CORONAT

Carvedilol is a racemic mixture where the S(-) enantiomer is both a beta and alpha-1 adrenoceptor blocker, and the R(+) enantiomer is an alpha-1 adrenoceptor blocker. 5, 6 It is currently used to treat heart failure, left ventricular dysfunction, and hypertension. 5, 6 The dual action of carvedilol is advantageous in combination therapies as moderate doses of 2 drugs have a decreased incidence of adverse effects compared to high dose monotherapy in the treatment of moderate hypertension.

Carvedilol was granted

FDA approval on 14 September 1995.

Carvedilol is indicated to treat mild to severe heart failure, left ventricular dysfunction after myocardial infarction with ventricular ejection fraction ≤40%, or hypertension. 5,

Carvedilol reduces tachycardia through beta adrenergic antagonism and lowers blood pressure through alpha-1 adrenergic antagonism. 5, 6 It has a long duration of action as it is generally taken once daily and has a broad therapeutic index as patients generally take 10-80 mg daily. 5, 6 Patients taking carvedilol should not abruptly stop taking this medication as this may exacerbate coronary artery disease. 5, 6.

Beta-1 adrenergic receptor Antagonist Beta-2 adrenergic receptor Antagonist Alpha-1B adrenergic receptor Antagonist + 2 more targets.

Carvedilol has a bioavailability of 25-35%. 4, 5, 6 Carvedilol has a T max of 1-2 hours.

Taking carvedilol with a meal increases T max without increasing AUC.

Carvedilol doses of 50 mg lead to a C max of 122-262 µg/L and an AUC of 717-1600 µg/L*h.

Carvedilol doses of 25 mg lead to a C max of 24-151 µg/L and an AUC of 272-947 µg/L*h.

Carvedilol doses of 12.5 mg lead to a C max of 58-69 µg/L and an AUC of 208-225 µg/L*h.

Carvedilol has a volume of distribution of 1.5-2 L/kg 4 or 115 L.

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.

Hover over products below to view reaction partners Carvedilol 8-Hydroxycarbazolylcarvedilol 4'-Hydroxyphenylcarvedilol 5'-Hydroxyphenylcarvedilol O-Desmethylcarvedilol 1-Hydroxyphenylcarvedilol Carvedilol Glucuronide.

16% of carvedilol is excreted in the urine with <2% excreted as unmetabolized drug.

Carvedilol is primarily excreted in the bile and feces. 5, 6.

The half life of carvedilol is between 7-10 hours, though significantly shorter half lives have also been reported. 4, 5, 6.

The plasma clearance of carvedilol has been reported as 0.52 L/kg 4 or 500-700 mL/min. 5, 6.

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Patients experiencing an overdose may present with hypotension, bradycardia, cardiac insufficiency, cardiogenic shock, and cardiac arrest. 5, 6 Patients should remain in a supine position and may be given atropine for bradycardia and glucagon followed by sympathomimetics to support cardiovascular function. 5, 6.

Bronchial asthma or related bronchospastic conditions.

• or third-degree AV block.

Sick sinus syndrome.

Severe bradycardia (unless permanent pacemaker in place).

Patients in cardiogenic shock or decompensated heart failure requiring the use of IV inotropic therapy.

Severe hepatic impairment.

History of serious hypersensitivity reaction (e.g., Stevens-Johnson syndrome, anaphylactic reaction, angioedema) to any component of this medication or other medications containing carvedilol.

Carvedilol tablets are contraindicated in the following conditions: Bronchial asthma or related bronchospastic conditions.

Deaths from status asthmaticus have been reported following single doses of carvedilol tablets.

Severe bradycardia (unless a permanent pacemaker is in place).

Patients with cardiogenic shock or who have decompensated heart failure requiring the use of intravenous inotropic therapy.

Such patients should first be weaned from intravenous therapy before initiating carvedilol tablets.

Patients with severe hepatic impairment.

Patients with a history of a serious hypersensitivity reaction (e.g., Stevens-Johnson syndrome, anaphylactic reaction, angioedema) to any component of this medication or other medications containing carvedilol.

Take with food.

Individualize dosage and monitor during up-titration.

Heart failure

Start at 3.125 mg twice daily and increase to 6.25, 12.5, and then 25 mg twice daily over intervals of at least 2 weeks.

Maintain lower doses if higher doses are not tolerated.

Left ventricular dysfunction following myocardial infarction

Start at 6.25 mg twice daily and increase to 12.5 mg then 25 mg twice daily after intervals of to 10 days.

A lower starting dose or slower titration may be used.

Start at 6.25 mg twice daily and increase if needed for blood pressure control to 12.5 mg and then 25 mg twice daily over intervals of to 2 weeks.

Carvedilol should be taken with food to slow the rate of absorption and reduce the incidence of orthostatic effects. 2.1 Heart Failure DOSAGE MUST BE INDIVIDUALIZED AND CLOSELY MONITORED BY A PHYSICIAN DURING UP-TITRATION.

Prior to initiation of

Carvedilol tablets, it is recommended that fluid retention be minimized.

The recommended starting dose of

Carvedilol tablets are 3.125 mg twice daily for 2 weeks.

If tolerated, patients may have their dose increased to 6.25, 12.5, and 25 mg twice daily over successive intervals of at least 2 weeks.

Patients should be maintained on lower doses if higher doses are not tolerated.

A maximum dose of 50 mg twice daily has been administered to patients with mild-to-moderate heart failure weighing over 85 kg (187 lbs).

Patients should be advised that initiation of treatment and (to a lesser extent) dosage increases may be associated with transient symptoms of dizziness or lightheadedness (and rarely syncope) within the first hour after dosing.

During these periods, patients should avoid situations such as driving or hazardous tasks, where symptoms could result in injury.

Vasodilatory symptoms often do not require treatment, but it may be useful to separate the time of dosing of Carvedilol tablets from that of the ACE inhibitor or to reduce temporarily the dose of the ACE inhibitor.

The dose of

Carvedilol tablets should not be increased until symptoms of worsening heart failure or vasodilation have been stabilized.

Fluid retention (with or without transient worsening heart failure symptoms) should be treated by an increase in the dose of diuretics.

Carvedilol tablets should be reduced if patients experience bradycardia (heart rate less than 55 beats per minute).

Episodes of dizziness or fluid retention during initiation of Carvedilol tablets can generally be managed without discontinuation of treatment and do not preclude subsequent successful titration of, or a favorable response to, carvedilol. 2.2 Left Ventricular Dysfunction following Myocardial Infarction DOSAGE MUST BE INDIVIDUALIZED AND MONITORED DURING UP-TITRATION.

Treatment with carvedilol tablets may be started as an inpatient or outpatient and should be started after the patient is hemodynamically stable and fluid retention has been minimized.

It is recommended that carvedilol tablets be started at 6.25 mg twice daily and increased after to 10 days, based on tolerability, to 12.5 mg twice daily, then again to the target dose of 25 mg twice daily.

A lower starting dose may be used (3.125 mg twice daily) and/or the rate of up-titration may be slowed if clinically indicated (e.g., due to low blood pressure or heart rate, or fluid retention).

The recommended dosing regimen need not be altered in patients who received treatment with an IV or oral β-blocker during the acute phase of the myocardial infarction. 2.3 Hypertension DOSAGE MUST BE INDIVIDUALIZED.

The recommended starting dose of carvedilol tablets are 6.25 mg twice daily.

If this dose is tolerated, using standing systolic pressure measured about 1 hour after dosing as a guide, the dose should be maintained for to 14 days, and then increased to 12.5 mg twice daily if needed, based on trough blood pressure, again using standing systolic pressure 1 hour after dosing as a guide for tolerance.

This dose should also be maintained for to 14 days and can then be adjusted upward to 25 mg twice daily if tolerated and needed.

The full antihypertensive effect of carvedilol tablets are seen within to 14 days.

Total daily dose should not exceed 50 mg. Concomitant administration with a diuretic can be expected to produce additive effects and exaggerate the orthostatic component of carvedilol action. 2.4 Hepatic Impairment Carvedilol tablets should not be given to patients with severe hepatic impairment.

USP, 3.125 mg are white to off-white, round, biconvex, film-coated tablets debossed with 'Z' on one side and '1' on other side and are supplied as follows: NDC-42708-181-60 in bottles of 60 tablets Storage Store at 20°C to 25°C (68°F to 77°F) .

Protect from moisture.

Dispense in a tight, light-resistant container.

Available data regarding use of carvedilol in pregnant women are insufficient to determine whether there are drug-associated risks of adverse developmental outcomes.

There are risks to the mother and fetus associated with poorly controlled hypertension in pregnancy.

The use of beta blockers during the third trimester of pregnancy may increase the risk of hypotension, bradycardia, hypoglycemia, and respiratory depression in the neonate.

In animal reproduction studies, there was no evidence of adverse developmental outcomes at clinically relevant doses.

Oral administration of carvedilol to pregnant rats during organogenesis resulted in post-implantation loss, decreased fetal body weight, and an increased frequency of delayed fetal skeletal development at maternally toxic doses that were 50 times the maximum recommended human dose (MRHD).

In addition, oral administration of carvedilol to pregnant rabbits during organogenesis resulted in increased post-implantation loss at doses 25 times the MRHD.

The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Maternal and/or Embryo/Fetal Risk: Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section and post-partum hemorrhage).

Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death.

Pregnant women with hypertension should be carefully monitored and managed accordingly.

Fetal/Neonatal Adverse Reactions: Neonates of women with hypertension who are treated with beta-blockers during the third trimester of pregnancy may be at increased risk for hypotension, bradycardia, hypoglycemia, and respiratory depression.

Observe newborns for symptoms of hypotension, bradycardia, hypoglycemia, and respiratory depression and manage accordingly.

Studies performed in rats and rabbits given carvedilol during fetal organogenesis revealed increased post-implantation loss in rats at a maternally toxic dose of 300 mg per kg per day (50 times the MRHD as mg per m 2 ) and in rabbits (in the absence of maternal toxicity) at doses of 75 mg per kg per day (25 times the MRHD as mg per m 2 ).

In the rats, there was also a decrease in fetal body weight at 300 mg per kg per day (50 times the MRHD as mg per m 2 ) accompanied by an increased incidence of fetuses with delayed skeletal development.

In rats, the no-effect level for embryo-fetal toxicity was 60 mg per kg per day (10 times the MRHD as mg per m 2 ); in rabbits, it was 15 mg per kg per day (5 times the MRHD as mg per m 2 ).

In a pre-and post-natal development study in rats administered carvedilol from late gestation through lactation, increased embryo-lethality was observed at a maternally toxic dose of 200 mg per kg per day (approximately 32 times the MRHD as mg per m 2 ), and pup mortality and delays in physical growth/development were observed at 60 mg per kg per day (10 times the MRHD as mg per m 2 ) in the absence of maternal toxicity.

The no-effect level was 12 mg per kg per day (2 times the MRHD as mg per m 2 ).

Carvedilol was present in fetal rat tissue.

There are no data on the presence of carvedilol in human milk, the effects on the breastfed infant, or the effects on milk production.

Carvedilol is present in the milk of lactating rats.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for carvedilol and any potential adverse effects on the breastfed infant from carvedilol or from the underlying maternal condition.

Effectiveness of carvedilol tablets in patients younger than 18 years has not been established.

In a double-blind trial, 161 children (mean age: 6 years; range: 2 months to 17 years; 45% younger than 2 years) with chronic heart failure [NYHA class II-IV, left ventricular ejection fraction less than 40% for children with a systemic left ventricle (LV), and moderate-severe ventricular dysfunction qualitatively by echo for those with a systemic ventricle that was not an LV] who were receiving standard background treatment were randomized to placebo or to 2 dose levels of carvedilol.

These dose levels produced placebo-corrected heart rate reduction of to 6 heart beats per minute, indicative of β-blockade activity.

Exposure appeared to be lower in pediatric subjects than adults.

After 8 months of follow-up, there was no significant effect of treatment on clinical outcomes.

Adverse reactions in this trial that occurred in greater than 10% of subjects treated with carvedilol and at twice the rate of placebo-treated subjects included chest pain (17% versus 6%), dizziness (13% versus 2%), and dyspnea (11% versus 0%).

Of the 765 subjects with heart failure randomized to carvedilol in US clinical trials, 31% were aged 65 years or older, and 7.3% were aged 75 years or older.

Of the 1,156 subjects randomized to carvedilol in a long-term, placebo-controlled trial in severe heart failure, 47% were aged 65 years or older, and 15% were aged 75 years or older.

Of 3,025 subjects receiving carvedilol in heart failure trials worldwide, 42% were aged 65 years or older.

Of the 975 subjects with myocardial infarction randomized to carvedilol tablets in the CAPRICORN trial, 48% were aged 65 years or older, and 11% were aged 75 years or older.

Of the 2,065 hypertensive subjects in US clinical trials of efficacy or safety who were treated with carvedilol tablets, 21% were aged 65 years or older.

Of 3,722 subjects receiving carvedilol tablets in hypertension clinical trials conducted worldwide, 24% were aged 65 years or older.

With the exception of dizziness in hypertensive subjects (incidence 8.8% in the elderly versus 6% in younger subjects), no overall differences in the safety or effectiveness were observed between the older subjects and younger subjects in each of these populations.

Similarly, other reported clinical experience has not identified differences in responses between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.