Decentralised Procedure. Public Assessment Report. Zolmitriptan Renantos 2.5 mg Orodispersible film 5 mg Orodispersible film DE/H/2295/ /DC

Transcription

1 Bundesinstitut für Arzneimittel und Medizinprodukte Decentralised Procedure Public Assessment Report Zolmitriptan Renantos 2.5 mg Orodispersible film 5 mg Orodispersible film DE/H/2295/ /DC Applicant: Renantos Pharmavertriebsges. mbh, Germany Reference Member State DE The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health. 1/7 Public AR

2 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... 5 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 /7 Public AR

3 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) Zolmitriptan Renantos 2.5 mg Orodispersible Films Zolmitriptan Renantos 5 mg Orodispersible Films Zolmitriptan N02CC03 Selective Serotonin 5-HT1 Agonist Orodispersible Films, 2.5 mg, 5 mg DE/H/2295/ /DC DE AT, BE, DK, ES, FI, FR, IE, IT, NL, NO, PL, PT, SE, UK Renantos Pharmavertriebsgesellschaft mbh Beethovenstraße Leipheim Germany 3/7 Public AR

4 I. INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for Zolmitriptan Renantos 2.5 and 5 mg Orodispersible Films in the acute treatment of migraine headache with or without aura, is approved. II. EXECUTIVE SUMMARY II.1 Problem statement This decentralised application concerns a generic version of zolmitriptan orodispersible tablets, under the trade name Zolmitriptan Renantos 2.5 mg and 5 mg orodispersible film. The data for this application are presented in accordance with Article 10(1) of Directive 2001/83/EC for a known active substance as a so called generic application (Art. 10(2)(b)) in combination with Art. 10(3), so-called hybrid application. Oral zolmitriptan is available in tablets containing 2.5 and 5 mg and Orally Disintegrating Tablets (ODT) containing 2.5 and 5 mg of zolmitriptan. The brand of the originator from Astra Zeneca is Zomig or AscoTop for tablets, Zomig Rapimelt or ZOMIG ZMT or AscoTop Schmelztabletten for the Orally Disintegrating Tablets. Regular tablets and orally disintegrating tablets are bioequivalent. The regulatory approach of combining Art. 10(1) and Art. 10(3) is considered appropriate since Zolmitriptan Renantos is a new pharmaceutical form of zolmitriptan intended to be essentially similar to Zomig Rapimelt in terms of oral bioavailability. The proposed panel of indication and method of administration of Zolmitriptan Renantos 2.5mg/5 mg are those already granted to ZOMIG Rapimelt. Essential similarity is claimed to the originator AscoTop 2.5 mg and 5 mg orodispersible tablets, AstraZeneca, which were licensed in Germany on With Germany acting as the Reference Member State in this Decentralised Procedure, the Applicant is applying for the Marketing Authorisations in AT, BE, DK, ES, FI, FR, IE, IT, NL, NO, PL, PT, SE and UK (both strengths each) as Concerned Member States. The MAA for the 5 mg dose strength was withdrawn in France II.2 About the product The selective serotonin 5-HT1B and 5-HT1D receptor agonist zolmitriptan is thought to interfere with two aspects implicated in the pathophysiology of migraine attacks, i.e. the abnormal dilation of cranial carotid blood vessels and the release of pro-inflammatory neuropeptides from trigeminal neuronal terminals. The reference product ZOMIG Rapimelt marketed by AstraZeneca, is an orally administered tablet formulation of zolmitriptan, which rapidly disintegrates on the tongue and does not require water to aid dissolution or swallowing. Zolmitriptan Renantos developed by APR-Labtec is a new oral formulation, essentially similar to Zomig Rapimelt or AscoTop Schmelztabletten. It uses the proprietary Rapidfilm technology which is a novel, non-mucoadhesive, fast dissolving oral dosage form based on a water soluble polymer. The film disintegrates rapidly within seconds when it is in contact with saliva, it releases the drug in the oral cavity and promotes gastrointestinal absorption which is comparable to immediate release oral solid dosage forms. Zolmitriptan Renantos is proposed to be indicated for the acute treatment of migraine headache with or without aura. 4/7 Public AR

5 II.3 General comments on the submitted dossier This application relates to two dose strengths of zolmitriptan orodispersible films, 2.5 and 5 mg. In line with applicable guidelines, the higher dose was selected for bioequivalence testing under single dose fasted conditions. In-vitro dissolution profiles demonstrated almost quantitative release within 5 minutes under three different ph conditions (ph 1, 4.5, 6.8) when comparing the two generic strengths and the in-vivo tested biobatch with the reference AscoTop. The compositions of both generic formulations are fully dose-proportional. Waiving the bioequivalence study for the lower 2.5 mg formulation is in line with the provisions of section Strength to be investigated of the Guideline on the investigation of bioequivalence, CPMP/QWP/1401/98 Rev.1. II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles With regard to the bioequivalence study APR-ZOL.ODF /102, documents and data are complete in the dossier that was submitted in support of this generic application. Validity and credibility of the study is currently not questionable and the Sponsor confirms that the submitted the bioequivalence study was performed in compliance with Good Laboratory Practice (GLP) / Good Clinical Practice (GCP), including the archiving of essential documents. III. III.1 SCIENTIFIC OVERVIEW AND DISCUSSION Quality aspects Drug substance The quality of the drug substance zolmitriptan is controlled in compliance with the corresponding inhouse monograph. The synthesis of the API has been described in detail. The description of the analytical methods used to analyse the drug substance are adequate, the validation reports and the validation results are plausible. The suitability of the monograph to test the drug substance has been verified. The specification limits set are acceptable. The retest period is stated with 36 months. Drug Product The ingredients and the manufacturing process of the drug product are considered suitable to produce a pharmaceutical product of the proposed quality. The excipients are well known and documented in detail. The product is a preservative-free formulation. The dissolution tests are in accordance with the ICH requirements. The manufacturing process is described in detail (based on processing laminates and orodispersible films). The batch-to-batch reproducibility is acceptable and proven by analysis results laid down. All relevant quality characteristics of the drug substance and the drug product (release and shelf life) are specified. The proposed specification limits are acceptable. The description of the analytical methods used to analyse the drug substance and drug product are adequate, the validation reports and the validation results are plausible. The stability data presently available justify a shelf life of 2 years without any special storage conditions for the package proposed for marketing. 5/7 Public AR

6 III.2 Nonclinical aspects Pharmacodynamic, pharmacokinetic and toxicological properties of zolmitriptan are well known. As zolmitriptan 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. The nonclinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology is adequate. There are no impurity issues from a toxicological perspective. SmPC and PL are essentially in line with the text of the reference product and are satisfactory. III.3 Clinical aspects Pharmacokinetics One bioequivalence study has been carried out with Zolmitriptan Renantos ( Rapidfilm ) 5 mg in comparison with the reference product AscoTop 5 mg Schmelztabletten: Randomized, two-way, crossover, open label, bioequivalence study of Zolmitriptan Rapidfilm 5 mg orodispersible film and AscoTop 5 mg Schmelztabletten (Reference product from AstraZeneca GmbH, Germany) following a single 5 mg oral dose to healthy subjects under fasting conditions (APR-ZOL.ODF /102). Plasma concentrations of zolmitriptan and N-desmethyl-zolmitriptan in human plasma were measured using high performance liquid chromatography (HPLC) with tandem mass spectrometric detection. The validated method allowed determination of zolmitriptan concentration in plasma over the range ng/ml. The 90% confidence intervals of the mean test/reference ratios for the primary variables AUC t, AUC, C max were completely within the predefined acceptance range of %. Therefore, bioequivalence of the test and the reference 5 mg formulation is demonstrated with regard to the rate and extent of absorption for zolmitriptan after single-dose administration under fasting conditions. Times to maximum concentration were similar for the test and reference formulations (2.7 h and 2.2 h, respectively. Data extrapolation to the 2.5 mg strength was justified in line with the provisions of section Strength to be investigated of the Guideline on the investigation of bioequivalence, CPMP/QWP/1401/98 Rev.1. Overall, the test methodology follows the guidelines of the European Commission (Guideline on the readability of the label and package leaflet of medicinal products for human use, Revision January 2009; Update of Directive 2001/83/EC as amended by Directive 2004/27/EC / Guidance concerning consultations with target patient groups for the packet leaflet, May 2006). User testing Both the first and the second test round met the success criteria of 90% of the subjects being able to locate the requested information, and of those, 90% being able to give the correct answer, to indicate that they understood the information presented. The general impression of the PL (Content, language and layout) was mostly positive. In conclusion, the user test for Zolmitriptan Rapidfilm 5 mg is considered acceptable. This result also applies to the leaflet for Zolmitriptan Rapidfilm 2.5 mg, which is identical, apart from the strength component in the product name. 6/7 Public AR

7 Description of Pharmacovigilance System The applicant has provided documents that set out a detailed description of the system of pharmacovigilance. 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. IV. BENEFIT RISK ASSESSMENT The application contains an adequate review of published clinical data and the bioequivalence has been shown in vivo for the 5 mg strength. Data extrapolation to the 2.5 mg strength was justified in line with the provisions of section Strength to be investigated of the Guideline on the investigation of bioequivalence, CPMP/QWP/1401/98 Rev.1. The application is approved. For intermediate amendments see current product information. 7/7 Public AR