Carvedilol

Pharmaceuticals -> Used in Switzerland

Pharmaceuticals

Pharmaceuticals -> Antihypertensives

log Kow = 4.19

3.8

3.9

88mg/mL

Freely soluble in dimethylsulfoxide; soluble in methylene chloride, methanol; sparingly soluble in ethanol, isopropanol; slightly soluble in ethyl ether

Practically insoluble in simulated gastric and intestinal fluid at pH 1.1 and 7.5, respectively

Practically insoluble in water

4.44e-03 g/L

Breast Feeding; Lactation; Milk, Human; Antihypertensive Agents; Adrenergic Beta-Antagonists; Antiarrhythmics

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Pharmaceuticals

Antianginal medicines

114-115 °C

114 - 115 °C

190 Ų [M+H]+ [CCS Type: TW; Method: Major Mix IMS/Tof Calibration Kit (Waters)]

189.68 Ų [M+K]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

189.1 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

H411 (86.8%): Toxic to aquatic life with long lasting effects [Hazardous to the aquatic environment, long-term hazard]

P273, P391, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 114 reports by companies from 16 notifications to the ECHA C&L Inventory.

Warning

H315 (100%): Causes skin irritation [Warning Skin corrosion/irritation]

P264, P264+P265, P280, P302+P352, P305+P354+P338, P317, P321, P332+P317, and P362+P364 (click each P-code to see the statement)

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/

Water spray, dry chemical, carbon dioxide, or foam as appropriate for surrounding fire and materials.

As with all fires, evacuate personnel to a safe area. Firefighters should use self-contained breathing equipment and protective clothing.

Wear approved respiratory protection, chemically compatible gloves, and protective clothing. Wipe up spillage or collect spillage using a high- efficiency vacuum cleaner. Avoid breathing dust. Place spillage in appropriately labeled container for disposal. Wash spill site.

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

This material is assumed to be combustible. As with all dry powders, it is advisable to ground mechanical equipment in contact with dry material to dissipate the potential buildup of static electricity.

As a general rule, when handling USP Reference Standards avoid all contact and inhalation of dust, mists, and/or vapors associated with the material. Wash thoroughly after handling.

SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

/Wear/ chemically compatible safety glasses or goggles. Protect exposed skin.

Engineering controls such as exhaust ventilation are recommended.

Use a NIOSH-approved respirator, if it is determined to be necessary by an industrial hygiene survey involving air monitoring. In the event that a respirator is not required, an approved dust mask should be used.

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/

C07AG02

C - Cardiovascular system

QC - Cardiovascular system

Carvedilol reduces tachycardia through beta adrenergic antagonism and lowers blood pressure through alpha-1 adrenergic antagonism. It has a long duration of action as it is generally taken once daily and has a broad therapeutic index as patients generally take 10-80mg daily. Patients taking carvedilol should not abruptly stop taking this medication as this may exacerbate coronary artery disease.

Carvedilol inhibits exercise induced tachycardia through its inhibition of beta adrenoceptors. Carvedilol's action on alpha-1 adrenergic receptors relaxes smooth muscle in vasculature, leading to reduced peripheral vascular resistance and an overall reduction in blood pressure. At higher doses, calcium channel blocking and antioxidant activity can also be seen. The antioxidant activity of carvedilol prevents oxidation of low density lipoprotein and its uptake into coronary circulation.

Carvedilol is a nonselective beta-adrenergic blocking agent with selective alpha1-adrenergic blocking activity. The principal physiologic action of carvedilol is to competitively block adrenergic stimulation of beta-receptors within the myocardium (beta1-receptors) and within bronchial and vascular smooth muscle (beta2-receptors), and to a lesser extent alpha1-receptors within vascular smooth muscle. The beta1-antagonist activity of carvedilol is similar to that of propranolol and greater than that of labetalol, and the duration of carvedilol's effect is longer than those of labetalol and propranolol.

Studies in animals indicate that the drug may exert an antioxidant effect on the myocardium and an antiproliferative effect on intimal tissue. The commercially available drug is a racemic mixture of the 2 enantiomers, (R)[+] and (S)[-], and both enantiomers have equal alpha1-adrenergic blocking activity; however, only the S(-)-enantiomer of carvedilol has beta-adrenergic blocking activity. Carvedilol does not exhibit intrinsic sympathomimetic (beta1-agonist) activity and possesses only weak membrane-stabilizing (local anesthetic) activity.

Vasodilation resulting in reduced total peripheral resistance mediated through carvedilol's alpha1-adrenergic blockade and reduced sympathetic tone appear to play a major role in the drug's hypotensive effect. Carvedilol causes reductions in cardiac output, exercise-induced tachycardia, isoproterenol-induced tachycardia, and reflex orthostatic tachycardia. Clinically important beta-adrenergic blocking activity of carvedilol usually is evident within 1 hour of oral administration, and the drug's hypotensive effect is similar to that of metoprolol. Carvedilol's alpha1-adrenergic blocking effects, which contribute to the drug's hypotensive effects, generally are evident within 30 minutes of oral administration and include reductions in phenylephrine-induced pressor effects, vasodilation, and decreased peripheral vascular resistance. The dose-dependent hypotensive effect of carvedilol results in blood pressure (systolic and diastolic) reductions of 5-46% with little, if any, reflex tachycardia. This hypotensive effect occurs approximately 30 minutes after oral administration and has a maximum effect 1.5-7 hours after oral administration.

The precise mechanism of the beneficial effects of carvedilol in the treatment of congestive heart failure has not been fully elucidated. beta1-Adrenergic blockade and vasodilation generally are associated with reflex tachycardia and peripheral vasoconstriction in therapeutic agents in which one of these pharmacologic effects predominates, but the combined effects of carvedilol appear to attenuate these two major untoward responses by balancing the potential adverse effects associated with adrenergic blockade and vasodilation. The drug's vasodilatory action appears to enable the patient to tolerate the negative inotropic effect of carvedilol during the initiation and titration of therapy in the treatment of compensated heart failure.

For more Mechanism of Action (Complete) data for CARVEDILOL (18 total), please visit the HSDB record page.

The half life of carvedilol is between 7-10 hours, though significantly shorter half lives have also been reported.

The half-life of carvedilol is 7-10 hours; 5-9 hours for R(+)-carvedilol, and 7-11 hours for S(-)-carvedilol.

The pharmacokinetics and absolute bioavailability of carvedilol have been studied in 20 male healthy volunteers in a randomised 4-period, cross-over trial. Carvedilol 12.5 mg was given i.v., 50 mg was administered p.o. as a suspension and 25 and 50 mg were given in a capsule formulation. For the 50 mg capsule Cmax was 66 micrograms.l-1, tmax 1.2 h, t1/2 6.4 h. The t1/2 after i.v. administration was 2.4 h, CL 589 ml/min and VZ 132 l. The absolute bioavailability was 24% (50 mg capsule). The kinetics after the 25 and 50 mg capsules were consistent with dose linearity.

Carvedilol can be hydroxlated at the 1 position by CYP2D6, CYP1A2, or CYP1A1 to form 1-hydroxypheylcarvedilol; at the 4 position by CYP2D6, CYP2E1, CYP2C9, or CYP3A4 to form 4'-hydroxyphenylcarvedilol; at the 5 position by CYP2D6, CYP2C9, or CYP3A4 to form 5'-hydroxyphenylcarvedilol; and at the 8 position by CYP1A2, CYP3A4, and CYP1A1 to form 8-hydroxycarbazolylcarvedilol. Carvedilol can also be demethylated by CYP2C9, CYP2D6, CYP1A2, or CYP2E1 to form O-desmethylcarvedilol. Carvedilol and its metabolites may undergo further sulfate conjugation or glucuronidation before elimination. Carvedilol can be O-glucuronidated by UGT1A1, UGT2B4, and UGT2B7 to form carvedilol glucuronide.

Carvedilol is metabolized primarily by aromatic ring oxidation and glucuronidation. The oxidative metabolites are further metabolized by conjugation via glucuronidation and sulfation.

Carvedilol is extensively metabolized; phenol ring demethylation and hydroxylation produce 3 metabolites with beta-adrenergic blocking activity and (weak) vasodilating activity. Plasma concentrations of active metabolites are about 10% those of carvedilol. The 4'-hydroxyphenyl metabolite is 13 times more potent than carvedilol in beta-adrenergic blocking activity.

Compared to 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.

For more Metabolism/Metabolites (Complete) data for CARVEDILOL (7 total), please visit the HSDB record page.

0K47UL67F2

CARVEDILOL

Mechanisms of Action [MoA] - Adrenergic alpha-Antagonists

Mechanisms of Action [MoA] - Adrenergic beta1-Antagonists

Mechanisms of Action [MoA] - Adrenergic beta2-Antagonists

Established Pharmacologic Class [EPC] - alpha-Adrenergic Blocker

Drugs that bind to but do not activate beta-adrenergic receptors thereby blocking the actions of beta-adrenergic agonists. Adrenergic beta-antagonists are used for treatment of hypertension, cardiac arrhythmias, angina pectoris, glaucoma, migraine headaches, and anxiety.

Drugs used in the treatment of acute or chronic vascular HYPERTENSION regardless of pharmacological mechanism. Among the antihypertensive agents are DIURETICS; (especially DIURETICS, THIAZIDE); ADRENERGIC BETA-ANTAGONISTS; ADRENERGIC ALPHA-ANTAGONISTS; ANGIOTENSIN-CONVERTING ENZYME INHIBITORS; CALCIUM CHANNEL BLOCKERS; GANGLIONIC BLOCKERS; and VASODILATOR AGENTS.

Naturally occurring or synthetic substances that inhibit or retard oxidation reactions. They counteract the damaging effects of oxidation in animal tissues.

A class of drugs that act by selective inhibition of calcium influx through cellular membranes.

Drugs used to cause dilation of the blood vessels.

Drugs that bind to and block the activation of ADRENERGIC ALPHA-1 RECEPTORS.

Carvedilol has a bioavailability of 25-35%. Carvedilol has a Tmax of 1 to 2 hours. Taking carvedilol with a meal increases Tmax without increasing AUC. Carvedilol doses of 50mg lead to a Cmax of 122-262µg/L and an AUC of 717-1600µg/L\*h. Carvedilol doses of 25mg lead to a Cmax of 24-151µg/L and an AUC of 272-947µg/L\*h. Carvedilol doses of 12.5mg lead to a Cmax of 58-69µg/L and an AUC of 208-225µg/L\*h.

16% of carvedilol is excreted in the urine with <2% excreted as unmetabolized drug. Carvedilol is primarily excreted in the bile and feces.

Carvedilol has a volume of distribution of 1.5-2L/kg or 115L.

The plasma clearance of carvedilol has been reported as 0.52L/kg or 500-700mL/min.

Carvedilol is rapidly and extensively absorbed following oral administration, with absolute bioavailability of approximately 25 percent to 35 percent due to a significant degree of first-pass metabolism.

Food decreases the rate of the drug's absorption (ie, increases time to peak plasma concentration), but not the extent (ie, no effect on bioavailability) of absorption. Administration with food may decrease the risk of orthostatic hypotension.

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