Carvedilol

Possible conduction disturbance, rarely with hemodynamic compromise. Blood pressure and ECG should be monitored during concomitant use /of carvedilol/ with diltiazem or verapamil.

/Concurrent administration of/ myocardial depressant general anesthetics (ether, cyclopropane, trichloroethylene) /has the/ potential to increased risk of hypotension and heart failure.

/Concurrent administration of/ antidiabetic agents (oral and parenteral [insulin]) /with carvedilol may/ increased /their/ hypoglycemic effect. Blood glucose concentrations should be monitored regularly.

/Concurrent administration of/ catecholamine-depleting agents (eg, reserpine, MAO inhibitors) /may have/ potentially additive effects (eg, hypotension, bradycardia). Patients should be monitored closely for symptoms (eg, vertigo, syncope, postural hypotension).

For more Interactions (Complete) data for CARVEDILOL (22 total), please visit the HSDB record page.

Mild-to-moderate elevations in serum aminotransferase levels occur in less than 2% of patients on carvedilol and are usually transient and asymptomatic, resolving even with continuation of therapy. Despite its wide spread use, carvedilol has been linked to only a single case of clinically apparent liver injury, with injury arising 6 months after starting therapy and a mixed pattern of enzyme elevations without jaundice or signs of hypersensitivity or autoimmunity, and rapid recovery on stopping. Thus, clinically apparent liver injury from carvediol is exceeding rare.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1.5X10+5(SRC), determined from a log Kow of 4.19(2) and a regression-derived equation(3), indicates that carvedilol is expected to be immobile in soil(SRC). The estimated pKa1 of carvedilol is 8.77 (secondary amine)(4), indicating that this compound will almost entirely exist in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(5). Volatilization from moist soil is not expected because the compound exists as an cation and cations do not volatilize. Carvedilol is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 5.9X10-14 mm Hg at 25 °C(SRC), determined from a fragment constant method(6). Biodegradation data in soil were not available(SRC, 2011).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1.5X10+5(SRC), determined from a log Kow of 4.19(2) and a regression-derived equation(3), indicates that carvedilol is expected to adsorb to suspended solids and sediment(SRC). An estimated pKa1 of 8.77 (secondary amine)(4) indicates carvedilol will exist almost entirely in the cation form at pH values of 5 to 9 and therefore volatilization from water surfaces and biococentration are not expected to be an important fate process(SRC). Biodegradation data in water were not available(SRC, 2011).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), carvedilol, which has an estimated vapor pressure of 5.9X10-14 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase carvedilol may be removed from the air by wet or dry deposition(SRC). Carvedilol does not contain chromophores that absorb at wavelengths >290 nm(3), and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

Carvedilol is a generally well-tolerated medication, exhibiting fewer frequent adverse events than other beta blockers, and adverse events are typically dose-related. A post-marketing surveillance study reported that only 7% of patients taking carvedilol had to discontinue treatment due to adverse events. The most prevalent adverse effect of carvedilol is undesired, excessive hypotension resulting from its vasodilating properties, leading to symptoms such as dizziness, lightheadedness, fatigue, and headaches. Additional adverse effects associated with the drug's beta-blocking properties include dyspnea, bronchospasm, bradycardia, malaise, and asthenia.

Toxicity is primarily treated with supportive care and acute stabilization through specific therapies based on the clinical features. Treatment for symptomatic bradycardia or heart block involves isotonic fluid administration and intravenous (IV) atropine. In cases of bronchospasm, options include beta-sympathomimetic agents (administered as aerosol or IV) or IV aminophylline. Depending on the extent of hemodynamic instability, interventions may involve the insertion of a temporary pacemaker or using inotropic or vasopressor medications. IV glucagon is commonly utilized as a first-line therapy and adjunct to supportive treatment for reversing the effects of beta-blocker toxicity.

The Koc of carvedilol is estimated as 790(SRC), using a log Kow of 4.19(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that carvedilol is expected to have low mobility in soil. The estimated pKa1 of carvedilol is 8.77 (secondary amine)(4), indicating that this compound will almost entirely exist in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(5).

/SIGNS AND SYMPTOMS/ Agents with non-selective beta-blocking activity may provoke chest pain in patients with Prinzmetal's variant angina. There has been no clinical experience with carvedilol in these patients although the alpha-blocking activity may prevent such symptoms. However, caution should be taken in the administration of carvedilol to patients suspected of having Prinzmetal's variant angina.

/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.

/CASE REPORTS/ Stevens-Johnson syndrome, related to carvedilol use, has not been previously reported as a serious adverse experience requiring hospitalization. We report this reaction in a 71-year-old man with stable ischemic cardiomyopathy.

/CASE REPORTS/ ... Two days after the initiation of carvedilol treatment, a 70-year old woman presented with skin eruptions in the form of maculous rash with blisters that rapidly progressed to epidermal necrolysis. Although the suspected drug was withdrawn, the reaction was extremely rapid in its development with fatal outcome. Carvedilol is not a drug commonly associated with toxic epidermal necrolysis (TEN). ... Because of the close temporal relationship between the initiation of carvedilol treatment and the appearance of skin eruptions, and because carvedilol was the only new medication the patient had taken, the etiology of TEN was most likely a reaction to this drug. ...

For more Human Toxicity Excerpts (Complete) data for CARVEDILOL (10 total), please visit the HSDB record page.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Carvedilol

vLess-DILI-concern

3

Adverse reactions

DOI:10.1016/j.drudis.2016.02.015

An estimated pKa1 of 8.77 (secondary amine(1) indicates carvedilol will exist almost entirely in the cation form at pH values of 5 to 9 and therefore volatilization from water surfaces is not expected to be an important fate process. Carvedilol is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 5.9X10-14 mm Hg(SRC), determined from a fragment constant method(2).

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ In 2 yr studies conducted in rats given carvedilol at doses up to 75 mg/kg/day (12 times the max recommended human dose (MRHD) when compared on a mg/sq m basis) or in mice given up to 200 mg/kg/day (16 times the MRHD on a mg/sq m basis), carvedilol had no carcinogenic effect.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ 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/sq m) and in rabbits at doses of 75 mg/kg/day (25 times the MRHD as mg/sq m). 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/sq m), 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/sq m); in rabbits it was 15 mg/kg/day (5 times the MRHD as mg/sq m).

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Studies in rats have shown that carvedilol and/or its metabolites (as well as other beta-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/sq m) and above during the last trimester through day 22 of lactation.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ At doses less than 200 mg/kg/day (>/=32 times the MRHD as mg/sq m) carvedilol was toxic to adult rats (sedation, reduced weight gain) and was associated with a reduced number of successful matings, prolonged mating time, significantly fewer corpora lutea and implants per dam, and complete resorption of 18 percent of the litters. The no-observed-effect dose level for overt toxicity and impairment of fertility was 60 mg/kg/day (10 times the MRHD as mg/sq m).

/GENOTOXICITY/ Carvedilol was negative when tested in a battery of genotoxicity assays, including the Ames and the CHO/HGPRT assays for mutagenicity and the in vitro hamster micronucleus and in vivo human lymphocyte cell tests for clastogenicity.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including carvedilol, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including carvedilol phosphate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Carvedilol phosphate/

MEDICATION

Use (kg; approx.) in Germany (2009): >2500

By condensation of 4-(2,3-epoxy-1-propyl)carbazole with 2-(2-methoxyphenoxy)ethyl amine.

Preparation: F. Wiedemann et al., DE 2815926; eidem, US 4503067 (1979, 1985 both to Boehringer Mannheim)

Carvedilol preparations: (AHFS, 2011)

BM 141 90; DQ 2466; Kredex; Dilatrend