Diazoxide

Diazoxide should be used with caution in patients with cardiac failure or impaired cardiac reserve in whom sodium and water retention may worsen or precipitate congestive heart failure. A direct effect on myocardium and cardiac function cannot be excluded.

Diazoxide should be used with care in patients with impaired cardiac or cerebral circulation and in patients with aortic coarctation, aortic stenosis, arteriovenous shunt, heart failure or other cardiovascular disorders in which an increase in cardiac output could be detrimental.

Retention of sodium and water is likely to necessitate therapy with an oral diuretic such as frusemide or ethacrynic acid. The dosage of either of the diuretics mentioned may be up to 1g daily. It must be appreciated that if diuretics are employed then both the hypotensive and hyperglycaemic activities of diazoxide will be potentiated and it is likely that the dosage of diazoxide will require adjustment downwards. In patients with severe renal failure it is desirable to maintain, with diuretic therapy, urinary volumes in excess of 1 litre daily. Hypokalaemia should be avoided by adequate potassium replacement.

The risk of hyperglycaemia may be increased by concurrent administration of corticosteroids or oestrogen-progestogen combinations.

Drugs potentiated by diazoxide therapy include: oral diuretics, antihypertensive agents and anticoagulants.

Phenytoin levels should be monitored as increased dosage may be needed if administered concurrently with diazoxide.

Diazoxide should be administered with caution to patients with hyperuricaemia or a history of gout, and it is advisable to monitor serum uric acid concentration.

Prolonged oral therapy of diazoxide during pregnancy has been reported to cause alopecia in the newborn.

Diazoxide injection should only be used in pregnant women when the indicated condition is deemed to be life-threatening to the mother.

Labor and delivery

Since intravenous administration of the drug during labor may cause cessation of uterine contractions, and administration of oxytocic agents may be required to reinstate labor, caution is advised in administering diazoxide at that time.

Diazoxide should not be given to nursing mothers as the safety of diazoxide during lactation has not been established.

No long-term animal dosing study has been done to evaluate the carcinogenic potential of diazoxide. No laboratory study of mutagenic potential or animal study of effects on fertility has been done.

None stated.

Oral administration

With oral therapy, nausea is common in the first two or three weeks and may require relief with an anti-nauseant. Prolonged therapy has given rise to reports of hypertrichosis lanuginosa, anorexia and hyperuricaemia.

Extra-pyramidal side-effects have been reported with oral diazoxide. It was found that extra-pyramidal effects such as parkinsonian tremor, cogwheel rigidity and oculogyric crisis could be easily suppressed by intravenous injection of an antiparkinsonian drug such as procyclidine and that they could be prevented by maintenance therapy with such a drug given orally.

Other adverse effects of diazoxide which have been reported are listed below.

Blood and lymphatic system disorders: Leucopenia, thrombocytopenia, decreased haemoglobin and/or haematocrit, eosinophilia, bleeding

Immune system disorders: Hypogammaglobulinaemia, hypersensitivity reactions such as rash, fever and leucopenia, decreased immunoglobulins (IgG) in infants,

Endocrine disorder: Hirsutism, galactorrhoea, pancreatitis, increased serum androgens

Metabolism and nutrition disorders: Hyperuricaemia (after prolonged therapy), hyperosmolar non-ketotic coma, inappropriate hyperglycaemia including ketoacidosis

Psychiatric disorders: Anorexia (after prolonged therapy), decreased libido

Nervous system disorders: Extra-pyramidal side-effects such as parkinsonian tremor, cogwheel rigidity and oculogyric crisis, headache, dizziness

Eye disorders: Blurred vision, transient cataracts, subconjunctival haemorrhage, ring scotoma, diplopia, lacrimation.

Ear and labyrinth disorders: Tinnitus

Cardiac disorders: Cardiomegaly, cardiac failure, arrhythmias

Vascular disorders: Inappropriate hypotension

Respiratory, thoracic and mediastinal disorders: Dysponea, pulmonary hypertension

Gastrointestinal disorders: Nausea, vomiting, abdominal pain, diarrhoea, ileus, constipation, dysgeusia

Hepatobiliary disorders: Increased AST and alkaline phosphate

Skin and subcutaneous tissue disorders: Pruritis, dermatitis, lichenoid eruption

Musculoskeletal and connective tissue disorders: Musculoskeletal pain

Renal and urinary disorders: Azotemia, decreased creatinine clearance, reversible nephritic syndrome, haematuria and albuminuria.

Congenital, familial and genetic disorders: Hypertrichosis lanuginose (after prolonged therapy)

General disorders and administration site disorders: Voice changes and abnormal faces in children (on long term therapy), sodium retention, fluids retention.

IV administration

In the treatment of hypertension the hyperglycaemia induced by diazoxide is generally inevitable. Each injection of diazoxide usually means a transient rise in blood sugar of about 10%. Fortunately the hyperglycaemia in hypertensive patients can be readily controlled with tolbutamide, or exceptionally with insulin.

A hypotensive effect in normotensive patients is of minor importance and rarely requires any specific therapy. An oral diuretic may be indicated to control sodium and water retention.

With diazoxide injection reflex tachycardia is not uncommon in the first few minutes after injection and is more frequent in digitalised patients. Orthostatic hypotension is unlikely but it may occur in those recently treated with adrenergic blocking agents. When it is used during labour for the treatment of toxaemia, the smooth muscle relaxant effect can cause delay in the second stage. This should be counteracted with oxytocic agents.

Other adverse effects of diazoxide injection which have been reported are hyperosmolar non-ketonic coma, cardiomegaly, leucopenia, thrombocytopenia, and hirsutism.