2.1 Important Information Before Conducting Metopirone Testing

Stop drugs affecting pituitary or adrenocortical function before administration of Metopirone in accordance with half-life of the drugs (consider at least 5 half-lives to avoid any interference with Metopirone testing). [see Drug Interactions (7.1)] .

Assess ability of patient's adrenals to respond to exogenous ACTH before Metopirone is employed as a test [see Warnings and Precautions (5.1)] .

2.2 Single-Dose Short Test- Recommended Dose and Interpretation

This test, usually given on an outpatient basis, determines plasma 11-desoxycortisol and/or ACTH levels after a single dose of Metopirone. Patients with suspected adrenocortical insufficiency based on the test results previously performed should be hospitalized overnight as a precautionary measure ( see Warnings and Precaution (5.1)).

5.1 Adrenal Insufficiency

Metopirone 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 the hospital with close monitoring in case of suspected adrenal insufficiency.

Ability of adrenals to respond to exogenous ACTH should be demonstrated before Metopirone is employed as a test.

In the presence of hypo‑ or hyperthyroidism, response to the Metopirone test may be subnormal.

If adrenocortical or anterior pituitary function is more severely compromised than indicated by the results of the test, Metopirone may trigger adrenal insufficiency. This can be corrected by giving appropriate doses of corticosteroids.

5.2 Dizziness and Sedation

Metopirone may cause dizziness and sedation. Patients should not drive or operate machinery until these effects have passed.

7.1 Effect of Other Drugs on Metopirone

Anticonvulsants, psychotropic drugs, hormone preparations, corticosteroids, antithyroid agents and cyproheptadine may affect the results of the Metopirone test.

If these drugs cannot be withdrawn, the necessity of carrying out the Metopirone test should be reviewed.

7.2 Effect of Metopirone on Other Drugs

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Metopirone is indicated, in combination with other diagnostic tests, for the diagnosis of adrenal insufficiency in pediatric patients [See Dosage and Administration (2.1)].

8.5 Geriatric Use

Clinical studies of Metopirone did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.

Other reported clinical experience has not identified differences in responses between patients 65 years of age and older and younger adult patients.

8.6 Hepatic Impairment

Patients with cirrhosis may have an impaired response to Metopirone.

Signs and Symptoms of Overdosage

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

• Cardiovascular System: Cardiac arrhythmias, hypotension, dehydration.
• Nervous System and Muscles: Anxiety, confusion, weakness, impairment of consciousness.
• Gastrointestinal System:Nausea, vomiting, epigastric pain, diarrhea.
• Laboratory Findings:Hyponatremia, hypochloremia, hyperkalemia.

In patients under treatment with insulin or oral antidiabetics, the signs and symptoms of acute overdosage with Metopirone may be aggravated or modified.

Treatment and Management of Overdosage

There is no specific antidote for Metopirone overdosage. Immediate treatment is essential in the management of Metopirone overdose.

Treatment with activated charcoal may be considered if the overdose has been taken within 1 hour. In addition to general measures, 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 and electrolyte balance should be monitored.

Consult with a regional poison control center (1-800-222-1222) for additional treatment recommendations.

12.1 Mechanism of Action

The pharmacological effect of Metopirone is to reduce cortisol and corticosterone production by inhibiting the 11-beta-hydroxylation reaction in the adrenal cortex. Removal of the strong inhibitory feedback mechanism exerted by cortisol results in an increase in adrenocorticotropic hormone (ACTH) production by the pituitary. With continued blockade of the enzymatic steps leading to production of cortisol and corticosterone, there is a marked increase in adrenocortical secretion of their immediate precursors, 11-desoxycortisol and desoxycorticosterone, which are weak suppressors of ACTH release, and a corresponding elevation of these steroids in the plasma and of their metabolites in the urine. These metabolites are readily determined by measuring urinary 17‑hydroxycorticosteroids (17-OHCS) or 17-ketogenic steroids (17-KGS). Because of these actions, Metopirone is used as a diagnostic test, with urinary 17-OHCS measured as an index of pituitary ACTH responsiveness. Metopirone may also suppress biosynthesis of aldosterone, resulting in a mild natriuresis.

12.2 Pharmacodynamics

Metopirone exposure-response relationships and the time course of pharmacodynamic response are unknown.

12.3 Pharmacokinetics

The mean C maxof metyrapone following a single 750 mg is 3.7 mcg/mL falling to 0.5 mcg/mL 4 hours after administration.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

How Supplied

Metopirone (metyrapone capsules) are supplied as 250 mg soft gelatin, white to yellowish‑white, oblong, opaque capsules, imprinted with "HRA" on one side in red ink.

Bottle of 18 capsules: NDC 76336-455-18

Storage and Handling

Store Metopirone bottles at room temperature 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].

Keep container tightly closed and protect from heat and moisture.