Hyperstat I.V. injection

HYPERSTAT I.V. Injection is a non-diuretic benzothiadiazine antihypertensive agent. Each ampule (20 mL) contains 300 mg diazoxide, USP, in a clear, sterile, colorless aqueous solution; the pH is adjusted to approximately 11.6 with sodium hydroxide.

Diazoxide has the following structural formula:

Diazoxide is 7-chloro-3-methyl-2 H -1,2,4-benzothiadiazine 1,1-dioxide, with the empirical formula C 8 H 7 CIN 2 O 2 S, and the molecular weight 230.7. It is a white crystalline powder practically insoluble to sparingly soluble in water.

HYPERSTAT I.V. Injection produces a prompt reduction of blood pressure in man by relaxing smooth muscle in the peripheral arterioles. Cardiac output is increased as blood pressure is reduced. Studies in animals demonstrate that coronary blood flow is maintained, while renal blood flow is increased after an initial decrease.

Transient hyperglycemia occurs in the majority of patients treated with HYPERSTAT, but usually requires treatment only in patients with diabetes mellitus. It will respond to the usual management measures, including insulin.

Blood glucose levels should be monitored, especially in patients with diabetes and in those requiring multiple injections of diazoxide. Cataracts have been observed in a few animals receiving repeated daily doses of intravenous diazoxide.

Since diazoxide causes sodium retention, repeated injections may precipitate edema and congestive heart failure. Increased volume of extracellular fluid may be a cause of treatment failure in nonresponsive patients. The increase in fluid volume characteristically responds to diuretic agents if adequate renal function exists. Concurrently administered thiazide diuretics may be expected to potentiate the antihypertensive and hyperuricemic actions of diazoxide. (See Drug Interactions .)

Diazoxide is extensively bound to serum protein (>90%). The plasma half-life is 28 ± 8.3 hours; however, the duration of its antihypertensive effect is variable, generally lasting less than 12 hours.

HYPERSTAT I.V. Injection is indicated for short-term use in the emergency reduction of blood pressure in severe, nonmalignant and malignant hypertension in hospitalized adults; and in acute severe hypertension in hospitalized children, when prompt and urgent decrease of diastolic pressure is required. Treatment with orally effective antihypertensive agents should not be instituted until blood pressure has stabilized. The use of HYPERSTAT I.V. Injection for longer than 10 days is not recommended.

HYPERSTAT I.V. Injection is ineffective against hypertension due to pheochromocytoma.

Rapid Decrease of Blood Pressure  Caution must be observed when reducing severely elevated blood pressure. Diazoxide should only be administered utilizing the new 150-mg minibolus dosage. The use of a 300-mg intravenous dose of diazoxide has been associated with angina and with myocardial and cerebral infarction. One instance of optic nerve infarction was reported when a 100-mmHg reduction in diastolic pressure occurred over ten minutes following a single 300-mg bolus. In one prospective trial conducted in patients with severe hypertension and coexistent coronary artery disease, a 50% incidence of ischemic changes in the electrocardiogram was observed following single 300-mg bolus injections of diazoxide. The desired blood pressure lowering should therefore be achieved over as long a period of time as is compatible with the patient's status. At least several hours and preferably 1 or 2 days is tentatively recommended.

Improved safety with equal efficacy can be achieved by administering HYPERSTAT I.V. Injection as a minibolus dose (1 to 3 mg/kg every 5 to 15 minutes up to a maximum of 150 mg in a single injection) until a diastolic blood pressure below 100 mmHg is achieved. HYPERSTAT I.V. Injection should not be administered in a bolus dose of 300 mg since this mode of administration is less predictable and less controllable than the minibolus dosage. If hypotension severe enough to require therapy results from the reduction in blood pressure, it will usually respond to the Trendelenberg maneuver. If necessary, sympathomimetic agents such as dopamine or norepinephrine may be administered.

Special attention is required for patients with diabetes mellitus and those in whom retention of salt and water may present serious problems.

Myocardial Lesions in Animals  Intravenous administration of diazoxide in dogs has induced subendocardial necrosis and necrosis of papillary muscles. These lesions, which are also produced by other vasodilator drugs (ie, hydralazine, minoxidil) and by catecholamines, are presumed to be related to anoxia resulting from a combination of reflex tachycardia and decreased perfusion.

It is reasonable to speculate that the currently recommended minibolus dosing regimen, which has replaced the 300-mg bolus dose in clinical practice, will result in adverse effects which are of similar character but of lesser frequency and severity.

In clinical experience with the rapid bolus administration of 300 mg, the most common adverse reactions reported were: hypotension (7%); nausea and vomiting (4%); dizziness and weakness (2%). Additional adverse reactions reported with bolus administration of 300 mg were as follows:

Cardiovascular:   sodium and water retention after repeated injections, especially important in patients with impaired cardiac reserve; hypotension to shock levels; myocardial ischemia, usually transient and manifested by angina, atrial and ventricular arrhythmias, and marked electrocardiographic changes, but occasionally leading to myocardial infarction; optic nerve infarction following too rapid decrease in severely elevated blood pressure; supraventricular tachycardia and palpitation; bradycardia; chest discomfort or nonanginal "tightness in the chest."

Central Nervous System:   cerebral ischemia, usually transient but occasionally leading to infarction and manifested by unconsciousness, convulsions, paralysis, confusion, or focal neurological deficit such as numbness of the hands; vasodilative phenomena, such as orthostatic hypotension, sweating, flushing, and generalized or localized sensations of warmth; various transient neurological findings secondary to alteration in regional blood flow to brain, such as headache (sometimes throbbing), dizziness, lightheadedness, sleepiness (also reported as lethargy, somnolence or drowsiness), euphoria or "funny feeling," ringing in the ears and momentary hearing loss, and weakness of short duration; apprehension or anxiety.

Gastrointestinal:   rarely, acute pancreatitis; nausea, vomiting and/or abdominal discomfort; anorexia; alteration in taste; parotid swelling; salivation; dry mouth; lacrimation; ileus; constipation and diarrhea.

Other:   hyperglycemia in diabetic patients, especially after repeated injections; hyperosmolar coma in an infant; transient hyperglycemia in nondiabetic patients; transient retention of nitrogenous wastes; various respiratory finding secondary to the relaxation of smooth muscle, such as dyspnea, cough and choking sensation; warmth or pain along the injected vein; cellulitis without sloughing and/or phlebitis at the injection site of extravasation; back pain and increased nocturia; hypersensitivity reactions, such as rash, leukopenia and fever; papilledema induced by plasma volume expansion secondary to the administration of diazoxide reported in a patient who had received eleven injections (300 mg/dose) over a 22-day period; malaise and blurred vision; transient cataract in an infant; hirsutism, and decreased libido.

HYPERSTAT I.V. Injection is supplied in a 20-mL ampule, containing 300 mg diazoxide, in a clear, sterile, colorless, aqueous solution; box of one ampule (NDC 0085-0201-05).

Protect from light and freezing. Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].

Schering Corporation

Kenilworth, NJ 07033

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