Carvedilol Phosphate (Page 3 of 9)

5.6 Effects on Blood Sugar

Betablockers may prevent early warning signs of hypoglycemia, such as tachycardia, and increase the risk for severe or prolonged hypoglycemia at any time during treatment, especially in patients with diabetes mellitus or children and patients who are fasting (i.e., surgery, not eating regularly, or are vomiting). If severe hypoglycemia occurs, patients should be instructed to seek emergency treatment.

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 carvedilol phosphate extended-release capsules 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

Beta-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 carvedilol phosphate extended-release capsules and the drug discontinued or dosage reduced if worsening of renal function occurs.

5.9 Major Surgery

Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and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

Beta-adrenergic blockade may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of beta-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 alpha-blocking agent should be initiated prior to the use of any beta-blocking agent. Although carvedilol has both alpha- and beta-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 beta-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 alpha-blocking activity may prevent such symptoms. However, caution should be taken in the administration of carvedilol phosphate extended-release capsules to patients suspected of having Prinzmetal’s variant angina.

5.13 Risk of Anaphylactic Reaction

While taking beta-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 (carvedilol phosphate extended-release capsules are 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.

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Carvedilol has been evaluated for safety in subjects with heart failure (mild, moderate, and severe), in subjects with left ventricular dysfunction following myocardial infarction, and in hypertensive subjects. The observed adverse event profile was consistent with the pharmacology of the drug and the health status of the subjects in the clinical trials. Adverse events reported for each of these populations reflecting the use of either carvedilol phosphate extended-release capsules or immediate-release carvedilol tablets are provided below. Excluded are adverse events considered too general to be informative, and those not reasonably associated with the use of the drug because they were associated with the condition being treated or are very common in the treated population. Rates of adverse events were generally similar across demographic subsets (men and women, elderly and non-elderly, blacks and non-blacks). Carvedilol phosphate extended-release capsules has been evaluated for safety in a 4-week (2 weeks of immediate­ release carvedilol tablets and 2 weeks of carvedilol phosphate extended-release capsules) clinical trial (n = 187) which included 157 subjects with stable mild, moderate, or severe chronic heart failure and 30 subjects with left ventricular dysfunction following acute myocardial infarction. The profile of adverse events observed with carvedilol phosphate extended-release capsules in this small, short-term trial was generally similar to that observed with immediate-release carvedilol tablets. Differences in safety would not be expected based on the similarity in plasma levels for carvedilol phosphate extended-release capsules and immediate-release carvedilol.

Heart Failure

The following information describes the safety experience in heart failure with immediate-release carvedilol.

Carvedilol has been evaluated for safety in heart failure in more than 4,500 subjects worldwide of whom more than 2,100 participated in placebo-controlled clinical trials. Approximately 60% of the total treated population in placebo-controlled clinical trials received carvedilol for at least 6 months and 30% received carvedilol for at least 12 months. In the COMET trial, 1,511 subjects with mild-to-moderate heart failure were treated with carvedilol for up to 5.9 years (mean 4.8 years). Both in U.S. clinical trials in mild-to-moderate heart failure that compared carvedilol in daily doses up to 100 mg (n = 765) with placebo (n = 437), and in a multinational clinical trial in severe heart failure (COPERNICUS) that compared carvedilol in daily doses up to 50 mg (n = 1,156) with placebo (n = 1,133), discontinuation rates for adverse experiences were similar in carvedilol and placebo subjects. In placebo-controlled clinical trials, the only cause of discontinuation greater than 1% and occurring more often on carvedilol was dizziness (1.3% on carvedilol, 0.6% on placebo in the COPERNICUS trial).

Table 2 shows adverse events reported in subjects with mild-to-moderate heart failure enrolled in

U.S. placebo-controlled clinical trials, and with severe heart failure enrolled in the COPERNICUS trial. Shown are adverse events that occurred more frequently in drug-treated subjects than placebo-treated 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 mild-to-moderate 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.

Table 2. Adverse Events (%) Occurring More Frequently with Immediate-Release Carvedilol than with Placebo in Subjects with Mild-to-Moderate 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)

Body System/Adverse Event

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 6 months and 53% received carvedilol for at least 12 months. 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 >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 >1% but ≤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 >1% and occurring more often on carvedilol was hypotension (1.5% on carvedilol, 0.2% on placebo).

Hypertension:Carvedilol phosphate extended-release capsules were evaluated for safety in an 8-week double-blind trial in 337 subjects with essential hypertension. The profile of adverse events observed with carvedilol phosphate extended-release capsules was generally similar to that observed with immediate-release carvedilol tablets. The overall rates of discontinuations due to adverse events were similar between carvedilol phosphate extended-release capsules and placebo.

Table 3. Adverse Events (%) Occurring More Frequently with Carvedilol Phosphate Extended-Release Capsules than with Placebo in Subjects with Hypertension (Incidence ≥1% in Subjects Treated with Carvedilol, Regardless of Causality)
Adverse Event Carvedilol Phosphate
Extended-Release Capsules
(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 6 months. In general, carvedilol was well tolerated at doses up to 50 mg 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 50 mg (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. placebo-controlled 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 6.25 mg to 50 mg as single or divided doses.

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

Table 4. Adverse Events (% Occurrence) in U.S. Placebo-Controlled Hypertension Trials with Immediate-Release Carvedilol Tablets (Incidence ≥1% in Subjects Treated with Carvedilol, Regardless of Causality) *
Adverse Event Carvedilol
(n = 1,142)
Placebo
(n = 462)
*
Shown are events with rate >1% rounded to nearest integer.

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

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 >0.1% 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 ≤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.

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