Metyrapone

SOURCE: UK SPC (eMC) for Metyrapone Esteve 250 mg Soft Capsules, §4.2 (https://www.medicines.org.uk/emc/product/101077/smpc). TITRATION: the daily dose should be adjusted after a few days aiming to lower mean plasma/serum cortisol and/or 24-hour urinary free cortisol to a normal target value or until the maximal tolerated dose is reached; mean serum/plasma cortisol may be calculated from the average of 5–6 samples throughout a day or from levels just before the morning dose; weekly monitoring of plasma/serum cortisol and/or 24-hour urinary free cortisol is necessary to allow further dose adjustment; the dose-adjustment period is usually 1 to 4 weeks, after which monthly or two-monthly monitoring suffices. BLOCK-AND-REPLACE: physiological corticosteroid replacement may be added to a complete cortisol blockade — started when serum or urine cortisol is in the normal range and metyrapone doses are increased to achieve complete suppression of cortisol secretion; also consider with rapid dose escalation or in cyclic Cushing's syndrome. DIAGNOSTIC — SHORT SINGLE-DOSE TEST (ACTH insufficiency): 30 mg/kg (maximum 3 g) at midnight with yoghurt or milk to minimise nausea and vomiting; blood sample for assay early the following morning (07:30–08:00); patients with suspected adrenocortical insufficiency should be hospitalised overnight as a precaution; a prophylactic dose of 50 mg cortisone acetate is then given. DIAGNOSTIC — MULTIPLE-DOSE TEST (ACTH insufficiency and differential diagnosis of adrenocortical hyperfunction in Cushing's syndrome): the patient must be hospitalised; on the second day 500–750 mg every 4 hours for 24 hours, giving a total dose of 3.0–4.5 g, with urinary steroids measured in two consecutive 24-hour samples. RESISTANT OEDEMA: the usual daily dose of 3 g (12 capsules) in divided doses, in conjunction with a glucocorticoid. ELDERLY: dosage as for adults; limited data in patients ≥65 years but no special regimen appears necessary. HEPATIC: patients with liver cirrhosis often show a delayed response due to delayed cortisol metabolism. The metyrapone diagnostic test should be restricted to referral hospital centres, and drugs affecting pituitary or adrenocortical function should be discontinued before testing.

SPC §4.2. For the MULTIPLE-DOSE test the paediatric recommendation (based on limited data) is 15 mg/kg body weight, with a minimum dose of 250 mg, every 4 hours for 6 doses. Capsules should be taken with milk or after meals to minimise nausea and vomiting. For THERAPEUTIC use in Cushing's syndrome the SPC states there is no specific paediatric dosage recommendation — case reports only — and the dose should be adjusted on an individual basis as a function of cortisol levels and tolerability.