Decentralised Procedure
Public Assessment Report
Buprenorphin Libra-Pharm 3 Tage 35 / 52,5 / 70 Mikrogramm/Stunde transdermales Pflaster
Buprenorphine
DE/H/4510/001-003/DC
Applicant: Libra-Pharm GmbH
Reference Member State DE TABLE OF CONTENTS I. INTRODUCTION ...... 4 II. EXECUTIVE SUMMARY ...... 4 II.1 About the product ...... 4 II.2 General comments on the submitted dossier ...... 4 II.3 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 Non-clinical aspects ...... 6 III.3 Clinical aspects ...... 6 IV. BENEFIT RISK ASSESSMENT ...... 8
Buprenorphin Libra-Pharm, DE/H/4510/001-003/DC Public AR Page 2/8 ADMINISTRATIVE INFORMATION
Proposed name of the medicinal Buprenorphin Libra-Pharm 3 Tage 35 / 52,5 / 70 product in the RMS Mikrogramm/Stunde transdermales Pflaster Name of the drug substance (INN Buprenorphine name): Pharmaco-therapeutic group N02AE01 (ATC Code): Pharmaceutical form(s) and transdermal patch; 35 / 52,5 / 70 micrograms/h strength(s): Reference Number(s) for the DE/H/4510/001-003/DC Decentralised Procedure Reference Member State: DE Concerned Member States: LU Libra-Pharm GmbH Zieglerstr. 6 Applicant (name and address) D-52078 Aachen Germany
Buprenorphin Libra-Pharm, DE/H/4510/001-003/DC Public AR Page 3/8 I. INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for Buprenorphin 3- Tagepflaster Libra-Pharm 35/52,5/70 Mikrogramm/h transdermales Pflaster with the following indication: Moderate to severe cancer pain and severe pain which does not respond to non-opioid analgesics.
II. EXECUTIVE SUMMARY II.1 About the product Buprenorphine is a centrally-acting-analgesic that binds to the opioid receptors with high affinity. It acts as a partial μ-opioid receptor agonist as well as a κ-opioid receptor antagonist that may contribute to the high analgesic potential that is associated with a relatively low dependence potential. Buprenorphine slowly dissociates from μ-opioid receptors, which results in a slow onset but relatively long duration of analgesic action.
Pharmacotherapeutic group: Analgesics, opioids, ATC code: N02 AE01
In pain models, buprenorphine showed a broad analgesic and antihyperalgesic profile and was more and longer effective than e.g. morphine or fentanyl. In contrast to other opiate analgesics, buprenorphine showed an antihyperalgesic effect and a ceiling effect on respiratory function at higher dosages.
Buprenorphine has been widely used for two decades and has proved to be a strong analgesic in relieving moderate to severe acute (e.g. post-operative) and chronic pain of malignant and non- malignant origin.
The present formulation of buprenorphine is a transdermal patch developed in three ascending patch sizes with corresponding three ascending loadings and release rates. These are buprenorphine 20 mg (35 μg/h), buprenorphine 30 mg (52.5 μg/h) and buprenorphine 40 mg (70 μg/h).
The proposed indication is:
Moderate to severe cancer pain and severe pain which does not respond to non-opioid analgesics.
The buprenorphine transdermal patch should be replaced after 72 hours at the latest.
II.2 General comments on the submitted dossier This application is considered a “auto-generic” application because the reference medicinal products in the EU (BUP-4 Tagepflaster LIBRAPHARM 35/52,5µg Mikrogramm/h transdermales Pflaster, approved in Germany since July 2001 (registration numbers 47058.00.00, 47058.01.00 and 47058.02.00), being Libra-Pharm GmbH the Marketing Authorization Holder) are identical to the medicinal products for which a Marketing Authorization Application is being submitted.
The present application is submitted under article 10(3) of Directive 2001/83/EC, as amended (“hybrid application”). The difference is the intended application time: Buprenorphin 3-Tagepflaster Libra- Pharm 35/52,5/70 Mikrogramm/h transdermales Pflaster are intended to be worn for 3 days whereas the reference medicinal products are intended to be worn for up to 4 days.
With Germany (DE) as the Reference Member State in this Decentralized Procedure, Libra-Pharm GmbH is applying for the Marketing Authorisations for Buprenorphin Libra-Pharm 3 Tage 35/52,5/70 µg/h in Luxembourg (CMS).
Buprenorphin Libra-Pharm, DE/H/4510/001-003/DC Public AR Page 4/8 II.3 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 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.
Regarding the statement on GMP for the active substance a statement/declaration is provided from the manufacturer responsible for manufacture of the finished product and batch release situated in the EU.
III. SCIENTIFIC OVERVIEW AND DISCUSSION III.1 Quality aspects Drug substance The drug substance buprenorphine used for the manufacture of the transdermal patches is officially supplied by manufacturer A which is holder of a valid CEP. In general, the chemical-pharmaceutical documentation in relation to the active substance buprenorphine is of sufficient quality in terms of the current European regulatory requirements. The control tests and specifications for drug substance product have been adequately drawn up.
The re-test period of the active substance is 3 years if stored in the double polyethylene bags placed inside a cardboard container.
Drug Product In general, the information presented on the quality of the drug product is considered acceptable to guarantee the quality of the buprenorphine transdermal patches.
The drug substance buprenorphine is manufactured by manufacturer B, but it is officially supplied by manufacturer A which is holder of a valid CEP.
The excipients, the manufacturing process and the in-process controls of the drug product correspond to the current standard of pharmaceutical technology and are suitable to guarantee an appropriate product quality.
The description of the analytical test methods is adequate. The validation results are plausible in general.
Relevant quality criteria are specified in accordance with internationally acknowledged pharmacopoeias.
A shelf-life of 36 months without any storage precaution has been proposed for the finished product. Stability data up to 36 months has been submitted for the storage conditions 25°C/60% RH and 40°C/75% RH. All results meet the specified limits. On the basis of the presented data, a shelf-life of 36 months without any storage precaution is accepted.
The following two commitments are made by the applicant: 1. The applicant commits to provide analytical data until 1st December 2016 at the latest of the following test: Formulation with and formulation without the levulinic acid should be manufactured and compared e.g. by means of permeation testing. Should no differences in terms of penetration/permeation behavior be realized between the two just mentioned formulations, the
Buprenorphin Libra-Pharm, DE/H/4510/001-003/DC Public AR Page 5/8 test of levulinic acid content needs not to be included in the finished product specification.
2. The applicant commits to get the primary packaging certified as child-resistant before bringing the proposed buprenorphine transdermal patches on the market.
III.2 Non-clinical aspects Pharmacology, Pharmacokinetics, Toxicology Pharmacodynamic, pharmacokinetic and toxicological properties of buprenorphine are well known. The applicant has submitted a non-clinical overview which adequately summarises the evidence available for the non-clinical pharmacology, pharmacokinetics and toxicology of buprenorphine as derived from studies performed by Grünenthal and/or publically available.
Local tolerance of the buprenorphine patches currently submitted for marketing authorisation has not been evaluated in non-clinical studies. However, this is considered acceptable, since the qualitative and quantitative composition of the transdermal patches is identical to that of the authorized reference patches (BUP-4 Tagepflaster LIBRAPHARM® 35/52,5/70 Mikrogramm/h transdermales Plaster), the only difference being the different application time (3 versus 4 days).
As buprenorphine is a widely used, well-known active substance, further non-clinical studies are not required.
Environmental Risk Assessment (ERA) Since the medicinal products are 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.3 Clinical aspects This application is considered an auto-generic application because the reference medicinal products in the EU (BUP-4 Tagepflaster LIBRAPHARM 35/52,5µg Mikrogramm/h transdermales Pflaster, approved in Germany since July 2001 (registration numbers 47058.00.00, 47058.01.00 and 47058.02.00), being Libra-Pharm GmbH the Marketing Authorization Holder) are identical to the medicinal products for which a Marketing Authorization Application is being submitted.
As the applicant and proposed future MAH of the present application (Libra-Pharm GmbH) and the MAH of the reference medicinal products (Libra-Pharm GmbH and SA Grünenthal N.V.) belong to the same group of companies, submission of bioequivalence studies to demonstrate equivalence are not deemed necessary.
The present application is submitted under article 10(3) of Directive 2001/83/EC, as amended (“hybrid application”). The difference is the intended application time: Buprenorphin Libra-Pharm 3 Tage 35/52,5/70 Mikrogramm/h transdermales Pflaster are intended to be worn for 3 days whereas the reference medicinal products are intended to be worn for up to 4 days.
The efficacy and safety of the reference medicinal product has been demonstrated for both application regimens of 3 and 4 days: • The reference medicinal product in the EU (BUP-4 Tagepflaster LIBRAPHARM® 35/52,5/70 Mikrogramm/h transdermales Pflaster) was first registered in Germany on 24 July 2001 with a 3-day application regimen under the trade name Tridol. The 3-day application regimen was used throughout all clinical trials performed during the initial product development. • On 20 September 2004 a variation to extend the application regimen to 4 days was submitted (procedure number DE/H/0308/001-003/II/006). One additional bioavailability study was submitted evaluating the absorption of buprenorphine from the patch over a 96h-period in comparison to a 72h-period (Study HP5303/04). This variation procedure was approved on 6 April 2005.
Overall, results of the original clinical development program provide evidence for the efficacy and safety of buprenorphine administered as transdermal application when replaced after 3 days.
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Legal Status Prescription only medicine, narcotic drug
User Testing The approved patient information leaflet (PIL) of Transtec 35 micrograms/h transdermal patch, which was successfully tested for readability in 2006 in accordance with article 59 (3) of the Council Directive 2001/83/EC on the target patient group, was used as basis for the preparation of the proposed PIL for Buprenorphin 3-Tagepflaster Libra-Pharm 35/52,5/70 Mikrogramm/h transdermales Pflaster. Since the readability test was performed in 2006, only minor changes in the PIL (e.g. in the section driving and using machines, application time) and adaptations to comply with the current QRD template have been made to the tested PIL. A comparison of the user-tested and the proposed PIL has been provided. No additional readability testing is necessary.
Summary Pharmacovigilance system The applicant has submitted a signed Summary of the applicant's and/or proposed future MAH's Pharmacovigilance System. Provided that the Pharmacovigilance System Master File fully complies with the new legal requirements as set out in the Commission Implementing Regulation and as detailed in the GVP module, the RMS considers the Summary acceptable.
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 buprenorphine transdermal patch.
Important identified risks • Respiratory depression • Drug dependence and withdrawal • Abuse, misuse and diversion • Accidental exposure Important potential risks • N/A Missing information • Safety and efficacy of use during pregnancy and lactation • Safety and efficacy of use in patients < 18 years of age
No additional pharmacovigilance or risk minimisation measures are considered necessary by the applicant.
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP.
An updated RMP should be submitted: - At the request of the RMS; - Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached.
If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the same time, but via different procedures.
Buprenorphin Libra-Pharm, DE/H/4510/001-003/DC Public AR Page 7/8 Periodic Safety Update Report (PSUR) With regard to PSUR submission, the MAH should take the following into account: • PSURs shall be submitted in accordance with the requirements set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. Marketing authorisation holders shall continuously check the European medicines web-portal for the DLP and frequency of submission of the next PSUR. • For medicinal products authorized under the legal basis of Article 10(1) or Article 10a of Directive 2001/83/EC, no routine PSURs need to be submitted, unless otherwise specified in the EURD list. For medicinal products that do not fall within the categories waived of the obligation to submit routine PSURs by the revised pharmacovigilance legislation, the MAH should follow the DLP according to the EURD list.
IV. BENEFIT RISK ASSESSMENT The present application is submitted under article 10(3) of Directive 2001/83/EC, as amended (“hybrid application”). The difference is the intended application time: Buprenorphin 3-Tagepflaster Libra- Pharm 35/52,5/70 Mikrogramm/h transdermales Pflaster are intended to be worn for 3 days whereas the reference medicinal products are intended to be worn for up to 4 days. The efficacy and safety of the reference medicinal product has been demonstrated for both application regimens of 3 and 4 days. Overall, the benefit-risk-balance for the product being subject of this procedure is positive. The application is approved. For intermediate amendments see current product information.
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