Carvedilol Phosphate

1 INDICATIONS AND USAGE Carvedilol phosphate extended-release capsules are an alpha-/beta-adrenergic blocking agent indicated for the treatment of: mild to severe chronic heart failure. ( 1.1 ) left ventricular dysfunction following myocardial infarction in clinically stable patients. ( 1.2 ) hypertension. ( 1.3 ) 1.1 Heart Failure Carvedilol phosphate extended-release capsules are indicated for the treatment of mild-to-severe chronic heart failure of ischemic or cardiomyopathic origin, usually in addition to diuretics, ACE inhibitors, and digitalis, to increase survival and, also, to reduce the risk of hospitalization [see Drug Interactions (7.4) , Clinical Studies (14.1) ]. 1.2 Left Ventricular Dysfunction following Myocardial Infarction Carvedilol phosphate extended-release capsules are indicated to reduce cardiovascular mortality in clinically stable patients who have survived the acute phase of a myocardial infarction and have a left ventricular ejection fraction of less than or equal to 40% (with or without symptomatic heart failure) [see Clinical Studies (14.2) ]. 1.3 Hypertension Carvedilol phosphate extended-release capsules are indicated for the management of essential hypertension [see Clinical Studies (14.3 , 14.4) ] . They can be used alone or in combination with other antihypertensive agents, especially thiazide-type diuretics [see Drug Interactions (7.2) ] .

2 DOSAGE AND ADMINISTRATION Carvedilol phosphate extended-release capsules are intended for once-daily administration. Patients controlled with immediate-release carvedilol tablets alone or in combination with other medications may be switched to carvedilol phosphate extended-release capsules based on the total daily doses shown in Table 1. Table 1. Dosing Conversion Daily Dose of Immediate-Release Carvedilol Tablets Daily Dose of Carvedilol Phosphate Extended-Release Capsules* 6.25 mg (3.125 mg twice daily) 10 mg once daily 12.5 mg (6.25 mg twice daily) 20 mg once daily 25 mg (12.5 mg twice daily) 40 mg once daily 50 mg (25 mg twice daily) 80 mg once daily * When switching from carvedilol 12.5 mg or 25 mg twice daily, a starting dose of carvedilol phosphate extended-release capsules 20 mg or 40 mg once daily, respectively, may be warranted for elderly patients or those at increased risk of hypotension, dizziness, or syncope. Subsequent titration to higher doses should, as appropriate, be made after an interval of at least 2 weeks. Carvedilol phosphate extended-release capsules should be taken once daily in the morning with food. Carvedilol phosphate extended-release capsules should be swallowed as a whole capsule. Carvedilol phosphate extended-release capsules and/or its contents should not be crushed, chewed, or taken in divided doses. Alternative Administration The capsules may be carefully opened and the beads sprinkled over a spoonful of applesauce. The applesauce should not be warm because it could affect the modified-release properties of this formulation. The mixture of drug and applesauce should be consumed immediately in its entirety. The drug and applesauce mixture should not be stored for future use. Absorption of the beads sprinkled on other foods has not been tested. Take with food. Do not crush or chew capsules. Individualize dosage and monitor during up-titration. ( 2 ) Heart failure: Start at 10 mg once daily and increase to 20 mg, 40 mg, and then 80 mg once daily over intervals of at least 2 weeks. Maintain lower doses if higher doses are not tolerated. ( 2.1 ) Left ventricular dysfunction following myocardial infarction: Start at 20 mg once daily and increase to 40 mg then 80 mg once daily after intervals of 3 to 10 days. A lower starting dose or slower titration may be used. ( 2.2 ) Hypertension: Start at 20 mg once daily and increase if needed for blood pressure control to 40 mg then 80 mg once daily over intervals of 1 to 2 weeks. ( 2.3 ) Elderly patients (greater than 65 years of age): When switching from higher doses of immediate-release carvedilol to carvedilol phosphate extended-release capsules, a lower starting dose should be considered to reduce the risk of hypotension and syncope. ( 2.5 ) 2.1 Heart Failure DOSAGE MUST BE INDIVIDUALIZED AND CLOSELY MONITORED BY A PHYSICIAN DURING UP-TITRATION. Prior to initiation of carvedilol phosphate extended-release capsules, it is recommended that fluid retention be minimized. The recommended starting dose of carvedilol phosphate extended-release capsule is 10 mg once daily for 2 weeks. Patients who tolerate a dose of 10 mg once daily may have their dose increased to 20 mg, 40 mg, and 80 mg over successive intervals of at least 2 weeks. Patients should be maintained on lower doses if higher doses are not tolerated. 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. Thus, during these periods, they 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 phosphate extended-release capsules from that of the ACE inhibitor or to reduce temporarily the dose of the ACE inhibitor. The dose of carvedilol phosphate extended-release cap …

3 DOSAGE FORMS AND STRENGTHS The hard gelatin capsules are filled with white to off-white spherical particles and are available in the following strengths: 10 mg – capsules with white opaque body imprinted with “H31” in black ink and dark green opaque cap. 20 mg – capsules with white opaque body imprinted with “H32” in black ink and bright orange opaque cap. 40 mg – capsules with bright orange opaque body imprinted with “H33” in black ink and dark green opaque cap. 80 mg – capsules with white opaque body imprinted with “H34” in black ink and white opaque cap. Capsules: 10 mg, 20 mg, 40 mg, 80 mg. ( 3 )

4 CONTRAINDICATIONS Carvedilol phosphate extended-release capsules are contraindicated in the following conditions: Bronchial asthma or related bronchospastic conditions. Deaths from status asthmaticus have been reported following single doses of immediate-release carvedilol. Second- or third-degree AV block. Sick sinus syndrome. 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 phosphate extended-release capsules. Patients with severe hepatic impairment. Patients with a history of a serious hypersensitivity reaction (e.g., Stevens-Johnson syndrome, anaphylactic reaction, angioedema) to carvedilol or any of the components of carvedilol phosphate extended-release capsules. Bronchial asthma or related bronchospastic conditions. ( 4 ) Second- or third-degree AV block. ( 4 ) Sick sinus syndrome. ( 4 ) Severe bradycardia (unless permanent pacemaker in place). ( 4 ) Patients in cardiogenic shock or decompensated heart failure requiring the use of IV inotropic therapy. ( 4 ) Severe hepatic impairment. ( 2.4 , 4 ) History of serious hypersensitivity reaction (e.g., Stevens-Johnson syndrome, anaphylactic reaction, angioedema) to carvedilol or any of the components of carvedilol phosphate extended-release capsules. ( 4 )

6 ADVERSE REACTIONS The safety profile of carvedilol phosphate extended-release capsules was similar to that observed for immediate-release carvedilol. Most common adverse events seen with immediate-release carvedilol ( 6.1 ): Heart failure and left ventricular dysfunction following myocardial infarction (≥10%): Dizziness, fatigue, hypotension, diarrhea, hyperglycemia, asthenia, bradycardia, weight increase. Hypertension (≥5%): Dizziness. To report SUSPECTED ADVERSE REACTIONS, contact Northstar Rx LLC at 1-800-206-7821 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Carvedilol has been evaluated for safety in subjects with heart failure (mild, moderate, and severe), in subjects with left ventricular dysfunction following myocardial infarction, and in hypertensive subjects. The observed adverse event profile was consistent with the pharmacology of the drug and the health status of the subjects in the clinical trials. Adverse events reported for each of these populations reflecting the use of either carvedilol phosphate extended-release capsules or immediate-release carvedilol tablets are provided below. Excluded are adverse events considered too general to be informative, and those not reasonably associated with the use of the drug because they were associated with the condition being treated or are very common in the treated population. Rates of adverse events were generally similar across demographic subsets (men and women, elderly and non-elderly, blacks and non-blacks). Carvedilol phosphate extended-release capsules has been evaluated for safety in a 4-week (2 weeks of immediate­ release carvedilol tablets and 2 weeks of carvedilol phosphate extended-release capsules) clinical trial (n = 187) which included 157 subjects with stable mild, moderate, or severe chronic heart failure and 30 subjects with left ventricular dysfunction following acute myocardial infarction. The profile of adverse events observed with carvedilol phosphate extended-release capsules in this small, short-term trial was generally similar to that observed with immediate-release carvedilol tablets. Differences in safety would not be expected based on the similarity in plasma levels for carvedilol phosphate extended-release capsules and immediate-release carvedilol. Heart Failure The following information describes the safety experience in heart failure with immediate-release carvedilol. Carvedilol has been evaluated for safety in heart failure in more than 4,500 subjects worldwide of whom more than 2,100 participated in placebo-controlled clinical trials. Approximately 60% of the total treated population in placebo-controlled clinical trials received carvedilol for at least 6 months and 30% received carvedilol for at least 12 months. In the COMET trial, 1,511 subjects with mild-to-moderate heart failure were treated with carvedilol for up to 5.9 years (mean 4.8 years). Both in U.S. clinical trials in mild-to-moderate heart failure that compared carvedilol in daily doses up to 100 mg (n = 765) with placebo (n = 437), and in a multinational clinical trial in severe heart failure (COPERNICUS) that compared carvedilol in daily doses up to 50 mg (n = 1,156) with placebo (n = 1,133), discontinuation rates for adverse experiences were similar in carvedilol and placebo subjects. In placebo-controlled clinical trials, the only cause of discontinuation greater than 1% and occurring more often on carvedilol was dizziness (1.3% on carvedilol, 0.6% on placebo in the COPERNICUS trial). Table 2 shows adverse events reported in subjects with mild-to-moderate heart failure enrolled in U.S. placebo-controlled clinical trials, and with severe heart failure enrolled in the COPERNIC …

7 DRUG INTERACTIONS CYP P450 2D6 enzyme inhibitors may increase and rifampin may decrease carvedilol levels. ( 7.1 , 7.5 ) Hypotensive agents (e.g., reserpine, MAO inhibitors, clonidine) may increase the risk of hypotension and/or severe bradycardia. ( 7.2 ) Cyclosporine or digoxin levels may increase. ( 7.3 , 7.4 ) Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. ( 7.4 ) Amiodarone may increase carvedilol levels resulting in further slowing of the heart rate or cardiac conduction. ( 7.6 ) Verapamil- or diltiazem-type calcium channel blockers may affect ECG and/or blood pressure. ( 7.7 ) Insulin and oral hypoglycemics action may be enhanced. ( 7.8 ) 7.1 CYP2D6 Inhibitors and Poor Metabolizers Interactions of carvedilol with potent inhibitors of CYP2D6 isoenzyme (such as quinidine, fluoxetine, paroxetine, and propafenone) have not been studied, but these drugs would be expected to increase blood levels of the R(+) enantiomer of carvedilol [see Clinical Pharmacology (12.3) ] . Retrospective analysis of side effects in clinical trials showed that poor 2D6 metabolizers had a higher rate of dizziness during up-titration, presumably resulting from vasodilating effects of the higher concentrations of the alpha-blocking R(+) enantiomer. 7.2 Hypotensive Agents Patients taking a beta-blocker and a drug that can deplete catecholamines (e.g., reserpine and monoamine oxidase inhibitors) should be observed closely for signs of hypotension and/or severe bradycardia. Concomitant administration of clonidine with a beta-blocker may cause hypotension and bradycardia. When concomitant treatment with a beta-blocker and clonidine is to be terminated, the beta-blocker should be discontinued first. Clonidine therapy can then be discontinued several days later by gradually decreasing the dosage. 7.3 Cyclosporine Modest increases in mean trough cyclosporine concentrations were observed following initiation of carvedilol treatment in 21 renal transplant subjects suffering from chronic vascular rejection. In about 30% of subjects, the dose of cyclosporine had to be reduced in order to maintain cyclosporine concentrations within the therapeutic range, while in the remainder no adjustment was needed. On the average for the group, the dose of cyclosporine was reduced about 20% in these subjects. Due to wide interindividual variability in the dose adjustment required, it is recommended that cyclosporine concentrations be monitored closely after initiation of carvedilol therapy and that the dose of cyclosporine be adjusted as appropriate. 7.4 Digitalis Glycosides Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia . Digoxin concentrations are increased by about 15% when digoxin and carvedilol are administered concomitantly. Therefore, increased monitoring of digoxin is recommended when initiating, adjusting, or discontinuing carvedilol phosphate extended-release capsules [see Clinical Pharmacology (12.5) ] . 7.5 Inducers/Inhibitors of Hepatic Metabolism Rifampin reduced plasma concentrations of carvedilol by about 70% [see Clinical Pharmacology (12.5) ] . Cimetidine increased area under the curve (AUC) by about 30% but caused no change in C max [see Clinical Pharmacology (12.5) ] . 7.6 Amiodarone Amiodarone and its metabolite desethyl amiodarone, inhibitors of CYP2C9, and P-glycoprotein increased concentrations of the S(-) enantiomer of carvedilol by at least 2-fold [see Clinical Pharmacology (12.5) ] . The concomitant administration of amiodarone or other CYP2C9 inhibitors such as fluconazole with carvedilol phosphate extended-release capsules may enhance the beta-blocking activity, resulting in further slowing of the heart rate or cardiac conduction. Patients should be observed for signs of bradycardia or heart block, particularly when one agent is ad …

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data regarding use of carvedilol phosphate extended-release capsules 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 (see Clinical Considerations ) . In animal reproduction studies, there was no evidence of adverse developmental outcomes at clinically relevant doses (see Data ) . 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 (see Data ). 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. Clinical Considerations Disease-Associated 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. Data Animal Data: 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. 8.2 Lactation Risk Summary 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 …

12.1 Mechanism of Action Carvedilol is a racemic mixture in which nonselective beta-adrenoreceptor blocking activity is present in the S(–) enantiomer and alpha 1 -adrenergic blocking activity is present in both R(+) and S(–) enantiomers at equal potency. Carvedilol has no intrinsic sympathomimetic activity.

11 DESCRIPTION Carvedilol phosphate is a nonselective beta-adrenergic blocking agent with alpha 1 -blocking activity. It is (2 RS )-1-(9 H -Carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]amino]propan-2-ol phosphate salt (1:1) hemiethanolate. It is a racemic mixture with the following structure: Carvedilol phosphate is a white to almost-white solid with a molecular weight of 527.47 (406.5 carvedilol free base) and a molecular formula of C 24 H 26 N 2 O 4 •H 3 PO 4 •1/2 EtOH. Carvedilol phosphate extended-release capsules are available for once-a-day administration as controlled-release oral capsules containing 10 mg, 20 mg, 40 mg, or 80 mg carvedilol phosphate. Carvedilol phosphate extended-release hard gelatin capsules are filled with carvedilol phosphate controlled-release microparticles that are drug-layered and then coated with methacrylic acid copolymers. Inactive ingredients include corn starch, crospovidone, hydrogenated cottonseed oil, hydroxypropyl cellulose, magnesium stearate, methacrylic acid copolymer type C, polyvinyl alcohol, povidone, silicon dioxide, soybean lecithin, sucrose, talc, titanium dioxide, triethyl citrate and xanthan gum. The 10 mg capsule shells contain D&C Yellow No. 10, FD&C Green No. 3, gelatin and titanium dioxide. The 20 mg capsule shells contain D&C Red No. 28, D&C Yellow No. 10, FD&C Red No. 40, gelatin and titanium dioxide. The 40 mg capsule shells contain D&C Red No. 28, D&C Yellow No. 10, FD&C Green No. 3, FD&C Red No. 40, gelatin and titanium dioxide. The 80 mg capsule shells contain gelatin and titanium dioxide. Additionally, the capsule imprint ink contains FD&C Blue No. 1, FD&C Blue No. 2, D&C Yellow No. 10, FD&C Red No. 40, iron oxide black and shellac. Chemical Structure

10 OVERDOSAGE Overdosage may cause severe hypotension, bradycardia, cardiac insufficiency, cardiogenic shock, and cardiac arrest. Respiratory problems, bronchospasms, vomiting, lapses of consciousness, and generalized seizures may also occur. The patient should be placed in a supine position and, where necessary, kept under observation and treated under intensive-care conditions. The following agents may be administered: For excessive bradycardia: Atropine, 2 mg IV. To support cardiovascular function: Glucagon, 5 to 10 mg IV rapidly over 30 seconds, followed by a continuous infusion of 5 mg per hour; sympathomimetics (dobutamine, isoprenaline, adrenaline) at doses according to body weight and effect. If peripheral vasodilation dominates, it may be necessary to administer adrenaline or noradrenaline with continuous monitoring of circulatory conditions. For therapy-resistant bradycardia, pacemaker therapy should be performed. For bronchospasm, beta-sympathomimetics (as aerosol or IV) or aminophylline IV should be given. In the event of seizures, slow IV injection of diazepam or clonazepam is recommended. NOTE: In the event of severe intoxication where there are symptoms of shock, treatment with antidotes must be continued for a sufficiently long period of time consistent with the 7- to 10-hour half-life of carvedilol. There is no experience of overdosage with carvedilol phosphate extended-release capsules. Cases of overdosage with carvedilol alone or in combination with other drugs have been reported. Quantities ingested in some cases exceeded 1,000 milligrams. Symptoms experienced included low blood pressure and heart rate. Standard supportive treatment was provided and individuals recovered.

16 HOW SUPPLIED/STORAGE AND HANDLING The hard gelatin extended-release capsules are available in the following strengths: 10 mg – capsules with white opaque body imprinted with “H31” in black ink and dark green opaque cap. Bottles of 30: NDC 69238-2577-3 Bottles of 90: NDC 69238-2577-9 Bottles of 100: NDC 69238-2577-1 Bottles of 1,000: NDC 69238-2577-2 20 mg – capsules with white opaque body imprinted with “H32” in black ink and bright orange opaque cap. Bottles of 30: NDC 69238-2578-3 Bottles of 90: NDC 69238-2578-9 Bottles of 100: NDC 69238-2578-1 Bottles of 1,000: NDC 69238-2578-2 40 mg – capsules with bright orange opaque body imprinted with “H33” in black ink and dark green opaque cap. Bottles of 30: NDC 69238-2579-3 Bottles of 90: NDC 69238-2579-9 Bottles of 100: NDC 69238-2579-1 Bottles of 1,000: NDC 69238-2579-2 80 mg – capsules with white opaque body imprinted with “H34” in black ink and white opaque cap. Bottles of 30: NDC 69238-2580-3 Bottles of 90: NDC 69238-2580-9 Bottles of 100: NDC 69238-2580-1 Bottles of 1,000: NDC 69238-2580-2 Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. DISPENSE IN A TIGHTLY CLOSED, LIGHT-RESISTANT CONTAINER AS DEFINED IN THE USP, WITH A CHILD-RESISTANT CLOSURE, AS REQUIRED. KEEP OUT OF THE REACH OF CHILDREN.