinal products. When considered necessary, withdrawal of entacapone and other dopaminergic treatment should proceed slowly, and if signs and/or symptoms occur despite a slow withdrawal of entacapone, an increase in levodopa dosage may be necessary. Entacapone therapy should be administered cautiously to patients with ischemic heart disease. Because of its mechanism of action, entacapone may interfere with the metabolism of medicinal products containing a catechol group and potentiate their action. Thus, entacapone should be administered cautiously to patients being treated with medicinal products metabolised by catechol-O-methyl transferase (COMT), e.g. rimiterole, isoprenaline, adrenaline, noradrenaline, dopamine, dobutamine, alpha-methyldopa, and apomorphine (see also section 4.5). Entacapone is always given as an adjunct to levodopa treatment. Hence, the precautions valid for levodopa treatment should also be taken into account for entacapone treatment. Entacapone increases the bioavailability of levodopa from standard levodopa/benserazide preparations 5-10% more than from standard levodopa/carbidopa preparations. Consequently, adverse dopaminergic reactions may be more frequent when entacapone is added to levodopa/benserazide treatment (see also section 4.8). To reduce levodopa-related dopaminergic adverse reactions, it is often necessary to adjust levodopa dosage within the first days to first weeks after initiating entacapone treatment, according to the clinical condition of the patient (see sections 4.2 and 4.8). Entacapone may aggravate levodopa-induced orthostatic hypotension. Entacapone should be given cautiously to patients who are taking other medicinal products which may cause orthostatic hypotension. In clinical studies, undesirable dopaminergic effects, e.g. dyskinesia, were more common in patients who received entacapone and dopamine agonists (such as bromocriptine), selegiline or amantadine compared to those who received placebo with this combination. The doses of other antiparkinsonian medicinal products may need to be adjusted when entacapone treatment is initiated. Entacapone in association with levodopa has been associated with somnolence and episodes of sudden sleep onset in patients with Parkinson’s disease and caution should therefore be exercised when driving or operating machines (see also section 4.7).


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For patients experiencing diarrhoea, a follow-up of weight is recommended in order to avoid potential excessive weight decrease. Prolonged or persistent diarrhoea appearing during use of entacapone may be a sign of colitis. In the event of prolonged or persistent diarrhoea, the drug should be discontinued and appropriate medical therapy and investigations considered. Pathological gambling, increased libido and hypersexuality have been reported in Parkinson’s disease patients treated with dopamine agonists and other dopaminergic treatments such as entacapone in association with levodopa. For patients who experience progressive anorexia, asthenia and weight decrease within a relatively short period of time, a general medical evaluation including liver function should be considered.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction of entacapone with carbidopa has been observed with the recommended treatment schedule. Pharmacokinetic interaction with benserazide has not been studied. In single-dose studies in healthy volunteers, no interactions were observed between entacapone and imipramine or between entacapone and moclobemide. Similarly, no interactions between entacapone and selegiline were observed in repeated-dose studies in parkinsonian patients. However, the experience of the clinical use of entacapone with several medicinal products, including MAO-A inhibitors, tricyclic antidepressants, noradrenaline reuptake inhibitors such as desipramine, maprotiline and venlafaxine, and medicinal products that are metabolised by COMT (e.g. catechol-structured compounds: rimiterole, isoprenaline, adrenaline, noradrenaline, dopamine, dobutamine, alpha-methyldopa, apomorphine, and paroxetine) is still limited. Caution should be exercised when these medicinal products are used concomitantly with entacapone (see also sections 4.3 and section 4.4). Entacapone may be used with selegiline (a selective MAO-B inhibitor), but the daily dose of selegiline should not exceed 10 mg. Entacapone may form chelates with iron in the gastrointestinal tract. Entacapone and iron preparations should be taken at least 2-3 hours apart (see section 4.8). Entacapone binds to human albumin binding site II which also binds several other medicinal products, including diazepam and ibuprofen. Clinical interaction studies with diazepam and non-steroidal anti-inflammatory medicinal products have not been carried out. According to in vitro studies, significant displacement is not anticipated at therapeutic concentrations of the medicinal products. Due to its affinity to cytochrome P450 2C9 in vitro (see section 5.2), entacapone may potentially interfere with medicinal products with metabolism dependent on this isoenzyme, such as S-warfarin. However, in an interaction study with healthy volunteers, entacapone did not change the plasma levels of S-warfarin, while the AUC for R-warfarin increased on average by 18% [CI90 11–26%]. The INR values increased on average by 13% [CI90 6–19%]. Thus, control of INR is recommended when entacapone treatment is initiated for patients receiving warfarin.

4.6 Fertility, Pregnancy and lactation

No overt teratogenic or primary foetotoxic effects were observed in animal studies in which the exposure levels of entacapone were markedly higher than the therapeutic exposure levels. As there is no experience in pregnant women, entacapone should not be used during pregnancy. In animal studies entacapone was excreted in milk. The safety of entacapone in infants is unknown. Women should not breast-feed during treatment with entacapone.

4.7 Effects on ability to drive and use machines

Entacapone Tablets in association with levodopa may have major influence on the ability to drive and use machines. Entacapone may, together with levodopa, cause dizziness and symptomatic orthostatism. Therefore, caution should be exercised when driving or using machines.

Patients being treated with entacapone in association with levodopa and presenting with somnolence and/or sudden sleep onset episodes must be instructed to refrain from driving or engaging in activities where impaired alertness may put themselves or others at risk of serious injury or death (e.g. operating machines) until such recurrent episodes have resolved (see also section 4.4).


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4.8 Undesirable effects The most frequent adverse reactions caused by entacapone relate to the increased dopaminergic activity and occur most commonly at the beginning of the treatment. Reduction of levodopa dosage decreases the severity and frequency of these reactions. The other major class of adverse reactions are gastrointestinal symptoms, including nausea, vomiting, abdominal pain, constipation and diarrhoea. Urine may be discoloured reddish-brown by entacapone, but this is a harmless phenomenon. Usually the adverse reactions caused by entacapone are mild to moderate. In clinical studies the most common adverse reactions leading to discontinuation of entacapone treatment have been gastrointestinal symptoms (e.g. diarrhoea, 2.5%) and increased dopaminergic adverse reactions of levodopa (e.g. dyskinesias, 1.7%). Dyskinesias (27%), nausea (11%), diarrhoea (8%), abdominal pain (7%) and dry mouth (4.2%) were reported significantly more often with entacapone than with placebo in pooled data from clinical studies involving 406 patients taking the medicinal product and 296 patients taking placebo. Some of the adverse reactions, such as dyskinesia, nausea, and abdominal pain, may be more common with the higher doses (1,400 to 2,000 mg per day) than with the lower doses of entacapone. The following adverse reactions, listed below in Table 1, have been accumulated both from clinical studies with entacapone and since the introduction of entacapone into the market. Table 1. Adverse drug reactions*

Psychiatric disorders Common: Insomnia, hallucinations, confusion, paroniria Very rare: Agitation

Nervous system disorders Very common: Dyskinesia Common: Parkinsonism aggravated, dizziness, dystonia, hyperkinesia Cardiac disorders** Common: Ischemic heart disease events other than myocardial infarction (e.g. angina pectoris) Uncommon: Myocardial infarction

Gastrointestinal disorders Very common: Nausea Common: Diarrhoea, abdominal pain, dry mouth, constipation, vomiting Very rare: Anorexia Not known: Colitis

Hepatobiliary disorders Rare: Hepatic function tests abnormal Not known: Hepatitis with mainly cholestatic features (see section 4.4.) Skin and subcutaneous tissue disorders Rare: Erythematous or maculopapular rash Very rare: Urticaria Not known: Skin, hair, beard and nail discolorations

Renal and urinary disorders Very common: Urine discoloration General disorders and administration site conditions Common: Fatigue, sweating increased, fall Very rare: Weight decrease

* Adverse reactions are ranked under headings of frequency, the most frequent first, using 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, since no valid estimate can be derived from clinical trials or epidemiological studies).

** The incidence rates of myocardial infarction and other ischemic heart disease events (0.43% and 1.54%, respectively) are derived from an analysis of 13 double-blind studies involving 2082 patients with end-of-dose motor fluctuations receiving entacapone.


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Entacapone in association with levodopa has been associated with isolated cases of excessive daytime somnolence and sudden sleep onset episodes. Parkinson’s disease patients treated with dopamine agonists and other dopaminergic treatments such as entacapone in association with levodopa, especially at high doses, have been reported as exhibiting signs of pathological gambling, increased libido and hypersexuality, which were generally reversible upon reduction of the dose or treatment discontinuation. Isolated cases of NMS have been reported following abrupt reduction or discontinuation of entacapone and other dopaminergic treatments. Isolated cases of rhabdomyolysis have been reported.

4.9 Overdose

The post-marketing data include isolated cases of overdose in which the reported highest daily dose of entacapone has been 16,000 mg. The acute symptoms and signs in these cases of overdose included confusion, decreased activity, somnolence, hypotonia, skin discolouration and urticaria. Management of acute overdose is symptomatic.

5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties

Pharmacotherapeutic group: other dopaminergic agents, ATC code: N04BX02. Entacapone belongs to a new therapeutic class, catechol-O-methyl transferase (COMT) inhibitors. It is a reversible, specific, and mainly peripherally acting COMT inhibitor designed for concomitant administration with levodopa preparations. Entacapone decreases the metabolic loss of levodopa to 3O-methyldopa (3-OMD) by inhibiting the COMT enzyme. This leads to a higher levodopa AUC. The amount of levodopa available to the brain is increased. Entacapone thus prolongs the clinical response to levodopa. Entacapone inhibits the COMT enzyme mainly in peripheral tissues. COMT inhibition in red blood cells closely follows the plasma concentrations of entacapone, thus clearly indicating the reversible nature of COMT inhibition. Clinical studies In two phase III double-blind studies in a total of 376 patients with Parkinson’s disease and end-ofdose motor fluctuations, entacapone or placebo was given with each levodopa/dopa decarboxylase inhibitor dose. The results are given in Table 2. In study I, daily ON time (hours) was measured from home diaries and in study II, the proportion of daily ON time. Table 2. Daily ON time (Mean ±SD) Study I: Daily On time (h) Entacapone

(n=85) Placebo (n=86) Difference

Baseline 9.3±2.2 9.2±2.5 Week 8-24 10.7±2.2 9.4±2.6 1 h 20 min (8.3%)

CI95% 45 min, 1 h 56 min

Study II: Proportion of daily On time (%) Entacapone

(n=103) Placebo (n=102) Difference

Baseline 60.0±15.2 60.8±14.0 Week 8-24 66.8±14.5 62.8±16.80 4.5% (0 h 35 min)

CI95% 0.93%, 7.97%

There were corresponding decreases in OFF time. The % change from baseline in OFF time was –24% in the entacapone group and 0% in the placebo group in study I. The corresponding figures in study II were –18% and –5%.


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5.2 Pharmacokinetic properties General characteristics of the active substance Absorption There are large intra- and interindividual variations in the absorption of entacapone. The peak concentration (Cmax) in plasma is usually reached about one hour after ingestion of a 200 mg entacapone tablet. The substance is subject to extensive first-pass metabolism. The bioavailability of entacapone is about 35% after an oral dose. Food does not affect the absorption of entacapone to any significant extent. Distribution After absorption from the gastrointestinal tract, entacapone is rapidly distributed to the peripheral tissues with a distribution volume of 20 litres at steady state (Vdss). Approximately 92 % of the dose is eliminated during ß-phase with a short elimination half-life of 30 minutes. The total clearance of entacapone is about 800 ml/min. Entacapone is extensively bound to plasma proteins, mainly to albumin. In human plasma the unbound fraction is about 2.0% in the therapeutic concentration range. At therapeutic concentrations, entacapone does not displace other extensively bound substances (e.g. warfarin, salicylic acid, phenylbutazone, or diazepam), nor is it displaced to any significant extent by any of these substances at therapeutic or higher concentrations. Metabolism A small amount of entacapone, the (E)-isomer, is converted to its (Z)-isomer. The (E)-isomer accounts for 95% of the AUC of entacapone. The (Z)-isomer and traces of other metabolites account for the remaining 5%. Data from in vitro studies using human liver microsomal preparations indicate that entacapone inhibits cytochrome P450 2C9 (IC50 �4 µM). Entacapone showed little or no inhibition of other types of P450 isoenzymes (CYP1A2, CYP2A6, CYP2D6, CYP2E1, CYP3A and CYP2C19) (see section 4.5). Elimination The elimination of entacapone occurs mainly by non-renal metabolic routes. It is estimated that 8090% of the dose is excreted in faeces, although this has not been confirmed in man. Approximately 1020% is excreted in urine. Only traces of entacapone are found unchanged in urine. The major part (95%) of the product excreted in urine is conjugated with glucuronic acid. Of the metabolites found in urine only about 1% have been formed through oxidation. Characteristics in patients The pharmacokinetic properties of entacapone are similar in both young and elderly adults. The metabolism of the medicinal product is slowed in patients with mild to moderate liver insufficiency (Child-Pugh Class A and B), which leads to an increased plasma concentration of entacapone in both the absorption and elimination phases (see section 4.3). Renal impairment does not affect the pharmacokinetics of entacapone. However, a longer dosing interval may be considered for patients who are receiving dialysis therapy.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential. In repeated dose toxicity studies, anaemia most likely due to iron chelating properties of entacapone was observed. Regarding reproduction toxicity, decreased foetal weight and a slightly delayed bone development were noticed in rabbits at systemic exposure levels in the therapeutic range.


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6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients

Core: Mannitol 25 Povidone K-30 Crospovidone Mannitol Silica, colloidal anhydrous Purified talc Magnesium stearate Coat: Opadry II 85G53680 Orange containing: Polyvinyl alcohol Talc Titanium dioxide (E171) Macrogol 3350 Lecithin (soya) (E322) Iron oxide yellow (E172) Iron oxide red (E172)

6.2 Incompatibilities

Not applicable 6.3 Shelf life

Alu-alu blister packs: 24 months HDPE container: 24 months (unopened). After first opening of the bottle use the medicinal product within six months.

6.4 Special precautions for storage

This medicinal product does not require any special temperature storage conditions.

6.5 Nature and contents of container Alu/Alu blister packs of 30, 60, 100, or 200 tablets. HDPE container with polypropylene screw cap closure of 30, 60, 100, or 200 tablets. Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements. 7 MARKETING AUTHORISATION HOLDER

Wockhardt UK Ltd Ash Road North Wrexham LL13 9UF UK

8 MARKETING AUTHORISATION NUMBER(S) PL 29831/0471

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

01/03/2012 10 DATE OF REVISION OF THE TEXT

01/03/2012


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Module 3


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Module 4


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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 Entacapone 200 mg Film-Coated Tablets (PL 29831/0471; UK/H/4846/001/DC) could be approved. The product is a prescription-only medicine (POM) indicated as an adjunct to standard preparations of levodopa/benserazide or levodopa/carbidopa for use in adult patients with Parkinson’s disease and end-of-dose motor fluctuations, who cannot be stabilised on those combinations. The active ingredient, entacapone, is a reversible, specific, and mainly peripherally acting catechol-O-methyl transferase (COMT) inhibitor designed for concomitant administration with levodopa preparations. Entacapone decreases the metabolic loss of levodopa to 3-O-methyldopa (3-OMD) by inhibiting the COMT enzyme; as a result, the amount of levodopa available to the brain is increased. Entacapone thus prolongs the clinical response to levodopa. This application was submitted using the Decentralised Procedure, with the UK as Reference Member State (RMS), and Germany and Malta as Concerned Member States (CMS). The application was submitted under Article 10(1) of Directive 2001/83/EC, as amended, claiming to be a generic medicinal product of Comtess 200mg film coated tablets (Orion Corporation, Finland) which was authorised in the EEA via the Centralised Procedure on 19 September 1998. No new non-clinical data have been submitted, which is acceptable given that that the application was based on being a generic medicinal product of an originator product that has been in clinical use for over 10 years. A single-dose, bioequivalence study was submitted to support this application, comparing the test product Entacapone 200 mg Film-Coated Tablets (Wockhardt UK Limited, UK) versus the reference product Comtess 200 mg film coated tablets (Orion Corporation, Finland). The bioequivalence study was carried out in accordance with Good Clinical Practice (GCP). The RMS has been assured that acceptable standards of Good Manufacturing Practice (GMP) are in place at all sites responsible for the manufacture, assembly and batch release of this product. For manufacturing sites within the community, the RMS has accepted copies of current manufacturer authorisations issued by inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those sites. For manufacturing sites outside the Community, the RMS has accepted copies of current GMP Certificates of satisfactory inspection summary reports, ‘close-out letters’ or ‘exchange of information’ issued by the inspection services of the competent authorities (or those countries with which the EEA has a Mutual Recognition Agreement for their own territories) as certification that acceptable standards of GMP are in place at those non-Community sites.


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The RMS and CMS considered that the application could be approved at the end of procedure (Day 210) on 18 January 2012. After a subsequent national phase, a licence was granted in the UK on 02 March 2012. II. ABOUT THE PRODUCT Name of the product in the Reference Member State

Entacapone 200 mg Film-Coated Tablets

Name of the active substance(s) (INN) Entacapone Pharmacotherapeutic classification (ATC code)

Other dopaminergic agents, (N04BX02).

Pharmaceutical form and strength(s) Film-coated tablets Reference number for the Mutual Recognition Procedure

UK/H/4846/001/DC

Reference Member State (RMS) United Kingdom Concerned Member States (CMS) Germany and Malta Marketing Authorisation Number PL 29831/0471 Name and address of the authorisation holder Wockhardt UK Limited

Ash Road North Wrexham LL13 9UF UK

III SCIENTIFIC OVERVIEW AND DISCUSSION III.1 QUALITY ASPECTS ACTIVE SUBSTANCE INN: Entacapone Chemical name: (2E)-2-Cyano-3-(3,4-dihydroxy-5-nitrophenyl-N,N diethylacrylamide Structure:

N CH3

CH3HO

O2NO

OH Molecular formula: C14H15N3O5 Molecular mass 305.3 Appearance: A yellow to orange yellow crystalline powder, practically insoluble in

water, soluble or sparingly soluble in acetone, slightly soluble in anhydrous ethanol.

Entacapone is not the subject of a European Pharmacopoeia monograph. Synthesis of the active substance from the designated starting materials has been adequately described and appropriate in-process controls and intermediate specifications are applied. Satisfactory specification tests are in place for all starting materials and reagents and these are supported by relevant Certificates of Analysis. Appropriate proof-of-structure data have been supplied. All potential known impurities have been identified and characterised. An appropriate specification is provided for the active substance. Analytical methods have been appropriately validated and are satisfactory for ensuring compliance with the relevant specification limits. Batch analysis data are provided and comply with the proposed specification.


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Satisfactory Certificates of Analysis have been provided for all working standards. Suitable specifications have been provided for all packaging used. The primary packaging has been shown to comply with current guidelines concerning contact with foodstuff. Appropriate stability data have been generated to support a suitable retest period for the active substance when stored in the proposed packaging Medicinal Product Other Ingredients Other ingredients consist of the pharmaceutical excipients mannitol 25, povidone K-30, crospovidone, mannitol, colloidal anhydrous silica, purified talc, magnesium stearate, (making up the tablet core), and Opadry II 85G53680 Orange (the tablet coating). Opadry II 85G53680 Orange contains polyvinyl alcohol, talc, titanium dioxide (E171), macrogol 3350, lecithin (soya) (E322), iron oxide yellow (E172) and iron oxide red (E172). Appropriate justification for the inclusion of each excipient has been provided. All excipients comply with their respective European Pharmacopoeia monograph, with the exception of lecithin (E322), iron oxide yellow (E172) and iron oxide yellow (E172) – these comply with suitable National Formulary specifications. In addition, the specifications for iron oxide yellow (E172) and iron oxide red (E172) are in compliance with current European Directives concerning use of colouring agents in foodstuffs. Satisfactory Certificates of Analysis have been provided for all excipients, showing compliance with the proposed specifications. With the exception of magnesium stearate, none of the excipients contain materials of animal or human origin. The supplier of magnesium stearate has provided a Certificate of Suitability from the European Directorate for the Quality of Medicines (EDQM) to show that it is manufactured in-line with current European guidelines concerning the minimising of risk of transmission of Bovine Spongiform Encephalopathy/Transmissible Spongiform Encephalopathies (BSE/TSE). No genetically modified organisms (GMO) have been used in the preparation of these excipients. Pharmaceutical Development The objective of the development programme was to formulate a safe, efficacious, stable product that could be considered a generic medicinal product of the reference product, Comtess 200 mg film coated tablets (Orion Corporation, Finland) Suitable pharmaceutical development data have been provided for this application. Comparative in-vitro dissolution profiles have been provided for this product and the reference product. Manufacturing Process A satisfactory batch formula has been provided for the manufacture of the product, along with an appropriate account of the manufacturing process. The manufacturing process has been validated with pilot-scale batches and has shown satisfactory results. The Marketing Authorisation Holder has committed to performing process validation studies on full-scale production batches as soon as they are available.


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Control of Finished Product The finished product specification is satisfactory. Test methods have been described and adequately validated, as appropriate. Batch data have been provided and comply with the release specification. Certificates of Analysis have been provided for any working standards used. Container-Closure System The tablets are packaged in either aluminium blisters strips or high-density polyethylene (HDPE) bottles, with polypropylene screw cap closures, in pack sizes of 30, 60, 100 and 200 film-coated tablets. Not all pack sizes may be marketed. Satisfactory specifications and Certificates of Analysis have been provided for all packaging. All primary packaging complies with the European Pharmacopoeia and relevant regulations regarding use of materials in contact with food. Stability of the product Finished product stability studies were performed in accordance with current guidelines on batches of finished product in the packaging proposed for marketing. Based on the results, the following shelf-life/storage conditions have been accepted:

- 24 months for the product packaged in blister packs, with no special storage temperature storage conditions.

- 24 months for the product packaged in unopened HDPE bottles and 6 months for the product once the bottle is opened, with no special storage temperature storage conditions.

. Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and, Labelling The SmPC, PIL and labelling are acceptable from a pharmaceutical perspective. 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 results indicate that the package leaflet is well-structured and organised, easy to understand and written in a comprehensive manner. The test shows that patients/users are able to act upon the information that it contains. MAA (Marketing Authorisation Application) form The MAA form is satisfactory. Expert report (Quality Overall Summary) The quality overall summary has been written by an appropriately qualified person and is a suitable summary of the pharmaceutical dossier. Conclusion The grant of a Marketing Authorisation is recommended.


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III.2 NON-CLINICAL ASPECTS As the pharmacodynamic, pharmacokinetic and toxicological properties of entacapone are well-known, no new non-clinical data have been submitted and none are required. The applicant’s non-clinical overview has been written by an appropriately qualified person and is satisfactory, providing an appropriate review of the relevant non-clinical pharmacology, pharmacokinetics and toxicology. Suitable justification has been provided for non-submission of an Environmental Risk Assessment As this product is intended for generic substitution with a product that is already marketed, no increase in environmental burden is anticipated. Thus, the justification for non-submission of an Environmental Risk Assessment is accepted. The grant of a Marketing Authorisation is recommended.


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III.3 CLINICAL ASPECTS The clinical pharmacology of entacapone is well-known. With the exception of data from the bioequivalence study described below, no new pharmacodynamic or pharmacokinetic data are provided or required for this application. Pharmacokinetics In support of the application, the Marketing Authorisation Holder submitted the following bioequivalence study: A randomised, open-label, two-treatment, four period, two-sequence, replicate, crossover comparative study to compare the test product Entacapone 200 mg Film-Coated Tablets (Wockhardt UK Limited, UK) versus the reference product Comtess 200 mg film-coated tablets (Orion Corporation, Finland) in healthy adults under fasting conditions The subjects were given a single dose of 200 mg of either the test or reference product with 240 ml of water, after at least a 10 hour overnight fast. Blood samples were collected before and up to 10 hours after each administration. The washout period between the treatment arms was at least 7 days. The pharmacokinetic results are presented below. Pharmacokinetic parameters (geometric least squares mean, ratios and 90% confidence intervals [CI] of

entacapone (n=51) Parameters (units)

Entacapone 200 mg (Test)

Comtess 200 mg (Reference)

Test/Ref Ratio (%)

90% CI

AUC0-t (ng.h/mL)

2058.6079 1964.5625 104.79 100.64-109.11

AUC0-inf (ng.h/mL)

2089.5803 2004.7691 104.23 100.10-108.54

Cmax (ng/mL)

1604.1226 1507.8285 106.39 97.18-116.46

AUC0-t area under the plasma concentration-time curve from time zero to t hours AUC0-inf area under the plasma concentration-time curve from time zero to infinity Cmax maximum plasma concentration Ratios and 90% CI calculated from ln-transformed data The 90% confidence intervals of the test/reference ratio for AUC0-t, AUC0-inf and Cmax lie within the acceptable limits of 80% to 125%, in line with the Note for Guidance on the Investigation Bioavailability and Bioequivalence (CPMP/EWP/QWP/1401/98). Thus, the data support the claim that the test product Entacapone 200 mg Film-Coated Tablets (Wockhardt UK Limited, UK) is bioequivalent to the reference product Comtess 200 mg film-coated tablets (Orion Corporation, Finland). Efficacy The efficacy of entacapone is well-known. No new efficacy data have been submitted and none are required for applications of this type.

Safety With the exception of the data generated during the bioequivalence study, no new safety data were submitted and none were required for this application. No new or unexpected safety issues were raised by the bioequivalence study data. 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


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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. Suitable justification has been provided for not submitting a Risk Management Plan for this product. Summary of Product Characteristics (SmPC), Product Information Leaflet (PIL), Labels The SmPC, PIL and labels are acceptable from a clinical perspective. The SmPC is consistent with that for the reference product. The PIL is consistent with the details in the SmPC and is in-line with the current guidelines. The labelling is in-line with the current guidelines. Clinical Expert Report (Clinical Overview) The clinical overview has been written by an appropriately qualified physician and is a suitable summary of the clinical aspects of the dossier. Conclusion The grant of a Marketing Authorisation is recommended.


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IV OVERALL CONCLUSION AND BENEFIT/RISK ASSESSMENT QUALITY The important quality characteristics of Entacapone 200 mg Film-Coated Tablets 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. EFFICACY With the exception of the bioequivalence study, no new data were submitted and none are required for this type of application. Bioequivalence has been demonstrated between the applicant’s Entacapone 200 mg Film-Coated Tablets and the reference product Comtess 200 mg film-coated tablets (Orion Corporation, Finland). SAFETY With the exception of the bioequivalence study, no new data were submitted and none are required for this type of application. As the safety profile of entacapone is well-known, no additional data were required. PRODUCT LITERATURE The SmPC, PIL and labelling are satisfactory and consistent with those for the reference product, where appropriate, and consistent with current guidelines. BENEFIT/RISK ASSESSMENT The quality of the product is acceptable and no new non-clinical or clinical safety concerns have been identified. Extensive clinical experience with entacapone is considered to have demonstrated the therapeutic value of the product. The benefit/risk is, therefore, considered to be positive.


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Module 6

STEPS TAKEN AFTER INITIAL PROCEDURE - SUMMARY

Date submitted

Application type

Scope Outcome

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