DIAZOXIDE (Generic for PROGLYCEM)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
Oral Liquid Formulations
-Shake well prior to administration. Administer using a calibrated measuring device.
-Protect from light.



Injectable Administration
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
Intermittent IV Injection
-No dilution necessary.
-Patient should be in the supine position prior to and immediately after IV injection. Keep patient in recumbent position for at least 60 minutes after injection. Take standing blood pressure prior to ambulation.
-Inject into a peripheral vein over 30 seconds or less.
-Patients should be switched to an oral antihypertensive regimen as soon as possible.

The development of abnormal facial features has been reported in 4 children receiving long-term (> 4 years) oral diazoxide therapy for hypoglycemia due to hyperinsulinism.

Sodium retention and fluid retention can occur frequently in patients receiving diazoxide. Patients at highest risk include those receiving multiple doses and young infants. Edema, weight gain, and congestive heart failure may result; diuretic therapy usually reverses the retention. In infants receiving diazoxide for congenital hyperinsulinemia, chlorothiazide is often given in conjunction with diazoxide to minimize these effects; chlorothiazide also potentiates the hyperglycemic and hyperuricemic effects of diazoxide.

Although the therapeutic intent of oral diazoxide is to raise blood glucose, excessive increases can occur. Diabetic ketoacidosis and nonketotic hyperosmolar coma may develop quickly. Patients with intercurrent illness or under other acute stress are at highest risk. Appropriate monitoring of blood glucose and urine glucose and ketones can aid early detection and treatment. Restoration of fluid and electrolytes, together with administration of insulin, is usually effective. Because diazoxide has a long half-life, monitor patients for a prolonged period until blood glucose stabilizes. A reduction in dosage at the first appearance of hyperglycemia may avoid progression to ketoacidosis and coma. Transient hyperglycemia also occurs after IV administration of diazoxide, but usually only requires treatment in patients with diabetes. It may also occur through overdosage of diazoxide via the oral or IV route.

Hypotension and hypertension both have been reported occasionally in those receiving oral diazoxide for hypoglycemia. Sinus tachycardia and palpitations are relatively common. Rarely, chest pain (unspecified) has also been reported. One of the most common adverse reactions after IV administration of diazoxide in clinical trials was hypotension (7%). The incidence of adverse reactions were originally published when 300 mg IV bolus doses were routinely given. Using the present, lower dosages, this effect is thought to be less common and less severe. Presently, hypotension is uncommon in patients being treated with IV diazoxide alone, but is common when diazoxide is used in combination with diuretics or other drugs with hypotensive effects. Severe hypotension may necessitate treatment with sympathomimetic agents. Myocardial ischemia can occur in patients receiving IV diazoxide. Myocardial ischemia may present as transient angina, ECG changes, atrial arrhythmias, or ventricular arrhythmias; occasionally myocardial infarction may occur. Sinus bradycardia and orthostatic hypotension have been observed after IV administration.

Pulmonary hypertension was reported in 11 neonates and infants treated with diazoxide for low blood sugar; in all cases, the pulmonary hypertension resolved or improved after diazoxide was stopped. Neonates and infants with the following risk factors may be at higher risk for the development of pulmonary hypertension: meconium aspiration syndrome, respiratory distress syndrome, transient tachypnea of the newborn, pneumonia, sepsis, congenital diaphragmatic hernia, and congenital heart disease. Instruct parents and caregivers to monitor their child carefully and seek immediate medical attention if the infant displays any signs of difficulty breathing.

Diazoxide can produce hirsutism of the lanugo type, especially during prolonged oral administration. Hypertrichosis occurs mainly on the forehead, back and limbs, and is more common in children and females. Withdrawal of diazoxide usually results in a regression. Coarsening of facial features has also been reported with chronic therapy.

Gastrointestinal adverse events associated with diazoxide use include nausea, vomiting, anorexia, dysgeusia (or a transient loss of taste), abdominal pain, diarrhea, constipation, xerostomia, salivation, parotid swelling, and ileus. Acute pancreatitis and pancreatic necrosis have been rarely reported after IV diazoxide administration.

Skin rash (unspecified) and fever have been occurred after oral and IV administration of diazoxide.

Thrombocytopenia due to diazoxide is more likely to occur after prolonged oral administration and may be accompanied by purpura. Thrombocytopenia may require discontinuation of therapy. Neutropenia due to diazoxide is usually of a transient nature and not accompanied by an increased susceptibility to infection. Leukopenia has been reported as part of a hypersensitivity syndrome. Other hematologic reactions including eosinophilia, decreased IgG, decreased hemoglobin and hematocrit (anemia), and excessive bleeding have been reported with oral use. Lymphadenopathy has also been reported.

Adverse CNS reactions have been reported during prolonged oral administration of diazoxide and include anxiety, dizziness, headache, insomnia, malaise, polyneuritis, paresthesias, weakness, and extrapyramidal signs. The most common central nervous system (CNS) adverse reactions after IV administration of diazoxide were dizziness and weakness (2%). The incidence of adverse reactions were originally published when 300 mg IV bolus doses were routinely given. Using the present, lower dosages, these effects are thought to be less common and less severe. Cerebral ischemia has been reported with the IV use of diazoxide and is usually transient but can occasionally cause infarction manifested by unconsciousness, seizures, muscle paralysis, confusion, or focal neurologic deficit such as numbness of the hands (paresthesias). Other CNS effects reported with IV diazoxide include those associated with findings secondary to alteration in regional blood flow to the brain such as headache (sometime throbbing), dizziness, lightheadedness, lethargy, drowsiness, euphoria, tinnitus, momentary hearing loss, weakness of short duration, apprehension, and anxiety. Other adverse reactions reported due to the vasodilating actions of IV diazoxide include headache, flushing, pruritus, and diaphoresis.

Ocular adverse reactions have been reported with intravenous and oral use of diazoxide and include transient cataracts, ocular hemorrhage, ring scotomata, blurred vision, lacrimation, and diplopia. Optic nerve infarction has occurred after a too rapid decrease of severely elevated blood pressure.

Elevated hepatic enzymes (AST, alkaline phosphatase) have been reported with the oral use of diazoxide.

Renal adverse reactions including decreased creatinine clearance and urinary output, azotemia, hematuria, albuminuria, and reversible nephrotic syndrome have been reported with the oral use of diazoxide. Hyperuricemia is relatively common; gout has also been reported.

Dyspnea, cough, and choking sensation, secondary to relaxation of smooth muscle, have been reported with the intravenous use of diazoxide.

Skeletal changes, specifically advance in bone age, has been reported with oral diazoxide. Alopecia, galactorrhea, and monilial dermatitis have also occurred.

Extravasation of diazoxide during IV administration can cause burning, cellulitis, or phlebitis. A feeling of warmth or pain can occur along the injected vein. Monitor patients receiving IV diazoxide for an injection site reaction.

Diazoxide inhibits glucagon-stimulated insulin release and causes a false-negative insulin response to glucagon.

Diazoxide injection is contraindicated in patients with sulfonamide hypersensitivity; both the injection and oral suspension are contraindicated in patients with thiazide diuretic hypersensitivity. Chemical structure similarities makes cross sensitivity reactions possible.

Oral diazoxide is contraindicated as a treatment for functional hypoglycemia (e.g., reactive or post-prandial hypoglycemia or hypoglycemia due to diabetic therapy). These conditions are more effectively treated with conventional measures. Hyperglycemic effects of diazoxide can be potentiated in patients with hypokalemia. Although the intended effect of oral diazoxide is to raise blood glucose, this effect can be exaggerated in some patients and may be an undesired effect in patients treated with intravenous diazoxide. Diazoxide can cause severe hyperglycemia in susceptible patients, particularly patients under acute stress. Monitoring blood glucose and urine glucose and ketones is recommended for patients receiving chronic diazoxide therapy, especially under times of stress. Patients with diabetes mellitus, hepatic disease, and those receiving antihypoglycemic agents are also at increased risk for hyperglycemia.

Administer diazoxide cautiously to patients in whom sodium and fluid retention could be detrimental (e.g., those with poor cardiac reserves, including those with uncompensated congestive heart failure). Chronic administration of oral diazoxide frequently causes sodium and fluid retention, which should respond to diuretics. Sudden reductions in blood pressure secondary to intravenous diazoxide can be hazardous to patients with cardiac disease or coronary artery disease, cerebrovascular disease or insufficiency, or mild tachycardia. Prolonged hypotension can exacerbate renal disease.

Use diazoxide with caution in neonates and infants, especially those with risk factors for pulmonary hypertension such as meconium aspiration syndrome, respiratory distress syndrome, transient tachypnea of the newborn, pneumonia, sepsis, congenital diaphragmatic hernia, and congenital heart disease. Pulmonary hypertension was reported in 11 neonates and infants treated with diazoxide for low blood sugar; in all cases, the pulmonary hypertension resolved or improved after diazoxide was stopped. Patients receiving diazoxide should be monitored for signs of difficulty breathing such as flaring nostrils, grunting, unusual movement of their child's chest, rapid breathing, difficulty feeding, or a bluish color of the lips or skin. Diazoxide should be stopped immediately if pulmonary hypertension is identified.

Use diazoxide with caution in patients with renal disease; monitor serum electrolytes and fluid status carefully in these patients. The half-life of diazoxide may be prolonged in patients with renal impairment. Accumulation of the drug and possible toxicity may result. Dosage adjustments may be required. Diazoxide is highly protein bound; uremia may cause displacement of the drug and a higher free fraction available for pharmacologic action. Clinical effects may be more pronounced. In addition, chronic use of diazoxide is often associated with fluid and sodium retention, which may worsen the fluid status of patients with renal failure.

Use diazoxide with caution in neonates with jaundice; diazoxide can displace bilirubin from albumin-binding sites and worsen hyperbilirubinemia.

Use diazoxide with caution in patients with a history of gout or hyperuricemia; diazoxide may cause an increase in serum uric acid concentrations.

Intravenous diazoxide is contraindicated in the management of hypertension due to aortic coarctation or arteriovenous shunt. The drug is ineffective against these conditions, and diazoxide-induced increases in cardiac output can be harmful.

Do not use diazoxide for the treatment of hypertension secondary to pheochromocytoma because the drug is ineffective against this disorder.

Do not give diazoxide via subcutaneous administration or intramuscular administration. Administer IV diazoxide intravenously through a peripheral vein, taking care to avoid extravasation. Diazoxide injection is an alkaline solution and may be irritating to tissues.

Description: Diazoxide is a nondiuretic benzothiadiazine derivative that is structurally similar to the thiazide diuretics. It is used orally as an antihypoglycemic agent and intravenously as an antihypertensive. The oral formulation is indicated for the management of hypoglycemia secondary to hyperinsulinemia. Oral preparations of diazoxide are not suited for chronic management of hypertension because of the drug's hyperglycemic and sodium-retaining properties. Sodium and fluid retention is a common adverse reaction to diazoxide therapy, especially in infants, and may require concomitant diuretic therapy. As an antihypertensive, diazoxide is used for the short-term, acute reduction of blood pressure in patients with malignant hypertension. Oral diazoxide is FDA approved in pediatric patients as young as neonates; diazoxide injection is FDA approved in pediatric patients as young as children (age not specified).

General dosing information for ORAL diazoxide:
-Oral diazoxide is FDA-approved in pediatric patients for management of hypoglycemia due to the following conditions: leucine sensitivity, islet cell hyperplasia, nesidioblastosis, extrapancreatic malignancy, islet cell adenoma, and adenomatosis.
-Diazoxide may be used preoperatively as a temporary measure and postoperatively, if hypoglycemia persists after surgery.


For the treatment of secondary hypoglycemia (e.g., hypoglycemia due to congenital hyperinsulinemia*):
Oral dosage:
Neonates and Infants: 10 mg/kg/day PO given in divided doses every 8 hours initially. The usual range is 8 to 15 mg/kg/day; however, 5 to 20 mg/kg/day PO divided every 8 to 12 hours has been reported. For congenital hyperinsulinemia, diazoxide is often given in combination with chlorothiazide (7 to 10 mg/kg/day PO divided every 12 hours) for its additive hyperglycemic effects and to minimize fluid retention associated with diazoxide. Higher doses may be necessary for refractory hypoglycemia. If diazoxide therapy is not effective in controlling hypoglycemia after 2 to 3 weeks, discontinue therapy. Pulmonary hypertension has been reported in neonates and infants receiving diazoxide; monitor patients for signs and symptoms of respiratory distress.
Children and Adolescents: 3 mg/kg/day PO given in divided doses every 8 hours initially. The usual dosage range is 3 to 8 mg/kg/day PO given in divided doses every 8 to 12 hours. Higher doses may be necessary for refractory hypoglycemia. If diazoxide therapy is not effective in controlling hypoglycemia after 2 to 3 weeks, discontinue therapy.

Maximum Dosage Limits:
-Neonates
Maximum oral dose is based on blood glucose concentrations; up to 20 mg/kg/day PO has been reported.
-Infants
Maximum oral dose is based on blood glucose concentrations; up to 20 mg/kg/day PO has been reported.
-Children
8 mg/kg/day PO is a typical upper limit, but higher doses may be required for refractory hypoglycemia.
-Adolescents
8 mg/kg/day PO is a typical upper limit, but higher doses may be required for refractory hypoglycemia.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; however, the elimination of diazoxide is reduced in patients with renal impairment. Dosage adjustments may be necessary based upon clinical response.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Diazoxide has two main therapeutic intents: to raise blood glucose in the setting of hyperinsulinemia (oral formulation) and for the short-term reduction of blood pressure (parenteral formulation).

Antihypoglycemic Effects
Diazoxide inhibits pancreatic secretion of insulin, stimulates the release of glucose from the liver, and causes catecholamine release. Insulin or tolbutamide will reverse the hyperglycemic effects of diazoxide, but diazoxide does not inhibit tolbutamide-induced insulin release. The inhibition of insulin release may be antagonized by alpha-adrenergic blocking agents.

Antihypertensive Effects
Diazoxide causes vasodilation of peripheral arterioles, resulting in a reduction in peripheral vascular resistance and blood pressure. Diazoxide exerts its effects by hyperpolarizing (and effectively relaxing) arterial smooth muscle cells by activating ATP-sensitive potassium channels. The degree of vasoconstriction appears to be an important factor in the hypotensive actions of diazoxide. Patients with malignant hypertension appear to receive the most benefit. Consequently, as an antihypertensive, diazoxide is most effective in the acute setting. During long-term therapy, sodium and fluid retention offset diazoxide's vasodilatory effect. Reflex tachycardia can occur. While the hypotensive effect of the intravenous formulation can be pronounced, the oral formulation typically does not cause a marked reduction in blood pressure.

Other Effects
Sodium and fluid retention are common effects with the prolonged use of diazoxide and may necessitate concomitant diuretic therapy. Diazoxide causes increased proximal tubular resorption of sodium and water. Renin increases during diazoxide therapy. Potassium, chloride, uric acid, and bicarbonate excretion is reduced during diazoxide therapy, and plasma free fatty acid concentrations are increased.

Pharmacokinetics: Diazoxide is administered orally for the treatment of hypoglycemia and intravenously for the short-term treatment of hypertension. Diazoxide is > 90% protein bound, and only unbound diazoxide is active. Diazoxide is renally eliminated. The half-life in adults ranges from 24-36 hours; however, the pharmacological effects do not typically last this long.

Affected cytochrome P450 isoenzymes: none


-Route-Specific Pharmacokinetics
Oral Route
Hyperglycemic effects begin approximately 1 hour after oral administration and persist about 8 hours in patients with normal renal function.

Intravenous Route
Hypotensive effects generally occur within 15 minutes after IV administration. The mean plasma half-life after IV administration has been reported as 28 +/- 8.3 hours. The duration of antihypertensive effect is variable. It has been reported to range from 4-24 hours, generally lasting < 12 hours.


-Special Populations
Pediatrics
Infants and Children
Limited data indicate that the half-life of diazoxide may be shorter in pediatric patients versus adult patients. After oral administration, the plasma half-life in 4 infants and children (4 months to 6 years of age) was reported to range from 9.5-24 hours after long-term administration compared to 24-36 hours in 2 adult patients.

Renal Impairment
Some data suggest that the elimination half-life of diazoxide increases in patients with renal disease in proportion to the reductions in creatinine clearance. A half-life of 20-53 hours has been reported in adults with renal failure.