VA Class:CV490
Diazoxide is a nondiuretic antihypoglycemic agent that is structurally related to the thiazide diuretics.
Diazoxide is administered orally in the management of hypoglycemia caused by hyperinsulinism associated with inoperable islet cell adenoma or carcinoma, or extrapancreatic malignancy in adults. In infants and children, diazoxide is used orally in the management of hypoglycemia associated with leucine sensitivity, islet cell hyperplasia, nesidioblastosis, extrapancreatic malignancy, islet cell adenoma, or adenomatosis. In these conditions, diazoxide may be used preoperatively as a temporary measure, and postoperatively if hypoglycemia persists. Diazoxide should be used only after diagnosis of hypoglycemia caused by one of the above conditions has been definitely established and when specific medical or surgical management has been unsuccessful or is not feasible. Diazoxide should not be used in the management of functional hypoglycemia.
Diazoxide is administered orally for the treatment of hypoglycemia. Although diazoxide also has been administered IV for the management of severe hypertension, a parenteral preparation of the drug is no longer commercially available in the US.
Dosage of oral diazoxide for the treatment of hypoglycemia must be individualized based on severity of the condition and the blood glucose concentration and clinical response of the patient. The usual initial oral dosage of diazoxide for the treatment of hypoglycemia in adults and children is 3 mg/kg daily divided into 3 equal doses and given every 8 hours. The usual maintenance dosage for these patients is 3-8 mg/kg daily given in 2 or 3 divided doses at 12 or 8 hour intervals, respectively. Patients with refractory hypoglycemia may require higher doses, and some investigators have used dosages as high as 10-15 mg/kg daily. The usual initial oral dosage for the treatment of hypoglycemia in infants and neonates is 10 mg/kg daily divided into 3 equal doses and given every 8 hours. The usual maintenance dosage in infants and neonates is 8-15 mg/kg per day divided in 2 or 3 equal doses and given every 12 or 8 hours, respectively. Some clinicians state that it is usually not necessary to increase the dosage of diazoxide as the child grows larger.
Patients should be observed closely when treatment with diazoxide is initiated and blood glucose concentrations should be monitored until the condition of the patient has stabilized; this usually requires several days. (See Cautions: Precautions and Contraindications.) If diazoxide is not effective after 2-3 weeks, the drug should be discontinued. In patients who respond to diazoxide, therapy must be continued for several years. The drug may be discontinued when insulin-glucose ratios and insulin responses to provocative tests are normal.
Pulmonary Hypertension in Neonates and Infants
Pulmonary hypertension has been reported in infants and neonates receiving diazoxide for the treatment of hyperinsulinemic hypoglycemia.600, 601, 602 At least 11 such cases of pulmonary hypertension have been reported since initial approval of the drug in 1973.600 In the reported cases, pulmonary hypertension developed within a day to a few months after initiating diazoxide.600, 601, 602 Although no fatalities occurred, affected patients required hospitalization or extended stays in the neonatal intensive care unit (NICU) and other interventions such as ventilatory support; in all of the cases, pulmonary hypertension resolved or improved upon discontinuance of diazoxide therapy.600, 601, 602 Most of the infants and neonates who developed pulmonary hypertension while receiving diazoxide had serious medical conditions including at least one risk factor for pulmonary hypertension.600
Infants and neonates receiving diazoxide should be monitored for manifestations of respiratory distress (e.g., tachypnea, flaring nostrils, grunting, chest wall retractions, feeding intolerance, cyanosis), particularly in those with risk factors for pulmonary hypertension.600 Common risk factors include meconium aspiration syndrome, respiratory distress syndrome, transient tachypnea of the newborn, pneumonia, sepsis, congenital diaphragmatic hernia, and congenital heart disease.600 Diazoxide therapy should be discontinued if pulmonary hypertension occurs.600
Hyperglycemic effects of diazoxide are potentiated in the presence of hypokalemia. Severe hyperglycemia and hyperosmolar coma have occurred rarely; in one infant, transient cataracts also developed. Nondiabetic hypertensive patients with impaired renal function may develop diabetic ketoacidosis following multiple IV or oral doses of diazoxide. If ketoacidosis occurs, insulin should be administered and fluid and electrolyte balance restored immediately.
Retention of sodium and water occurs frequently in patients receiving multiple doses of diazoxide orally and may result in edema, weight gain, congestive heart failure (especially in uremic patients), and refractoriness to the hypotensive effects of the drug. Tachycardia and palpitations are reported frequently in patients receiving diazoxide. Hypotension occurs occasionally in patients receiving oral diazoxide for the treatment of hypoglycemia; transient hypertension has also been reported.
Nausea, vomiting, abdominal discomfort, anorexia, alteration of taste, diarrhea, ileus, and constipation may occur in patients receiving oral or IV diazoxide. Acute pancreatitis occurred in one patient with renal failure after 4 months of oral diazoxide therapy.
When diazoxide is administered IV, pain or a feeling of warmth frequently occurs along the injected vein, and severe burning, cellulitis, and/or phlebitis may result from extravasation. If diazoxide injection leaks into subcutaneous tissue, the area should be treated with warm compresses or other palliative measures; dilution of the extravasated alkaline solution by administration of sodium chloride injection or administration of a local anesthetic has been used to relieve the pain.
Hirsutism is a common adverse effect of prolonged oral diazoxide therapy, especially in women and children. One case of hair growth on the head of a man who had been bald has been reported. Hirsutism may decrease as the dose of diazoxide decreases in relationship to the size of the child. Hirsutism regresses when the drug is discontinued.
Extrapyramidal symptoms such as restlessness, oculogyrus, trismus, rigidity, and tremor have been reported in patients treated chronically with oral diazoxide. Increased incidence of extrapyramidal symptoms appears to be associated with increased serum concentrations of diazoxide and may occur in patients with or without renal impairment. These symptoms disappeared when diazoxide was discontinued or the dosage was reduced. Extrapyramidal symptoms induced by diazoxide have been treated with diazepam or an anticholinergic antiparkinsonian agent.
Sensitivity reactions such as rash, leukopenia, and fever have occurred after oral or IV administration of diazoxide. Eosinophilia, transient neutropenia, thrombocytopenia (with or without purpura), lymphadenopathy, decreased hemoglobin concentration and/or hematocrit, excessive bleeding, hypogammaglobulinemia, increased serum alkaline phosphatase concentration, azotemia, decreased creatinine clearance, reversible nephrotic syndrome, decreased urinary output, hematuria, and albuminuria have also been reported. Hemolytic anemia has been reported in one patient receiving oral diazoxide for the management of hypertension. The development of abnormal facial features has been reported in a few children receiving long-term (greater than 4 years) treatment with diazoxide for hyperinsulinism.
Other adverse effects of diazoxide include tightness in the chest, back pain, severe muscle cramps, chest discomfort, dyspnea, cough, choking sensation, parotid swelling, salivation, dry mouth, polyneuritis, paresthesia, tinnitus, increased serum amylase concentration, hyperuricemia, increased nocturia, insomnia, dizziness, and euphoria. Apprehension or anxiety, malaise, blurred vision, lacrimation, subconjunctival hemorrhage, ring scotoma, and diplopia have occurred. Papilledema secondary to plasma volume expansion occurred in a patient who had received repeated IV injections of diazoxide over a 3-week period. Monilial dermatitis, herpes, advanced bone age, loss of scalp hair, galactorrhea, decreased libido, and enlargement of a lump in the breast have been reported.
Precautions and Contraindications
Patients receiving diazoxide should be carefully observed for possible development of severe hyperglycemia. This is especially important in patients with renal disease or carbohydrate metabolism disorders such as diabetes mellitus or liver disease, and in those taking other drugs that may increase blood glucose concentrations. (See Drug Interactions.) In patients receiving diazoxide orally in the treatment of hypoglycemia, blood glucose concentrations should be monitored carefully until the patient's condition has stabilized. Patients receiving chronic oral diazoxide therapy should be instructed to test their urine for glucose and ketones at least once daily, and to report any abnormalities or unusual symptoms to their clinicians.
Diazoxide should be administered with caution in patients in whom retention of sodium and water may be hazardous (e.g., those with impaired cardiac reserve). Caution also should be exercised when administering diazoxide to uremic patients, since these patients may experience a greater hypotensive effect. Hematologic monitoring may be advisable in patients who receive diazoxide for longer than a few days; serum uric acid concentration should be monitored in patients with hyperuricemia or a history of gout.
Diazoxide is contraindicated in patients who are hypersensitive to the drug or other thiazide derivatives unless the potential benefits to the patient outweigh the possible risks. Oral diazoxide is contraindicated in the management of functional hypoglycemia.
Mutagenicity and Carcinogenicity
Studies to evaluate the mutagenic and carcinogenic potentials of diazoxide have not been performed to date.
Pregnancy, Fertility, and Lactation
Although there are no adequate and controlled studies to date in humans, diazoxide has been shown to cause fetal skeletal anomalies, an increased incidence of fetal resorptions, and delayed parturition in rats receiving the drug orally, and evidence of skeletal and cardiac teratogenic effects have occurred in the offspring of rabbits receiving the drug IV. Evidence from reproduction studies in animals indicates that the adverse effects of diazoxide on normal fetal development may occur as a result of altered glucose metabolism. In pregnant sheep, goats, and swine, diazoxide has produced appreciable increases in fetal blood glucose concentration and degeneration of fetal pancreatic islet cells.
IV administration of diazoxide (parenteral preparation no longer commercially available in US) during labor may cause cessation of uterine contractions, and administration of oxytocic agents may be required to reinstate labor. Therefore, caution is advised if oral diazoxide is administered during labor. In addition, the drug may produce fetal or neonatal hyperbilirubinemia, thrombocytopenia, altered carbohydrate metabolism, and possibly other adverse effects that have occurred in adults. Alopecia and hypertrichosis lanuginosa have occurred in infants whose mothers received oral diazoxide during the last 19-60 days of pregnancy for the treatment of preeclampsia. Diazoxide should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.
Studies to evaluate the effects of diazoxide on fertility in animals have not been performed to date.
It is not known if diazoxide is distributed into milk. Because of the potential for serious adverse reactions to diazoxide in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.
Diuretics and Hypotensive Agents
Concomitant administration of diazoxide and diuretics may result in potentiation of the hyperglycemic, hyperuricemic, or hypotensive effects of diazoxide. Diazoxide may potentiate the hypotensive effect of other antihypertensive drugs; the possibility that dosage adjustments may be required when oral diazoxide is used concomitantly with other antihypertensive agents should be considered.
Children receiving both diazoxide and phenytoin have been reported to fail to achieve therapeutic serum concentrations of phenytoin even when receiving usual therapeutic dosages. Conversely, phenytoin toxicity has been reported in a child in whom phenytoin was added to diazoxide therapy. It has been suggested that diazoxide may increase the metabolism and/or decrease the plasma protein binding of phenytoin. The risk of hyperglycemia may be increased in some patients receiving diazoxide concomitantly with phenytoin.
Diazoxide has been reported to displace warfarin from its protein binding sites in vitro and this possibility must be considered when diazoxide is administered in patients receiving warfarin or other highly protein-bound drugs. The half-life of diazoxide was decreased in a child who was also receiving phenobarbital and phenytoin, and it has been suggested that metabolism of diazoxide may be stimulated by one or both of these drugs. The risk of hyperglycemia may be increased in some patients receiving diazoxide concomitantly with corticosteroids or estrogen-progestogen combinations. A single dose of chlorpromazine administered to a child receiving diazoxide apparently precipitated diabetic pre-coma.
Diazoxide inhibits glucagon-stimulated insulin release and will cause a false-negative insulin response to glucagon.
Overdosage of diazoxide produces hyperglycemia and possibly ketoacidosis, which should be treated promptly with insulin and restoration of fluid and electrolyte balance. Prolonged monitoring of patients who have received an overdosage is recommended, since diazoxide has a long half-life. Hemodialysis or peritoneal dialysis may be of only limited benefit.
Diazoxide increases blood glucose concentration by inhibiting pancreatic insulin secretion, by stimulating release of catecholamines, and/or by increasing hepatic release of glucose. The precise mechanism of inhibition of insulin release has not been elucidated, but may possibly result from an effect of diazoxide on cell-membrane calcium flux. Although diazoxide increases pancreatic insulin content, the drug apparently does not affect the synthesis of insulin. Diazoxide has a marked inhibitory effect on glucose- and glucagon-induced insulin secretion. Plasma free fatty acid concentrations are increased and plasma insulin concentrations are decreased during diazoxide administration.
Diazoxide-induced hyperglycemia may be reversed by administration of insulin or tolbutamide. Diazoxide administration in diabetic and nondiabetic patients causes an increased insulin response to combined glucagon and tolbutamide stimulation. Diazoxide does not block tolbutamide-induced insulin release.
Diazoxide reduces peripheral vascular resistance and blood pressure as a result of a direct vasodilatory effect on smooth muscle in peripheral arterioles. The precise mechanism of the hypotensive effect has not been fully elucidated, but it has been postulated that antagonism of calcium is involved. Diazoxide-induced decreases in blood pressure are accompanied by increased heart rate, cardiac output, and left ventricular ejection rate, probably resulting from a reflex response to the decreased peripheral vascular resistance. In contrast to the thiazide diuretics, diazoxide causes sodium and water retention and decreased urinary output which can result in expansion of plasma and extracellular fluid volume, edema, and congestive heart failure, especially during prolonged administration. The sodium- and water-retaining effects of diazoxide may be reversed by administration of a diuretic. It has been suggested that sodium retention may result from increased proximal tubular reabsorption of the cation and decreased glomerular filtration rate. Diazoxide also reduces excretion of potassium, chloride, bicarbonate, and uric acid; renin secretion is increased. Effects of the drug on renal plasma flow and glomerular filtration rate are variable, but they are usually transiently decreased. Diazoxide has no known direct action on the CNS.
The smooth muscle relaxant effect of IV diazoxide (parenteral preparation no longer commercially available in US) also causes inhibition of contractions in both the term uterus during labor and the nongravid uterus.
Blood concentrations of diazoxide required for a hyperglycemic effect are not known. Following oral administration of a single diazoxide dose of 10 mg/kg in one study, peak blood concentrations of 16 mcg/mL were attained in 4 hours when the drug was given as a suspension and peak blood concentrations of 10 mcg/mL were achieved in 12 hours when capsules were given. After oral administration of diazoxide suspension, the hyperglycemic effect begins within 1 hour and lasts approximately 8 hours in patients with normal renal function.
In animals, highest concentrations of diazoxide are present in the kidneys with relatively high concentrations in the liver and adrenal glands.
Approximately 90% of the diazoxide in the blood is bound to plasma proteins. In patients with chronic uremia, there is a substantial reduction of binding of diazoxide to plasma proteins, probably resulting from decreased serum albumin in these patients. Diazoxide is less bound to cord plasma proteins than to adult plasma proteins. The high degree of protein binding is responsible for the prolonged half-life.
Diazoxide crosses the placenta and the blood-brain barrier. It has not been determined whether the drug is distributed into milk.
The terminal elimination half-life of diazoxide following a single oral or IV dose has been reported to range from 21-45 hours in adults with normal renal function; limited data suggest that the terminal elimination half-life may be somewhat shorter in children than in adults. In patients with renal impairment, the half-life is prolonged in proportion to decreases in creatinine clearance.
Diazoxide is partially metabolized by oxidation and sulfate conjugation and is excreted slowly in urine by glomerular filtration as unchanged drug and metabolites. In one patient, 2% of an orally administered dose of diazoxide was recovered in feces. Diazoxide and its metabolites are removed by hemodialysis and peritoneal dialysis, but dialysance is relatively low because of the extensive protein binding.
Diazoxide is a nondiuretic antihypoglycemic agent that is structurally related to the thiazide diuretics. Diazoxide occurs as white to creamy-white crystals or crystalline powder and is practically insoluble to sparingly soluble in water. The drug is soluble in alkaline solutions. Diazoxide has a pKa of 8.5.
Diazoxide oral suspension should be stored at 2-30°C. The oral suspension will darken when exposed to light and should be protected from light, heat, and freezing. Darkened oral suspensions may be subpotent and should not be used.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions April 15, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
Only references cited for selected revisions after 1984 are available electronically.
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600. US Food and Drug Administration. FDA Drug Safety Communication: FDA warns about a serious lung condition in infants and newborns treated with Proglycem (diazoxide). Silver Spring, MD; 2015 Jul 16. From FDA website. Accessed 2016 Aug 23. [Web]
601. Yildizdas D, Erdem S, Küçükosmanoglu O et al. Pulmonary hypertension, heart failure and neutropenia due to diazoxide therapy. Adv Ther . 2008; 25:515-9. [PubMed 18512033]
602. Demirel F, Unal S, Çetin II et al. Pulmonary hypertension and reopening of the ductus arteriosus in an infant treated with diazoxide. J Pediatr Endocrinol Metab . 2011; 24:603-5. [PubMed 21932611]