1. Name Of The Medicinal Product
Eucardic 6.25mg Tablets
2. Qualitative And Quantitative Composition
Each tablet contains 6.25mg carvedilol.
Excipients: lactose, sucrose.
Each tablet contains 51.8mg lactose and 21.25mg sucrose.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Tablet.
Round yellow tablet, scored on both sides, marked BM on one side and F1 on the other.
4. Clinical Particulars
4.1 Therapeutic Indications
Symptomatic chronic heart failure (CHF)
Eucardic 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
Eucardic is indicated for the treatment of hypertension.
Angina
Eucardic is indicated for the prophylactic treatment of stable angina.
4.2 Posology And Method Of Administration
The tablets should be taken with fluid. For CHF patients Eucardic should be given with food.
Symptomatic chronic heart failure
Initiation of therapy with Eucardic should only be under the supervision of a hospital physician, following a thorough assessment of the patient's 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 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 for all patients with severe CHF and for patients with mild to moderate CHF weighing less than 85kg (187lbs). 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 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.
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.
Patients with co-existing hepatic disease
Eucardic is contraindicated in patients with hepatic dysfunction (see sections 4.3 Contraindications 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 the active substance 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 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 < 85mmHg).
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 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 drugsmay 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 < 100mmHg), 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.
Bronchospatic 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 leaflet:
Packaging
Do not take this medicine if you have a history of wheezing due to asthma or other lung diseases.
Leaflet
Do not take Eucardic if you have ever had wheezing due to asthma or other lung diseases. If you are not sure, talk to your doctor or pharmacist before taking Eucardic.
Diabetes: Care should be taken in the administration of Eucardic to patients with diabetes mellitus as the early signs 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 since beta-blockers can precipitate or aggravate symptoms of arterial insufficiency. However as Eucardic 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 (Raynaud's phenomenon) as there may be exacerbation of symptoms.
Thyrotoxicosis: Eucardic, as with other agents with beta-blocking activity, may mask 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).
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 of the use of carvedilol in this condition. Therefore, caution should be taken in the administration of Eucardic 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 Eucardic 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: 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 2 weeks).
Lactose: This medicinal product contains lactose, therefore patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.
Sucrose: This medicinal product contains sucrose, therefore patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency 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 Scarvedilol 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 Eucardic 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 Eucardic 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, 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 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 Pregnancy And Lactation
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 breast milk. Breast feeding is therefore not recommended during administration of carvedilol.
4.7 Effects On Ability To Drive And Use Machines
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 Eucardic 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
Common
Uncommon
Rare
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 gammaglutamyltransferase (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 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.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Alpha and beta blocking agents. ATC code: C07AG02.
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, Eucardic has demonstrated anti-ischaemic and anti-anginal properties. Acute haemodynamic studies demonstrated that Eucardic 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 (COPERNICUS), 2289 patients with severe stable CHF of ischaemic or non-ischaemic 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 metabolised by CYP2C9 and to a lesser extend 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,
Demethylation and hydroxylation at the phenol ring produce 3 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
Sucrose
Povidone
Crospovidone
Colloidal silicon dioxide
Magnesium stearate
Yellow iron oxide E172
6.2 Incompatibilities
Not applicable.
6.3 Shelf Life
3 years.
6.4 Special Precautions For Storage
This medicinal product does not require any special temperature storage conditions.
Store in the original package in order to protect from moisture.
Keep the blister strips in the outer carton in order to protect from light.
6.5 Nature And Contents Of Container
Blister packs, OPA/Aluminium/PVC of 28 or 56 tablets.
Not all pack sizes may be marketed.
6.6 Special Precautions For Disposal And Other Handling
No special requirements.
7. Marketing Authorisation Holder
Roche Products Limited, 6 Falcon Way, Shire Park, Welwyn Garden City, AL7 1TW, United Kingdom.
8. Marketing Authorisation Number(S)
PL 00031/0551
9. Date Of First Authorisation/Renewal Of The Authorisation
20 July 2003
10. Date Of Revision Of The Text
11 July 2011
LEGAL STATUS
POM
Eucardic is a registered trade mark.
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