Posology Diagnostic Applications (i) Short single-dose test – diagnosis of ACTH insufficiency This can be performed on an ambulatory basis. In this test, plasma 11-desoxycortisol and/or ACTH levels are determined after a single dose of Metyrapone Esteve.
The patient is given 30 mg/kg (maximum 3 g Metyrapone Esteve) at midnight with yoghurt or milk to minimise nausea and vomiting. Patients with suspected adrenocortical insufficiency should be hospitalised overnight as a precautionary measure.
Paediatric population The same dose as in adults is recommended in children. The blood sample for the assay is taken early in the morning (7:30 – 8:00 hours). The plasma should be frozen as soon as possible. The patient is then given a prophylactic dose of 50 mg cortisone acetate.
Evaluation:
Normal values will depend on the method used to determine ACTH and 11- desoxycortisol levels. 2 micromol/L (70 microg/L). Healthy individuals have an ACTH response of 42 to 690 pg/mL (9 to 210 pmol/L). In general, patients with partial secondary adrenal insufficiency have ACTH responses from 10 to 200 pg/mL (2 to 44 pmol/L), while patients with primary adrenal insufficiency have higher responses.
Because of this overlap, the ACTH response alone cannot be used to distinguish between healthy individuals and those with adrenal insufficiency. (ii) Multiple-dose test – diagnosis of ACTH insufficiency and differential diagnosis of adrenocortical hyperfunction in Cushing’s syndrome.
The patient must be hospitalised. In this test, urinary steroid levels are measured. The first day, baseline values are determined for the 24 hours preceding the test. 5 g. The effect is evaluated in two consecutive 24-hour urinary samples.
Maximum urine steroid excretion may occur on the fourth day. If urinary steroid excretion increases in response to Metyrapone Esteve, this suggests the high levels of circulatory cortisol are due to adrenocortical hyperplasia following excessive ACTH production rather than a cortisol- producing adrenal tumour.
Paediatric population The paediatric dosage recommendation is based on limited data. In children the dosage should be 15 mg/kg body weight, with a minimum dose of 250 mg every 4 hours for 6 doses. It is recommended that patients take the capsules with milk or after meals to minimise nausea and vomiting.
Evaluation:
ACTH deficiency: If the anterior pituitary is functioning normally, Metyrapone Esteve brings about a marked increase in 17-hydroxycorticosteroids (17–OHCS) or 17 ketogenic steroids (17–KGS) in the urine (to at least twice baseline levels).
Lack of response indicates secondary adrenocortical insufficiency.
Cushing’s syndrome:
An excessive increase in 17–OHCS or 17–KGS in the urine after administration of Metyrapone Esteve indicates over-production of ACTH which has led to adrenocortical hyperplasia (Cushing’s syndrome). Such an increase can be taken as an indication that there is no adrenocortical tumour producing cortisol autonomously.
Therapeutic use Adults For the management of Cushing’s syndrome, the initial dose of metyrapone may vary from 250 to 1500 mg/day depending on the severity of hypercortisolism and the cause of Cushing’s syndrome. Metyrapone may be initiated at doses of 750 mg/day for patients with moderate Cushing’s syndrome.
For patients with severe Cushing’s syndrome, initiation doses may be higher, up to 1500 mg/day. Lower starting doses may be used in cases of mild Cushing’s disease or adrenal adenoma or hyperplasia. The usual maintenance dose varies between 500 and 6000 mg/day.
The dose should be given in three or four divided doses. The daily dose should be adjusted after a few days with the aim of lowering the mean plasma/serum cortisol levels and/or the 24-hour urinary free-cortisol levels to a normal target value or until the maximal tolerated dose of metyrapone is reached.
Mean serum/plasma cortisol levels may be calculated from the average of 5 to 6 plasma/serum samples obtained throughout a day or from cortisol levels obtained just before the morning dose. Once weekly monitoring of plasma/serum cortisol levels and/or a 24-hour free urinary cortisol levels is necessary to allow further dose adjustments if needed.
The dose-adjustment period is usually 1 to 4 weeks. When cortisol levels are close to the optimal levels, longer periods (generally once a month or every 2 months) are sufficient for the monitoring. A physiological corticosteroid replacement therapy may be added to a complete cortisol blockade by metyrapone (block-and-replace regimen).
This should be started when the serum or urine cortisol is in the normal range and the metyrapone doses are increased to achieve complete suppression of cortisol secretion. In case of rapid dose-escalation or for patients with cyclic Cushing’s syndrome, a physiological corticosteroid replacement therapy may be added.
For the treatment of resistant oedema:
The usual daily dose of 3g (12 capsules) should be given in divided doses in conjunction with a glucocorticoid.
Special populations Paediatric population:
The paediatric dosage recommendation is based on limited data. Case reports showed that there is no specific dosage recommendation for paediatric use in the treatment of Cushing’s syndrome. The dose should be adjusted on an individual basis as a function of cortisol levels and tolerability.
Elderly population:
Dosage as for adults. There is limited data available on the use of metyrapone in elderly (≥ 65 years old). Clinical evidence would indicate that no special dosage regimen is necessary. Method of administration The capsules should be taken with milk or after a meal, to minimise nausea and vomiting, which can lead to impaired absorption.