Presentation and Status in Health Basket
30 x 6.25 mg
30 x 12.5 mg
Posology and method of administration: The tablets should be taken with food. The tablets are intended for oral use. The recommended dose for the initiation 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 and 50mg twice daily in patient weighing more than 85kg. Prior to each dose increase, the patient should be examined by a physician with regard to any symptoms relating to deteriorating heart failure and/or vascular dilation. Occasional deterioration of heart failure or increased fluid retention should be treated with increased dosage of diuretics. Under these circumstances, the dose of Carvedexxon should not be increased until symptoms of worsening heart failure or vasodilatation have been established. Sometimes it may become necessary to decrease the dose of Carvedilol or temporally discontinue Carvedilol treatment. If Carvedilol is discontinued for more than two weeks, therapy should be recommenced at 3.125 mg 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.
Patients with co-existing hepatic disease: Carvedilol is contra-indicated 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.
Treatment of symptomatic congestive heart failure. Carvedexxon may be used as adjunct to standard therapy, but may also be used in those patients unable to tolerate an ACE inhibitor, or those who are not receiving digitalis, hydralazine or nitrate therapy.
Carvedilol is contra-indicated in patients with marked fluid retention or overload requiring intravenous inotropic support. Patients with obstructive airways disease, liver dysfunction, hypersensitivity to carvedilol or any other constituents of the tablets. As with other beta-blocking agents: History of bronchospasm or asthma, 2nd and 3rd degree A-V heart block, severe bradycardia (< 50 bpm), cardiogenic shock, sick sinus syndrome (including sino-atrial block), severe hypotension (systolic blood pressure < 85mmHg), metabolic acidosis and phaeochromocytoma (unless adequately controlled by alpha blockade).
In chronic heart failure patients, worsening cardiac failure or fluid retention may occur during up-titration of carvedilol. If such symptoms occur, the dose of diuretic should be adjusted and the carvedilol dose should not be advanced until clinical stability resumes. Occasionally it may be necessary to lower the Carvedilol dose or temporarily discontinue it. Such episodes do not preclude subsequent successful titration of Carvedilol. In hypertensive patients who have chronic heart failure controlled with digoxin, diuretics and/or an ACE inhibitor, Carvedilol should be used with caution since both digoxin and Carvedilol may slow A-V conduction. As with other drugs with beta-blocking activity, Carvedilol may mask the early signs of acute hypoglycaemia in patients with diabetes mellitus. Alternatives to beta-blocking agents are generally preferred in insulin-dependent patients. In 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.
Reversible deterioration of renal function has been observed with Carvedilol 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 Carvedilol and the drug discontinued or dosage reduced if worsening of renal failure occurs Wearers of contact lenses should be advised of the possibility of reduced lacrimation. Although angina has not been reported on stopping treatment, discontinuation should be gradual (1 – 2 weeks) particularly in patients with ischaemic heart disease, as Carvedilol has beta-blocking activity.
Carvedilol may be used in patients with peripheral vascular disease. Pure beta-blockers can precipitate or aggravate symptoms of arterial insufficiency. However as Carvedilol also has alpha-blocking properties this effect is largely counterbalanced. Carvedilol, as with other agents with beta-blocking activity, may mask the symptoms of thyrotoxicosis. If Carvedilol induces bradycardia, with a decrease in pulse rate to less than 55 beats per minute, the dosage of Carvedilol tablets should be reduced. 3 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. In patients suffering from the peripheral circulatory disorder Raynaud’s phenomenon, there may be exacerbation of symptoms. Patients with a history of psoriasis associated with beta-blocker therapy should be given Carvedilol only after consideration of the risk-benefit ratio.In patients with phaeochromocytoma, an alpha-blocking agent should be initiated prior to the use of any beta-blocking agent. There is no experience of the use of carvedilol in this condition. Therefore, caution should be taken in the administration of Carvedilol to patients suspected of having phaeochromocytoma. 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. However, caution should be taken in the administration of Carvedilol to patients suspected of having Prinzmetal’s variant angina. In patients with a tendency to bronchospastic reactions, respiratory distress can occur as a result of a possible increase in airway resistance.
most common: Symptomatic postural hypotension, mainly on the initiation of therapy or when increasing the dose, may occur but the incidence is minimised when the drug is used as recommended. Commonly dizziness, headache, fatigue, gastrointestinal upset (nausea, abdominal pain, diarrhoea, hyperglycemia, hypercholesterolemia; infrequently constipation and vomiting), bradycardia and hypotension (infrequently syncope) have been observed. These effects are usually mild, transient and occur early in the course of treatment. Other common effects have included pain in the extremities and reduced lacrimation and, in predisposed patients, there may be asthma and dyspnoea. Infrequently there may be depressed mood, sleep disturbance, paraesthesia, wheezing, flu-like symptoms, rare or isolated cases of skin reactions (e.g. allergic exanthema, in isolated cases urticaria, pruritus and lichen planus-like reactions). Psoriatic skin lesions may occur or existing lesions may be exacerbated. Diminished peripheral circulation (cold extremities) or peripheral oedema may occur infrequently. Rarely there may be A-V block, syncope, angina pectoris, acute renal failure. Renal abnormalities in patients with diffuse vascular disease and/or impaired renal function has been reported. Rarely there can be exacerbation of symptoms in patients suffering from intermittent claudication, Raynaud’s phenomenon, or progression of heart failure. Stuffy nose may occur infrequently. Isolated cases of changes in serum transaminases, thrombocytopenia and leucopenia have been reported. There have also been rare cases of sexual impotence, disturbed vision, eye irritation, dryness of the mouth and disturbances of micturition.
Due to the beta-blocking properties it is also possible for latent diabetes mellitus to become manifest, manifest diabetes to be aggravated, and blood glucose counter-regulation to be inhibited.
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. Isolated cases of conduction disturbance (rarely with haemodynamic disruption) have been observed when Carvedilol and diltiazem were given concomitantly. Therefore, as with other drugs with beta-blocking activity, careful monitoring of ECG and blood pressure should be undertaken when co-administering calcium channel blockers of the verapamil or diltiazem type, or class I anti-arrhythmic drugs. These types of drugs should not be co-administered intravenously in patients receiving Carvedilol.
The effects of insulin or oral hypoglycaemics may be intensified. Regular monitoring of blood glucose is therefore recommended. Trough plasma digoxin levels may be increased by approximately 16% in hypertensive patients co-administered Carvedilol and digoxin. Increased monitoring of digoxin levels is recommended when initiating, adjusting or discontinuing Carvedilol. Concomitant administration of Carvedilol and cardiac glycosides may prolong AV conduction time. When treatment with Carvedilol and clonidine together is to be terminated, Carvedilol should be withdrawn first, several days before gradually decreasing the dosage of clonidine. Care may be required in those receiving inducers of mixed function oxidases e.g. rifampicin, as serum levels of carvedilol may be reduced or inhibitors of mixed function oxidases e.g. cimetidine, as serum levels may be increased. During general anaesthesia, attention should be paid to the potential synergistic negative inotropic effects of carvedilol and anaesthetic drugs.
Pregnancy and Lactation
There is no adequate experience with Carvedilol in pregnant women. Carvedilol should not be used in pregnancy or in breast feeding mothers unless the anticipated benefits outweigh the potential risks. 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. 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 is excreted in breast milk 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.
For full details see Physician Information Leaflet, as approved by the Israeli Ministry of Health.
Symptoms and signs: Profound cardiovascular effects such as hypotension and bradycardia would be expected after massive overdose. Heart failure, cardiogenic shock and cardiac arrest may follow. 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 10mg i.v. (followed by a slow i.v. infusion of 2 to 5mg/hour if necessary) may be given when bradycardia is present. Pacemaker therapy may be necessary. For excessive hypotension, intravenous fluids may be administered. In addition, norepinephrine may be given, either 5 to 10 micrograms i.v., repeated according to blood pressure response, or 5 micrograms per minute by infusion titrated to blood pressure. Bronchospasm may be treated using salbutamol or other beta2-agonists given as aerosol or, if necessary, by the intravenous route. In the event of seizures, slow i.v. 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.