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Metyrapone: Drug information

Metyrapone: Drug information
(For additional information see "Metyrapone: Pediatric drug information" and see "Metyrapone: Patient drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Brand Names: US
  • Metopirone
Pharmacologic Category
  • Diagnostic Agent
Dosing: Adult

ACTH function testing: Oral:

Single-dose/overnight test: 30 mg/kg (maximum: 3 g) at midnight

Multiple-dose test: 750 mg every 4 hours for 6 doses

Cushing syndrome (off-label use): Oral: Dosages based on retrospective/observational data and clinical experience. Metyrapone may be administered as monotherapy or occasionally in combination with other agents (eg, ketoconazole and/or mitotane); refer to protocols for details.

Initial: 500 mg/day to 1 g/day in 2 to 4 divided doses; higher initial doses (eg, 1.5 g/day) may be considered in patients with ectopic ACTH syndrome or adrenocortical carcinoma (Biller 2008; Ceccato 2018; Daniel 2015a; Daniel 2015b; Endocrine Society [Nieman 2015]).

Titration: Adjust daily dose in increments of 250 to 500 mg based on cortisol response (Ceccato 2018; Daniel 2015b). Usual dosage range: 500 mg/day to 4.5 g/day (Ceccato 2018; Daniel 2015a; Kamenicky 2011).

Maximum: 6 g/day (Endocrine Society [Nieman 2015]).

Dosing: Kidney Impairment: Adult

There are no dosage adjustments provided in the manufacturer’s labeling.

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the manufacturer’s labeling.

Dosing: Pediatric

(For additional information see "Metyrapone: Pediatric drug information")

ACTH function, diagnostic test:

Single-dose/overnight test: Note: Due to potential precipitation of acute adrenal insufficiency (crisis) in some patients, experts suggest that metyrapone should be used with extreme caution in an outpatient setting; consider administration in an inpatient environment (Kliegman 2016; Uçar 2016).

Children and Adolescents: Oral: 30 mg/kg as a single dose given at midnight the night before the test; maximum dose: 3,000 mg/dose

Multiple-dose test: Children and Adolescents: Oral: 15 mg/kg/dose every 4 hours for 6 doses; minimum dose: 250 mg/dose; maximum dose: 750 mg/dose

Dosing: Kidney Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer's labeling.

Dosing: Hepatic Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer's labeling.

Dosing: Older Adult

Refer to adult dosing.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Metopirone: 250 mg

Generic Equivalent Available: US

No

Prescribing and Access Restrictions

Metopirone is available from HRA Pharma via special allocation only. Contact the manufacturer for additional information at 855-674-7663.

Administration: Adult

Oral:

ACTH function testing:

Single-dose test: Administer to patients with adequate waking cortisol concentrations (>200 nmol/L) (Wallace 2009). Administer dose at midnight with yogurt or milk. Blood samples are taken the following morning (7:30-8:00 am). Administer prophylactic dose of cortisone acetate 50 mg after samples are obtained.

Multiple-dose test: Administer with milk or snack 3 days following ACTH test. Urine is collected for 24 hours following the last day of administration.

Cushing syndrome: Administer with food or milk to minimize GI disturbance (Endocrine Society [Nieman 2015]).

Administration: Pediatric

Oral:

Single-dose/overnight test: Note: Due to potential precipitation of acute adrenal insufficiency (crisis) in some patients, experts suggest that metyrapone should be used with extreme caution in an outpatient setting; consider administration in an inpatient environment (Kliegman 2016; Uçar 2016). Administer dose at midnight with yogurt or milk. Blood samples should be collected the following morning (7:30 to 8:00 am). Administer prophylactic dose of cortisone acetate after samples are obtained.

Multiple-dose test: Administer with milk or snack 3 days following ACTH test. Urine is collected for 24 hours following administration of last dose.

Use: Labeled Indications

ACTH function testing: Diagnostic test for hypothalamic-pituitary ACTH function

Use: Off-Label: Adult

Cushing syndrome

Medication Safety Issues
Sound-alike/look-alike issues:

MetyraPONE may be confused with metyroSINE

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

Frequency not defined:

Cardiovascular: Hypotension

Central nervous system: Dizziness, headache, sedated state

Dermatologic: Allergic skin rash

Gastrointestinal: Abdominal discomfort, abdominal pain, nausea, vomiting

Hematologic & oncologic: Bone marrow depression, decreased white blood cell count

Postmarketing: Edema (long-term use [ES (Nieman 2015); Verhelst 1991]), hirsutism (long-term use [ES (Nieman 2015); Verhelst 1991]), hypertension (long-term use [ES (Nieman 2015); Verhelst 1991]), hypokalemia (long-term use [ES (Nieman 2015); Verhelst 1991])

Contraindications

Hypersensitivity to metyrapone or any component of the formulation; patient with adrenal cortical insufficiency

Warnings/Precautions

Concerns related to adverse effects:

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).

Disease-related concerns:

• Reduced adrenal secretory capacity: Acute adrenal insufficiency may be induced in patients with reduced adrenal secretory capacity.

• Thyroid disease: Response to test may be subnormal in patients with hypo- or hyperthyroidism.

Warnings: Additional Pediatric Considerations

Administration of metyrapone may induce acute adrenal insufficiency in patients with reduced adrenal secretory capacity; should be used with extreme caution in an outpatient setting; consider administration in an inpatient environment. Patients should be observed closely during administration and the following day; should only be administered under the supervision of a qualified physician experienced in the use of metyrapone (Kliegman 2016; Uçar 2016).

Metabolism/Transport Effects

None known.

Drug Interactions

Acetaminophen: MetyraPONE may increase the serum concentration of Acetaminophen. More importantly, by inhibiting the conjugative metabolism of acetaminophen, metyrapone may shift the metabolism towards the oxidative route that produces a hepatotoxic metabolite. Risk C: Monitor therapy

Fosphenytoin: May decrease the serum concentration of MetyraPONE. The oral metyrapone test would thus be unreliable unless the metapyrone dosage was substantially increased (eg, 750 mg every 2 hours). Management: Results of the metyrapone test may be unreliable in patients receiving phenytoin within 2 weeks of metyrapone. Consider doubling the dose of metyrapone to overcome increased metyrapone metabolism. Risk D: Consider therapy modification

Phenytoin: May decrease the serum concentration of MetyraPONE. The oral metyrapone test would thus be unreliable unless the metyrapone dosage was substantially increased (eg, 750 mg every 2 hours). Management: Results of the metyrapone test may be unreliable in patients receiving phenytoin within 2 weeks of metyrapone. Consider doubling the dose of metyrapone to overcome increased metyrapone metabolism. Risk D: Consider therapy modification

Propacetamol: MetyraPONE may increase serum concentrations of the active metabolite(s) of Propacetamol. Specifically, metyrapone may increase acetaminophen exposure. More importantly, by inhibiting the conjugative metabolism of acetaminophen, metyrapone may shift the metabolism toward the oxidative route that produces a hepatotoxic metabolite. Risk C: Monitor therapy

Pregnancy Considerations

Metyrapone crosses the placenta (Azzola 2020).

When used as a diagnostic test during the second and third trimesters of pregnancy, the fetal pituitary responded to the enzymatic block. A subnormal response to testing may occur in patients who are pregnant.

Untreated Cushing syndrome during pregnancy may cause adverse events in the mother and fetus (Bronstein 2015; Brue 2018; Kamoun 2014). Information related to metyrapone for the treatment of Cushing disease (off-label use) during pregnancy is limited. Medication may be considered for patients when surgery is not an option or for symptomatic control at initial diagnosis (ES [Nieman 2015]; ESE [Luger 2021]. When medical therapy is needed, treatment is generally started in the second or third trimesters (Bronstein 2015).

Breastfeeding Considerations

Metyrapone and the active metabolite metyrapol are present in breast milk.

Information related to the presence of metyrapone in breast milk is available from case reports following maternal use for Cushing syndrome secondary to an adrenal adenoma diagnosed during pregnancy:

• In one report, the mother had been taking metyrapone 250 mg 4 times daily for 9 weeks and was 1 week postpartum when milk samples were obtained. Multiple milk samples taken ~1 to 5 hours after the dose contained average concentrations of metyrapone 11.2 mcg/L and metyrapol 48.5 mcg/L over the dosing interval. The relative infant dose (RID) for metyrapone and metyrapol was calculated to be 0.1% of the weight adjusted maternal dose. The infant was not breastfed (Hotham 2009).

• In a second report, the mother was taking metyrapone 250 mg 3 times daily following her diagnosis at 24 weeks' gestation. Breast milk samples were obtained beginning 5 weeks postpartum on 4 different days. On the first day, sampling occurred prior to the maternal dose and every 30 minutes until the next dose. Peak breast milk concentrations of metyrapone and metyrapol occurred 30 minutes after the dose and were 761.7 mcg/L and 1,250 mcg/L, respectively. The average breast milk concentrations over the dosing interval were 176.31 mcg/L (metyrapone) and 310.16 mcg/L (metyrapol), providing a RID of 0.69% for metyrapone and 1.21% for metyrapol. This RID of metyrapone is based on a 15 mg/kg pediatric dose used diagnostically for Cushing syndrome. On a second day of sampling, breast milk was only collected every 60 minutes following the maternal dose. The RID of metyrapone and metyrapol were 0.04% and 0.074% based on this data. The infant was breastfed once lactation was established, receiving ~50% maternal milk and ~50% formula for 7 months. Infant serum was also sampled with breast milk at 5 weeks postpartum. Maternal (and infant) plasma concentrations were 41.5 mcg/L (0.05 mcg/L) for metyrapone and 338 mcg/L (4 mcg/L) for metyrapol. There were no adverse events on neonatal adrenocortical function. Authors of this report note infant exposure could be further decreased by minimizing nursing for 2 to 3 hours after each maternal dose (Duke 2019).

The manufacturer recommends that caution be exercised when administering metyrapone to breastfeeding patients. In general, breastfeeding is considered acceptable when the RID of a medication is <10% (Anderson 2016; Ito 2000).

Dietary Considerations

Take with milk or snack.

Monitoring Parameters

ACTH function testing:

Single-dose test: 11-deoxycortisol concentrations <200 nmol/L are diagnostic for adrenal insufficiency (Wallace 2009)

Multiple-dose test: Normal response following the test is a two- to fourfold urinary increase in 17-OHCS excretion or doubling of 17-KGS excretion.

Cushing syndrome (Endocrine Society [Nieman 2015]; Daniel 2015b): Cortisol (either serum cortisol or 24-hour urinary-free cortisol [baseline, day 3, then weekly to facilitate dosage adjustment; periodically thereafter]); serum potassium; blood pressure; signs/symptoms of edema, hirsutism

Reference Range

Normal 24-hour urinary excretion of 17-OHCS: 3 to 12 mg (increases to 15 to 45 mg following ACTH infusion of 50 units over 8 hours)

Mechanism of Action

Metyrapone inhibits 11 beta-hydroxylase, preventing the conversion of 11-deoxycortisol to cortisol; blockade can be measured by the urinary increase of the metabolites of cortisol precursors in the urine (17-hydroxycorticosteroids [17-OHCS] and 17-ketogenic steroids [17-KGS]).

Pharmacokinetics

Onset: Peak steroid excretion: Within 24 hours of administration

Absorption: Oral: Well absorbed; rapid

Metabolism: Reduced to metyrapol (active metabolite); parent drug and metabolite also undergo glucuronide conjugation

Half-life elimination: Metyrapone: 1.9 ± 0.7 hours; Metyrapol (active metabolite): Takes twice as long as metyrapone to be eliminated

Time to peak: 1 hour

Excretion: Urine; ~5% as metyrapone (primarily as glucuronide conjugate) and ~38% as metyrapol (primarily as glucuronide conjugate)

Pricing: US

Capsules (Metopirone Oral)

250 mg (per each): $48.31

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Metopiron (CH, GB, JP, NO, SE);
  • Metopirone (AU, CZ, FR, GR, HK, IE, IL, MT, NZ, PL);
  • Metycor (BE, NO)


For country abbreviations used in Lexicomp (show table)

REFERENCES

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  3. Biller BM, Grossman AB, Stewart PM, et al. Treatment of adrenocorticotropin-dependent Cushing's syndrome: A consensus statement. J Clin Endocrinol Metab. 2008;93(7):2454-2462. doi: 10.1210/jc.2007-2734. [PubMed 18413427]
  4. Bronstein MD, Machado MC, Fragoso MC. Management of endocrine disease: Management of pregnant patients with Cushing's syndrome. Eur J Endocrinol. 2015;173(2):R85-R91. doi: 10.1530/EJE-14-1130. [PubMed 25872515]
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  10. Hotham NJ, Ilett KF, Hackett LP, et al, "Transfer of Metyrapone and its Metabolite, Rac-Metyrapol, Into Breast Milk," J Hum Lact, 2009, 25(4):451-4. [PubMed 19759353]
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