Bundesinstitut für Arzneimittel und Medizinprodukte

Decentralised Procedure

Public Assessment Report

Excedrin AP

Acetylsalicylic Acid 250mg 250mg 65 mg

DE/H/1804/001/DC

Applicant: Consumer Health Care

Date: 10.08.2009

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. 4

III SCIENTIFIC OVERVIEW AND DISCUSSION 5

III.1 QUALITY ASPECTS 5 III.2 NONCLINICAL ASPECTS 5 III.3 CLINICAL ASPECTS 7

IV BENEFIT RISK ASSESSMENT 8

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ADMINISTRATIVE INFORMATION

Proposed name of the medicinal Excedrin AP product in the RMS Acetylsalicyic acid 250 mg, paracetamol 250 mg, caffeine INN (or common name) of the active 65 mg substance(s): N02BA Pharmaco-therapeutic group (ATC Code): Film-coated tablets; 250 mg / 250 mg / 65 mg Pharmaceutical form(s) and strength(s): DE/H/1804/001/DC Reference Number for the Decentralised Procedure Germany Reference Member State: DE/H/1804/001/DC Member States concerned: United Kingdom Applicant (name and address) Novartis Consumer Health GmbH Zielstattstr. 40 81379 München Names and addresses of Novartis Consumer Health GmbH, Zielstattstraße 40 manufacturers responsible for batch DE - 81379 München release in the EEA

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I INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the application for Excedrin, in the acute treatment of headache and of migraine attacks with or without aura accompanied by pain of at least moderate intensity is approved.

II EXECUTIVE SUMMARY

II.1 Problem statement Excedrin 250mg/250mg/65mg film-coated tablets were first registered by Bristol Myers in the USA in 1977. The product is currently approved in 25 countries worldwide with Novartis Consumer Health as the Marketing Authorisation Holder. Similar formulations of the fixed APC-combination are also approved and marketed all over Europe (Austria, Belgium, Bulgaria, Czech Republic, France, Germany, Greece, Italy, Lithuania, The Netherlands, Poland, Portugal, Romania, Slovak Republic, Slovenia, Spain and the UK) in partly different dose relations (e.g. 250mg / 250mg / 50mg or 250mg / 200mg / 50mg APC in the RMS).

II.2 About the product Acetylsalicylic acid and paracetamol are well known substances with and antipyretic properties extensively used for the treatment of mild to moderate pain or fever. Acetylsalicylic acid has additional anti-inflammatory properties. Caffeine has been shown to potentiate the analgesic effect of acetylsalicylic acid as well as of paracetamol and also other and is widely used in various combination products. The claimed indication is the acute treatment of headache and of migraine attacks with or without aura accompanied by pain of at least moderate intensity

II.3 General comments on the submitted dossier This decentralised application concerns a fixed combination of acetylsalicylic acid, paracetamol and caffeine (APC) under several trade names. In this Assessment Report, the name EXCEDRIN is used. As safety and efficacy of the three active substances are well known from single drug products as well as from various APC-combination products the application submitted under Article 8 (3) of Directive 2001/83/EC is based in part on bibliographic data supported by original data concerning the new product.

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.

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III SCIENTIFIC OVERVIEW AND DISCUSSION

III.1 Quality aspects

Drug substance Validation of the process, including reference to starting materials, critical steps and controls is provided in the assessment of all manufacturer to the EDQM. The active substances are described in the European Pharmacopoeia (Ph. Eur.). The quality of the drug substances are controlled in compliance with the corresponding monograph of the European Pharmacopoeia (Ph Eur). The suitability of the monograph to test the drug substance has been verified and is documented with help of the EDQM. Actual CEP´s for all substances have been submitted.

Drug product The product is presented as coated oblong direct compressed tablet. The excipients used in the products are conventional pharmaceutical ingredients. The function of each ingredient included in the product has been described. Levels of excipients have been selected on the basis of optimisation studies. Preliminary compatibility studies were performed using potentially useful excipients for the intended formulations. Dissolution profiles have been presented.

The finished product specifications are in compliance with the general pharmacopoeial requirements and the batch data submitted, and are controlled with valid methods. A shelf life of 24 months is accepted.

III.2 Nonclinical aspects

Pharmacodynamic, pharmacokinetic and toxicological properties of the single actives are well known. Combination products containing acetylsalicylic acid, paracetamol and caffeine as actives can also be considered well established. No new non-clinical studies have been submitted which would alter the positive benefit-risk ratio for this clinically established combination. This submission is based on bibliographic review of the active ingredients and several study reports on the combination of acetylsalicylic acid, paracetamol and caffeine. None of the data presented in this application are formally GLP-compliant or respectively GLP status of these cannot be verified. The quality of the data provided is nonetheless considered acceptable, because the results have in generally been confirmed by different authors and by clinical experience.

Pharmacology Clinically pharmacodynamic interactions, particularly potentiation of paracetamol- and acetylsalicylic acid-induced analgesia by caffeine, have been demonstrated in a number of animal studies and were confirmed in clinical studies (potentiation of paracetamol- and acetylsalicylic acid-induced analgesia by caffeine). No information however is given about the most effective ratio between acetylsalicylic acid, paracetamol and caffeine. This will be documented on clinical level.

Pharmacokinetics The kinetics of paracetamol, acetylsalicylic acid, and caffeine, singly and in combination, are clinically well established. Animal studies on combinations of the active substances show that acetylsalicylic acid marginally increases the absorption of paracetamol after oral administration, and paracetamol marginally slows plasma elimination of salicylate. At low (therapeutic) doses in both rats and dogs, the kinetics of oral paracetamol and acetylsalicylic acid are not significantly affected by combined administration with each other, with or without caffeine in the same proportions as in Excedrin. It is concluded from these data that pharmacokinetic interactions between the constituents of the combination product are minor and are unlikely to have a clinically significant effect on pharmacodynamics or toxicity.

Toxicology Clinical toxicity of the single substances is well known. There is also large clinical experience for the triple combination acetaminophen, acetylsalicylic acid and caffeine.

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The acute oral toxicity of various formulations of tablets containing the triple combination 250 mg acetaminophen, 250 mg acetylsalicylic acid and 65 mg caffeine was tested in female mice (Internal study Bristol-Myers – see module 4). Comparing the doses of acetaminophen and acetylsalicylic acid in the triple combination product at median lethal doses (i.e. both just below 500 mg/kg) to the LD50 values for the individual active substances (338 and 250 mg/kg, respectively; table 2.6.6-1) there was no potentiation of acute toxicity when the three active substances are administered in combination.

Repeat dose toxic effects of all three actives are also well characterized. The most prominent toxic effects of the combination are gastrointestinal and renal toxicity, similar to the effects of the individual active ingredient. The non-clinical data indicate that there is no potentiation of either gastrointestinal or renal toxicity by the combination in comparison to the individual active substances. In fact, paracetamol was found to block the gastrointestinal toxicity induced by acetylsalicylic acid in repeat dose toxicity studies in rodents. In the kidney, animal data show that acetylsalicylic acid may deplete glutathione and potentially increase paracetamol-induced renal toxicity (via its active metabolite, NAPQI). In renal medullary cells in vitro, caffeine enhances the cytotoxicity of paracetamol at relatively high concentrations, but potentiation of renal toxicity by paracetamol plus acetylsalicylic acid has not been seen in vivo in animal and human epidemiological studies.

There are no mutagenicity data for the combination of the active substances acetylsalicylic acid, paracetamol and caffeine. Paracetamol and caffeine are both clastogenic due to direct effects on DNA synthesis (inhibition of ribonucleotide reductase and poly(ADP-ribose)polymerase, respectively). This could have a variety of effects on cell viability and neoplastic cell survival. It is difficult to predict whether this might lead to any interactions, if they exist, would be adverse or beneficial, i.e. pro- or anticarcinogenic. Overall, for the single active substances there were no clinically relevant genotoxic and carcinogenic effects.

No non-clinical studies on reproduction toxicology with the combination of the three active substances acetylsalicylic acid, paracetamol and caffeine have been performed. Toxicity to reproduction for the single substances is however, well known. Although available data for toxicity of acetylsalicylic acids on reproduction is still controversially discussed, PhVWP has agreed in April, respectively May 2004 (Doc. Ref: EMEA/12148/04/Final, CPMP/PhVWP/3519/01 Rev.3) upon warning statements to be included in the SPCs and PILs of NSAIDs and acetylsalicylic acids > 500 mg/day. These statements conveys information on acetylsalicylic acid and miscarriage/malformations and the message that NSAIDS acetylsalicylic acids > 500 mg/day may impair female fertility because of their COX/prostaglandin synthesis inhibiting activity. In animal studies, the no observed effect level (NOEL) for fetotoxicity of paracetamol plus concomitant caffeine (delayed fetal growth but no malformations) was higher than the NOEL for the separate active substances, suggesting some potentiation of fetotoxicity. However, due to the presence of acetylsalicylic acid in this combination the use of the product during pregnancy is adequately restricted. There are no further data on the reproductive toxicity of the combination.

A final conclusion on the environmental risk could not be reached, because valid long term effect data on daphnids (OECD 211), fish (OECD 210) and activated sludge (OECD 209) for the substance paracetamol and valid long term effect data on fishes (OECD 210) and activated sludge (OECD 209) for the substance acetylsalicylic acid as required in the guideline EMEA/CHMP/SWP/4447/00 are still missing. Therefore the provided ERA for the product Excedrin APC® can be assessed as incomplete. In consequence, concerning environmental toxicity there are still open issues.

According to the applicant the impurity and degradation specifications for Excedrin conform to the limits set for the individual active substances in the U.S. and European Pharmacopoeia.

The excipients used in the finished product are well known and are described in international pharmacopoeia and/or are approved for human use: hydroxypropyl cellulose, microcrystalline cellulose, stearic acid, and a coating containing hypromellose, propylene glycol, titanium dioxide and purified water.

In conclusion, non-clinical safety data indicate that the safety profile of Excedrin 250/250/65 is acceptable, and that no unusual unacceptable toxicity is to be expected from this combination when 6/8 Public AR taken in therapeutically recommended doses under the conditions mentioned in the SPC. This has been confirmed by the huge clinical experience with Excedrin and similar combination products.

III.3 Clinical aspects

The safety and efficacy profiles of acetylsalicylic acid and paracetamol are well known, as both substances are approved and marketed extensively all over Europe as single-substance drugs as well as in various combination products (acetylsalicylic acid plus caffeine, paracetamol plus caffeine, acetylsalicylic acid plus paracetamol as well as fixed triple combinations). Also the co-analgesic effect of caffeine especially in the combination with acetylsalicylic acid and also with paracetamol is well described in the literature and can be regarded as well established, too. Thus, in accordance with the EMEA guideline on fixed combination medicinal products (CPMP/EWP/240/95 Rev.1) the combination rationale can be derived from the literature (e.g. Diener et al. 2005). In addition, clinical studies to confirm safety and efficacy of Excedrin 250mg / 250mg / 65mg have been submitted.

To support the application, the applicant has submitted as report 16 clinical trials with 2 metaanalysis and one bioavailability/bioequivalence study. No specific dose selection trials have been performed. The doses of the active compounds in the combined preparation were based on those that have been well-established for separate use. The rationale for missing dose selection trials must be regarded in the light of the long term use of this triple combination. Since more than 30 years Excedrin is approved in the same dose relation in the USA and other countries, while e.g. on the German market slightly different dose relations (250mg / 200mg / 50mg and 250mg / 250mg / 50 mg APC) were approved more than 20 years ago. A clinical relevant difference regarding the safety and efficacy profile is not to be expected from a difference of 15mg caffeine per tablet, especially when taking into account common possible additional caffeine intake via food and beverages (e.g. 60-180 mg in 240 ml drip brewed coffee, 20-80 mg in 150 ml black tea, 36-55 mg in 360 ml cola). In conclusion, the slightly higher caffeine content in the single tablet can be accepted.

Overall three placebo-controlled and two active and placebo-controlled, double-blind, randomized, single-dose studies were performed to demonstrate efficacy in the relief of acute migraine. As these studies were performed prior to the issuance of the Guideline on clinical investigation of Medicinal products for the treatment of migraine (CHMP/EWP/788/01 Rev. 1) there are some deficiencies in the study designs (e.g. decision of the beginning of treatment, study variables, observation period). Nevertheless, efficacy of APC could be demonstrated by means of various efficacy variables consistently in all of the provided studies for the observation period (4 or 6 hours).

Although the TTH- studies have not been conducted strictly according current guidelines, the conclusion, that the APC combination is effective in relieving tension-type headache can be accepted as well as the safety profile generated in a large patient population of >3000 patients.

Acetylsalicylic acid, paracetamol and caffeine have an acceptable level of safety used as single substances in corresponding doses. There is no evidence from the data submitted that the safety profile of the fixed APC combination is substantially different. From the large safety data pool (almost 5000 patients) and the post marketing experience as well an acceptable safety profile can be concluded.

3 dental pain studies have been submitted as report to support the evidence for the analgesic properties and safety of APC.

Pharmacovigilance system

The applicant has provided documents that set out a detailed description of the system of pharmacovigilance (DDPS Template Version 9.0 dated 03 April 2009 [see section 14, pg. 25], procedure Version 3.0 released 03 April 2009). 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.

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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 overall benefit-risk ratio is positive. Based on the review of the data on quality, safety and efficacy, application for Excedrin, in the acute treatment of headache and of migraine attacks with or without aura accompanied by pain of at least moderate intensity is approved.

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