Metopirone 250

/ CTS

Single-dose short test to diagnose latent ACTH deficiency:
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 Metopirone. The patient is given 30 mg/kg (maximum 3 g Metopirone) at midnight with yoghurt or milk to minimize nausea and vomiting. The same dose is recommended in children. The blood sample for the assay is taken early the following morning (7.30to 8.00 as described in [1,2]). 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. An intact ACTH reserve is generally indicated by an increase in plasma ACTH to at least 44 pmol/L (200 ng/L) or by an increase in 11-desoxycortisol to over 0.2 micromol/L (70 micrograms/L). Patients with suspected adrenocortical insufficiency should be hospitalised overnight as a precautionary measure, although no cases of acute adrenocortical insufficiency have been reported to date in association with the single-dose short test.
Multiple-dose test to diagnose latent ACTH deficiency:
The patient must be hospitalised. In this test, urinary steroid levels are measured. First, baseline values are determined for the 24 hours preceding the test. Then 500 to 750 mg Metopirone is administered every 4 hours for 24 hours, giving a total dose of 3.0 to 4.5 g. 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 minimize nausea and vomiting. The maximum effect of Metopirone on urinary steroid values should be reached within the next 24 hours.
Evaluation: ACTH deficiency: If the anterior pituitary is functioning normally, Metopirone 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.
Adults
For the management of Cushing’s syndrome: the initial dose of metyrapone may vary from 250 to 1,000 mg/day depending on the severity of hypercortisolism and the cause of Cushing’s syndrome. Metyrapone 250 may be initiated at doses of 750 mg/day. 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 dosage of metyrapone should be adjusted on an individual basis to meet patient’s requirements and depending on tolerability. The usual maintenance dose varies between 500 and 6,000 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.
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 indicates that no special dosage recommendations are required in all
indications.
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.
For full details see prescribing information.

Diagnostic test of secondary adrenocortical insufficiency, treatment of resistant edema associated with increase of aldosterone secretion.
Management of patients with endogenous Cushing’s syndrome.

Hypersensitivity to the active substance  or to any of it’s excipients.
Primary adrenocortical insufficiency.

Diagnostic applications
The metyrapone diagnostic test should be restricted to hospital.
Patients with reduced adrenal secretory capacity and serious hypopituitarism
The ability of the adrenal cortex to respond to exogenous ACTH should be demonstrated before Metopirone is employed as a test, because Metopirone may induce acute adrenal insufficiency in patients with reduced adrenal secretory capacity as well as in patients with global pituitary insufficiency. The test should be performed in hospital with close monitoring in case of suspected adrenocortical insufficiency.
Reduced liver function
Patients with liver cirrhosis often show a delayed response to Metopirone due to liver damage delaying the plasma elimination half-life of cortisol.
Patients with hypothyroidism or taking drugs affecting the hypothalamo-pituitary adrenal axis
In cases of thyroid hypofunction, urinary steroid levels may rise very slowly, or not at all, in response to Metopirone. Before the Metopirone test is carried out, drugs affecting pituitary or adrenocortical function should be discontinued. If adrenocortical or anterior pituitary function is more severely compromised than indicated by the results of the test, Metopirone may trigger transient adrenocortical insufficiency. This can be rapidly corrected by giving appropriate doses of corticosteroids.
Therapeutic use
Supervision
The product should only be used under the supervision of specialists having available the appropriate facilities for monitoring of clinical and biochemical responses. Treatment with Metopirone leads to rapid decrease in circulating levels of cortisol and potentially to hypocortisolism/hypoadrenalism. It is therefore necessary to monitor and instruct patients on the signs and symptoms associated with hypocortisolism (e.g. weakness, fatigue, anorexia, nausea, vomiting, hypotension, hyperkalaemia, hyponatraemia, hypoglycaemia). In the event of documented hypocortisolism, temporary exogenous steroid (glucocorticoid) replacement therapy and/or dose reduction or interruption of Metopirone therapy may be necessary.
Patients with severe Cushing’s syndrome
Severe Cushing’s syndrome is known to increase the risk of opportunistic infections such as Pneumocystis jirovecii pneumonia due to immunosuppression and anti-inflammatory effect of hypercortisolism. Generally, infection must be anticipated in such patients and careful management is warranted. Initiation of an appropriate prophylactic treatment may be considered.
Hypertension
Long-term treatment with Metopirone can cause hypertension as the result of excessive secretion of desoxycorticosterone.
Hypokalaemia
Hypokalaemia can occur in patients with Cushing’s syndrome and during {Invented Name} treatment. Potassium levels should be checked before therapy start and monitored periodically during therapy.
Any hypokalaemia prior to {Invented Name} administration and/or during therapy should be corrected.
QTc prolongation
In a clinical study performed in patients with Cushing’s syndrome treated with metyrapone, three patients had an asymptomatic increase in QTcF interval above 60 ms. No patient had an increase of QTcF interval above 480 ms.
Metyrapone should be used with caution in patients with relevant pre-existing cardiac diseases and/or electrolyte disturbances. If signs of cardiac arrhythmia occur during treatment with {Invented Name}, monitoring of ECG and electrolytes are recommended.

Very common: adrenal insufficiency, decreased appetite, headach, dizziness, hypertension, nausea, abdominal pain, diarrhea, hypersensitivity reactions including rash, pruritus and urticarial, arthralgia, asthenic conditions, peripheral oedema.
Common: hypokalaemia, sedation, hypotension, vomiting, hirsutism, acne, myalgia.
For full details see prescribing information.

The interaction potential of metyrapone is partly unknown and therefore caution is advised when initiating and discontinuing treatment with other medicinal products. If changes to the effect and/or safety profile of metyrapone or
the concomitant drug are seen, suitable action should be taken.
Observed interactions: Anticonvulsants (e.g. phenytoin, barbiturates), psychotropic drugs (e.g. amitriptyline, chlorpromazine, alprazolam), hormone preparations, corticosteroids, antithyroid agents and cyproheptadine may affect the results of the Metopirone test.
Anticipated interactions: Metopirone may potentiate paracetamol (acetaminophen) toxicity in humans.

Pregnancy:
There are no or a limited amount of data from the use of metyrapone in pregnant women. Animal studies are insufficient with respect to reproductive toxicity. This medicinal product is not recommended during pregnancy when used as a diagnostic test or for the management of endogenous Cushing’s syndrome unless the potential benefit outweighs the risks (in this case, blood pressure should be monitored and hypertension managed appropriately to avoid complications such as pre-eclampsia) and in women of childbearing potential not using contraception.
Transplacental passage of metyrapone has been shown in animals and humans. Therefore, if metyrapone is required during the pregnancy, cortisol and electrolytes levels in neonate should be monitored at birth and the week after or until resolution, to monitor for the potential risk of adrenal insufficiency (rare cases of transient low cortisol have been reported in neonates exposed in utero). Glucocorticoid replacement may be needed.   
Breast-feeding
There is insufficient information on the excretion of metyrapone in human milk. A risk to newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with Metopirone.
Fertility
The effect of metyrapone on human fertility has not been investigated in clinical studies. In animals, metyrapone has been shown to cause adverse effects on spermatogenesis and ovarian follicular development; however no formal fertility studies have been conducted.

Signs and Symptoms: The clinical picture of poisoning with Metopirone is characterised by gastrointestinal symptoms and signs of acute adrenocortical insufficiency. Laboratory findings: hyponatraemia, hypochloraemia, hyperkalaemia. In patients under treatment with insulin or oral antidiabetics, the signs and symptoms of acute poisoning with Metopirone may be aggravated or modified.
Treatment: There is no specific antidote. In addition to general measures to eliminate the drug and reduce absorption, a large dose of hydrocortisone should be administered at once, together with saline and glucose infusions. For a few days blood pressure and fluid and electrolyte balance should be monitored.