Roche Products (Ireland) Ltd

Eucardic 25mg Tablets

Each tablet contains Carvedilol 25mg

Excipients: Each tablet contains 10mg lactose monohydrate and 25mg sucrose.

For a full list of excipients, see section 6.1.

Tablet.

Round, white to pale beige tablets, scored on both sides, marked BM on one side and D5 on the other.

The tablet can be divided into equal halves.

Adjunctive therapy for the treatment of symptomatic congestive heart failure to reduce morbidity and increase patient well-being.

Treatment of hypertension.

Long-term management of stable angina pectoris.

The tablets should be taken with fluid. For Congestive Heart Failure (CHF) patients Eucardic should be given with food to slow the rate of absorption and reduce the incidence of orthostatic effects.

Symptomatic congestive heart failure

The dosage must be titrated to individual requirements and monitored during up-titration.

For those patients receiving diuretics and/or digoxin and/or ACE inhibitors, dosing of these other drugs should be stabilised prior to initiation of Eucardic 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 in patients weighing less than 85kg (187lbs) and 50mg twice daily in patients weighing more than 85kg.

Before each dose increase the patient should be evaluated by the physician for symptoms of worsening heart failure or vasodilation. Transient worsening of heart failure, vasodilation or fluid retention may be treated with increased doses of diuretics or ACE inhibitors or by modifying or temporarily discontinuing Eucardic treatment. Under these circumstances, the dose of Eucardic should not be increased until symptoms of worsening heart failure or vasodilation have been stabilised.

If Eucardic 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

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

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. If necessary, the dose may be titrated up to 50mg twice a day.

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

Elderly

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

Children

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

Hypersensitivity to the active substance or to any of the excipients.

Unstable/decompensated heart failure requiring intravenous inotropic support

Clinically manifest liver dysfunction

As with other beta-blocking agents:

History of bronchospasm or asthma

2nd and 3rd degree A-V heart 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).

Chronic congestive heart failure: In congestive heart failure patients, worsening cardiac failure or fluid retention may occur during up-titration of Eucardic. If such symptoms occur, diuretics should be increased and the Eucardic dose should not be advanced until clinical stability resumes. Occasionally it may be necessary to lower the Eucardic dose or, in rare cases, temporarily discontinue it. Such episodes do not preclude subsequent successful titration of Eucardic.

Eucardic should be used with caution in combination with digitalis glycosides, since 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 Eucardic 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 Eucardic and the drug discontinued or dosage reduced if worsening of renal failure occurs.

Chronic obstructive pulmonary disease: Carvedilol should be used with caution, in patients with chronic obstructive pulmonary disease (COPD) with a bronchospastic component who are not receiving oral or inhaled medication, and only if the potential benefit outweighs the potential risk. In patients with a tendency to bronchospasm, respiratory distress can occur as a result of a possible increase in airway resistance. Patients should be closely monitored during initiation and up-titration of carvedilol and the dose of Eucardic should be reduced if any evidence of bronchospasm is observed during treatment.

Diabetes: Care should be taken in the administration of Eucardic 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 Eucardic may be associated with worsening control of blood glucose. Therefore, regular monitoring of blood glucose is required in diabetics when Eucardic is initiated or up-titrated and hypoglycaemic therapy adjusted accordingly (see section 4.5).

Peripheral vascular disease: Eucardic should be used with caution in patients with peripheral vascular disease as beta-blockers can precipitate or aggravate symptoms of arterial insufficiency.

Raynaud's phenomenon: Carvedilol should be used with caution in patients suffering from peripheral circulatory disorders (eg Raynaud's phenomenon) as there may be exacerbation of symptoms.

Thyrotoxicosis: Eucardic 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: Eucardic may induce bradycardia. If the patient's pulse rate decreases to less than 55 beats per minute, the dosage of Eucardic should be reduced.

Hypersensitivity: Care should be taken in administering Eucardic 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 Eucardic 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).

Pheochromocytoma: In patients with pheochromocytoma, an alpha-blocking agent should be initiated prior to the use of any beta-blocking agent. Although Eucardic has both alpha and beta blocking pharmacological activities, there is no experience of the use of carvedilol in this condition. Therefore, caution should be taken in the administration of Eucardic to patients suspected of having pheochromocytoma.

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 Eucardic may prevent such symptoms. However, caution should be taken in the administration of Eucardic to patients suspected of having Prinzmetal's variant angina.

Contact lenses: Wearers of contact lenses should be advised of the possibility of reduced lacrimation.

Withdrawal syndrome: Although angina has not been reported on stopping treatment, discontinuation should be gradual (over a period of 2 weeks), particularly in patients with ischaemic heart disease, as Eucardic has beta-blocking activity.

Lactose: This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Sucrose: This medicinal product contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Usage of carvedilol in patients with symptomatic congestive heart failure has not been shown to reduce mortality.

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 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 hypolycaemics. 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 or other antiarrhythmics: 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 is administered with diltiazem. 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. These drugs should not be administered intravenously.

Antihypertensives: As with other agents with beta-blocking activity, Eucardic 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 attention must be paid during general anaesthesia to the synergistic negative inotropic and hypertensive effects of carvedilol and anaesthetic drugs.

NSAIDs: The concurrent use of non-steroidal anti-inflammatory drugs (NSAIDs) and beta-adrenergic 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.

Pregnancy

There is no adequate clinical 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 demonstrated that carvedilol or its metabolites are excreted in breast milk. It is not known whether carvedilol is excreted in human breast milk. Breast feeding is therefore not recommended during the administration of carvedilol.

No studies of the effects on ability to drive and use machines have been performed.

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.

(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) Tabulted 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: Thrombocytopenia

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 generalised, 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 Raynaud's phenomenon)

Respiratory, thoracic and mediastinal disorders

Common: Dyspnoea, pulmonary oedema, asthma in predisposed patients

Rare: Nasal congestion, 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, 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.

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 supportive treatment, the vital parameters 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 10mg 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, beta-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.

Pharmacotherapeutic group: Alpha and beta blocking agents. ATC code: C07AG02.

Carvedilol is a vasodilating non-selective beta blocking agent. 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.

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 left ventricular dysfunction or congestive heart failure, carvedilol has demonstrated favourable effects on haemodynamics and improvements in left ventricular ejection fraction and dimensions.

In patients with stable angina, Eucardic has demonstrated anti-ischaemic and anti-anginal properties. Acute haemodynamic studies demonstrated that Eucardic reduces both cardiac pre-load and after- load with consequent improvement in left ventricular systolic and diastolic function without substantial changes in the cardiac output.

Eucardic has no adverse affects on the metabolic risk factors of coronary heart disease. It does not impair the normal serum lipid profile and in hypertensive patients with dyslipidaemia favourable effects on the serum lipids have been reported after six months of oral therapy.

In two studies, Eucardic 25mg b.i.d. was compared with other anti-anginal drugs of recognised value in patients with chronic stable exertional angina. The dose regimens that were chosen were those widely used in clinical practice. Both trials had a double-blind, parallel group design. The primary objective was total exercise time (TET).

The results of both trials clearly demonstrated that for TET at trough blood drug levels after 12 weeks of therapy there was no statistically significant difference between treatment groups. However the risk ratios obtained from the Cox proportional hazards model showed a trend in favour of carvedilol indicating that on average carvedilol was 114% as effective as verapamil (90% CI: 85-152%) and 134% as effective as ISDN (90%CI: 96-185%). This was also true for time to angina (TTA) and ST-segment depression (TST) at trough. The increase in TET was about 50 seconds in all groups; the improvements for TTA and TST were about 30 seconds, which is clinically relevant.

In study 060, 48h Holter monitoring data measurements demonstrated a reduction of number and duration of ST-segment depressions (silent myocardial ischaemia) in both treatment groups. Carvedilol also decreased premature atrial and ventricular contractions (PAC, PVC), couplets and runs.

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 capsules (bioequivalent to the tablet formulation intended for marketing) was 22% in humans (range 10 to 49%).

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

The R-enantiomer is predominantly metabolised 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.

Serum levels peak 1 to 3 hours after an oral dose. There is a linear relationship between the dose and serum concentrations. The average elimination half-life is 6 hours. The primary route of excretion is via the faeces.

Food does not affect bioavailability, residence time or the maximum serum concentration, although the time to reach maximum serum concentration is delayed.

Special populations

Elderly: Age has no statistically significant effect on the pharmacokinetics of carvedilol in hypertensive patients.

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.

Heart failure: In a study in 24 Japanese 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 in Japanese patients.

There is no evidence from animal studies that carvedilol has any teratogenic effects. Embryotoxicity was observed only after large doses in rabbits. The relevance of these findings for humans is uncertain. 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 (although see section 4.6).

Lactose monohydrate

sucrose

povidone

crospovidone

colloidal anhydrous silica

magnesium stearate (E572)

Not applicable.

5 years.

This medicinal product does not require any special storage precautions. Store in the original package. Keep blisters in the outer carton.

Oriented Polyamide/Aluminium/PVC blister

Blisters are packed in cartons containing 14, 28, 30 or 100 tablets.

Not all pack sizes may be marketed.

No special requirements.

Roche Products Limited

6 Falcon Way

Shire Park

Welwyn Garden City

AL7 1TW

United Kingdom.

PA 50/142/3

Date of first authorisation: 19 January 1995

Date of last renewal: 3 April 2008

16 February 2012

Further information is available from Roche Products (Ireland) Limited, 3004 Lake Drive, City West, Naas Road, Dublin 24, Ireland.

Eucardic is a registered trade mark