SUMMARY OF PRODUCT CHARACTERISTICS, LABELLING AND PACKAGE LEAFLET
SUMMARY OF PRODUCT CHARACTERISTICS
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SUMMARY OF PRODUCT CHARACTERISTICS
1. NAME OF THE MEDICINAL PRODUCT
{Invented Name} 250mg Capsules, soft
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each {Invented Name} Capsule contains 250 mg metyrapone.
Excipients with known effect: Each capsule contains 0.71 mg of sodium ethyl parahydroxybenzoate and 0.35 mg sodium propyl parahydroxybenzoate.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Soft capsules.
White to yellowish-white, oblong, opaque, soft gelatin capsule printed with word “HRA” in red ink and having faintly yellowish viscous to jelly-like contents.
4. CLINICAL PARTICULARS
4.1 Therapeutic Indications
As a diagnostic test for ACTH insufficiency and in the differential diagnosis of ACTH-dependent Cushing’s syndrome.
For the management of patients with endogenous Cushing’s syndrome.
4.2 Posology and method of administration
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 {Invented Name}. The patient is given 30 mg/kg (maximum 3 g {Invented Name}) at midnight with yoghurt or milk to minimise nausea and vomiting.
Paediatric population: The same dose as in adults is recommended in children.
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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 plasma ACTH to at least 44 pmol/L (200 ng/L) or by an increase in 11-desoxycortisol to over 0.2 µmol/L (70 µg/L). Patients with suspected adrenocortical insufficiency should be hospitalised overnight as a precautionary measure.
(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 {Invented Name} 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. The maximum effect of {Invented Name} on urinary steroid values should be reached within the next 24 hours.
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, {Invented Name} 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 {Invented Name} 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 1,000 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 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.
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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.
4.3 Contraindications
- Manifest primary adrenocortical insufficiency. - Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
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 {Invented Name} is employed as a test, because {Invented Name} 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 {Invented Name} due to liver damage delaying the plasma elimination half-life of cortisol.
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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 {Invented Name}. Before the {Invented Name} 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, {Invented Name} 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 {Invented Name} 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 {Invented Name} 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 ectopic Cushing’s syndrome Patients with ectopic Cushing’s syndrome are at risk for opportunistic infections such as Pneumocystis jirovecii pneumonia during {Invented Name} treatment. Appropriate prophylactic treatment may be considered in this population.
Hypertension Long-term treatment with {Invented Name} can cause hypertension as the result of excessive secretion of desoxycorticosterone.
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 {Invented Name} (see section 4.6).
Excipients The presence of the excipients sodium ethyl parahydroxybenzoate and sodium propyl parahydroxybenzoate can cause allergic reactions, which might be delayed.
4.5 Interaction with other medicinal products and other forms of interaction
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.
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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 cyprohepatadine may influence the results of the {Invented Name} test.
If these drugs cannot be withdrawn, the necessity of carrying out the {Invented Name} test should be reviewed.
Anticipated interactions
{Invented Name} may potentiate paracetamol (acetaminophen) toxicity in humans.
4.6 Fertility, pregnancy and lactation
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). {Invented Name} is not recommended during pregnancy when used as a diagnostic test or for the management of endogenous Cushing’s syndrome unless clearly necessary (in this case, blood pressure should be monitored and hypertension managed appropriately) and in women of childbearing potential not using contraception.
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 {Invented Name} (see section 4.4).
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).
4.7 Effects on ability to drive and use machines
{Invented Name} has a minor influence on the ability to drive and use machines. Since {Invented Name} may cause dizziness and sedation, patients should not drive or operate machinery until these effects have passed.
4.8 Undesirable effects
Safety data are derived from spontaneous reports and published literature. 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).
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Table 1 Adverse drug reactions Frequency SOC / Preferred Term Blood and lymphatic system disorders Not known: Bone marrow failure Endocrine disorders Rare: Adrenal insufficiency 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: Hirsutism, allergic dermatitis Not known: Alopecia
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 the national reporting system listed in Appendix V*. [*For the printed material, please refer to the guidance of the annotated QRD template.]
4.9 Overdose
Signs and symptoms: The clinical picture of acute {Invented Name} poisoning is characterised by gastro– intestinal symptoms and acute adreno-cortical insufficiency.
Laboratory findings: hyponatraemia, hypochloraemia, and hyperkalaemia. In patients under treatment with insulin or oral anti-diabetics, the signs and symptoms of acute poisoning with {Invented Name} may be aggravated or modified.
Treatment: There is no specific antidote. Gastric lavage (only in case of serious intoxication and if it can be performed shortly after ingestion) and forced emesis should be employed to reduce the absorption of the drug. 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 electrolyte balance should be monitored.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Diagnostic agent, test for pituitary function, ATC code: V04CD01
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{Invented Name} acts by inhibiting adrenocorticosteroid synthesis. It reduces cortisol and corticosterone production by inhibiting the 11β-hydroxylation reaction in the adrenal cortex. Removal of the strong inhibitory feedback mechanism exerted by cortisol results in an increase in adrenocorticotrophic 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). {Invented Name} 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. {Invented Name} may also suppress biosynthesis of aldosterone, resulting in mild natriuresis.
5.2 Pharmacokinetic properties
Metyrapone is rapidly absorbed and eliminated from the plasma after oral administration
Absorption: Peak plasma concentrations are usually reached one hour after oral administration;
Distribution: After administration of 750 mg mean peak plasma concentrations are 3.7 µg/ml falling to 0.5 µg/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 in the plasma is 1: 1.5. Metyrapol takes about twice as long as metyrapone to be eliminated in the plasma.
Elimination: The plasma elimination half-life of metyrapone is about 2 hours after oral administration. Seventy–two hours after a first daily dose of 4.5 g {Invented Name} (750 mg 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, the principal active metabolite (8.1% in free form and 91.9% conjugated with glucuronic acid).
5.3 Preclinical safety data
Preclinical data for {Invented Name} (metyrapone) 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 {Invented Name}. 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 {Invented Name}.
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6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Ethylvanillin Gelatin Glycerol Macrogol 400 Macrogol 4000 P-methoxy acetophenone Sodium ethyl parahydroxybenzoate (E215) Sodium propyl parahydroxybenzoate (E217) Titanium dioxide (E171) Purified water
Printing Ink (Red): Carminic acid (E120) Aluminium chloride hexahydrate Sodium hydroxide Hypromellose Propylene glycol
6.2 Incompatibilities
Not applicable
6.3 Shelf life
3 years After opening: 2 months
6.4 Special Precautions for Storage
Keep the bottle tightly closed in order to protect from moisture. Store below 30oC.
6.5 Nature and Contents of Container
HDPE (high-density polyethylene) bottle with tamper evident screw cap containing 50 capsules.
6.6 Special precautions for disposal
No special requirements.
7. MARKETING AUTHORISATION HOLDER
[To be completed nationally]
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8. MARKETING AUTHORISATION NUMBER
[To be completed nationally]
9. DATE OF FIRST AUTHORISATION / RENEWAL OF AUTHORISATION
[To be completed nationally]
10. DATE OF (PARTIAL) REVISION OF THE TEXT
[To be completed nationally]
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LABELLING
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
1. NAME OF THE MEDICINAL PRODUCT
{Invented Name}® 250 mg Capsules, soft Metyrapone
2. STATEMENT OF ACTIVE SUBSTANCE(S)
Each capsule contains 250 mg metyrapone.
3. LIST OF EXCIPIENTS and includes Sodium ethyl parahydroxybenzoate (E215), Sodium propyl parahydroxybenzoate (E217). See leaflet for further information.
4. PHARMACEUTICAL FORM AND CONTENTS
50 capsules, soft
5. METHOD AND ROUTE(S) OF ADMINISTRATION
For oral use only. Read the package leaflet before use.
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN
Keep the medicine out of the sight and reach of children.
7. OTHER SPECIAL WARNING(S), IF NECESSARY
8. EXPIRY DATE
EXP Use within 2 months of opening.
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9. SPECIAL STORAGE CONDITIONS
Keep the bottle tightly closed in order to protect from moisture. Store below 30°C.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
[To be completed nationally]
12. MARKETING AUTHORISATION NUMBER(S)
[To be completed nationally]
13. BATCH NUMBER
LOT
14. GENERAL CLASSIFICATION FOR SUPPLY
[To be completed nationally]
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
{Invented Name}
17. UNIQUE IDENTIFIER – 2D BARCODE
<2D barcode carrying the unique identifier included.>
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA
< PC: {number} [product code] SN: {number} [serial number] NN: {number} [national reimbursement number or other national number identifying the medicinal product]>
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PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
BOTTLE LABEL
1. NAME OF THE MEDICINAL PRODUCT
{Invented Name}® 250 mg Capsules, soft Metyrapone
2. STATEMENT OF ACTIVE SUBSTANCE(S)
Each capsule contains 250 mg metyrapone
3. LIST OF EXCIPIENTS and includes Sodium ethyl parahydroxybenzoate (E215), Sodium propyl parahydroxybenzoate (E217). See leaflet for further information.
4. PHARMACEUTICAL FORM AND CONTENTS
50 capsules, soft.
5. METHOD AND ROUTE(S) OF ADMINISTRATION
For oral use only. Read the package leaflet before use.
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN
Keep out of the sight and reach of children.
7. OTHER SPECIAL WARNING(S), IF NECESSARY
8. EXPIRY DATE
EXP Use within two months of opening.
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9. SPECIAL STORAGE CONDITIONS
Keep the bottle tightly closed in order to protect from moisture. Store below 30°C.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
[To be completed nationally]
12. MARKETING AUTHORISATION NUMBER(S)
[To be completed nationally]
13. BATCH NUMBER
LOT
14. GENERAL CLASSIFICATION FOR SUPPLY
[To be completed nationally]
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
[To be completed nationally]
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PACKAGE LEAFLET
Package leaflet: Information for the patient
{Invented Name} 250 mg Capsules Metyrapone
Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or nurse. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. See section 4.
What is in this leaflet
1. What {Invented Name} is and what it is used for 2. What you need to know before you take {Invented Name} 3. How to take {Invented Name} 4. Possible side effects 5. How to store {Invented Name} 6. Contents of the pack and other information
1. What {Invented Name} is and what it is used for
{Invented Name} contains 250 mg of metyrapone. Metyrapone belongs to a group of medicines known as tests for pituitary function evaluation. Metyrapone is used as a diagnostic test to identify if you have an insufficient level of ACTH, a hormone secreted by the pituitary gland which controls cortisol secretion; or Metyrapone may be used to help diagnose a specific type of Cushing’s syndrome.
The medicine can also be used to treat the signs and symptoms of endogenous Cushing’s syndrome by lowering the elevated levels of cortisol (a hormone produced by the adrenal glands). Cushing’s syndrome is a set of symptoms resulting from high levels of the hormone cortisol produced in your body by the adrenals.
2. What you need to know before you take {Invented Name}
Do not take {Invented Name} as a diagnostic test for ACTH insufficiency: - 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 take {Invented Name}: - if you are allergic to metyrapone or any of the other ingredients of this medicine listed in section 6.
If you are not sure if you should take {Invented Name}, ask your doctor or pharmacist.
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Warnings and precautions
Talk to your doctor before taking {Invented Name} for a diagnostic test if:
- you have, or think you may have, a condition in which your hormone levels are low (eg. reduced adrenal gland production of cortisol or severe hypopituitarism). Your doctor will need to perform a test to make sure {Invented Name} is right for you. - you have a liver disease or damage to the liver, as this may cause the medicine to work more slowly. - you are taking any medicines such as glucocorticoids as your doctor may decide to not do the {Invented Name} test as you will need to stop taking these.
During treatment with {Invented Name} {Invented Name} may temporarily lower the amount of hormones produced by your adrenal gland (cortisol) but your doctor will correct this using appropriate hormone medication. If you have Cushing's syndrome, your doctor may also give you medicine to prevent infections developing. But if you develop shortness of breath and fever over hours or days, contact your doctor as soon as possible as you may be developing a serious lung infection.
Talk to your doctor if you experience any of the following symptoms: weakness, fatigue, loss of appetite, nausea or vomiting. These symptoms and also low blood pressure, high levels of potassium, low levels of sodium or low levels of glucose in the blood may be signs of hypocortisolism (insufficient levels of cortisol in the blood). Your doctor will therefore check your blood pressure and perform a blood test. If you are diagnosed with hypocortisolism, your doctor may decide to temporarily administer a steroid (glucocorticoid) replacement therapy and/or reduce the dose or interrupt the treatment with {Invented Name}.
Breast-feeding Breast-feeding should be discontinued during treatment with {Invented Name} as there is a possibility that metyrapone may be passed to your baby in breast milk.
If you take {Invented Name} for a long time Your blood pressure may increase when taking this medicine.
Other medicines and {Invented Name} Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines as they may influence the results of the test with this medicine. The following medicines may affect the results of the Metapirone test:
• Anticonvulsants used to control epilepsy (e.g. phenytoin, barbiturates) • Anti-depressants and neuroleptics used to treat anxiety, depression or psychiatric problems (e.g. amitriptyline, chlorpromazine, alprazolam) • Hormones that affect the hypothalamo-pituitary axis which regulate many body processes such as stress, emotions, energy levels, digestion and the immune system (e.g. cortisol, hydrocortisone, ACTH, tetracosactin) • Corticosteroids • Antithyroid agents used to treat thyroid conditions (e.g. thyroxine, liothyroxine, carbimazole) • Cyprohepatadine used to treat allergies (e.g. Periactin)
{Invented Name} should not be taken with paracetamol without consulting your doctor.
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Pregnancy, breast-feeding and fertility
Use in pregnancy Do not use {Invented Name} if you are pregnant, think you are pregnant or are planning to become pregnant. {Invented Name} is not recommended in women of childbearing potential who are not using contraception.
Use in breast-feeding Breast-feeding should be discontinued during treatment with {Invented Name} as there is a possibility that metyrapone may be passed to your baby in breast milk.
Driving and using machines If you feel dizzy or drowsy after taking this medicine, you should not drive or operate machinery until these effects have passed.
{Invented Name} contains sodium parahydroxybenzoates (E215 and E217) which may cause allergic reactions (possibly delayed).
Monitoring and supervision When used as a diagnostic test, you should only be given this medicine when a healthcare professional is present, as they will need to monitor your body’s responses to the medicine.
3. How to take {Invented Name}
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure. If you are being given {Invented Name} to diagnose Cushing’s Syndrome, you will need to go into hospital for some tests.
Use in adults If you are having a short single-dose test (to test pituitary function): You will be asked to swallow the capsule(s) with yoghurt or milk at about midnight. You will then have a blood sample taken in the morning which will be reviewed by the doctor. The recommended dose is 30 mg/kg. The same dose is used in children.
If you are having a multiple-dose test (to test pituitary function and to help diagnose a specific type of Cushing’s syndrome): Your doctor will start taking samples of your urine 24 hours before you are given this medicine. You will then be given 2-3 capsules (500 – 750 mg) every 4 hours for the next 24 hours. You should take the capsules with milk or after a meal. Your doctor will then take more urine samples over the next 24 hours.
If you are treated for the signs and symptoms of endogenous Cushing’s Syndrome The dose you are given will be specific to you, and may range from 1 capsule (250 mg) to 24 capsules (6 g) per day in three or four divided doses. The {Invented Name} dose may be periodically adjusted by your doctor with the aim to restore normal cortisol levels.
You should always follow the doctors instructions closely and never change your dose unless your doctor tells you to.
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Use in children For the multiple-dose test children should be given 15 mg/kg with a minimum dose of 250 mg every 4 hours.
For management of Cushing’s syndrome, the dose should be adjusted on an individual basis as a function of cortisol levels and tolerability.
If you take more {Invented Name} than you should If you take too many capsules, tell your doctor or nurse immediately, or go to your nearest Casualty Department. You may feel sick and have stomach ache and/or diarrhoea. You may also feel dizzy, tired, have a headache, begin sweating and you blood pressure increase. You may need to have your stomach contents emptied and be given hydrocortisone.
If you forget to take {Invented Name} If you accidentally forget to take a dose of capsules, you should take it as soon as you remember. If it is nearly time for your next dose, do not double up your dose to make up for the one you have missed, but carry on taking your capsules as usual.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
4. Possible side effects
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Some side effects may be serious:
Not known (frequency cannot be estimated from the available data) • Bone marrow failure (occurs in individuals who produce an insufficient amount of red blood cells, white blood cells or platelets and the symptoms may include: bleeding or bruising lasting longer than normal, blood seen in the gums, nose or skin and feeling tired most of the time, shortness of breath, colds that keep coming back)
See also Section 2 “During treatment with {Invented Name}”.
Other side effects:
Common side effects (may affect up to 1 in 10 people): • Dizziness • Feeling tired or sleepy • Headache • Hypotension (low blood pressure) • Nausea (feeling sick) • Vomiting
Rare side effects (may affect up to 1 in 1000 people): • Adrenal insufficiency (low hormone production): the signs may be one or more of the following: weakness, fatigue, anorexia, nausea, vomiting, hypotension (low blood pressure), high potassium levels, low sodium levels, low glucose levels • Abdominal (stomach) pain • Hirsutism (hair growth in unusual areas, eg. chest hair in women)
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• Allergic skin reactions (such as rash, redness, inflammation and itching)
Not known (frequency cannot be estimated from the available data) • Hypertension (high blood pressure) • Alopecia (hair loss)
Reporting of side effects If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V*. By reporting side effects you can help provide more information on the safety of this medicine. [*For the printed material, please refer to the guidance of the annotated QRD template.]
5. How to store {Invented Name}
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the bottle and on the carton after EXP. The expiry date refers to the last day of that month. Use within two months of opening.
Keep the bottle tightly closed in order to protect from moisture. Store below 30°C
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.
6. Contents of the pack and other information
What {Invented Name} contains • The active substance is metyrapone. Each capsule contains 250 mg metyrapone. • The other ingredients are: Ethylvanillin, gelatin, glycerol, macrogol 400, macrogol 4000, P-methoxy acetophenone, sodium ethyl parahydroxybenzoate (E215), Sodium propyl parahydroxybenzoate (E217), titanium dioxide (E171) and purified water. The printing ink (red) on the capsules contains: carminic acid (E120), aluminium chloride hexahydrate, sodium hydroxide, hypromellose and propylene glycol.
What {Invented Name} looks like and contents of the pack A white to yellowish-white, oblong, opaque, soft gelatin capsule printed with word “HRA” in red ink and having faintly yellowish viscous to jelly-like contents. Each plastic bottle contains 50 capsules.
Marketing Authorisation Holder Manufacturer
[To be completed nationally] DELPHARM LILLE S.A.S Parc d’activités Roubaix-Est
22 Rue de Toufflers CS 50070 LYS LEZ LANNOY 59452 France This medicinal product is authorised in the Member States of the EEA under the following names: < {Name of the Member State} > < {Name of the medicinal product} >
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< {Name of the Member State} > < {Name of the medicinal product} >
This leaflet was last revised in MM/YYYY.
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