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General: Abrupt Cessation of Therapy: In patients with heart failure treated chronically with carvedilol, abrupt cessation of therapy may lead to deterioration. Therefore discontinuation of carvedilol should be done gradually, if possible.
Patients with ischemic heart disease should be warned against abrupt discontinuation of beta-adrenergic blocking agents. There have been reports of severe exacerbation of angina, and of myocardial infarction or ventricular arrhythmias occurring in patients with angina pectoris, following abrupt discontinuation of beta-blocker therapy.
The last two complications may occur with or without preceding exacerbation of angina pectoris. Therefore, when discontinuing carvedilol in patients with angina pectoris, the dosage should be gradually reduced over a period of about 2 weeks and the patient should be carefully observed. The same frequency of administration should be maintained. In situations of greater urgency, carvedilol therapy should be discontinued stepwise and under conditions of closer observation. If angina markedly worsens or acute coronary insufficiency develops, it is recommended that treatment with the drug be re-instituted promptly, at least temporarily.
Oculomucocutaneous Syndrome: Various skin rashes and conjunctival xerosis have been reported with beta-blockers. A severe syndrome (oculomucocutaneous syndrome) whose signs include conjunctivitis sicca and psoriasiform rashes, otitis, and sclerosing serositis has occurred with the chronic use of one beta-adrenergic blocking agent (practolol). This syndrome has not been observed in association with carvedilol or any other such agent. However, physicians should be alert to the possibility of such reactions and should discontinue treatment in the event that they occur.
Cardiovascular: Cardiac Failure: Worsening cardiac failure may occur during initiation and up-titration of carvedilol. Sympathetic stimulation is a vital component supporting circulatory function in congestive heart failure, and inhibition with beta-blockade may further depress myocardial contractility.
Cardiac failure should be controlled for at least 4 weeks before carvedilol treatment is initiated. In clinical trials of mild to moderate heart failure, patients were required to be on stable doses of diuretics and ACE inhibitors (if tolerated) prior to the initiation of carvedilol. Despite these steps to ensure stability, a small number of patients with mild to moderate heart failure developed worsening heart failure. During the initiation of therapy (doses of 3.125 to 6.25 mg b.i.d. over 2 to 4 weeks) 6.0% of patients developed worsening congestive heart failure. During up-titration (12.5 to 50 mg b.i.d. over 2 to 6 weeks), worsening heart failure was reported in 5.1% of treated patients treated with carvedilol and in 4.1% of placebo patients.
In a placebo-controlled trial of patients with severe heart failure (COPERNICUS trial), worsening heart failure occurred during up-titration although the frequency reported during the first 3 months was similar with carvedilol (15.4%) and with placebo (14.8%). When treatment was maintained beyond 3 months, worsening heart failure was reported less frequently in patients treated with carvedilol than with placebo. Worsening heart failure observed during long-term therapy is more likely to be related to the patients' underlying disease than to treatment with carvedilol.
Administration of carvedilol to patients with controlled heart failure must be carried out under careful supervision. If symptoms occur, diuretics should be increased and the carvedilol dose not advanced or even lowered until clinical stability resumes (see Dosage & Administration). However, it may be necessary to discontinue carvedilol. Such episodes may not preclude subsequent successful titration of the drug or a favorable response to carvedilol.
Hypotension: Hypotension and postural hypotension in congestive heart failure patients occurred with a higher incidence in carvedilol-treated than in placebo-treated patients (see Adverse Reactions). The risk of these events was highest during initiation of therapy and during the first 30 days of dosing corresponding to the up-titration period. Therefore, it is of critical importance that the dosing recommendation be followed (see Dosage & Administration).
Peripheral Vascular Disease: Beta-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Caution should be exercised in such individuals.
Primary Regurgitative Valvular Heart Disease: Carvedilol should be used with caution in patients with primary regurgitative valvular disease as experience in this patient population is limited.
Prinzmetal's Angina: Beta-blocking agents may provoke chest pain in patients with Prinzmetal's angina. There has been no clinical experience with carvedilol in these patients. Caution should be taken in the administration of carvedilol to patients suspected of having Prinzmetal's variant angina.
Sinus Bradycardia: Severe sinus bradycardia may occur with the use of carvedilol. In such cases, dosage should be discontinued.
In clinical trials, patients with a resting heart rate of less than or equal to 68 beats/minute prior to initiation of carvedilol were not studied.
Endocrine and Metabolism: Diabetes: Carvedilol should be administered with caution to patients subject to spontaneous hypoglycemia, or to diabetic patients (especially those with labile diabetes) who are receiving insulin or oral hypoglycemic agents. Beta-adrenergic blocking drugs may enhance hypoglycemia, in patients prone to this condition. Also, diabetics on insulin or oral hypoglycemic medication may have an increased tendency towards hypoglycemia when treated with these drugs. It may also be necessary to adjust the dosage of oral hypoglycemics or insulin. Early signs of acute hypoglycemia, especially tachycardia, may be masked or attenuated. Regular monitoring of blood glucose is therefore recommended when carvedilol is initiated, adjusted or discontinued.
Hyperthyroidism: In patients with thyrotoxicosis, possible deleterious effects from long-term use of carvedilol have not been appraised. Beta-blockade, in general, may mask the clinical signs of continuing hyperthyroidism or complications, and give a false impression of improvement. Therefore, abrupt withdrawal of carvedilol may be followed by an exacerbation of the symptoms of hyperthyroidism, including thyroid storm.
Pheochromocytoma: The effect of carvedilol in patients with pheochromocytoma has not been studied. Since paradoxical hypertensive responses have been reported in a few patients with this tumor when treated with β-blockers, physicians should use caution when administering carvedilol to patients with pheochromocytoma.
Hepatic: Hepatocellular injury, confirmed by rechallenge, has occurred rarely with carvedilol therapy.
Hepatic injury has been reversible and has occurred after short- and/or long-term therapy with minimal clinical symptomatology. No deaths due to liver function abnormalities have been reported in association with the use of carvedilol.
At the first symptom/sign of liver dysfunction (e.g. pruritus, dark urine, persistent anorexia, jaundice, right upper quadrant tenderness or unexplained "flu-like" symptoms) laboratory testing should be performed. If the patient has laboratory evidence of liver injury or jaundice, carvedilol treatment should be stopped and not restarted.
Hepatic Impairment: Since carvedilol undergoes first-pass metabolism in the liver, reduced hepatic metabolism could lead to greater systemic bioavailability of carvedilol in patients with hepatic impairment. Care should be taken in selecting an appropriate dosage regimen for these patients (see Contraindications and Dosage & Administration). Physicians should be aware of the potential for increased manifestations of vasodilation (dizziness, postural hypotension, hypotension, syncope) or beta-blockade (bradycardia, AV block) in patients with mild hepatic impairment receiving carvedilol (see Dosage & Administration).
Immune: Allergic Reaction: There may be increased difficulty in treating an allergic-type reaction in patients on beta-blockers. In these patients, the reaction may be more severe due to pharmacological effects of beta-blockers and problems with fluid changes. Epinephrine should be administered with caution since it may not have its usual effects in the treatment of anaphylaxis.
On the one hand, larger doses of epinephrine may be needed to overcome the bronchospasm, while on the other; these doses can be associated with excessive alpha-adrenergic stimulation with consequent hypertension, reflex bradycardia and heart block and possible potentiation of bronchospasm. Alternatives to the use of large doses of epinephrine include vigorous supportive care such as fluids and the use of beta agonists including parenteral salbutamol or isoproterenol to overcome bronchospasm and norepinephrine to overcome hypotension.
Ophthalmologic: Contact Lens Use: Wearers of contact lenses should bear in mind the possibility of reduced lacrimation.
Uveal Binding: Animal studies have shown that carvedilol binds to the melanin of the uveal tract. The significance of this in humans is not known but periodic ophthalmic examinations are advisable while the patient is taking carvedilol.
Peri-Operative Considerations: Because of the synergistic negative inotropic and vasodilating effects of carvedilol and anesthetic drugs, the potential for pronounced hypotension during anesthesia exists. If carvedilol treatment is to be continued preoperatively, particular care should be taken when anesthetic agents which depress myocardial function are used.
Renal: Rarely, use of carvedilol in patients with congestive heart failure has resulted in acute renal failure and deterioration of renal function, likely on a pre-renal basis. Patients at risk appear to be those with low blood pressure (systolic BP < 100 mmHg), ischemic heart disease and diffuse vascular disease, and/or underlying renal insufficiency. Renal function has returned to baseline when carvedilol was stopped. In patients with these risk factors it is recommended that renal function be monitored during up-titration of carvedilol and the drug discontinued or dosage reduced if worsening of renal function occurs (see Dosage & Administration).
Respiratory: Bronchospasm (e.g. chronic bronchitis and emphysema): Patients with bronchospastic disease should, in general, not receive β-blockers (see Contraindications).
In clinical trials of patients with congestive heart failure, patients with bronchospastic disease were enrolled if they did not require oral or inhaled medication to treat their bronchospastic disease. In such patients, it is recommended that carvedilol be used with caution. The dosing recommendations should be followed closely and the dose should be lowered if any evidence of bronchospasm is observed during up-titration.
Use in the Elderly: Pharmacokinetic studies indicate that AUC and Tmax values are increased in elderly patients. Plasma levels of carvedilol averaged about 38% higher in elderly compared to young subjects. Therefore, dosage adjustments should be made with particular caution (see Dosage & Administration).
Use in Lactation: Carvedilol and/or its metabolites are excreted in breast milk. Therefore, breast feeding is not recommended during administration of carvedilol.
Use in Children: Safety and efficacy in children have not been established.
Use in Pregnancy: There have been no clinical studies carried out to specifically examine the use of carvedilol in pregnant women. Beta-blockers reduce placental perfusion, which may result in intrauterine fetal death, immature and premature deliveries. In addition, adverse effects (especially hypoglycemia and bradycardia) may occur in the fetus and neonate. There is an increased risk of cardiac and pulmonary complications in the neonate in the postnatal period.
Animal reproduction studies have revealed no teratogenic potential for carvedilol. Embryotoxicity was observed only after large doses in rabbits. The relevance of these findings for humans is uncertain.
Carvedilol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
