Carvedilol
Drug Nomenclature
Pharmacopoeias. In Europe.
European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Carvedilol). A white or almost white crystalline powder. It exhibits polymorphism. Practically insoluble in water; slightly soluble in alcohol; practically insoluble in dilute acids.
Adverse Effects, Treatment, and Precautions
As for Beta Blockers.
Liver function abnormalities, reversible on stopping treatment with carvedilol, have been reported rarely. Carvedilol is extensively metabolised in the liver and is not recommended in patients with hepatic impairment. Acute renal failure and renal abnormalities have been reported in patients with heart failure who also suffered from diffuse vascular disease and/or renal impairment. The risk of hypotension may be reduced by taking carvedilol with food to decrease the rate of absorption.
Effects on the liver. Pruritus and elevated serum transaminase concentrations occurred in a man who had been taking carvedilol for 6 months. Liver function tests returned to normal within 3 weeks of stopping carvedilol. However, pruritus recurred when the patient was started on metoprolol about 1 year later.
Interactions
The interactions associated with beta blockers are discussed on site.
Pharmacokinetics
Carvedilol is well absorbed from the gastrointestinal tract but is subject to considerable first-pass metabolism in the liver; the absolute bioavailability is about 25%. Peak plasma concentrations occur 1 to 2 hours after an oral dose. It has high lipid solubility. Carvedilol is more than 98% bound to plasma proteins. It is extensively metabolised in the liver, primarily by the cytochrome P450 isoenzymes CYP2D6 and CYP2C9, and the metabolites are excreted mainly in the bile. The elimination half-life is about 6 to 10 hours. Carvedilol has been shown to accumulate in breast milk in animals.
Uses and Administration
Carvedilol is a non-cardioselective beta blocker. It has vasodilating properties, which are attributed mainly to its blocking activity at alpha] receptors; at higher doses calcium-channel blocking activity may contribute. It also has antoxidant properties. Carvedilol is reported to have no intrinsic sympathomimetic activity and only weak membrane-stabilising activity.
Carvedilol is used in the management of hypertension and angina pectoris, and as an adjunct to standard therapy in symptomatic heart failure. It is also used to reduce mortality in patients with left ventricular dysfunction after myocardial infarction.
In hypertension carvedilol is given in an initial oral dose of 12.5 mg once daily, increased after two days to 25 mg once daily. Alternatively, an initial dose of 6.25 mg is given twice daily, increased after one to two weeks to 12.5 mg twice daily. The dose may be increased further, if necessary, at intervals of at least two weeks, to 50 mg once daily or in divided doses. A dose of 12.5 mg once daily may be adequate for elderly patients.
In angina pectoris an initial oral dose of 12.5 mg is given twice daily, increased after two days to 25 mg twice daily.
In heart failure, the initial oral dose is 3.125 mg twice daily. It should be taken with food to reduce the risk of hypotension. If tolerated, the dose should be doubled after two weeks to 6.25 mg twice daily and then increased gradually, at intervals of not less than two weeks, to the maximum dose tolerated; this should not exceed 25 mg twice daily in patients with severe heart failure or in those weighing less than 85 kg, or 50 mg twice daily in patients with mild to moderate heart failure weighing more than 85 kg. For doses in children, see below.
In patients with left ventricular dysfunction after myocardial infarction, the initial dose is 6.25 mg twice daily, increased after 3 to 10 days, if tolerated, to 12.5 mg twice daily and then to a target dose of 25 mg twice daily. A lower initial dose may be used in symptomatic patients.
A controlled-release preparation containing carvedilol phosphate hemihydrate is available in some countries.
Administration in children. Carvedilol has been used in children with heart failure, although experience is limited. Beneficial effects have been reported, including improvement in symptoms and ejection fraction, and delaying the need for heart transplantation, and carvedilol appears to be well tolerated. Doses used have varied, with initial oral doses ranging from 10 to 180 micrograms/kg daily and average oral maintenance doses ranging from 200 to 700 micrograms/kg (maximum 50 mg) daily, usually given in two divided doses. However, a randomised study in 161 children and adolescents with heart failure found that carvedilol was not significantly better than placebo: clinical improvement occurred in 56% of those taking carvedilol and 56% of those taking placebo.
In the UK, the BNFC recommends that children aged 2 to 18 years with heart failure may be given an initial oral dose of 50 micrograms/kg (maximum 3.125 mg) twice daily, increased as tolerated, by doubling the dose at intervals of at least 2 weeks, to a maintenance dose of 350 micrograms/kg (maximum 25 mg) twice daily.
Administration in the elderly. Licensed product information for carvedilol recommends an initial dose of 12.5 mg daily for all adults with hypertension. A study in 16 elderly hypertensive patients (mean age 70 years) given single doses of 12.5 mg and 25 mg found a high incidence of orthostatic hypotension and the authors suggested that a starting dose lower than 12.5 mg may be necessary in elderly patients.
A retrospective study found that standard initial doses for heart failure (see Uses and Administration, above) were well tolerated in elderly patients and that the mean achieved dose was similar in those aged under 70 years and those aged 70 years and older, after adjustment for weight. Adverse effects were more common in the older group, but could generally be managed without stopping carvedilol.
Preparations
Proprietary Preparations
Argentina: Antibloc; Bidecar; Carvedil; Carvel †; Corafen; Coritensil; Corubin; Dilatrend; Duobloc; Filten; Hipoten; Isobloc; Kollosteril; Rodipal; Rudoxil; Veraten; Vicardol;
Australia: Dilatrend; Kredex;
Austria; Dilatrend; Hybridil;
Belgium: Dimitone; Kredex;
Brazil: Cardilol; Carvedilat; Coreg; Dilatrend; Divelol; Ictus; Karvil;
Canada: Coreg;
Chile: Betaplex; Blocar; Dilatrend; Dualten; Lodipres; Novocar †; Off-Ten;
Czech Republic: Apo-Carve; Atram; Carvedigamma; Carvesan; Carvetrend; Coryol; Dilatrend; Talliton;
Denmark: Carvetone; Dimitone;
Finland: Cardiol;
France: Kredex;
Germany: CarLich; Carve; Carve-Q; Carvecard; Carvedigamma; Dilatrend; Dimetil; Querto;
Greece: Carvedilen; Carvepen; Dilatrend;
Hong Kong: Dilatrend;
Hungary: Carvedigamma; Carvol; Coryol; Dilatrend Talliton;
India: Carloc; Carvil; Cevas;
Indonesia: Carbloxal; Dilbloc; V-Bloc
Ireland: Biocard; Eucardic;
Israel: Carvedexxon; Dimitone;
Italy:Carvipress Colver; Dilatrend; Dilocar;
Malaysia: Caslot, Cavel; Dilatrend;
Mexico: Dilatrend;
The Netherlands: Eucardic;
Norway: Kredex;
New Zealand: Dilatrend;
Philippines: Dilatrend;
Poland: Atram; Carvedigamma; Carvetrend; Coryol; Dilatrend; Vivacor;
Portugal: Dilbloc;
Russia: Acridilole (Акридилол); Cardivas (Кардивас); Carvetrend (Карветренд); Carvidil (Карвидил); Coryol (Кориол); Talliton (Таллитон);
South Africa: Carloc; Carvetrend; Dilatrend;
Singapore; Dilatrend;
Spain: Coropres;
Sweden: Kredex;
Switzerland: Dilatrend;
Thailand: Dilatrend;
Turkey: Dilatrend;
United Kingdom (UK): Eucardic;
US: Coreg;
Venezuela: Carbatil; Carvedil; Coventrol; Dilatrend.
Multi-ingredient
Argentina: Carvedil D;
Austria: Co-Dilatrend; Dilaplus.
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