Consumer medicine information

Metopirone

Metyrapone

BRAND INFORMATION

Brand name

Metopirone

Active ingredient

Metyrapone

Schedule

What is in this leaflet

This leaflet answers some common questions about METOPIRONE. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking METOPIRONE against the benefits they expect it will have for you.

If you have any concerns about this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What METOPIRONE is used for

METOPIRONE belongs to a group of medicines called diagnostic agents. It acts by reducing the production of the adrenal gland hormones, cortisol and corticosterone (which are also called corticosteroids).

METOPIRONE is used as a test to find out if ACTH (adrenocorticotropic hormone, a natural body hormone acting on corticosteroid secretion), is being produced properly.

Changes in the production of ACTH may happen for several reasons, for example, due to changes in the function of the adrenal or pituitary gland, or due to treatment with certain medicines.

Ask your doctor if you have any questions about how this medicine works or why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

This medicine is only available with a doctor's prescription. It is not addictive.

Before you take METOPIRONE

When you must not take it

If any of the following apply to you, tell your doctor without taking METOPIRONE.

Do not take METOPIRONE if you have ever had an allergic reaction to metyrapone (the active ingredient) or to any of the other ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

shortness of breath
wheezing or difficulty breathing
swelling of the face, lips, tongue or other parts of the body
rash, itching or hives on the skin.

Do not take METOPIRONE if you suffer from a condition whereby your adrenal glands do not produce enough steroid hormones (cortisol or aldosterone) known as Addison's disease.

Do not breast-feed while you are having the METOPIRONE test. There is not enough information to recommend breast-feeding while you are having the test.

Do not take METOPIRONE after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. In that case, return it to your pharmacist.

Before you start to take it

Tell your doctor if you have allergies to other medicines, foods, dyes or preservatives.

Tell your doctor if you have any of the following medical conditions:

impaired liver function or cirrhosis of the liver (a chronic liver disorder leading to progressive loss of liver function)
an underactive thyroid gland (which can cause weight gain, dry brittle hair, cold intolerance, constipation, forgetfulness, or personality changes)
an underactive pituitary gland (which can cause an imbalance of some hormones)
high blood pressure.

The results of the test may be affected by these medical conditions.

If you are pregnant or think you are pregnant, tell your doctor before you have the METOPIRONE test. There is not enough information to recommend its use during pregnancy. If there is an urgent need for you to have the METOPIRONE test, your doctor can advise you about the risks and benefits.

Taking other medicines

Tell your doctor if you are taking any other medicines, including medicines that you buy without a prescription from a pharmacy, supermarket or health food shop.

Some medicines may affect the results of the METOPIRONE test. These include:

corticosteroid medicines
any hormone treatments (e.g. tetracosactide, growth hormone, treatments for infertility, the birth control pill and hormone replacement therapy (HRT))
medicines to treat epilepsy (e.g. phenytoin or barbiturates)
medicines to treat anxiety, depression (feelings of deep sadness), psychosis (a severe mental condition in which the person loses contact with reality and is unable to think and judge clearly) (e.g. amitriptyline, alprazolam, or chlorpromazine)
medicines for your thyroid gland (e.g. levothyroxine, carbimazole, propylthiouracil)
cyproheptadine, a medicine used for treatment of allergic disorders
paracetamol, a medicine used for the treatment of fever and pain.

Tell your doctor if you are taking insulin or oral medicines for diabetes. Your doctor may ask you stop taking some of your medicines during the test. If you are unsure whether any of the medicines you are taking will affect the test, your doctor can advise you.

If you have not told your doctor about any of these things, tell him/her before you have the METOPIRONE test.

How to take METOPIRONE

How the test is done

There are two types of METOPIRONE test. Your doctor will advise you which one you will have.

Short single dose test:
This test can either be done at home or you may be admitted to hospital overnight. At around midnight you will take a number of METOPIRONE capsules calculated by your doctor, according to your body weight. This may be up to maximum 3 grams (12 capsules). Eight hours later, a blood sample will be taken. After the test you may also have to take a dose of 50 mg cortisone to prevent any unwanted effects on your adrenal glands.
Multiple dose test:
This test is always done in hospital. First, your urine is collected for 24 hours. Then you will take 500 to 750 mg (2 to 3 capsules) of METOPIRONE every 4 hours for the next 24 hours. Your urine will be collected again for the following 24 hours and the results of the urine tests will be compared.

How much to take

Your doctor will decide how many METOPIRONE capsules you need, depending on your body weight.

Do not exceed the recommended dose.

Follow all of your doctor's instructions carefully. They may differ from the general information contained in this leaflet.

How to take it

Take the capsules with milk or yoghurt or after a meal to minimise nausea and vomiting. Do not chew the capsules. This will help to prevent stomach upset.

Things to be careful of

METOPIRONE may temporarily lower the amount of hormones produced by your adrenal gland. Your doctor will correct this using appropriate hormone medication.

If you feel dizzy or drowsy after taking this medicine, you should not drive or operate machinery until these effects have passed.

Children should avoid doing things like riding bicycles or climbing trees.

Contact your doctor as soon as possible if you develop shortness of breath and fever over hours or days. You may be developing a serious lung infection.

METOPIRONE capsules contain sodium propyl hydroxybenzoate and sodium ethyl hydroxybenzoate. These preservatives can cause skin rashes and (rarely) breathing difficulties. This product also contains glycerol, which can cause headaches, stomach upsets, and diarrhoea in high doses.

If you take too much (overdose)

Immediately telephone your doctor or Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at your nearest hospital if you think that you may have taken more capsules than you have been told to take, or if anyone else has accidentally taken any METOPIRONE capsules.

Make sure that you take this leaflet and any remaining capsules in the packet with you to show them to the medical staff.

Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

Some of the symptoms of an overdose may include: nausea, vomiting, stomach pain, diarrhoea, anxiety, dizziness, confusion, dehydration and weakness.

Side effects

Tell your doctor or hospital staff as soon as possible if you do not feel well while you are having the METOPIRONE test, even if you don't think it is connected with the medicine.

All medicines can have side effects. Sometimes they are serious, but most of the time they are not. You may need medical treatment if you get some of the side effects.

Tell your doctor or hospital staff as soon as possible if you notice any of the following and they worry you:

rash, itching or hives on the skin
dizziness or light headedness
drowsiness, tiredness or weakness
low or high blood pressure
nausea (feeling sick) or vomiting
pain in the abdomen
headache
frequent infections such as fever, severe chills, sore throat or mouth ulcers
tiredness, headaches, being short of breath when exercising, dizziness and looking pale
bleeding or bruising more easily than normal.

The above list includes side effects that may require medical attention.

Tell your doctor if you notice anything else that is making you feel unwell. Other side effects not listed above may also occur in some people.

Product description

What it looks like

METOPIRONE capsules are white to yellowish white oblong soft gelatin capsules marked "HRA" on one side in red ink. Each bottle contains 50 capsules.

Ingredients

Active
Each METOPIRONE capsule contains metyrapone 250 mg.

Inactive ingredients
METOPIRONE capsules also contain:

acetanisole
ethyl vanillin
gelatin
glycerol
macrogol 400 and 4000
sodium propyl hydroxybenzoate
sodium ethyl hydroxybenzoate
titanium dioxide
purified water
Edible ink Red (PI 3115).

After using METOPIRONE

Storage

If you must keep METOPIRONE capsules at home before you have the test:

Store them in the original container in a cool dry place where the temperature stays below 25°C
Do not store your medicine in the bathroom or near a sink
Do not leave it in the car or on a window sill.

Keep the medicine where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Sponsor

METOPIRONE is supplied in Australia by:

Chiesi Australia Pty Ltd
Suite 3, 22 Gillman Street
Hawthorn East, Victoria 3123
Email: [email protected]
Website: www.chiesi.com.au

®= Registered Trademark

Australian Registration Number
AUST R 11043

This leaflet was prepared in July 2023.

Published by MIMS September 2023

BRAND INFORMATION

Brand name

Metopirone

Active ingredient

Metyrapone

Schedule

1 Name of Medicine

Metyrapone.

2 Qualitative and Quantitative Composition

Metopirone is supplied as soft gelatin capsules each containing 250 mg of metyrapone.

Excipients with known effects.

Sodium ethyl hydroxybenzoate, sodium propyl hydroxybenzoate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Metopirone capsules 250 mg are white to yellowish white oblong soft gelatin capsules marked HRA on one side in red ink.

4 Clinical Particulars

4.1 Therapeutic Indications

Diagnostic use.

For the diagnosis of latent ACTH deficiency such as in cases of known pituitary dysfunction or of a suspected pituitary tumour, as well as before and after surgical intervention in the region of the pituitary; and, to assess the degree of ACTH suppression during or after glucocorticoid therapy.
For the differential diagnosis of states of adrenocortical hyperfunction in Cushing's syndrome.

4.2 Dose and Method of Administration

Dose as a diagnostic agent.

i) Short single dose test (which can be carried out in ambulant patients) for the diagnosis of latent ACTH deficiency.

Adults.

In the short single dose test, 11-desoxycortisol (compound S) and/or ACTH are determined in the plasma following a single dose of Metopirone. At around midnight, the patient is given 30 mg/kg (maximum 3 g metyrapone).
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.

Paediatric population.

The same dose as in adults is recommended in children.

Assessment.

The accepted normal values employed will depend on the method used for assaying ACTH and 11-desoxycortisol and may vary in different laboratories. A rise in plasma ACTH to at least 44 picomol/L (200 nanogram/L), or in 11-desoxycortisol to over 0.2 micromol/L (70 microgram/L), usually indicates a normal ACTH reserve.
Patients in whom adrenocortical insufficiency is suspected, and who cannot be adequately supervised at home, should be hospitalised for the night as a precautionary measure.
ii) Multiple dose test (which can only be carried out in hospital) for the diagnosis of latent ACTH deficiency and the differential diagnosis of states of adrenocortical hyperfunction in Cushing's syndrome.

Adults.

The patient must be hospitalised. The urinary excretion of steroids is measured. First, baseline values are determined for the 24 hours preceding the test. Then, on the second day, 500 to 750 mg metyrapone is administered every 4 hours for 24 hours, to a total of 3.0 to 4.5 g.
The effect is evaluated in two consecutive 24-hour urinary samples. The effect on the urinary steroid values can be expected to reach its maximum within this 24-hour period.

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.

Assessment.

ACTH deficiency. When the anterior pituitary is functioning normally Metopirone causes a pronounced increase (to double or more) in the urinary excretion of 11-desoxycortisol and other 11-desoxycorticosteroids. The absence of such an increase indicates secondary adrenocortical insufficiency.
Cushing's syndrome. If the urinary excretion of 11-desoxycorticosteroids increases in response to Metopirone, this indicates that excessive production of ACTH has led to adrenocortical hyperplasia (Cushing's disease). Such an increase can be taken as a sign that there is no adrenocortical tumour producing cortisol autonomously.

Method of administration.

Oral administration.

It is recommended that the capsules be taken together with yoghurt or milk or after meals to minimise nausea and vomiting which can lead to impaired absorption.

4.3 Contraindications

Adrenocortical insufficiency.
Hypersensitivity to metyrapone or to any of the excipients listed in Section 6.1 List of Excipients.

4.4 Special Warnings and Precautions for Use

The metyrapone multiple dose diagnostic test should be restricted to the hospital setting.

Identified precautions.

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.

Patients taking drugs affecting the hypothalamo-pituitary adrenal axis.

Before the Metopirone test is carried out, drugs affecting pituitary or adrenocortical function should be discontinued (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
In cases where adrenocortical or anterior pituitary function is more severely impaired, Metopirone may provoke transient adrenocortical insufficiency. This can be rapidly overcome by administering a corticosteroid.

Patients with hypothyroidism.

In cases of thyroid hypofunction, the urinary steroid excretion may rise very slowly or not at all, in response to Metopirone.

Opportunistic infections.

Patients with severe Cushing's syndrome are at risk for opportunistic infections such as Pneumocystis jirovecii pneumonia during Metopirone treatment. 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 or worsen existing hypertension due to excessive secretion of desoxycorticosterone.

Excipients.

The presence of the excipients sodium ethyl parahydroxybenzoate and sodium propyl parahydroxybenzoate can cause allergic reactions, which might be delayed. This medicine contains less than 1 mmol sodium (23 mg) per capsule. It is essentially 'sodium free'.

Use in hepatic impairment.

Patients with liver cirrhosis often show a delayed response to Metopirone, because the liver damage results in prolonging the plasma elimination half-life of cortisol.

Use in the elderly.

Clinical studies of Metopirone did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects.
Clinical evidence would indicate that no special dosage regimen is required. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Paediatric use.

See Section 4.2 Dose and Method of Administration.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

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), psychoactive drugs (e.g. amitriptyline, chlorpromazine, and alprazolam), hormone preparations that affect the hypothalamo-pituitary axis, corticosteroids, cyproheptadine and antithyroid agents may exert an influence on the results of the Metopirone test.
If these drugs cannot be withdrawn, the necessity of carrying out the Metopirone test should be reviewed.

Anticipated interactions.

Metopirone may potentiate paracetamol (acetaminophen) toxicity in humans.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The effect of Metopirone on human fertility has not been investigated in clinical studies. No dedicated animal fertility studies have been conducted with metyrapone. In repeat-dose toxicity studies, metyrapone has been shown to cause adverse effects on spermatogenesis (loss of spermatogonia, spermatocytes and spermatozoa in dogs at 20 mg/kg/day intraperitoneally [IP]) and ovarian follicular development (reduced ovary and uterus weights, underdeveloped uterus in mice at 100 mg/kg/day IP). Metyrapone can decrease reproductive hormones by targeting adrenal androgenesis.
(Category B3)
There are no adequate data on the use of Metopirone in pregnant women.
Metopirone is not recommended during pregnancy when used as a diagnostic test unless the potential benefit outweighs the risks clearly necessary (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.

Human data.

The Metopirone test was administered to pregnant women in their second and third trimester of pregnancy and evidence was found that the fetal pituitary responded to the enzymatic block. Transplacental passage of Metopirone has been shown in humans. There are a few published reports of low cortisol levels at birth in infants exposed in utero following chronic use of metyrapone in pregnant females.

Animal data.

Maternal administration of metyrapone during pregnancy caused reduction in implantations and increased fetal malformation in mice (40 mg/kg/day SC). Embryofetal effects were seen in rats at a cumulative dose of at least 60 mg/animal SC over 1 or 2 days (adrenal hypertrophy, reduced serum corticosterone levels) during the period of organogenesis. Transplacental passage of metyrapone has been shown in rabbits.
There is insufficient information on the presence of metyrapone in human milk, the effects on the breastfed infant, or the effects on milk production. A risk to newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with Metopirone.

4.7 Effects on Ability to Drive and Use Machines

Since Metopirone may cause dizziness and sedation, patients should not drive or operate machinery until these effects have passed.

4.8 Adverse Effects (Undesirable Effects)

Adverse drug reactions 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.

Blood and the lymphatic system disorders.

Not known: leukopenia, anaemia, thrombocytopenia.

Endocrine disorders.

Rare: adrenal insufficiency.

Nervous system disorders.

Common: dizziness, sedation, headache.
Not known: lightheadedness.

Vascular disorders.

Common: hypotension.
Not known: hypertension.

Gastrointestinal disorders.

Common: nausea, vomiting.
Rare: abdominal pain.

Skin and subcutaneous tissue disorders.

Rare: allergic skin reactions.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

Signs and symptoms.

The clinical picture of overdosage 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. 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.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

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

5.1 Pharmacodynamic Properties

Mechanism of action.

Metopirone inhibits reversibly the biosynthesis of cortisol, corticosterone, and aldosterone in the adrenal cortex by blocking enzymatic 11-beta-hydroxylation in the steroid ring. In the normal person, a compensatory increase in ACTH release follows and the secretion of 11-desoxycortisol, 11-desoxycorticosterone and 17-hydroxycorticoids is markedly accelerated.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

Metyrapone is rapidly absorbed after administration by mouth and is also rapidly eliminated from the plasma. Peak concentrations are usually attained in plasma 1 hour after ingestion of Metopirone.

Distribution.

Following a dose of 750 mg, the mean peak concentration is 3.7 microgram/mL and decreases to a mean value of 0.5 microgram/mL 4 hours after ingestion.

Metabolism.

The plasma elimination half-life of metyrapone is about 2 hours after oral administration. Metyrapol (reduced metyrapone) is the principal active metabolite. The metyrapone/ metyrapol ratio in the plasma 8 hours after a single oral dose is 1/1.5.

Excretion.

Following a total dosage of 4.5 g metyrapone (750 mg every 4 hours), the quantities excreted in the urine 72 hours after the first dose averaged 5.3% of the total dosage in the form of 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).

5.3 Preclinical Safety Data

Genotoxicity.

No studies for genotoxicity have been performed with Metopirone.

Carcinogenicity.

No studies for carcinogenicity have been performed with Metopirone.

Teratogenicity.

Animal reproduction studies, adequate to evaluate teratogenicity and postnatal development, have not been conducted.

6 Pharmaceutical Particulars

6.1 List of Excipients

It also contains sodium ethyl hydroxybenzoate, ethyl vanillin, gelatin, glycerol, acetanisole, Macrogol 400, Macrogol 4000, sodium propyl hydroxybenzoate, titanium dioxide, purified water and Edible ink Red (PI 3115) as excipients.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C. Protect from moisture. Keep out of the reach and sight of children.

6.5 Nature and Contents of Container

Each HDPE bottle with polypropylene child resistant closure with a liner for induction seal contains 50 capsules.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

Chemical name: 2-methyl-1,2-di-3-pyridyl-1-propanone.
Molecular formula: C₁₄H₁₄N₂O.
Molecular weight: 226.27 g/mol.
Structural formula:

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