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Carvedilol

Pronunciation

Pronunciation: KAR-ve-dil-ole
Class: Alpha-adrenergic blocking agent, Beta-adrenergic blocking agent

Trade Names

Coreg
- Tablets 3.125 mg
- Tablets 6.25 mg
- Tablets 12.5 mg
- Tablets 25 mg

Coreg CR
- Capsules, extended-release 10 mg
- Capsules, extended-release 20 mg
- Capsules, extended-release 40 mg
- Capsules, extended-release 80 mg

Apo-Carvedilol (Canada)
PMS-Carvedilol (Canada)
RAN-Carvedilol (Canada)
ratio-Carvedilol (Canada)

Pharmacology

Blocks alpha-1 receptors and nonselective beta-receptors to decrease BP.

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Pharmacokinetics

Absorption

Rapidly and extensively absorbed. Bioavailability is approximately 25% to 35% because of first-pass metabolism. Food decreases the rate of absorption. Instruct patients to take with food.

Distribution

More than 98% protein bound, primarily to albumin. Lipophilic, with a Vd of about 115 L. Plasma Cl is 500 to 700 mL/min.

Metabolism

Undergoes first-pass metabolism. Metabolized by aromatic ring oxidation and glucuronidation; 3 active metabolites are formed, 1 of which is about 13 times more potent than carvedilol. CYP-450 enzymes are involved in carvedilol metabolism.

Elimination

The t ½ is 7 to 10 h. Less than 2% is excreted unchanged in urine. Metabolites are excreted via the bile into feces.

Special Populations

Renal Function Impairment

Plasma concentrations may be higher (40% to 50% in those with moderate to severe renal function impairment).

Hepatic Function Impairment

Cirrhotic liver disease patients have a 4- to 7-fold increase in concentrations. Use in patients with hepatic function impairment is not recommended.

Elderly

Plasma levels are about 50% higher in elderly patients.

CHF

AUC and C max are increased.

Indications and Usage

Management of essential hypertension; treatment of mild to severe heart failure of ischemic or cardiomyopathic origin; reduction of CV mortality in clinically stable patients who have survived the acute phase of MI and have a left ventricular ejection fraction of 40% or less.

Unlabeled Uses

Angina pectoris.

Contraindications

Decompensated cardiac failure requiring use of IV inotropic therapy; bronchial asthma or related bronchospastic conditions; second- or third-degree AV block; sick sinus syndrome (unless a permanent pacemaker is in place); cardiogenic shock; severe bradycardia; hepatic function impairment; hypersensitivity to the drug.

Dosage and Administration

Individualize dose and monitor during up-titration.

Essential Hypertension
Adults Tablets

PO Start with 6.25 mg twice daily. If tolerated (based on standing BP about 1 h after dosing), maintain the dosage for 7 to 14 days, then increase to 12.5 mg twice daily. If tolerated, maintain the dosage for 7 to 14 days, then increase to 25 mg twice daily if tolerated and needed (max, 50 mg/day).

Extended-release (ER) capsules

PO Start with 20 mg once daily. If tolerated (based on standing BP about 1 h after dosing), maintain the dosage for 7 to 14 days, then increase to 40 mg once daily if needed. If tolerated, maintain the dosage for 7 to 14 days, then increase to 80 mg once daily if needed, maintaining the patient at lower doses if higher doses not tolerated (max, 80 mg once daily).

CHF
Adults Tablets

PO Start with 3.125 mg twice daily for 14 days. If tolerated, dosage may be increased to 6.25 mg twice daily; dosing may be doubled every 2 wk to the highest amount tolerated by patient (max, 25 mg twice daily for patients less than 85 kg [187 lbs]; 50 mg twice daily for patients more than 85 kg).

ER capsules

PO Start with 10 mg once daily for 14 days. If tolerated, dosage may be increased to 20, 40, and 80 mg once daily over successive intervals of at least 14 days, maintaining the patient at lower doses if higher doses not tolerated.

Left Ventricular Dysfunction (LVD) Following MI
Adults Tablets

PO Start treatment once patient is stable and fluid retention is minimized. The recommended starting dosage is 6.25 mg twice daily and increased to 12.5 mg twice daily after 3 to 10 days, based on tolerability. The dosage may be increased again to the target dosage of 25 mg twice daily. A lower starting dosage may be used (3.125 mg twice daily) and/or, the rate of up-titration may be slowed if clinically indicated (eg, because of low BP or heart rate, or fluid retention). Patients may be maintained at lower dose if higher doses are not tolerated. The recommended dosing regimen need not be altered in patients receiving treatment with an IV or oral beta-blocker during the acute phase of the MI.

ER capsules

PO Start with 20 mg once daily and increase after 3 to 10 days if tolerated to 40 mg once daily, then again to the target dosage of 80 mg once daily, maintaining the patient at lower doses if higher doses not tolerated.

General Advice

  • The ER capsules may be opened and the beads sprinkled over applesauce and consumed immediately.
  • Give each dose with food to minimize risk of orthostatic hypotension.
  • Do not chew or crush. Instruct patient to swallow tablet or capsule whole.

Storage/Stability

Store tablets below 86°F. Store capsules at 59° to 86°F. Protect from moisture.

Drug Interactions

Alcohol

May affect the modified-release properties of the capsules.

Antidiabetic agents (insulin and oral agents)

Blood glucose-lowering effect may be enhanced.

Calcium channel blockers (eg, diltiazem)

Conduction disturbances may occur and BP may be altered.

Catecholamine-depleting agents (eg, reserpine)

Monitor for hypotension or severe bradycardia.

Clonidine

Heart rate- and BP-lowering effects may be potentiated.

Cyclosporine, digoxin

Plasma levels may be elevated by carvedilol, increasing the therapeutic and adverse reactions.

Inhibitors of CYP2D6 (eg, fluoxetine, paroxetine, propafenone, quinidine), poor metabolizers of debrisoquine

Expected to increase carvedilol blood levels.

Rifampin

May reduce carvedilol plasma levels, decreasing the pharmacologic effect.

Salicylates (eg, aspirin)

Increased risk of hypertension due to inhibition of prostaglandin biosynthesis by salicylates.

SSRIs (eg, citalopram, fluoxetine)

Increased risk of excessive beta blockade (bradycardia) due to increased beta-blocker serum levels resulting from inhibition of beta-blocker metabolism (CYP2D6).

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Hypotension (14%); bradycardia (10%); syncope (8%); angina pectoris (6%); aggravated angina pectoris, AV block, cerebrovascular accident, fluid overload, hypertension, palpitation, postural hypotension (1% to 3%).

CNS

Dizziness (32%); fatigue (24%); asthenia (11%); headache (8%); lung edema (for treatment of LVD following MI) (more than 3%); depression, hypesthesia, insomnia, malaise, paresthesia, somnolence, vertigo (1% to 3%).

Dermatologic

Purpura (1% to 3%).

EENT

Abnormal vision (5%); blurred vision, pharyngitis (1% to 3%).

GI

Diarrhea (12%); nausea (9%); vomiting (6%); GI pain, melena, periodontitis (1% to 3%).

Genitourinary

Albuminuria, hematuria, impotence, renal insufficiency, UTI (1% to 3%); urinary incontinence (postmarketing).

Hematologic

Anemia (for treatment of LVD following MI) (more than 3%); prothrombin decreased, thrombocytopenia (1% to 3%); aplastic anemia, leukopenia (postmarketing).

Hepatic

ALT and AST increased (1% to 3%).

Metabolic

Hyperglycemia, weight increase (12%); peripheral edema (7%); BUN and nonprotein nitrogen increase, edema generalized (6%); edema dependent, hypercholesterolemia (4%); creatinine increased, diabetes mellitus, gamma-glutamyl transpeptidase increased, glycosuria, hyperkalemia, hypertriglyceridemia, hyperuricemia, hypervolemia, hypoglycemia, hyponatremia, increased alkaline phosphatase, leg edema, weight loss (1% to 3%).

Musculoskeletal

Arthralgia (6%); back pain, muscle cramps (1% to 3%).

Respiratory

Upper respiratory tract infection (18%); increased cough (8%); bronchitis, sinusitis (5%); rales (4%); dyspnea (for treatment of LVD following MI) (more than 3%); interstitial pneumonitis (postmarketing).

Miscellaneous

Pain (9%); allergy, arthritis, fever, flu syndrome, hypotonia, hypovolemia, infection, peripheral vascular disorder, viral infection (1% to 3%).

Precautions

Monitor

Blood sugar

Monitor blood sugar in diabetic patients when drug is initiated, adjusted, or discontinued.

BP

Monitor and record BP and pulse in hypertensive patients. Should hypotension occur, hold medication.

Orthostatic hypotension

Monitor CHF patients for orthostatic hypotension (eg, dizziness, light-headedness, change in BP) for 1 h after first dose and at initiation of each dose increase.

Weight/Respiratory status

Monitor weight and respiratory status in CHF patients.


Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

Carvedilol plasma levels average 50% higher in elderly compared with young subjects; however, there were no notable differences in efficacy or adverse reactions.

Renal Function

May result in deterioration of renal function.

Special Risk Patients

Use with caution in patients with CHF, pheochromocytoma, or Prinzmetal variant angina.

Anaphylactic reaction

Patients receiving a beta-blocking agent and who have a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.

Anesthesia and major surgery

If carvedilol is continued perioperatively, use with caution with anesthetic agents that depress myocardial function (eg, ether).

Bronchial asthma

Death in patients with status asthmaticus has occurred.

Diabetes and hypoglycemia

May mask symptoms of hypoglycemia, particularly tachycardia; may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels.

Discontinuation

Because carvedilol has beta-blocking activity, do not discontinue abruptly. Severe exacerbation of angina and occurrence of MI and ventricular arrhythmias have been reported. Discontinue over 1 or 2 weeks.

Hepatic toxicity

Mild hepatocellular injury may occur. Perform laboratory testing at first signs or symptoms of liver dysfunction. If there is laboratory evidence of liver injury or jaundice, stop carvedilol therapy and do not restart.

Nonallergic bronchospasm

In general, patients with bronchospastic disease should not receive beta-blocker therapy. In patients who do not respond to, or cannot tolerate, other antihypertensive agents, carvedilol may be used with caution and in the smallest effective dose so that inhibition of endogenous or exogenous beta-agonists is minimized.

Peripheral vascular disease

Because symptoms of arterial insufficiency may be aggravated or precipitated in patients with peripheral vascular disease, use with caution in such patients.

Thyrotoxicosis

May mask signs of hyperthyroidism, such as tachycardia; abrupt withdrawal may exacerbate symptoms of hyperthyroidism and precipitate thyroid storm.

Overdosage

Symptoms

Bradycardia, bronchospasms, cardiac arrest, cardiac insufficiency, cardiogenic shock, generalized seizures, lapses of consciousness, respiratory problems, severe hypotension, vomiting.

Patient Information

  • Advise patient that medication is started at a low dose and gradually increased as needed and tolerated.
  • Instruct patient not to interrupt therapy or discontinue drug abruptly.
  • Remind patient to take each dose with food to reduce risk of orthostatic hypotension.
  • Caution patient to avoid sudden position changes to prevent orthostatic hypotension.
  • Instruct patient to lie or sit down if experiencing dizziness or light-headedness when standing.
  • Instruct patient in BP and pulse measurement skills.
  • Instruct CHF patient to measure and record BP, pulse, weight, and symptoms daily and to report abnormal measurements. Take record to each follow-up office visit.
  • Emphasize importance of a healthy lifestyle (eg, weight control, regular exercise, smoking cessation, moderate intake of alcohol and salt) to hypertensive patient.
  • Advise patient to separate the administration of this medication from alcohol consumption, including ethanol-containing prescription and OTC medicines, by at least 2 h.
  • Instruct patient not to crush or chew this medication and to swallow whole. Alternatively, capsules may be opened and the beads sprinkled over a spoonful of applesauce.
  • Instruct diabetic patient to monitor blood glucose more frequently when dose is changed or drug is stopped. Patient should inform health care provider of any changes in readings.
  • Advise patients who wear contact lenses that drug may cause decreased tearing and dry eyes.
  • Instruct patient to report any of these symptoms to health care provider: bradycardia, dark urine, fainting or persistent dizziness when arising from a sitting or lying position, fatigue, increasing shortness of breath, persistent anorexia, pruritus, right upper quadrant tenderness, swelling of feet or ankles, unexplained flu-like symptoms, or weight gain.
  • Caution patient that drug may cause dizziness or fainting and to avoid driving or performing other hazardous tasks until tolerance is determined.
  • Remind CHF patients that they should be seen by health care provider before each dose change and to keep appointments.

Copyright © 2009 Wolters Kluwer Health.

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