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MHRA-UKPAR – Carvedilol 3.125mg, 6.25mg, 12.5mg and 25mg Tablets PL 36390/0019-22 - 1 -

CARVEDILOL 3.125MG, 6.25MG, 12.5MG & 25MG TABLETS PL 36390/0019-22

UKPAR

TABLE OF CONTENTS Lay Summary

Page 2

Scientific discussion

Page 3

Steps taken for assessment

1

Steps taken after authorisation – summary

Page 12

Summary of Product Characteristics Page 13

Patient Information Leaflet

Page 26

Labelling Page 28



LAY SUMMARY The Medicines and Healthcare products Regulatory Agency granted STD Chemicals Ltd, Marketing Authorisations for the medicinal products, Carvedilol 3.125mg, 6.25mg, 12.5mg and 25mg tablets (PL 36390/0019-22) on 5 January 2012. The products are prescription-only (POM) medicines. Carvedilol Tablets contain the active ingredient carvedilol, which belongs to a group of medicines called beta blockers and vasodilators. Carvedilol Tablets are used for the treatment of angina (pains in the chest caused by blockages in the arteries leading to the heart) and mild to moderate heart failure (when the heart cannot pump blood properly to the rest of the body). Carvedilol is also used to treat hypertension (high blood pressure). Carvedilol works by relaxing and widening blood vessels. This helps to lower blood pressure; makes it easier for the heart to pump blood around the body in patients who suffer from chronic heart failure and helps stop chest pain in patients who suffer from angina. These applications are considered to be identical to the previously granted licences for Carvedilol 3.125mg, 6.25mg, 12.5mg and 25mg tablets (PL 08137/0123-0126) on 17 January 2007 to NeoLab Ltd. No new or unexpected safety concerns arose from this application and it was, therefore, Carvedilol 3.125mg, 6.25mg, 12.5mg and 25mg tablets (PL 08137/0123-0126) judged that the benefits of taking Carvedilol 3.125mg, 6.25mg, 12.5mg and 25mg tablets outweigh the risks; hence Marketing Authorisations have been granted.


CARVEDILOL 3.125MG, 6.25MG, 12.5MG & 25MG TABLETS

PL 36390/0019-22

SCIENTIFIC DISCUSSION

TABLE OF CONTENTS Introduction

Page 4

Pharmaceutical assessment

Page 5

Non-Clinical assessment

Page 8

Clinical assessment

Page 9

Overall conclusions and risk benefit assessment Page 10


INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the MHRA granted STD Chemicals Ltd., Marketing Authorisations for the medicinal products, Carvedilol 3.125mg, 6.25mg, 12.5mg and 25mg Tablets (PL 36390/0019-22), on 5 January 2012. The products are prescription-only medicines.

These are simple, abridged, ‘informed consent’ applications submitted according to Article 10(c) of EC Directive 2001/83 (as amended), cross-referencing the Marketing Authorisation for Carvedilol 3.125mg, 6.25mg, 12.5mg and 25mg tablets (PL 08137/0123-0126), licensed to Neolab Ltd on 17 January 2007. The reference products cross-refer to the innovator products Eucardic 3.125, 6.25, 12.5 and 25 granted on 20 July 1998 to Boehringer Mannheim UK; the licences have since undergone a change of ownership and are currently authorised to Roche Products Limited (PL 00031/0550-3) since 1 April 1999. The innovator products has been authorised in the EEA for over 10 years. Carvedilol is a vasodilating non-selective beta blocking agent with antioxidant properties. Vasodilation is predominantly mediated through alpha1 receptor antagonism.

Carvedilol reduces the peripheral vascular resistance through vasodilation and suppresses the renin-angiotensin-aldosterone system through beta blockade. No new data were submitted nor were they necessary for these simple applications, as the data is identical to that of the previously granted cross-reference products. A Public Assessment Report (PAR) has been generated for the reference products Carvedilol 3.125mg, 6.25mg, 12.5mg and 25mg tablets (PL 08137/0123-0126).


PHARMACEUTICAL ASSESSMENT LICENCE NO: PL 36390/0019-22 PROPRIETARY NAME: Carvedilol 3.125 mg, 6.25 mg, 12.5 mg and 25 mg Tablets ACTIVE: Carvedilol COMPANY NAME: STD Chemicals Ltd E.C. ARTICLE: Article 10c of Directive 2001/83/EC LEGAL STATUS: POM 1. INTRODUCTION These are simple, informed consent applications for Carvedilol 3.125 mg, 6.25 mg, 12.5 mg and 25 mg Tablets submitted under Article 10c of Directive 2001/83/EC. The proposed Marketing Authorisation Holder is STD Chemicals Ltd, Hillbrow House, Hillbrow Road, Esher, Surrey, KT10 9NW, UK. The applications cross-refer to Carvedilol 3.125mg, 6.25mg, 12.5mg and 25mg tablets (PL 08137/0123-0126) authorised to Neolab Ltd since 17 January 2007. The current applications are considered valid. 2. MARKETING AUTHORISATION APPLICATION FORM 2.1 Name The proposed name of the products are Carvedilol 3.125 mg, 6.25 mg, 12.5 mg and 25 mg Tablets. The products have been named in line with current requirements. 2.2 Strength, pharmaceutical form, route of administration, container and pack sizes One uncoated tablet contains 3.125 mg, 6.25 m g, 12.5 mg or 25 mg respectively, of the active ingredient, carvedilol. The medicinal product is licensed for marketing in polyethylenevinylcholride (PVC)/polyvinylidene chloride (PVdC)/aluminium blister strips, which are packed with the Patient Information Leaflet (PIL) into cardboard outer cartons, in pack sizes of 28 tablets. The container closure systems and pack sizes are identical to those for the reference products.

The approved shelf-life (2 years) with the storage instructions, “Store in original package” is identical to the details registered for the cross-reference product. 2.3 Legal status These products are a prescription-only medicines. 2.4 Marketing authorisation holder/Contact Persons/Company The proposed Marketing Authorisation Holder is STD Chemicals Ltd, Hillbrow House, Hillbrow Road, Esher, Surrey, KT10 9NW, UK

The Quality Person (QP) responsible for pharmacovigilance is stated and their curriculum vita has been included. 2.5 Manufacturers The proposed manufacturing sites are consistent with those registered for the cross-reference products and evidence of GMP compliance has been provided.


2.6 Qualitative and quantitative composition The proposed composition is consistent with the details registered for the cross-reference products. 2.7 Manufacturing process The proposed manufacturing process is consistent with the details registered for the cross-reference products and the maximum batch size is stated. 2.8 Finished product/shelf-life specification The proposed finished product specification is in-line with the details registered for the cross-reference products. 2.9 Drug substance specification The proposed drug substance specification is consistent with the details registered for the cross-reference products. 2.10 TSE Compliance With the exception of lactose monohydrate, none of the other excipients contained or used in the manufacturing process for the proposed products contain material derived from animal or human origin. The applicant has provided a declaration that milk used in the production of lactose is sourced from healthy animals under the same conditions as that for human consumption. None of the excipients are soureced from genticially modified organisms. This is consistent with the cross-reference product. 3. EXPERT REPORT A satisfactory quality overall summary has been prepared by an appropriately qualified expert. The CV of the expert was provided. 4. PRODUCT NAME & APPEARANCE See 2.1 for details of the proposed product name. The appearance of the product (cream coloured round tablets marked with “NEO” on one face and either C3, C6, C12 or C25 on the other face) respectively for the different strengths of the product is identical to that of the cross-reference products. 5. SUMMARY OF PRODUCT CHARACTERISTICS (SmPC) The approved SmPCs are consistent with the details registered for the cross-reference products. 6. PATIENT INFORMATION LEAFLET (PIL)/CARTON PIL The PIL is satisfactory and in line with the approved SmPCs and has been prepared in the user-tested format. To support the proposed patient leaflet, a user testing report has been provided for the approved reference products, Carvedilol 3.125mg, 6.25mg, 12.5mg and 25mg tablets (PL 08137/0123-0126) authorised to Neolab Ltd. The patient leaflet for the reference products met all criteria for successful user testing. The proposed layout and content of the proposed patient leaflet is identical to that of the approved reference product. As a result, bridging justification is acceptd for the proposed products without the need for further user testing.


Carton and label Mock-ups of the labelling have been provided and are satisfactory. The approved artwork is comparable to the artwork registered for the cross-reference product and complies with statutory requirements. In line with current legislation the applicant has included the name of the product in Braille on the outer packaging. 7. CONCLUSIONS The data submitted with these applications are acceptable. Marketing Authorisations were, therefore, granted.


NON-CLINICAL ASSESSMENT These are simple, abridged, ‘informed consent’ applications made under Article 10c of EC Directive 2001/83 (as amended). These applications are identical to the reference products Carvedilol 3.125mg, 6.25mg, 12.5mg and 25mg tablets (PL 08137/0123-0126) authorised to Neolab Ltd on 17 January 2007 in the UK, therefore, no new non-clinical data has been supplied with these applications and none are required. A non-clinical overview report has been written by a suitably qualified person and is satisfactory. The CV of the non-clinical expert has been supplied. The marketing authorisation holder has provided adequate justification for not submitting an Environment Risk Assessment (ERA). As these applications are identical to already authorised reference products, it is not expected that the environmental exposure to carvedilol will increase following the marketing approval of the proposed product.


CLINICAL ASSESSMENT

These are simple, abridged, ‘informed consent’ applications made under Article 10(c) of EC Directive 2001/83 (as amended), cross-referring to Carvedilol 3.125mg, 6.25mg, 12.5mg and 25mg tablets (PL 08137/0123-0126) authorised to Neolab Ltd on 17 January 2007 in the UK. No new clinical data has been supplied with these applications and none are required. A clinical overview has been written by a suitably qualified person and is satisfactory. The CV of the clinical expert has been supplied. The marketing authorisation holder (MAH) has provided adequate justification for not submitting a Risk Management Plan (RMP). As these applications are identical to already authorised reference products, for which safety concerns requiring additional risk minimisation have not been identified, a risk minimisation system is not considered necessary. The reference products have been in use for many years and the safety profile of the active is well-established. The MAH has provided a suitable pharmacovigilance system that 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.


OVERALL CONCLUSION AND RISK BENEFIT ASSESSMENT QUALITY The data for these applications are consistent with those previously assessed for the cross-reference products and as such has been judged to be satisfactory. NON-CLINICAL No new non-clinical data were submitted and none are required for applications of this type. EFFICACY These applications are considered identical to the previously granted licences for Carvedilol 3.125mg, 6.25mg, 12.5mg and 25mg tablets (PL 08137/0123-0126) authorised to Neolab Ltd since 17 January 2007 in the UK. No new or unexpected safety concerns arise from this application. PRODUCT LITERATURE The approved SmPCs, PILs and labelling are satisfactory, and consistent with those for the cross-reference products. A user testing report has been provided for the approved reference products, Carvedilol 3.125mg, 6.25mg, 12.5mg and 25mg tablets (PL 08137/0123-0126). The patient leaflet for the reference products met all criteria for successful user testing. The proposed layout and content of the new patient leaflet is identical to that of the approved reference products. As a result, bridging justification is accepted for the proposed products without the need for further user testing. Mock-ups of the labeling have been provided and are satisfactory. The labeling artwork complies with statutory requirements. In line with current legislation, the name of the product in Braille appears on the outer packaging. The MAH has committed to submitting mock-ups for currently unmarketed packs to the UK regulatory authority for approval before those packs are commercially marketed. RISK BENEFIT ASSESSMENT The quality of the product is acceptable and no new non-clinical or clinical safety concerns have been identified. The applicant’s products are identical to the cross-reference products. The benefit; risk ratio is, therefore, considered to be positive.


CARVEDILOL 3.125MG, 6.25MG, 12.5MG & 25MG TABLETS

PL 36390/0019-22

STEPS TAKEN FOR ASSESMENT

1 The MHRA received the marketing authorisation application on 4 May 2011.

2 Following standard checks and communication with the applicant the MHRA considered the application valid on 1 June 2011.

3 Following assessment of the application the MHRA requested further information relating to the quality dossier on 17 August 2011.

4 The applicant responded to the MHRA’s requests, providing further information on 4 October 2011.

5 The application was determined on 5 January 2012.



STEPS TAKEN AFTER ASSESSMENT

Date submitted

Application type

Scope Outcome



SUMMARY OF PRODUCT CHARACTERISTICS

The UK Summary of Product Characteristics (SmPC) for Carvedilol 3.125 mg, 6.25 mg, 12.5 mg and 25 mg Tablets (PL 36390/0019-22) are as follows: Difference between the SmPCs are highlighted in yellow. 1 NAME OF THE MEDICINAL PRODUCT

Carvedilol 3.125 mg Tablets. Carvedilol 6.25 mg Tablets. Carvedilol 12.5 mg Tablets. Carvedilol 25 mg Tablets.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Carvedilol 3.125 mg Tablets. Each Carvedilol 3.125 mg Tablet contains 3.125 mg carvedilol. Each tablet contains 15.74 mg lactose monohydrate. Carvedilol 6.25 mg Tablets. Each Carvedilol 6.25 mg Tablet contains 6.25 mg carvedilol. Each tablet contains 31.47 mg lactose monohydrate. Carvedilol 12.5 mg Tablets. Each Carvedilol 12.5 mg Tablet contains 12.5 mg carvedilol. Each tablet contains 62.94 mg lactose monohydrate.

Carvedilol 25 mg Tablets. Each Carvedilol 25 mg Tablet contains 25 mg carvedilol. Each tablet contains 125.88 mg lactose monohydrate. For a full list of excipients, see Section 6.1.

3 PHARMACEUTICAL FORM

Uncoated tablet.

Carvedilol 3.125 mg Tablets. Cream coloured round tablet marked ‘NEO’ on one face and ‘C3’ on the reverse face. Carvedilol 6.25 mg Tablets. Cream coloured round tablet marked ‘NEO’ on one face and ‘C6’ on the reverse face. Carvedilol 12.5 mg Tablets. Cream coloured round tablet marked ‘NEO’ on one face and ‘C12’ on the reverse face. Carvedilol 25 mg Tablets. Cream coloured round tablet marked ‘NEO’ on one face and ‘C25’ on the reverse face.

4 CLINICAL PARTICULARS 4.1 Therapeutic indications

Symptomatic chronic heart failure (CHF)

Carvedilol is indicated for the treatment of stable mild, moderate and severe chronic heart failure as adjunct to standard therapies e.g. diuretics, digoxin and ACE inhibitors in patients with euvolemia.


Hypertension Carvedilol is indicated for the treatment of hypertension. Angina Carvedilol is indicated for the prophylactic treatment of stable angina.

4.2 Posology and method of administration For oral administration. The tablets should be taken with fluid. For CHF patients carvedilol should be given with food.

Symptomatic chronic heart failure

Initiation of therapy with carvedilol should only be under the supervision of a hospital physician, following a thorough assessment of the patients' condition.

Prior to any subsequent titration of the dose, the patient must be clinically evaluated on the day of up - titration by a health-care professional experienced in the management of heart failure to ensure that the clinical status has remained stable. The dose of carvedilol should not be increased in any patient with deteriorating heart failure since last visit or with signs of decompensated or unstable chronic heart failure.

The dosage must be titrated to individual requirements. For those patients receiving diuretics and/or digoxin and/or ACE inhibitors, dosing of these other drugs should be stabilized prior to initiation of carvedilol treatment.

Adults

The recommended dose for the initiation of therapy is 3.125mg twice a day for two weeks. If this dose is tolerated, the dosage should be increased subsequently, at intervals of not less than two weeks, to 6.25mg twice daily, followed by 12.5mg twice daily and thereafter 25mg twice daily. Dosing should be increased to the highest level tolerated by the patient.

The recommended maximum daily dose is 25mg given twice daily for all patients with severe CHF and for patients with mild to moderate CHF weighing less than 85kg (187 lbs). In patients with mild or moderate CHF weighing more than 85kg, the recommended maximum dose is 50mg twice daily.

During up-titration of the dose in patients with systolic blood pressure < 100mmHg, deterioration of renal and/or cardiac functions may occur. Therefore, before each dose increase these patients should be evaluated by the physician for renal function and symptoms of worsening heart failure or vasodilation. Transient worsening of heart failure, vasodilation or fluid retention may be treated by adjusting doses of diuretics or ACE inhibitors or by modifying or temporarily discontinuing carvedilol treatment. Under these circumstances, the dose of carvedilol should not be increased until symptoms of worsening heart failure or vasodilation have been stabilised.

If carvedilol is discontinued for more than two weeks, therapy should be recommenced at 3.125mg twice daily and up-titrated in line with the above dosing recommendation.

Elderly

As for adults.

Children


Safety and efficacy in children (under 18 years) has not been established.

Hypertension

Once daily dosing is recommended.

Adults

The recommended dose for initiation of therapy is 12.5mg once a day for the first two days. Thereafter the recommended dosage is 25mg once a day. Although this is an adequate dose in most patients, if necessary the dose may be titrated up to a recommended daily maximum dose of 50mg given once a day or in divided doses.

Dose titration should occur at intervals of at least two weeks.

Elderly

An initial dose of 12.5mg daily is recommended. This has provided

satisfactory control in some cases. If the response is inadequate the dose may be titrated up to the recommended daily maximum dose of 50mg given once a day or in divided doses.

Children


Angina

Adults

The recommended dose for initiation of therapy is 12.5mg twice a day for the first two days. Thereafter, the recommended dosage is 25mg twice a day.

Elderly

The recommended maximum daily dose is 50mg given in divided doses.

Children


Patients with co-existing hepatic disease

Carvedilol is contra-indicated in patients with hepatic dysfunction (see sections 4.3 Contra-indications and 5.2 Pharmacokinetic properties).

Patients with co-existing renal dysfunction

No dose adjustment is anticipated as long as systolic blood pressure is above 100mmHg (see also sections 4.4 Special warnings and precautions for use and 5.2 Pharmacokinetic properties).

4.3 Contraindications Hypersensitivity to carvedilol or to any of the excipients. Unstable/decompensated heart failure. Marked fluid retention or overload requiring intravenous inotropic support.


Obstructive airways disease. Clinically manifest liver dysfunction. History of bronchospasm or asthma. 2nd and 3rd degree AV block (unless a permanent pacemaker is in place). Severe bradycardia (<50 bpm). Cardiogenic shock. Sick sinus syndrome (including sino-atrial block). Severe hypotension (systolic blood pressure <85 mmHg). Metabolic acidosis. Phaeochromocytoma (unless adequately controlled by alpha blockade).

4.4 Special warnings and precautions for use Chronic congestive heart failure: In congestive heart failure patients, worsening cardiac failure or fluid retention may occur during up-titration of carvedilol. If such symptoms occur, diuretics should be increased and the carvedilol dose should not be advanced until clinical stability resumes. Occasionally, it may be necessary to lower the carvedilol dose or, in rare cases, temporarily discontinue it. Such episodes do not preclude subsequent successful titration of carvedilol. Carvedilol should be used with caution in combination with digitalis glycosides, as both drugs slow A-V conduction (see section 4.5). Renal function in congestive heart failure: Reversible deterioration of renal function has been observed with carvedilol therapy in chronic heart failure patients with low blood pressure (systolic BP <100 mmHg), ischaemic heart disease and diffuse vascular disease, and/or underlying renal insufficiency. In CHF patients with these risk factors, renal function should be monitored during up-titration of carvedilol and the drug discontinued or dosage reduced if worsening of renal failure occurs. Bronchospastic reactions: In patients with a tendency to bronchospastic reactions, respiratory distress can occur as a result of a possible increase in airway resistance. The following warnings will be included on the outer packaging and patient information leaflet: Outer packaging: Do not take this medicine if you have a history of wheezing due to asthma or other lung diseases. Patient Information Leaflet: Do not take this medicine if you have a history of wheezing due to asthma or other lung diseases. Consult your doctor or pharmacist first. Diabetes: Care should be taken in the administration of carvedilol to patients with diabetes mellitus, as the early signs and symptoms of acute hypoglycaemia may be masked or attenuated. Alternatives to beta-blocking agents are generally preferred in insulin-dependent patients. In chronic heart failure patients with diabetes, the use of carvedilol may be associated with worsening control of blood glucose. Therefore, regular monitoring of blood glucose is required in diabetics when carvedilol is initiated or up-titrated and hypoglycaemic therapy adjusted accordingly (see section 4.5). Peripheral vascular disease: Carvedilol should be used with caution in patients with peripheral vascular disease since beta--blockers can precipitate or aggravate symptoms of arterial insufficiency. However as carvedilol also has alpha-blocking properties this effect is largely counterbalanced.


Raynaud's phenomenon: Carvedilol should be used with caution in patients suffering from peripheral circulatory disorders (e.g. Raynaud's phenomenon) as there may be exacerbation of symptoms. Thyrotoxicosis: Carvedilol, as with other agents with beta-blocking activity, may obscure the symptoms of thyrotoxicosis. Anaesthesia and major surgery: Caution should be exercised in patients undergoing general surgery, because of the synergistic negative inotropic effects of carvedilol and anaesthetic drugs (see section 4.5). Bradycardia: Carvedilol may induce bradycardia. If the patient’s pulse rate decreases to less than 55 beats per minute, the dosage of carvedilol should be reduced. Hypersensitivity: Care should be taken in administering carvedilol to patients with a history of serious hypersensitivity reactions, and in those undergoing desensitisation therapy, as beta-blockers may increase both the sensitivity towards allergens and the seriousness of anaphylactic reactions. Psoriasis: Patients with a history of psoriasis associated with beta-blocker therapy should be given carvedilol only after consideration of the risk-benefit ratio. Concomitant use of calcium channel blockers: Careful monitoring of ECG and blood pressure is necessary in patients receiving concomitant therapy with calcium channel blockers of the verapamil or diltiazem type or other antiarrhythmic drugs (see section 4.5). Phaeochromocytoma: In patients with phaeochromocytoma, an alpha-blocking agent should be initiated prior to the use of any beta-blocking agent. Although carvedilol has both alpha and beta-blocking pharmacological activities, there is no experience with its use in this condition. Caution should therefore be taken in the administration of carvedilol to patients suspected of having phaeochromocytoma. Prinzmetal's variant angina: Agents with non-selective beta-blocking activity may provoke chest pain in patients with Prinzmetal's variant angina. There is no clinical experience with carvedilol in these patients although the alpha-blocking activity of carvedilol may prevent such symptoms. Caution should, however, be taken in the administration of carvedilol to patients suspected of having Prinzmetal's variant angina. Contact lenses: Wearers of contact lenses should bear in mind the possibility of reduced lacrimation. Withdrawal syndrome: Carvedilol treatment should not be discontinued abruptly, particularly in patients suffering from ischaemic heart disease. The withdrawal of carvedilol should be gradual (over a period of two weeks). The tablets also contain lactose (see section 6.1). Patients with rare hereditary problems of galactose intolerance, the Lapp lactose deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction Pharmacokinetic interactions

Carvedilol is a substrate as well as an inhibitor of P-glycoprotein. Therefore the bioavailability of drugs transported by P-glycoprotein may be increased with concomitant administration of carvedilol. In addition, the bioavailability of carvedilol can be modified by inducers or inhibitors of P-glycoprotein.


Inhibitors as well as inducers of CYP2D6 and CYP2C9 can modify the systemic and/or presystemic metabolism of carvedilol stereoselectively, leading to increased or decreased plasma concentrations of R and S-carvedilol. (see section 5.2). Some examples observed in patients or in healthy subjects are listed below but the list is not exhaustive.

Digoxin: Digoxin concentrations are increased by about 15% when digoxin and carvedilol are administered concomitantly. Increased monitoring of digoxin levels is recommended when initiating, adjusting or discontinuing carvedilol (see section 4.4).

Ciclosporin: Two studies in renal and cardiac transplant patients receiving oral ciclosporin have shown an increase in ciclosporin plasma concentration following the initiation of carvedilol. It appears that carvedilol increases the absorption of ciclosporin po through inhibition of P-glycoprotein activity in the intestine. In an attempt to maintain therapeutic ciclosporin levels, an average 10-20% reduction of the ciclosporin dose was necessary. Therefore, due to wide interindividual variability of ciclosporin levels, it is recommended that ciclosporin concentrations are monitored closely after initiation of carvedilol therapy and that the dose of ciclosporin be adjusted as appropriate. In case of iv administration of ciclosporin, no interaction with carvedilol is expected.

Rifampicin: In a study in 12 healthy subjects, rifampicin administration decreased the carvedilol plasma levels most likely by induction of P-glycoprotein leading to a decrease of the intestinal absorption of carvedilol and a decrease of the antihypertensive effect.

Amiodarone: In patients with heart failure, amiodarone decreased the clearance of S-carvedilol likely by inhibition of CYP2C9. The mean R-carvedilol plasma concentration was not altered. Consequently, there is a potential risk of increased beta-blockade caused by a raised of the plasma S-carvedilol concentration.

Fluoxetine: In a randomized, cross-over study in 10 patients with heart failure, coadministration of fluoxetine, a strong inhibitor of CYP2D6, resulted in stereoselective inhibition of carvedilol metabolism with a 77% increase in mean R(+) enantiomer AUC. However, no difference in adverse events, blood pressure or heart rate were noted between treatment groups.

Pharmacodynamic interactions

Insulin or oral hypoglycaemics: Agents with beta-blocking properties may enhance the blood-sugar-reducing effect of insulin and oral hypoglycaemics. The signs of hypoglycaemia may be masked or attenuated (especially tachycardia). In patients taking insulin or oral hypoglycaemics, regular monitoring of blood glucose is therefore recommended (see section 4.4).

Catecholamine-depleting agents: Patients taking both agents with beta-blocking properties and a drug that can deplete catecholamines (e.g. reserpine and monoamine oxidase inhibitors) should be observed closely for signs of hypotension and/or severe bradycardia.

Verapamil, diltiazem, amiodarone or other antiarryhthmics: In combination with carvedilol can increase the risk of AV conduction disturbances (see section 4.4).

Clonidine: Concomitant administration of clonidine with agents with beta-blocking properties may potentiate blood pressure and heart rate lowering effects. When concomitant treatment with agents with beta-blocking properties and clonidine is to be terminated, the beta-blocking agent should be discontinued first. Clonidine therapy can then be discontinued several days later by gradually decreasing the dosage.

Calcium channel blockers (see section 4.4): Isolated cases of conduction disturbance (rarely with haemodynamic compromise) have been observed when carvedilol and diltiazem were given concomitantly. As with other agents with beta-blocking properties, if carvedilol is to be administered orally with calcium channel blockers of the verapamil or diltiazem type, it is recommended that ECG and blood pressure be monitored.

Antihypertensives: As with other agents with beta-blocking activity, carvedilol may potentiate the effect of other concomitantly administered drugs that are anti-hypertensive in action (e.g. alpha1-receptor antagonists) or have hypotension as part of their adverse effect profile.

Anaesthetic agents: Careful monitoring of vital signs is recommended during anaesthesia due to the synergistic negative inotropic and hypertensive effects of carvedilol and anaesthetic drugs (see section 4.4).


NSAIDs: The concurrent use of non-steroidal anti-inflammatory drugs (NSAIDs) and betaadrenergic blockers may result in an increase in blood pressure and lower blood pressure control.

Beta-agonist bronchodilatators: Non-cardioselective beta blockers oppose the bronchodilator effects of beta-agonist bronchodilators.

4.6 Fertility, Pregnancy and lactation Pregnancy

There is no adequate experience with carvedilol in pregnant women.

Animal studies are insufficient with respect to effects on pregnancy, embryonal/foetal development, parturition and postnatal development (see section 5.3). The potential risk for humans is unknown.

Carvedilol should not be used during pregnancy unless the potential benefit outweighs the potential risk.

Beta blockers reduce placental perfusion, which may result in intrauterine foetal death, and immature and premature deliveries. In addition, adverse effects (especially hypoglycaemia and bradycardia) may occur in the foetus and neonate. There may be an increased risk of cardiac and pulmonary complications in the neonate in the postnatal period. Animal studies have not shown substantive evidence of teratogenicity with carvedilol (see also section 5.3).

Lactation

Animal studies have shown that carvedilol and its metabolites are excreted in breast milk. It is not known whether carvedilol is excreted in human milk.

Breast feeding is therefore not recommended during the administration of

carvedilol.

4.7 Effects on ability to drive and use machines As for other drugs which produce changes in blood pressure, patients taking carvedilol should be warned not to drive or operate machinery if they experience dizziness or related symptoms. This applies particularly when starting or changing treatment and in conjunction with alcohol.

4.8 Undesirable effects (a) Summary of the safety profile

The frequency of adverse reactions is not dose-dependent, with the exception of dizziness, abnormal vision and bradycardia.

(b) Tabulated list of adverse reactions

The risk of most adverse reactions associated with carvedilol is similar across all indications. Exceptions are described in subsection (c).

Frequency categories are as follows:

Very common ≥ ≥ 1/10

Common ≥ 1/100 and < 1/10

Uncommon ≥ ≥ 1/1,000 and < 1/100

Rare ≥ ≥ 1/10,000 and < 1/1,000

Very rare < < 1/10,000

Infections and infestations Common: Bronchitis, pneumonia, upper respiratory tract infection, urinary tract infection Blood and lymphatic system disorders Common: Anaemia


Rare: Thrombocytopaenia Very rare: Leukopenia Immune system disorders Very rare: Hypersensitivity (allergic reaction) Metabolism and nutrition disorders Common: Weight increase, hypercholesterolaemia, impaired blood glucose control (hyperglycaemia, hypoglycaemia) in patients with pre-existing diabetes Psychiatric disorders Common: Depression, depressed mood Uncommon: Sleep disorders Nervous system disorders Very common: Dizziness, headache Uncommon: Presyncope, syncope, paraesthesia Eye disorders Common: Visual impairment, lacrimation decreased (dry eye), eye irritation Cardiac disorders Very common: Cardiac failure Common: Bradycardia, oedema (including generalized, peripheral dependent and genital oedema, oedema of the legs), hypervolaemia, fluid overload Uncommon: Atrioventricular block, angina pectoris Vascular disorders Very common: Hypotension Common: Orthostatic hypotension, disturbances of peripheral circulation (cold extremities, peripheral vascular disease, exacerbation of intermittent claudication and Reynaud’s phenomenon) Respiratory, thoracic and mediastinal disorders Common: Dyspnoea, pulmonary oedema, asthma in predisposed patients Rare: Nasal congestion, wheezing and flu-like symptoms Gastrointestinal disorders Common: Nausea, diarrhoea, vomiting, dyspepsia, abdominal pain Uncommon: Constipation Rare: Dry mouth Hepatobiliary disorders


Very rare: Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyltransferase (GGT) increased Skin and subcutaneous tissue disorders Uncommon: Skin reactions (e.g. allergic exanthema, dermatitis, increased sweating, urticaria, pruritus, psoriatic and lichen planus like skin lesions), alopecia Musculoskeletal and connective tissue disorders Common: Pain in extremities Renal and urinary disorders Common: Renal failure and renal function abnormalities in patients with diffuse vascular disease and/or underlying renal insufficiency, micturition disorders Very rare: Urinary incontinence in women Reproductive system and breast disorders Uncommon: Erectile dysfunction General disorders and administration site conditions Very common: Asthenia (fatigue) Common: Pain

(c) Description of selected adverse reactions

Dizziness, syncope, headache and asthenia are usually mild and are more likely to occur at the beginning of treatment.

In patients with congestive heart failure, worsening cardiac failure and fluid retention may occur during up-titration of carvedilol dose (see section 4.4).

Cardiac failure is a commonly reported adverse event in both placebo and carvedilol-treated patients (14.5% and 15.4% respectively, in patients with left ventricular dysfunction following acute myocardial infarction).

Reversible deterioration of renal function has been observed with carvedilol therapy in chronic heart failure patients with low blood pressure, ischaemic heart disease and diffuse vascular disease and/or underlying renal insufficiency (see section 4.4).

As a class, beta-adrenergic receptor blockers may cause latent diabetes to become manifest, manifest diabetes to be aggravated, and blood glucose counter-regulation to be inhibited.

Carvedilol may cause urinary incontinence in women which resolves upon discontinuation of the medication.

4.9 Overdose Symptoms and signs

In the event of overdose, there may be severe hypotension, bradycardia, heart failure, cardiogenic shock and cardiac arrest. There may also be respiratory problems, bronchospasm, vomiting, disturbed consciousness and generalised seizures.

Treatment

Gastric lavage or induced emesis may be useful in the first few hours after ingestion.


In addition to general procedures, vital signs must be monitored and corrected, if necessary under intensive care conditions.

Patients should be placed in the supine position. Atropine, 0.5mg to 2mg i.v. and/or glucagon 1 to 10 mg i.v. (followed by a slow i.v. infusion of 2 to 5mg/hour if necessary) may be given when bradycardia is present. To support ventricular function intravenous glucagon or sympathomimetics (dobutamine, isoprenaline) are recommended. If positive inotropic effect is required, phosphodiesterase inhibitors (PDE) should be considered. Pacemaker therapy may be necessary. For excessive hypotension, intravenous fluids may be administered. If peripheral vasodilation dominates the intoxication profile then norepinephrine or noradrenaline should be administered, with continuous monitoring of the circulation, either 5 to 10 micrograms i.v., repeated according to blood pressure response, or 5 micrograms per minute by infusion titrated to blood pressure.

In the case of drug-resistant bradycardia, pacemaker therapy should be initiated.

For bronchospasm, β-sympathomimetics (as aerosol or intravenous) should be given, or aminophylline may be administered intravenously by slow injection or infusion. In the event of seizures, slow intravenous injection of diazepam or clonazepam is recommended.

In cases of severe overdose with symptoms of shock, supportive treatment as described should be continued for a sufficiently long period of time, i.e. until the patient stabilises, since prolonged elimination half life and redistribution of carvedilol from deeper compartments can be expected.

5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Alpha and beta blocking agents

ATC Code CO7A G02.

Carvedilol is a vasodilating non-selective beta blocking agent with antioxidant properties. Vasodilation is predominantly mediated through alpha1 receptor antagonism.

Carvedilol reduces the peripheral vascular resistance through vasodilation and suppresses the renin-angiotensin-aldosterone system through beta blockade. The activity of plasma renin is reduced and fluid retention is rare.

Carvedilol has no intrinsic sympathomimetic activity and like propranolol, it has membrane stabilising properties.

Carvedilol is a racemate of two stereoisomers. Beta-blockade is attributed to the S(-) enantiomer; in contrast, both enantiomers exhibit the same α1-blocking activity.

Carvedilol is a potent antioxidant, a scavenger of reactive oxygen radicals and an anti-proliferative agent. The properties of carvedilol and its metabolites have been demonstrated in in vitro and in vivo animal studies and in vitro in a number of human cell types.

Clinical studies have shown that the balance of vasodilation and beta-blockade provided by carvedilol results in the following effects:

- In hypertensive patients, a reduction in blood pressure is not associated with a concomitant increase in total peripheral resistance, as observed with pure beta-blocking agents. Heart rate is slightly decreased. Renal blood flow and renal function are maintained. Peripheral blood flow is maintained, therefore, cold extremities, often observed with drugs possessing beta-blocking activity, are rarely seen.


- In patients with stable angina, carvedilol has demonstrated anti ischaemic and anti-anginal properties. Acute haemodynamic studies demonstrated that carvedilol reduces ventricular pre- and after-load.

- In patients with left ventricular dysfunction or chronic heart failure, carvedilol has demonstrated favourable effects on haemodynamics and improvements in left ventricular ejection fraction and dimensions.

- In a large, multi-centre, double-blind, placebo-controlled mortality trial, 2289 patients with severe stable CHF of ischaemic or nonischaemic origin, on standard therapy, were randomised to either carvedilol (1156 patients) or placebo (1133 patients). Patients had left ventricular systolic dysfunction with a mean ejection fraction of < 20%. All-cause mortality was reduced by 35% from 19.7% in the placebo group to 12.8% in the carvedilol group (Cox proportional hazards, p = 0.00013).

Combined secondary endpoints of mortality or hospitalisation for heart failure, mortality or cardiovascular hospitalisation and mortality or all cause hospitalisation were all significantly lower in the carvedilol group than placebo (31%, 27% and 24% reductions, respectively, all p < 0.00004).

The incidence of serious adverse events during the study was lower in the carvedilol group (39.0% vs 45.4%). During initiation of treatment, the incidence of worsening heart failure was similar in both carvedilol and placebo groups. The incidence of serious worsening heart failure during the study was lower in the carvedilol group (14.6% vs 21.6%).

Serum lipid profile and electrolytes are not affected.

5.2 Pharmacokinetic properties Carvedilol is a substrate of the intestinal efflux transporter P-glycoprotein which plays a major role in the bioavailability of certain drugs. The absolute bioavailability of carvedilol is approximately 25% in humans. Bioavailability is stereo-selective, 30% for the R-form and 15% for the S-form. Serum levels peak at approximately 1 hour after an oral dose. There is a linear relationship between the dose and serum concentrations. Food does not affect bioavailability or the maximum serum concentration although the time to reach maximum serum concentration is delayed.

Carvedilol is highly lipophilic, approximately 98% to 99% is bound to plasma proteins. The distribution volume is approximately 2 l/kg and increased in patients with liver cirrhosis.

In humans, carvedilol is extensively metabolized in the liver via oxidation and conjugation into a variety of metabolites that are eliminated mainly in the bile. The first pass effect after oral administration is approximately 60 - 75%; enterohepatic circulation of the parent substance has been shown in animals.

The oxidative metabolism of carvedilol is stereoselective. The R-enantiomer is predominantly metabolized by CYP2D6 and CYP1A2, while the S-enantiomer is mainly metabolized by CYP2C9 and to a lesser extent by CYP2D6. Other CYP450 isoenzyemes involved in the metabolism of carvedilol include CYP3A4, CYP2E1 and CYP2C19. The maximal plasma concentration of R-carvedilol are approximately 2 fold higher than S-carvedilol.

The R-enantiomer is predominantly metabolized through hydroxylation.


In slow metabolisers of CYP2D6 an increase of the plasma concentration of carvedilol, mainly the R-enantiomer may occur, leading to an increase in the alpha-blocking activity.

Demethylation and hydroxylation at the phenol ring produce three metabolites with beta-receptor blocking activity.

The average elimination half-life ranges from 6 to 10 hours. Plasma clearance is approximately 590ml/min. Elimination is mainly biliary. The primary route of excretion is via the faeces. A minor portion is eliminated via the kidneys in the form of various metabolites.

Elderly: The pharmacokinetics of carvedilol are affected by age; plasma levels of carvedilol are approximately 50% higher in the elderly compared to young subjects.

Hepatic impairment: In a study in patients with cirrhotic liver disease, the bioavailability of carvedilol was four times greater and the peak plasma level five times higher than in healthy subjects.

Renal impairment: Since carvedilol is primarily excreted via the faeces, significant accumulation in patients with renal impairment is unlikely. In patients with

impaired liver function, bioavailability is raised to as much as 80% due to a reduced first pass effect.

Heart failure: In a study in 24 patients with heart failure, the clearance of R- and S-carvedilol was significantly lower than previously estimated in healthy volunteers. These results suggested that the pharmacokinetics of R- and S-carvedilol is significantly altered by heart failure.

5.3 Preclinical safety data There is no evidence from animal studies that Eucardic has any teratogenic effects. Embryotoxicity was observed only after large doses in rabbits. The relevance of these findings for humans is uncertain. Beta-blockers reduce placental perfusion which may result in intrauterine foetal death and immature and premature deliveries. In addition, animal studies have shown that carvedilol crosses the placental barrier and therefore the possible consequences of alpha and beta-blockade in the human foetus and neonate should also be borne in mind. With other alpha and beta-blocking agents, effects have included perinatal and neonatal distress (bradycardia, hypotension, respiratory depression, hypoglycaemia, hypothermia). There is an increased risk of cardiac and pulmonary complications in the neonate in the postnatal period.

6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients

Lactose monohydrate Microcyrstalline cellulose Low substituted hydroxypropyl cellulose Maize starch Yellow iron oxide (E172) Colloidal anhydrous silica Talc Magnesium stearate

6.2 Incompatibilities Not applicable.

6.3 Shelf life 2 years.


6.4 Special precautions for storage Store in the original package.

6.5 Nature and contents of container Packs of 28 tablets.

Blister strips comprising of PVC/PVdC/Aluminium foil enclosed in an outer carton.

6.6 Special precautions for disposal Not applicable.

7 MARKETING AUTHORISATION HOLDER

STD Chemicals Limited, Hillbrow House, Hillbrow Road, Esher, Surrey, KT10 9NW

8 MARKETING AUTHORISATION NUMBER(S)

PL 36390/0019 PL 36390/0020 PL 36390/0021

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 05/01/2012 10 DATE OF REVISION OF THE TEXT

05/01/2012



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