Public Assessment Report. Scientific discussion. Citalopram Jubilant 10 mg, 20 mg, 30 mg and 40 mg, film-coated tablets.

Transcription

1 Public Assessment Report Scientific discussion Citalopram Jubilant 10 mg, 20 mg, 30 mg and 40 mg, film-coated tablets (citalopram) NL/H/2919/ /DC Date: 28 October 2014 This module reflects the scientific discussion for the approval of Citalopram Jubilant 10 mg, 20 mg, 30 mg and 40 mg, film-coated tablets. The procedure was finalised at 22 April For information on changes after this date please refer to the module Update. This report includes a summary, on pages 9-11.

2 I. INTRODUCTION Based on the review of the quality, safety and efficacy data, the Member States have granted a marketing authorisation for Citalopram Jubilant 10 mg, 20 mg, 30 mg and 40 mg, film-coated tablets from Jubilant Pharmaceuticals N.V. The product is indicated for: Treatment of episodes of major depression. Treatment of panic disorder with or without agoraphobia. A comprehensive description of the indications and posology is given in the SmPC. This decentralised procedure concerns a generic application claiming essential similarity with the innovator products Cipramil 10, 20 and 40 mg tablets (NL License RVG ) which were first registered in the Netherlands in 1997 by Lundbeck B.V. The 10 mg strength is no longer registered. The marketing authorisation has been granted pursuant to Article 10(1) of Directive 2001/83/EC. For Citalopram Jubilant 30 mg the application is based on legal basis Article 10(3) Directive 2001/83, a hybrid application because it concerns a different strength. Reference is made to Cipramil 20 mg tablets. The concerned member states (CMS) involved in this procedure were Cyprus (20 mg only), Denmark, Germany, Sweden and the United Kingdom (10, 20, 40 mg). II. QUALITY ASPECTS II.1 Introduction Citalopram Jubilant 10 mg is a white, round, film-coated tablet debossed with F7 on one side and plain on the other side. Citalopram Jubilant 20 mg is a white oval shaped, biconvex, film-coated tablet with a scoreline on one side, debossed with F on the left side and 8 on the right side of the scoreline and plain on the other side. The tablet can be divided into equal doses. Citalopram Jubilant 30 mg is a white, modified capsule shaped, biconvex, film-coated tablet with a scoreline on both sides, debossed with F and 9 on either side of the scoreline on one side of the tablet. The tablet can be divided into equal doses. Citalopram Jubilant 40 mg is a white oval shaped, biconvex, film-coated tablet with a scoreline on one side, debossed with G on the left side and 1 on the right side of the scoreline and plain on the other side. The tablet can be divided into equal doses. The tablets are packed in Alu/PVC/PVdC or Alu/Alu blisters. The excipients are: Tablet core - microcrystalline cellulose (E460), lactose monohydrate, copovidone (E1201), croscarmellose sodium (E468), maize starch, magnesium stearate (E470b), hypromellose (E464), glycerol (E422) Tablet coating hypromellose, titanium dioxide (E171), macrogol (E1521) The tablet strengths are fully dose proportional. II.2 Drug Substance The active substance is citalopram hydrobromide, an established active substance described in the European Pharmacopoeia (Ph.Eur.). It is a white or almost white crystalline powder which is sparingly soluble in water. Existence of polymorphism was not reported in the literature for this active substance. Citalopram contains one asymmetric carbon; hence, two enantiomers are possible. The CEP procedure is used for the active substance. Under the official Certification Procedures of the EDQM of the Council of Europe, manufacturers or suppliers of substances for pharmaceutical use can 2/11

3 apply for a certificate of suitability concerning the control of the chemical purity and microbiological quality of their substance according to the corresponding specific monograph, or the evaluation of reduction of Transmissible Spongiform Encephalopathy (TSE) risk, according to the general monograph, or both. This procedure is meant to ensure that the quality of substances is guaranteed and that these substances comply with the European Pharmacopoeia. Manufacturing process A CEP has been submitted; therefore no details on the manufacturing process have been included. Quality control of drug substance The active substance specification is considered adequate to control the quality. Analytical methods are validated where necessary. Batch analysis showed satisfactory results. Stability of drug substance Stability data on the active substance have been provided. Assessment thereof was part of granting the CEP and has been granted by the EDQM. A retest period of 4 or 5 years is applied. II.3 Medicinal Product Pharmaceutical development The development of the product has been described, the choice of excipients is justified and their functions explained. The objective was to develop a product having pharmaceutical quantities as close as possible to the innovator product, Cipramil. The choices of the packaging and manufacturing process are justified in relation to the innovator. The manufacture and composition of the bio-batch used in the bioequivalence study is identical to the proposed marketed product. The dissolution tests are in conformity with the bioequivalence guideline. At ph 1.5, 4.5 and 6.8, dissolution profiles of the lower tablet strengths are similar to the 40 mg batch used in the bioequivalence study, since more than 85% of the drug is released in 15 minutes. Dissolution profiles of the Citalopram Jubilant tablets were demonstrated to be similar to the innovator product. The MAH used the test as described in the Ph.Eur. for testing breakability of the 20 mg, 30 mg and 40 mg tablets. Results for these three tablet strengths show the efficacy of the break marks. The pharmaceutical development of the product has been adequately performed. Manufacturing process The tablets are manufactured by wet granulation. The manufacturing process is considered a standard process and has been adequately validated according to relevant European guidelines. Validation data on the product has been presented for 3 pilot-scale batches. Control of excipients The excipients comply with the Ph.Eur. These specifications are acceptable. Quality control of drug product The product specification includes tests for appearance, identification of active substance and colorant, assay, uniformity of dosage units (by content uniformity), subdivision (20, 30 and 40 mg), water content, dissolution, related substances and microbiological quality. The analytical methods are adequately described and validated. Where relevant, the stability indicating nature of analytical procedures is demonstrated. Batch analytical data from the proposed production site have been provided on two pilot/production-scale batches of each tablet strength, demonstrating compliance with the release specification. Stability of drug product Stability data on the product has been provided for two pilot-scales batches of each tablet strength, stored at 25 C/60%RH (12 months) and 40 C/75%RH (6 months). The conditions used in the stability studies are according to the ICH stability guideline. The batches were stored in the proposed package. No significant changes or trends were observed in any of the parameters. Based on the data of 12 months, the claimed shelf life of 2 years is acceptable. No special storage condition is needed. Specific measures concerning the prevention of the transmission of animal spongiform encephalopathies Lactose monohydrate is prepared from milk and calf rennet. Milk is sourced from healthy animals in the same conditions as milk collected for human consumption (Complies EU food hygiene regulations). The production of calf rennet complies with the requirements defined in regulation 3/11

4 999/2001 and other applicable EU legislation. The excipients have been declared by the respective supplier to be without risk of TSE/BSE contamination. Magnesium stearate is manufactured from fatty acid derived from vegetable sources. However, magnesium stearate that is manufactured from fatty acids derived from animal sources may also be used provided the material complies with the recommendations outlined in current version of EMA s Note for guidance on minimizing the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products (EMA/410/01). The TSE/BSE declarations are added. II.4 Discussion on chemical, pharmaceutical and biological aspects Based on the submitted dossier, the member states consider that Citalopram Jubilant has a proven chemical-pharmaceutical quality. Sufficient controls have been laid down for the active substance and finished product. No post-approval commitments were made. III. III.1 NON-CLINICAL ASPECTS Ecotoxicity/environmental risk assessment (ERA) Since Citalopram Jubilant is intended for generic substitution, this will not lead to an increased exposure to the environment. An environmental risk assessment is therefore not deemed necessary. III.2 Discussion on the non-clinical aspects This product is a generic formulation of Cipramil, which is available on the European market. Reference is made to the preclinical data obtained with the innovator product. A non-clinical overview on the pharmacology, pharmacokinetics and toxicology has been provided, which is based on up-todate and adequate scientific literature. The overview justifies why there is no need to generate additional non-clinical pharmacology, pharmacokinetics and toxicology data. Therefore, the member states agreed that no further non-clinical studies are required. IV. IV.1 CLINICAL ASPECTS Introduction Citalopram is a well-known active substance with established efficacy and tolerability. A clinical overview has been provided, which is based on scientific literature. The overview justifies why there is no need to generate additional clinical data. Therefore, the member states agreed that no further clinical studies are required. For this generic application, the MAH has submitted a bioequivalence study, which is discussed below. IV.2 Pharmacokinetics The MAH conducted a bioequivalence study in which the pharmacokinetic profile of the test product Citalopram Jubilant 40 mg (Jubilant Pharmaceuticals N.V., Belgium) is compared with the pharmacokinetic profile of the reference product Cipramil 40 mg tablets (H. Lundbeck A/S-Kobenhavn, Denmark). The choice of the reference product in the bioequivalence study has been justified by comparison of compositions of reference products in different member states. The formula and preparation of the bioequivalence batch is identical to the formula proposed for marketing. Biowaiver Based on the data submitted the following requirements for waiving additional strengths were met: The pharmaceutical products are manufactured by the same manufacturing process. The qualitative composition of the different strengths is the same. 4/11

5 The composition of the strengths are quantitatively proportional. The dissolution profiles of the additional 10, 20 and 30 mg strengths are similar to the profiles of the biobatch 40 mg as a dissolution of ± 85% was achieved within 15 minutes in the relevant ph of 1.5, 4.5 and 6.8. In addition, bioequivalence was shown between the test 40 mg and reference 40mg (see below). A waiver for the additional strengths, Citalopram Jubilant 10 mg, 20 mg and 30 mg, can therefore be granted. Bioequivalence study Design A single-dose, randomised, two-period, two-treatment, two-sequence, crossover bioequivalence study was carried out under fasted conditions in 28 healthy male subjects, aged years. Each subject received a single dose (40 mg) of one of the 2 citalopram formulations. The tablet was orally administered with 240 ml water after an overnight fast. There were 2 dosing periods, separated by a washout period of 15 days. Blood samples were collected pre-dose and at 0.50, 1.00, 1.50, 2.00, 2.33, 2.67, 3.00, 3.33, 3.67, 4.00, 4.33, 4.67, 5.00, 5.33, 5.67, 6.00, 7.00, 8.00, 12.00, 18.00, 24.00, and hours after administration of the products. The design of the study is acceptable. A study in the fasting condition is appropriate as citalopram can be taken with or without food. The wash-out period of 15 days (i.e. at least 5 terminal half-lives to exclude carry-over effects) is agreed. Analytical/statistical methods The analytical method has been adequately validated and is considered acceptable for analysis of the plasma samples. The methods used in this study for the pharmacokinetic calculations and statistical evaluation are considered acceptable. Citalopram is a racemic mixture of 50% S-enantiomer and 50% R-enantiomer. However, only the S- enantiomer is pharmacologically active. According to guideline, if one enantiomer is pharmacologically active and the other is inactive or has a low contribution to activity, it is sufficient to demonstrate bioequivalence for the active enantiomer. Both enantiomers were measured in the study. Bioequivalence was based on the S-citalopram and results from R-citalopram were reported as supportive information. This is agreed. Results One subject was withdrawn prior to dosing in period II and one subject dropped out of the study. Twenty-six subjects completed the study and were eligible for pharmacokinetic analysis. Table 1. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, t max (median, range)) of S-citalopram under fasted conditions. Treatment N=26 AUC 0-72 ng.h/ml C max ng/ml t max h Test 1141 ± ± ( ) t 1/2 h 28.6 ± 8 Reference 1158 ± ± (1.5 7) *Ratio (90% CI) 0.98 ( ) 1.00 ( ) 30.8 ± AUC 0-72 area under the plasma concentration-time curve from time zero to 72 hours C max maximum plasma concentration t max time for maximum concentration t 1/2 half-life *ln-transformed values Table 2. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, t max (median, range)) of R-citalopram under fasted conditions. Treatment AUC 0-72 C max t max t 1/2 5/11

6 N=26 ng.h/ml ng/ml h h Test 1483 ± ± ( ) Reference 1507 ± ± ( ) *Ratio (90% CI) 0.98 ( ) 1.00 ( ) 41.3 ± ± AUC 0-72 area under the plasma concentration-time curve from time zero to 72 hours C max maximum plasma concentration t max time for maximum concentration t 1/2 half-life *ln-transformed values Conclusion on bioequivalence study: The 90% confidence intervals calculated for AUC 0-72 and C max are within the bioequivalence acceptance range of Based on the submitted bioequivalence study Citalopram Jubilant 40 mg is considered bioequivalent with Citapramil 40 mg tablets. The MEB has been assured that the bioequivalence study has been conducted in accordance with acceptable standards of Good Clinical Practice (GCP, see Directive 2005/28/EC) and Good Laboratory Practice (GLP, see Directives 2004/9/EC and 2004/10/EC). IV.3 Risk Management Plan The MAH 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 Citalopram Jubilant. No additional risk management measures are required, which is in line with the innovator product. 6/11

7 IV.4 Discussion on the clinical aspects For this authorisation, reference is made to the clinical studies and experience with the innovator product Cipramil tablets. No new clinical studies were conducted. The MAH demonstrated through a bioequivalence study that the pharmacokinetic profile of the product is similar to the pharmacokinetic profile of this reference product. Risk management is adequately addressed. This generic medicinal product can be used instead of the reference product. 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 testing method included 22 participants. The initial testing involved 2 participants to identify any major changes needed to the PIL. The 1st round of testing involved the initial interviewing and testing of 10 participants. The 2nd round of testing involved the interviewing and testing of 10 additional participants. The questionnaire included 22 questions (19 specific to the medicine and 3 general questions about the format of the leaflet). Both rounds of testing showed that 100% of the participants were able to trace the information for the questions 100% of the time. 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. VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION Citalopram Jubilant 10 mg, 20 mg and 40 mg, film-coated tablets have a proven chemicalpharmaceutical quality and are generic forms of Cipramil 10, 20 and 40 mg tablets, a well-known medicinal product with an established favourable efficacy and safety profile. Citalopram Jubilant 30 mg is approved following a hybrid application. Bioequivalence has been shown to be in compliance with the requirements of European guidance documents. There was no discussion in the CMD(h). Agreement between member states was reached during a written procedure. The member states, on the basis of the data submitted, considered that essential similarity has been demonstrated for Citalopram Jubilant 10 mg, 20 mg and 40 mg film-coated tablets with the reference product, and have therefore granted a marketing authorisation. The decentralised procedure was finalised with a positive outcome on 22 April There were no post-approval commitments made during the procedure. 7/11

8 STEPS TAKEN AFTER THE FINALISATION OF THE INITIAL PROCEDURE - SUMMARY Scope Procedure number Type of modification Date of start of the procedure Date of end of the procedure Approval/ non approval Assessment report attached 8/11

9 Summary Public Assessment Report Generics Citalopram Jubilant 10 mg, 20 mg, 30 mg and 40 mg, film-coated tablets (citalopram) NL/H/2919/ /DC Date: 28 October /11

10 Summary Public Assessment Report Generics Citalopram Jubilant 10 mg, 20 mg, 30 mg and 40 mg, film-coated tablets Active substance: citalopram This is a summary of the public assessment report (PAR) for Citalopram Jubilant 10 mg, 20 mg, 30 mg and 40 mg, film-coated tablets. It explains how this medicine was assessed and its authorisation recommended as well as its conditions of use. It is not intended to provide practical advice on how to use Citalopram Jubilant. For practical information about using this medicine, patients should read the package leaflet or contact their doctor or pharmacist. What is Citalopram Jubilant and what is it used for? Citalopram Jubilant is a generic medicine. This means that it is similar to a reference medicine already authorised in the European Union (EU) called Cipramil tablets. This medicine is used in the treatment of episodes of major depression. Citalopram is also beneficial in relieving symptoms of patients who tend to suffer from panic attacks. How does this medicine work? Citalopram is a Selective Serotonin Reuptake Inhibitor (SSRI) and belongs to a group of medicines known as antidepressants. These medicines help to correct certain chemical imbalances in the brain that are causing the symptoms of major depression or panic disorders. How is this medicine used? The pharmaceutical form of Citalopram Jubilant is a film-coated tablet and the route of administration is oral. The medicine can only be obtained with a prescription. Please read section 3 of the PL for detailed information on dosing recommendations, the route of administration, and the duration of treatment. How has this medicine been studied? Because this is a generic medicine, studies in patients have been limited to tests to determine that it is bioequivalent to the reference medicine, Cipramil. Two medicines are bioequivalent when they produce the same levels of the active substance in the body. What are the possible side effects of this medicine? Because Citalopram Jubilant is a generic medicine and is bioequivalent to the reference medicine, its benefits and possible side effects are taken as being the same as the reference medicine. For the full list of all side effects reported with this medicine, see section 4 of the package leaflet. Why is this medicine approved? It was concluded that, in accordance with EU requirements, this medicine has been shown to have comparable quality and to be bioequivalent to the reference medicine Cipramil. Therefore, the Medicines Evaluation Board of the Netherlands decided that, as for the reference medicine, the benefits are greater than its risk and recommended that it can be approved for use. What measures are being taken to ensure the safe and effective use of this medicine? A risk management plan has been developed to ensure that Citalopram Jubilant is used as safely as possible. Based on this plan, safety information has been included in the summary of product characteristics and the package leaflet for this medicine, including the appropriate precautions to be followed by healthcare professionals and patients. Known side effects are continuously monitored. Furthermore new safety signals reported by patients/healthcare professionals will be monitored/reviewed continuously as well. 10/11

11 Other information about this medicine In the Netherlands, the marketing authorisation for Citalopram Jubilant 10 mg, 20 mg, 30 mg and 40 mg, film-coated tablets was granted on 19 June The full PAR for this medicine can be found on the website For more information about treatment with this medicine, read the package leaflet ( or contact your doctor or pharmacist. This summary was last updated in October /11