Summary Of Safety-Related Drug Labeling
Changes Approved By FDA Center for Drug
Evaluation and Research (CDER)
November 2001

(Posted: 12/17/2001)

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Revised for ATACAND Tablets and added as a new subsection to the ATACAND HCT Tablets.

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4^th paragraph revised

Among 839 patients with NYHA class II-III heart failure treated for 26 to 52 weeks in 4 U.S. placebo-controlled trials, the average left ventricular ejection fraction (EF) measured by radionuclide ventriculography increased by 8 9 EF units (%) in Coreg patients and by 2 EF units in placebo patients ( between group difference of 6 EF units) This treatment effect was. at a target dose of 25-50 mg b.i.d. The effects of carvedilol on ejection fraction were related to dose. Doses of 6.25 mg b.i.d., 12.5 mg b.i.d. and 25 mg b.i.d. were associated with placebo-corrected increases in EF of 5 EF units, 6 EF units and 8 EF units, respectively; each of these effects were nominally statistically significant in each trial.

revised

Coreg had a consistent and beneficial effect on all-cause mortality as well as the combined endpoints of all-cause mortality plus hospitalization (total, CV or for heart failure) in the overall study population and in all subgroups examined, including men and women, elderly and non-elderly, black and non-black.

Four U.S. multicenter, double-blind, placebo-controlled studies enrolled 1094 patients (696 randomized to carvedilol) with NYHA class II-III heart failure and ejection fraction <0.35. The vast majority were on digitalis, diuretics, and an ACE inhibitor at study entry. Patients were assigned to the studies based upon exercise ability. An Australia-New Zealand double-blind, placebo-controlled study enrolled 415 patients (half randomized to carvedilol) with less severe heart failure. All protocols excluded patients expected to undergo cardiac surgery during the 6 to 12 months of double-blind follow-up transplantation during the 7.5 to 15 months of double-blind follow-up.. All randomized patients had tolerated a 2-week course on carvedilol 6.25 mg b.i.d.

Mortality: Mortality was not a planned end-point in any of the U.S. or Austrailia-New Zealand studies. Overall, in the U.S. trials, mortality was reduced, nominally significantly so in 2 studies, but the actual effect size and statistical significance of this observation are difficult to define.

Mortality: Overall, in these four U.S. trials, mortality was reduced, nominally significantly so in 2 studies.

first paragraph revised

Coreg is indicated for the treatment of mild or moderate (NYHA class II or III) severe heart failure of ischemic or car-diomyopathic origin, in conjunction with usually in addition to diuretics, ACE inhibitor and digitalis, diuretics, and ACE inhibitor, to reduce the progression of disease as evidenced by cardiovascular death, cardiovascular hospitalization, or the need to adjust other heart failure medications. to increase survival and, also, to reduce the risk of hospitalization.

first paragraph revised

Coreg is contraindicated in patients with NYHA class IV decompensated cardiac failure requiring intravenous inotropic therapy, bronchial asthma (two cases of death from status asthmaticus have been reported in patients receiving single doses of Coreg ) or related bronchospastic conditions, second- or third-degree AV block, sick sinus syndrome or severe bradycardia (unless a permanent pacemaker is in place) ); or in patients with cardiogenic shock or severe bradycardia. who have decompensated heart failure requiring the use of intravenous inotropic therapy. Such patients should first be weaned from intravenous therapy before initiating Coreg.

2^nd and 3^rd paragraphs revised

In controlled studies of primarily mild-to-moderate congestive heart failure, the incidence of liver function abnormalities reported as adverse experiences was 5.0% (38 of 765 patients) in patients receiving Coreg and 4.6% (20 of 437 patients) in those receiving placebo. Three patients receiving carvedilol Coreg (0.4%) and two patients receiving placebo (0.5%) in placebo-controlled trials withdrew for abnormal hepatic function. Similarly, in a long-term, placebo-controlled trial in severe heart failure, there was no difference in the incidence of liver function abnormalities reported as adverse experiences between patients receiving Coreg and those receiving placebo. No patients receiving Coreg and one patient receiving placebo (0.09%) withdrew for hepatitis. In addition, patients treated with Coreg had lower values for hepatic transaminases than patients treated with placebo, possibly because Coreg-induced improvements in cardiac function led to less hepatic congestion and/or improved hepatic blood flow.

Hepatic injury has been reversible and has occurred after short- and/or long-term therapy with minimal clinical symptomatology. No deaths due to liver function abnormalities have been reported in association with the use of Coreg.

first sentence revised

In general, b -blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia.

first paragraph revised

Since Coreg (carvedilol) has b -blocking activity, it should not be discontinued abruptly, particularly in patients with ischemic heart disease. Instead, it should be discontinued over 1 to 2 weeks, whenever possible.

3^rd paragraph revised

In clinical trials of primarily mild-to-moderate heart failure, Hhypotension and postural

hypotension occurred in 9.7% and syncope in 3.4% of patients receiving carvedilolCoreg compared to 3.6% and 2.5% of placebo patients, 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 carvedilolCoreg patients, compared to 0.4% of placebo patients. 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 heart failure patients receiving Coreg compared to 8.7% and 2.3% of placebo patients, respectively. These events were a cause for discontinuation of therapy in 1.1% of Coreg patients, compared to 0.8% of placebo patients.

7^th paragraph revised

Worsening cardiac heart failure or fluid retention may occur during up-titration of carvedilol. If such symptoms occur, diuretics should be increased and the carvedilol dose should not be advanced until clinical stability resumes (see DOSAGE AND ADMINISTRATION). Occasionally, it is necessary to lower the carvedilol dose or temporarily discontinue it. Such episodes do not preclude subsequent successful titration of or a favorable response to carvedilol. In a placebo-controlled trial of patients with severe heart failure, worsening heart failure during the first 3 months was reported to a similar degree with carvedilol and with placebo. When treatment was maintained beyond 3 months, worsening heart failure was reported less frequently in patients 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.

Deleted

Hypertensive Patients with Left Ventricular Failure: In hypertensive patients who have congestive heart failure controlled with digitalis, diuretics and/or an angiotensin-converting enzyme inhibitor, Coreg (carvedilol) may be used. However, since it is likely that such patients are dependent, in part, on sympathetic stimulation for circulatory support, it is recommended that dosing follow the instructions for patients with congestive heart failure.

first paragraph revised

Of the 765 patients with congestive heart failure randomized to Coreg in U.S. clinical trials, 31% (235) were 65 years of age or older. Of 1,869 patients receiving Coreg in congestive heart failure trials worldwide, 39% were 65 years of age or older. Of the 1156 patients randomized to Coreg in a long-term, placebo-controlled trial in severe heart failure, 47% (547) were 65 years of age or older. Of 3,025 patients receiving Coreg in congestive heart failure trials worldwide, 42% were 65 years of age or older. There were no notable differences in efficacy or the incidence of adverse events between older and younger patients.

revised

Coreg has been evaluated for safety in congestive heart failure in more than 1,900 3,000 patients worldwide of whom 1,300 more than 2100 participated in U.S. placebo-controlled clinical trials. Approximately 54% 60%of the total treated population received Coreg for at least 6 months and 20% 30% received Coreg for at least 12 months. The adverse experience profile of Coreg in congestive heart failure patients was consistent with the pharmacology of the drug and the health status of the patients. In U.S. clinical trials comparing Coreg in in mild-to-moderate heart failure that compared Coreg daily doses up to 100 mg (n=765) to placebo (n=437), 5.4% of Coreg patients discontinued for adverse experiences vs. 8.0% of placebo patients. In a multinational clinical trial in severe heart failure (COPERNICUS) that compared Coreg in daily doses up to 50 mg (n=1156) with placebo (n=1133), 9.4% of Coreg patients discontinued treatment for adverse experiences vs. 11.2% of placebo patients.

Table 1 2 shows adverse events reported in patients with mild-to-moderate heart failure enrolled in U.S. placebo-controlled clinical trials of congestive heart failure patients that occurred with an incidence of greater than 2% regardless of causality and were more frequent in drug-treated patients than placebo-treated patients. Median study medication exposure was 6.33 months for both Coreg (carvedilol) and placebo patients. Shown are adverse events that occurred more frequently in drug-treated patients than placebo-treated patients with an incidence >2% regardless of causality. Median study medication exposure was 6.33 months for both carvedilol and placebo patients.

2^nd paragraph and the table revised

Table 2 4 shows adverse events in U.S. placebo-controlled clinical trials for hypertension that occurred with an incidence of greater than 1% regardless of causality, and that were more frequent in drug-treated patients than placebo-treated patients.

Table 4. Adverse Events in U.S. Placebo-Controlled Hypertension Trials

In addition to the events in Table 24, abdominal pain, back pain, chest pain, dependent edema, dyspepsia, dyspnea, fatigue, headache, injury, nausea, pain, rhinitis, sinusitis somnolence, and upper respiratory tract infection were also reported, but rates were at least as great in placebo-treated patients.

The following adverse events not described above were reported as possibly or probably related to Coreg in worldwide open or controlled trials with Coreg (carvedilol) in patients with hypertension or congestive heart failure.

deleted

Urinary System: Micturition frequency increased.

Metabolic and Nutritional: Hypokalemia, diabetes mellitus, hypertriglyceridemia

Rates of adverse events were generally similar across demographic subsets (men and women, elderly and non-elderly, blacks and non-blacks).

revised

DOSAGE MUST BE INDIVIDUALIZED AND CLOSELY MONITORED BY A PHYSICIAN DURING UP-TITRATION. Prior to initiation of Coreg, the dosing of digitalis, diuretics and ACE inhibitors (if used) should be stabilized it is recommended that fluid retention be minimized. The recommended starting dose of Coreg is 3.125 mg twice daily for two weeks. If this dose is tolerated, it can then be increased to 6.25 mg twice daily. Dosing should then be doubled every 2 weeks to the highest level tolerated by the patient. At initiation of each new dose, patients should be observed for signs of dizziness or light-headedness for one hour. The maximum recommended dose is 25 mg twice daily in patients weighing less than 85 kg (187 lbs) and 50 mg twice daily in patients weighing more than 85 kg. Coreg (carvedilol) should be taken with food to slow the rate of absorption and reduce the incidence of orthostatic effects.

The following BOX WARNING: is added:

INDICATIONS AND USAGE:

revised

INAPSINE (droperidol) is indicated:

CONTRAINDICATIONS:

Revised

WARNINGS:

revised

FLUIDS AND OTHER COUNTERMEASURES TO MANAGE HYPOTENSION SHOULD BE READILY AVAILABLE.

As with other CNS depressant drugs, patients who have received INAPSINE (droperidol) should have appropriate surveillance.

It is recommended that opioids, when required, initially be used in reduced doses. As with other neuroleptic agents, very rare reports of neuroleptic malignant syndrome (altered consciousness, muscle rigidity and autonomic instability) have occurred in patients who have received INAPSINE (droperidol).

Since it may be difficult to distinguish neuroleptic malignant syndrome from malignant hyperpyrexia in the perioperative period, prompt treatment with dantrolene should be considered if increases in temperature, heart rate or carbon dioxide production occur.

fourth paragraph revised

Vital signs and ECG should be monitored routinely.

Drug Interactions:

added

Potentially Arrhythmogenic Agents: Any drug known to have the potential to prolong the QT interval should not be used together with INAPSINE. Possible pharmacodynamic interactions can occur between INAPSINE and potentially arrhythmogenic agents such as class I or III antiarrhythmics, antihistamines that prolong the QT interval, antimalarials, calcium channel blockers, neuroleptics that prolong the QT interval, and antidepressants.

CNS Depressant Drugs: Other CNS depressant drugs (e.g., barbiturates, tranquilizers, opioids, and general anesthetics) have additive or potentiating effects with INAPSINE. When patients have received such drugs, the dose of INAPSINE required will be less than usual. Following the administration of INAPSINE, the dose of other CNS depressant drugs should be reduced.

ADVERSE REACTIONS:

added

OVERDOSAGE:

1^st paragraph revised

Manifestations: The manifestations of INAPSINE (droperidol) overdosage are an extension of its pharmacologic actions and may include QT prolongation and serious arrhythmias (e.g., torsade de pointes) (see BOX WARNING, WARNINGS, and PRECAUTIONS).

4^th paragraph revised

The intravenous LD₅₀ Median Lethal Dose of INAPSINE is 20-43 mg/kg in mice; 30 mg/kg in rats: 25 mg/kg in dogs and 11-13 mg/kg in rabbits. The intramuscular intravenous LD₅₀ Median Lethal Dose of INAPSINE is 195 mg/kg in mice; 104-110 mg/kg in rats; 97 mg/kg in rabbits and 200 mg/kg in guinea pigs.

DOSAGE AND ADMINISTRATION:

Revised

Vital signs and ECG should be monitored routinely.