Bundesinstitut für Arzneimittel und Medizinprodukte
Decentralised Procedure
RMS Public Assessment Report
DE/H/0742/001/DC Ebastion 10mg DE/H/0742/002/DC Ebastion 20mg Ebastine
Applicant: Lindopharm
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TABLE OF CONTENTS
I. RECOMMENDATION ...... 3 II. EXECUTIVE SUMMARY...... 3 II.1 Problem statement...... 3 II.2 About the product ...... 3 II.3 General comments on the submitted dossier ...... 4 II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles.... 4 II.5 Pharmacovigilance System / Risk Management Plan ...... 4 III. SCIENTIFIC OVERVIEW AND DISCUSSION ...... 4 III.1 Quality aspects...... 4 III.2 Nonclinical aspects ...... 4 III.3 Clinical aspects ...... 5 IV. BENEFIT RISK ASSESSMENT ...... 6 V. PROPOSED CONDITIONS FOR MARKETING AUTHORISATION AND PRODUCT INFORMATION ...... 6 V.1 Proposed list of follow-up measures
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I. RECOMMENDATION
Based on the review of the data and the Applicant’s response to the questions raised by RMS and CMS on quality, safety and efficacy, the RMS considers that the application for Ebastion 10 mg/20 mg film coated tablets in the treatment of allergic rhinitis and Urticaria is approvable provided that the applicant commits to perform a number of post authorisation follow- up measures to be reported back to the Member States within predefined timeframes. A list of such follow-up measures are described in this report.
II. EXECUTIVE SUMMARY
II.1 Problem statement There is mounting evidence of a rise in the prevalence of allergic diseases, including rhinitis, over recent decades. Lifestyle factors may be important given the high prevalence of rhinitis and other allergic diseases found in westernised countries. The increased prevalence in asthma and allergic disease does not seem to be due to a change in genetic risk factors. It can be observed that a number of environmental factors seem to coincide with the onset of allergic disease and when the disease is established, these factors also act as triggers of symptoms.
Antihistamines are still considered the mainstay of therapy for patients with allergic rhinitis. They reduce the symptoms of itching, sneezing, and rhinorrhea, but they have minimal effectiveness with nasal congestion.
Antihistamines have been studied and used for long-term treatment and prophylactic treatment of seasonal and perennial allergic rhinitis. ARIA guidelines indicate that oral antihistamines have a place in treatment of mild intermittent rhinitis, mild persistent rhinitis, and moderate-severe intermittent rhinitis; but they are not recommended for moderate-severe persistent rhinitis unless symptoms persist. Intranasal corticosteroids are considered first-line treatment in this case.
II.2 About the product
Ebastion® 10 & 20 mg film coated tablets are manufactured for its oral use against allergic rhinitis and chronic idiopathic urticaria. Ebastine is an antihistamine with selective peripheral H1-receptor antagonist activity. It belongs to the second generation of non sedative antihistamines as the drug (including its active metabolite) does not cross the blood brain barrier. The new generation of antihistamines is characterized by negligible anticholinergic and antiserotoninergic properties and the lack of sedative effects which first-generation drugs such as diphenhydramine, promethazine, chlorpheniramine, and hydroxyzine exhibit. Chemically ebastine [4'-tert-butyl-4-[4-(diphenylmethoxy)piperidino]butyrophenone, CAS 90729-43- 4] is a well known and well studied agent, quickly absorbed and undergo first pass metabolism to its pharmacologically active, acid metabolite carebastine [4-[4-(4-diphenylmethoxy-1-piperidinyl)-1- oxobutyl]- , -dimethylbenzeneacetic acid, CAS 90729-42-3] and other (inactive) metabolites. The unchanged form was virtually absent from plasma at clinical doses.
Ebastine differs from its earlier antihistamines as it is characterized by its lack of typical adverse effects, such as QT prolongation or torsades de pointes, which have been reported for the clinical use of terfenadine, another new-generation antihistamine, under certain conditions.
Ebastine has been shown to be effective for the treatment of allergic rhinitis or chronic idiopathic urticaria, with only single daily doses. Evidence has been compiled from bibliographical references to demonstrate the clinical efficacy and clinical safety of the proposed medicinal product.
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II.3 General comments on the submitted dossier None.
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 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.
II.5 Pharmacovigilance System / Risk Management Plan A risk management plan is not required.
III. SCIENTIFIC OVERVIEW AND DISCUSSION
III.1 Quality aspects
Drug substance
The drug substance ebastine is described in the European Pharmacopoeia. An ASMF was submitted for the active substance ebastine by the active substance manufacturer. Generally speaking the manufacturing process is adequately described. The drug substance is sufficiently characterized and controlled. The batch results show compliance with the specification. Adequate stability studies have been performed with the drug substance. No significant changes in any parameters were observed. The proposed retest period of 4 years is justified.
Drug Product
The drug products are white film-coated scored tablets containing 10 mg and 20 mg ebastine, respectively. 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 has been performed on 3 pilot scale batches of the 10 mg tablets as well as on two pilot-scale batches and one production batch of the 20 mg tablets. The batch analysis results show that the finished products meet the specifications proposed. Results covering a period of 18 months for long-term and a period of 12 months for intermediate stability studies were submitted. The drug products remained stable under both storage conditions. Although no accelerated storage has been done so far, a limited shelf-life extrapolation of 3 months, corresponding to a shelf-life of 21 months can be regarded as justified.
III.2 Nonclinical aspects
Pharmacology Ebastin is a potent non-sedative H1-receptor antagonist and belongs to the piperidine group of H1- anithistamines. The pharmacology of ebastine is well known. No new data has been submitted and none is considered required.
Pharmacokinetics The pharmacokinetics of ebastine is well known. No new data has been submitted and none is required.
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Orally administered ebastine is absorbed via the intestine and rapidly metabolised to the pharmacologically active first-pass metabolite carebastine via hydroxylation. Beside hydroxylation, dealkylation has been observed. The human enzymes responsible for hydroxylation and N- dealkylation of ebastine have been identified as CYP 3A4 for dealkylation and CYP 2J2 as the predominant hydroxylase in human intestinal microsomes. Due to metabolism via cytochrome P450 oxidases, a substantial pharmacokinetic drug interaction occurs with cytochrome P450-, and especially CYP 3A4 inhibitors.
Toxicology The toxicological properties of ebastine are well known. No new data has been submitted and none is required. Based on conventional studies of acute and repeat dose toxicity, genotoxicity, carcinogenicity and toxicity to reproduction no safety alerts for the clinical use of ebastine have been identified. The reported data on the cardiotoxic potential of ebastine indicates that the parent drug has a substantial arrhythmogenic potential, which is absent from its first-pass metabolite carebastine. Thus, even high dosages of orally administered ebastine, exceeding normal therapeutic doses up to 100 times, are well tolerated, unless first-pass metabolism is blocked by CYP 3A4 inhibitors like e.g. ketokonazole.
III.3 Clinical aspects
Pharmacokinetics The documentation indicates that current standards have been observed for the bioequivalence study with two 20 mg ebastine tablet formulations. Although ebastine is deemed the absorbed parent compound, exclusively the main pharmacodynamically active metabolite carebastine has been evaluated in terms of bioavailability and bioequivalence. Ebastine concentrations amount to approximately 10 – 20 % of carebastine (concentrations e.g. 8.6 vs. 150 ng/ml reported e.g. by Rohatagi, S. et al. Int J Clin Pharmacol Ther 39 (2001) 126) and pronounced variability of the parent compound has been reported (e.g. Lasseter, K. et al. Clin Pharmacokinet 43 (2004) 121). From a clinical/therapeutic point of view systemic ebastine concentrations are considered of minor relevance. Accordingly, the bioequivalence decision based on carebastine only can be regarded acceptable.
The results of the present study with 20 mg formulations can be extrapolated to the 10 mg strength, according to conditions in Note for Guidance on the Investigation of Bioavailability and Bioequivalence CPMP/EWP/QWP/1401/98, section 5.4.
Clinical efficacy and safety Ebastine is a well known and studied substance, so the applicant did not perform own studies to determine clinical efficacy of ebastine. Therefore the evidence of efficacy is literature based (bibliographic). Out of all studies identified on ebastine, 15 studies comprising of 708 patients were included for meta analysis of idiopathic urticaria and 15 studies comprising 4540 patients were included for meta analysis of allergic rhinitis. Studies eligible for metaanalysis were selected on the basis of primary evaluative analyses, which has been performed according to the table of Hierarchy of methodological quality of the studies, i.e. only evidence level Ib studies were included, and on the basis of the Jadad et al. (1996) tool. The studies were published between 1991 and 2003. The meta-analysis compared ebastine mono-therapy with placebo or with other antihistamines (reference treatment). Evidence was found that ebastine in doses 10-20 mg once daily is effective in the treatment of chronic idiopathic urticaria and allergic rhinitis, with equal or better tolerability in comparison to other available therapeutic antihistaminic options.
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IV. BENEFIT RISK ASSESSMENT The application contains an adequate review of published clinical data and the bioequivalence has been shown. The open issues to the concerns with respect to the validity of the bioanalytical measurements were solved. The benefit-risk-relation is considered positive. Overall, Ebastion 10 mg / 20 mg film coated tablets for treatment of allergic rhinitis and Urticaria can be approved.
V. PROPOSED CONDITIONS FOR MARKETING AUTHORISATION AND PRODUCT INFORMATION
V.1 Proposed list of follow-up measures
Follow-up measures: Quality
The following commitments were made:
1. The applicant has made a commitment to perform stability testing on the next three produced production scale batches of each strength under ICH long term conditions at least for the proposed shelf-life and under ICH accelerated conditions for 6 months.
2. A commitment has been made to update the DMF after approval.
Post-authorisation procedures:
The shelf-life of the finished product is now 27 Months (DE/H/0742/001-002/IB/001) The name of the product in the RMS is now Ebastin Lindopharm 10 / 20 mg fct (DE/H/0742/001- 002/IB/002) The commitment regarding the EDMF update has been fulfilled (DE/H/0742/001-002/II/003)
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