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SOLCO HEALTHCAR
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43547025750

carvedilol 25 mg tablet (generic coreg)

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Uses

Carvedilol is used for the management of hypertension and heart failure. Carvedilol also is used to reduce the risk of cardiovascular mortality in clinically stable patients with left ventricular dysfunction (manifested as a left ventricular ejection fraction [LVEF] of 40% or less) with or without symptomatic heart failure following an acute myocardial infarction.

The choice of a β-adrenergic blocking agent (β-blocker) depends on numerous factors, including intended use, pharmacologic properties (e.g., relative β-selectivity, intrinsic sympathomimetic activity, membrane-stabilizing activity, lipophilicity), pharmacokinetics, and adverse effect profile, as well as the patient's coexisting disease states or conditions, response, and tolerance. While specific pharmacologic properties and other factors may appropriately influence the choice of a β-blocker in individual patients, evidence of clinically important differences among the agents in terms of overall efficacy and/or safety is limited. Patients who do not respond to or cannot tolerate a given β-blocker may be successfully treated with a different one.

Hypertension

Carvedilol is used alone or in combination with other classes of antihypertensive agents in the management of hypertension. Although a β-blocker was previously considered a drug of choice for the initial management of hypertension, most current guidelines no longer recommend these drugs as first-line therapy because of the lack of established superiority over other recommended drug classes and at least one study demonstrating that they may be less effective than angiotensin II receptor antagonists in preventing cardiovascular death, myocardial infarction, or stroke. However, β-blockers may still be considered in hypertensive patients who have a compelling indication (e.g., prior myocardial infarction, ischemic heart disease, heart failure) for their use or as add-on therapy in those who do not respond adequately to the preferred drug classes (angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, or thiazide diuretics). and in )

In general, black hypertensive patients tend to respond better to monotherapy with thiazide diuretics or calcium-channel blocking agents than to monotherapy with β-blockers. Although β-blockers have lowered blood pressure in all races studied, monotherapy with these agents has produced a smaller reduction in blood pressure in black hypertensive patients; however, this population difference in response does not appear to occur during combined therapy with a β-blocker and a thiazide diuretic. and in

For additional information on the role of nonselective β-adrenergic/selective α1-blocking agents in the management of hypertension, or on the role of β-blockers in the management of hypertension, and in . For information on overall principles and expert recommendations for treatment of hypertension, For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients,

Heart Failure

Carvedilol is used (usually in conjunction with other heart failure therapies) in the management of mild to severe (New York Heart Association [NYHA] class II-IV) heart failure of ischemic or cardiomyopathic origin to increase survival and to reduce the risk of hospitalization. Current guidelines for the management of heart failure in adults generally recommend a combination of drug therapies to reduce morbidity and mortality, including neurohormonal antagonists (e.g., ACE inhibitors, angiotensin II receptor antagonists, angiotensin receptor-neprilysin inhibitors [ARNIs], β-blockers, aldosterone receptor antagonists), that inhibit the detrimental compensatory mechanisms in heart failure. Additional agents (e.g., cardiac glycosides, diuretics, sinoatrial modulators [i.e., ivabradine]) added to a heart failure treatment regimen in selected patients have been associated with symptomatic improvement of heart failure and/or reduction in heart failure-related hospitalizations. Experts recommend that all asymptomatic patients with reduced LVEF (American College of Cardiology Foundation [ACCF]/American Heart Association [AHA] stage B heart failure) receive therapy with an ACE inhibitor and a β-blocker to prevent symptomatic heart failure and reduce morbidity and mortality. In patients with prior or current symptoms of chronic heart failure and reduced LVEF (ACCF/AHA stage C heart failure), ACCF, AHA, and the Heart Failure Society of America (HFSA) recommend inhibition of the renin-angiotensin-aldosterone (RAA) system with an ACE inhibitor, angiotensin II receptor antagonist, or ARNI in conjunction with a β-blocker, and an aldosterone antagonist in selected patients, to reduce morbidity and mortality. While ACE inhibitors have been the preferred drugs for inhibition of the RAA system because of their established benefits in patients with heart failure and reduced ejection fraction, some evidence indicates that therapy with an ARNI (sacubitril/valsartan) may be more effective than ACE inhibitor therapy (enalapril) in reducing cardiovascular death and heart failure-related hospitalization in such patients. ACCF, AHA, and HFSA recommend that patients with chronic symptomatic heart failure and reduced LVEF (NYHA class II or III) who are able to tolerate an ACE inhibitor or angiotensin II receptor antagonist be switched to therapy containing an ARNI to further reduce morbidity and mortality.

Because of favorable effects on survival and disease progression, therapy with a clinical trial-proven β-blocker (bisoprolol, carvedilol, extended-release metoprolol succinate) should be initiated as soon as the patient is diagnosed with heart failure and reduced LVEF. While bisoprolol, carvedilol, and extended-release metoprolol have been effective in reducing the risk of death in patients with chronic heart failure, these positive findings should not be considered indicative of a β-blocker class effect. Even when symptoms are mild or improve with other therapies, β-blocker therapy should not be delayed until symptoms return or the disease progresses. Despite concerns about β-blockade potentially masking some signs of hypoglycemia, patients with diabetes mellitus may be particularly likely to experience a reduction in morbidity and mortality with the use of β-blockers. If a patient cannot tolerate a β-blocker or if increasing the β-blocker dosage to optimal levels is ineffective, ivabradine should be considered an alternative or additional treatment option. Some evidence suggests that ivabradine is effective in reducing hospitalizations related to heart failure, but unlike β-blockers, ivabradine has not been shown to reduce cardiovascular mortality.

In individualizing the decision to use a β-blocker, clinicians should consider that clinical studies establishing the effects of these drugs on morbidity and mortality excluded patients who were hospitalized or had unstable symptoms and enrolled few patients with current or recent NYHA class IV symptoms. The efficacy of β-blockers in such patients is not known, and they may be at particular risk of deterioration following initiation of therapy with β-blockers. In the Carvedilol Prospective Randomized Cumulative Survival Trial (COPERNICUS) evaluating such patients with severe but stable heart failure (patients with marked fluid retention or severe pulmonary disease or requiring intensive care, IV vasodilators, or positive inotropic agents were excluded), carvedilol decreased the rate of death and the combined risk of death and hospitalization for any reason compared with placebo.

The beneficial effects of β-blockers in the management of heart failure are thought to result principally from inhibition of the effects of the sympathetic nervous system.(See Description.) Although the specific effects on the heart and circulation that are responsible for progression of heart failure remain to be established, sympathetic activity can increase ventricular volumes and pressure secondary to peripheral vasoconstriction and by impairing sodium excretion by the kidneys. Other sympathetic effects (e.g., induction of cardiac hypertrophy, arrhythmogenic activity) also may be involved. The beneficial effect of carvedilol in patients with severe heart failure may be the result of other effects (α-adrenergic blockade, antioxidant activity, antiendothelin effects) in addition to β-adrenergic blockade. Collective experience indicates that long-term therapy with β-blockers, like that with ACE inhibitors, can reduce heart failure symptoms and improve clinical status in patients with chronic heart failure and also can decrease the risk of death as well as the combined risk of death and hospitalization. These beneficial effects were demonstrated in patients already receiving an ACE inhibitor, suggesting that combined inhibition of the renin-angiotensin system and sympathetic nervous system can produce additive effects.

β-Blockers should not be used in patients with acutely decompensated heart failure requiring IV inotropic therapy and those with substantial fluid retention requiring intensive diuresis. In the absence of hemodynamic instability or contraindications, it has been recommended that patients with heart failure and a reduced ejection fraction who are hospitalized for a symptomatic exacerbation continue to receive maintenance treatment with standard oral therapy for heart failure (e.g., β-blocker, ACE inhibitor). Withholding of or reduction in β-blocker therapy should be considered only in patients hospitalized after recent initiation or increase in β-blocker therapy or in those with marked volume overload or low/marginal cardiac output. Initiation of β-blocker therapy in hospitalized patients is recommended once the patient's condition is stabilized (i.e., after optimization of volume status and successful discontinuance of IV diuretics, vasodilators, and inotropic agents). Caution should be used when initiating β-blockers in patients who have required inotrope therapy during hospitalization.

Carvedilol has been shown in controlled studies to improve left ventricular function, symptoms, and submaximal exercise tolerance (although not in all studies) in patients with wide-ranging severity of manifestations. Change in NYHA classification was a secondary endpoint in all of the studies, and a trend toward improvement in NYHA class was reported in all studies. Subjective quality-of-life determined by a standard questionnaire was not improved in patients receiving carvedilol compared with those receiving placebo; however, global assessments by patients and clinicians supported an improvement in such assessments in patients receiving carvedilol.

Left Ventricular Dysfunction after Acute Myocardial Infarction

Carvedilol is used to reduce the risk of cardiovascular mortality following myocardial infarction in clinically stable patients with left ventricular dysfunction (manifested as an ejection fraction of 40% or less) with or without symptomatic heart failure. In these patients, when compared with those receiving placebo, carvedilol therapy initiated within 21 days after an acute myocardial infarction reduced mortality from any cause by about 23%; all-cause mortality or cardiovascular hospitalization was reduced by 8%, which was not statistically significant. In addition, a 40% reduction in fatal and nonfatal myocardial infarction was observed in patients receiving carvedilol. This evidence of efficacy was obtained from a large, double-blind, placebo-controlled, multicenter long-term (about 16 months) study (Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction Study; CAPRICORN).

Dosage and Administration

Administration

Carvedilol and carvedilol phosphate are administered orally. Food has little, if any, effect on the oral bioavailability of carvedilol immediate-release tablets but may decrease the rate of absorption, resulting in reduced and delayed peak plasma concentrations. Therefore, to potentially decrease the risk of orthostatic hypotension, it is recommended that carvedilol be administered with food. In addition, the manufacturer suggests that manifestations of vasodilation in patients receiving concomitant therapy with an angiotensin-converting enzyme (ACE) inhibitor may be reduced by administering carvedilol 2 hours prior to the latter drug.

Food increases the bioavailability of carvedilol phosphate extended-release capsules and the manufacturer states that the extended-release capsules should be taken with food. Carvedilol extended-release capsules should be taken once daily in the morning and should be swallowed whole; the capsule and/or its contents should not be crushed, chewed, or taken in divided doses. However, carvedilol extended-release capsules may be opened carefully and the entire contents sprinkled over a spoonful of applesauce, immediately prior to administration. The applesauce should not be warm, and the drug and applesauce mixture should be consumed in entirety. The drug and applesauce mixture should not be stored for future use. The absorption of the beads sprinkled on foods other than applesauce has not been studied.

Dosage

Patients whose conditions are controlled with immediate-release carvedilol tablets alone or in combination with other drugs may be switched to carvedilol phosphate extended-release capsules. Patients who are receiving a daily carvedilol dosage of 6.25 (3.125 mg twice daily), 12.5 (6.25 mg twice daily), 25 (12.5 mg twice daily), or 50 mg (25 mg twice daily) as immediate-release tablets may be switched to a dosage of 10, 20, 40, or 80 mg once daily, respectively, as carvedilol phosphate extended-release capsules. Subsequent titration to higher or lower dosages may be necessary and should be guided by the patient's clinical response.

Hypertension

Dosage of carvedilol must be individualized and adjusted according to the patient's blood pressure response and tolerance.

In hypertensive patients with left ventricular dysfunction, including those with heart failure who already are receiving a cardiac glycoside, diuretic, and/or an ACE inhibitor, the manufacturer states that the usual carvedilol dosages and instructions recommended for the treatment of heart failure should be followed instead of those for hypertension, since such patients generally depend, at least in part, on β-adrenergic stimulation for maintaining cardiovascular compensation.(See Heart Failure under Dosage and Administration: Dosage.)

Usual Dosage

For the management of hypertension in adults, the usual initial dosage of carvedilol (as immediate-release tablets) is 6.25 mg twice daily. The manufacturer recommends that patient response and tolerance to the initial dosage and subsequent dosage adjustments be evaluated by measurement of standing systolic blood pressure 1 hour after administration of carvedilol (trough blood pressure). In patients whose blood pressure is not controlled adequately with the initial carvedilol dosage, dosage can be increased gradually (usually increasing dosage every 7-14 days), as tolerated up to a maximum of 50 mg daily. For patients who received an initial dosage of 6.25 mg twice daily, the dosage may be increased to 12.5 mg twice daily and, if needed, to 25 mg twice daily.

For the management of hypertension in adults, the usual initial dosage of carvedilol phosphate extended-release capsules is 20 mg once daily. The manufacturer recommends that patient tolerance to the initial dosage and subsequent dosage adjustments be evaluated by measurement of standing systolic blood pressure 1 hour after administration of carvedilol phosphate extended-release capsules. In patients whose blood pressure is not controlled adequately with the initial carvedilol phosphate dosage (given as extended-release capsules), dosage can be increased gradually (usually increasing dosage every 7-14 days) up to a maximum of 80 mg once daily (given as carvedilol phosphate extended-release capsules).

Addition of a diuretic to carvedilol therapy or of carvedilol to diuretic therapy can be expected to produce additive effects. When carvedilol and a thiazide diuretic are used concomitantly, an additive hypotensive response, including an increased risk of orthostatic hypotension, can be expected.

The panel members appointed to the Eighth Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 8 expert panel) state that evidence-based dosing information (i.e., dosages shown in randomized controlled trials to reduce complications of hypertension) should be used when available to determine target dosages of antihypertensive agents. Target dosages of antihypertensive agents generally can be achieved within 2-4 weeks, but it may take up to several months. In patients who experience intolerable adverse effects with carvedilol, dosage reduction should be considered; if adverse effects worsen or fail to resolve, it may be necessary to discontinue the β-adrenergic blocking agent (β-blocker) and initiate another class of antihypertensive agent.

Blood Pressure Monitoring and Treatment Goals

Careful monitoring of blood pressure during initial titration or subsequent upward adjustment in dosage of carvedilol is recommended.

The goal of hypertension management and prevention is to achieve and maintain optimal control of blood pressure; specific target levels of blood pressure should be individualized based on consideration of multiple factors, including patient age and comorbidities, and the currently available evidence from clinical studies.

For additional information on initiating and adjusting carvedilol dosage in the management of hypertension,

Heart Failure

Prior to initiation of carvedilol therapy for heart failure, fluid retention should be minimized, and patients who are receiving treatment that includes a cardiac glycoside, diuretic, and/or ACE inhibitor should be stabilized with respect to the dosage of these drugs. Initiation of carvedilol therapy for heart failure and subsequent dosage adjustments should occur under very close medical supervision, since the risk of cardiac decompensation and/or severe hypotension is highest during the initial 30 days of therapy.

For the management of mild to severe (NYHA class II-IV) heart failure, carvedilol often is administered in conjunction with other agents such as a cardiac glycoside, ACE inhibitor, and/or diuretic. Treatment with carvedilol should be initiated at a very low dosage. The usual initial carvedilol dosage as immediate-release tablets for the management of heart failure in adults is 3.125 mg twice daily for 2 weeks. The usual initial dosage of carvedilol phosphate extended-release capsules for the management of heart failure in adults is 10 mg once daily for 2 weeks. Prior to dosage increases, the patient's response and tolerance to carvedilol therapy should be determined in a clinical setting and should include an assessment of manifestations of declining cardiovascular status, vasodilation (e.g., dizziness, light-headedness, symptomatic hypotension), and bradycardia.

If the patient experiences increases in manifestations of heart failure such as edema during the initiation and titration phases of carvedilol therapy, further increases in carvedilol dosage should be delayed until the patient regains clinical stability; such manifestations may require an increase in diuretic dosage. If increased manifestations of heart failure do not resolve in response to an increase in diuretic dosage, consideration should be given to decreasing the carvedilol dosage or temporarily discontinuing the drug. The occurrence of increased manifestations of heart failure during initiation of carvedilol therapy or dosage titration that require dosage decreases or discontinuance of the drug should not prevent future consideration of resuming therapy with or increasing dosage of carvedilol. If the patient develops manifestations of vasodilation, consideration should be given to decreasing the patient's dosage of diuretic or ACE inhibitor; however, if these dosage reductions do not result in improved circulatory status, carvedilol dosage may be decreased. Separating the time of dosing of carvedilol from that of the ACE inhibitor also may reduce vasodilatory symptoms. If the patient becomes bradycardic (heart rate less than 55 beats/minute), carvedilol dosage should be reduced. If the patient develops manifestations of worsening heart failure or vasodilation, carvedilol dosage should not be increased until the patient's cardiovascular status is stable.

If the patient tolerates the initial dosage, carvedilol dosage may be increased to 6.25 mg twice daily as the immediate-release tablets or to 20 mg once daily as carvedilol phosphate extended-release capsules for 2 weeks. When increases in dosage are considered, the patient should be observed in a clinical setting for manifestations of hypotension (e.g., dizziness, light-headedness) for 1 hour after administration of the initial dose at the increased dosage. Dosage of carvedilol as the immediate-release tablets and carvedilol phosphate as extended-release capsules can be doubled every 2 weeks if necessary (with strict adherence to the monitoring regimen described above) to the highest tolerated dosage that does not exceed the maximum recommended dosage of 50 mg daily (in patients weighing less than 85 kg) and 100 mg daily (in those weighing more than 85 kg) as carvedilol immediate-release tablets and of 80 mg once daily as carvedilol phosphate extended-release capsules.

Left Ventricular Dysfunction after Acute Myocardial Infarction

Prior to initiation of carvedilol therapy for left ventricular dysfunction following acute myocardial infarction, fluid retention should be minimized, and patients should be hemodynamically stable. Initiation of carvedilol therapy and subsequent dosage adjustments should occur under very close medical supervision, since the risk of cardiac decompensation and/or severe hypotension is highest during the initial 30 days of therapy. Therapy may be initiated on an inpatient or outpatient basis after the patient is hemodynamically stable and fluid retention is minimized.

To decrease the likelihood of syncope or excessive hypotension, treatment with carvedilol should be initiated at a low dosage of 6.25 mg twice daily as the immediate-release tablets or 20 mg of carvedilol phosphate once daily as the extended-release capsules. If the patient tolerates the initial dosage, carvedilol dosage may be increased after 3-10 days to 12.5 mg twice daily as the immediate-release tablets or 40 mg once daily as carvedilol phosphate extended-release capsules, and then to the target dosage of 25 mg twice daily as the immediate-release tablets or 80 mg of carvedilol phosphate once daily as the extended-release capsules. A lower initial dosage of 3.125 mg twice daily as the immediate-release tablets or 10 mg of carvedilol phosphate once daily as the extended-release capsules and/or a slower rate of dosage titration may be used when clinically indicated (e.g., low blood pressure or heart rate, fluid retention). Alteration of the recommended dosage regimen is not necessary in patients who received IV or oral treatment with a β-blocker during the acute phase of the myocardial infarction.

Special Populations

Use of carvedilol is not recommended in patients with clinical manifestations of hepatic impairment or with otherwise severe impairment.(See Contraindications.)

Although the manufacturer makes no specific recommendations for dosage adjustments in patients with renal impairment, plasma concentrations of carvedilol based on comparison of mean plasma concentration-time curves (AUC) reportedly are 40-50% higher in patients with hypertension and moderate to severe renal impairment compared with patients with hypertension and normal renal function receiving carvedilol therapy as the immediate-release tablets. Although the ranges of AUC values were similar for both groups, mean peak plasma concentrations were approximately 12-26% higher in patients with impaired renal function compared with those in patients with no such impairment. Carvedilol does not appear to be removed by hemodialysis.

If a deterioration in renal function is detected in patients with heart failure, dosage of carvedilol should be decreased or the drug should be discontinued.

Some clinicians suggest using a reduced initial carvedilol dosage in geriatric patients, since such patients are at increased risk of developing orthostatic hypotension and experience is limited regarding the use of the drug in patients 75 years of age or older.

Cautions

Contraindications

Bronchial asthma or related bronchospastic conditions.

Second or third degree AV block.

Sick sinus syndrome or severe bradycardia (unless permanent pacemaker is in place).

Cardiogenic shock or decompensated heart failure requiring IV inotropic therapy; initiate carvedilol only after the patient is weaned from IV therapy.

Clinically apparent or otherwise severe hepatic impairment.

History of serious hypersensitivity reaction (e.g., Stevens-Johnson syndrome, anaphylactic reaction, angioedema) to carvedilol or any ingredient in the formulation.

Warnings/Precautions

Warnings

Abrupt Withdrawal of Therapy

Abrupt withdrawal of carvedilol may exacerbate angina symptoms and/or precipitate myocardial infarction and ventricular arrhythmias in patients with coronary artery disease or may precipitate thyroid storm in patients with thyrotoxicosis. Therefore, patients receiving carvedilol (especially those with ischemic heart disease) should be warned not to interrupt or discontinue therapy without consulting their clinician. Because coronary artery disease is common and may be undiagnosed, abrupt withdrawal also should be avoided in patients receiving carvedilol for other conditions (e.g., hypertension). When carvedilol is discontinued in patients with coronary artery disease or suspected thyrotoxicosis, the patient should be observed carefully; patients with coronary artery disease should be advised to temporarily limit their physical activity. If exacerbation of angina occurs or acute coronary insufficiency develops after carvedilol therapy is interrupted or discontinued, treatment with the drug should be reinstituted, at least temporarily.

If carvedilol therapy, alone or combined with another antihypertensive agent (e.g., a thiazide diuretic), is to be discontinued, dosage should be reduced gradually in a deliberate and progressive manner, if possible. When such cessation of therapy is planned, the manufacturer recommends that therapy with the drug be withdrawn gradually over approximately 1-2 weeks. Patients should be monitored closely during this period and, if manifestations of withdrawal (e.g., angina, exacerbation of hypertension) develop, dosage should be increased or the drug reinstituted, at least temporarily.

Peripheral Vascular Disease

Possible precipitation or aggravation of arterial insufficiency in patients with peripheral vascular disease. Use with caution.

Anesthesia and Major Surgery

If carvedilol therapy is continued perioperatively, use particular caution when anesthetic agents that depress myocardial function (e.g., ether, cyclopropane, trichloroethylene) are used.(See Drug Interactions.)

Diabetes and Hypoglycemia

β-Adrenergic blocking agents (β-blockers) may mask some of the manifestations of hypoglycemia (e.g., tachycardia). Non-selective β-blockers (e.g., carvedilol) are more likely to potentiate insulin-induced hypoglycemia and delay recovery of serum glucose concentrations.

In patients with heart failure and diabetes mellitus, blood glucose should be monitored when carvedilol therapy is initiated or discontinued or the dosage adjusted, since carvedilol therapy may worsen hyperglycemia.

Thyrotoxicosis

β-Adrenergic blockade may mask clinical signs of hyperthyroidism (e.g., tachycardia). Abrupt withdrawal of β-blockade may be followed by an exacerbation of symptoms of hyperthyroidism or may precipitate thyroid storm.

General Precautions

Carvedilol shares the toxic potentials of β-adrenergic and α1-adrenergic blocking agents; observe the usual precautions recommended with these agents.

Bradycardia

May cause bradycardia; dosage should be reduced if heart rate is less than 55 beats/minute.

Hypotension

May cause hypotension, postural hypotension, or syncope. Risk is highest in first 30 days of therapy in patients with heart failure. To decrease risk of orthostatic hypotension, administer with food and strictly adhere to the usual starting dose and titration recommendations.(See Dosage and Administration.)

Pheochromocytoma

In patients with pheochromocytoma, an α-adrenergic blocking agent should be administered before using a β-blocker. Although carvedilol has both α- and β-blocking pharmacologic activities, there has been no experience with its use in this condition; use with caution.

Prinzmetal's Variant Angina

Nonselective β-blockers may provoke chest pain in patients with Prinzmetal's variant angina; use with caution.

History of Anaphylactic Reactions

Possible increased reactivity to a variety of allergens; patients may be unresponsive to usual doses of epinephrine used to treat anaphylactic reactions.

Bronchospastic Disease

Bronchospasm reported rarely; deaths secondary to status asthmaticus have been reported following single doses of carvedilol. Patients with bronchospastic disease (e.g., chronic bronchitis, emphysema) generally should not receive β-blockers. Carvedilol should be used in patients with bronchospastic disease only when they are nonresponsive or intolerant of other antihypertensive agents; if used in such patients, the drug should be administered with caution and at the lowest dosage that achieves the desired clinical effect to minimize the drug's inhibition of endogenous or exogenous β-adrenergic agonists.(See Contraindications under Cautions.) If bronchospasm occurs, dosage should be reduced.

The manufacturer recommends that carvedilol be used with caution and strict adherence to recommendations regarding dosage titration in patients with heart failure and bronchospastic disease. If any evidence of bronchospasm occurs during initiation and/or titration of carvedilol, the dosage should be reduced.

Specific Populations

Pregnancy

Category C.

Crosses the placenta in rats. Perinatal and neonatal distress have been reported with other α- and β-blockers.

Lactation

Distributed into milk in rats; not known whether distributed into human milk. Because of the risk of adverse effects in the infant, discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Pediatric Use

Safety and efficacy not established in children younger than 18 years of age.

In a clinical trial in pediatric patients (mean age 6 years, range 2 months to 17 years) with chronic heart failure (NYHA class II-IV), carvedilol resulted in β-blockade activity as demonstrated by a placebo-corrected heart rate reduction of 4-6 beats/minute; however, no clinically important effect on treatment outcome was observed after 8 months of follow-up. Common adverse effects included chest pain, dizziness, and dyspnea.

Geriatric Use

No substantial differences in safety or efficacy relative to younger adults, but possibility exists of increased sensitivity to carvedilol in some individuals. Some clinicians suggest using a reduced initial carvedilol dosage in geriatric patients, since such patients are at increased risk of developing orthostatic hypotension and experience is limited regarding the use of the drug in patients 75 years of age or older. Plasma concentrations of carvedilol are about 50% higher in geriatric individuals than in younger individuals.

Hepatic Impairment

Not recommended for use in patients with manifestations of hepatic impairment or severe hepatic impairment.(See Contraindications under Cautions.)

Patients with hepatic cirrhosis developed plasma drug concentrations approximately 4-7 times higher than those in healthy individuals after a single dose of immediate-release carvedilol tablets.

Renal Impairment

Deterioration of renal function has been reported in patients receiving carvedilol.

Patients at risk appear to be those with low blood pressure (systolic blood pressure less than 100 mm Hg), ischemic heart disease and diffuse vascular disease, and/or underlying renal insufficiency. Renal function should be monitored in these patients during the dosage titration period; the drug should be discontinued or dosage reduced if worsening of renal function occurs.

Common Adverse Effects

Adverse effects reported in 5% or more of patients with heart failure receiving immediate-release carvedilol tablets include dizziness, headache, fatigue, asthenia, arthralgia, hypotension, bradycardia, generalized edema, diarrhea, nausea, vomiting, hyperglycemia, weight gain, increased BUN, increased nonprotein nitrogen (NPN), increased cough, and abnormal vision.

Adverse effects reported in patients with left ventricular dysfunction following myocardial infarction receiving immediate-release carvedilol tablets generally were similar to those in patients receiving the drug for the treatment of heart failure. Additional adverse effects reported in 3% or more of such patients include anemia, dyspnea, and pulmonary edema.

Adverse effects reported in 2% or more of patients receiving immediate-release carvedilol tablets for the treatment of hypertension include dizziness, bradycardia, diarrhea, insomnia, and postural hypotension.

Adverse effects reported in 2% or more of patients receiving extended-release carvedilol phosphate capsules for the treatment of hypertension include nasopharyngitis, dizziness, nausea, and peripheral edema.

Drug Interactions

Metabolized by cytochrome P-450 (CYP) isoenzymes, principally CYP2D6 and CYP2C9; also metabolized to a lesser extent by CYP3A4, CYP2C19, CYP1A2, CYP2E1.

Drugs Affecting Hepatic Microsomal Enzymes

Potent inhibitors of CYP2D6 (e.g., fluoxetine, paroxetine, propafenone, quinidine): potential pharmacokinetic interaction (increased plasma concentrations of R(+)-carvedilol); however interactions with carvedilol have not been studied.

Antidiabetic Agents (Oral and Parenteral [Insulin])

Possible increased hypoglycemic effect. Blood glucose concentrations should be monitored regularly.

Calcium-channel Blocking Agents

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

Cardiac Glycosides

Potential pharmacokinetic and pharmacodynamic interaction. Digoxin concentrations are increased by about 15% in patients receiving concomitant therapy with digoxin and carvedilol. Both cardiac glycosides and carvedilol slow AV conduction and decrease heart rate; concomitant use may increase risk of bradycardia. Digoxin therapy should be carefully monitored when carvedilol dosage is initiated, adjusted, or discontinued.

Catecholamine-depleting Agents (e.g., reserpine, MAO inhibitors)

Potential additive effects (e.g., hypotension, bradycardia). Patients should be monitored closely for symptoms (e.g., vertigo, syncope, postural hypotension).

Cimetidine

Potential decreased carvedilol metabolism and increased (by 30%) bioavailability (area under the plasma concentration-time curve [AUC]) of carvedilol. No apparent change in peak plasma concentration of carvedilol.

Clonidine

Potential additive effects (e.g., hypotension, bradycardia). If carvedilol is used concomitantly with clonidine, caution should be exercised, particularly when discontinuing therapy; carvedilol generally should be discontinued first, and clonidine continued for several days thereafter with gradual downward dosage titration.

Cyclosporine

Possible increased cyclosporine concentrations. Cyclosporine concentrations should be closely monitored during carvedilol dosage titration; adjust cyclosporine dosage as necessary.

Fluoxetine

Potential pharmacokinetic and pharmacodynamic interaction; potential for increased plasma concentrations of R(+)-carvedilol that may result in increased α-adrenergic blockade effects (vasodilation).

Glyburide

Pharmacokinetic interaction unlikely.

Hydrochlorothiazide

Pharmacokinetic interaction unlikely.

Myocardial Depressant General Anesthetics (ether, cyclopropane, trichloroethylene)

Potential for increased risk of hypotension and heart failure. Use with caution.

Pantoprazole

No clinically important increases in AUC and peak plasma concentrations of carvedilol reported with concomitant administration of carvedilol and pantoprazole.

Paroxetine

Potential pharmacokinetic and pharmacodynamic interaction; potential for increased plasma concentrations of R(+)-carvedilol that may result in increased α-adrenergic blockade effects (vasodilation).

Propafenone

Potential pharmacokinetic interaction; potential for increased plasma concentrations of R(+)-carvedilol that may result in increased α-adrenergic blockade effects (vasodilation).

Quinidine

Potential pharmacokinetic interaction: potential for increased plasma concentrations of R(+)-carvedilol that may result in increased α-adrenergic blockade effects (vasodilation).

Rifampin

In a pharmacokinetic study, rifampin decreased peak plasma concentration (by 70%) and AUC (by 70%) of carvedilol.

Torsemide

Pharmacokinetic interaction unlikely.

Warfarin

No effect on steady-state prothrombin times or warfarin pharmacokinetics.

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