Public Assessment Report. Decentralised Procedure

Transcription

1 Public Assessment Report Decentralised Procedure Bisoprolol Fumarate 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg Film-Coated Tablets UK/H/1683/001-6/DC UK licence no: PL 32256/ Applicant: Aurobindo Pharma (Malta) Limited - 1 -

2 LAY SUMMARY The MHRA granted Aurobindo Pharma (Malta) Limited Marketing Authorisations (licences) for the medicinal products Bisoprolol Fumarate 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg Film-Coated Tablets on 26 October These are prescription-only medicines. Bisoprolol Fumarate 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg Film-Coated Tablets belong to a group of medicines called beta blockers. Bisoprolol fumarate slows down the heart rate and makes the heart more efficient at pumping blood around the body. Bisoprolol fumarate is used to treat stable heart failure. Bisoprolol is given as an additional treatment to other medications for heart failure. No new or unexpected safety concerns arose from these applications and it was therefore judged that the benefits of using Bisoprolol Fumarate 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg Film-Coated Tablets outweigh the risks; hence Marketing Authorisations have been granted

3 TABLE OF CONTENTS Module 1: Information about initial procedure Page 4 Module 2: Summary of Product Characteristics Page 5 Module 3: Product Information Leaflets Page 53 Module 4: Labelling Page 57 Module 5: Scientific Discussion Page 62 1 Introduction Page 62 2 Quality aspects Page 65 3 Non-clinical aspects Page 68 4 Clinical aspects Page 68 5 Overall conclusions Page 71 Module 6 Steps taken after initial procedure Page

4 Module 1 Product Name Bisoprolol Fumarate 1.25 mg film-coated tablets Bisoprolol Fumarate 2.5 mg film-coated tablets Bisoprolol Fumarate 3.75 mg film-coated tablets Bisoprolol Fumarate 5 mg film-coated tablets Bisoprolol Fumarate 7.5 mg film-coated tablets Bisoprolol Fumarate 10 mg film-coated tablets Type of Application Generic, Article 10.1 Active Substance Form Strength Bisoprolol Fumarate Film-Coated Tablets 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg MA Holder Aurobindo Pharma (Malta) Limited, Vault 14, Level 2, Valletta Waterfront, Floriana FRN 1913, Malta Reference Member UK State (RMS) CMS Germany, Italy and Poland Procedure Number UK/H/1683/001-6/DC Timetable Day th October

5 Module 2 Summary of Product Characteristics The UK Summary of Product Characteristics (SPC) for Bisoprolol Fumarate filmcoated tablets is as follows: 1 NAME OF THE MEDICINAL PRODUCT Bisoprolol Fumarate 1.25 mg film-coated tablets Bisoprolol Fumarate 2.5 mg film-coated tablets Bisoprolol Fumarate 3.75 mg film-coated tablets Bisoprolol Fumarate 5 mg film-coated tablets Bisoprolol Fumarate 7.5 mg film-coated tablets Bisoprolol Fumarate 10 mg film-coated tablets 2 QUALITATIVE AND QUANTITATIVE COMPOSITION Bisoprolol Fumarate 1.25 mg film-coated tablets: Each film-coated tablet contains 1.25 mg bisoprolol fumarate equivalent to 1.06 mg bisoprolol. Bisoprolol Fumarate 2.5 mg film-coated tablets: Each film-coated tablet contains 2.5 mg bisoprolol fumarate equivalent to 2.12 mg bisoprolol. Bisoprolol Fumarate 3.75 mg film-coated tablets Each film-coated tablet contains 3.75 mg bisoprolol fumarate equivalent to 3.18 mg bisoprolol. Bisoprolol Fumarate 5 mg film-coated tablets Each film-coated tablet contains 5 mg bisoprolol fumarate equivalent to 4.24 mg bisoprolol. Bisoprolol Fumarate 7.5 mg film-coated tablets Each film-coated tablet contains 7.5 mg bisoprolol fumarate equivalent to 6.36 mg bisoprolol. Bisoprolol Fumarate 10 mg film-coated tablets Each film-coated tablet contains 10 mg bisoprolol fumarate equivalent to 8.48 mg bisoprolol. For a full list of excipients, see section PHARMACEUTICAL FORM Film-coated tablet Bisoprolol Fumarate 1.25 mg film-coated tablets White, circular, biconvex, film-coated tablets debossed with P on one side and 1 on the other side. Bisoprolol Fumarate 2.5 mg film-coated tablets White, circular, biconvex, film-coated tablets debossed with P and score line on one side and 2 on the other side. The tablet can be divided into equal halves. Bisoprolol Fumarate 3.75 mg film-coated tablets White, circular, biconvex, film-coated tablets debossed with P and score line on one side and 3 on the other side. The tablet can be divided into equal halves. Bisoprolol Fumarate 5 mg film-coated tablets White, circular, biconvex, film-coated tablets debossed with P and break line on one side and 5 on the other side. The tablet can be divided into equal halves

6 Bisoprolol Fumarate 7.5 mg film-coated tablets: White, circular, biconvex, film-coated tablets debossed with P and score line on one side and 7 on the other side. The tablet can be divided into equal halves. Bisoprolol Fumarate 10 mg film-coated tablets: White, circular, biconvex, film-coated tablets debossed with P and score line on one side and 10 on the other side. The tablet can be divided into equal halves. 4 CLINICAL PARTICULARS 4.1 Therapeutic indications 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). 4.2 Posology and method of administration Method of administration Bisoprolol tablets should be taken in the morning and can be taken with food. They should be swallowed with liquid and should not be chewed. Treatment of stable chronic heart failure Standard treatment of CHF consists of an ACE inhibitor (or an angiotensin receptor blocker in case of intolerance to ACE inhibitors), a beta-blocking agent, diuretics, and when appropriate cardiac glycosides. Patients should be stable (without acute failure) when bisoprolol treatment is initiated. It is recommended that the treating physician should be experienced in the management of chronic heart failure. Transient worsening of heart failure, hypotension, or bradycardia may occur during the titration period and thereafter. Titration phase The treatment of stable chronic heart failure with bisoprolol requires a titration phase. The treatment with bisoprolol is to be started with a gradual up titration according to the following steps: 1.25 mg once daily for 1 week, if well tolerated increase to 2.5 mg once daily for a further week, if well tolerated increase to 3.75 mg once daily for a further week, if well tolerated increase to 5 mg once daily for the 4 following weeks, if well tolerated increase to 7.5 mg once daily for the 4 following weeks, if well tolerated increase to 10 mg once daily for the maintenance therapy. The maximum recommended dose is 10 mg once daily. Close monitoring of vital signs (heart rate, blood pressure) and symptoms of worsening heart failure is recommended during the titration phase. Symptoms may already occur within the first day after initiating the therapy. Treatment modification If the maximum recommended dose is not well tolerated, gradual dose reduction may be considered. In case of transient worsening of heart failure, hypotension, or bradycardia reconsideration of the dosage of the concomitant medication is recommended. It may also be necessary to temporarily lower the dose of bisoprolol or to consider discontinuation. The reintroduction and/or uptitration of bisoprolol should always be considered when the patient becomes stable again. If discontinuation is considered, gradual dose decrease is recommended, since abrupt withdrawal may lead to acute deterioration of the patients condition. Treatment of stable chronic heart failure with bisoprolol is generally a long-term treatment

7 Renal or liver insufficiency There is no information regarding pharmacokinetics of bisoprolol in patients with chronic heart failure and with impaired liver or renal function. Uptitration of the dose in these populations should therefore be made with additional caution. Elderly No dosage adjustment is required. Children There is no experience with bisoprolol in children, therefore its use cannot be recommended for children. 4.3 Contraindications Bisoprolol is contra-indicated in patients with: - hypersensitivity to bisoprolol or to any of the excipients - acute heart failure or during episodes of heart failure decompensation requiring i.v. inotropic therapy - cardiogenic shock - Second or third degree AV block (without a pacemaker) - sick sinus syndrome - sinoatrial block - symptomatic bradycardia - symptomatic hypotension - severe bronchial asthma or severe chronic obstructive pulmonary disease - severe forms of peripheral arterial occlusive disease or severe forms of Raynaud's syndrome - untreated phaeochromocytoma (see 4.4) metabolic acidosis 4.4 Special warnings and precautions for use Special Warnings The treatment of stable chronic heart failure with bisoprolol has to be initiated with a special titration phase (see section 4.2). Especially in patients with ischaemic heart disease the cessation of therapy with bisoprolol must not be done abruptly unless clearly indicated, because this may lead to transitional worsening of heart condition (see section 4.2). Precautions The initiation of treatment of stable chronic heart failure with bisoprolol necessitates regular monitoring. For the posology and method of administration please refer to section 4.2. There is no therapeutic experience of bisoprolol treatment in heart failure in patients with the following diseases and conditions: - insulin dependent diabetes mellitus (type I) - severely impaired renal function - severely impaired liver function - restrictive cardiomyopathy - congenital heart disease - haemodynamically significant organic valvular disease - myocardial infarction within 3 months Bisoprolol must be used with caution in: - diabetes mellitus with large fluctuations in blood glucose values; symptoms of hypoglycaemia (e.g. tachycardia, palpitations or sweating) can be masked - strict fasting - 7 -

8 - ongoing desensitisation therapy. As with other beta-blockers, bisoprolol may increase both the sensitivity towards allergens and the severity of anaphylactic reactions. Epinephrine treatment may not always yield the expected therapeutic effect. - First degree AV block - Prinzmetal s angina - peripheral arterial occlusive disease. Aggravation of symptoms may occur especially when starting therapy. Patients with psoriasis or with a history of psoriasis should only be given beta-blockers (e.g. bisoprolol) after a careful balancing of benefits against risks. The symptoms of a thyrotoxicosis may be masked under treatment with bisoprolol In patients with phaeochromocytoma bisoprolol must not be administered until after alphareceptor blockade. In patients undergoing general anaesthesia beta-blockade reduces the incidence of arrhythmias and myocardial ischemia during induction and intubation and the post-operative period. It is currently recommended that maintenance beta-blockade be continued perioperatively. The anaesthetist must be aware of beta-blockade because of the potential for interactions with other medicinal products, resulting in bradyarrhythmias, attenuation of reflex tachycardia and decreased reflex ability to compensate for blood loss. If it is thought necessary to withdraw beta-blocker therapy before surgery, this should be done gradually and completed about 48 hours before anaesthesia. In bronchial asthma or other chronic obstructive lung diseases, which may cause symptoms, concomitant bronchodilating therapy is recommended. Occasionally an increase of the airway resistance may occur in patients with asthma, therefore the dose of beta 2 -stimulants may have to be increased. The initiation of treatment with bisoprolol necessitates regular monitoring. For the posology and method of administration please refer to section Interaction with other medicinal products and other forms of interaction Combinations not recommended Class-I antiarrhythmic drugs (e.g. quinidine, disopyramide, lidocaine, phenytoin, flecainide, propafenone): effect on atrio-ventricular conduction time may be potentiated and negative inotropic effect increased. Calcium antagonists of the verapamil type and to a lesser extent of the diltiazem type: negative effect on contractility and atrio-ventricular conduction. Intravenous administration of verapamil in patients on beta-blocker treatment may lead to profound hypotension and atrioventricular block. Centrally-acting antihypertensive drugs (e.g. clonidine, methyldopa, moxonidine, rilmenidine): concomitant use of centrally-acting antihypertensive drugs may further decrease the central sympathetic tonus and may thus lead to reduction of heart rate and cardiac output and to vasodilatation. Abrupt withdrawal, particularly if prior to beta-blocker discontinuation, may increase the risk of rebound hypertension. Combinations to be used with caution Calcium antagonists of the dihydropyridine type such as felodipine and amlodipine: Concomitant use may increase the risk of hypotension, and an increase in the risk of a further deterioration of the ventricular pump function in patients with heart failure cannot be excluded. Class-III antiarrhythmic medicinal product (e.g. amiodarone): Effect on atrio-ventricular conduction time may be potentiated. Parasympathomimetic medicinal products: Concomitant use may increase atrio-ventricular conduction time and the risk of bradycardia

9 Topical beta-blocking agents (e.g. eye drops for glaucoma treatment) may add to the systemic effects of bisoprolol. Insulin and oral antidiabetic medicinal products: Increase of blood sugar lowering effect. Blockade of beta-adrenoreceptors may mask symptoms of hypoglycaemia. Anaesthetic agents: Attenuation of the reflex tachycardia and increase of the risk of hypotension (for further information on general anaesthesia see also section 4.4.). Digitalis glycosides: Increase of atrio-ventricular conduction time, reduction in heart rate. Non-steroidal anti-inflammatory medicinal products (NSAIDs): NSAIDs may reduce the hypotensive effect of bisoprolol. β-sympathomimetic agents (e.g. isoprenaline, dobutamine): Combination with bisoprolol may reduce the effect of both agents. Sympathomimetics that activate both β- and α-adrenoceptors (e.g. norepinephrine, epinephrine): Combination with bisoprolol may unmask the α-adrenoceptor-mediated vasoconstrictor effects of these agents leading to blood pressure increase and exacerbated intermittent claudication. Such interactions are considered to be more likely with nonselective β-blockers. Concomitant use with antihypertensive agents as well as with other medicinal products with blood pressure lowering potential (e.g. tricyclic antidepressants, barbiturates, phenothiazines) may increase the risk of hypotension. Combinations to be considered Mefloquine: increased risk of bradycardia Monoamine oxidase inhibitors (except MAO-B inhibitors): Enhanced hypotensive effect of the beta-blocking agents but also risk for hypertensive crisis. Rifampicin: Slight reduction of the half-life of bisoprolol possible due to the induction of hepatic drug metabolising enzymes. Normally no dosage adjustment is necessary. Ergotamine derivatives: Exacerbation of peripheral circulatory disturbances. 4.6 Fertility, Pregnancy and lactation Pregnancy: Bisoprolol has pharmacological effects that may cause harmful effects on pregnancy and/or the fetus/newborn. In general, beta-adrenoceptor blocking agents reduce placental perfusion, which has been associated with growth retardation, intrauterine death, abortion or early labour. Adverse effects (e.g. hypoglycaemia and bradycardia) may occur in the fetus and newborn infant. If treatment with beta-adrenoceptor blocking agents is necessary, beta 1 - selective adrenoceptor blocking agents are preferable. Bisoprolol is not recommended during pregnancy unless clearly necessary. If treatment with bisoprolol is considered necessary, the uteroplacental blood flow and fetal growth should be monitored. In case of harmful effects on pregnancy or the fetus alternative treatment should be considered. The newborn infant must be closely monitored. Symptoms of hypoglycaemia and bradycardia are generally to be expected within the first 3 days. Lactation: There are no data on the excretion of bisoprolol in human breast milk or the safety of bisoprolol exposure in infants. Therefore, breastfeeding is not recommended during administration of bisoprolol. 4.7 Effects on ability to drive and use machines In a study with coronary heart disease patients, bisoprolol did not impair driving performance. However, depending on the individual patients response to treatment an effect on the ability - 9 -

10 to drive a vehicle or to use machines cannot be excluded. This needs to be considered particularly at start of treatment, upon change of medication, or in conjunction with alcohol. 4.8 Undesirable effects The following definitions apply to the frequency terminology used hereafter: Very common ( 1/10) Common ( 1/100, < 1/10) Uncommon ( 1/1,000, < 1/100) Rare ( 1/10,000, < 1/1,000) Very rare (< 1/10,000) Not known (can not be estimated from the available data) Cardiac disorders: Very common: bradycardia. Common: worsening of heart failure Uncommon: AV-conduction disturbances. Investigations: Rare: increased triglycerides, increased liver enzymes (ALT, AST). Nervous system disorders: Common: dizziness, headache. Rare: syncope Eye disorders: Rare: reduced tear flow (to be considered if the patient uses lenses). Very rare: conjunctivitis. Ear and labyrinth disorders: Rare: hearing disorders Respiratory, thoracic and mediastinal disorders: Uncommon: bronchospasm in patients with bronchial asthma or a history of obstructive airways disease. Rare: allergic rhinitis. Gastrointestinal disorders: Common: gastrointestinal complaints such as nausea, vomiting, diarrhoea, constipation. Skin and subcutaneous tissue disorders: Rare: hypersensitivity reactions such as itching, flush, rash. Very rare: beta-blocking agents may provoke or worsen psoriasis or induce psoriasis-like rash, alopecia. Musculoskeletal and connective tissue disorders: Uncommon: muscle weakness, muscle cramps. Vascular disorders: Common: feeling of coldness or numbness in the extremities, hypotension. General disorders: Common: asthenia, fatigue. Hepatobiliary disorders: Rare: hepatitis. Reproductive system and breast disorders: Rare: potency disorders. Psychiatric disorders: Uncommon: sleep disorders, depression

11 Rare: nightmares, hallucinations. 4.9 Overdose The most common signs expected with overdose of a beta-blocker are bradycardia, hypotension, bronchospasm, acute cardiac insufficiency and hypoglycaemia. There is limited experience with overdose of bisoprolol, only a few cases of overdose with bisoprolol have been reported. Bradycardia and/or hypotension were noted. All patients recovered. There is a wide inter-individual variation in sensitivity to one single high dose of bisoprolol and patients with heart failure are probably very sensitive. In general, if overdose occurs, discontinuation of bisoprolol treatment and supportive and symptomatic treatment is recommended. Based on the expected pharmacologic actions and recommendations for other beta-blocking agents, the following general measures should be considered when clinically warranted. Bradycardia: Administer intravenous atropine. If the response is inadequate, isoprenaline or another agent with positive chronotropic properties may be given cautiously. Under some circumstances, transvenous pacemaker insertion may be necessary. Hypotension: Intravenous fluids and vasopressors should be administered. Intravenous glucagon may be useful. AV block (second or third degree): Patients should be carefully monitored and treated with isoprenaline infusion or temporary pacing. Acute worsening of heart failure: Administer i.v. diuretics, inotropic agents, vasodilating agents. Bronchospasm: Administer bronchodilator therapy such as isoprenaline, beta 2 - sympathomimetic medicinal products and/or aminophylline. Hypoglycaemia: Administer i.v. glucose. Limited data suggest that bisoprolol is hardly dialysable. 5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Beta blocking agents, selective. ATC Code: C07AB07 Bisoprolol is a highly beta 1 -selective-adrenoceptor blocking agent, lacking intrinsic sympathomimetic and relevant membrane stabilising activity. It only shows low affinity to the beta 2 -receptor of the smooth muscles of bronchi and vessels as well as to the beta 2 -receptors concerned with metabolic regulation. Therefore, bisoprolol is generally not to be expected to influence the airway resistance and beta 2 -mediated metabolic effects. Its beta 1 -selectivity extends beyond the therapeutic dose range. In total 2647 patients were included in the CIBIS II trial. 83% (N = 2202) were in NYHA class III and 17% (N = 445) were in NYHA class IV. They had stable symptomatic systolic heart failure (ejection fraction 35%, based on echocardiography). Total mortality was reduced from 17.3% to 11.8% (relative reduction 34%). A decrease in sudden death (3.6% vs 6.3%, relative reduction 44%) and a reduced number of heart failure episodes requiring hospital admission (12% vs 17.6%, relative reduction 36%) was observed. Finally, a significant improvement of the functional status according to NYHA classification has been shown. During the initiation and titration of bisoprolol hospital admission due to bradycardia (0.53%), hypotension (0.23%), and acute decompensation (4.97%) were observed, but they were not more frequent than in the placebo-group (0%, 0.3% and 6.74%). The numbers of fatal and disabling strokes during the total study period were 20 in the bisoprolol group and 15 in the placebo group

12 The CIBIS III trial investigated 1010 patients aged 65 years with mild to moderate chronic heart failure (CHF; NYHA class II or III) and left ventricular ejection fraction 35%, who had not been treated previously with ACE inhibitors, beta-blocking agents, or angiotensin receptor blockers. Patients were treated with a combination of bisoprolol and enalapril for 6 to 24 months after an initial 6 months treatment with either bisoprolol or enalapril. There was a trend toward higher frequency of chronic heart failure worsening when bisoprolol was used as the initial 6 months treatment. Non inferiority of bisoprolol-first versus enalapril-first treatment was not proven in the per-protocol analysis, although the two strategies for initiation of CHF treatment showed a similar rate of the primary combined endpoint death and hospitalization at study end (32.4% in the bisoprolol-first group vs % in the enalapril-first group, per-protocol population). The study shows that bisoprolol can also be used in elderly chronic heart failure patients with mild to moderate disease. Bisoprolol is also used for the treatment of hypertension and angina pectoris. In acute administration in patients with coronary heart disease without chronic heart failure bisoprolol reduces the heart rate and stroke volume and thus the cardiac output and oxygen consumption. In chronic administration the initially elevated peripheral resistance decreases. 5.2 Pharmacokinetic properties 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. The half-life in plasma of hours gives a 24 hour effect after dosing once daily. 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. Since the elimination takes place in the kidneys and the liver to the same extent a dosage adjustment is not required for patients with impaired liver function or renal insufficiency. The pharmacokinetics in patients with stable chronic heart failure and with impaired liver or renal function has not been studied. The kinetics of bisoprolol are linear and independent of age. In patients with chronic heart failure (NYHA stage III) the plasma levels of bisoprolol are higher and the half-life is prolonged compared to healthy volunteers. Maximum plasma concentration at steady state is 64±21 ng/ml at a daily dose of 10 mg and the half-life is 17±5 hours. 5.3 Preclinical safety data Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or carcinogenicity. Like other betablocking agents, bisoprolol caused maternal (decreased food intake and decreased body weight) and embryo/fetal toxicity (increased incidence of resorptions, reduced birth weight of the offspring, retarded physical development) at high doses but was not teratogenic. 6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients Tablet core: Cellulose, Microcrystalline Calcium Hydrogen Phosphate, Anhydrous Silica Colloidal Anhydrous Crospovidone (Type A) Magnesium Stearate Tablet coat: Hypromellose 6cP (E464) Titanium Dioxide (E171) Macrogol

13 6.2 Incompatibilities Not applicable. 6.3 Shelf life 2 years In use shelf life for HDPE bottle pack [500 tablets]: 6 months 6.4 Special precautions for storage Store below 25ºC. Store in the original package in order to protect from light. 6.5 Nature and contents of container Bisoprolol Fumarate film-coated tablets are available in cold form Aluminum -Aluminum blisters with pealable lidding foil and HDPE bottle packs. Pack sizes: Blister pack: 20, 28, 30, 50, 90, 100 film-coated tablets Bottle pack: 30, 500 film-coated tablets Not all pack sizes may be marketed. 6.6 Special precautions for disposal Any unused product or waste material should be disposed of in accordance with local requirement 7 MARKETING AUTHORISATION HOLDER Aurobindo Pharma (Malta) Limited Vault 14, Level 2, Valletta Waterfront Floriana FRN 1913 Malta 8 MARKETING AUTHORISATION NUMBER(S) PL 32256/0083 PL 32256/0084 PL 32256/0085 PL 32256/0086 PL 32256/0087 PL 32256/ DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 26/10/ DATE OF REVISION OF THE TEXT 26/10/

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30 Module 5 Scientific discussion during initial procedure I INTRODUCTION On 5 October 2011, Germany, Italy, Poland and the UK agreed to grant Marketing Authorisations (MAs) to Aurobindo Pharma (Malta) Limited for the medicinal products Bisoprolol Fumarate 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg Film-Coated Tablets. The MAs were granted via a Decentralised Procedure (DCP), with the UK as Reference Member State (RMS UK/H/1683/001-6/DC). After the national phase, MAs were granted in the UK on 26 October 2011 (PL 32256/ ). These products are prescription-only medicines. These are generic applications for Bisoprolol Fumarate 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg Film-Coated Tablets submitted under Article 10.1 of 2001/83/EC, as amended. The applications refer to Cardicor 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg film-coated tablets marketed by Merck Germany and first authorised in Sweden on 4 June The UK reference products are Cardicor 1.25 mg (PL 00493/0179), 2.5 mg (PL 00493/0180), 3.75 mg (PL 00493/0181), 5 mg (PL 00493/0182), 7.5 mg (PL 00493/0183) and 10 mg (PL 00493/0184), authorised to E. Merck Ltd on 24 December 1999 via an incoming mutual recognition procedure. The reference products have been registered in the EEA for more than 10 years, hence the period of data exclusivity has expired. Bisoprolol is a highly beta1-selective-adrenoceptor blocking agent, without intrinsic sympathomimetic and relevant membrane stabilising activity. It only shows low affinity to the beta2-receptor of the smooth muscles of bronchi and vessels as well as to the beta2-receptors concerned with metabolic regulation. Therefore, bisoprolol is generally not to be expected to affect airway resistance and beta2-mediated metabolic effects. Bioequivalence has been demonstrated between the applicant s Bisoprolol Fumarate (2 x 1.25 mg) Film-Coated Tablets and the reference product Cardicor (2 x 1.25 mg) Film-Coated Tablets (E Merck Limited, UK) and Bisoprolol Fumarate 10 mg Film- Coated Tablets and the reference product Cardicor 10 mg Film-Coated Tablets (E Merck Limited, UK) under fasting conditions. The bioequivalence study was carried out in accordance with Good Clinical Practice (GCP). No new non-clinical or clinical efficacy studies were conducted for these applications, which is acceptable given that the applications are based on essential similarity to products that have been licensed for over 10 years. 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 prior to granting its national authorisation. For manufacturing sites outside the community, the RMS has accepted copies of current GMP Certificates or satisfactory inspection summary reports, close-out letters or exchange of information issued by the inspection services of the competent authorities (or those countries with which the EEA has a Mutual

31 Recognition Agreement for their own territories) as certification that acceptable standards of GMP are in place at those non-community sites. The RMS considers that the pharmacovigilance system as described by the MAH fulfils the requirements and provides adequate evidence that the MAH 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. The Marketing Authorisation holder (MAH) has provided adequate justification for not submitting a Risk Management Plan (RMP). As the application is for a generic version of an already authorised reference product, for which new safety concerns requiring additional minimisation have not been identified, routine pharmacovigilance activities are proposed and a risk minimisation system is not considered necessary. The reference product has been in use for many years and the safety profile of the active substance is well-established. The MAH has provided adequate justification for not submitting an Environmental Risk Assessment (ERA). This is an application for a generic product and there is no reason to conclude that marketing of this product will change the overall use pattern of the existing market. The excipients used in the product formulation are commonly used pharmaceutical compounds. There are no environmental concerns associated with the method of manufacture or formulation of the product

32 II. ABOUT THE PRODUCT Name of the product in the Reference Member State Name(s) of the active substance(s) (INN) Pharmacotherapeutic classification (ATC code) Pharmaceutical form and strength(s) Reference numbers for the Mutual Recognition Procedure Reference Member State Bisoprolol Fumarate 1.25 mg film-coated tablets Bisoprolol Fumarate 2.5 mg film-coated tablets Bisoprolol Fumarate 3.75 mg film-coated tablets Bisoprolol Fumarate 5 mg film-coated tablets Bisoprolol Fumarate 7.5 mg film-coated tablets Bisoprolol Fumarate 10 mg film-coated tablets Bisoprolol Fumarate C07AB mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg film-coated tablets UK/H/1683/001-6/DC United Kingdom Member States concerned Germany, Italy and Poland Marketing Authorisation Number(s) PL 32256/ Name and address of the Aurobindo Pharma (Malta) Limited, Vault 14, authorisation holder Level 2, Valletta Waterfront, Floriana FRN 1913, Malta

33 III SCIENTIFIC OVERVIEW AND DISCUSSION III.1 QUALITY ASPECTS DRUG SUBSTANCE rinn name: Bisoprolol fumarate Chemical name: (RS)-1-[4-[[2-(1- methylethoxy)ethoxy]methyl]phenoxy]-3-[(1-methylethyl) amino]propan-2-ol fumarate (±)-1-[4-[[2-(1-methylethoxy)ethoxy]methyl]phenoxy]-3-[(1- methylethyl)amino]-2- Propanol,(E)-2-butenedioate (2:1) (salt) (±)-1-[[α-(2-Isoproproxyethoxy)-p-tolyl]oxy]-3-isopropylamino)-2-propanol Fumarate (2:1)(salt) Molecular formula: C 40 H 66 N 2 O 12 Molecular weight: 767 g/mol Structure General properties Description: Bisoprolol fumarate is a white or almost white powder Solubility: Very soluble in water and freely soluble in methanol The active substance, Bisoprolol fumarate, is the subject of a European Pharmacopoeia (EP) monograph. Manufacture All aspects of the manufacture and control of the active substance Bisoprolol fumarate are covered by a European Directorate for the Quality of Medicines (EDQM) Certificate of Suitability

34 DRUG PRODUCT Description and Composition Bisoprolol Fumarate 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg Film-Coated Tablets are presented as white, circular, biconvex, film-coated tablets, debossed with P on one side and either 1, 2, 3, 5, 7 or 10 on the other side depending on the strength of the tablet. All the tablet strengths have a score line on one side so that the tablet can be divided into equal halves, with the exception of the 1.25 mg strength tablet which has no score-line. Full descriptions of the individual tablets and their markings may be found by referring to the SmPCs or patient information leaflet text. Other ingredients consist of pharmaceutical excipients, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, silica colloidal anhydrous, cropovidone (Type A) and magnesium stearate making up the tablet core; hypromellose 6cP (E464), titanium dioxide (E171) and macrogol 400 making up the tablet coat. All excipients used comply with their respective European Pharmacopoeial monograph. Satisfactory Certificates of Analysis have been provided for all excipients. Appropriate justification for the inclusion of each excipient has been provided. The applicant has provided a declaration confirming that there are no materials of human or animal origin contained in, or used in the manufacturing process for the proposed product. Furthermore, no genetically modified organisms are used in the manufacture of any of the excipients. Pharmaceutical development Details of the pharmaceutical development of the medicinal product have been supplied and are satisfactory. The objective was to develop a robust, stable generic formulation bioequivalent to the innovator product, Cardicor 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg film-coated tablets, authorised to E Merck Limited (PL 00493/ ). Comparative dissolution and impurity profiles were provided for the test and reference products and were found to be similar. Manufacture A description and flow-chart of the manufacturing method has been provided. In-process controls are appropriate considering the nature of the product and the method of manufacture. Process validation studies have been conducted and are accepted. The validation data demonstrated consistency of the manufacturing process. Finished Product Specification Finished product specifications are provided for both release and shelf-life, and are satisfactory; they provide an assurance of the quality and consistency of the finished product. Acceptance limits have been justified with respect to conventional pharmaceutical requirements and, where appropriate, safety. Test methods have been described and adequately validated, as appropriate. Satisfactory batch analysis data are provided and accepted. The data demonstrate that the batches are compliant with the proposed specifications. Certificates of Analysis have been provided for any reference standards used

35 Container-Closure System The finished products are licensed for marketing in aluminium/aluminium blister strips with pealable lidding foil or in high density polyethylene (HDPE) bottle packs, which are placed with the Patient Information Leaflet (PIL) into cardboard outer cartons. The blister strips are packaged in pack sizes of 20, 28, 30, 50, 90, 100 filmcoated tablets; HDPE bottles are licensed in pack sizes of 30 or 500 film-coated tablets. The Marketing Authorisation Holder (MAH) has stated that not all pack sizes may be marketed. However, the MAH has committed to submitting the proposed packaging/labelling for any pack size before it is marketed. Satisfactory specifications and Certificates of Analysis for all packaging components used have been provided. All primary product packaging complies with EU legislation, Directive 2002/72/EC (as amended), and is suitable for contact with foodstuffs. Stability Finished product stability studies have been conducted in accordance with current guidelines and results were within the proposed specification limits. Based on the results, a shelf-life of 2 years has been approved; the exception being the in-use shelflife for HDPE bottle pack (500 tablets) which has been approved at 6 months which is satisfactory. Storage conditions are Store below 25 o C and Store in original package in order to protect from light. Bioequivalence Studies The applicant submitted two bioequivalence studies in support of these applications. Bioequivalence has been demonstrated between the applicant s Bisoprolol Fumarate (2 x 1.25 mg) Film-Coated Tablets and the reference product Cardicor (2 x 1.25 mg) Film-Coated Tablets (E Merck Limited, UK) and Bisoprolol Fumarate 10 mg Film- Coated Tablets and the reference product Cardicor 10 mg Film-Coated Tablets (E Merck Limited, UK) under fasting conditions. An evaluation of the bioequivalence studies can be found in the Clinical Aspects section of this report. Quality Overall Summary A satisfactory quality overview is provided and has been prepared by an appropriately qualified expert. The curriculum vitae of the expert has been provided. Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL), Labels The SmPC, PIL and labelling are pharmaceutically acceptable. Colour mock-ups of the labelling and PIL have been provided. The Marketing Authorisation Holder (MAH) has stated that not all the pack sizes may be marketed. In accordance with medicines legislation, the MAH has provided a commitment to submit mock-ups for all packaging for assessment before those pack sizes are commercially marketed. The labelling is satisfactory and fulfils the statutory requirements for Braille. The applicant has submitted results of PIL user testing. The results indicate that the PIL is well-structured and organised, easy to understand and written in a comprehensive manner. The test shows that the patients/users are able to understand and act upon the information that the PIL contains

36 MAA Form The MAA forms are pharmaceutically satisfactory. Conclusion There are no objections to the approval of Bisoprolol Fumarate 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg an 10 mg Film-Coated Tablets from a pharmaceutical point of view. III.2 NON-CLINICAL ASPECTS The pharmacodynamic, pharmacokinetic and toxicological properties of bisoprolol fumarate are well-known. Therefore, no further studies are required and the applicant has provided none. ENVIRONMENTAL RISK ASSESSMENT No formal Environmental Risk Assessment has been provided. The applicant has justified the absence adequately. As a generic product, the use of this product is not expected to increase the overall use of bisoprolol fumarate and so no additional increase in environmental risk has been identified. NON-CLINICAL OVERVIEW The non-clinical overview was written by a suitably qualified person and is satisfactory. The curriculum vitae of the expert has been provided. SUMMARY OF PRODUCT CHARACTERISTICS (SmPCs) The SmPCs are satisfactory from a non-clinical viewpoint and is consistent with that for the reference products. There are no objections to the approval of Bisoprolol Fumarate 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg an 10 mg Film-Coated Tablets from a non-clinical point of view. III.3 CLINICAL ASPECTS INDICATIONS Bisoprolol fumarate is indicated in the treatment of stable chronic heart failure with reduced systolic left ventricular function in addition to ACE inhibitors, and diuretics, and optionally cardiac glycosides. The indications are consistent with those for the reference products and are satisfactory. POSOLOGY AND METHOD OF ADMINISTRATION Bisoprolol tablets should be taken in the morning and can be taken with food. They should be swallowed with liquid and should not be chewed. Full details concerning the posology are provided in the SmPC. The posology is consistent with that for the reference products and is satisfactory. TOXICOLOGY The toxicology of bisoprolol fumarate is well-known. No new data have been

37 submitted and none are required for these types of applications. CLINICAL PHARMACOLOGY The clinical pharmacology of bisoprolol fumarate is well-known. No novel pharmacodynamic or pharmacokinetic data are supplied or required for these applications. Pharmacokinetics In support of this application, the marketing authorisation holder has submitted two bioequivalence studies (one study with the 10mg presentation and one study with the 1.25mg presentation). Leopold G (1986) Balanced pharmacokinetics and metabolism of bisoprolol J Cardiovasc Pharmacol 8 (Suppl 11), has demonstrated that the pharmacokinetics of bisoprolol are linear between 2.5mg and 10mg: the applicant has therefore done one bioequivalence study with the 10mg presentation (the highest strength being applied for and in accordance with section 5.4 of CPMP/EWP/QWP/1401/98 July 2001) and one bioequivalence study with the 1.25mg presentation (the strength that lies outside the accepted, published linear range). Study 1 This is an open label, randomized, two-treatment, two-sequence, two-period, crossover, single-dose comparative oral bioavailability study of the test product, Bisoprolol fumarate 1.25 mg (2 x 1.25 mg) tablets and the reference product, Cardicor 1.25 mg (2 x 1.25 mg) tablets Merck Pharmaceuticals (a division of Merck Ltd.), UK in 28 healthy, adult, male, human subjects under fasting conditions. The study was conducted in compliance with Good Clinical Practice (ICH-GCP) and Good Laboratory Practice. Study design Subjects were admitted to the study facility on the evening before the start of the study and fasted overnight for 10hrs. Subjects then received a single oral dose of study medication with 240ml of water. Subjects were fasted for a further 4hrs. Subjects were discharged from the facility at 48hrs. Serial blood sampling before dosing and up to 48 hours after drug administration was carried out. A washout period of 8 days was maintained between dosing periods in each group which is sufficient time for bisoprolol fumarate to be eliminated from the body. A validated LC-MS/MS analytical methodology was used for quantification of valsartan from the human plasma samples. Primary variables analysed were: C max and AUC. Pre-defined bioequivalence acceptance criteria Bioequivalence of the test product versus the reference products was concluded if the 90% Confidence Intervals (CI) fell within the acceptance range, for logtransformed C max and AUC. ratios

38 Results: Bioequivalence results for log-transformed test/reference ratios with 90% Confidence Intervals: Conclusion on bioequivalence study: The results of the bioequivalence study show that the test and reference products are bioequivalent under fasting conditions, as the confidence intervals for Cmax and AUC for bisoprolol fumarate fall within the acceptance criteria ranges of %, in line with current CHMP guidelines. Study 2 This is an open label, randomized, two-treatment, two-sequence, two-period, crossover, single-dose comparative oral bioavailability study of the test product, Bisoprolol fumarate 10 mg tablets and the reference product, Cardicor 10 mg tablets Merck Pharmaceuticals (a division of Merck Ltd.), UK in 28 healthy, adult, male, human subjects under fasting conditions. The study was conducted in compliance with Good Clinical Practice (ICH-GCP) and Good Laboratory Practice. Study design Subjects were admitted to the study facility on the evening before the start of the study and fasted overnight for 10hrs. Subjects then received a single oral dose of study medication with 240ml of water. Subjects were fasted for a further 4hrs. Subjects were discharged from the facility at 48hrs. Serial blood sampling before dosing and up to 48 hours after drug administration was carried out

39 A washout period of 12 days was maintained between dosing periods in each group which is sufficient time for bisoprolol fumarate to be eliminated from the body. A validated LC-MS/MS analytical methodology was used for quantification of valsartan from the human plasma samples. Primary variables analysed were: C max and AUC. Pre-defined bioequivalence acceptance criteria Bioequivalence of the test product versus the reference products was concluded if the 90% Confidence Intervals (CI) fell within the acceptance range, for logtransformed C max and AUC. ratios. Results: Bioequivalence results for log-transformed test/reference ratios with 90% Confidence Intervals: Conclusion on bioequivalence study: The results of the bioequivalence study show that the test and reference products are bioequivalent under fasting conditions, as the confidence intervals for Cmax and AUC for bisoprolol fumarate fall within the acceptance criteria ranges of %, in line with current CHMP guidelines. Satisfactory justification is provided for a bio-waiver for Bisoprolol fumarate 2.5 mg, 3.75 mg, 5 mg and 7.5 mg presentations. As Bisoprolol Fumarate 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg film-coated tablets meet the criteria specified in the Note for Guidance on the investigation of bioavailability and bioequivalence

40 (CPMP/EWP/QWP/1401/98 Rev.1 Corr**), the results and conclusions of the bioequivalence studies on the 1.25 mg and 10 mg strength tablets can be extrapolated to the 2.5 mg, 3.75 mg, 5 mg and 7.5 mg presentations. The biowaiver claim is acceptable. Pharmacodynamics No new pharmacodynamic data have been submitted and none are required for these applications. Clinical efficacy No new efficacy data have been submitted and none are required for these applications. Clinical safety No new safety data have been submitted and none are required for these generic applications. As valsartan is a well-known product with an acceptable adverse event profile, this is satisfactory. Expert Report A satisfactory clinical overview is provided, and has been prepared by an appropriately qualified physician. The curriculum vitae of the expert has been provided. Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL), Labels The SmPCs and PIL are medically acceptable, and consistent with those for the reference product. The labelling is medically acceptable and in-line with current requirements. MAA form The MAA forms are medically satisfactory. Conclusion There are no objections to approval of Bisoprolol Fumarate 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg film-coated tablets from a clinical point of view

41 IV OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT QUALITY The important quality characteristics of Bisoprolol Fumarate 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg film-coated tablets are well-defined and controlled. The specifications and batch analytical results indicate consistency from batch to batch. There are no outstanding quality issues that would have a negative impact on the benefit/risk balance. NON-CLINICAL No new non-clinical data were submitted and none are required for applications of this type. EFFICACY The applicant has submitted two bioequivalence studies in support of these applications.bioequivalence has been demonstrated between the applicant s Bisoprolol Fumarate (2 x 1.25 mg) Film-Coated Tablets and the reference product Cardicor (2 x 1.25 mg) Film-Coated Tablets (E Merck Limited, UK) and Bisoprolol Fumarate 10 mg Film-Coated Tablets and the reference product Cardicor 10 mg Film-Coated Tablets (E Merck Limited, UK) under fasting conditions. No new or unexpected safety concerns arise from these applications. PRODUCT LITERATURE The SmPCs and PILs are acceptable, and consistent with those for the reference product. The labelling is acceptable and in-line with current requirements. The package leaflet has been evaluated via a user consultation study in accordance with the requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC. The results show that the package leaflet meets the criteria for readability as set out in the Guideline on the readability of the label and package leaflet of medicinal products for human use. BENEFIT/RISK ASSESSMENT The quality of the product is acceptable, and no new preclinical or clinical safety concerns have been identified. The qualitative and quantitative assessment supports the claim that the applicant s products Bisoprolol Fumarate 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg film-coated tablets and the reference products Cardicor 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg film-coated tablets (E Merck Limited UK), are interchangeable. Extensive clinical experience with bisoprolol fumarate is considered to have demonstrated the therapeutic value of the active substance. The benefit/risk is, therefore, considered to be positive

42 Module 6 STEPS TAKEN AFTER INITIAL PROCEDURE - SUMMARY Date submitted Application type Scope Outcome