DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS AND STRENGTHS The hard gelatin capsules are filled with white to off-white microparticles and are available in the following strengths: 10mg white and green capsule shell printed with GSK COREGCR and 10mg 20mg white and yellow capsule shell printed with GSK COREGCR and 20mg 40mg yellow and green capsule shell printed with GSK COREGCR and 40mg 80mg white capsule shell printed with GSK COREGCR and 80mg Capsules: 10 mg, 20 mg, 40 mg, 80mg (3)

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PRINICIPAL DISPLAY PANEL NDC 0007-3388-13 COREG CR (carvedilol phosphate) Extended-release Capsules 80 mg ONCE-A-DAY DOSING 30 Capsules Rx only www.CoregCR.com Call 1-888-825-5249 Each extended-release capsule contains 80 mg of carvedilol phosphate. Store at 25oC (77oF) [see USP]. Do not accept if membrane seal under cap is missing or broken. Dosage: See prescribing information for complete dosing information. This extended-release capsule formulation differs in strength from COREG tablets. Keep this and all drugs out of the reach of children. In case of accidental overdose, seek professional help or contact a poison control center immediately. GlaxoSmithKline, RTP, NC 27709 Made in Canada 2019 GSK group of companies or its licensor. Rev. 8/19 62000000042458

ADVERSE REACTIONS SECTION.


6 ADVERSE REACTIONS The safety profile of COREG CR 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 GlaxoSmithKline at 1-888-825-5249 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 COREGCR or immediate-release carvedilol 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 nonelderly, blacks and nonblacks). COREGCR has been evaluated for safety in a 4-week (2 weeks of immediate-release carvedilol and 2 weeks of COREGCR) 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 COREGCR in this small, short-term trial was generally similar to that observed with immediate-release carvedilol. Differences in safety would not be expected based on the similarity in plasma levels for COREGCR 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 placebocontrolled clinical trials. Approximately 60% of the total treated population in placebocontrolled clinical trials received carvedilol for at least 6months and 30% received carvedilol for at least 12months. In the COMET trial, 1,511 subjects with mildtomoderate heart failure were treated with carvedilol for up to 5.9 years (mean: 4.8 years). Both in U.S. clinical trials in mildtomoderate heart failure that compared carvedilol in daily doses up to 100mg (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 50mg (n=1,156) with placebo (n=1,133), discontinuation rates for adverse experiences were similar in carvedilol and placebo subjects. In placebocontrolled 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 mildtomoderate heart failure enrolled in U.S. placebocontrolled clinical trials, and with severe heart failure enrolled in the COPERNICUS trial. Shown are adverse events that occurred more frequently in drugtreated subjects than placebotreated subjects with an incidence of greater than 3% in subjects treated with carvedilol regardless of causality. Median trial medication exposure was 6.3 months for both carvedilol and placebo subjects in the trials of mildtomoderate heart failure and 10.4 months in the trial of subjects with severe heart failure. The adverse event profile of carvedilol observed in the long-term COMET trial was generally similar to that observed in the U.S. Heart Failure Trials. Body System/ Adverse Event Table 2. Adverse Events (%) Occurring More Frequently with Immediate-Release Carvedilol than with Placebo in Subjects with MildtoModerate Heart Failure (HF) Enrolled in U.S. Heart Failure Trials or in Subjects with Severe Heart Failure in the COPERNICUS Trial (Incidence >3% in Subjects Treated with Carvedilol, Regardless of Causality) Mild-to-Moderate HF Severe HF Carvedilol Placebo Carvedilol Placebo (n=765) (n=437) (n=1,156) (n=1,133) Body as a Whole Asthenia 7 7 11 9 Fatigue 24 22 Digoxin level increased 5 4 2 1 Edema generalized 5 3 6 5 Edema dependent 4 2 Cardiovascular Bradycardia 9 1 10 3 Hypotension 9 3 14 8 Syncope 3 3 8 5 Angina pectoris 2 3 6 4 Central Nervous System Dizziness 32 19 24 17 Headache 8 7 5 3 Gastrointestinal Diarrhea 12 6 5 3 Nausea 9 5 4 3 Vomiting 6 4 1 2 Metabolic Hyperglycemia 12 8 5 3 Weight increase 10 7 12 11 BUN increased 6 5 NPN increased 6 5 Hypercholesterolemia 4 3 1 1 Edema peripheral 2 1 7 6 Musculoskeletal Arthralgia 6 5 1 1 Respiratory Cough increased 8 9 5 4 Rales 4 4 4 2 Vision Vision abnormal 5 2 Cardiac failure and dyspnea were also reported in these trials, but the rates were equal or greater in subjects who received placebo. The following adverse events were reported with a frequency of greater than 1% but less than or equal to 3% and more frequently with carvedilol in either the U.S. placebo-controlled trials in subjects with mild-to-moderate heart failure or in subjects with severe heart failure in the COPERNICUS trial. Incidence greater than 1% to less than or equal to 3% Body as a Whole: Allergy, malaise, hypovolemia, fever, leg edema. Cardiovascular: Fluid overload, postural hypotension, aggravated angina pectoris, AV block, palpitation, hypertension. Central and Peripheral Nervous System: Hypesthesia, vertigo, paresthesia. Gastrointestinal: Melena, periodontitis. Liver and Biliary System: SGPT increased, SGOT increased. Metabolic and Nutritional: Hyperuricemia, hypoglycemia, hyponatremia, increased alkaline phosphatase, glycosuria, hypervolemia, diabetes mellitus, GGT increased, weight loss, hyperkalemia, creatinine increased. Musculoskeletal: Muscle cramps. Platelet, Bleeding, and Clotting: Prothrombin decreased, purpura, thrombocytopenia. Psychiatric: Somnolence. Reproductive, male: Impotence. Special Senses: Blurred vision. Urinary System: Renal insufficiency, albuminuria, hematuria. Left Ventricular Dysfunction following Myocardial Infarction The following information describes the safety experience in left ventricular dysfunction following acute myocardial infarction with immediate-release carvedilol. Carvedilol has been evaluated for safety in survivors of an acute myocardial infarction with left ventricular dysfunction in the CAPRICORN trial which involved 969 subjects who received carvedilol and 980 who received placebo. Approximately 75% of the subjects received carvedilol for at least 6months and 53% received carvedilol for at least 12months. Subjects were treated for an average of 12.9 months and 12.8 months with carvedilol and placebo, respectively. The most common adverse events reported with carvedilol in the CAPRICORN trial were consistent with the profile of the drug in the U.S. heart failure trials and the COPERNICUS trial. The only additional adverse events reported in CAPRICORN in greater than 3% of the subjects and more commonly on carvedilol were dyspnea, anemia, and lung edema. The following adverse events were reported with a frequency of greater than 1% but less than or equal to 3% and more frequently with carvedilol: flu syndrome, cerebrovascular accident, peripheral vascular disorder, hypotonia, depression, gastrointestinal pain, arthritis, and gout. The overall rates of discontinuations due to adverse events were similar in both groups of subjects. In this database, the only cause of discontinuation greater than 1% and occurring more often on carvedilol was hypotension (1.5% on carvedilol, 0.2% on placebo). Hypertension COREGCR was evaluated for safety in an 8-week double-blind trial in 337 subjects with essential hypertension. The profile of adverse events observed with COREGCR was generally similar to that observed with immediate-release carvedilol. The overall rates of discontinuations due to adverse events were similar between COREGCR and placebo. Table 3. Adverse Events (%) Occurring More Frequently with COREG CR than with Placebo in Subjects with Hypertension (Incidence 1% in Subjects Treated with Carvedilol, Regardless of Causality) Adverse Event COREGCR (n=253) Placebo (n=84) Nasopharyngitis 4 0 Dizziness 2 1 Nausea 2 0 Edema peripheral 2 1 Nasal congestion 1 0 Paresthesia 1 0 Sinus congestion 1 0 Diarrhea 1 0 Insomnia 1 0 The following information describes the safety experience in hypertension with immediate-release carvedilol. Carvedilol has been evaluated for safety in hypertension in more than 2,193 subjects in U.S. clinical trials and in 2,976 subjects in international clinical trials. Approximately 36% of the total treated population received carvedilol for at least 6months. In general, carvedilol was well tolerated at doses up to 50mg daily. Most adverse events reported during carvedilol therapy were of mild to moderate severity. In U.S. controlled clinical trials directly comparing carvedilol monotherapy in doses up to 50mg (n=1,142) with placebo (n=462), 4.9% of carvedilol subjects discontinued for adverse events versus 5.2% of placebo subjects. Although there was no overall difference in discontinuation rates, discontinuations were more common in the carvedilol group for postural hypotension (1% versus 0). The overall incidence of adverse events in U.S. placebocontrolled trials was found to increase with increasing dose of carvedilol. For individual adverse events this could only be distinguished for dizziness, which increased in frequency from 2% to 5% as total daily dose increased from 6.25mg to 50mg as single or divided doses. Table 4 shows adverse events in U.S. placebocontrolled clinical trials for hypertension that occurred with an incidence of greater than or equal to 1% regardless of causality and that were more frequent in drugtreated subjects than placebotreated subjects. Adverse Event Table 4. Adverse Events (% Occurrence) in U.S. Placebo-Controlled Hypertension Trials with Immediate-Release Carvedilol (Incidence 1% in Subjects Treated with Carvedilol, Regardless of Causality)a Carvedilol (n=1,142) Placebo (n=462) Cardiovascular Bradycardia 2 Postural hypotension 2 Peripheral edema 1 Central Nervous System Dizziness 6 5 Insomnia 2 1 Gastrointestinal Diarrhea 2 1 Hematologic Thrombocytopenia 1 Metabolic Hypertriglyceridemia 1 aShown are events with rate >1% rounded to nearest integer. Dyspnea and fatigue were also reported in these trials, but the rates were equal or greater in subjects who received placebo. The following adverse events not described above were reported as possibly or probably related to carvedilol in worldwide open or controlled trials with carvedilol in subjects with hypertension or heart failure. Incidence greater than 0.1% to less than or equal to 1% Cardiovascular: Peripheral ischemia, tachycardia. Central and Peripheral Nervous System: Hypokinesia. Gastrointestinal: Bilirubinemia, increased hepatic enzymes (0.2% of hypertension patients and 0.4% of heart failure patients were discontinued from therapy because of increases in hepatic enzymes) [see Adverse Reactions (6.2)]. Psychiatric: Nervousness, sleep disorder, aggravated depression, impaired concentration, abnormal thinking, paroniria, emotional lability. Respiratory System: Asthma [see Contraindications (4)]. Reproductive, male: Decreased libido. Skin and Appendages: Pruritus, rash erythematous, rash maculopapular, rash psoriaform, photosensitivity reaction. Special Senses: Tinnitus. Urinary System: Micturition frequency increased. Autonomic Nervous System: Dry mouth, sweating increased. Metabolic and Nutritional: Hypokalemia, hypertriglyceridemia. Hematologic: Anemia, leukopenia. The following events were reported in less than or equal to 0.1% of subjects and are potentially important: complete AV block, bundle branch block, myocardial ischemia, cerebrovascular disorder, convulsions, migraine, neuralgia, paresis, anaphylactoid reaction, alopecia, exfoliative dermatitis, amnesia, GI hemorrhage, bronchospasm, pulmonary edema, decreased hearing, respiratory alkalosis, increased BUN, decreased HDL, pancytopenia, and atypical lymphocytes. Laboratory Abnormalities Reversible elevations in serum transaminases (ALT or AST) have been observed during treatment with carvedilol. Rates of transaminase elevations (2 to 3 times the upper limit of normal) observed during controlled clinical trials have generally been similar between subjects treated with carvedilol and those treated with placebo. However, transaminase elevations, confirmed by rechallenge, have been observed with carvedilol. In a long-term, placebo-controlled trial in severe heart failure, subjects treated with carvedilol had lower values for hepatic transaminases than subjects treated with placebo, possibly because carvedilol-induced improvements in cardiac function led to less hepatic congestion and/or improved hepatic blood flow. Carvedilol therapy has not been associated with clinically significant changes in serum potassium, total triglycerides, total cholesterol, HDL cholesterol, uric acid, blood urea nitrogen, or creatinine. No clinically relevant changes were noted in fasting serum glucose in hypertensive subjects; fasting serum glucose was not evaluated in the heart failure clinical trials. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of COREG or COREG CR. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders Aplastic anemia. Immune System Disorders Hypersensitivity (e.g., anaphylactic reactions, angioedema, urticaria). Renal and Urinary Disorders Urinary incontinence. Respiratory, Thoracic, and Mediastinal Disorders Interstitial pneumonitis. Skin and Subcutaneous Tissue Disorders Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme.

INDICATIONS & USAGE SECTION.


1 INDICATIONS AND USAGE COREGCR is 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 COREGCR is 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 COREGCR is 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 COREGCR is indicated for the management of essential hypertension [see Clinical Studies (14.3, 14.4)]. It can be used alone or in combination with other antihypertensive agents, especially thiazidetype diuretics [see Drug Interactions (7.2)].

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION COREGCR is an extended-release capsule intended for oncedaily administration. Patients controlled with immediaterelease carvedilol tablets alone or in combination with other medications may be switched to COREGCR extendedrelease 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 COREGCR Capsulesa 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 a When switching from carvedilol 12.5 mg or 25 mg twice daily, a starting dose of COREG CR 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. COREGCR should be taken once daily in the morning with food. COREGCR should be swallowed as a whole capsule. COREGCR 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 10mg once daily and increase to 20, 40, and then 80mg 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 20mg once daily and increase to 40 mg then 80 mg once daily after intervals of 3 to 10days. A lower starting dose or slower titration may be used. (2.2) Hypertension: Start at 20mg once daily and increase if needed for blood pressure control to 40mg then 80mg once daily over intervals of 1to2 weeks. (2.3) Elderly patients (>65 years of age): When switching from higher doses of immediate-release carvedilol to COREG CR, 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 UPTITRATION. Prior to initiation of COREGCR, it is recommended that fluid retention be minimized. The recommended starting dose of COREGCR is 10mg once daily for 2 weeks. Patients who tolerate a dose of 10mg once daily may have their dose increased to 20, 40, and 80mg 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 COREGCR from that of the ACE inhibitor or to reduce temporarily the dose of the ACE inhibitor. The dose of COREGCR 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. The dose of COREGCR should be reduced if patients experience bradycardia (heart rate less than 55beats per minute). Episodes of dizziness or fluid retention during initiation of COREGCR can generally be managed without discontinuation of treatment and do not preclude subsequent successful titration of, or a favorable response to, COREGCR. 2.2 Left Ventricular Dysfunction following Myocardial Infarction DOSAGE MUST BE INDIVIDUALIZED AND MONITORED DURING UPTITRATION. Treatment with COREGCR 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 COREGCR be started at 20mg once daily and increased after 3 to 10days, based on tolerability, to 40mg once daily, then again to the target dose of 80mg once daily. A lower starting dose may be used (10mg once daily) and/or the rate of uptitration may be slowed if clinically indicated (e.g., due to low blood pressure or heart rate, or fluid retention). Patients should be maintained on lower doses if higher doses are not tolerated. The recommended dosing regimen need not be altered in patients who received treatment with an IV or oral blocker during the acute phase of the myocardial infarction. 2.3 Hypertension DOSAGE MUST BE INDIVIDUALIZED. The recommended starting dose of COREGCR is 20mg once daily. If this dose is tolerated, using standing systolic pressure measured about 1hour after dosing as a guide, the dose should be maintained for 7 to 14days, and then increased to 40mg once 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 7 to 14days and can then be adjusted upward to 80mg once daily if tolerated and needed. Although not specifically studied, it is anticipated the full antihypertensive effect of COREGCR would be seen within 7 to 14days as had been demonstrated with immediaterelease carvedilol. Total daily dose should not exceed 80mg. Concomitant administration with a diuretic can be expected to produce additive effects and exaggerate the orthostatic component of carvedilol action. 2.4 Hepatic Impairment COREGCR should not be given to patients with severe hepatic impairment [see Contraindications (4)]. 2.5 Geriatric Use When switching elderly patients (aged 65 years or older) who are taking the higher doses of immediate-release carvedilol tablets (25 mg twice daily) to COREG CR, a lower starting dose (40 mg) of COREG CR is recommended to minimize the potential for dizziness, syncope, or hypotension [see Dosage and Administration (2)]. Patients who have switched and who tolerate COREG CR should, as appropriate, have their dose increased after an interval of at least 2 weeks [see Use in Specific Populations (8.5)].

HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGE AND HANDLING The hard gelatin capsules are available in the following strengths: 10mg white and green capsule shell printed with GSK COREGCR and 10mg 20mg white and yellow capsule shell printed with GSK COREGCR and 20mg 40mg yellow and green capsule shell printed with GSK COREGCR and 40mg 80mg white capsule shell printed with GSK COREGCR and 80mg 10mg bottles of 30: NDC 0007-3370-13 20mg bottles of 30: NDC 0007-3371-13 40mg bottles of 30: NDC 0007-3372-13 80mg bottles of 30: NDC 0007-3373-13 Store at 25C (77F); excursions 15 to 30C (59 to 86F). Dispense in a tight, light-resistant container.

DESCRIPTION SECTION.


11 DESCRIPTION Carvedilol phosphate is a nonselective adrenergic blocking agent with 1-blocking activity. It is (2RS)-1-(9H-Carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]amino]propan-2-ol phosphate salt (1:1) hemihydrate. It is a racemic mixture with the following structure: Carvedilol phosphate is a white-to-almost white solid with a molecular weight of 513.5 (406.5 carvedilol free base) and a molecular formula of C24H26N2O4H3PO41/2 H2O. COREGCR is available for once-a-day administration as controlled-release oral capsules containing 10, 20, 40, or 80mg carvedilol phosphate. COREGCR hard gelatin capsules are filled with carvedilol phosphate immediate-release and controlled-release microparticles that are drug-layered and then coated with methacrylic acid copolymers. Inactive ingredients include crospovidone, hydrogenated castor oil, hydrogenated vegetable oil, magnesium stearate, methacrylic acid copolymers, microcrystalline cellulose, and povidone.

OVERDOSAGE SECTION.


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, 2mg IV. To support cardiovascular function: Glucagon, 5 to 10mg IV rapidly over 30seconds, followed by a continuous infusion of 5mg 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, 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 COREGCR. Cases of overdosage with carvedilol alone or in combination with other drugs have been reported. Quantities ingested in some cases exceeded 1,000milligrams. Symptoms experienced included low blood pressure and heart rate. Standard supportive treatment was provided and individuals recovered.

SPL PATIENT PACKAGE INSERT SECTION.


PATIENT INFORMATION COREGCR (Co-REG) (carvedilol phosphate) Extended-release Capsules Read the Patient Information that comes with COREGCR before you start taking it and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment. If you have any questions about COREGCR, ask your doctor or pharmacist. What is the most important information I should know about COREGCR? It is important for you to take your medicine every day as directed by your doctor. If you stop taking COREGCR suddenly, you could have chest pain and a heart attack. If your doctor decides that you should stop taking COREGCR, your doctor may slowly lower your dose over time before stopping it completely. What is COREGCR? COREGCR is a prescription medicine that belongs to a group of medicines called beta-blockers. COREGCR is used, often with other medicines, for the following conditions: to treat patients with certain types of heart failure to treat patients who had a heart attack that worsened how well the heart pumps to treat patients with high blood pressure (hypertension) COREGCR is not approved for use in children under 18 years of age. Who should not take COREGCR? Do not take COREGCR if you: have severe heart failure and require certain intravenous medicines that help support circulation. have asthma or other breathing problems. have a slow heartbeat or certain conditions that cause your heart to skip a beat (irregular heartbeat). have liver problems. are allergic to any of the ingredients in COREGCR. See What are the ingredients in COREG CR? What should I tell my doctor before taking COREGCR? Tell your doctor about all of your medical conditions, including if you: have asthma or other lung problems (such as bronchitis or emphysema). have problems with blood flow in your feet and legs (peripheral vascular disease). COREGCR can make some of your symptoms worse. have diabetes. have thyroid problems. have a condition called pheochromocytoma. have had severe allergic reactions. are scheduled for surgery and will be given anesthetic agents. are scheduled for cataract surgery and have taken or are currently taking COREG CR. are pregnant or trying to become pregnant. It is not known if COREGCR is safe for your unborn baby. You and your doctor should talk about the best way to control your high blood pressure during pregnancy. are breastfeeding. It is not known if COREGCR passes into your breast milk. Talk with your doctor about the best way to feed your baby if you are taking COREG CR. Tell your doctor about all of the medicines you take including prescription and over-the-counter medicines, vitamins, and herbal supplements. COREGCR and certain other medicines can affect each other and cause serious side effects. COREGCR may affect the way other medicines work. Also, other medicines may affect how well COREGCR works. Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist before you start a new medicine. How should I take COREGCR? Take COREGCR exactly as prescribed. Take COREGCR one time each day with food. It is important that you take COREG CR only one time each day. To lessen possible side effects, your doctor might begin with a low dose and then slowly increase the dose. Swallow COREGCR capsules whole. Do not chew or crush COREG CR capsules. If you have trouble swallowing COREG CR whole: The capsule may be carefully opened and the beads sprinkled over a spoonful of applesauce which should be eaten right away. The applesauce should not be warm. Do not sprinkle beads on foods other than applesauce. Do not stop taking COREGCR and do not change the amount of COREGCR you take without talking to your doctor. If you miss a dose of COREGCR, take your dose as soon as you remember, unless it is time to take your next dose. Take your next dose at the usual time. Do not take 2 doses at the same time. If you take too much COREGCR, call your doctor or poison control center right away. What should I avoid while taking COREGCR? COREGCR can cause you to feel dizzy, tired, or faint. Do not drive a car, use machinery, or do anything that needs you to be alert if you have these symptoms. What are possible side effects of COREGCR? Serious side effects of COREG CR include: chest pain and heart attack if you suddenly stop taking COREG CR. See What is the most important information I should know about COREG CR? slow heart beat. low blood pressure (which may cause dizziness or fainting when you stand up). If these happen, sit or lie down, and tell your doctor right away. worsening heart failure. Tell your doctor right away if you have signs and symptoms that your heart failure may be worse, such as weight gain or increased shortness of breath. changes in your blood sugar. If you have diabetes, tell your doctor if you have any changes in your blood sugar levels. masking (hiding) the symptoms of low blood sugar, especially a fast heartbeat. new or worsening symptoms of peripheral vascular disease. leg pain that happens when you walk, but goes away when you rest no feeling (numbness) in your legs or feet while you are resting cold legs or feet masking the symptoms of hyperthyroidism (overactive thyroid), such as a fast heartbeat. worsening of severe allergic reactions. Medicines to treat a severe allergic reaction may not work as well while you are taking COREG CR. rare but serious allergic reactions (including hives or swelling of the face, lips, tongue, and/or throat that may cause difficulty in breathing or swallowing) have happened in patients who were on COREG or COREG CR. These reactions can be life-threatening. In some cases, these reactions happened in patients who had been on COREG before taking COREG CR. Common side effects of COREGCR include shortness of breath, weight gain, diarrhea, and tiredness. If you wear contact lenses, you may have fewer tears or dry eyes that can become bothersome. Call your doctor if you have any side effects that bother you or dont go away. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store COREGCR? Store COREGCR at less than 86F (30C). Safely throw away COREGCR that is out of date or no longer needed. Keep COREGCR and all medicines out of the reach of children. General information about COREGCR Medicines are sometimes prescribed for conditions other than those described in patient information leaflets. Do not use COREGCR for a condition for which it was not prescribed. Do not give COREGCR to other people, even if they have the same symptoms you have. It may harm them. This leaflet summarizes the most important information about COREGCR. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about COREGCR that is written for healthcare professionals. What are the ingredients in COREGCR? Active ingredient: carvedilol phosphate Inactive ingredients: crospovidone, hydrogenated castor oil, hydrogenated vegetable oil, magnesium stearate, methacrylic acid copolymers, microcrystalline cellulose, and povidone COREGCR capsules come in the following strengths: 10mg, 20mg, 40mg, 80mg. What is high blood pressure (hypertension)? Blood pressure is the force of blood in your blood vessels when your heart beats and when your heart rests. You have high blood pressure when the force is too much. High blood pressure makes the heart work harder to pump blood through the body and causes damage to blood vessels. COREG CR can help your blood vessels relax so your blood pressure is lower. Medicines that lower blood pressure may lower your chance of having a stroke or heart attack. COREGCR and COREG are trademarks owned by or licensed to the GSK group of companies. GlaxoSmithKline Research Triangle Park, NC 27709 2017 the GSK group of companies or its licensor September 2017 CCR:8PIL

WARNINGS AND PRECAUTIONS SECTION.


5 WARNINGS AND PRECAUTIONS In clinical trials of COREGCR in subjects with hypertension (338 subjects) and in subjects with left ventricular dysfunction following a myocardial infarction or heart failure (187subjects), the profile of adverse events observed with carvedilol phosphate was generally similar to that observed with the administration of immediaterelease carvedilol. Therefore, the information included within this section is based on data from controlled clinical trials with COREGCR as well as immediaterelease carvedilol. Acute exacerbation of coronary artery disease upon cessation of therapy: Do not abruptly discontinue. (5.1) Bradycardia, hypotension, worsening heart failure/fluid retention may occur. Reduce the dose as needed. (5.2, 5.3, 5.4) Non-allergic bronchospasm (e.g., chronic bronchitis and emphysema): Avoid blockers. (4) However, if deemed necessary, use with caution and at lowest effective dose. (5.5) Diabetes: Monitor glucose as blockers may mask symptoms of hypoglycemia or worsen hyperglycemia. (5.6) 5.1 Cessation of Therapy Patients with coronary artery disease, who are being treated with COREGCR, should be advised against abrupt discontinuation of therapy. Severe exacerbation of angina and the occurrence of myocardial infarction and ventricular arrhythmias have been reported in patients with angina following the abrupt discontinuation of therapy with blockers. The last 2 complications may occur with or without preceding exacerbation of the angina pectoris. As with other blockers, when discontinuation of COREGCR is planned, the patients should be carefully observed and advised to limit physical activity to a minimum. COREGCR should be discontinued over 1 to 2 weeks whenever possible. If the angina worsens or acute coronary insufficiency develops, it is recommended that COREGCR be promptly reinstituted, at least temporarily. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue therapy with COREGCR abruptly even in patients treated only for hypertension or heart failure. 5.2 Bradycardia In clinical trials with immediaterelease carvedilol, bradycardia was reported in about 2% of hypertensive subjects, 9% of subjects with heart failure, and 6.5% of subjects with myocardial infarction and left ventricular dysfunction. Bradycardia was reported in 0.5% of subjects receiving COREGCR in a trial of subjects with heart failure and subjects with myocardial infarction and left ventricular dysfunction. There were no reports of bradycardia in the clinical trial of COREGCR in hypertension. However, if pulse rate drops below 55 beats per minute, the dosage of COREGCR should be reduced. 5.3 Hypotension In clinical trials of primarily mildtomoderate heart failure with immediaterelease carvedilol, hypotension and postural hypotension occurred in 9.7% and syncope in 3.4% of subjects receiving carvedilol compared with 3.6% and 2.5% of placebo subjects, respectively. The risk for these events was highest during the first 30days of dosing, corresponding to the uptitration period and was a cause for discontinuation of therapy in 0.7% of carvedilol subjects, compared with 0.4% of placebo subjects. In a longterm, placebocontrolled trial in severe heart failure (COPERNICUS), hypotension and postural hypotension occurred in 15.1% and syncope in 2.9% of subjects with heart failure receiving carvedilol compared with 8.7% and 2.3% of placebo subjects, respectively. These events were a cause for discontinuation of therapy in 1.1% of carvedilol subjects, compared with 0.8% of placebo subjects. In a trial comparing subjects with heart failure switched to COREG CR or maintained on immediate-release carvedilol, there was a 2-fold increase in the combined incidence of hypotension, syncope, or dizziness in elderly subjects (older than 65 years) switched from the highest dose of carvedilol (25 mg twice daily) to COREG CR 80 mg once daily [see Dosage and Administration (2), Use in Specific Populations (8.5)]. In the clinical trial of COREGCR in hypertensive subjects, syncope was reported in 0.3% of subjects receiving COREGCR compared with 0% of subjects receiving placebo. There were no reports of postural hypotension in this trial. Postural hypotension occurred in 1.8% and syncope in 0.1% of hypertensive subjects receiving immediaterelease carvedilol, primarily following the initial dose or at the time of dose increase, and was a cause for discontinuation of therapy in 1% of subjects. In the CAPRICORN trial of survivors of an acute myocardial infarction with left ventricular dysfunction, hypotension or postural hypotension occurred in 20.2% of subjects receiving carvedilol compared with 12.6% of placebo subjects. Syncope was reported in 3.9% and 1.9% of subjects, respectively. These events were a cause for discontinuation of therapy in 2.5% of subjects receiving carvedilol, compared with 0.2% of placebo subjects. Starting with a low dose, administration with food, and gradual up-titration should decrease the likelihood of syncope or excessive hypotension [see Dosage and Administration (2.1, 2.2, 2.3)]. During initiation of therapy, the patient should be cautioned to avoid situations such as driving or hazardous tasks, where injury could result should syncope occur. 5.4 Heart Failure/Fluid Retention Worsening heart failure or fluid retention may occur during uptitration of carvedilol. If such symptoms occur, diuretics should be increased and the dose of COREGCR should not be advanced until clinical stability resumes [see Dosage and Administration (2)]. Occasionally it is necessary to lower the dose of COREGCR or temporarily discontinue it. Such episodes do not preclude subsequent successful titration of, or a favorable response to, COREGCR. In a placebocontrolled trial of subjects with severe heart failure, worsening heart failure during the first 3months was reported to a similar degree with immediate-release carvedilol and with placebo. When treatment was maintained beyond 3months, worsening heart failure was reported less frequently in subjects treated with carvedilol than with placebo. Worsening heart failure observed during longterm therapy is more likely to be related to the patients underlying disease than to treatment with carvedilol. 5.5 Non-allergic Bronchospasm Patients with bronchospastic disease (e.g., chronic bronchitis, emphysema) should, in general, not receive blockers. COREGCR may be used with caution, however, in patients who do not respond to, or cannot tolerate, other antihypertensive agents. It is prudent, if COREGCR is used, to use the smallest effective dose, so that inhibition of endogenous or exogenous agonists is minimized. In clinical trials of subjects with heart failure, subjects with bronchospastic disease were enrolled if they did not require oral or inhaled medication to treat their bronchospastic disease. In such patients, it is recommended that COREGCR be used with caution. The dosing recommendations should be followed closely and the dose should be lowered if any evidence of bronchospasm is observed during uptitration. 5.6 Glycemic Control in Type 2 Diabetes In general, blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective blockers may potentiate insulininduced hypoglycemia and delay recovery of serum glucose levels. Patients subject to spontaneous hypoglycemia or diabetic patients receiving insulin or oral hypoglycemic agents should be cautioned about these possibilities. In patients with heart failure and diabetes, carvedilol therapy may lead to worsening hyperglycemia, which responds to intensification of hypoglycemic therapy. It is recommended that blood glucose be monitored when dosing with COREGCR is initiated, adjusted, or discontinued. Trials designed to examine the effects of carvedilol on glycemic control in patients with diabetes and heart failure have not been conducted. In a trial designed to examine the effects of immediaterelease carvedilol on glycemic control in a population with mildtomoderate hypertension and well-controlled type 2 diabetes mellitus, carvedilol had no adverse effect on glycemic control, based on HbA1c measurements [see Clinical Studies (14.4)]. 5.7 Peripheral Vascular Disease blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Caution should be exercised in such individuals. 5.8 Deterioration of Renal Function Rarely, use of carvedilol in patients with heart failure has resulted in deterioration of renal function. Patients at risk appear to be those with low blood pressure (systolic blood pressure less than 100mm Hg), ischemic heart disease and diffuse vascular disease, and/or underlying renal insufficiency. Renal function has returned to baseline when carvedilol was stopped. In patients with these risk factors it is recommended that renal function be monitored during uptitration of COREGCR and the drug discontinued or dosage reduced if worsening of renal function occurs. 5.9 Major Surgery Chronically administered -blocking therapy should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures. 5.10 Thyrotoxicosis adrenergic blockade may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of blockade may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate thyroid storm. 5.11 Pheochromocytoma In patients with pheochromocytoma, an blocking agent should be initiated prior to the use of any blocking agent. Although carvedilol has both and blocking pharmacologic activities, there has been no experience with its use in this condition. Therefore, caution should be taken in the administration of carvedilol to patients suspected of having pheochromocytoma. 5.12 Prinzmetals Variant Angina Agents with nonselective blocking activity may provoke chest pain in patients with Prinzmetals variant angina. There has been no clinical experience with carvedilol in these patients although the blocking activity may prevent such symptoms. However, caution should be taken in the administration of COREGCR to patients suspected of having Prinzmetals variant angina. 5.13 Risk of Anaphylactic Reaction While taking blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction. 5.14 Intraoperative Floppy Iris Syndrome Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in some patients treated with alpha-1 blockers (COREG CR is an alpha/beta blocker). This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs, and potential prolapse of the iris toward the phacoemulsification incisions. The patients ophthalmologist should be prepared for possible modifications to the surgical technique, such as utilization of iris hooks, iris dilator rings, or viscoelastic substances. There does not appear to be a benefit of stopping alpha-1 blocker therapy prior to cataract surgery.

DRUG INTERACTIONS SECTION.


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 -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 blocking R(+) enantiomer. 7.2 Hypotensive Agents Patients taking a 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 blocker may cause hypotension and bradycardia. When concomitant treatment with a blocker and clonidine is to be terminated, the 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 21renal 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 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 COREGCR [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 Cmax [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 COREG CR may enhance the 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 added to pre-existing treatment with the other. 7.7 Calcium Channel Blockers Conduction disturbance (rarely with hemodynamic compromise) has been observed when COREG CR is coadministered with diltiazem. As with other blockers, if COREGCR is administered with calcium channel blockers of the verapamil or diltiazem type, it is recommended that ECG and blood pressure be monitored. 7.8 Insulin or Oral Hypoglycemics blockers properties may enhance the bloodsugarreducing effect of insulin and oral hypoglycemics. Therefore, in patients taking insulin or oral hypoglycemics, regular monitoring of blood glucose is recommended [see Warnings and Precautions (5.6)]. 7.9 Proton Pump Inhibitors There is no clinically meaningful increase in AUC and Cmax with concomitant administration of carvedilol extendedrelease capsules with pantoprazole. 7.10 Anesthesia If treatment with COREGCR is to be continued perioperatively, particular care should be taken when anesthetic agents that depress myocardial function, such as ether, cyclopropane, and trichloroethylene, are used [see Overdosage (10)].

NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility In 2year studies conducted in rats given carvedilol at doses up to 75mg per kg per day (12times the MRHD as mg per m2) or in mice given up to 200mg per kg per day (16times the MRHD as mg per m2), carvedilol had no carcinogenic effect. Carvedilol was negative when tested in a battery of genotoxicity assays, including the Ames and the CHO/HGPRT assays for mutagenicity and the in vitro hamster micronucleus and in vivo human lymphocyte cell tests for clastogenicity. In a combined fertility/developmental/post-natal toxicity study, rats were given carvedilol (12, 60, 300 mg per kg per day) orally by gavage for 2 weeks before mating and through mating, gestation, and weaning for females and for 62 days prior to and through mating for males. At a dosage of 300mg per kg per day (greater than or equal to 50times the MRHD as mg per m2) carvedilol was toxic to adult rats (sedation, reduced weight gain) and was associated with a reduced number of successful matings, prolonged mating time, fewer corpora lutea and implants per dam, fewer live pups per litter, and delays in physical growth/development. The no-effect level for overt toxicity and impairment of fertility was 60mg per kg per day (10times the MRHD as mg per m2).

USE IN SPECIFIC POPULATIONS SECTION.


8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data regarding use of COREG CR 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 postimplantation loss in rats at a maternally toxic dose of 300mg per kg per day (50times the MRHD as mg per m2) and in rabbits (in the absence of maternal toxicity) at doses of 75mg per kg per day (25times the MRHD as mg per m2). In the rats, there was also a decrease in fetal body weight at 300mg per kg per day (50times the MRHD as mg per m2) accompanied by an increased incidence of fetuses with delayed skeletal development. In rats, the no-effect level for embryo-fetal toxicity was 60mg per kg per day (10times the MRHD as mg per m2); in rabbits, it was 15mg per kg per day (5times the MRHD as mg per m2). 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 m2), and pup mortality and delays in physical growth/development were observed at 60mg per kg per day (10times the MRHD as mg per m2) in the absence of maternal toxicity. The no-effect level was 12 mg per kg per day (2times the MRHD as mg per m2). 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 mothers clinical need for COREGCR and any potential adverse effects on the breastfed infant from COREGCR or from the underlying maternal condition. 8.4 Pediatric Use Effectiveness of carvedilol in patients younger than 18years 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 4 to 6 heart beats per minute, indicative of -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 immediate-release 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%). 8.5 Geriatric Use The initial clinical trials of COREGCR in subjects with hypertension, heart failure, and left ventricular dysfunction following myocardial infarction did not include sufficient numbers of subjects aged 65years or older to determine whether they respond differently from younger patients. A randomized trial (n = 405) comparing subjects with mild to severe heart failure switched to COREG CR or maintained on immediate-release carvedilol included 220 subjects who were aged 65 years or older. In this elderly subgroup, the combined incidence of dizziness, hypotension, or syncope was 24% (18/75) in subjects switched from the highest dose of immediate-release carvedilol (25 mg twice daily) to the highest dose of COREG CR (80 mg once daily) compared with 11% (4/36) in subjects maintained on immediate-release carvedilol (25 mg twice daily). When switching from the higher doses of immediate-release carvedilol to COREG CR, a lower starting dose is recommended for elderly patients [see Dosage and Administration (2.5)]. The following information is available for trials with immediate-release carvedilol. Of the 765subjects with heart failure randomized to carvedilol in U.S. clinical trials, 31% (235) were aged 65years or older, and 7.3% (56) were aged 75years or older. Of the 1,156subjects randomized to carvedilol in a longterm, placebocontrolled trial in severe heart failure, 47% (547) were aged 65years or older, and 15% (174) were aged 75years or older. Of 3,025subjects receiving carvedilol in heart failure trials worldwide, 42% were aged 65years or older. Of the 975subjects with myocardial infarction randomized to carvedilol in the CAPRICORN trial, 48% (468) were aged 65years or older, and 11% (111) were aged 75years or older. Of the 2,065 hypertensive subjects in U.S. clinical trials of efficacy or safety who were treated with carvedilol, 21% (436) were aged 65years or older. Of 3,722 subjects receiving immediate-release carvedilol in hypertension clinical trials conducted worldwide, 24% were aged 65years 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 (see Figures 2 and 4) 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.

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Patients taking COREGCR should be advised of the following: Patients should not interrupt or discontinue using COREGCR without a physicians advice. Patients with heart failure should consult their physician if they experience signs or symptoms of worsening heart failure such as weight gain or increasing shortness of breath. Patients may experience a drop in blood pressure when standing, resulting in dizziness and, rarely, fainting. Patients should sit or lie down when these symptoms of lowered blood pressure occur. If experiencing dizziness or fatigue, patients should avoid driving or hazardous tasks. Patients should consult a physician if they experience dizziness or faintness, in case the dosage should be adjusted. Patients should not crush or chew COREGCR capsules. Patients should take COREGCR with food. Diabetic patients should report any changes in blood sugar levels to their physician. Contact lens wearers may experience decreased lacrimation. COREGCR and COREG are trademarks owned by or licensed to the GSK group of companies. The other brand listed is a trademark owned by or licensed to its owner and is not owned by or licensed to the GSK group of companies. The maker of this brand is not affiliated with and does not endorse the GSK group of companies or its products. GlaxoSmithKline Research Triangle Park, NC 27709 2017 GSK group of companies or its licensor. CCR:19PI PHARMACISTDETACH HERE AND GIVE INSTRUCTIONS TO PATIENT

CLINICAL STUDIES SECTION.


14 CLINICAL STUDIES Support for the use of COREGCR extended-release capsules for the treatment of mild-to-severe heart failure and for patients with left ventricular dysfunction following myocardial infarction is based on the equivalence of pharmacokinetic and pharmacodynamic (1blockade) parameters between COREGCR and immediate-release carvedilol [see Clinical Pharmacology (12.2, 12.3)]. The clinical trials performed with immediate-release carvedilol in heart failure and left ventricular dysfunction following myocardial infarction are presented below. 14.1 Heart Failure A total of 6,975 subjects with mild-to-severe heart failure were evaluated in placebo-controlled and active-controlled trials of immediate-release carvedilol. Mild-to-Moderate Heart Failure Carvedilol was studied in 5 multicenter, placebocontrolled trials, and in 1 active-controlled trial (COMET trial) involving subjects with mild-to-moderate heart failure. Four U.S. multicenter, doubleblind, placebocontrolled trials enrolled 1,094subjects (696 randomized to carvedilol) with NYHA class IIIII heart failure and ejection fraction less than or equal to 0.35. The vast majority were on digitalis, diuretics, and an ACE inhibitor at trial entry. Subjects were assigned to the trials based upon exercise ability. An AustraliaNew Zealand doubleblind, placebocontrolled trial enrolled 415 subjects (half randomized to immediaterelease carvedilol) with less severe heart failure. All protocols excluded subjects expected to undergo cardiac transplantation during the 7.5 to 15months of doubleblind followup. All randomized subjects had tolerated a 2week course on immediaterelease carvedilol 6.25mg twice daily. In each trial, there was a primary end point, either progression of heart failure (1 U.S. trial) or exercise tolerance (2 U.S. trials meeting enrollment goals and the AustraliaNew Zealand trial). There were many secondary end points specified in these trials, including NYHA classification, patient and physician global assessments, and cardiovascular hospitalization. Other analyses not prospectively planned included the sum of deaths and total cardiovascular hospitalizations. In situations where the primary end points of a trial do not show a significant benefit of treatment, assignment of significance values to the other results is complex, and such values need to be interpreted cautiously. The results of the U.S. and AustraliaNew Zealand trials were as follows: Slowing Progression of Heart Failure: One U.S. multicenter trial (366subjects) had as its primary end point the sum of cardiovascular mortality, cardiovascular hospitalization, and sustained increase in heart failure medications. Heart failure progression was reduced, during an average followup of 7months, by 48% (P=0.008). In the AustraliaNew Zealand trial, death and total hospitalizations were reduced by about 25% over 18 to 24months. In the 3 largest U.S. trials, death and total hospitalizations were reduced by 19%, 39%, and 49%, nominally statistically significant in the last 2 trials. The AustraliaNew Zealand results were statistically borderline. Functional Measures: None of the multicenter trials had NYHA classification as a primary end point, but all such trials had it as a secondary end point. There was at least a trend toward improvement in NYHA class in all trials. Exercise tolerance was the primary end point in 3trials; in none was a statistically significant effect found. Subjective Measures: Health-related quality of life, as measured with a standard questionnaire (a primary end point in 1 trial), was unaffected by carvedilol. However, patients and investigators global assessments showed significant improvement in most trials. Mortality: Death was not a pre-specified end point in any trial, but was analyzed in all trials. Overall, in these 4 U.S. trials, mortality was reduced, nominally significantly so in 2trials. The COMET Trial In this double-blind trial, 3,029 subjects with NYHA class II-IV heart failure (left ventricular ejection fraction less than or equal to 35%) were randomized to receive either carvedilol (target dose: 25mg twice daily) or immediate-release metoprolol tartrate (target dose: 50mg twice daily). The mean age of the subjects was approximately 62 years, 80% were males, and the mean left ventricular ejection fraction at baseline was 26%. Approximately 96% of the subjects had NYHA class II or III heart failure. Concomitant treatment included diuretics (99%), ACE inhibitors (91%), digitalis (59%), aldosterone antagonists (11%), and statin lipid-lowering agents (21%). The mean duration of follow-up was 4.8 years. The mean dose of carvedilol was 42mg per day. The trial had 2 primary end points: all-cause mortality and the composite of death plus hospitalization for any reason. The results of COMET are presented in below. All-cause mortality carried most of the statistical weight and was the primary determinant of the trial size. All-cause mortality was 34% in the subjects treated with carvedilol and was 40% in the immediate-release metoprolol group (P=0.0017; hazard ratio=0.83, 95% CI: 0.74 to 0.93). The effect on mortality was primarily due to a reduction in cardiovascular death. The difference between the 2 groups with respect to the composite end point was not significant (P=0.122). The estimated mean survival was 8.0 years with carvedilol and 6.6 years with immediate-release metoprolol. Table 5. Results of COMET End Point Carvedilol n=1,511 Metoprolol n=1,518 Hazard Ratio (95% CI) All-cause mortality 34% 40% 0.83 0.74 0.93 Mortality + all hospitalization 74% 76% 0.94 0.86 1.02 Cardiovascular death 30% 35% 0.80 0.70 0.90 Sudden death 14% 17% 0.81 0.68 0.97 Death due to circulatory failure 11% 13% 0.83 0.67 1.02 Death due to stroke 0.9% 2.5% 0.33 0.18 0.62 It is not known whether this formulation of metoprolol at any dose or this low dose of metoprolol in any formulation has any effect on survival or hospitalization in patients with heart failure. Thus, this trial extends the time over which carvedilol manifests benefits on survival in heart failure, but it is not evidence that carvedilol improves outcome over the formulation of metoprolol (TOPROL-XL) with benefits in heart failure. Severe Heart Failure (COPERNICUS) In a double-blind trial, 2,289 subjects with heart failure at rest or with minimal exertion and left ventricular ejection fraction less than 25% (mean 20%), despite digitalis (66%), diuretics (99%), and ACE inhibitors (89%), were randomized to placebo or carvedilol. Carvedilol was titrated from a starting dose of 3.125mg twice daily to the maximum tolerated dose or up to 25mg twice daily over a minimum of 6weeks. Most subjects achieved the target dose of 25mg. The trial was conducted in Eastern and Western Europe, the United States, Israel, and Canada. Similar numbers of subjects per group (about 100) withdrew during the titration period. The primary end point of the trial was allcause mortality, but causespecific mortality and the risk of death or hospitalization (total, cardiovascular [CV], or heart failure [HF]) were also examined. The developing trial data were followed by a data monitoring committee, and mortality analyses were adjusted for these multiple looks. The trial was stopped after a median followup of 10months because of an observed 35% reduction in mortality (from 19.7% per patient-year on placebo to 12.8% on carvedilol: hazard ratio 0.65, 95% CI: 0.52 to 0.81, P=0.0014, adjusted) (see Figure 1). The results of COPERNICUS are shown in Table 6. Table 6. Results of COPERNICUS Trial in Subjects with Severe Heart Failure End Point Placebo (n=1,133) Carvedilol (n=1,156) Hazard Ratio (95% CI) % Reduction Nominal Pvalue Mortality 190 130 0.65 (0.52 0.81) 35 0.00013 Mortality + all hospitalization 507 425 0.76 (0.67 0.87) 24 0.00004 Mortality + CV hospitalization 395 314 0.73 (0.63 0.84) 27 0.00002 Mortality + HF hospitalization 357 271 0.69 (0.59 0.81) 31 0.000004 Cardiovascular = CV; Heart failure = HF. Figure 1. Survival Analysis for COPERNICUS (Intent-to-Treat) The effect on mortality was principally the result of a reduction in the rate of sudden death among subjects without worsening heart failure. Patients' global assessments, in which carvediloltreated subjects were compared with placebo, were based on pre-specified, periodic patient self-assessments regarding whether clinical status post-treatment showed improvement, worsening, or no change compared with baseline. Subjects treated with carvedilol showed significant improvements in global assessments compared with those treated with placebo in COPERNICUS. The protocol also specified that hospitalizations would be assessed. Fewer subjects on immediaterelease carvedilol than on placebo were hospitalized for any reason (372 versus 432, P=0.0029), for cardiovascular reasons (246 versus 314, P=0.0003), or for worsening heart failure (198 versus 268, P=0.0001). Immediaterelease carvedilol had a consistent and beneficial effect on allcause mortality as well as the combined end points of allcause mortality plus hospitalization (total, CV, or for heart failure) in the overall trial population and in all subgroups examined, including men and women, elderly and nonelderly, blacks and nonblacks, and diabetics and non-diabetics (see Figure 2). Figure 2. Effects on Mortality for Subgroups in COPERNICUS Although the clinical trials used twice-daily dosing, clinical pharmacologic and pharmacokinetic data provide a reasonable basis for concluding that once-daily dosing with COREGCR should be adequate in the treatment of heart failure. 14.2 Left Ventricular Dysfunction following Myocardial Infarction CAPRICORN was a doubleblind trial comparing carvedilol and placebo in 1,959 subjects with a recent myocardial infarction (within 21days) and left ventricular ejection fraction of less than or equal to 40%, with (47%) or without symptoms of heart failure. Subjects given carvedilol received 6.25mg twice daily, titrated as tolerated to 25mg twice daily. Subjects had to have a systolic blood pressure greater than 90mm Hg, a sitting heart rate greater than 60beats per minute, and no contraindication to blocker use. Treatment of the index infarction included aspirin (85%), IV or oral blockers (37%), nitrates (73%), heparin (64%), thrombolytics (40%), and acute angioplasty (12%). Background treatment included ACE inhibitors or angiotensin-receptor blockers (97%), anticoagulants (20%), lipidlowering agents (23%), and diuretics (34%). Baseline population characteristics included an average age of 63years, 74% male, 95% Caucasian, mean blood pressure 121/74mm Hg, 22% with diabetes, and 54% with a history of hypertension. Mean dosage achieved of carvedilol was 20mg twice daily; mean duration of followup was 15months. Allcause mortality was 15% in the placebo group and 12% in the carvedilol group, indicating a 23% risk reduction in subjects treated with carvedilol (95% CI: 2% to 40%, P=0.03), as shown in Figure 3. The effects on mortality in various subgroups are shown in Figure 4. Nearly all deaths were cardiovascular (which were reduced by 25% by carvedilol), and most of these deaths were sudden or related to pump failure (both types of death were reduced by carvedilol). Another trial end point, total mortality and all-cause hospitalization, did not show a significant improvement. There was also a significant 40% reduction in fatal or non-fatal myocardial infarction observed in the group treated with carvedilol (95% CI: 11% to 60%, P=0.01). A similar reduction in the risk of myocardial infarction was also observed in a meta-analysis of placebo-controlled trials of carvedilol in heart failure. Figure 3. Survival Analysis for CAPRICORN (Intent-to-Treat) Figure 4. Effects on Mortality for Subgroups in CAPRICORN Although the clinical trials used twice-daily dosing, clinical pharmacologic and pharmacokinetic data provide a reasonable basis for concluding that once-daily dosing with COREGCR should be adequate in the treatment of left ventricular dysfunction following myocardial infarction. 14.3 Hypertension A double-blind, randomized, placebo-controlled, 8-week trial evaluated the blood pressure-lowering effects of COREGCR 20mg, 40mg, and 80mg once daily in 338 subjects with essential hypertension (sitting diastolic blood pressure [DBP] greater than or equal to 90 and less than or equal to 109mmHg). Of 337 evaluable subjects, a total of 273 subjects (81%) completed the trial. Of the 64 (19%) subjects withdrawn from the trial, 10 (3%) were due to adverse events, 10 (3%) were due to lack of efficacy; the remaining 44 (13%) withdrew for other reasons. The mean age of the subjects was approximately 53years, 66% were male, and the mean sitting systolic blood pressure (SBP) and DBP at baseline were 150mmHg and 99mmHg, respectively. Dose titration occurred at 2week intervals. Statistically significant reductions in blood pressure as measured by 24hour ambulatory blood pressure monitoring (ABPM) were observed with each dose of COREGCR compared with placebo. Placebo-subtracted mean changes from baseline in mean SBP/DBP were 6.1/4.0 mmHg, 9.4/7.6 mmHg, and 11.8/9.2 mmHg for COREGCR 20mg, 40mg, and 80mg, respectively. Placebo-subtracted mean changes from baseline in mean trough (average of hours 20 to 24) SBP/DBP were 3.3/2.8 mmHg, 4.9/5.2 mmHg, and 8.4/7.4 mmHg for COREGCR 20mg, 40mg, and 80mg, respectively. The placebo-corrected trough-to-peak (3 to 7h) ratio was approximately 0.6 for COREGCR 80mg. In this trial, assessments of 24hour ABPM monitoring demonstrated statistically significant blood pressure reductions with COREGCR throughout the dosing period (Figure 5). Figure 5. Changes from Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Measured by 24-Hour ABPM Immediaterelease carvedilol was studied in 2 placebocontrolled trials that utilized twicedaily dosing at total daily doses of 12.5 to 50mg. In these and other trials, the starting dose did not exceed 12.5 mg. At 50mg per day, COREG reduced sitting trough (12hour) blood pressure by about 9/5.5 mm Hg; at 25mg per day the effect was about 7.5/3.5 mmHg. Comparisons of troughtopeak blood pressure showed a troughtopeak ratio for blood pressure response of about 65%. Heart rate fell by about 7.5 beats per minute at 50mg per day. In general, as is true for other blockers, responses were smaller in black than nonblack subjects. There were no age or genderrelated differences in response. The doserelated blood pressure response was accompanied by a doserelated increase in adverse effects [see Adverse Reactions (6)]. 14.4 Hypertension with Type 2 Diabetes Mellitus In a double-blind trial (GEMINI), carvedilol, added to an ACE inhibitor or angiotensin receptor blocker, was evaluated in a population with mildtomoderate hypertension and well-controlled type 2 diabetes mellitus. The mean HbA1c at baseline was 7.2%. COREG was titrated to a mean dose of 17.5 mg twice daily and maintained for 5 months. COREG had no adverse effect on glycemic control, based on HbA1c measurements (mean change from baseline of 0.02%, 95% CI: 0.06 to 0.10, P=NS) [see Warnings and Precautions (5.6)].

CLINICAL PHARMACOLOGY SECTION.


12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Carvedilol is a racemic mixture in which nonselective adrenoreceptor blocking activity is present in the S(-) enantiomer and 1adrenergic blocking activity is present in both R(+) and S(-) enantiomers at equal potency. Carvedilol has no intrinsic sympathomimetic activity. 12.2 Pharmacodynamics Heart Failure and Left Ventricular Dysfunction following Myocardial Infarction The basis for the beneficial effects of carvedilol in patients with heart failure and in patients with left ventricular dysfunction following an acute myocardial infarction is not known. The concentration-response relationship for 1blockade following administration of COREGCR is equivalent (20%) to immediate-release carvedilol tablets. Hypertension The mechanism by which blockade produces an antihypertensive effect has not been established. adrenoreceptor blocking activity has been demonstrated in animal and human studies showing that carvedilol (1) reduces cardiac output in normal subjects, (2) reduces exercise- and/or isoproterenol-induced tachycardia, and (3) reduces reflex orthostatic tachycardia. Significant adrenoreceptor blocking effect is usually seen within 1hour of drug administration. 1adrenoreceptor blocking activity has been demonstrated in human and animal studies, showing that carvedilol (1)attenuates the pressor effects of phenylephrine, (2)causes vasodilation, and (3)reduces peripheral vascular resistance. These effects contribute to the reduction of blood pressure and usually are seen within 30minutes of drug administration. Due to the 1receptor blocking activity of carvedilol, blood pressure is lowered more in the standing than in the supine position, and symptoms of postural hypotension (1.8%), including rare instances of syncope, can occur. Following oral administration, when postural hypotension has occurred, it has been transient and is uncommon when immediate-release carvedilol is administered with food at the recommended starting dose and titration increments are closely followed [see Dosage and Administration (2)]. In a randomized, double-blind, placebo-controlled trial, the 1blocking effect of COREGCR, as measured by heart rate response to submaximal bicycle ergometry, was shown to be equivalent to that observed with immediate-release carvedilol at steady state in adult subjects with essential hypertension. In hypertensive subjects with normal renal function, therapeutic doses of carvedilol decreased renal vascular resistance with no change in glomerular filtration rate or renal plasma flow. Changes in excretion of sodium, potassium, uric acid, and phosphorus in hypertensive patients with normal renal function were similar after carvedilol and placebo. Carvedilol has little effect on plasma catecholamines, plasma aldosterone, or electrolyte levels, but it does significantly reduce plasma renin activity when given for at least 4weeks. It also increases levels of atrial natriuretic peptide. 12.3 Pharmacokinetics Absorption Carvedilol is rapidly and extensively absorbed following oral administration of immediate-release carvedilol tablets, with an absolute bioavailability of approximately 25% to 35% due to a significant degree of first-pass metabolism. COREGCR extended-release capsules have approximately 85% of the bioavailability of immediate-release carvedilol tablets. For corresponding dosages [see Dosage and Administration (2)], the exposure (AUC, Cmax, trough concentration) of carvedilol as COREGCR extended-release capsules is equivalent to those of immediate-release carvedilol tablets when both are administered with food. The absorption of carvedilol from COREGCR is slower and more prolonged compared with the immediate-release carvedilol tablet with peak concentrations achieved approximately 5hours after administration. Plasma concentrations of carvedilol increase in a dose-proportional manner over the dosage range of COREGCR 10 to 80mg. Within-subject and between-subject variability for AUC and Cmax is similar for COREGCR and immediate-release carvedilol. Effect of Food: Administration of COREGCR with a high-fat meal resulted in increases (~20%) in AUC and Cmax compared with COREGCR administered with a standard meal. Decreases in AUC (27%) and Cmax (43%) were observed when COREGCR was administered in the fasted state compared with administration after a standard meal. COREGCR should be taken with food. In a trial with adult subjects, sprinkling the contents of the COREGCR capsule on applesauce did not appear to have a significant effect on overall exposure (AUC) compared with administration of the intact capsule following a standard meal, but did result in a decrease in Cmax (18%). Distribution Carvedilol is more than 98% bound to plasma proteins, primarily with albumin. The plasma-protein binding is independent of concentration over the therapeutic range. Carvedilol is a basic, lipophilic compound with a steady-state volume of distribution of approximately 115L, indicating substantial distribution into extravascular tissues. Metabolism and Excretion Carvedilol is extensively metabolized. Following oral administration of radiolabelled carvedilol to healthy volunteers, carvedilol accounted for only about 7% of the total radioactivity in plasma as measured by AUC. Less than 2% of the dose was excreted unchanged in the urine. Carvedilol is metabolized primarily by aromatic ring oxidation and glucuronidation. The oxidative metabolites are further metabolized by conjugation via glucuronidation and sulfation. The metabolites of carvedilol are excreted primarily via the bile into the feces. Demethylation and hydroxylation at the phenol ring produce 3 active metabolites with receptor blocking activity. Based on preclinical studies, the 4'-hydroxyphenyl metabolite is approximately 13times more potent than carvedilol for blockade. Compared with carvedilol, the 3 active metabolites exhibit weak vasodilating activity. Plasma concentrations of the active metabolites are about one-tenth of those observed for carvedilol and have pharmacokinetics similar to the parent. Carvedilol undergoes stereoselective first-pass metabolism with plasma levels of R(+)-carvedilol approximately 2 to 3times higher than S(-)-carvedilol following oral administration of COREGCR in healthy subjects. Apparent clearance is 90 L per h and 213 L per h for R(+)- and S(-)-carvedilol, respectively. The primary P450 enzymes responsible for the metabolism of both R(+) and S(-)-carvedilol in human liver microsomes were CYP2D6 and CYP2C9 and to a lesser extent CYP3A4, 2C19, 1A2, and 2E1. CYP2D6 is thought to be the major enzyme in the 4- and 5-hydroxylation of carvedilol, with a potential contribution from 3A4. CYP2C9 is thought to be of primary importance in the O-methylation pathway of S(-)-carvedilol. Carvedilol is subject to the effects of genetic polymorphism with poor metabolizers of debrisoquin (a marker for cytochrome P450 2D6) exhibiting 2- to 3-fold higher plasma concentrations of R(+)-carvedilol compared with extensive metabolizers. In contrast, plasma levels of S(-)-carvedilol are increased only about 20% to 25% in poor metabolizers, indicating this enantiomer is metabolized to a lesser extent by cytochrome P450 2D6 than R(+)-carvedilol. The pharmacokinetics of carvedilol do not appear to be different in poor metabolizers of S-mephenytoin (patients deficient in cytochrome P450 2C19). 12.4 Specific Populations Heart Failure Following administration of immediate-release carvedilol tablets, steadystate plasma concentrations of carvedilol and its enantiomers increased proportionally over the dose range in subjects with heart failure. Compared with healthy subjects, subjects with heart failure had increased mean AUC and Cmax values for carvedilol and its enantiomers, with up to 50% to 100% higher values observed in 6 subjects with NYHA class IV heart failure. The mean apparent terminal elimination halflife for carvedilol was similar to that observed in healthy subjects. For corresponding dose levels [see Dosage and Administration (2)], the steady-state pharmacokinetics of carvedilol (AUC, Cmax, trough concentrations) observed after administration of COREGCR to subjects with chronic heart failure (mild, moderate, and severe) were similar to those observed after administration of immediate-release carvedilol tablets. Hypertension For corresponding dose levels [see Dosage and Administration (2)], the pharmacokinetics (AUC, Cmax, and trough concentrations) observed with administration of COREGCR were equivalent (20%) to those observed with immediate-release carvedilol tablets following repeat dosing in subjects with essential hypertension. Geriatric Plasma levels of carvedilol average about 50% higher in the elderly compared with young subjects after administration of immediate-release carvedilol. Hepatic Impairment No trials have been performed with COREGCR in subjects with hepatic impairment. Compared with healthy subjects, subjects with severe liver impairment (cirrhosis) exhibit a 4- to 7-fold increase in carvedilol levels. Carvedilol is contraindicated in patients with severe liver impairment. Renal Impairment No trials have been performed with COREGCR in subjects with renal impairment. Although carvedilol is metabolized primarily by the liver, plasma concentrations of carvedilol have been reported to be increased in patients with renal impairment after dosing with immediate-release carvedilol. Based on mean AUC data, approximately 40% to 50% higher plasma concentrations of carvedilol were observed in subjects with hypertension and moderate to severe renal impairment compared with a control group of subjects with hypertension and normal renal function. However, the ranges of AUC values were similar for both groups. Changes in mean peak plasma levels were less pronounced, approximately 12% to 26% higher in subjects with impaired renal function. Consistent with its high degree of plasma protein binding, carvedilol does not appear to be cleared significantly by hemodialysis. 12.5 Drug-Drug Interactions Since carvedilol undergoes substantial oxidative metabolism, the metabolism and pharmacokinetics of carvedilol may be affected by induction or inhibition of cytochrome P450 enzymes. The following drug interaction trials were performed with immediate-release carvedilol tablets. Amiodarone In a pharmacokinetic trial conducted in 106 Japanese subjects with heart failure, coadministration of small loading and maintenance doses of amiodarone with carvedilol resulted in at least a 2-fold increase in the steady-state trough concentrations of S(-)-carvedilol [see Drug Interactions (7.6)]. Cimetidine In a pharmacokinetic trial conducted in 10 healthy male subjects, cimetidine (1,000mg per day) increased the steady-state AUC of carvedilol by 30% with no change in Cmax [see Drug Interactions (7.5)]. Digoxin Following concomitant administration of carvedilol (25mg once daily) and digoxin (0.25mg once daily) for 14days, steady-state AUC and trough concentrations of digoxin were increased by 14% and 16%, respectively, in 12 subjects with hypertension [see Drug Interactions (7.4)]. Glyburide In 12 healthy subjects, combined administration of carvedilol (25mg once daily) and a single dose of glyburide did not result in a clinically relevant pharmacokinetic interaction for either compound. Hydrochlorothiazide A single oral dose of carvedilol 25mg did not alter the pharmacokinetics of a single oral dose of hydrochlorothiazide 25mg in 12 subjects with hypertension. Likewise, hydrochlorothiazide had no effect on the pharmacokinetics of carvedilol. Rifampin In a pharmacokinetic trial conducted in 8 healthy male subjects, rifampin (600mg daily for 12days) decreased the AUC and Cmax of carvedilol by about 70% [see Drug Interactions (7.5)]. Torsemide In a trial of 12 healthy subjects, combined oral administration of carvedilol 25mg once daily and torsemide 5mg once daily for 5days did not result in any significant differences in their pharmacokinetics compared with administration of the drugs alone. Warfarin Carvedilol (12.5 mg twice daily) did not have an effect on the steady-state prothrombin time ratios and did not alter the pharmacokinetics of R(+)- and S(-)-warfarin following concomitant administration with warfarin in 9 healthy volunteers.

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS COREG CR is 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 thirddegree 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 COREG CR. 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 COREG CR. Bronchial asthma or related bronchospastic conditions. (4) Second-orthird-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 COREG CR. (4)