Download Decentralised Procedure Public Assessment Report Excedrin AP

Bundesinstitut für Arzneimittel
und Medizinprodukte
Decentralised Procedure
Public Assessment Report
Excedrin AP
Acetylsalicylic Acid 250mg
Paracetamol 250mg
Caffeine 65 mg
DE/H/1804/001/DC
Applicant: Novartis 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.
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TABLE OF CONTENTS
I
INTRODUCTION
II
4
EXECUTIVE SUMMARY
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II.1
II.2
II.3
II.4
PROBLEM STATEMENT
ABOUT THE PRODUCT
GENERAL COMMENTS ON THE SUBMITTED DOSSIER
GENERAL COMMENTS ON COMPLIANCE WITH GMP, GLP, GCP AND AGREED ETHICAL
PRINCIPLES.
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III
5
III.1
III.2
III.3
IV
SCIENTIFIC OVERVIEW AND DISCUSSION
QUALITY ASPECTS
NONCLINICAL ASPECTS
CLINICAL ASPECTS
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5
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BENEFIT RISK ASSESSMENT
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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)
Excedrin AP
Acetylsalicyic acid 250 mg, paracetamol 250 mg, caffeine
65 mg
N02BA
Film-coated tablets; 250 mg / 250 mg / 65 mg
DE/H/1804/001/DC
Germany
DE/H/1804/001/DC
United Kingdom
Novartis Consumer Health GmbH
Zielstattstr. 40
81379 München
Names and addresses of
manufacturers responsible for batch
release in the EEA
Novartis Consumer Health GmbH, Zielstattstraße 40
DE - 81379 München
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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 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 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
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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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