COREG CR (Page 3 of 11)

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Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and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

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.

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

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 COREG CR 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 non‑elderly, blacks and non‑blacks). COREG CR has been evaluated for safety in a 4-week (2 weeks of immediate-release carvedilol and 2 weeks of COREG CR) 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 COREG CR 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 COREG CR 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 US 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 US 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 US 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 US 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 US 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.

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