carvedilol phosphate 20 MG 24 HR Extended Release Oral Capsule

Generic Name: CARVEDILOL PHOSPHATE
Brand Name: COREG CR
  • Substance Name(s):
  • CARVEDILOL PHOSPHATE

DRUG INTERACTIONS

7 •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 β-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 α‑blocking R(+) enantiomer.

7.2 Hypotensive Agents Patients taking a β‑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 β‑blocker may cause hypotension and bradycardia.

When concomitant treatment with a β‑blocker and clonidine is to be terminated, the β‑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 β‑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 COREG CR [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 β‑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 COREG CR 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 β‑blockers properties may enhance the blood‑sugar‑reducing 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 extended‑release capsules with pantoprazole.

7.10 Anesthesia If treatment with COREG CR 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)].

OVERDOSAGE

10 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, β‑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 COREG CR.

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.

DESCRIPTION

11 Carvedilol phosphate is a nonselective β‑adrenergic blocking agent with α1-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 C24H26N2O4•H3PO4•1/2 H2O.

COREG CR is available for once-a-day administration as controlled-release oral capsules containing 10, 20, 40, or 80 mg carvedilol phosphate.

COREG CR 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.

carvedilol phosphate chemical structure

CLINICAL STUDIES

14 Support for the use of COREG CR 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 (β1‑blockade) parameters between COREG CR 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, placebo‑controlled trials, and in 1 active-controlled trial (COMET trial) involving subjects with mild-to-moderate heart failure.

Four U.S.

multicenter, double‑blind, placebo‑controlled trials enrolled 1,094 subjects (696 randomized to carvedilol) with NYHA class II‑III 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 Australia‑New Zealand double‑blind, placebo‑controlled trial enrolled 415 subjects (half randomized to immediate‑release carvedilol) with less severe heart failure.

All protocols excluded subjects expected to undergo cardiac transplantation during the 7.5 to 15 months of double‑blind follow‑up.

All randomized subjects had tolerated a 2‑week course on immediate‑release carvedilol 6.25 mg 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 Australia‑New 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 Australia‑New Zealand trials were as follows: Slowing Progression of Heart Failure: One U.S.

multicenter trial (366 subjects) 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 follow‑up of 7 months, by 48% (P = 0.008).

In the Australia‑New Zealand trial, death and total hospitalizations were reduced by about 25% over 18 to 24 months.

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 Australia‑New 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 3 trials; 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 2 trials.

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: 25 mg twice daily) or immediate-release metoprolol tartrate (target dose: 50 mg 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 42 mg 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 3.125 mg twice daily to the maximum tolerated dose or up to 25 mg twice daily over a minimum of 6 weeks.

Most subjects achieved the target dose of 25 mg.

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 all‑cause mortality, but cause‑specific 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 follow‑up of 10 months 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 P value 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 carvedilol‑treated 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 immediate‑release 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).

Immediate‑release carvedilol had a consistent and beneficial effect on all‑cause mortality as well as the combined end points of all‑cause 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 non‑elderly, blacks and non‑blacks, 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 COREG CR should be adequate in the treatment of heart failure.

Figure 1.

Survival Analysis for COPERNICUS (intent-to-treat) Figure 2.

Effects on Mortality for Subgroups in COPERNICUS 14.2 Left Ventricular Dysfunction following Myocardial Infarction CAPRICORN was a double‑blind trial comparing carvedilol and placebo in 1,959 subjects with a recent myocardial infarction (within 21 days) and left ventricular ejection fraction of less than or equal to 40%, with (47%) or without symptoms of heart failure.

Subjects given carvedilol received 6.25 mg twice daily, titrated as tolerated to 25 mg twice daily.

Subjects had to have a systolic blood pressure greater than 90 mm Hg, a sitting heart rate greater than 60 beats per minute, and no contraindication to β‑blocker use.

Treatment of the index infarction included aspirin (85%), IV or oral β‑blockers (37%), nitrates (73%), heparin (64%), thrombolytics (40%), and acute angioplasty (12%).

Background treatment included ACE inhibitors or angiotensin-receptor blockers (97%), anticoagulants (20%), lipid‑lowering agents (23%), and diuretics (34%).

Baseline population characteristics included an average age of 63 years, 74% male, 95% Caucasian, mean blood pressure 121/74 mm Hg, 22% with diabetes, and 54% with a history of hypertension.

Mean dosage achieved of carvedilol was 20 mg twice daily; mean duration of follow‑up was 15 months.

All‑cause 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 COREG CR should be adequate in the treatment of left ventricular dysfunction following myocardial infarction.

Figure 3.

Survival Analysis for CAPRICORN (intent-to-treat) Figure 4.

Effects on Mortality for Subgroups in CAPRICORN 14.3 Hypertension A double-blind, randomized, placebo-controlled, 8-week trial evaluated the blood pressure-lowering effects of COREG CR 20 mg, 40 mg, and 80 mg 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 109 mm Hg).

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 53 years, 66% were male, and the mean sitting systolic blood pressure (SBP) and DBP at baseline were 150 mm Hg and 99 mm Hg, respectively.

Dose titration occurred at 2‑week intervals.

Statistically significant reductions in blood pressure as measured by 24‑hour ambulatory blood pressure monitoring (ABPM) were observed with each dose of COREG CR compared with placebo.

Placebo-subtracted mean changes from baseline in mean SBP/DBP were ‑6.1/‑4.0 mm Hg, ‑9.4/‑7.6 mm Hg, and ‑11.8/‑9.2 mm Hg for COREG CR 20 mg, 40 mg, and 80 mg, respectively.

Placebo-subtracted mean changes from baseline in mean trough (average of hours 20 to 24) SBP/DBP were ‑3.3/‑2.8 mm Hg, ‑4.9/‑5.2 mm Hg, and ‑8.4/‑7.4 mm Hg for COREG CR 20 mg, 40 mg, and 80 mg, respectively.

The placebo-corrected trough-to-peak (3 to 7 h) ratio was approximately 0.6 for COREG CR 80 mg.

In this trial, assessments of 24‑hour ABPM monitoring demonstrated statistically significant blood pressure reductions with COREG CR throughout the dosing period (Figure 5).

Figure 5.

Changes from Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Measured by 24-Hour ABPM Immediate‑release carvedilol was studied in 2 placebo‑controlled trials that utilized twice‑daily dosing at total daily doses of 12.5 to 50 mg.

In these and other trials, the starting dose did not exceed 12.5 mg.

At 50 mg per day, COREG reduced sitting trough (12‑hour) blood pressure by about 9/5.5 mm Hg; at 25 mg per day the effect was about 7.5/3.5 mm Hg.

Comparisons of trough‑to‑peak blood pressure showed a trough‑to‑peak ratio for blood pressure response of about 65%.

Heart rate fell by about 7.5 beats per minute at 50 mg per day.

In general, as is true for other β‑blockers, responses were smaller in black than non‑black subjects.

There were no age‑ or gender‑related differences in response.

The dose‑related blood pressure response was accompanied by a dose‑related increase in adverse effects [see Adverse Reactions (6)].

Figure 5.

Changes from Baseline in Systolic Blood Pressure and Diastolic Blood Pressure Measured by 24-Hour ABPM 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 mild‑to‑moderate 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)].

HOW SUPPLIED

16 /STORAGE AND HANDLING The hard gelatin capsules are available in the following strengths: •10 mg – white and green capsule shell printed with “GSK COREG CR” and “10 mg” •20 mg – white and yellow capsule shell printed with “GSK COREG CR” and “20 mg” •40 mg – yellow and green capsule shell printed with “GSK COREG CR” and “40 mg” •80 mg – white capsule shell printed with “GSK COREG CR” and “80 mg” •10 mg bottles of 30: NDC 0007-3370-13 •20 mg bottles of 30: NDC 0007-3371-13 •40 mg bottles of 30: NDC 0007-3372-13 •80 mg bottles of 30: NDC 0007-3373-13 Store at 25°C (77°F); excursions 15° to 30°C (59° to 86°F).

Dispense in a tight, light-resistant container.

GERIATRIC USE

8.5 Geriatric Use The initial clinical trials of COREG CR in subjects with hypertension, heart failure, and left ventricular dysfunction following myocardial infarction did not include sufficient numbers of subjects aged 65 years 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 765 subjects with heart failure randomized to carvedilol in U.S.

clinical trials, 31% (235) were aged 65 years or older, and 7.3% (56) were aged 75 years or older.

Of the 1,156 subjects randomized to carvedilol in a long‑term, placebo‑controlled trial in severe heart failure, 47% (547) were aged 65 years or older, and 15% (174) were aged 75 years or older.

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

Of the 975 subjects with myocardial infarction randomized to carvedilol in the CAPRICORN trial, 48% (468) were aged 65 years or older, and 11% (111) were aged 75 years 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 65 years or older.

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

With the exception of dizziness in hypertensive subjects (incidence 8.8% in the elderly versus 6% in younger subjects), no overall differences in the safety or effectiveness (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.

DOSAGE FORMS AND STRENGTHS

3 The hard gelatin capsules are filled with white to off-white microparticles and are available in the following strengths: •10 mg – white and green capsule shell printed with “GSK COREG CR” and “10 mg” •20 mg – white and yellow capsule shell printed with “GSK COREG CR” and “20 mg” •40 mg – yellow and green capsule shell printed with “GSK COREG CR” and “40 mg” •80 mg – white capsule shell printed with “GSK COREG CR” and “80 mg” Capsules: 10 mg, 20 mg, 40 mg, 80 mg (3)

MECHANISM OF ACTION

12.1 Mechanism of Action Carvedilol is a racemic mixture in which nonselective β‑adrenoreceptor blocking activity is present in the S(-) enantiomer and α1‑adrenergic blocking activity is present in both R(+) and S(-) enantiomers at equal potency.

Carvedilol has no intrinsic sympathomimetic activity.

INDICATIONS AND USAGE

1 COREG CR 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 COREG CR 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 COREG CR 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 COREG CR 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 thiazide‑type diuretics [see Drug Interactions (7.2)].

PEDIATRIC USE

8.4 Pediatric Use Effectiveness of carvedilol in patients younger than 18 years has not been established.

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

These dose levels produced placebo-corrected heart rate reduction of 4 to 6 heart beats per minute, indicative of β-blockade activity.

Exposure appeared to be lower in pediatric subjects than adults.

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

Adverse reactions in this trial that occurred in greater than 10% of subjects treated with 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%).

PREGNANCY

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 post‑implantation loss in rats at a maternally toxic dose of 300 mg per kg per day (50 times the MRHD as mg per m2) 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 m2).

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 m2) 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 m2); in rabbits, it was 15 mg per kg per day (5 times 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 60 mg per kg per day (10 times the MRHD as mg per m2) in the absence of maternal toxicity.

The no-effect level was 12 mg per kg per day (2 times the MRHD as mg per m2).

Carvedilol was present in fetal rat tissue.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS In clinical trials of COREG CR in subjects with hypertension (338 subjects) and in subjects with left ventricular dysfunction following a myocardial infarction or heart failure (187 subjects), the profile of adverse events observed with carvedilol phosphate was generally similar to that observed with the administration of immediate‑release carvedilol.

Therefore, the information included within this section is based on data from controlled clinical trials with COREG CR as well as immediate‑release 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 β‑blockers.

(4) However, if deemed necessary, use with caution and at lowest effective dose.

(5.5) •Diabetes: Monitor glucose as β‑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 COREG CR, 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 β‑blockers.

The last 2 complications may occur with or without preceding exacerbation of the angina pectoris.

As with other β‑blockers, when discontinuation of COREG CR is planned, the patients should be carefully observed and advised to limit physical activity to a minimum.

COREG CR should be discontinued over 1 to 2 weeks whenever possible.

If the angina worsens or acute coronary insufficiency develops, it is recommended that COREG CR 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 COREG CR abruptly even in patients treated only for hypertension or heart failure.

5.2 Bradycardia In clinical trials with immediate‑release 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 COREG CR 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 COREG CR in hypertension.

However, if pulse rate drops below 55 beats per minute, the dosage of COREG CR should be reduced.

5.3 Hypotension In clinical trials of primarily mild‑to‑moderate heart failure with immediate‑release 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 30 days of dosing, corresponding to the up‑titration period and was a cause for discontinuation of therapy in 0.7% of carvedilol subjects, compared with 0.4% of placebo subjects.

In a long‑term, placebo‑controlled 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 COREG CR in hypertensive subjects, syncope was reported in 0.3% of subjects receiving COREG CR 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 immediate‑release 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 up‑titration of carvedilol.

If such symptoms occur, diuretics should be increased and the dose of COREG CR should not be advanced until clinical stability resumes [see Dosage and Administration (2)].

Occasionally it is necessary to lower the dose of COREG CR or temporarily discontinue it.

Such episodes do not preclude subsequent successful titration of, or a favorable response to, COREG CR.

In a placebo‑controlled trial of subjects with severe heart failure, worsening heart failure during the first 3 months was reported to a similar degree with immediate-release carvedilol and with placebo.

When treatment was maintained beyond 3 months, worsening heart failure was reported less frequently in subjects treated with carvedilol than with placebo.

Worsening heart failure observed during long‑term 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 β‑blockers.

COREG CR may be used with caution, however, in patients who do not respond to, or cannot tolerate, other antihypertensive agents.

It is prudent, if COREG CR is used, to use the smallest effective dose, so that inhibition of endogenous or exogenous β‑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 COREG CR 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 up‑titration.

5.6 Glycemic Control in Type 2 Diabetes In general, β‑blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia.

Nonselective β‑blockers may potentiate insulin‑induced 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 COREG CR 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 immediate‑release carvedilol on glycemic control in a population with mild‑to‑moderate 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 β‑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 100 mm 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 up‑titration of COREG CR and the drug discontinued or dosage reduced if worsening of renal function occurs.

5.9 Major Surgery Chronically administered β-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 β‑adrenergic blockade may mask clinical signs of hyperthyroidism, such as tachycardia.

Abrupt withdrawal of β‑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 α‑blocking agent should be initiated prior to the use of any β‑blocking agent.

Although carvedilol has both α‑ and β‑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 Prinzmetal’s Variant Angina Agents with non‑selective β‑blocking activity may provoke chest pain in patients with Prinzmetal’s variant angina.

There has been no clinical experience with carvedilol in these patients although the α‑blocking activity may prevent such symptoms.

However, caution should be taken in the administration of COREG CR to patients suspected of having Prinzmetal’s variant angina.

5.13 Risk of Anaphylactic Reaction While taking β‑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 patient’s 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.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information).

Patients taking COREG CR should be advised of the following: •Patients should not interrupt or discontinue using COREG CR without a physician’s 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 COREG CR capsules.

•Patients should take COREG CR with food.

•Diabetic patients should report any changes in blood sugar levels to their physician.

•Contact lens wearers may experience decreased lacrimation.

COREG CR 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 PHARMACIST─DETACH HERE AND GIVE INSTRUCTIONS TO PATIENT

DOSAGE AND ADMINISTRATION

2 COREG CR is an extended-release capsule intended for once‑daily administration.

Patients controlled with immediate‑release carvedilol tablets alone or in combination with other medications may be switched to COREG CR 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 COREG CR 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.

COREG CR should be taken once daily in the morning with food.

COREG CR should be swallowed as a whole capsule.

COREG CR 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, 40, 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 (>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 UP‑TITRATION.

Prior to initiation of COREG CR, it is recommended that fluid retention be minimized.

The recommended starting dose of COREG CR 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, 40, 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 COREG CR from that of the ACE inhibitor or to reduce temporarily the dose of the ACE inhibitor.

The dose of COREG CR 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 COREG CR should be reduced if patients experience bradycardia (heart rate less than 55 beats per minute).

Episodes of dizziness or fluid retention during initiation of COREG CR can generally be managed without discontinuation of treatment and do not preclude subsequent successful titration of, or a favorable response to, COREG CR.

2.2 Left Ventricular Dysfunction following Myocardial Infarction DOSAGE MUST BE INDIVIDUALIZED AND MONITORED DURING UP‑TITRATION.

Treatment with COREG CR 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 COREG CR be started at 20 mg once daily and increased after 3 to 10 days, based on tolerability, to 40 mg once daily, then again to the target dose of 80 mg once daily.

A lower starting dose may be used (10 mg once daily) and/or the rate of up‑titration may be slowed if clinically indicated (e.g., due to low blood pressure or heart rate, or fluid retention).

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 β‑blocker during the acute phase of the myocardial infarction.

2.3 Hypertension DOSAGE MUST BE INDIVIDUALIZED.

The recommended starting dose of COREG CR is 20 mg once daily.

If this dose is tolerated, using standing systolic pressure measured about 1 hour after dosing as a guide, the dose should be maintained for 7 to 14 days, and then increased to 40 mg 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 14 days and can then be adjusted upward to 80 mg once daily if tolerated and needed.

Although not specifically studied, it is anticipated the full antihypertensive effect of COREG CR would be seen within 7 to 14 days as had been demonstrated with immediate‑release carvedilol.

Total daily dose should not exceed 80 mg.

Concomitant administration with a diuretic can be expected to produce additive effects and exaggerate the orthostatic component of carvedilol action.

2.4 Hepatic Impairment COREG CR 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)].