Carvedilol

(BAN, USAN, rINN)
Carvedilol Chemical formula
Synonyms: BM-14190; Carvédilol; Carvedilolum; Karvedilol; Karvediloli; Karvedilolis. 1-Carbazol-4-yloxy-3-[2-(2-methoxyphenoxy)ethylamino]propan-2-ol.
Cyrillic synonym: Карведилол.

💊 Chemical information

Chemical formula: C24H26N2O4 = 406.5.
CAS — 72956-09-3.
ATC — C07AG02.
ATC Vet — QC07AG02.

Pharmacopoeias.

In Eur..

Ph. Eur. 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 occurred1 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.
1. Hagmeyer KO, Stein J. Hepatotoxicity associated with carvedilol. Ann Pharmacother 2001; 35: 1364–6.

💊 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.
1. McTavish D, et al. Carvedilol: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy. Drugs 1993; 45: 232–58
2. Morgan T. Clinical pharmacokinetics and pharmacodynamics of carvedilol. Clin Pharmacokinet 1994; 26: 335–46
3. Tenero D, et al. Steady-state pharmacokinetics of carvedilol and its enantiomers in patients with congestive heart failure. J Clin Pharmacol 2000; 40: 844–53.

💊 Uses and Administration

Carvedilol is a non-cardioselective beta blocker. It has vasodilating properties, which are attributed mainly to its blocking activity at alpha 1 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.
1. Ruffolo RR, et al. The pharmacology of carvedilol. Eur J Clin Pharmacol 1990; 38: S82–S88
2. McTavish D, et al. Carvedilol: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy. Drugs 1993: 45: 232–58
3. Morgan T. Clinical pharmacokinetics and pharmacodynamics of carvedilol. Clin Pharmacokinet 1994; 26: 335–46
4. Louis WJ, et al. A risk-benefit assessment of carvedilol in the treatment of cardiovascular disorders. Drug Safety 1994; 11: 86–93
5. Dunn CJ, et al. Carvedilol: a reappraisal of its pharmacological properties and therapeutic use in cardiovascular disorders. Drugs 1997; 54: 161–85
6. Frishman WH. Carvedilol. N Engl J Med 1998; 339: 1759–65
7. Keating GM, Jarvis B. Carvedilol: a review of its use in chronic heart failure. Drugs 2003; 63: 1697–1741
8. Naccarelli GV, Lukas MA. Carvedilol’s antiarrhythmic properties: therapeutic implications in patients with left ventricular dysfunction. Clin Cardiol 2005; 28: 165–73.

Administration in children.

Carvedilol has been used in children with heart failure, although experience is limited.1 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 study2 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.
1. Greenway SC, Benson LN. The use of carvedilol in pediatric heart failure. Cardiovasc Hematol Disord Drug Targets 2006; 6: 35–42
2. Shaddy RE, et al. Carvedilol for children and adolescents with heart failure: a randomized controlled trial. JAMA 2007; 298: 1171–9.

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 hypotension1 and the authors suggested that a starting dose lower than 12.5 mg may be necessary in elderly patients. A retrospective study2 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.
1. Krum H, et al. Postural hypotension in elderly patients given carvedilol. BMJ 1994; 309: 775–6
2. Lawless CE, et al. Titration of carvedilol in elderly heart failure patients. Am J Geriatr Cardiol 2005; 14: 230–5.

💊 Preparations

Proprietary Preparations

Arg.: Antibloc; Bidecar; Carvedil; Carvel†; Corafen; Coritensil; Corubin; Dilatrend; Duobloc; Filten; Hipoten; Isobloc; Kollosteril; Rodipal; Rudoxil; Veraten; Vicardol; Austral.: Dilatrend; Kredex; Austria: Dilatrend; Hybridil; Belg.: Dimitone; Kredex; Braz.: Cardilol; Carvedilat; Coreg; Dilatrend†; Divelol; Ictus; Karvil; Canad.: Coreg; Chile: Betaplex; Blocar; Dilatrend; Dualten; Lodipres; Novocar†; Off-Ten; Cz.: Apo-Carve; Atram; Carvedigamma; Carvesan; Carvetrend; Coryol; Dilatrend; Talliton; Denm.: Carvetone; Dimitone; Fin.: Cardiol; Fr.: Kredex; Ger.: CarLich; Carve; Carve-Q; Carvecard; Carvedigamma; Dilatrend; Dimetil; Querto; Gr.: Carvedilen; Carvepen; Dilatrend; Hong Kong: Dilatrend; Hung.: Carvedigamma; Carvol; Coryol; Dilatrend; Talliton; India: Carloc; Carvil; Cevas; Indon.: Carbloxal; Dilbloc; V-Bloc; Irl.: Biocard; Eucardic; Israel: Carvedexxon; Dimitone; Ital.: Carvipress; Colver; Dilatrend; Dilocar; Malaysia: Caslot; Cavel; Dilatrend; Mex.: Dilatrend; Neth.: Eucardic; Norw.: Kredex; NZ: Dilatrend; Philipp.: Dilatrend; Pol.: Atram; Carvedigamma; Carvetrend; Coryol; Dilatrend; Vivacor; Port.: Dilbloc; Rus.: Acridilole (Акридилол); Cardivas (Кардивас); Carvetrend (Карветренд); Carvidil (Карвидил); Coryol (Кориол); Talliton (Таллитон); S.Afr.: Carloc; Carvetrend; Dilatrend; Singapore: Dilatrend; Spain: Coropres; Swed.: Kredex; Switz.: Dilatrend; Thai.: Dilatrend; Turk.: Dilatrend; UK: Eucardic; USA: Coreg; Venez.: Carbatil; Carvedil; Coventrol; Dilatrend. Multi-ingredient: Arg.: Carvedil D; Austria: Co-Dilatrend; Dilaplus.
Published January 08, 2019.