Action And Clinical Pharmacology: Diazoxide, a benzothiadiazine derivative, when 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 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 And Clinical Uses: 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.
Infants and 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.
Contra-Indications: 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.
Manufacturers’ Warnings In Clinical States: Pregnancy and Lactation: Diazoxide should not be used in women of child-bearing age except in life-threatening situations. Diazoxide may pass into the breast milk of nursing mothers. 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.
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.
Precautions: Treatment should be initiated under close clinical supervision, with careful monitoring of blood glucose and clinical response until the patient’s condition has stabilized. This usually requires several days. If not effective in 2 or 3 weeks, the drug should be discontinued.
Prolonged treatment requires regular monitoring of the urine for sugar and ketones, especially under stress conditions, with prompt reporting of any abnormalities to the physician. Additionally, blood sugar levels should be monitored periodically by the physician to determine the need for dose adjustment.
The effects of diazoxide on the hematopoietic system and the level of serum uric acid should be kept in mind; the latter should be considered particularly in patients with hyperuricemia or a history of gout.
In some patients, higher blood levels have been observed with the liquid than with the capsule formulation. Dosage should be adjusted as necessary in individual patients if changed from 1 formulation to the other.
Since the plasma half-life of diazoxide is prolonged in patients with impaired renal function, a reduced dosage should be considered. Serum electrolyte levels should also be evaluated for such patients.
The antihypertensive effect of other drugs may be enhanced by diazoxide and this should be kept in mind when administering it concomitantly with antihypertensive agents.
Because of protein binding, administration of diazoxide with coumarin or its derivatives may require reduction in the dosage of the anticoagulant, although there has been no reported evidence of excessive anticoagulant effect. In addition, it may possibly displace bilirubin from albumin; this should be kept in mind particularly when treating newborns with increased bilirubinemia.
Drug Interactions: 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.
Phenytoin: The concomitant administration of diazoxide to phenytoin treated patients can cause loss of seizure control.
Chlorpromazine: The hyperglycemic action of diazoxide may be enhanced by concomitant administration of chlorpromazine.
Adverse Reactions: Frequent and serious: Sodium and fluid retention is most common in young infants and in adults and may precipitate congestive heart failure in patients with compromised cardiac reserve. It usually responds to diuretic therapy (see Precautions, Drug Interactions).
Infrequent but serious: Diabetic ketoacidosis and hyperosmolar non-ketotic coma may develop very rapidly. Conventional therapy with insulin and restoration of fluid and electrolyte balance are usually effective if instituted promptly. Prolonged surveillance is essential in view of the long half-life of diazoxide (see Overdose).
Other frequent adverse reactions: Hirsutism of the lanugo type mainly on the forehead, back and limbs which occurs most commonly in children and women may be cosmetically unacceptable. It subsides on discontinuation of the drug.
Hyperglycemia or glycosuria may require reduction in dosage in order to avoid progression to ketoacidosis or hyperosmolar coma.
Gastrointestinal intolerance may include anorexia, nausea, vomiting, abdominal pain, ileus, diarrhea, transient loss of taste. Tachycardia, palpitations, increased levels of serum uric acid are common.
Thrombocytopenia with or without purpura may require discontinuation of the drug. Neutropenia is transient, is not associated with increased susceptibility to infection and ordinarily does not require discontinuation of the drug. Skin rash, headache, weakness and malaise may also occur.
Other adverse reactions which have been observed:
Cardiovascular: 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.
Hematologic: eosinophilia; decreased hemoglobin/hematocrit; excessive bleeding; decreased IgG.
Hepato-Renal: increased AST, alkaline phosphatase, azotemia, decreased creatinine clearance, reversible nephrotic syndrome, decreased urinary output, hematuria, albuminuria.
Neurologic: anxiety, dizziness, insomnia, polyneuritis, paresthesia, pruritus, extrapyramidal signs.
Ophthalmologic: transient cataracts, subconjunctival hemorrhage, ring scotoma, blurred vision, diplopia, lacrimation. Skeletal/Integumentary: monilial dermatitis, herpes, advance in bone age; loss of scalp hair.
Systemic: fever, lymphadenopathy.
Other: gout, acute pancreatitis/pancreatic necrosis, galactorrhea, enlargement of lump in breast.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: 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 And Administration: 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.
Infants and Newborns: The usual daily dosage is 8 to 15 mg/kg, divided into 2 or 3 equal doses every 8 to 12 hours. An appropriate starting dosage is 10 mg/kg/day, divided into 3 equal doses every 8 hours.
Availability And Storage: Capsules: Each opaque orange capsule, contains: diazoxide USP 100 mg. Nonmedicinal ingredients: lactose and magnesium stearate. Tartrazine-free. Bottles of 100.
Suspension: Each mL of chocolate-mint flavored suspension contains: diazoxide USP 50 mg. Nonmedicinal ingredients: alcohol
PROGLYCEM® Schering Diazoxide Hyperglycemic Agent