Excipients/Inactive Ingredients: Ethyl and propyl paraben, sodium salt (E215, E217).
ATC Code: V04CD01.
Pharmacology: Pharmacodynamics: Mechanism of action: Metyrapone inhibits adrenocorticosteroid synthesis. It reduces cortisol and corticosterone production by inhibiting the enzymatic 11-beta-hydroxylation reaction in the adrenal cortex. Removal of the strong inhibitory feedback mechanism exerted by cortisol results in an increase in adrenocorticotropic hormone (ACTH) production by the pituitary gland. Continued blockade of the enzymatic reactions leading to production of cortisol and corticosterone produces a marked increase in adrenocortical secretion of their immediate precursors, 11-desoxycortisol and desoxycorticosterone, which are weak suppressors of ACTH release, and a corresponding increase in plasma levels of these steroids and of their metabolites in the urine. These metabolites can easily be determined by measuring urinary 17-hydroxycorticosteroids (17-OHCS) or 17-ketogenic steroids (17-KGS). Metopirone is used as a diagnostic test on the basis of these properties, with plasma 11-desoxycortisol and urinary 17-OHCS and 17-KGS measured as an index of pituitary ACTH responsiveness. In patients with the following conditions, the test shows no considerable increase of the glucocorticoid precursors: when suffering from adrenal cortex-related Cushing's syndrome or ectopic ACTH production (due to suppression of the pituitary gland) and in case of ACTH deficiency (in patients with secondary adrenocortical insufficiency). Metyrapone may also suppress biosynthesis of aldosterone, resulting in mild natriuresis.
The effect of metyrapone depends on the time of day during which it is administered.
Pharmacokinetics: Absorption/distribution: Metyrapone, the active ingredient of Metopirone, is rapidly absorbed and eliminated from the plasma after oral administration. Peak plasma concentrations are usually reached 1 hour after administration. After administration of 750 mg, mean peak plasma concentrations are 3.7 μg/ml, falling to 0.5 μg/mL 4 hours after administration.
Metabolism: Metyrapol, the reduced form of metyrapone, is the main active metabolite. Eight hours after a single oral dose, the ratio of metyrapone to metyrapol in the plasma is 1:1.5.
Elimination: The plasma elimination half-life of metyrapone is 20 to 26 minutes. After administration of 4.5 g metyrapone (750 mg every 4 hours), an average of 5.3% of the dose was excreted in the urine in the form of metyrapone (9.2% free and 90.8% glucuronised) and 38.5% in the form of metyrapol (8.1% free and 91.9% glucuronised) within 72 hours after the first dose was given.
Metyrapol takes about twice as long as metyrapone to be eliminated from the plasma.
Kinetics of special patient groups: To date no pharmacokinetic data is available for patients with renal or hepatic dysfunctions.
Toxicology: Preclinical safety data: Pre-clinical data for metyrapone reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity. Metopirone was not mutagenic with or without metabolic activation in three strains of bacteria. Animal reproduction studies adequate to evaluate teratogenicity and postnatal development have not been conducted with Metopirone. Currently, there are no available non-clinical studies conducted to investigate the genotoxicity, or carcinogenic potential of Metopirone.
Effects in pre-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
Metopirone is used as a diagnostic drug for testing the function of the anterior pituitary-adrenal axis. It can also be used for therapeutic purposes.
Diagnosis of latent ACTH deficiency, in case of a known pituitary dysfunction or suspected pituitary tumour as well as before and after surgery in the pituitary region; during or after glucocorticoid therapy for the assessment of the ACTH suppression.
The precondition for the applicability of the Metopirone test is that the adrenal cortex responds normally to ACTH, i.e. if morning cortisol and/or cortisol values as determined by the Synacthen test that are within, or at least very close to, the normal range.
Differential diagnosis of adrenocortical hyperactivity in Cushing's syndrome: In Cushing's syndrome with ectopic ACTH production, however, the reliability of the metyrapone test has not been proven.
Metopirone can be employed as supplementary therapy in conditions associated with overproduction of glucocorticoids and mineralocorticoids, particularly when causal treatment is not possible.
Cushing's syndrome, especially when related to adrenal tumours.
Preconditions for the feasibility of the test: see Precautions.
1. Diagnostic application: a) Single-dose short test to diagnose latent ACTH deficiency (can be performed on an ambulatory basis): In this test, plasma 11-desoxycortisol (Compound S) and/or ACTH levels are determined after a single dose of Metopirone.
The patient is given 1-2 g of Metopirone (30 mg/kg, the same dose is recommended in children) at midnight with yoghurt or milk. The blood sample for the assay of 11-desoxycortisol and ACTH is taken at 8.00 am the following morning, according to JUBIZ. STAUB recommends taking the blood sample at 7.30 am. 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 in the laboratory. According to STAUB, an intact ACTH reserve is generally indicated by an increase in plasma ACTH to at least 44 pmol/l (200 ng/l) or (according to other authors) by an increase in 11-desoxycortisol to over 0.2 μmol/l (70 μg/l). Patients with suspected adrenocortical insufficiency, where monitoring by someone close-by is not guaranteed, 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.
b) Multiple-dose test to diagnose latent ACTH deficiency and for differential diagnosis of adrenocortical hyperactivity in case of Cushing's syndrome (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. The maximum effect of Metopirone on urinary steroid values should be reached within the next 24 hours.
Evaluation: ACTH deficiency: If the anterior lobe of the pituitary gland 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 in patients with adrenocortical insufficiency indicates ACTH deficiency with a corresponding secondary adrenocortical insufficiency.
Cushing's syndrome: In case of a hyperproduction of glucocorticoids (and usually in case of ectopic ACTH production) caused by the adrenal cortex, the pituitary gland is suppressed. No substantial increase of the cortisol precursors is observed during the test in such cases.
An increase in 17-hydroxycorticosteroids (17-OHCS) or 17-ketogenic steroids (17-KGS) in the urine (for the extent of such increase see above) after administration of Metopirone indicates overproduction of ACTH, which has led to adrenocortical hyperplasia (Morbus Cushing).
Such an increase can be taken as an indication that there is no adrenocortical tumour producing cortisol autonomously.
2. Therapeutic applications: Please take Metopirone after the meal in order to minimise nausea and vomiting.
Cushing's syndrome: The dosage must be adapted to the individual patient's needs. The dosage required to normalise cortisol values ranges from 250 mg to 6 g daily.
Hyperaldosteronism: The usual daily dosage is 3 g Metopirone given in divided doses. In the case of hyperaldosteronism, Metopirone should be given with a glucocorticoid. In resistant oedema Metopirone has been used in combination with a diuretic therapy and for short periods of time.
The application and safety of Metopirone capsules for therapeutic purposes has not been tested to date in children and adolescents.
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 medicinal product and reduce absorption, a large dose of hydrocortisone must be administered at once, together with saline and glucose infusions.
For a few days blood pressure as well as fluid and electrolyte balance must be monitored.
Manifest primary adrenocortical insufficiency; hypersensitivity to Metopirone or to any of the excipients.
The ability of the adrenal cortex to respond to exogenous ACTH must be demonstrated before Metopirone is employed as a test, because Metopirone may induce acute adrenocortical insufficiency in patients with reduced adrenal secretory capacity as well as in patients with gross hypopituitarism.
Metopirone can cause hypertension due to excessive secretion of desoxycorticosterone.
Before the Metopirone test is carried out, drugs affecting pituitary or adrenocortical function must be discontinued (see Interactions).
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.
Patients with ectopic Cushing's syndrome are at risk for opportunistic infections such as Pneumocystis jirovecii pneumonia as a result of the immunosuppression. The treatment with Metopirone causes the glucocortoid levels to fall and therefore, the immunosuppressive effect is reduced. This can subsequently cause a pronounced infection-related inflammatory reaction. Since elimination of cortisol is slower when hepatic function is impaired, patients with liver cirrhosis often respond to Metopirone more slowly. In patients with hypothyroidism, the Metopirone-induced increase in steroid values may be delayed or absent. Metopirone may cause acute porphyria.
Influence on diagnostic methods: Anticonvulsive drugs (e.g. phenytoin, barbiturates), psychotropic drugs (e.g. amitriptyline, chlorpromazine, alprazolam), hormone preparations, corticosteroids, thyreostatic drugs and cyproheptadine may affect the results of the Metopirone test.
Effects on the ability to drive and use machines: Since Metopirone may cause dizziness and sedation, patients should exercise caution when driving or operating machinery.
No controlled studies in pregnant women have been carried out and therefore, this product should only be administered to pregnant women if it is absolutely necessary. Furthermore, reduced responsiveness has to be expected in pregnant patients treated with Metopirone for ACTH suppression.
It cannot be ruled out that metyrapone impairs the biosynthesis of foetal-placental steroids. Animal reproduction studies adequate to evaluate teratogenicity and postnatal development have not been conducted with Metopirone (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Since it is not known whether metyrapone passes into the breast milk, women who are being treated with Metopirone should not breast-feed.
Frequencies: "Very common" (≥ 1/10), "common" (≥ 1/100, < 1/10), "uncommon" (≥ 1/1,000, < 1/100), "rare" (≥ 1/10,000, < 1/1,000), "very rare" (< 1/10,000).
Not known: Opportunistic infections (such as Pneumocystis jirovecii
pneumonia) in patients with ectopic Cushing's syndrome (due to impaired immune defence of these patients).
Blood and the lymphatic system disorders:
Very rare: Bone marrow suppression.
Rare: Adrenal insufficiency.
Nervous system disorders:
Common: Dizziness, sedation, headache.
Heart and vascular disorders:
Common: Hypotension; Rare: Hypertension.
Common: Nausea, vomiting; Rare: Abdominal pain.
Skin and subcutaneous tissue disorders:
Rare: Hirsutism, allergic dermatitis; Very rare: Alopecia.
Metopirone may potentiate Paracetamol toxicity in humans.
Protect from moisture and heat.
Metopirone must be kept out of reach and sight of children.
V04CD01 - metyrapone ; Belongs to the class of diagnostic agents used to test for pituitary function.