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.

General

HYPERSTAT (diazoxide) I.V. Injection is an effective antihypertensive agent requiring close monitoring of the patient's blood pressure at frequent intervals. Its administration may occasionally cause hypotension requiring treatment with sympathomimetic drugs. Therefore, HYPERSTAT I.V. Injection should be used primarily in the hospital or where adequate facilities exist to treat such untoward responses.

HYPERSTAT I.V. Injection should be administered only into a peripheral vein. Because the alkalinity of the solution is irritating to tissue, avoid extravascular injection or leakage. Subcutaneous administration has produced inflammation and pain without subsequent necrosis. If leakage into subcutaneous tissue occurs, the area should be treated with warm compresses and rest.

HYPERSTAT I.V. Injection should be used with care in patients who have impaired cerebral or cardiac circulation, that is, patients in whom abrupt reduction in blood pressure might be detrimental or those in whom mild tachycardia or decreased blood perfusion may be deleterious (see WARNINGS). Prolonged hypotension should be avoided so as not to aggravate preexisting renal failure.

Information for Patients

During and immediately following intravenous injection of HYPERSTAT I.V. Injection, the patient should remain supine.

Laboratory Tests

Diagnostic laboratory tests necessary to establish the patient's condition and status should be carried out prior to treatment with HYPERSTAT I.V. Injection. During and following treatment with HYPERSTAT I.V. Injection, laboratory tests to monitor the effects of treatment with this drug and the patient's condition should be done. Among the tests (not necessarily inclusive) are: hematologic (hematocrit, hemoglobin, white blood cell and platelet counts); metabolic (glucose, uric acid, total protein, albumin); electrolyte (sodium, potassium) and osmolality; renal function (creatinine, urine-protein); electrocardiogram.

Drug Interactions

Diazoxide is highly bound to serum protein. It can be expected to displace other substances which are also bound to protein, such as bilirubin or coumarin and its derivatives; resulting in higher blood levels of these substances.

An undesirable hypotension may result when diazoxide is administered to patients who have received other antihypertensive medication within 6 hours.

One patient in a clinical study exhibited excessive hypotension after concomitant administration of HYPERSTAT with hydralazine and methyldopa. An episode of maternal hypotension and fetal bradycardia occurred in a patient in labor who received both reserpine and hydralazine prior to administration of diazoxide. Neonatal hyperglycemia following intrapartum administration of HYPERSTAT I.V. Injection has also been reported.

HYPERSTAT I.V. Injection should not be administered within 6 hours of the administration of: hydralazine, reserpine, alphaprodine, methyldopa, beta-blockers, prazosin, minoxidil, the nitrites and other papaverine-like compounds.

Concomitant administration with thiazides or other commonly used diuretics may be expected to potentiate the hyperuricemic and antihypertensive effects of diazoxide.

Drug/Laboratory Test Interactions

The hyperglycemic and hyperuricemic effects of diazoxide preclude proper assessment of these metabolic states. Increased renin secretion, IgG concentrations and decreased cortisol secretion have also been noted. Diazoxide inhibits glucagon-stimulated insulin release and will cause a false-negative insulin response to glucagon. In the rat, dog, and monkey, diazoxide increased serum free fatty acids and decreased plasma insulin levels.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term animal dosing study has been done to evaluate the carcinogenic potential of diazoxide. No laboratory studies of mutagenic potential or animal studies of effects on fertility have been done.

Pregnancy Category C

Diazoxide has been shown to reduce fetal and/or pup survival; and to reduce fetal growth in rats, rabbits, and dogs at daily doses of 30, 21, or 10 mg/kg, respectively. In rats treated at term, diazoxide, at doses of 10 mg/kg and above, prolonged parturition.

The safety of HYPERSTAT I.V. Injection in pregnancy has not been established.

Nonteratogenic Effects

Diazoxide crosses the placental barrier and appears in cord blood. When given to the mother prior to delivery, the drug may produce fetal or neonatal hyperbilirubinemia, thrombocytopenia, altered carbohydrate metabolism, and possibly other side effects that have occurred in adults.

Labor and Delivery

HYPERSTAT I.V. Injection is not indicated for use in pregnancy. Intravenous administration of the drug during labor may cause cessation of uterine contractions, requiring administration of an oxytocic agent.

Nursing Mothers

Information is not available concerning the passage of HYPERSTAT in breast milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from diazoxide, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

See INDICATIONS AND USAGE.

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.