Data Sheet
METOPIRONE®
Metyrapone
250 mg, Capsules
Qualitative and quantitative composition
Active substance: metyrapone. Capsules containing 250 mg active substance with colourless, viscous to jelly-like contents, branded in brown with CIBA on one side and LN on the other side. The yellowish/white opaque capsules are approximately 18.5mm in length and 7.5mm in diameter.
For a full list of excipients, see List of excipients.
Pharmaceutical form
Capsules for oral administration.
Clinical particulars
Therapeutic indications
Metopirone is a diagnostic drug for testing the function of the anterior pituitary-adrenal axis. It can also be used for therapeutic purposes.
Diagnostic applications
- Diagnosis of latent ACTH deficiency:
The Metopirone test can only be employed if the adrenal cortex responds normally to ACTH, i.e. if morning cortisol and/or cortisol values as determined by the Synacthen® test are within, or at least very close to, the normal range.
The test can be used:
- in confirmed disturbances of pituitary function or suspected pituitary tumours, and before and after surgery in the pituitary region;
- to assess ACTH suppression during or after glucocorticoid therapy.
- Differential diagnosis of adrenocortical hyperactivity in Cushing's syndrome
Therapeutic applications
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
- Hyperaldosteronism, resistant oedema
Dosage and method of administration
Diagnostic applications
- 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. The same dose is recommended in children. The blood sample for the assay is taken early the following morning (7.30 to 8.00). 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 and for differential diagnosis of adrenocortical hyperactivity in 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 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.
Cushing's syndrome: An excessive increase in 17-OHCS or 17-KGS in the urine after administration of Metopirone indicates overproduction 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 applications
Cushing's syndrome, especially when related to adrenal tumours: the dosage should be adapted to the individual patient's needs. The dosage required to normalise cortisol values ranges from 250 mg to 6 g daily.
Hyperaldosteronism, resistant oedema: 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.
Contraindications
Manifest primary adrenocortical insufficiency; hypersensitivity to metyrapone or to any of the excipients.
Special warnings and precautions for use
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 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 should be discontinued (see 'Interactions with other drugs and other types of interaction'). 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.
Since the plasma elimination half-life of cortisol is longer 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.
Interaction with other medicinal products and other forms of interaction
Anticonvulsants (e.g. phenytoin, barbiturates), psychotropic drugs (e.g. amitriptyline, chlorpromazine), hormone preparations, corticosteroids and antithyroid agents may affect the results of the Metopirone test.
Pregnancy and lactation
Pregnancy
Unless the potential benefit outweighs the risk to the foetus Metopirone should not be given to pregnant women, since the drug can impair the biosynthesis of foetal-placental steroids.
Lactation
Since it is not known whether metyrapone passes into the breast milk, Metopirone should not be given to breast-feeding women.
Fertility
No data are available from animal reproduction studies.
Effects on ability to drive and use machines
Since Metopirone may cause dizziness and sedation, patients should exercise caution when driving or operating machinery.
Adverse effects
Adverse drug reactions (Table 1) are ranked under heading of frequency, the most frequent first, using the following convention: 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 (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness.
Table 1
| Blood and the lymphatic system disorders | ||
|---|---|---|
| Not known: | Bone marrow failure | |
| Endocrine disorders | ||
| Rare: | Hypoadrenalism, hirsutism | |
| Nervous system disorders | ||
| Common: | Dizziness, sedation, headache | |
| Vascular disorders | ||
| Common: | Hypotension | |
| Not known: | Hypertension | |
| Gastrointestinal disorders | ||
| Common: | Nausea, vomiting | |
| Rare: | Abdominal pain | |
| Skin and subcutaneous tissue disorders | ||
| Rare: | Allergic skin reactions | |
| Not known: | Alopecia | |
Overdose
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.
Pharmacological properties
Pharmacodynamic properties
Pharmacotherapeutic group: Diagnostic agent, test for pituitary function, ATC code:V04CD01
Metyrapone inhibits adrenocorticosteroid synthesis. It reduces cortisol and corticosterone production by inhibiting the 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. Continued blockade of the enzymatic steps 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 measured as an index of pituitary ACTH responsiveness. Metopirone may also suppress biosynthesis of aldosterone, resulting in mild natriuresis.
Pharmacokinetic properties
Metyrapone is rapidly absorbed and eliminated from the plasma after oral administration.
Absorption
Peak plasma concentrations are usually reached 1 hour after administration.
Distribution
After administration of 750 mg, mean peak plasma concentrations are 3.7 micrograms/mL, falling to 0.5 micrograms/mL 4 hours after administration.
Biotransformation
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. Metyrapol takes about twice as long as metyrapone to be eliminated from the plasma.
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.
Precinical safety data
Pre-clinical data for Metopirone (metyrapone) reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity, teratogenicity and reproduction toxicity. Currently, there are no available non-clinical studies conducted to investigate the genotoxicity, mutagenicity, 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.
Pharmaceutical particulars
List of excipients
Sodium salt of ethyl parahydroxybenzoate (E215), ethylvanillin, gelatin, glycerol, p-methoxy acetophenone, macrogol 400, macrogol 4000, sodium salt of propyl parahydroxybenzoate (E217), titanium dioxide.
Incompatibilities
None known.
Shelf life
3 years.
Special precautions for storage
Protect from moisture and heat (store below 25°C).
Metopirone must be kept out of reach and sight of children.
Nature and contents of container
Bottles of 50 capsules
Medicine classification
Prescription Medicine
Name and address
Novartis New Zealand Limited
Private Bag 65904
Mairangi Bay
Auckland 0754
Building G, 5 Orbit Drive
Rosedale
Auckland 0632
Telephone: 09 361 8100
Date of preparation
7 August 2009
(Ref: BPI 27 July 2009)