Phenoxybenzamine

INDICATION AND USAGE Phenoxybenzamine hydrochloride capsules are indicated in the treatment of pheochromocytoma, to control episodes of hypertension and sweating. If tachycardia is excessive, it may be necessary to use a beta -blocking agent concomitantly.

CLINICAL PHARMACOLOGY Phenoxybenzamine hydrochloride is a long-acting, adrenergic, alpha -receptor-blocking agent, which can produce and maintain “chemical sympathectomy” by oral administration. It increases blood flow to the skin, mucosa and abdominal viscera, and lowers both supine and erect blood pressures. It has no effect on the parasympathetic system. 20 percent to 30 percent of orally administered phenoxybenzamine appears to be absorbed in the active form 1 . The half-life of orally administered phenoxybenzamine hydrochloride is not known; however, the half-life of intravenously administered phenoxybenzamine hydrochloride is approximately 24 hours. Demonstrable effects with intravenous administration persist for at least 3 to 4 days, and the effects of daily administration are cumulative for nearly a week 1 .

DOSAGE AND ADMINISTRATION The dosage should be adjusted to fit the needs of each patient. Small initial doses should be slowly increased until the desired effect is obtained or the side effects from blockade become troublesome. After each increase, the patient should be observed on that level before instituting another increase . The dosage should be carried to a point where symptomatic relief and/or objective improvement are obtained, but not so high that the side effects from blockade become troublesome. Initially, 10 mg of phenoxybenzamine hydrochloride twice a day. Dosage should be increased every other day, usually to 20 mg to 40 mg 2 or 3 times a day, until an optimal dosage is obtained, as judged by blood pressure control. Long-term use of phenoxybenzamine is not recommended (see PRECAUTIONS - Carcinogenesis and Mutagenesis ).

ADVERSE REACTIONS The following adverse reactions have been observed, but there are insufficient data to support an estimate of their frequency. Autonomic Nervous System*: Postural hypotension, tachycardia, inhibition of ejaculation, nasal congestion, miosis. *These so-called “side effects” are actually evidence of adrenergic blockade and vary according to the degree of blockade. Miscellaneous: Gastrointestinal irritation, drowsiness, fatigue. To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

WARNING Phenoxybenzamine hydrochloride-induced alpha -adrenergic blockade leaves beta -adrenergic receptors unopposed. Compounds that stimulate both types of receptors may, therefore, produce an exaggerated hypotensive response and tachycardia.

CONTRAINDICATIONS Conditions where a fall in blood pressure may be undesirable; hypersensitivity to the phenoxybenzamine hydrochloride capsules, or any of its components.

OVERDOSAGE SYMPTOMS - These are largely the result of blocking of the sympathetic nervous system and of the circulating epinephrine. They may include postural hypotension, resulting in dizziness or fainting; tachycardia, particularly postural; vomiting; lethargy; shock. Treatment When symptoms and signs of overdosage exist, discontinue phenoxybenzamine hydrochloride capsules. Treatment of circulatory failure, if present, is a prime consideration. In cases of mild overdosage, recumbent position with legs elevated usually restores cerebral circulation. In the more severe cases, the usual measures to combat shock should be instituted. Usual pressor agents are not effective. Epinephrine is contraindicated because it stimulates both alpha - and beta - receptors; since alpha- receptors are blocked, the net effect of epinephrine administration is vasodilation and a further drop in blood pressure (epinephrine reversal). The patient may have to be kept flat for 24 hours or more in the case of overdose, as the effect of the drug is prolonged. Leg bandages and an abdominal binder may shorten the period of disability. Intravenous infusion of levarterenol bitartrate** may be used to combat severe hypotensive reactions, because it stimulates alpha - receptors primarily. Although phenoxybenzamine hydrochloride is an alpha -adrenergic blocking agent, a sufficient dose of levarterenol bitartrate will overcome this effect. The oral LD 50 for phenoxybenzamine hydrochloride is approximately 2,000 mg/kg in rats and approximately 500 mg/kg in guinea pigs.