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«Decentralised Procedure Public Assessment report Optalidon akut gegen Kopfschmerzen Acetylsalicylic Acid 250 mg Paracetamol 250 mg Caffeine 65 mg ...»

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Bundesinstitut für Arzneimittel

und Medizinprodukte

Decentralised Procedure

Public Assessment report

Optalidon akut gegen Kopfschmerzen

Acetylsalicylic Acid 250 mg

Paracetamol 250 mg

Caffeine 65 mg

DE/H/1494/001/DC

Applicant: Novartis Consumer Health GmbH

DE

Reference Member State

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.

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

2/8 Public AR

ADMINISTRATIVE INFORMATION

Optalidon akut gegen Kopfschmerzen Proposed name of the medicinal 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/1494/001/DC Reference Number for the Decentralised Procedure Germany

Reference Member State:

Austria, Belgium, Bulgaria, Czech Republic, France,

Member States concerned:

Greece, Ireland, Italy, Luxemburg, Netherlands, Poland, Portugal, Romania, Slovenia, Sl

–  –  –

Based on the review of the data on quality, safety and efficacy, the application for Optalidon, in the acute treatment of headache and migraine attacks with or without aura is approved.

II EXECUTIVE SUMMARY

II.1 Problem statement Optalidon 250 mg/250 mg/65 mg 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 acetylsalicylic acid / paracetamol / caffeine – combination (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. 250 mg / 250 mg / 50 mg or 250 mg / 200 mg / 50 mg APC in the RMS).

II.2 About the product Acetylsalicylic acid and paracetamol are well known substances with analgesic 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 analgesics and is widely used in various combination products.

The claimed indication is the acute treatment of headache and migraine attacks with or without aura with a single dose of two tablets (500 mg acetylsalicylic acid / 500 mg paracetamol / 130 mg caffeine).

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 OPTALIDON 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.

–  –  –

III.1 Quality aspects Drug substance The acetylsalicylic acid is manufactured by two different pharmaceutical companies.

The paracetamol is manufactured by another two different pharmaceutical companies The caffeine is manufactured by a fith pharmaceutical company.

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. There are no open questions. Actual CEP´s for all substances have been submitted.





Drug product The finished product is manufactured by a sixth pharmaceutical company and finally the manufacturer responsible for batch release in the EEA is Novartis Consumer Health GmbH, 81379 München, Germany.

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 general 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 further developed in section III.3 Clinical aspects.

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 5/8 Public AR Optalidon. 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 The toxicity profile of the single substances is well known. There is also large clinical experience for the triple combination paracetamol, acetylsalicylic acid and caffeine.

The acute oral toxicity of various formulations of tablets containing the triple combination 250 mg paracetamol, 250 mg acetylsalicylic acid and 65 mg caffeine was tested in female mice Comparison of the median lethal doses of paracetamol and acetylsalicylic acid in the triple combination product to the LD50 values for the individual active substances indicated that 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 and whether they 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 characterized.

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 convey 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 (ie, Optalidon is contraindicated for the last trimester of pregnancy). 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. Paracetamol and acetylsalicylic acid, however, have had a long history of use in prescription, non-prescription and generic drug products. Therefore, the provided ERA for the product Optalidon APC® can be assessed as incomplete. In consequence, concerning environmental toxicity there are still open issues. The MAH has commited to provide data on long term effects as indicated above.

–  –  –

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 low substitution, microcrystalline cellulose, stearic acid, and a coating containing hypromellose, propylene glycol, titanium dioxide, benzoic acid and carnauba wax and purified water.

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

III.3 Clinical aspects



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