Diazoxide

Diazoxide is a non-diuretic sulphonamide of the benzothiadiazine family. Its glucose-raising (hyperglycaemic) effect comes mainly from inhibiting the release of insulin by the pancreas, and it also stimulates catecholamines released by the adrenal medulla. In addition it inhibits smooth muscle fibres, including those of arterioles, the uterus and the digestive tract.

Mechanism of Action

• Insulin suppression: diazoxide binds the sulfonylurea receptor subunit of the ATP-sensitive potassium (KATP) channel on pancreatic beta cells and promotes potassium efflux. The cell membrane hyperpolarises and calcium influx falls, so insulin release is inhibited and blood glucose rises (DrugBank).
• Catecholamines: the SmPC adds a stimulating action on catecholamines of adrenal medullary origin.
• Smooth muscle and blood pressure: DrugBank describes relaxation of arteriolar smooth muscle that lowers vascular resistance, but notes that hypotensive effects are usually not detected after oral dosing. The SmPC lists hypotension among the side effects.
• Onset and duration: after oral dosing, the rise in blood glucose is dose-dependent. In patients with normal renal function it appears within an hour and lasts no more than eight hours (DrugBank).
• Limits of response: severe neonatal hyperinsulinism is most often resistant to diazoxide and appears to be linked to particular mutations of the sulfonylurea receptor gene.

Pharmacokinetics

• Absorption: easy and rapid from the gut. DrugBank gives a bioavailability of about 91% and notes that absorption depends on the dissolution rate of the dosage form.
• Distribution: strongly bound to plasma proteins (more than 90%). Diazoxide crosses the placental barrier.
• Metabolism: according to DrugBank, part of the dose is metabolised, mainly by CYP1A2 and to a lesser extent by CYP3A4, to inactive metabolites. The SmPC states that urinary excretion is mostly of unchanged drug.
• Elimination: excreted in the urine by glomerular filtration, essentially unchanged. After oral dosing the elimination half-life is 24 to 36 hours in adults and shorter in young children (9.5 to 24 hours).
• Special populations: the half-life is shorter in young children, as above. The SmPC gives no separate dosing for renal or hepatic impairment.

The SmPC (French RCP for Proglicem 25 mg capsules) states the following indications.

• In infants and children:
  • hypoglycaemia due to persistent hyperinsulinism, in particular those starting in infancy;
  • leucine-sensitive hypoglycaemia;
  • certain hypoglycaemias occurring in glycogen storage diseases.
• In adults and children: hypoglycaemia due to hyperinsulinism of benign or malignant pancreatic or extra-pancreatic tumour origin.

• Hypersensitivity to diazoxide or to any of the excipients.
• Breastfeeding: the SmPC lists this medicine as not recommended during breastfeeding in the same section (see Special Instructions).

The SmPC lists the following reactions (MedDRA version 26.0). Their frequencies are undetermined, so all are classed as not known.

Not known:

• Gastrointestinal: nausea and vomiting, notably at the start of treatment if the dose is raised too quickly; necrotising enterocolitis in newborns.
• Skin: pruritus, rash; hirsutism (mainly in children, of unknown origin, appearing at high doses and reversible when treatment stops); drug reaction with eosinophilia and systemic symptoms (DRESS).
• Blood: neutropenia, eosinophilia; thrombocytopenia with or without purpura.
• Heart and circulation: tachycardia, palpitations; pericardial effusion; hypotension.
• Respiratory: pulmonary hypertension in newborns, infants and children, which in most cases improved after treatment was stopped.
• General and investigations: malaise; decreased immunoglobulins.
• Metabolism and nutrition: fluid and sodium retention; hypokalaemia; hyperuricaemia; diabetic ketoacidosis (exceptional, and only without monitoring in patients in poor general condition); severe hyperosmolarity (possible without careful monitoring of blood glucose).

The most serious reactions are necrotising enterocolitis (some cases fatal), pulmonary hypertension in young patients, thrombocytopenia, DRESS, and severe hyperosmolarity or ketoacidosis when monitoring is inadequate.

• Thiazide diuretics: they potentiate the hyperglycaemic effect of diazoxide. The diazoxide dose may need to be adjusted.
• Vitamin K antagonists: their plasma levels rise, because diazoxide binds strongly to serum proteins. The dose of the vitamin K antagonist may need to be adjusted.

Treatment is started in hospital and monitored regularly, clinically and with laboratory tests, particularly when it is prolonged. The capsules are taken by mouth. For infants and children under 6 years, the contents of the capsules may be mixed with food to make administration easier. Diazoxide is practically insoluble in water, with effective solubility only at a very alkaline pH.

Recommended Dose

• General rule: 5 to 10 mg/kg per day. The dose may be raised gradually to 15 mg/kg per day in young children and newborns.
• Titration: the effective maintenance dose is best reached gradually.
• Duration: maintenance treatment may be continued for years under monitoring.
• The SmPC gives the daily dose per kilogram only. How the daily amount is divided between doses is not stated, so the prescribing team sets the schedule.

Special Populations

• Infants and young children: the dose may go up to 15 mg/kg per day, and the capsule contents may be mixed with food. Severe neonatal hyperinsulinism is most often resistant to diazoxide.
• Adults and other groups: the SmPC gives the same general per-kilogram rule and no separate dosing for the elderly or for renal or hepatic impairment.

Hospital Start and Monitoring

Treatment is started in a hospital setting, with regular clinical and laboratory monitoring, especially in prolonged treatment. Because of the hyperglycaemic properties of diazoxide, eye examinations are recommended during prolonged treatment. Its effects on the blood-forming system and on serum uric acid must be considered, so a blood count and a uric acid level are checked periodically.

Thrombocytopenia

If thrombocytopenia occurs, with or without purpura, treatment must be stopped.

Necrotising Enterocolitis in Newborns

Cases of necrotising enterocolitis, some fatal, have been reported in newborns treated with diazoxide. Patients should be watched for vomiting, abdominal distension, bloody stools and lethargy, especially those with extra risk factors such as premature newborns. Diazoxide is stopped if necrotising enterocolitis is suspected and appropriate clinical care is started.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: animal studies showed a foetotoxic effect, and there are no clinical data relevant enough to assess a possible malformative or foetotoxic effect. Surgery is the treatment of choice for insulinomas. If a pregnancy makes it necessary to postpone surgery, diazoxide should be considered, because maternal hypoglycaemia is a significant risk for foetal development. Because of its hypotensive properties, the mother’s cardiovascular status must be monitored, and the newborn’s blood pressure and blood glucose as well.
• Breastfeeding: there are no data on passage into breast milk, so the medicine is not recommended during breastfeeding.
• Fertility: the SmPC gives no information.

Lactose

Each capsule contains 194.45 mg of lactose. Patients with rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take it.

Effect on Driving

The SmPC marks this section as not applicable.

Do not store above 25 °C. No refrigeration is needed. The capsules are supplied in PVC/aluminium blisters, in packs of 100. Keep out of the sight and reach of children.

2 years. Do not use after the expiry date on the pack.

Prescription only (Rx). The SmPC requires treatment to be started in hospital and monitored regularly, so it is prescribed by the team that starts and monitors it. The capsules are taken by mouth, so after the start of treatment they are supplied to the patient or to the treating clinic on prescription. No cold chain is needed. The medicine is authorised nationally, for example as Proglicem in France and Italy, so availability and the product information depend on the member state.