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.
(For additional information see "Metyrapone: Drug information")
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]).
There are no dosage adjustments provided in the manufacturer’s labeling.
There are no dosage adjustments provided in the manufacturer’s labeling.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Metopirone: 250 mg
No
Metopirone is available from HRA Pharma via special allocation only. Contact the manufacturer for additional information at 855-674-7663.
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.
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]).
Store at 15°C to 25°C (59°F to 77°F); protect from heat. Protect from moisture.
Diagnostic agent for testing hypothalamic-pituitary ACTH function (FDA approved in pediatric patients [age not specified] and adults)
MetyraPONE may be confused with metyroSINE
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])
Hypersensitivity to metyrapone or any component of the formulation; patient 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:
• 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.
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).
None known.
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
Take with milk or snack.
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).
Single-dose test: ACTH, cortisol and 11-deoxycortisol concentrations measured at 8 am (Uçar 2016); 11-deoxycortisol concentrations diagnostic for adrenal insufficiency:
Infants, Children, and Adolescents: <210 nmol/L (Uçar 2016)
Adults: <200 nmol/L (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.
Normal 24-hour urinary excretion of 17-OHCS: 3 to 12 mg (increases following ACTH infusion)
Normal response to metyrapone:
Plasma ACTH: 44 pmol/L (200 ng/L)
Plasma 11-desoxycortisol: Pediatric: 0.21 micromoles/L (Uçar 2016); Adult: 0.2 micromoles/L (70 mcg/L)
24 hour urinary excretion of 17-OHCS: 2 to 4 time increase
24 hour urinary excretion of 17-KGS: 2 time increase
A subnormal response may be indicative of panhypopituitarism or partial hypopituitarism. An excessive response is suggestive of Cushing syndrome associated with adrenal hyperplasia.
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]).
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)
Capsules (Metopirone Oral)
250 mg (per each): $48.31
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