WARNING AND CAUTIONS

5.

WARNINGS AND PRECAUTIONS • 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 carvedilol tablets, 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 angina patients 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 carvedilol tablets is planned, the patients should be carefully observed and advised to limit physical activity to a minimum.

Carvedilol tablets should be discontinued over 1 to 2 weeks whenever possible.

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

5.2 Bradycardia In clinical trials, carvedilol tablets caused bradycardia in about 2% of hypertensive patients, and 6.5% of myocardial infarction patients with left ventricular dysfunction.

If pulse rate drops below 55 beats/minute, the dosage should be reduced.

5.3 Hypotension Postural hypotension occurred in 1.8% and syncope in 0.1% of hypertensive patients, primarily following the initial dose or at the time of dose increase and was a cause for discontinuation of therapy in 1% of patients.

In the CAPRICORN study of survivors of an acute myocardial infarction, hypotension or postural hypotension occurred in 20.2% of patients receiving carvedilol tablets compared to 12.6% of placebo patients.

Syncope was reported in 3.9% and 1.9% of patients, respectively.

These events were a cause for discontinuation of therapy in 2.5% of patients receiving carvedilol tablets, compared to 0.2% of placebo patients.

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)].

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 carvedilol dose should not be advanced until clinical stability resumes [see DOSAGE AND ADMINISTRATION ( 2 ) ].

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.

5.5 Non-allergic Bronchospasm Patients with bronchospastic disease (e.g., chronic bronchitis and emphysema) should, in general, not receive β-blockers.

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

It is prudent, if carvedilol tablets are used, to use the smallest effective dose, so that inhibition of endogenous or exogenous β-agonists is minimized.

In clinical trials, patients 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 carvedilol 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.

Studies designed to examine the effects of carvedilol on glycemic control in patients with diabetes and heart failure have not been conducted.

In a study designed to examine the effects of 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 <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 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 carvedilol 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 (carvedilol 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.