Pharmacology
Diazoxide administered orally produces a prompt dose-related increase in blood glucose level, due primarily to an inhibition of insulin release from the pancreas and also to an extrapancreatic effect.
The hyperglycemic effect begins within an hour and generally lasts no more than 8 hours in the presence of normal renal function.
Diazoxide decreases the excretion of sodium and water, resulting in fluid retention which may be clinically significant.
The effects on blood pressure are usually not marked with the oral preparation. This contrasts with the i.v. preparation (see Adverse Effects). Other pharmacologic actions include increased pulse rate; increased serum uric acid levels due to decreased excretion; increased serum levels of free fatty acids; decreased chloride excretion; decreased para-aminohippuric acid (PAH) clearance with no appreciable effect on glomerular filtration rate. The concomitant administration of a benzothiazide diuretic may intensify the hyperglycemic and hyperuricemic effects of diazoxide. In the presence of hypokalemia, hyperglycemic effects are also potentiated. Diazoxide-induced hyperglycemia is reversed by the administration of insulin or tolbutamide.
The inhibition of insulin release by diazoxide is antagonized by alpha-adrenergic blocking agents. Diazoxide is extensively bound (more than 90%) to serum proteins and is excreted by the kidneys. The plasma half-life following i.v. administration is about 28+/−8.3 hours. Limited data on oral administration revealed a half-life of 24 and 36 hours in 2 adults. In 4 children aged 4 months to 6 years, the plasma half-life varied from 9.5 to 24 hours on long-term oral administration. The half-life may be prolonged following overdosage and in patients with impaired renal function.
Indications
Oral diazoxide is useful in the management of hypoglycemia due to hyperinsulinism associated with the following conditions:
Adults: inoperable islet cell adenoma or carcinoma or extrapancreatic malignancy.
Children: leucine sensitivity, islet cell hyperplasia, nesidioblastosis, extrapancreatic malignancy, islet cell adenoma, or adenomatosis. It may be used preoperatively as a temporary measure and post-operatively if hypoglycemia persists.
Diazoxide should be used only after a diagnosis of hypoglycemia due to one of the above conditions has been definitely established. When other specific medical therapy or surgical management either has been unsuccessful or is not feasible, treatment with diazoxide should be considered.
Precautions
Diuretics: The hyperglycemic and hyperuricemic actions of diazoxide may be potentiated by the concomitant administration of thiazides or other commonly used diuretics.
Coumarin Anticoagulants: The administration of diazoxide to patients treated with coumarin and its derivatives may result in potentiation of hypoprothrombic action and may necessitate a decrease of anticoagulant dosage.
Diphenyldydantoin: The concomitant administration of diazoxide to diphenyldydantoin treated patients can cause loss of seizure control.
Chlorpromazine: The hyperglycemic action of diazoxide may be enhanced by concomitant administration of chlorpromazine.
Supplied
Each opaque orange capsule, contains: diazoxide USP 100 mg. Nonmedicinal ingredients: lactose and magnesium stearate. Tartrazine-free. Bottles of 100. Store between 15 and 30°C.
Contraindications
The use of diazoxide for functional hypoglycemia is contraindicated. The drug should not be used in patients hypersensitive to diazoxide or to other thiazides unless the potential benefits outweigh the possible risks.
Warnings
Diazoxide may pass into the breast milk of nursing mothers.
The antidiuretic property of diazoxide may lead to significant fluid retention, which in patients with compromised cardiac reserve may precipitate congestive heart failure. The fluid retention will respond to conventional therapy with diuretics.
It should be noted that concomitantly administered thiazides may potentiate the hyperglycemic and hyperuricemic actions of diazoxide (see Precautions, Drug Interactions).
Ketoacidosis and non-ketotic hyperosmolar coma have been reported in patients treated with recommended doses, usually during intercurrent illness. Prompt recognition and treatment are essential (see Overdose) and prolonged surveillance following the acute episode is necessary because of the long drug half-life of approximately 30 hours. The occurrence of these serious events may be reduced by careful education of patients regarding the need for monitoring the urine for sugar and ketones and for prompt reporting of abnormal findings and unusual symptoms to the physician.
In the presence of hypokalemia, the hyperglycemia effects of diazoxide are potentiated.
Transient cataracts occurred in association with hyperosmolar coma in an infant and subsided on correction of the hyperosmolarity. Cataracts have been observed in several animals receiving daily doses of i.v. or oral diazoxide.
Diazoxide should not be used in women of child-bearing age except in life-threatening situations. Reproduction studies using the oral preparation in rats have revealed increased fetal resorptions and delayed parturition, as well as fetal skeletal anomalies. Evidence of skeletal and cardiac teratogenic effects in rabbits has been noted with the i.v. administration. The drug has also been demonstrated to cross the placental barrier in animals and cause degeneration of the fetal pancreatic beta cells. Since there are no adequate data on fetal effects of this drug when given to pregnant women, safety in pregnancy has not been established.
When its use in pregnant women is considered, the indications should be limited to those specified above for adults (see Indications) and the potential benefits to the mother must be weighed against possible harmful effects to the fetus.
Adverse Effects
gout, acute pancreatitis/pancreatic necrosis, galactorrhea, enlargement of lump in breast.
eosinophilia; decreased hemoglobin/hematocrit; excessive bleeding; decreased IgG.
transient cataracts, subconjunctival hemorrhage, ring scotoma, blurred vision, diplopia, lacrimation.
increased AST, alkaline phosphatase, azotemia, decreased creatinine clearance, reversible nephrotic syndrome, decreased urinary output, hematuria, albuminuria.
monilial dermatitis, herpes, advance in bone age; loss of scalp hair.
anxiety, dizziness, insomnia, polyneuritis, paresthesia, pruritus, extrapyramidal signs.
hypotension occurs occasionally which may be augmented by thiazide diuretics given concurrently. A few cases of transient hypertension, for which no explanation is apparent have been noted. Chest pain has been reported rarely.
Overdose
An overdose of diazoxide causes marked hyperglycemia which may be associated with ketoacidosis.
It will respond to prompt insulin administration and restoration of fluid and electrolyte balance. Because of the drug's long half-life (approximately 30 hours), the symptoms of overdosage require prolonged surveillance for periods up to 7 days, until the blood sugar level stabilizes within the normal range. One investigator reported successful lowering of diazoxide blood levels by peritoneal dialysis in 1 patient and by hemodialysis in another.
Dosage
Patients should be under close clinical observation when treatment is initiated. The clinical response and blood glucose level should be carefully monitored until the patient's condition has stabilized satisfactorily; in most instances, this may be accomplished in several days. If administration of diazoxide is not effective after 2 or 3 weeks, the drug should be discontinued.
The dosage must be individualized based on the severity of the hypoglycemic condition and the blood glucose level and the clinical response of the patient. The dosage should be adjusted until the desired clinical and laboratory effects are produced with the least amount of the drug. Special care should be taken to assure accuracy of dosage in infants and young children.
Adults and Children: The usual daily dosage is 3 to 8 mg/kg, divided into 2 or 3 equal doses every 8 or 12 hours. In certain instances, patients with refractory hypoglycemia may require higher dosages. Ordinarily, an appropriate starting dosage is 3 mg/kg/day, divided into 3 equal doses every 8 hours. Thus, an average adult would receive a starting dosage of approximately 200 mg daily.
