HyperStat (Diazoxide)

HYPERSTAT® I.V. INJECTION

Schering

Diazoxide

Antihypertensive

Action And Clinical Pharmacology: Diazoxide injection produces a prompt reduction in blood pressure by relaxing smooth muscle in the peripheral arterioles. Cardiac output is increased as blood pressure is reduced by diazoxide; coronary and cerebral blood flow are maintained. Renal blood flow is increased after an initial decrease. Diazoxide has no known direct action on the CNS. Patients refractory to other antihypertensive agents usually remain responsive to diazoxide.

Diazoxide is extensively bound to serum proteins (>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.

Indications And Clinical Uses: The emergency reduction of blood pressure in malignant hypertension in hospitalized patients, when prompt and urgent decrease of diastolic pressure is required. Hyperstat injection is especially valuable in the emergency treatment of hypertensive crises associated with acute congestive heart failure, acute hypertensive encephalopathy, acute glomerular nephritis, cerebral hemorrhage. It is also indicated in severe pre-eclamptic toxemia or eclampsia resistant to conventional antihypertensive therapy.

Treatment with orally effective antihypertensive agents should be instituted as soon as the hypertensive emergency is controlled.

Diazoxide injection is ineffective against hypertension due to pheochromocytoma.

Contra-Indications: Diazoxide injection should not be used in the treatment of compensatory hypertension, such as that associated with aortic coarctation or arteriovenous shunt.

The drug should not be used in patients hypersensitive to diazoxide or other thiazides, unless the potential benefits outweigh the possible risks.

Manufacturers’ Warnings In Clinical States: Hypotension may occasionally result from the administration of diazoxide injection. If hypotension, severe enough to require therapy occurs, it will usually respond to the administration of sympathomimetic agents, such as norepinephrine.

Hyperglycemia occurs in the majority of patients, but usually requires treatment only in patients with diabetes mellitus; it will respond to the usual management, including insulin. Therefore, blood glucose levels should be monitored, especially in patients with diabetes or in those patients requiring multiple injections of diazoxide.

Hyperglycemia and hyperosmolar coma associated with transient cataracts developed in one infant receiving repeated daily doses of oral diazoxide. The disturbed carbohydrate metabolism was successfully treated with insulin. Cataracts have been observed in a few animals receiving repeated daily doses of i.v. or oral diazoxide.

Since diazoxide causes sodium retention, repeated injections may precipitate edema and congestive heart failure. This retention responds characteristically to diuretic agents if adequate renal function exists. It should be noted that concurrently administered thiazides may potentiate the antihypertensive, hyperglycemic, and hyperuricemia actions of diazoxide (see Drug Interactions).

Since increased volume of extracellular fluid may be a cause of treatment failure in nonresponsive patients, it may be advisable to reduce this increased volume by means of a diuretic agent (see Drug Interactions).

Although no evidence of excessive anticoagulant effects has been reported, patients, especially those who are hypoalbuminemic and receive diazoxide injection and coumarin or its derivatives, may require reduction in dosage of the anticoagulant (see Drug Interactions).

Diazoxide injection should be administered with caution to patients being treated concurrently with methyldopa or reserpine, or with drugs which act by direct peripheral vasodilatation, especially hydralazine, the nitrites and papaverine-like compounds.

Pregnancy: Like other thiazides, diazoxide crosses the placenta and published animal experiments on sheep and goats indicate it can cause hyperglycemia effects in the newborn apparently through damage to the islets of Langerhans. However, published human clinical evidence indicates the use of diazoxide in eclamptic patients is compatible with the delivery of normal infants. In any case, if diazoxide injection is administered to pregnant women, the potential benefit should be weighed against the possible hazards to the fetus. As with thiazides, diazoxide crosses the placental barrier and appears in cord blood. They may produce fetal or neonatal hyperbilirubinemia, thrombocytopenia, altered carbohydrate metabolism, and possibly other adverse reactions that have occurred in adults; similar reactions may occur with diazoxide.

Precautions: Diazoxide injection is a potent 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, adequate facilities to treat such untoward reactions should be available when diazoxide injection is used.

Diazoxide injection should be administered only into a peripheral vein. Because the alkalinity of the solution is irritating to tissue, extravascular injection or leakage should be avoided; s.c. administration has produced inflammation and pain without subsequent necrosis. If leakage into s.c. tissue occurs, the area should be treated conservatively.

Maximal antihypertensive effects occur after rapid administration (within 30 seconds) into the vein; a slower injection may fail to reduce blood pressure or produce a very brief response.

As with any potent antihypertensive agent, diazoxide injection should be used with care in patients who have impaired cerebral or cardiac circulation, that is, patients in whom abrupt and brief reductions in blood pressure might be detrimental or those in whom concurrent tachycardia may be deleterious.

Special attention is required for patients with diabetes mellitus and those in whom retention of salt and water may present serious problems (see Warnings). Nondiabetic patients, may have a transient, reversible, and clinically insignificant increase in blood glucose following diazoxide injection.

Since peritoneal dialysis or hemodialysis can reduce levels of diazoxide in the blood, patients undergoing dialysis may require more than one injection.

Adverse Reactions: Frequent and serious adverse reactions: Sodium and water retention after repeated injections, especially important in patients with impaired cardiac reserve; hyperglycemia frequently requiring treatment in diabetic patients, especially after repeated injections.

Infrequent but serious adverse reactions: Hypotension to shock levels; myocardial ischemia, usually transient but possibly leading to thrombosis and manifested by angina, atrial and ventricular arrhythmias, and marked electrocardiographic changes; cerebral ischemia, usually transient but possibly leading to thrombosis and manifested by unconsciousness, convulsions, paralysis, confusion or focal neurological deficit, such as numbness of the hands; persistent retention of nitrogenous wastes after repeated injections; hypersensitivity reactions, such as rash, leukopenia, and fever. Rarely, acute pancreatitis has been reported. Papilledema induced by plasma volume expansion secondary to the administration of diazoxide, was reported in one patient who had received 11 injections over a 22 day period.

Others: Vasodilative phenomena, such as orthostatic hypotension, sweating, flushing, and generalized or localized sensations of warmth; supraventricular tachycardia and palpitation; bradycardia; various transient neurological findings secondary to alterations in regional blood flow to the 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; chest discomfort or non-anginal “tightness in the chest”; transient hyperglycemia in nondiabetic patients, transient retention of nitrogenous wastes, and various respiratory and gastrointestinal findings secondary to the relaxation of smooth muscle, such as dyspnea, cough and choking sensation; nausea and vomiting and/or abdominal discomfort, anorexia, alteration in taste, parotid swelling, salivation, dry mouth, lacrimation, ileus, constipation and diarrhea. Also, warmth or pain along the injected vein; cellulitis without sloughing and/or phlebitis at the site of extravasation; back pain and increased nocturia. Apprehension or anxiety, malaise and blurred vision occurred on single occasions.

Drug Interactions: Since diazoxide is highly bound to serum protein, it may 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. A drug interaction has also been reported for oral diazoxide and phenytoin, such that their concomitant administration may result in a loss of seizure control. These potential interactions must be considered when administering diazoxide injection. The concomitant administration of diazoxide with thiazides or other commonly used potent diuretics may potentiate the hyperglycemia, hyperuricemic and antihypertensive effects of diazoxide.

Diazoxide injection should be administered with caution to patients being treated concurrently with methyldopa or reserpine, or with drugs which act by direct peripheral vasodilatation, especially hydralazine, the nitrites and papaverine-like compounds.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Overdosage of diazoxide injection may cause an undesirable hypotension. Usually, this can be controlled with sympathomimetic agents, such as norepinephrine; failure of the blood pressure to rise in response to such an agent suggests that the hypotension may have been caused by something other than diazoxide. Excessive hyperglycemia resulting from an overdosage will respond to conventional therapy.

Diazoxide may be removed from the blood by peritoneal dialysis or hemodialysis.

Dosage And Administration: Diazoxide injection is administered undiluted and rapidly by i.v. injections of 1 to 3 mg/kg, up to a maximum of 150 mg. This dose may then be repeated at intervals of 5 to 15 minutes until a satisfactory reduction in blood pressure has been achieved.

Recent studies have shown that minibolus administration of diazoxide injection (doses of 1 to 3 mg/kg repeated at intervals of 5 to 15 minutes) is as effective as the administration of 300 mg in a single dose in reducing blood pressure while offering improved safety. Minibolus administration provides a more gradual reduction in blood pressure and thus avoids the circulatory and neurological risks associated with acute hypotension.

It should only be given into a peripheral vein. Do not administer it i.m., s.c., or into body cavities. Avoid extravasation of the drug into s.c. tissues.

The response to diazoxide injection varies from patient to patient. Generally, blood pressure decreases within 5 minutes, often within 1 to 2 minutes, to the lowest level achieved. The blood pressure increases relatively rapidly in the next 10 to 30 minutes, and then more slowly over the following 2 to 12 hours, nearly reaching but rarely exceeding the pretreatment level. The response to successive injections is frequently better than that to the initial injection.

Treatment of hypertensive emergencies with diazoxide injection should be limited to a few days and a regimen of oral antihypertensive medications should be instituted as soon as possible.

With the patient recumbent, the calculated dose of diazoxide injection is administered i.v. in 30 seconds or less. Slow i.v. injection may fail to reduce the blood pressure or may produce an exceedingly short response.

Repeated administration of diazoxide injection at intervals of 4 to 24 hours usually will maintain the blood pressure below pretreatment levels until a regimen of oral antihypertensive medication becomes effective. The interval between injections may be adjusted by the duration of the response to each injection. It is usually unnecessary to continue treatment with diazoxide injection for more than 4 to 5 days.

Following the use of diazoxide injection, the blood pressure should be monitored closely until it has stabilized. Thereafter, measurements taken hourly during the balance of the effect will indicate any unusual responses. A further decrease in blood pressure at 30 minutes or more after injection should be investigated for causes other than the action of diazoxide injection. It is preferable that the patient remain recumbent for half an hour after injection. In ambulatory patients, the blood pressure should be measured with the patient standing before surveillance is ended.

Since repeated administration of diazoxide injection can lead to sodium and water retention, administration of a diuretic may be necessary both for maximal blood pressure reduction and to avoid congestive failure (see Drug Interactions).

Availability And Storage: Each 20 mL ampul contains: diazoxide 300 mg in a clear, colorless, aqueous solution. The pH is adjusted to approximately 11.6 with sodium hydroxide. Protect from light and freezing; store between 2 and 30°C.

HYPERSTAT® I.V. INJECTION Schering Diazoxide Antihypertensive

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