Bundesinstitut für Arzneimittel und Medizinprodukte Decentralised Procedure Public Assessment Report IBU-Lysin-ratiopharm 342 mg Filmtabletten IBU-Lysin-ratiopharm 684 mg Filmtabletten Ibu-Lysin AbZ Migräne 684 mg Filmtabletten Ibu-Lysin Hexal 684 mg Filmtabletten Ibu-Lysin-CT 342 mg / 684 mg Filmtabletten Ibuprofen-DL-Lysine DE/H/2589-2590, 2592-2593/001/DC DE/H/2591/001-002/DC ratiopharm GmbH AbZ-Pharma GmbH HEXAL AG CT Arzneimittel GmbH 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... 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... 8 2/8 Public AR
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) IBU-Lysin-ratiopharm 342 mg Filmtabletten IBU-Lysin-ratiopharm 684 mg Filmtabletten Ibu-Lysin AbZ Migräne 684 mg Filmtabletten Ibu-Lysin Hexal 684 mg Filmtabletten Ibu-Lysin-CT 342 mg / 684 mg Filmtabletten Ibuprofen lysine M01AE01 342mg/ 684mg film-coated tablets DE/H/2589-2590,2592-2593/001/DC DE/H/2591/001-002/DC DE AT,EE, FI, HU, LV, LT, LU DE/H/2589-2590/001/DC ratiopharm GmbH Graf-Arco-Strasse 3 89079 Ulm, Germany DE/H/2592/001/DC AbZ-Pharma GmbH Dr. Georg-Spohn-Strasse 7 89143 Blaubeuren, Germany DE/H/2593/001/DC HEXAL AG Industriestraße 25 83607 Holzkirchen, Germany DE/H/2591/001-002/DC CT Arzneimittel GmbH Lengeder Strasse 42a 13407 Berlin, Germany 3/8 Public AR
I. INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for Ibuprofen Lysinate 342 / 684 mg film-coated tablets in the symptomatic treatment of {DE/H/2589-2591/DC and DE/H/2593/DC} - mild to moderate pain such as headache, period pain, dental pain, and fever and pain associated with common cold - acute migraine headaches with or without aura {DE/H/2592/DC} - acute migraine headaches with or without aura, is approved. II. EXECUTIVE SUMMARY II.1 Problem statement This decentralised application concerns a generic version of ibuprofen lysine. In this overview, the name Ibuprofen Lysinate is used. The originator product is Doctril 200 mg comprimé pelliculé, film-coated tablets by McNeil GmbH Co. ohg, France, registered since 02.09.1996 and the German reference medicinal product is Dolormin Migräne Filmtabletten, 684 mg, Film-coated tablet by McNeil GmbH Co.oHG, registered since 22.09.1999. The German reference medicinal product is intended to serve as European Reference Product (ERP) for the concerned member states EE, FI, LV, LT and LU where no medicinal reference products are granted and /or marketed nationally. II.2 About the product The drug under consideration is composed of ibuprofen lysine as active ingredient in a film coated tablet. Ibuprofen has analgesic, antipyretic, and anti-inflammatory activities. It is an inhibitor of cyclooxygenase (COX) and belongs to the pharmacological class of nonsteroidal anti-inflammatory drugs (NSAIDs). Ibuprofen is used for relief of symptoms of arthritis, primary dysmenorrhea, fever, and as an analgesic, especially when there is an inflammatory component. It is a core medicine in the World Health Organization's "Essential Drugs List", which is a list of minimum medical needs for a basic health care system (WHO 2005). Ibuprofen was derived from propionic acid during the 1960s (Adams 1992, Nichol 1999). The drug (acid ibuprofen) was launched as a treatment for rheumatoid arthritis in the United Kingdom in 1969, and in the United States in 1974. Low doses of ibuprofen (200 mg and 400 mg) are available over the counter (OTC) in most countries. In Europe, Australia and New Zealand, ibuprofen lysine (the lysine salt of ibuprofen) is licensed for treatment of similar conditions as ibuprofen. The lysine salt increases the water solubility of acid ibuprofen (hereinafter ibuprofen ), allowing the medication to be administered intravenously, too. Intravenous (i.v.) ibuprofen lysine is indicated for closure of a patent ductus arteriosus in premature infants (AHFS-DI 2009, Drugdex 2009). Chemically, ibuprofen lysine is designated as α-methyl-4-(2-methyl propyl) benzeneacetic acid lysine with a molecular weight of 352.48. The indications for Ibuprofen Lysinate are: {DE/H/2589-2591/DC and DE/H/2593/DC} Symptomatic treatment of mild to moderate pain such as headache, period pain, dental pain, and fever and pain in the common cold. Symptomatic treatment of acute migraine headaches with or without aura. Ibuprofen lysine film-coated tablets is indicated in children over 20 kg body weight (around 6 years old), adolescents and adults. 4/8 Public AR
{DE/H/2592/DC} Symptomatic treatment of acute migraine headaches with or without aura. Ibuprofen lysine film-coated tablets is indicated in children over 20 kg body weight (around 6 years old), adolescents and adults. As with other NSAIDs, the lowest dose should be sought for each patient. Ibuprofen lysine 200 and 400 mg (with regards to ibuprofen) immediate release tablets are for short-term use only (maximum of 4 days). The maximum recommended daily dose should not be exceeded. A time period of 6 h should elapse between two successive administrations. Ibuprofen Lysinate is contraindicated in children under 20 kg body weight, as this dosage strength is unsuitable, due to the high quantity of active substance. II.3 General comments on the submitted dossier This is a hybrid application, according to article 10.3 of Directive 2001/83/EC for a medicinal product referring to a so-called reference medicinal product with a Marketing Authorisation in a Member State or in the Community (change in therapeutic indications and/or change in strength, i.e. quantitative change to the active substance). To support the application, the applicant has submitted as report one bioequivalence study (reference number IT-MPA-0802/SPC 25-34). The submitted documentation in relation to the proposed product is of sufficient high quality in view of the current European regulatory requirements. 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 the manufacturing sites. III. SCIENTIFIC OVERVIEW AND DISCUSSION III.1 Quality aspects Drug substance The drug substance ibuprofen lysinate is obtained from the starting materials ibuprofen and D,Llysine 50% aqueous solution obtained form L-lysine hydrochloride. Both starting materials are obtained from suppliers holding currently valid certificates of suitability issued by the EDQM which assures that these starting materials can be sufficiently tested according the demands of their pharmacopoeia monographs and the additional demands written the certificates. Therefore an adequate quality of ibuprofen and L-lysine hydrochloride and also of the active substance ibuprofen lysinate can be presumed. Drug Product In view to the simple pharmaceutical form of a film coated tablet the information presented appears to be acceptable and sufficient to guarantee the quality of the medicinal products. The RMS is assured that acceptable standards of GMP are in place in the context of the manufacture of ibuprofen lysinate film coated tablets. The data submitted on the quality of the drug substances and the drug product reflects professional researched and well defined products. The ingredients, the manufacturing process and the in-process controls of the drug products correspond to the current standard of pharmaceutical technology and are suitable to guarantee an appropriate product quality. The description of the analytical test methods is adequate. The validation results are plausible. 5/8 Public AR
All relevant quality criteria are specified in accordance with internationally acknowledged pharmacopoeias. The specified limits are in line with the requirements of the CHMP Guidelines and are guarded by the finished product. A shelf life of 24 months is accepted together with the storage condition Do not store above 25 C. In subsumption, Ibuprofen Lysine 342 mg or 684 mg film coated tablets is a standardised medicinal product which can be produced reliable at any manufacturer which is used to produce film coated tablets and has sufficient experience in granulation and compacting technology. III.2 Nonclinical aspects Pharmacology, Pharmacokinetics, Toxicology Nonclinical pharmacodynamic, pharmacokinetic and toxicological properties of ibuprofen are well known. As ibuprofen is a widely used, well-known active substance, no further nonclinical studies are required and the applicant provides none. An adequate nonclinical overview on the preclinical pharmacology, pharmacokinetics and toxicology of ibuprofen lysine is included in the application. From a nonclinical point of view, marketing authorisation is recommended. Environmental Risk Assessment The applicant provides a revised ERA with new literature on PEC refinement in Phase II Tier B of the active ingredient ibuprofen. In conclusion, in Phase II Tier B all risk quotients are below the trigger value of 1, so it is unlikely that ibuprofen poses a risk for the environment. III.3 Clinical aspects Clinical data from studies with oral ibuprofen lysine are sparse. However, as ibuprofen lysine and ibuprofen produce the same AUC following oral intake with a somewhat higher absorption rate for the lysine salt, it can easily be inferred that the efficacy data generated for ibuprofen do also apply to ibuprofen lysine. There might be a difference in the onset of pain relief though (in favour of ibuprofen lysine). No further clinical studies are required for this application and the applicant provides none. Overview based on literature review is, thus, appropriate. The indications for Ibuprofen Lysinate are: {DE/H/2589-2591/DC and DE/H/2593/DC} Symptomatic treatment of mild to moderate pain such as headache, period pain, dental pain, and fever and pain in the common cold. Symptomatic treatment of acute migraine headaches with or without aura. Ibuprofen lysine film-coated tablets is indicated in children over 20 kg body weight (around 6 years old), adolescents and adults. {DE/H/2592/DC} Symptomatic treatment of acute migraine headaches with or without aura. Ibuprofen lysine film-coated tablets is indicated in children over 20 kg body weight (around 6 years old), adolescents and adults. Pharmacokinetics The applicant submitted one bioequivalence study which is acceptable. Study IT-MPA-0802/SPC 25-34 was an open-label, randomised, 3-treatment, 3-period, 6-sequence, single-dose cross-over, comparative oral bioavailability study in 24 healthy volunteers under fasting condition. 6/8 Public AR
Ibuprofen lysine immediate release tablet by Mepha AG, Switzerland (batch No. 1270 182) has been compared to Reference 1: Algifor L Forte tablet (Vifor AG) (Batch No: 31516, from Switzerland, 03/2010) and to Reference 2: Dolormin Migräne tablet (McNeil GmbH Co.oHG) (Batch No: 7DL3NOO, from Germany, exp. date 03/2010). The 95% CIs for Cmax, AUC0-t(last) and AUC0-inf of ibuprofen were well within the acceptable bioequivalence ranges. Moreover, mean and median tmax were comparable between formulations. Therefore, based on the results of this study, it can be concluded that the three ibuprofen lysine 684 mg immediate release formulations tested are bioequivalent and interchangeable. Essential similarity is given and consequently all data available for the originator products do also apply to the ibuprofen lysine immediate release tablet formulation of the applicant. Pharmacodynamics No new data have been submitted. The pharmacodynamic profile of ibuprofen is well characterised in literature. Pharmacodynamically, ibuprofen lysine has been shown to provide a quicker relief of pain than do conventional ibuprofen formulations/salts, most likely as a result of the more rapid onset of absorption from the GI tract compared with ibuprofen. Clinical safety Clinical safety and tolerability data from studies with oral ibuprofen lysine are sparse. However, as ibuprofen lysine and ibuprofen produce the same AUC following oral intake with only a slightly higher absorption rate for the lysine salt, it can be inferred that the safety data generated for ibuprofen do also apply to ibuprofen lysine. The latter has been confirmed by dedicated GI tolerance studies. Based on the results of the bioequivalence study the ibuprofen lysine immediate release tablet can be considered essentially similar to the reference products Algifor-L Forte and Dolormin Migräne tablets. Consequently, all safety data available for the originator products that have been marketed for many years do also apply to the ibuprofen lysine immediate release tablet. User Testing The applicant demonstrated readability of the PL by making reference to already tested leaflets, i.e. the package leaflet of Ibuprofen 2% syrup (MRP No. DE/H/861/002). The following prerequisites are fulfilled: - Same route of administration - Same safety issues identified - Same class of medicinal product - Same active ingredient This is accepted. There are differences between the patients who receive the medicinal products. Ibuprofen 2 % syrup is used to treat infants whereas Ibuprofen lysine 342/684 mg film-coated tablets is used by adolescents and adults aged 12/15 and over. However, this is not relevant for the demonstration of readability, because the user group of the PILs is the same: in both cases adolescents and adults are reading the PILs and the PILs should be easy to read and understand for this user group. Ibuprofen 2 % syrup and Ibuprofen lysine 342/684 mg film-coated tablets both have the status of non-prescription medicinal product (OTC): Pharmacovigilance system DE/H/2589-2590, 2592/001/DC, DE/H/2591/001-002/DC: Description of Pharmacovigilance System Details have been provided of the Teva pharmacovigilance system (Version 10 dated January 2011). 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. 7/8 Public AR
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. DE/H/2593/001/DC: The applicant has provided documents that set out a detailed description of the system of pharmacovigilance (Version 9.0 effective 01 May 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. 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 nonclinical and clinical data and the bioequivalence to the reference product has been shown. Based on the review of the data on quality, safety and efficacy, the application for Ibuprofen Lysinate 342mg/684mg, is approved. For intermediate amendments see current product information. 8/8 Public AR