Summary Public Assessment Report. Generics. Pregabalina Biofarmoz PT/H/1292/ /DC

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1 Summary Public Assessment Report Generics 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, capsules, hard (Pregabalin) Summary PAR Generics 1/11

2 Summary Public Assessment Report Generics Pregabalin 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, capsules, hard This is a summary of the public assessment report (PAR) for. It explains how 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. For practical information about using, patients should read the package leaflet or contact their doctor or pharmacist. What is and what is it used for? is a generic medicine. This means that is similar to a reference medicine already authorised in the European Union (EU) called Lyrica 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 300 mg, Capsule, hard by Pfizer Limited, registered since belongs to a group of medicines used to treat epilepsy and Generalised Anxiety Disorder (GAD) in adults. Epilepsy: is used to treat a certain form of epilepsy (partial seizures with or without secondary generalisation) in adults. Your doctor will prescribe [Invented name] for you to help treat your epilepsy when your current treatment is not controlling your condition. You should take [Invented name] in addition to your current treatment. [Invented name] is not intended to be used alone, but should always be used in combination with other anti-epileptic treatment. Generalised Anxiety Disorder: is used to treat Generalised Anxiety Disorder (GAD). The symptoms of GAD are prolonged excessive anxiety and worry that are difficult to control. GAD can also cause restlessness or feeling keyed up or on edge, being easily fatigued (tired), having difficulty concentrating or mind going blank, feeling irritable, having muscle tension or sleep disturbance. This is different to the stresses and strains of everyday life. How does work? Pharmacotherapeutic group: Antiepileptics, other antiepileptics. The active substance, pregabalin, is a gamma-aminobutyric acid analogue ((S)-3-(aminomethyl)-5- methylhexanoic acid). Mechanism of action Pregabalin binds to an auxiliary subunit (α 2 -δ protein) of voltage-gated calcium channels in the central nervous system. Summary PAR Generics 2/11

3 How is used? The pharmaceutical form of is capsules, hard and the route of administration is oral. Please read section 3 of the PL for detailed information on dosing recommendations, the route of administration, and the duration of treatment. The medicine can only be obtained with a prescription. What benefits of have been shown in studies? Because is a generic medicine, studies in patients have been limited to tests to determine that it is bioequivalent to the reference medicine, Lyrica. Two medicines are bioequivalent when they produce the same levels of the active substance in the body. The company provided data from the published literature on Pregabalin. What are the possible side effects of? Because 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 restrictions, see the package leaflet. Why is approved? It was concluded that, in accordance with EU requirements, has been shown to have comparable quality and to be bioequivalent/be comparable to the reference medicine. Therefore, the INFARMED, I.P. decided that, as for reference medicine called Lyrica 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 Pregabalina Biofarmoz? A risk management plan - Version 01, DLP 31 May has been developed to ensure that 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, 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. Other information about The marketing authorisation for was granted on The full PAR for can be found on the website For more information about treatment with read the package leaflet or contact your doctor or pharmacist. Summary PAR Generics 3/11

4 Public Assessment Report Scientific discussion 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, capsules, hard (Pregabalin) This module reflects the scientific discussion for the approval of. The procedure was finalised at For information on changes after this date please refer to the module Update. Summary PAR Generics 4/11

5 I. INTRODUCTION Based on the review of the quality, safety and efficacy data, the Member States have agreed in granting a marketing authorisation for 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, capsules, hard, from Biofarmoz - Sociedade Técnico-Medicinal, Unipessoal Lda. The product is indicated for: Epilepsy is indicated as adjunctive therapy in adults with partial seizures with or without secondary generalisation. Generalised Anxiety Disorder is indicated for the treatment of Generalised Anxiety Disorder (GAD) in adults. Posology: The dose range is 150 to 600 mg per day given in either two or three divided doses. Epilepsy Pregabalin treatment can be started with a dose of 150 mg per day given as two or three divided doses. Based on individual patient response and tolerability, the dose may be increased to 300 mg per day after 1 week. The maximum dose of 600 mg per day may be achieved after an additional week. Generalised Anxiety Disorder The dose range is 150 to 600 mg per day given as two or three divided doses. The need for treatment should be reassessed regularly. treatment can be started with a dose of 150 mg per day. Based on individual patient response and tolerability, the dose may be increased to 300 mg per day after 1 week. Following an additional week the dose may be increased to 450 mg per day. The maximum dose of 600 mg per day may be achieved after an additional week. With Portugal as the Reference Member State in this Decentralized Procedure, Biofarmoz - Sociedade Técnico-Medicinal, Unipessoal Lda. is applying for the Marketing Authorisations for Pregabalina Biofarmoz in CMS-IT, The marketing authorization was granted on based on Directive 2001/83/EC article 10.1 (a) (iii) first paragraph (generic medicinal product) and the Marketing Authorisation Holder is Biofarmoz - Sociedade Técnico-Medicinal, Unipessoal Lda. The originator product is Lyrica, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 300 mg, Capsule, hard (strengths, pharmaceutical form) by Pfizer Limited, registered since 6 July Summary PAR Generics 5/11

6 II. QUALITY ASPECTS II.1 Introduction The pharmaceutical form for 25 mg, 50 mg, 75 mg, 100 mg, 150 mg is capsules, hard 25 mg: Hard capsules with white body and white cap. The excipients are: lactose monohydrate, maize starch and talc. Capsules 25 mg shells contain gelatin and titanium dioxide (E171). 50 mg: Hard capsules with white body and white cap. The excipients are: lactose monohydrate, maize starch and talc. Capsules 50 mg shells contain gelatin and titanium dioxide (E171). 75 mg: Hard capsules with white body and red cap. The excipients are: lactose monohydrate, maize starch and talc. Capsules 75 mg shells contain gelatin and titanium dioxide (E171) [body and cap], erythrosine FD&C Red 3 (E127), yellow iron oxide (E172) and red iron oxide (E172) [cap]. 100 mg: Hard capsules with red body and red cap. The excipients are: lactose monohydrate, maize starch and talc. Capsules 100 mg shells contain gelatin, titanium dioxide (E171), erythrosine FD&C Red 3 (E127), yellow iron oxide (E172) and red iron oxide (E172) [body and cap]. 150 mg: Hard capsules with white body and white cap. The excipients are: lactose monohydrate, maize starch and talc. Capsules 150 mg shells contain gelatin and titanium dioxide (E171). Pregabalina Tecnigen 25 mg is available in PVC/PE/PVdC+Aluminium/PVdC blisters containing 14 hard capsules. Pregabalina Tecnigen 50 mg and 100 mg are available in PVC/PE/PVdC+Aluminium/PVdC blisters containing 21 hard capsules. Pregabalina Tecnigen 75 mg and 150 mg are available in PVC/PE/PVdC+Aluminium/PVdC blisters containing 14 and 56 hard capsules (each strength). Not all pack sizes may be marketed. II.2 Drug Substance General Information Nomenclature Recommended international nonproprietary name and other nonproprietary names (BAN, USAN): Pregabalin, Pregabalina, Pregabaline, Pregabalinum Summary PAR Generics 6/11

7 Chemical name: 3-(Aminomethyl)-5-methyl-(3S)- IUPAC Name: (3S)-3-(Aminomethyl)-5-methylhexanoic acid Structure Structural formula Molecular formula C8H17NO2 Molecular weight Appearance Pregabalin is a white to off-white crystalline powder Morphology ManufacturerAPI's crystalline Pregabalin crystallizes as rod and plate shaped particles. Solubility in water in different ph Solubility of Pregabalin was analyzed in its saturated solution at room temperature by HPLC Assay method SI The solutions were stirred for 24 hours. The solubility was checked in water at different ph by using Buffer solutions prepared as recommended in USP. The results of solubility in saturated solutions of Pregabalin are presented in the following table: Name of solvent Solubility in mg/ml Description Water buffer ph Soluble Water buffer ph Soluble Water buffer ph Soluble Water buffer ph Soluble Water buffer ph Sparingly soluble Water buffer ph Soluble Solubility in organic solvents Pregabalin drug substance shows low solubility (upon heating) in 2-Butanol, Methylethyl ketone, Diethyl carbonate, Ethylene glycol and DMSO. Melting point Melting point observed is about 191 C Summary PAR Generics 7/11

8 Comment: There is difference between the melting point result obtained in the capillary (191 C) and the onset temperature observed in the DSC thermogram. This difference most probably relates to the different techniques and the heating rates. Hygroscopicity Hygroscopicity of Crystalline Pregabalin was evaluated according to European Pharmacopoeia 5.02, chapter 5.11, 01/2005. Crystalline Pregabalin was exposed to 80% relative humidity for 24 hours. The sample was weighed before and after storage. No weight increase was observed after 24 hours. In conclusion, according to European Pharmacopoeia 5.02, chapter 5.11, 01/2005: Crystalline Pregabalin is non-hygroscopic. pka pka of Pregabalin are 4.2 and Partition Coefficient* Log P = Elemental Analysis The analysis was performed on a sample of reference standard. The results for 4956ST02-VK-4038 are: C H N Calculated 60.29% 10.68% 8.79% Found 60.38% 10.71% 9.05% * Calculated using Advanced Chemistry Development (ACD/Labs) Software V8.14 for Solaris. Polymorphism Pregabalin exists in one crystalline form according to the research preformed by Manufacturer API. Manufacturer API consistently produces this crystalline form. Latest patent applications describe three crystalline forms and an amorphous form with no X-ray powder pattern or other physical characterization. These forms are not relevant to Teva s process and are not encountered during production or stability of Teva's active ingredient product. Crystalline Pregabalin is anhydrous. It is characterized by XRPD pattern and IR spectrum. The chemical-pharmaceutical documentation and Quality Overall Summary in relation to pregabalin are of sufficient quality in view of the present European regulatory requirements. The control tests and specifications for drug substance product are adequately drawn up. Stability studies have been performed with the drug substance. No significant changes in any parameters were observed. II.3 Medicinal Product The development of the product has been described, the choice of excipients is justified and their functions explained. The product specifications cover appropriate parameters for this dosage form. Validations of the analytical methods have been presented. Batch analysis was provided for 3 batches of Pregabalin 25 mg and 50 mg. For Pregabalin 75 mg, 100 mg and 150 mg, batch analysis was only provided for 2 batches and data on an additional batch is being presented for these dosage strengths. The batch analysis results show that the finished products meet the specifications proposed. Summary PAR Generics 8/11

9 The conditions used in the stability studies are according to the ICH stability guideline. The control tests and specifications for drug product are adequately drawn up. The proposed shelf-life of 36 months without any special storage condition, when packed in transparent PVC/PE/PVdC-Alu/PVdC blisters for the drug product is considered acceptable. III. NON-CLINICAL ASPECTS Pharmacodynamic, pharmacokinetic and toxicological properties of pregabalin are well known. As pregabalin is a widely used, well-known active substance, the applicant has not provided additional studies and further studies are not required. An overview based on literature review is, thus, appropriate. III.1 Ecotoxicity/environmental risk assessment (ERA) Since 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. IV. IV.1 CLINICAL ASPECTS Pharmacokinetics To support the application, the applicant has submitted, as report, two bioequivalence studies, namely, Study PEI-P1-504 a pivotal bioequivalence study in 40 healthy subjects for the 300 mg strength and Study PEI-P1-725, a pivotal bioequivalence study in 30 healthy subjects for the 50 mg strength Study PEI-P1-504: Single dose crossover comparative bioavailability study of pregabalin 300 mg capsules in healthy male volunteers Study PEI-P1-725: Single dose crossover comparative bioavailability study of pregabalin 50 mg capsules in healthy male volunteers The application concerns an immediate release formulation, as capsules of Pregabalin, with 5 different strengths. In principle, the number of studies is sufficient for the applied product. Biowaiver: The general conditions for biowaiver are observed, namely: a) the pharmaceutical products are manufactured by the same manufacturing process, b) the qualitative composition of the different strengths is the same, c) the composition of the strengths are quantitatively proportional d) appropriate in vitro dissolution data confirm the adequacy of waiving additional in vivo bioequivalence testing Assessment of justification for Biowaiver: Study PEI-P1-504 with the 300 mg strength can be used to waive the strengths 75mg, 100mg, 150mg,, as the general conditions for biowaiver are directly applied. Study PEI-P1-725 with the 50 mg Summary PAR Generics 9/11

10 strength can be used to waive the strength 25mg, as again the general conditions for biowaiver are directly applied. Conclusion on bioequivalence studies: Based on the submitted bioequivalence studies 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, capsules, hard is considered bioequivalent with Lyrica, 25 mg, 50 mg, 75 mg, 100 mg, and 150 mg, Capsule, hard. IV.2 Risk Management Plan The MAH has submitted a risk management plan - Version 01, DLP 31 May 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. Summary of Safety Concerns: Summary PAR Generics 10/11

11 Discussion on the clinical aspects This type of application refers to information that is contained in the pharmacological-toxicological and clinical part of the dossier of the authorisation of the reference product. A reference product is a medicinal product authorised and marketed on the basis of a full dossier, i.e. including chemical, biological, pharmaceutical, pharmacological-toxicological and clinical data. This information is not fully available in the public domain. Authorisations for generic products are therefore linked to the original authorized medicinal product, which is legally allowed once the data protection time of the dossier of the reference product has expired. For this kind of application, it has to be demonstrated that the pharmacokinetic profile of the product is similar to the pharmacokinetic profile of the reference product. This generic product can be used instead of its reference product. V. USER CONSULTATION A user consultation with target patient groups on the package information leaflet (PIL) has been performed on the basis of a bridging report making reference to Lyrica 25 mg, hard capsules from Pfizer Limited approved on , procedure nº.eu/1/04/279/ and Pregabalin Pfizer 25 mg, hard capsules from Pfizer Limited approved on , procedure nº.eu/114/916/ the bridging report, submitted by the applicant on June 2014 has been found acceptable. VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION The application for 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, capsules, hard contains adequate quality, non-clinical and clinical data and the bioequivalence has been shown. A benefit/risk ratio comparable to the reference product can therefore be concluded. Summary PAR Generics 11/11