Version May 2024
Diagnostic aid, adrenal insufficiency: Oral: 30 mg/kg (maximum: 3 g) at midnight.
Cushing syndrome (off-label use): Note: 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: Oral: 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; ES [Nieman 2015]).
Dosage adjustment: Oral: 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 (ES [Nieman 2015]).
There are no dosage adjustments provided in the manufacturer’s labeling.
There are no dosage adjustments provided in the manufacturer's labeling. Diagnostic response to metyrapone may be impaired in patients with cirrhosis.
Refer to adult dosing.
(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
There are no dosage adjustments provided in the manufacturer's labeling.
There are no dosage adjustments provided in the manufacturer's labeling.
The following adverse drug reactions are derived from product labeling unless otherwise specified. Reported adverse reactions may be derived for off-label long-term use for Cushing syndrome.
Postmarketing:
Cardiovascular: Edema (including peripheral edema) (Ceccato 2018; Nieman 2015; Verhelst 1991), hypertension (Nieman 2015; Verhelst 1991), hypotension
Dermatologic: Allergic skin rash (including allergic dermatitis) (Ceccato 2018), alopecia (Ceccato 2018; Harries-Jones 1990), exacerbation of acne (Jeffcoate 1977; Nieman 2015)
Endocrine: Adrenocortical insufficiency (Daniel 2015), hirsutism (Nieman 2015; Verhelst 1991), hypokalemia (Nieman 2015; Verhelst 1991)
Gastrointestinal: Abdominal distress, abdominal pain (including upper abdominal pain) (Ceccato 2018; Mancini 2010), decreased appetite (Ceccato 2018), gastric distress (Daniel 2015), nausea (Ceccato 2018), vomiting
Hematologic & oncologic: Anemia, leukopenia, thrombocytopenia
Nervous system: Asthenia (Ceccato 2018), dizziness (Ceccato 2018), headache, sedated state
Neuromuscular & skeletal: Myalgia (Ceccato 2018; Daniel 2015)
Hypersensitivity to metyrapone or any component of the formulation; patients with adrenal cortical insufficiency.
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:
• Hepatic impairment: Diagnostic response to metyrapone may be impaired in patients with cirrhosis.
• 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.
Other warnings and precautions:
• Appropriate use: Discontinue use of drugs affecting pituitary or adrenocortical function prior to administration; consider ≥5 half-lives to avoid interference. Prior to testing, assess the ability of the patient's adrenal glands to respond to exogenous ACTH.
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).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Metopirone: 250 mg
No
Capsules (Metopirone Oral)
250 mg (per each): $55.56
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.
Metopirone is available from HRA Pharma via special allocation only. Contact the manufacturer for additional information at 1-800-320-2112 (for outpatient prescriptions), 1-844-597-6373 (for hospital and institutional orders), or https://metopirone.com/.
Oral:
Diagnostic aid, adrenal insufficiency: Administer dose at midnight with milk/yogurt or snack. Blood samples are taken early the following morning (7:30 am to 8:00 am). May administer a prophylactic dose of glucocorticoid after samples are obtained to reduce the risk of acute adrenal insufficiency.
Cushing syndrome: Administer with food or milk to minimize GI disturbance (ES [Nieman 2015]).
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.
Diagnostic aid, adrenal insufficiency: Diagnostic test (in combination with other diagnostic tests) for the diagnosis of adrenal insufficiency in pediatric and adult patients.
Cushing syndrome
MetyraPONE may be confused with metyroSINE
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
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 X: Avoid combination
Antiseizure Agents: May diminish the diagnostic effect of MetyraPONE. Management: Consider alternatives to the use of the metyrapone test in patients taking antiseizure agents. Risk D: Consider therapy modification
Antithyroid Agents: May diminish the diagnostic effect of MetyraPONE. Management: Consider alternatives to the use of the metyrapone test in patients taking antithyroid agents. Risk D: Consider therapy modification
Corticosteroids (Systemic): May diminish the diagnostic effect of MetyraPONE. Management: Consider alternatives to the use of the metyrapone test in patients taking systemic corticosteroids. Risk D: Consider therapy modification
Cyproheptadine: May diminish the diagnostic effect of MetyraPONE. Management: Consider alternatives to the use of the metyrapone test in patients taking cyproheptadine. Risk D: Consider therapy modification
Estrogen Derivatives: May diminish the diagnostic effect of MetyraPONE. Management: Consider alternatives to the use of the metyrapone test in patients taking estrogen derivatives. Risk D: Consider therapy modification
Progestins: May diminish the diagnostic effect of MetyraPONE. Management: Consider alternatives to the use of the metyrapone test in patients taking progestins. 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 X: Avoid combination
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 pregnant patients.
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).
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).
Take with milk/yogurt or snack.
Diagnostic aid, adrenal insufficiency: 11-deoxycortisol concentrations <70 mcg/L (<200 nmol/L) are diagnostic for adrenal insufficiency (Wallace 2009; manufacturer's labeling).
Cushing syndrome: 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 (Daniel 2015b; ES [Nieman 2015]).
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)
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]).
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): ~4 hours.
Time to peak: ~1 hour.
Excretion: Urine; ~5% as metyrapone (primarily as glucuronide conjugate) and ~38% as metyrapol (primarily as glucuronide conjugate).
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