Metyrapone HRA 250mg soft capsules

Metyrapone HRA is indicated as a diagnostic aid for ACTH insufficiency and in the differential diagnosis of ACTH-dependent Cushing's syndrome.

Metyrapone HRA is indicated for the management of patients with endogenous Cushing's syndrome.

In conjunction with glucocorticosteroids in the treatment of resistant oedema due to increased aldosterone secretion in patients suffering from cirrhosis, nephrosis and congestive heart failure.

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 HRA. The patient is given 30 mg/kg (maximum 3 g Metyrapone HRA) 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. An intact ACTH reserve is generally indicated by an increase in 11-desoxycortisol to over 0.2 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. The second day, 500-750 mg Metyrapone HRA are administered every 4 hours for 24 hours, giving a total dose of 3.0-4.5 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 HRA, 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 HRA 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 HRA 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.

Primary adrenocorticol insufficiency.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Diagnostic applications

The metyrapone diagnostic test should be restricted to referral hospital centers.

Patients with reduced adrenal secretory capacity and serious hypopituitarism

The ability of the adrenal cortex to respond to exogenous ACTH should be demonstrated before Metyrapone HRA is employed as a test, as Metyrapone HRA 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.

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 Metyrapone HRA. Before the Metyrapone HRA test is carried out, drugs affecting pituitary or adrenocortical function should be discontinued (see section 4.5).

If adrenocortical or anterior pituitary function is more severely compromised than indicated by the results of the test, Metyrapone HRA may trigger transient adrenocortical insufficiency. This can be rapidly corrected by giving appropriate doses of corticosteroids.

Reduced liver function

Patients with liver cirrhosis often show a delayed response to Metyrapone HRA, due to liver damage delaying the metabolism of cortisol.

Therapeutic use

Hypocortisolism

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 Metyrapone HRA 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 Metyrapone HRA therapy may be necessary.

Assay methods

A reliable assay without cross-reactivity with steroids precursors, such as a specific immuno-assay or a liquid chromatography-mass spectrometry (LC-MS/MS) method, to measure plasma/serum and urine cortisol levels is recommended to allow accurate metyrapone dose adjustment.

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 Metyrapone HRA can cause hypertension as the result of excessive secretion of desoxycorticosterone.

Hypokalaemia

Hypokalaemia can occur in patients with Cushing's syndrome and during Metyrapone HRA treatment. Potassium levels should be checked before therapy start and monitored periodically during therapy. Any hypokalaemia prior to Metyrapone HRA administration and/or during therapy should be corrected.

QTc prolongation

In a clinical study performed in patients with Cushing's syndrome treated with metyrapone (PROMPT, prospective single-arm, open-label study, 50 patients included in safety data set), 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 Metyrapone HRA, monitoring of ECG and electrolytes are recommended.

Excipients

The presence of the excipients sodium ethyl parahydroxybenzoate (E215) and sodium propyl parahydroxybenzoate (E217) may cause allergic reactions (possibly delayed).

This medicine contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially 'sodium free'.

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

In relation to use as a diagnostic aid: Anticonvulsants (e.g. phenytoin, barbiturates), anti-depressants and neuroleptics (e.g. amitriptyline, chlorpromazine, alprazolam), hormones that affect the hypothalamo-pituitary axis, corticosteroids, antithyroid agents and cyproheptadine may influence the results of the Metyrapone HRA test.

If these drugs cannot be withdrawn, the necessity of carrying out the Metyrapone HRA test should be reviewed.

Anticipated interactions

Metyrapone HRA 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 (see section 5.3). Metyrapone HRA 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 HRA 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 Metyrapone HRA..

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 (see section 5.3).

Metyrapone HRA has minor influence on the ability to drive and use machines. Since Metyrapone HRA may cause dizziness and sedation, patients should not drive or operate machinery until these effects have passed.

Safety data are derived from spontaneous reports, published literature and PROMPT study (prospective single-arm, open-label study, 50 patients included in safety data set). Adverse drug reactions (Table 1) are listed according to system organ classes and preferred terms in MedDRA 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).

Table 1. Adverse drug reactions

* Mainly during titration period / dose increase

**Reported cases occurred in the PROMPT study following treatment of 12 to 36 weeks duration

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Signs and symptoms: The clinical picture of acute Metyrapone HRA poisoning is characterised by gastrointestinal symptoms and 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 Metyrapone HRA may be aggravated or modified.

Treatment: There is no specific antidote. Immediate treatment is essential in the management of metyrapone overdose, patients should be referred to hospital urgently for immediate medical attention. Treatment with activated charcoal may be considered if the overdose has been taken within 1 hour. In addition to general measures, a large dose of hydrocortisone should be administered at once, together with IV saline and glucose. This should be repeated as necessary in accordance with the patient's clinical condition. For a few days, blood pressure and fluid and electrolyte balance should be monitored.

Pharmacotherapeutic group: Diagnostic agent, test for pituitary function, ATC code: V04CD01.

Metyrapone HRA inhibits the enzyme responsible for the 11β -hydroxylation stage in the biosynthesis of cortisol and to a lesser extent, aldosterone. The fall in plasma concentration of circulating glucocorticoids stimulates ACTH secretion, via the feedback mechanism which accelerates steroid biosynthesis. As a result, 11- desoxycortisol, the precursor of cortisol, is released into the circulation, metabolised by the liver and excreted in the urine. Unlike cortisol, 11-desoxycortisol does not suppress ACTH secretion and its urinary metabolites may be measured.

These metabolites can easily be determined by measuring urinary 17- hydroxycorticosteroids (17-OHCS) or 17-ketogenic steroids (17-KGS). Metyrapone HRA 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. Metyrapone HRA may also suppress biosynthesis of aldosterone, resulting in mild natriuresis.

Metyrapone is rapidly absorbed and eliminated from the plasma.

Absorption

Peak plasma levels usually occur one hour after ingestion of Metyrapone HRA;

Distribution

after a dose of 750mg Metyrapone HRA, plasma drug levels average 3.7µ g/ml. Plasma drug levels decrease to a mean value of 0.5µ g/ml 4 hours after dosing.

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 in the plasma.

Elimination

The half-life of elimination of Metyrapone HRA from the plasma is about 2 hours after oral administration.Seventy-two hours after a first daily dose of 4.5g Metyrapone HRA (750mg every 4 hours), 5.3% of the total dose was excreted in the urine as metyrapone (9.2% in free form and 90.8% conjugated with glucuronic acid), and 38.5% in the form of metyrapol (8.1% in free form and 91.9% conjugated with glucuronic acid).

Non-clinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity. Metyrapone was not mutagenic and genotoxic in in vitro and in vivo test systems.

Animal reproduction studies adequate to evaluate teratogenicity and postnatal development have not been conducted with Metyrapone HRA. Metyrapone inhibits testosterone synthesis in male rodents, dogs and non-human primates, and affects steroidogenesis in rat ovarian granulosa and thecal cells. These effects were abolished in animals co-administered with metyrapone and corticosterone and were therefore attributed to metyrapone inhibition of corticosterone synthesis. Treatment of male dogs and langurs with metyrapone for 40 or 30 days, respectively, caused a marked loss of spermatogonia, spermatocytes and spermatozoa. Young mice (30 days old) treated with metyrapone for 21 days showed underdeveloped uteri, as well as atretic tertiary follicles in the ovary. The relevance of these findings for Cushing's syndrome patients is currently not clear. In a rabbit study, metyrapone has been shown to cross the placenta. Currently, there are no available non-clinical studies conducted to investigate the carcinogenic potential of Metyrapone HRA.

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.

Capsule contents: Glycerin, polyethylene glycol 400, polyethylene glycol 4000 and water.

Capsule shell: Sodium ethyl parahydroxybenzoate (E215), ethyl vanillin, gelatin, glycerin 85%, p- methoxy acetophenone, sodium propyl parahydroxybenzoate (E217) and titanium oxide (E171).

Not applicable.

3 years

Store below 25° C. Keep the bottle tightly closed in order to protect from moisture.

High density polyethylene bottles of 100 capsules with child resistant polypropylene closure.

No special requirements.