Carvedilol
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Abdurahman Khalil, M.D. [2]
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Overview
Carvedilol is an Alpha-adrenergic blocker, Beta-adrenergic blocker that is FDA approved for the {{{indicationType}}} of Heart failure of ischemic or cardiomyopathic origin, hypertension. Common adverse reactions include Fatigue, hypotension, dizziness, hyperglycemia.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
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- Dosing Information
- (Dosage)
Off-Label Use and Dosage (Adult)
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Carvedilol FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Contraindications
There is limited information regarding Carvedilol Contraindications in the drug label.
Warnings
There is limited information regarding Carvedilol Warnings' in the drug label.
Adverse Reactions
Clinical Trials Experience
There is limited information regarding Carvedilol Clinical Trials Experience in the drug label.
Postmarketing Experience
There is limited information regarding Carvedilol Postmarketing Experience in the drug label.
Drug Interactions
There is limited information regarding Carvedilol Drug Interactions in the drug label.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA): C
Studies performed in pregnant rats and rabbits given carvedilol revealed increased post-implantation loss in rats at doses of 300 mg/kg/day (50 times the maximum recommended human dose [MRHD] as mg/m2) and in rabbits at doses of 75 mg/kg/day (25 times the MRHD as mg/m2). In the rats, there was also a decrease in fetal body weight at the maternally toxic dose of 300 mg/kg/day (50 times the MRHD as mg/m2), which was accompanied by an elevation in the frequency of fetuses with delayed skeletal development (missing or stunted 13th rib). In rats the no-observed-effect level for developmental toxicity was 60 mg/kg/day (10 times the MRHD as mg/m2); in rabbits it was 15 mg/kg/day (5 times the MRHD as mg/m2). There are no adequate and well-controlled studies in pregnant women. COREG should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Carvedilol in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Carvedilol during labor and delivery.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Studies in rats have shown that carvedilol and/or its metabolites (as well as other β-blockers) cross the placental barrier and are excreted in breast milk. There was increased mortality at one week post-partum in neonates from rats treated with 60 mg/kg/day (10 times the MRHD as mg/m2) and above during the last trimester through day 22 of lactation. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from β-blockers, especially bradycardia, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. The effects of other α- and β-blocking agents have included perinatal and neonatal distress.
Pediatric Use
Effectiveness of carvedilol in patients younger than 18 years has not been established.
In a double-blind trial, 161 children (mean age: 6 years, range: 2 months to 17 years; 45% younger than 2 years) with chronicheart failure [NYHA class II-IV, left ventricular ejection fraction <40% for children with a systemic left ventricle (LV), and moderate-severe ventricular dysfunction qualitatively by echo for those with a systemic ventricle that was not an LV] who were receiving standard background treatment were randomized to placebo or to 2 dose levels of carvedilol. These dose levels produced placebo-corrected heart rate reduction of 4 to 6 heart beats per minute, indicative of β -blockade activity. Exposure appeared to be lower in pediatric subjects than adults. After 8 months of follow-up, there was no significant effect of treatment on clinical outcomes. Adverse reactions in this trial that occurred in greater than 10% of subjects treated with carvedilol and at twice the rate of placebo-treated subjects included chest pain (17% versus 6%), dizziness (13% versus 2%), and dyspnea (11% versus 0%).
Geriatic Use
Plasma levels of carvedilol average about 50% higher in the elderly compared with young subjects.
Gender
There is no FDA guidance on the use of Carvedilol with respect to specific gender populations.
Race
There is no FDA guidance on the use of Carvedilol with respect to specific racial populations.
Renal Impairment
Although carvedilol is metabolized primarily by the liver, plasma concentrations of carvedilol have been reported to be increased in patients with renal impairment. Based on mean AUC data, approximately 40% to 50% higher plasma concentrations of carvedilol were observed in hypertensive subjects with moderate to severe renal impairment compared to a control group of hypertensive subjects with normal renal function. However, the ranges of AUC values were similar for both groups. Changes in mean peak plasma levels were less pronounced, approximately 12% to 26% higher in subjects with impaired renal function.
Consistent with its high degree of plasma protein‑binding, carvedilol does not appear to be cleared significantly by hemodialysis.
Hepatic Impairment
Compared with healthy subjects, patients with severe liver impairment (cirrhosis) exhibit a 4- to 7-fold increase in carvedilol levels. Carvedilol is contraindicated in patients with severe liver impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Carvedilol in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Carvedilol in patients who are immunocompromised.
Heart Failure
Steady‑state plasma concentrations of carvedilol and its enantiomers increased proportionally over the 6.25 to 50 mg dose range in subjects with heart failure. Compared with healthy subjects, heart failure subjects had increased mean AUC and Cmax values for carvedilol and its enantiomers, with up to 50% to 100% higher values observed in 6 subjects with NYHA class IV heart failure. The mean apparent terminal elimination half‑life for carvedilol was similar to that observed in healthy subjects.
Administration and Monitoring
Administration
There is limited information regarding Carvedilol Administration in the drug label.
Monitoring
There is limited information regarding Carvedilol Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Carvedilol and IV administrations.
Overdosage
Acute Overdose
Signs and Symptoms
Overdosage may cause severe hypotension, bradycardia, cardiac insufficiency, cardiogenic shock, and cardiac arrest. Respiratory problems, bronchospasms, vomiting, lapses of consciousness, and generalized seizures may also occur.
Management
- The patient should be placed in a supine position and, where necessary and kept under observation
- The patient should be treated under intensive-care conditions.
- Gastric lavage or pharmacologically induced emesis may be used shortly after ingestion.
The following agents may be administered for excessive bradycardia:
- Atropine, 2 mg IV.
To support cardiovascular function:
- Glucagon, 5 to 10 mg IV rapidly over 30 seconds, followed by a continuous infusion of 5 mg/hour
- Sympathomimetics (dobutamine, isoprenaline, adrenaline) at doses according to body weight and effect.
- Glucagon, 5 to 10 mg IV rapidly over 30 seconds, followed by a continuous infusion of 5 mg/hour
If peripheral vasodilation dominates:
- Administer adrenaline ornoradrenaline with continuous monitoring of circulatory conditions.
For therapy-resistant bradycardia
- pacemaker therapy should be performed.
For bronchospasm
- β-sympathomimetics (as aerosol or IV) or Aminophylline IV should be given.
In the event of seizures
- Administer slow IV injection of diazepam or clonazepam is recommended.
NOTE: In the event of severe intoxication where there are symptoms of shock, treatment with antidotes must be continued for a sufficiently long period of time consistent with the 7-10 hour half-life of carvedilol.
Cases of overdosage with COREG alone or in combination with other drugs have been reported. Quantities ingested in some cases exceeded 1,000 milligrams. Symptoms experienced included low blood pressure and heart rate. Standard supportive treatment was provided and individuals recovered.
Pharmacology
There is limited information regarding Carvedilol Pharmacology in the drug label.
Mechanism of Action
Carvedilol is a racemic mixture in which nonselective β-adrenoreceptor blocking activity is present in the S(-) enantiomer and α1-adrenergic blocking activity is present in both R(+) and S(-) enantiomers at equal potency. Carvedilol has no intrinsic sympathomimetic activity.
Structure
There is limited information regarding Carvedilol Structure in the drug label.
Pharmacodynamics
Heart Failure
- The basis for the beneficial effects of carvedilol in heart failure is not established.
- Two placebo‑controlled trials compared the acute hemodynamic effects of carvedilol with baseline measurements in 59 and 49 subjects with NYHA class II‑IV heart failure receiving diuretics, ACE inhibitors, and digitalis. There were significant reductions in systemic blood pressure, pulmonary artery pressure, pulmonary capillary wedge pressure, and heart rate. Initial effects on cardiac output, stroke volume index, and systemic vascular resistance were small and variable.
- These trials measured hemodynamic effects again at 12 to 14 weeks. carvedilol significantly reduced systemic blood pressure, pulmonary artery pressure, right atrial pressure, systemic vascular resistance, and heart rate, while stroke volume index was increased.
- Among 839 subjects with NYHA class II‑III heart failure treated for 26 to 52 weeks in 4 US placebo‑controlled trials, average left ventricular ejection fraction (EF) measured by radionuclide ventriculography increased by 9 EF units (%) in subjects receiving carvedilol and by 2 EF units in placebo subjects at a target dose of 25 to 50 mg twice daily.
- The effects of carvedilol on ejection fraction were related to dose. Doses of 6.25 mg twice daily, 12.5 mg twice daily, and 25 mg twice daily were associated with placebo‑corrected increases in EF of 5 EF units, 6 EF units, and 8 EF units, respectively; each of these effects were nominally statistically significant.
Left Ventricular Dysfunction Following Myocardial Infarction
The basis for the beneficial effects of carvedilol in patients with left ventricular dysfunction following an acute myocardial infarction is not established.
Hypertension
The mechanism by which β-blockade produces an antihypertensive effect has not been established.
- β-adrenoreceptor blocking activity has been demonstrated in animal and human studies showing that carvedilol (1) reduces cardiac output in normal subjects; (2) reduces exercise- and/or isoproterenol-induced tachycardia; and (3) reduces reflex orthostatic tachycardia. Significant β-adrenoreceptor blocking effect is usually seen within 1 hour of drug administration.
- α1-adrenoreceptor blocking activity has been demonstrated in human and animal studies, showing that carvedilol (1) attenuates the pressor effects of phenylephrine; (2) causes vasodilation; and (3) reduces peripheral vascular resistance. These effects contribute to the reduction of blood pressure and usually are seen within 30 minutes of drug administration.
- Due to the α1-receptor blocking activity of carvedilol, blood pressure is lowered more in the standing than in the supine position, and symptoms of postural hypotension (1.8%), including rare instances of syncope, can occur. Following oral administration, when postural hypotension has occurred, it has been transient and is uncommon when carvedilol is administered with food at the recommended starting dose and titration increments are closely followed [see Dosage and Administration (2)].
- In hypertensive patients with normal renal function, therapeutic doses of carvedilol decreased renal vascular resistance with no change in glomerular filtration rate or renal plasma flow. Changes in excretion of sodium, potassium, uric acid, and phosphorus in hypertensive patients with normal renal function were similar after carvedilol and placebo.
- carvedilol has little effect on plasma catecholamines, plasma aldosterone, or electrolyte levels, but it does significantly reduce plasma renin activity when given for at least 4 weeks. It also increases levels of atrial natriuretic peptide.
Pharmacokinetics
- carvedilol is rapidly and extensively absorbed following oral administration, with absolute bioavailability of approximately 25% to 35% due to a significant degree of first-pass metabolism. Following oral administration, the apparent mean terminal elimination half-life of carvedilol generally ranges from 7 to 10 hours. Plasma concentrations achieved are proportional to the oral dose administered. When administered with food, the rate of absorption is slowed, as evidenced by a delay in the time to reach peak plasma levels, with no significant difference in extent of bioavailability. Taking carvedilol with food should minimize the risk oforthostatic hypotension.
- Carvedilol is extensively metabolized. Following oral administration of radiolabelled carvedilol to healthy volunteers, carvedilol accounted for only about 7% of the total radioactivity in plasma as measured by area under the curve (AUC). Less than 2% of the dose was excreted unchanged in the urine. Carvedilol is metabolized primarily by aromatic ring oxidation and glucuronidation. The oxidative metabolites are further metabolized by conjugation via glucuronidation and sulfation. The metabolites of carvedilol are excreted primarily via the bile into the feces. Demethylation and hydroxylation at the phenol ring produce 3 active metabolites with β-receptor blocking activity. Based on preclinical studies, the 4'-hydroxyphenyl metabolite is approximately 13 times more potent than carvedilol for β-blockade.
- Compared with carvedilol, the 3 active metabolites exhibit weak vasodilating activity. Plasma concentrations of the active metabolites are about one-tenth of those observed for carvedilol and have pharmacokinetics similar to the parent.
- Carvedilol undergoes stereoselective first-pass metabolism with plasma levels of R(+)-carvedilol approximately 2 to 3 times higher than S(-)-carvedilol following oral administration in healthy subjects. The mean apparent terminal elimination half-lives for R(+)-carvedilol range from 5 to 9 hours compared with 7 to 11 hours for the S(-)-enantiomer.
- The primary P450 enzymes responsible for the metabolism of both R(+) and S(-)-carvedilol in human liver microsomes were CYP2D6 and CYP2C9 and to a lesser extent CYP3A4, 2C19, 1A2, and 2E1. CYP2D6 is thought to be the major enzyme in the 4’- and 5’-hydroxylation of carvedilol, with a potential contribution from 3A4. CYP2C9 is thought to be of primary importance in the O-methylation pathway of S(-)-carvedilol.
- Carvedilol is subject to the effects of geneticpolymorphism with poor metabolizers of debrisoquin (a marker for cytochrome P450 2D6) exhibiting 2- to 3-fold higher plasma concentrations of R(+)-carvedilol compared with extensive metabolizers. In contrast, plasma levels of S(-)-carvedilol are increased only about 20% to 25% in poor metabolizers, indicating this enantiomer is metabolized to a lesser extent by cytochrome P450 2D6 than R(+)-carvedilol. The pharmacokinetics of carvedilol do not appear to be different in poor metabolizers of S-mephenytoin (patients deficient in cytochrome P450 2C19).
- Carvedilol is more than 98% bound to plasma proteins, primarily with albumin. The plasma-protein binding is independent of concentration over the therapeutic range. Carvedilol is a basic, lipophilic compound with a steady-state volume of distribution of approximately 115 L, indicating substantial distribution into extravascular tissues. Plasma clearance ranges from 500 to 700 mL/min.
Nonclinical Toxicology
There is limited information regarding Carvedilol Nonclinical Toxicology in the drug label.
Clinical Studies
There is limited information regarding Carvedilol Clinical Studies in the drug label.
How Supplied
There is limited information regarding Carvedilol How Supplied in the drug label.
Storage
There is limited information regarding Carvedilol Storage in the drug label.
Images
Drug Images
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Package and Label Display Panel
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Patient Counseling Information
There is limited information regarding Carvedilol Patient Counseling Information in the drug label.
Precautions with Alcohol
Alcohol-Carvedilol interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
Brand Names
There is limited information regarding Carvedilol Brand Names in the drug label.
Look-Alike Drug Names
There is limited information regarding Carvedilol Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.