Bundesinstitut für Arzneimittel und Medizinprodukte Decentralised Procedure Public Assessment Report Buprenorphine SUN 2 mg/ 8 mg Sublingual tablets Buprenorphine hydrochloride DE/H/1577/001-002/DC Applicant: Sun Pharmaceuticals Industries Ltd Reference Member State DE The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health. 1/8 Public AR
TABLE OF CONTENTS I. INTRODUCTION... 4 II. EXECUTIVE SUMMARY... 4 II.1 Problem statement... 4 II.2 About the product... 4 II.3 General comments on the submitted dossier... 4 II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles..5 III. SCIENTIFIC OVERVIEW AND DISCUSSION... 5 III.1 Quality aspects... 5 III.2 Nonclinical aspects... 6 III.3 Clinical aspects... 6 IV. BENEFIT RISK ASSESSMENT... 8 2/8 Public AR
ADMINISTRATIVE INFORMATION Proposed name of the medicinal product in the RMS INN (or common name) of the active substance(s): Pharmaco-therapeutic group (ATC Code): Pharmaceutical form(s) and strength(s): Reference Number for the Decentralised Procedure Reference Member State: Member States concerned: Applicant (name and address) Names and addresses of manufacturers responsible for batch release in the EEA Buprenorphine SUN 2 mg, Sublingual tablets Buprenorphine SUN 8 mg, Sublingual tablets Buprenorphine hydrochloride N07BC01 Sublingual tablets, 2 mg / 8mg DE/H/1577/001-002/DC DE ES, FR, NL, IT, UK SUN Pharmaceutical Industries Europe Ltd. Polarisavenue 87 2132 JH Hoofddorp Netherlands SUN Pharmaceutical Industries Europe Ltd. Polarisavenue 87 2132 JH Hoofddorp Netherlands 3/8 Public AR
I. INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for Buprenorphine Sun 2mg & 8mg sublingual tablets, indicated for substitution treatment for opioid drug dependence, within a framework of medical, social and psychological treatment, is approved. II. EXECUTIVE SUMMARY II.1 Problem statement This application is submitted in accordance with Article 10(1) of Directive 2001/83/EC. The reference medicinal product is Subutex 8 mg Sublingual tablets, marketing authorisation holder Schering- Plough, registered in France since 1995-07-31. The product under discussion is based on generic application in reference to the originator products already marketed in several European countries. II.2 About the product Buprenorphine is a synthetic, lipophilic, potent (20-40 times greater analgesic potency than morphine) opioid analgesic effective in the treatment of opioid dependence. It is classified as a partial agonist at µ-opioid receptors. Whereas full µ-receptor agonists, like e.g. heroin or methadone, show a linear dose/effect response, the partial agonist buprenorphine shows a plateaued dose/effect response. The effect is maximal at a defined level and if the dose is increased, no additional effect is observed (e.g. ceiling effect with regard to respiratory depression). With partial agonists, overdose is less likely and less common than with full µ-receptor agonists. The particular aspect of partial agonists is that they can act as antagonists by competing with any full µ-receptor agonist at the µ-receptor binding site. Thus, if a patient is actively using high doses of heroin, administration of buprenorphine could cause withdrawal reactions. Therefore, buprenorphine sublingual tablets are to be taken not earlier than four hours after the last administration of another opioid in opioid-dependent drug addicts who have not undergone previous withdrawal. Buprenorphine s activity in opioid maintenance treatment is attributed to its slowly reversible binding at µ-receptor binding sites which, over a prolonged period, minimises the need of the addicted patient for drugs. Low oral bioavailability (approx. 14%), caused largely by hepatic first-pass metabolism, makes sublingual administration an attractive alternative for treatment. According to literature reports, buprenorphine s sublingual bioavailability is estimated at 51.4% with considerable inter-individual variability (range 12.8-92.2%, Kuhlman JJ et al. 1996). The proposed indication is: Substitution treatment for opioid drug dependence, within a framework of medical, social and psychological treatment. Treatment is intended for use in adults and adolescents aged 16 years or older who have agreed to be treated for addiction. II.3 General comments on the submitted dossier To investigate the pharmacokinetic profile of Buprenorphine Sun 2 mg and 8 mg sublingual tablets, the Applicant has conducted one bioequivalence study comparing the higher 8 mg strength with Subutex 8 mg SL tablets by making reference to section 5.4 of the Note for Guidance on 4/8 Public AR
Bioequivalence and Bioavailability, CPMP/EWP/QWP/1401/98 with regard to data extrapolation to the lower 2 mg strength. The clinical overview (dated 30/09/09) has been written by Dr. Shravanti Bhowmik, M.D. who is currently employed at Sun Pharma Advanced Research Company Ltd. as Medical Advisor. It refers to 17 publications up to year 2009 and meets the expectations on a Clinical Overview for a Decentralised Procedure. II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles. The RMS has been assured that acceptable standards of GMP are in place for these product types at all sites responsible for the manufacture and assembly of this product. 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. The bioequivalence study PKD_08_140 is claimed to adhere to the CHMP guidelines Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95) and has been approved by Ethical Committee to ensure compliance with the Declaration of Helsinki. A quality assurance certificate is included in the final study report. III. SCIENTIFIC OVERVIEW AND DISCUSSION III.1 Quality aspects Drug substance The active substance buprenorphine hydrochloride is described in the European Pharmacopoeia (Ph. Eur.). The quality of the drug substance buprenorphine hydrochloride is controlled according to the methods and specifications described in the ASMF. The suitability of the manufacturing process and the respective controls have been verified and documented in the open and restricted part of the ASMF. Stability studies have been performed with the drug substance. No significant changes in any parameters were observed. The proposed retest period of 24 months is justified. Drug Product The ingredients and the manufacturing process of the sublingual tablets are considered suitable to produce a pharmaceutical product of the proposed quality. As required in Directive 2001/83/EC, the documentation basically provides an adequate synopsis of the method of preparation, mentioning the various stages of production, the in-process controls and batch formula. The manufacturing process demonstrated the consistency of the specifications for the pilot scale batches. The process has been validated adequately by investigating the critical manufacturing steps. The excipients are appropriately controlled, using Ph. Eur. Monograph testing. Satisfactory Certificates of Analysis are supplied. Almost all relevant quality characteristics of the drug substance and the drug product (release and shelf-life) are specified. The proposed limits are acceptable. The description of the analytical methods used to analyse the drug substance and drug product are adequate, the validation results seem plausible. The stability data available justify a shelf life of 30 months. 5/8 Public AR
III.2 Nonclinical aspects Pharmacodynamic, pharmacokinetic and toxicological properties of buprenorphine hydrochloride are well known. As buprenorphine hydrochloride is a widely used, well-known active substance, no further studies are required and the applicant provides none. Overview based on literature review is, thus, appropriate. SmPC and PL are acceptable from the nonclinical point of view. III.3 Clinical aspects Pharmacokinetics Absorption After oral administration buprenorphine undergoes extensive first-pass hepatic metabolism with N- dealkylation and glucuro-conjugation in the small intestine. The use of this medication by the oral route is therefore inappropriate. Even after sublingual administration, absorption of buprenorphine is comparatively slow with peak plasma concentrations being achieved after 90 min. The maximal dose-concentration relationship is reported to be linear between 2 mg and 16 mg. Distribution Absorption of buprenorphine is followed by a rapid distribution phase with a half-life of 2-5 hours. Biotransformation Buprenorphine is metabolised by 14-N-dealkylation and glucuronidation of the parent molecule and the dealkylated metabolite. N-desalkyl-buprenorphine is an µ-agonist with intrinsic activity. Norbuprenorphine contributes to the overall pharmacological effect, however, it is unknown to what extent. Elimination Elimination of buprenorphine is bi-or tri-exponential, with a long terminal elimination phase of 20 to 25 hours, due in part to reabsorption of buprenorphine after intestinal hydrolysis of the conjugated derivative, and in part to the highly lipophilic nature of the molecule. Buprenorphine is essentially eliminated in the faeces by biliary excretion of the glucuro-conjugated metabolites (80%), the rest being eliminated in the urine. To support the application, the Applicant has submitted one fasting single dose bioequivalence study (PKD_08_140) to demonstrate bioequivalence for the higher 8 mg strength with the originator Subutex 8 mg sublingual tablets. The compositions of the two dose strengths applied for within this procedure are fully dose proportional. Buprenorphine was shown to display linear pharmacokinetics in the dose range of 2-16 mg. There is no specific information on any food recommendation (either concomitant water administration or meals) in the originator s SPC. Partial biowaiver to the lower 2 mg strength is applied for by reference to section 5.4 of the Note for Guidance on Bioequivalence and Bioavailability, CPMP/EWP/QWP/1401/98. In bioequivalence study PKD_08_140 it could be demonstrated that the 90% CI for AUC0-t and Cmax were within the 80-125% acceptance range. Maximum plasma concentrations were shown to be reached after about 2 hours. Although both the parent substance buprenorphine and the main metabolite norbuprenorphine were measured, the decision on bioequivalence was based on the parameters calculated for buprenorphine only. This approach is acceptable and in line with the provisions of section 4.1.5 Characteristics to be investigated of the Guideline on the Investigation of Bioequivalence, CPMP/QWP/EWP/1401/98 Rev.1. 6/8 Public AR
Pharmacodynamics N/A Clinical efficacy / Clinical safety The pharmacological and clinical profile of buprenorphine, either administered as intravenous injection, transdermal patch or sublingual tablet, is well established both for analgesia and in substitution therapy for opioid dependence. No further data were provided by the Applicant and none are requested. Pharmacovigilance system Description of Pharmacovigilance System The applicant has provided documents that set out a detailed description of the Sun system of pharmacovigilance (Version 7 dated December 2010). A statement signed by the applicant and the qualified person for pharmacovigilance, indicating that the applicant has the services of a qualified person responsible for pharmacovigilance and the necessary means for the notification of any adverse reaction occurring either in the Community or in a third country has been provided. The Pharmacovigilance system as described by the applicant fulfils the requirements as described in Volume 9A of the Rules Governing Medicinal Products in the European Union 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. Risk Management Plan Based upon a comment made by CMS France on Day 100 a risk management plan is considered to be required for Buprenorphine SUN. In August 2010 the Applicant committed to submit the RMP before finalisation of this procedure. In September 2010 the Applicant made the commitment to submit to AFSSAPS (Agence Française de Sécurité Sanitaire des Produits de Santé) a risk management plan according to the requirements of the RMP already in place for the medicines containing buprenorphine commercialised in France. A short overview of the already established risk management plan for medicinal products containing buprenorphine registered in France has been provided by the Applicant. However, the submitted documents could not be accepted, as they are not targeting Buprenorphine SUN. Additionally the format for EU risk management plans should be used. Therefore, in the Day 120 Assessment Report the Applicant was requested to submit a risk management plan for Buprenorphine SUN in Module 1.8.2 of the updated application dossier before finalisation of this procedure, based on the Template for EU Risk Management Plan (Doc.Ref. EMEA/192632/2006). In response to this request the Applicant submitted an EU RMP based on the above mentioned template. However, the submitted RMP could not be accepted as it was not completely in accordance with the Template for EU Risk Management Plan (Doc.Ref. EMEA/192632/2006). Furthermore, the RMP seemed to be incomplete as some important information was missing. Therefore, in the Day 180 Assessment Report the Applicant was requested to revise the Risk Management Plan closely following the EU template and addressing the following comments: Section 1.5.2 is not in accordance with the EU template. Sections 1.7.2 and 1.7.3 seem to be not complete as further information about comorbidities, epidemiology etc. is missing. In section 2 of the submitted RMP no relevant information is given. Please refer to the template. In section 3 some safety concerns are missing, e.g. hepatitis/hepatic events. 7/8 Public AR
Section 4 is not in accordance with the template. For each important identified or potential risk for which additional risk minimisation measures are planned, information in a table should be provided. Observational studies actually are additional risk minimisation activities. In the table in section 5 of the submitted document information about several safety concerns is missing, for example respiratory depression or hepatitis/hepatic events. No annexes to the RMP have been provided by the Applicant. For example SmPC and Package Leaflet should be attached, but also protocols for proposed studies. In the Day 180 Assessment Report it was stated that the revised version of the Risk Management Plan has to be submitted by the Applicant and assessed by the Reference Member State before the product will be launched on the market. CMS France shared the comments raised by the RMS on the Risk Management Plan and added the following points: Adverse drug reactions (ADR) as a whole should not be considered as an important identified risk but each ADR should be considered separately, if relevant. Epidemiological data on the indication should be provided in section 1.7.1. The answer not applicable is not acceptable. Potential for overdose and for transmission of infectious agents are currently not discussed and should be addressed again. Indeed, regarding overdose, only overdose caring is mentioned. Pharmacovigilance plan (section 2) should be expanded with routine and additional activities. Sections 3 and 4: The MAA should distinguish pharmacovigilance from minimisation activities: intensive monitoring of Pharmacovigilance (accurate documentation of cases, monthly report of Pharmacovigilance ) and observational studies are considered as Pharmacovigilance activities and not a risk minimisation one. Section 4: the MAA should not detail observational studies that were set up by the other pharmaceutical companies marketing Buprenorphine. Those studies should just be mentioned ( Afssaps required observational studies to be performed in order to evaluate the impact of the generics marketing on potential misuse of BHD ). Mention about the further observational study, which is currently under consideration, should be updated once the protocol will be finalised. The protocol should also be provided when available. On Day 204 the Applicant submitted a revised version of the EU Risk Management Plan in Module 1.8.2. As stated in the Day 180 Assessment Report, due date for this submission and the assessment of the submitted documents was before the product will be launched on the market. The revised version of the Risk Management Plan will be assessed by the Reference Member State within 6 weeks after closure of this procedure. The Applicant should commit to revise the Risk Management Plan if necessary depending on the outcome of this assessment. IV. BENEFIT RISK ASSESSMENT The overall risk-benefit balance appears positive. Bioequivalence between Buprenorphine Sun SL Tablets and the originator Subutex SL Tablets was demonstrated. The application is approved. 8/8 Public AR