RECOMMENDATION
Based on the review of the data on quality, safety and efficacy, the Reference Member State (RMS) considers that the applications for Bisoprolol Fumarate 1.25 mg, 2.5 mg, 5 mg and 10 mg Tablets is approvable for the following:
• Treatment of stable chronic heart failure with reduced systolic left ventricular function in addition to ACE inhibitors, and diuretics, and optionally cardiac glycosides (for additional information see section 5.1).
• Treatment of hypertension.
• Treatment of chronic, stable angina pectoris.
EXECUTIVE SUMMARY About the product
Bisoprolol is a highly beta1-selective-adrenoceptor blocking agent, lacking intrinsic stimulating and relevant membrane stabilising activity.
The originator product is Emcor 10mg tablets by E Merck Ltd, Denmark, registered since 11 February 1988.
The UK reference product is Cardicor 1.25 mg film-coated tablets (PL 00493/0179), licensed to E Merck Ltd.
Bisoprolol is absorbed and has a biological availability of about 90% after oral administration. The plasma protein binding of bisoprolol is about 30%. The distribution volume is 3.5 l/kg. Total clearance is approximately 15 l/h. Peak plasma concentrations are reached 2 to 4 hours after oral doses. The half-life in plasma of 10- 12 hours gives a 24 hour effect after dosing once daily.
Bisoprolol is a racemic mixture with the levorotatory form S(-) enantiomer possessing 30 to 80 times the greater β blocking activity than the dextrorotatory form. Data have been provided to assure that no stereo selective disposition occurs (Dutta 1994). Bisoprolol is excreted from the body by two routes. 50% is metabolised by the liver to inactive metabolites, which are then excreted by the kidneys. The remaining 50% is excreted by the kidneys in an unmetabolised form. The kinetics of bisoprolol are linear and independent of age.
General comments on the submitted dossier
The applicant summarizes the grounds and evidence used for demonstrating that the medicinal product is essentially similar to an authorised medicinal product, based on a pharmacokinetic bioequivalence study using the 10mg strength tablets, comparative dissolution and impurity profiles. A biowaver has been requested for the 1.25 mg, 2.5 mg, and 5mg strengths. Critical assessment of these data is summarised later in this report.
With UK as the Reference Member State in this Decentralized Procedure, Orifarm Generics A/S is applying for a Marketing Authorisations for Bisoprolol Fumarate 1.25 mg, 2.5 mg, 5 mg and 10 mg Tablets in the Denmark, Sweden and Norway.
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. The RMS has been assured that acceptable standards of GCP were in place for the bioequivalence study. Copies of signed documents were provided to support ethical approval.
SCIENTIFIC OVERVIEW AND DISCUSSION Quality aspects
Drug substance
The chemical-pharmaceutical documentation and Expert Report in relation to bisoprolol fumarate are of sufficient quality in view of the present European regulatory requirements. The active substance, bisoprolol fumarate, which is the subject of a Ph. Eur. monograph, is controlled by appropriate drug substance specifications. Stability studies have been performed with the drug substance. No significant changes in any parameters were observed. An adequate re-test period has been defined based on conducted stability studies.
Drug Product
The development of the products has been described, the choice of excipients is justified and their functions explained. The product specifications cover appropriate parameters for this dosage form. Validations data supporting the analytical methods have been presented. The batch analysis results show that the finished products meet the specifications proposed. The conditions used in the stability studies are according to the ICH stability guideline. The control tests and specifications for the drug products are adequately drawn up. The proposed shelf-life of 3 years is acceptable. This medicinal product does not require any special storage conditions.
NON CLINICAL ASPECTS
Specific non-clinical studies have not been performed, which is acceptable for this application for a generic product. The non-clinical overview provides a review of the known pharmacological, pharmacokinetic and toxicological properties of bisoprolol fumarate.
The lack of an environmental risk assessment is justified since the products are generic versions of an already approved one and it is not likely to change the total market of bisoprolol fumarate.
CLINICAL ASPECTS Pharmacokinetics
To support the application, the applicant has submitted as a report, one bioequivalence study using the 10mg strength tablets. The bioequivalence study was an open label, balanced, randomised, analyst blind, two treatments, two period, two-sequence, cross over single dose, bioequivalence study in healthy male human subjects under fasting conditions with a wash out period of nine days between periods.
The applicant has requested a biowaiver for the 1.25mg, 2.5mg and 5mg strengths of the test product on the basis of the Note for guidance of on investigation of bioavailability and bioequivalence noting that the pharmacokinetics are linear from 2.5 mg to 100 mg, the concentration of active is <5%, the ratio of active to excipients is similar and in vitro dissolution data are similar for the different strengths. This is acceptable.
Test product
Bisoprolol fumarate 10mg
Reference product
Cardicor 10mg Bisoprolol fumarate 10mg, Merck Pharmaceuticals UK
Methods
The study recruited healthy, adult, male, human subjects, aged between 18 and 55 years. All 28 volunteers complying with the requirements of the protocol were enrolled in the study. All 28 subjects completed both periods of the study successfully. There were some protocol deviations: one subject smoked 5-7 cigarettes per day and three subjects deviated from restrictions on certain drinks 2 days before dosing. There were nine deviations on late sampling times: however, the impact was considered as minimal by the applicant as Kel could be defined for these subjects. The subjects fasted for at least 10 hours prior to administration of the study drug. They were provided with lunch 4 hours post-dose. They were not allowed access to drinking water from 1 hour pre-dose till 2 hours post dose administration, except during administration of the dose. A dose of 10 mg of bisoprolol fumarate tablets test or reference product was orally administered as a single dose followed by 240 ml of water at ambient temperature in both periods.
Concentration of bisoprolol was measured in plasma samples of the subjects. Sampling was done pre-dose (0h00) and up to and 72h00 hours post dose. The plasma samples of subjects were analyzed by an HPLC method. The bioanalytical method used in the biostudy has been adequately validated.
The In-transformed least square means and 90% Confidence Interval based on least square mean obtained from ANOVA and ratio of test and reference formulations for the pharmacokinetic parameters Cmax, AUC0-t and AUC0-inf, for bisoprolol are summarised in the following table:
Table 1. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD) Bisoprolol plasma concentrations
Treatment AUC0-t ng/ml/h AUC0-∞ ng/ml/h Cmax ng/ml tmax h T1/2 h Test 582.91(120.29) 630.78(119.02) 43.86(6.84) 2.32(0.9) 10.07 (0.9) Reference 571.56(111.81) 622.43(110.58) 43.77(7.07) 2.26(0.88) 9.74(2.54) *Ratio (90% CI) 101.97 (98.44-105.62) 101.29 (97.94-104.75) 100.30 (96.69- 104.03) CV (%) 7.73% 7.39% 8.04%
AUC0-∞ area under the plasma concentration-time curve from time zero to infinity
AUC0-t area under the plasma concentration-time curve from time zero to t hours
Cmax maximum plasma concentration
Tmax time for maximum concentration
T1/2 half-life
*ln-transformed values
The 90 % confidence intervals, for the geometric mean ratios of drug formulations of Cmax, AUC0-t and AUC0-inf for bisoprolol meet the prespecified bioequivalence criteria.
Pharmacodynamics
No new data have been submitted or are required.
Clinical efficacy
No new data have been submitted or are required.
Clinical safety
No new data have been submitted or are required.
Pharmacovigilance system
The RMS considers that the pharmacovigilance system as described by the applicant fulfils the requirements 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.
Risk Management Plan
Bisoprolol Fumarate 1.25 mg, 2.5 mg, 5 mg and 10 mg Tablets are generic products. As with the reference medicinal product, no special important risks or potential risks have been identified which require additional risk minimization activities other than the global pharmacovigilance system.
Product literature
All product literature (SPC, PIL and labelling) is satisfactory. The package leaflet was submitted to the MHRA along with results of consultations with target patient groups ("user testing"), in accordance with Article 59 of Council Directive 2001/83/EC. The results indicate that the package leaflet is well-structured and organised, easy to understand and written in a comprehensive manner. The test shows that the patients/users are able to act upon the information that they contain.
BENEFIT RISK ASSESSMENT