General Administration Information
For storage information, see the specific product information within the How Supplied section.
-Administer with food to minimize the risk of orthostatic hypotension.
Oral Solid Formulations
Extended-release capsules (Coreg CR)
-Administer once daily in the morning with food; do not crush or chew the capsules.
-The capsules can be carefully opened and the beads sprinkled over a spoonful of applesauce. The applesauce should not be warm because the modified-release properties could be affected. Administer the mixture of drug and applesauce immediately in its entirety; do not store for future use. Absorption of the extended-release capsule beads sprinkled on other foods has not been tested.
Extemporaneous Preparations for Oral Suspensions
-Several recipes resulting in DIFFERENT final concentrations have been described.
-Shake well prior to each use. Administer with appropriate calibrated oral device to ensure accurate dosing.
- Method 1 (0.1 mg/ml suspension):
-Place one (1) carvedilol 3.125 mg tablet and 5 ml purified water in a glass amber bottle for 10 minutes, then swirl the mixture lightly for 30 seconds to allow disintegration.
-Add 10 ml Ora-Sweet SF and 15 ml Oral-Plus to the mixture. Then, cap the bottle and shake vigorously for 30 seconds for adequate mixing.
-The final product is 30 ml of a viscous, white (pinkish tinge), opaque suspension.
-Storage: Store at room temperature (approximately 25 degrees Celsius or 77 degrees Farenheit) for up to 84 days.[data on file; personal communication with GlaxoSmithKline on June 21, 2006].
- Method 2 (1.25 mg/ml suspension):
-Pulverize five (5) carvedilol 25 mg tablets in a mortar.
-Add 15 ml purified water and mix to form a smooth paste.
-Geometrically incorporate Ora-Blend to a total volume of 100 ml.
-Storage: Store in a light-resistant container at room temperature for up to 84 days.
- Method 3 (1.67 mg/ml suspension):
-Place two (2) carvedilol 25 mg carvedilol tablets and 5 ml purified water in a glass amber bottle for 10 minutes, then swirl the mixture lightly for 30 seconds to allow disintegration.
-Add 10 ml Ora-Sweet SF and 15 ml Oral-Plus to the mixture, then cap the bottle and shake vigorously for 30 seconds for adequate mixing.
-The final product is 30 ml of a viscous, white (pinkish tinge), opaque suspension.
-Storage: Store at room temperature (approximately 25 degrees Celsius or 77 degrees Farenheit) for up to 84 days.[data on file; personal communication with GlaxoSmithKline on June 21, 2006].
Adverse reactions observed in pediatric patients receiving carvedilol for cardiac failure are similar to those observed in adults. The reported incidence of adverse reactions ranges from 21-54% with drug discontinuation rates of approximately 6-13% from limited clinical trials and manufacturer information on file.
Most adverse reactions to carvedilol are associated with its pharmacological effects. In pediatric trials, dizziness (8-19%) and hypotension (8-14%) were among the most common adverse reactions. Chest pain (unspecified) (17% vs. 6% placebo) was another frequent adverse event in a randomized, placebo-controlled trial in 161 pediatric patients (ages 2 months-17 years) with heart failure. In observational studies of pediatric patients with heart failure (n = 24-46, ages 0-19 years), orthostatic hypotension (7%), bradycardia (4%), AV block (4%), chest pain (2%), atrial flutter (2%), and syncope (2%) were reported in patients receiving carvedilol. When beginning treatment with carvedilol, patients may experience worsening heart failure or fluid retention/edema during the initial up-titration period. In these individuals, the dosage of carvedilol may need to be reduced or temporarily discontinued; subsequent increases in carvedilol dosage is not precluded in these patients. In observational studies, worsening heart failure (4%) and edema (5%) were reported in pediatric patients receiving carvedilol. Abruptly discontinuing beta-blocker therapy in patients with coronary artery disease may result in exacerbation of angina or the development of a myocardial infarction or ventricular arrhythmia; thus, gradual discontinuance of carvedilol therapy over a 1-2 week period is recommended. In addition to the adverse events reported in pediatric trials, the following events have been reported in adult trials of carvedilol: angina (2-6%), myocardial infarction (< 0.1%), bundle-branch block (<= 0.1%), peripheral edema (1-7%), palpitations (> 1% and <= 3%), hypertension (> 1% and <= 3%), and sinus tachycardia (0.1-1%). The profile of adverse reactions observed with extended-release carvedilol capsules is generally similar to that observed with immediate-release carvedilol tablets.
Central nervous system (CNS) effects can occur with beta-blocker therapy. In observational studies of pediatric patients with heart failure (n = 24-46, age 0-19 years), headache (4-14%) and fatigue (7%) were reported in patients receiving carvedilol. It has been proposed that lipophilic beta-blockers, such as carvedilol, are more likely to be associated with CNS reactions; however, this theory has been debated based on clinical experience with beta-blockers. CNS adverse reactions reported in adults receiving carvedilol include fatigue (24%), headache (5-8%), vertigo (2-3%), somnolence (drowsiness) (2-3%), insomnia (2%), hypoesthesia (> 1% and <= 3%), paresthesias (> 1% and <= 3%), and depression (0.1-3%). Other CNS adverse reactions reported at an incidence of 0.1-1% during adult carvedilol clinical trials included anxiety or nervousness, impaired cognition, abnormal thinking, paroniria or nightmares, and emotional lability. Amnesia, migraine, and convulsions or tremor have also been reported in <= 0.1% of carvedilol recipients.
Beta-blockers have been shown to increase the risk of developing diabetes mellitus in adult hypertensive patients ; however, any related risk in pediatric patients has not been defined. Beta-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. In addition, nonselective beta-blockers, such as carvedilol, may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose concentrations. In studies of adult congestive heart failure patients, worsening of hyperglycemia occurred in 5-12% of carvedilol-treated patients. During these same studies, hypoglycemia and diabetes mellitus were reported in 2-3% of carvedilol recipients.
Beta-blockers can cause bronchospasm, dyspnea, and/or wheezing in patients with asthma or pulmonary disease. Non-selective beta-blockers such as carvedilol are more likely than selective agents to precipitate pulmonary disorders. In a randomized, placebo-controlled trial in pediatric patients with heart failure (n = 161, ages 2 months-17 years), dyspnea occurred in 11% of patients receiving carvedilol compared to 0% receiving placebo. In observational studies of pediatric patients with heart failure (n = 24-46, ages 0-19 years), reactive airway disease (8%) and dyspnea (7%) were reported in patients receiving carvedilol. Adverse pulmonary reactions reported during carvedilol clinical trials in adults included asthma (0.1-1%), bronchospasm (<= 0.1%), cough (5-8%), dyspnea (11%), rales (4%), pulmonary edema (0.1-3%), and respiratory alkalosis (<= 0.1%). Patients with preexisting bronchospastic disease are at greater risk. Cases of asthma-related death have been reported in patients receiving single doses of carvedilol. Rare post-marketing reports describing interstitial pneumonitis associated with carvedilol therapy do exist.
Dermatological reactions reported during carvedilol therapy in adults (incidence 0.1-1%, regardless of causality) include: rash (unspecified), pruritus, erythematous rash, maculopapular rash, psoriaform rash, and photosensitivity. Severe skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme) have been reported during post-marketing experience. Other dermatologic reactions reported in <= 0.1% of carvedilol recipients have included reversible alopecia and exfoliative dermatitis.
Hypersensitivity reactions including anaphylactoid reactions, angioedema, and urticaria have been reported in post-marketing experience for the regular-release and extended-release formulations of carvedilol, including cases occurring after the initiation of extended-release capsules in patients previously treated with the regular-release tablets.
Hyperbilirubinemia (0.1-1%) and elevated hepatic enzymes (0.1-3%) have been observed during carvedilol therapy in adult patients. Generally, the elevations (2-3 times the upper limit of normal) occur at a similar or lower rate than placebo during clinical trials. In severe heart failure patients, the rate of elevated transaminases has been reported to be lower than placebo, possibly due to improved cardiac output and reduced hepatic congestion. Use of carvedilol is contraindicated in persons with severe hepatic impairment. If hepatic enzyme concentrations indicate hepatic injury, or there is clinical jaundice and liver function tests confirm possible liver injury, discontinue carvedilol therapy.
Decreased renal function, glycosuria, proteinuria or albuminuria, hematuria (all > 1 to <= 3%), and increased urinary frequency (0.1-1%) have been reported in adults treated with carvedilol. Rare post-marketing reports exist of urinary incontinence in women, which resolved upon discontinuation of carvedilol therapy.
Hematologic adverse reactions in adult recipients of carvedilol during clinical trials include anemia (0.1-3%), leukopenia (0.1-1%), pancytopenia (<= 0.1%), and thrombocytopenia (1-3%). Additionally, decreases in prothrombin or hypoprothrombinemia (2-3%) and the development of bleeding disorders such as purpura (2-3%) and GI bleeding (<= 0.1%) have occurred after treatment with carvedilol. Aplastic anemia has also been reported rarely after administration of carvedilol during post-marketing experience.
Pain, discomfort, and generalized weakness have been reported after treatment with carvedilol. During clinical trials in adults, recipients of carvedilol reported experiencing the following symptoms: asthenia or weakness (7-11%), arthralgia (1-6%), neuralgia or neuropathic pain (<= 0.1%), malaise (2-3%), arthritis (2-3%), gout (2-3%), periodontitis (2-3%), hypotonia (2-3%), muscle cramps (2-3%), hypokinesia or dyskinesia (0.1-1%), and paresis (<= 0.1%).
In observational studies of pediatric patients with heart failure (n = 24-46, ages 0-19 years), gastroesophageal reflux (2%) and vomiting (4-9%) were reported in patients receiving carvedilol. Gastrointestinal adverse reactions reported with carvedilol therapy in adult patients include weight gain (10-12%), weight loss (2-3%), abdominal pain (2-3%), diarrhea (1-12%), nausea (2-9%), vomiting (1-6%), melena (2-3%), and xerostomia or dry mouth (0.1-1%).
During clinical trials, visual impairment (5%), including blurred vision (2-3%), was reported in adult patients receiving carvedilol.
Laboratory abnormalities have been reported during carvedilol clinical trials in adult patients. These abnormalities include hypercholesterolemia (1-4%), increased BUN (0.1-6%), elevated hepatic enzymes (0.1-3%), elevated creatinine (2-3%), hyponatremia (2-3%), hyperuricemia (2-3%), hyperkalemia (2-3%), hypokalemia (0.1-1%), hypertriglyceridemia (0.1-1%), hyperbilirubinemia (0.1-1%), and decreased HDL (<= 0.1%).
Cases of tinnitus (0.1-1%), some resulting in decreased hearing (incidence <= 0.1%), were reported by adult patients receiving carvedilol during clinical trials.
General adverse reactions reported by adult patients receiving treatment with carvedilol during clinical trials include peripheral vascular disorder (2-3%), fever (2-3%), hypervolemia (2-3%), hypovolemia (2-3%), cerebrovascular accident or stroke (0.1-3%), peripheral vasoconstriction or ischemia (0.1-1%), and hyperhidrosis (sweating, 0.1-1%). Adverse reactions reported in adult patients receiving extended-release carvedilol include pharyngitis reported as nasopharyngitis (4%), nasal congestion (1%), and sinus congestion (1%).
Withdrawal symptoms, including headache, diaphoresis, palpitations, sinus tachycardia, tremor, and hypertension, have been associated with abrupt discontinuation of beta-blockers in hypertensive patients. Gradual tapering and/or prolonged administration of small doses of carvedilol prior to complete cessation may prevent adverse reactions.
Intraoperative floppy iris syndrome (IFIS) has been observed during cataract surgery in some patients treated with alpha-1 blockers. It is not known whether carvedilol, an alpha/beta blocker, is associated with this condition; however, the product labeling of labetalol, another alpha/beta blocker, warns clinicians to be prepared for possible modifications to the surgical technique, such as the utilization of iris hooks, iris dilator rings, or viscoelastic substances. The syndrome is characterized by a triad of features that distinguish it: 1) a flaccid iris that billows in response to intraoperative irrigation currents, 2) progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs, and 3) potential prolapse of the iris toward the phacoemulsification incisions. There does not appear to be a benefit of stopping alpha-1 blocker therapy prior to cataract surgery.
Carvedilol is contraindicated in patients who have demonstrated a serious hypersensitivity reaction (e.g. Stevens-Johnson syndrome, anaphylaxis, or angioedema) to the drug. Do not use carvedilol in patients with known beta-blocker hypersensitivity. Cross-sensitivity between beta-blockers may occur. Use carvedilol with caution in patients with a history of anaphylactic reaction to any allergen. These patients may have a more severe reaction if rechallenge to the allergen occurs while receiving a beta-blocker. The patient may also be unresponsive to the usual doses of epinephrine used to treat the reaction.
If carvedilol is to be discontinued, gradually withdraw therapy over 1-2 weeks whenever possible, and instruct patients to avoid significant physical activity during the withdrawal. Abrupt discontinuation of beta-blockers in adult patients has been associated with severe angina, myocardial infarction, ventricular arrhythmias, and hypertension, particularly in patients with preexisting cardiac disease. The clinical significance of this in pediatric patients is unknown. Advise patients and caregivers against interruption or cessation of therapy without the advice of their physician.
Use carvedilol with caution in patients with hyperthyroidism or thyrotoxicosis because the drug can mask tachycardia, which is a useful monitoring parameter in thyroid disease. Abrupt withdrawal of beta-blockers in a patient with hyperthyroidism can precipitate thyroid storm. However, certain beta-blockers are generally useful in the symptomatic treatment of hyperthyroid-related states, like thyrotoxicosis.
Because beta-blockers depress conduction through the AV node, these drugs are contraindicated in patients with severe bradycardia (unless a functioning pacemaker is present), sick sinus syndrome, or second- or third-degree AV block. Although carvedilol is used for the treatment of patients with chronic heart failure, it is contraindicated in patients with acute heart failure or cardiogenic shock requiring IV inotropic therapy. Wean off inotropic therapy in these patients prior to initiating carvedilol. Use carvedilol cautiously in patients with acute pulmonary edema; prior to initiating carvedilol therapy, treat and minimize fluid retention due to acute left ventricular dysfunction (e.g., with the use of diuretics). Hypotension and orthostatic hypotension are commonly encountered during the initial dosing period; use with caution in patients predisposed to low blood pressure or receiving other medications that may lower blood pressure. Dose reduction or discontinuation may be needed to manage significant bradycardia, hypotensive effects, or syncope. Starting with a low dose, careful monitoring of blood pressure, administration with food, and gradual titration help minimize the risk of bradycardia, hypotension, or syncope in the early dosing period.
Carvedilol is a non-selective beta-blocker and is contraindicated in patients with bronchial asthma or related bronchospastic conditions; deaths from status asthmaticus have occurred after a single dose of carvedilol. If possible, avoid the use of carvedilol in patients with other pulmonary disease in which acute bronchospasm would put them at risk (e.g., chronic lung disease (CLD)). If carvedilol must be used in these patients, use the smallest effective dose and reduce the dose if bronchospasm occurs.
Carvedilol, like other beta-blockers, can cause dizziness or drowsiness in some patients. Carvedilol use has also been associated with postural hypotension and syncope, especially during initiation of therapy. Advise patients and their caregivers to use caution when performing activities requiring coordination and concentration (e.g., riding a bicycle) until the response is known, especially during dosage titration.
Use carvedilol with caution in patients with diabetes mellitus because the drug can mask some of the symptoms of hypoglycemia such as tachycardia, palpitations, tremor, and anxiety. However, carvedilol usually does not mask other symptoms of hypoglycemia (sweating and hypertension). In addition, beta-blockers may potentiate insulin-induced hypoglycemia and delay the recovery of serum glucose concentrations by interfering with glycogenolysis. In adult patients with heart failure, carvedilol may lead to worsening hyperglycemia, which responds to intensification of hypoglycemic therapy; however, in adults with mild to moderate hypertension and type 2 diabetes, no adverse effects on glycemic control as measured by HbA1c occurred in a trial designed to examine the effects of carvedilol on glycemic control in this population. Neither the risk of worsening glycemic control in diabetic patients nor the risk of new onset hyperglycemia have been defined in pediatric patients receiving carvedilol. The FDA-approved product labeling recommends monitoring of blood glucose during initiation of carvedilol therapy, after dosage adjustments, and after drug discontinuation in patients with diabetes.
The practice of withdrawing beta-blocker therapy prior to major surgery continues to be controversial; evaluate the risks versus benefits in individual patients. The risks specific to pediatric patients have not been clearly defined; most of the discussion around this topic has been in the context of adult patients receiving beta-blockers. The American Heart Association (AHA) states that perioperative beta-blocker withdrawal should be avoided unless necessary. The recommendation to continue beta-blocker therapy in the perioperative period is a Class I indication; however, the AHA continues to recognize the risks of perioperative beta-blockade (e.g., significant bradycardia and hypotension). The FDA-approved product labeling also recommends against routine withdrawal of chronically-administered carvedilol prior to major surgery. If carvedilol is continued throughout the perioperative period, the ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures. Monitor patients receiving carvedilol carefully for bradycardia, hypotension, and early signs of heart failure, especially if they receive drugs with a negative inotropic effect during surgery. Severe, protracted hypotension and difficulty in restarting the heart have been reported after surgery in some patients receiving beta-blockers. Consider the type of surgery (e.g., cardiac vs. noncardiac), anesthetic strategy, and co-existing health conditions. The anesthetic technique may be modified to reduce the risk of concurrent beta-blocker therapy. If needed, the negative inotropic effects of beta-blockers may be cautiously reversed by sufficient doses of adrenergic agonists such as isoproterenol, dopamine, dobutamine, or norepinephrine. Vagal dominance, if it occurs, may be corrected with atropine. If carvedilol is withdrawn prior to surgery, gradual withdrawal with careful monitoring is recommended.
Carvedilol is contraindicated in patients with severe hepatic disease. Adult patients with cirrhotic hepatic disease have significantly higher concentrations of carvedilol (approximately 4-7 fold) compared to healthy patients; data in pediatric patients with hepatic disease are not available. Studies of adult patients with cirrhosis (mean Child-Pugh score 7.4 +/- 0.5) receiving carvedilol have reported reduced portal pressure and significant hypotensive effects, with some patients not being able to tolerate a 25 mg dose of carvedilol.
Rarely, use of carvedilol in patients with congestive heart failure has resulted in deterioration of renal function. Patients at risk appear to be those with hypotension, ischemic heart disease, and diffuse vascular disease, and/or underlying renal disease or renal impairment; renal function has returned to baseline when carvedilol was discontinued. In patients with these risk factors it is recommended that renal function be monitored during up-titration of carvedilol and the drug discontinued or dosage reduced if worsening of renal function occurs. Patients with renal impairment or renal failure may have higher plasma concentrations of carvedilol; however, no dosage adjustments are needed. Because beta-blockers can produce or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease, administer carvedilol cautiously to these patients.
Carvedilol has been associated with aggravated depression ; use with caution in patients with major depression. It has been proposed that lipophilic beta-blockers (e.g., carvedilol) are more likely to be associated with CNS effects than hydrophilic drugs; however, this theory has been debated based on clinical experience with beta-blockers.
Beta-blockers, such as carvedilol, may exacerbate psoriasis.
Beta-blockers, such as carvedilol, may potentiate muscle weakness and double vision in patients with myasthenia gravis.
Carvedilol may cause decreased lacrimation, which may make the eyes dry. Patients wearing contact lenses may have an increased awareness or blurred vision. The use of lubricating drops may be necessary.
Use carvedilol cautiously in patients with pheochromocytoma or vasospastic angina (Prinzmetal's angina). In patients with pheochromocytoma, use an alpha-blocking agent prior to the initiation of a beta-blocking agent. Non-selective beta-blocker therapy has led to chest pain in patients with vasospastic angina (Prinzmetal's angina). Although carvedilol has both alpha-blocking and beta-blocking actions, clinical experience is lacking in patients with these conditions.
Because of potential effects of beta-blockade on blood pressure and pulse, use carvedilol with caution in patients with cerebrovascular insufficiency (cerebrovascular disease) or stroke. If signs or symptoms suggesting reduced cerebral blood flow develop after initiation of a beta-blocker, consider alternative therapy.
Description: Carvedilol is a combined alpha- and nonselective beta-blocker. Although it has some pharmacologic similarities to labetalol, the ratio of beta to alpha-1 effects is much greater for carvedilol than for labetalol. Carvedilol is a lipophilic beta-blocker and lacks intrinsic sympathomimetic activity (ISA). Carvedilol also possesses antioxidant properties. The commercial product is a racemic mixture of two enantiomers, R(+) and S(-), both of which are important for the desired clinical effect. Several large studies in adults with mild to severe chronic heart failure have demonstrated reduced rates of hospitalization and mortality with carvedilol treatment. The clinical efficacy in pediatric patients with heart failure is less clear. Although improved heart failure outcomes were not found in one randomized placebo-controlled clinical trial, smaller clinical trials and observational studies have shown improved left ventricular function, symptoms, and/or functional class when used as adjunctive therapy in pediatric patients with heart failure, including patients with dilated cardiomyopathy. Although not FDA-approved, carvedilol is used off-label in pediatric patients as young as infants.
General dosing information:
-Prior to initiation, assure other CHF medications are stabilized and fluid retention is minimized (do not use carvedilol for acute, decompensated CHF requiring inotropic therapy).
-Before each dosage increase, closely evaluate patient for symptoms of worsening CHF, bradycardia, or adverse vasodilatory effects (e.g., dizziness, light-headedness, symptomatic hypotension). Dose increases may be associated with transient symptoms of dizziness (and rarely syncope) within the first hour after administration. Vasodilatory symptoms often do not require treatment, but it may be useful to separate the administration time of carvedilol from an ACE inhibitor or to temporarily reduce the dose of the ACE inhibitor. Do not increase the carvedilol dose until symptoms of worsening CHF or vasodilatory adverse effects have been stabilized. Reduce the dose for bradycardia.
-Transient worsening of CHF may be treated with increased diuretic doses; however, it may be necessary to reduce or temporarily hold the carvedilol dose.
For the treatment of heart failure* (ischemic origin or cardiomyopathy*) usually in conjunction with digoxin, diuretics, or ACE inhibitor therapy:
Oral dosage (immediate-release tablets):
Infants, Children, and Adolescents: 0.04 to 0.05 mg/kg PO twice daily (Max: 3.125 mg/dose) is a commonly reported initial dosage; however, lower doses (e.g., 0.02 mg/kg) have also been used. Typically, dosages are titrated at approximately 2 week intervals as tolerated to a maximum of about 0.8 mg/kg/day (Max: 50 mg/day). Infants and young children younger than 3.5 years of age have faster carvedilol clearance suggesting that a higher mg/kg dose and/or more frequent administration (3 times daily) may be necessary to achieve therapeutic response in these patients. Conflicting data are available regarding the efficacy of carvedilol for the treatment of heart failure in pediatric patients. Although several small trials and case series report improved left ventricular function, symptoms, and/or functional class in pediatric patients , no difference was found between placebo and carvedilol with regard to the improvement or worsening of heart failure in a randomized, double-blind, placebo-controlled trial (n = 161, age 2 months to 17 years).
Oral dosage (extended-release capsules):
Adolescents: Safety and efficacy have not been established. When converting from immediate-release tablets to extended-release capsules, FDA-approved labeling recommends the following dosage conversion information for adults: 3.125 mg PO twice daily immediate-release = 10 mg PO once daily extended-release; 6.25 mg PO twice daily immediate-release = 20 mg PO once daily extended-release; 12.5 mg PO twice daily immediate-release = 40 mg PO once daily extended-release; 25 mg PO twice daily immediate-release = 80 mg PO once daily extended-release.
Maximum Dosage Limits:
Safety and efficacy have not been established.
Safety and efficacy have not been established. A common maximum target dose of 0.8-1 mg/kg/day PO is used off-label, and up to 2 mg/kg/day has been reported in one infant.
Safety and efficacy have not been established; however, a common maximum target dose of 0.8-1 mg/kg/day PO (Max: 50 mg/day) has been studied off-label.
Safety and efficacy have not been established; however, a common maximum target dose of 0.8-1 mg/kg/day PO (Max: 50 mg/day) using immediate-release tablets has been studied off-label.
Patients with Hepatic Impairment Dosing
Contraindicated in patients with severe hepatic impairment.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears no dosage adjustments are needed.
Due to its high degree of plasma protein-binding, carvedilol is not likely to be significantly removed by hemodialysis. No supplemental dosage is needed.
Monograph content under development
Mechanism of Action: Carvedilol has multiple actions that make it a useful cardiovascular drug. Carvedilol antagonizes both alpha1- and beta-receptors; the ratio of beta-blockade to alpha1-blockade is in the order of 10-100:1. Beta-antagonism is due primarily to the S(-) carvedilol enantiomer, whereas alpha1-antagonism is essentially equal for both carvedilol enantiomers. It is thought that alpha1-receptor antagonism is mainly responsible for the vasodilatory actions of carvedilol but calcium channel antagonism, which appears in some vascular beds at higher doses, may also contribute. Carvedilol lowers standing blood pressure more than supine; orthostatic hypotension may occur. Reflex tachycardia does not occur due to beta-blockade. In addition, the alpha1-blocking properties offset peripheral vasoconstriction that might be expected with beta-blockade. Carvedilol has no intrinsic sympathomimetic activity.
Other mechanisms have been proposed to contribute to carvedilol's beneficial cardiovascular effects including antimitogenic effects, free radical scavenging effects, and an antioxidant effect (an effect not shared by other beta-blockers). Carvedilol is a potent inhibitor of lipid peroxidation and has been shown to prevent oxygen free radical depletion of vitamin E in brain homogenates. Its antioxidant effect is greater than that of pindolol or propranolol. During chronic therapy, carvedilol does not decrease glomerular filtration rate (GFR) or renal blood flow (RBF) , nor does it significantly alter glucose tolerance tests or fasting and postprandial glucose levels in non-insulin-dependent diabetics without congestive heart failure. Long-term carvedilol therapy has been reported to have a beneficial effect on serum lipids by decreasing total cholesterol by 11%, LDL-C by 16%, and triglycerides by 13% and increasing HDL-C by 11%.
Patients with chronic heart failure demonstrate increased sympathetic stimulation leading to downregulation of beta1-receptors, both in number and in their sensitivity to adrenergic stimuli. The beneficial effects of carvedilol in heart failure primarily result from its blockade of beta1-receptors. Beta1-blockade causes an up-regulation of myocardial beta1-receptors, which restores the response to increased sympathetic stimulation. Due to its alpha-blocking effects (vasodilation), carvedilol also counterbalances the negative inotropic effects resulting from beta-blockade.
Carvedilol therapy appears to reduce left ventricular hypertrophy (LVH). The effects of carvedilol on LVH were examined in a study involving adult patients with elevated diastolic blood pressure and objective evidence of LVH. There was a significant reduction in the left ventricular wall thickness after 6 months of therapy with carvedilol.
Pharmacokinetics: Carvedilol is administered orally. It is lipophilic and has a large volume of distribution (approximately 115 L in adults), indicating substantial distribution to extravascular tissues. Carvedilol is approximately 98% protein bound, primarily to albumin. Carvedilol undergoes extensive hepatic metabolism, primarily by aromatic ring oxidation and glucuronidation. The oxidative metabolites are further metabolized by conjugation via glucuronidation and sulfation. Carvedilol's 3 active metabolites exhibit beta receptor blocking activity and weak vasodilating activity. One metabolite, 4'-hydroxyphenylcarvedilol, is approximately 13 times more potent than carvedilol as a beta-blocker. Approximately 60% of the metabolites are excreted in the bile and eliminated in the feces, and 16% are excreted in the urine. Less than 2% is excreted unchanged in the urine. The terminal elimination half-life in adults ranges from 7-11 hours for the S(-) enantiomer and 5-9 hours for the R(+) enantiomer.
Affected cytochrome P450 isoenzymes and drug transporters: CYP2D6, CYP2C9, CYP3A4, CYP2C19, CYP1A2, CYP2E1, and P-glycoprotein (P-gp)
CYP2D6 and CYP2C9 are the primary enzymes responsible for carvedilol's metabolism. To a lesser extent CYP3A4, CYP2C19, CYP1A2, and CYP2E1 also contribute to carvedilol's metabolism. Carvedilol is a substrate and inhibitor of P-glycoprotein. Carvedilol is subject to the effects of genetic polymorphism with poor metabolizers of debrisoquin (marker for CYP2D6 metabolism).
Carvedilol is rapidly and extensively absorbed after oral administration; however, the absolute bioavailability is relatively low (< 40%) due to extensive first-pass metabolism. Because the first-pass metabolism is stereoselective, plasma concentrations of R(+)-carvedilol are about 2-3 times higher than S(-)-carvedilol after administration to healthy subjects.
-Carvedilol immediate-release tablets: The overall oral bioavailability of the immediate-release tablets is about 25-35% due to extensive first-pass elimination. Peak plasma concentrations and antihypertensive effects are reached in about 1-2 hours and are linearly related to the dose. Food decreases the rate but not the extent of absorption. Administering with food may minimize the risk of developing orthostatic hypotension. Accumulation does not occur with repeated administration.
-Carvedilol extended-release capsules: Carvedilol extended-release capsules are controlled-release oral capsules containing carvedilol phosphate immediate-release and controlled-release microparticles, which are drug-layered and coated with methacrylic acid copolymers. The extended-release capsules have a bioavailability of about 85% relative to the immediate-release tablets; however, for comparable dosage conversion, the systemic exposure (AUC, Cmax, and serum trough concentrations) of extended-release capsules is considered equivalent to immediate-release tablets when both are administered with food. The absorption of carvedilol from the extended-release capsules is slower and more prolonged compared to the immediate-release tablet with peak serum concentrations attained about 5 hours after administration. Plasma concentrations increase in a dose-related manner over the recommended dosage range. Administration of extended-release capsules with a high-fat meal results in increased AUC and Cmax by approximately 20% compared to administration with a standard meal. Decreases in the AUC (27%) and Cmax (43%) are observed when extended-release carvedilol is administered in the fasted state compared to administration after a standard meal. Sprinkling the contents of extended-release carvedilol capsules on applesauce does not appear to significantly affect the overall exposure (AUC) of carvedilol compared to administration of the intact capsule after a standard meal; however Cmax is decreased by about 18%. In a randomized, double-blind, placebo-controlled trial of adult patients with essential hypertension, the beta1-blocking effect of extended-release carvedilol (measured by heart rate response to submaximal bicycle ergometry) has been shown to be equivalent to that observed with immediate-release tablets at steady state.
Infants, Children, and Adolescents
Carvedilol is rapidly absorbed in pediatric patients with peak plasma concentrations occurring 0.5-2.5 hours after administration of immediate-release formulations. The elimination half-life of carvedilol has been reported to be approximately 50% shorter for pediatric patients with heart failure than that of healthy adults. Systemic exposure is lower in younger pediatric patients compared to older pediatric patients as evidenced by increasing AUC and half-life with age. The half life of carvedilol has been reported to be 2.2 hours in infants and young children < 3.5 years old (n = 8) and 3.6 hours in older children 5.5-19.3 years old (n = 7).
Oral bioavailability after administration of immediate-release carvedilol tablets is increased significantly in patients with hepatic disease. Adult patients with cirrhotic liver disease have approximately 4-7 fold higher plasma concentrations compared to healthy patients.
Plasma concentrations of carvedilol may be increased in patients with renal impairment. Based on mean AUC data, approximately 40-50% higher plasma concentrations of carvedilol were observed in hypertensive adult patients with moderate to severe renal impairment compared to control hypertensive patients with normal renal function. However, the ranges of AUC values were similar for both groups. The changes in mean peak plasma levels were less pronounced (approximately 12-26% higher) in patients with impaired renal function. Carvedilol is not cleared significantly by hemodialysis.
The elimination half-life of carvedilol has been reported to be approximately 50% shorter in pediatric patients with heart failure compared to the half-life in healthy adults. In adult patients with NYHA class IV heart failure, mean AUC and Cmax values were increased up to 50-100% compared to those of healthy adult volunteers after administration of immediate-release carvedilol; however, the mean terminal half-life was similar between groups.