Metyrapone

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Metyrapone
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]

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Overview

Metyrapone is a inhibitor of endogenous adrenal corticosteriod synthesis that is FDA approved for the diagnosis of adrenal insufficiency and testing hypothalamic‑pituitary ACTH function. Common adverse reactions include {{{adverseReactions}}}.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Single-Dose Short Test

This test, usually given on an outpatient basis, determines plasma 11-desoxycortisol and/or ACTH levels after a single dose of Metopirone. The patient is given 30 mg/kg (maximum 3 g Metopirone) at midnight with yogurt or milk. The same dose is recommended in children. The blood sample for the assay is taken early the following morning (7:30-8:00 a.m.). The plasma should be frozen as soon as possible. The patient is then given a prophylactic dose of 50 mg cortisone acetate.

Interpretation

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 (70µg/L). Patients with suspected adrenocortical insufficiency should be hospitalized overnight as a precautionary measure.

Multiple-Dose Test
  • Day 1: Control period - Collect 24-hour urine for measurement of 17-OHCS or 17-KGS.
  • Day 2: ACTH test to determine the ability of adrenals to respond - Standard ACTH test such as infusion of 50 units ACTH over 8 hours and measurement of 24-hour urinary steroids. If results indicate adequate response, the Metopirone test may proceed.
  • Day 3-4: Rest period.
  • Day 5: Administration of Metopirone: Recommended with milk or snack.
    • Dosage:
      • Adults: 750 mg orally, every 4 hours for 6 doses. A single dose is approximately equivalent to 15 mg/kg.
  • Day 6: After administration of Metopirone - Determination of 24-hour urinary steroids for effect.
Interpretation
ACTH Test

The normal 24-hour urinary excretion of 17-OHCS ranges from 3 to 12 mg. Following continuous intravenous infusion of 50 units ACTH over a period of 8 hours, 17-OHCS excretion increases to 15 to 45 mg per 24 hours.

  • Metopirone
    • Normal response: In patients with a normally functioning pituitary, administration of Metopirone is followed by a two‑ to four‑fold increase of 17-OHCS excretion or doubling of 17-KGS excretion.
    • Subnormal response: Subnormal response in patients without adrenal insufficiency is indicative of some degree of impairment of pituitary function, either panhypopituitarism or partial hypopituitarism (limited pituitary reserve).
      • Panhypopituitarism is readily diagnosed by the classical clinical and chemical evidences of hypogonadism, hypothyroidism, and hypoadrenocorticism. These patients usually have subnormal basal urinary steroid levels. Depending upon the duration of the disease and degree of adrenal atrophy, they may fail to respond to exogenous ACTH in the normal manner. Administration of Metopirone is not essential in the diagnosis, but if given, it will not induce an appreciable increase in urinary steroids.
      • Partial hypopituitarism or limited pituitary reserve is the more difficult diagnosis as these patients do not present the classical signs and symptoms of hypopituitarism. Measurements of target organ functions often are normal under basal conditions. The response to exogenous ACTH is usually normal, producing the expected rise of urinary steroids (17-OHCS or 17-KGS). The response, however, to Metopirone is subnormal; that is, no significant increase in 17‑OHCS or 17‑KGS excretion occurs.

This failure to respond to metyrapone may be interpreted as evidence of impaired pituitary‑adrenal reserve. In view of the normal response to exogenous ACTH, the failure to respond to metyrapone is inferred to be related to a defect in the CNS‑pituitary mechanisms which normally regulate ACTH secretions. Presumably the ACTH secreting mechanisms of these individuals are already working at their maximal rates to meet everyday conditions and possess limited “reserve” capacities to secrete additional ACTH either in response to stress or to decreased cortisol levels occurring as a result of metyrapone administration. Subnormal response in patients with Cushing’s syndrome is suggestive of either autonomous adrenal tumors that suppress the ACTH-releasing capacity of the pituitary or nonendocrine ACTH-secreting tumors.

  • Excessive response: An excessive excretion of 17-OHCS or 17-KGS after administration of Metopirone is suggestive of Cushing’s syndrome associated with adrenal hyperplasia. These patients have an elevated excretion of urinary corticosteroids under basal conditions and will often, but not invariably, show a “supernormal” response to ACTH and also to Metopirone, excreting more than 35 mg per 24 hours of either 17-OHCS or 17-KGS.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Metyrapone in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Metyrapone in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Single-Dose Short Test

This test, usually given on an outpatient basis, determines plasma 11-desoxycortisol and/or ACTH levels after a single dose of Metopirone. The patient is given 30 mg/kg (maximum 3 g Metopirone) at midnight with yogurt or milk. The same dose is recommended in children. The blood sample for the assay is taken early the following morning (7:30-8:00 a.m.). The plasma should be frozen as soon as possible. The patient is then given a prophylactic dose of 50 mg cortisone acetate.

Interpretation

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 (70µg/L). Patients with suspected adrenocortical insufficiency should be hospitalized overnight as a precautionary measure.

Multiple-Dose Test
  • Day 1: Control period - Collect 24-hour urine for measurement of 17-OHCS or 17-KGS.
  • Day 2: ACTH test to determine the ability of adrenals to respond - Standard ACTH test such as infusion of 50 units ACTH over 8 hours and measurement of 24-hour urinary steroids. If results indicate adequate response, the Metopirone test may proceed.
  • Day 3-4: Rest period.
  • Day 5: Administration of Metopirone: Recommended with milk or snack.
    • Dosage:
      • Children: 15 mg/kg orally every 4 hours for 6 doses. A minimal single dose of 250 mg is recommended.
  • Day 6: After administration of Metopirone - Determination of 24-hour urinary steroids for effect.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Metyrapone in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Metyrapone in pediatric patients.

Contraindications

Metopirone is contraindicated in patients with adrenal cortical insufficiency, or hypersensitivity to Metopirone or to any of its excipients.

Warnings

Metopirone may induce acute adrenal insufficiency in patients with reduced adrenal secretory capacity.

Adverse Reactions

Clinical Trials Experience

There is limited information regarding Metyrapone Clinical Trials Experience in the drug label.

Postmarketing Experience

There is limited information regarding Metyrapone Postmarketing Experience in the drug label.

Drug Interactions

Drugs affecting pituitary or adrenocortical function, including all corticosteroid therapy, must be discontinued prior to and during testing with Metopirone.

The metabolism of Metopirone is accelerated by phenytoin; therefore, results of the test may be inaccurate in patients taking phenytoin within two weeks before. A subnormal response may occur in patients on estrogen therapy.

Metopirone inhibits the glucuronidation of acetaminophen and could possibly potentiate acetaminophen toxicity.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): C A subnormal response to Metopirone may occur in pregnant women. Animal reproduction studies have not been conducted with Metopirone. The Metopirone test was administered to 20 pregnant women in their second and third trimester of pregnancy and evidence was found that the fetal pituitary responded to the enzymatic block. It is not known if Metopirone can affect reproduction capacity. Metopirone should be given to a pregnant woman only if clearly needed.

Animal reproduction studies adequate to evaluate teratogenicity and postnatal development have not been conducted with Metopirone.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Metyrapone in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Metyrapone during labor and delivery.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Metopirone is administered to a nursing woman.

Pediatric Use

There is no FDA guidance on the use of Metyrapone in pediatric settings.

Geriatic Use

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. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. 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.

Gender

There is no FDA guidance on the use of Metyrapone with respect to specific gender populations.

Race

There is no FDA guidance on the use of Metyrapone with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Metyrapone in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Metyrapone in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Metyrapone in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Metyrapone in patients who are immunocompromised.

Administration and Monitoring

Administration

There is limited information regarding Metyrapone Administration in the drug label.

Monitoring

There is limited information regarding Metyrapone Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Metyrapone and IV administrations.

Overdosage

Acute Toxicity
  • One case has been recorded in which a 6‑year‑old girl died after two doses of Metopirone, 2 g.
  • Oral LD50 in animals (mg/kg): rats, 521; maximum tolerated intravenous dose in one dog, 300.
Signs and Symptoms

The clinical picture of poisoning with Metopirone is characterized by gastrointestinal symptoms and by signs of acute adrenocortical insufficiency.

Manifestations by Organs and Systems=
Combined Poisoning

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. Besides general measures to eliminate the drug and reduce its absorption, a large dose of hydrocortisone should be administered at once, together with saline and glucose infusions.

Surveillance: For a few days blood pressure and fluid and electrolyte balance should be monitored.

Pharmacology

There is limited information regarding Metyrapone Pharmacology in the drug label.

Mechanism of Action

There is limited information regarding Metyrapone Mechanism of Action in the drug label.

Structure

There is limited information regarding Metyrapone Structure in the drug label.

Pharmacodynamics

There is limited information regarding Metyrapone Pharmacodynamics in the drug label.

Pharmacokinetics

There is limited information regarding Metyrapone Pharmacokinetics in the drug label.

Nonclinical Toxicology

There is limited information regarding Metyrapone Nonclinical Toxicology in the drug label.

Clinical Studies

There is limited information regarding Metyrapone Clinical Studies in the drug label.

How Supplied

There is limited information regarding Metyrapone How Supplied in the drug label.

Storage

There is limited information regarding Metyrapone Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Metyrapone Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Metyrapone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Metyrapone Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Metyrapone Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

Metyrapone
File:Metyrapone structure.svg
Clinical data
Pregnancy
category
Routes of
administration		Oral
ATC code
Pharmacokinetic data
Elimination half-life1.9 ±0.7 hours.
Identifiers
CAS Number
PubChem CID
DrugBank
E number{{#property:P628}}
ECHA InfoCard{{#property:P2566}}Lua error in Module:EditAtWikidata at line 36: attempt to index field 'wikibase' (a nil value).
Chemical and physical data
FormulaC14H14N2O
Molar mass226.274 g/mol

Metyrapone (Metopirone™) is a drug used in the diagnosis of adrenal insufficiency, and occasionally the treatment, of Cushing's syndrome (hypercortisolism). Metyrapone blocks cortisol synthesis by inhibiting steroid 11-beta-hydroxylase. This stimulates ACTH secretion, which in turn increases plasma 11- deoxycortisol levels. When excess ACTH secretion is the cause of hypercortisolism, the metyrapone test helps clarify if the source of the ACTH is pituitary or ectopic (non-pituitary). The effects of metyrapone were first noticed by mistake in transgenic mice by TE Vanguard at the University of Tennessee in Memphis while testing a similar drug known as metradione which was being studied for its effects on corticosteroid uptake.

Metyrapone can be used in the diagnosis of Adrenal insufficiency. Metyrapone 30mg/kg, maximum dose 300omg, is administered at midnight usually with a snack. The plasma cortisol and 11-deoxycortisol are measured the next morning between 08:00hrs and 09:00hrs. A plasma cortisol less than 220nmol/l indicates adequate inhibition of 11beta-hydroxylase. In patients with intact Hypothamalmo-pituitary-adrenal axis, CRH and ACTH levels rise as a response to the falling cortisol levels. This results in an increase of the steroid precursors in the pathway. Therefore if 11-deoxycortisol levels do not rise and remains less than 7mcg/dl then it is highly suggestive of impaired HPA axis.

Metyrapone test may aid in verifying the cause of Cushing's Syndrome. Most patients with pituitary dysfunction and/or pituitary microadenoma will increase ACTH secretion in response to metyrapone, while most ectopic ACTH - producing tumors will not. Pituitary macroadenomas do not always respond to metyrapone. Template:Pharma-stub Template:WikiDoc Sources

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