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| Product NDC Code | 76336-455 | ||||
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| Drug Name | Metopirone |
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| Type | Brand | ||||
| Pharm Class | Adrenal Steroid Synthesis Inhibitor [EPC], Adrenal Steroid Synthesis Inhibitors [MoA] |
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| Route | ORAL | ||||
| Dosage Form | CAPSULE, GELATIN COATED | ||||
| RxCUI drug identifier | 105450, 199772 |
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| Application Number | NDA012911 | ||||
| Labeler Name | HRA Pharma Rare Diseases | ||||
| Packages |
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Overdosage of Metopirone
Information about signs, symptoms, and laboratory findings of acute ovedosage and the general principles of overdose treatment.10 OVERDOSAGE Death occurred in a child after two doses of Metopirone 2 g. 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.
Adverse reactions
Information about undesirable effects, reasonably associated with use of the drug, that may occur as part of the pharmacological action of the drug or may be unpredictable in its occurrence. Adverse reactions include those that occur with the drug, and if applicable, with drugs in the same pharmacologically active and chemically related class. There is considerable variation in the listing of adverse reactions. They may be categorized by organ system, by severity of reaction, by frequency, by toxicological mechanism, or by a combination of these.6 ADVERSE REACTIONS The following adverse reactions associated with the use of Metopirone were identified in clinical trials or postmarketing reports. Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiovascular System: Hypotension Gastrointestinal System: Nausea, vomiting, abdominal discomfort or pain Central Nervous System: Headache, dizziness, sedation Dermatologic System: Allergic rash Hematologic System: Leukopenia, anemia, and/or thrombocytopenia Adverse reactions include: hypotension, nausea, vomiting, abdominal discomfort or pain, headache, dizziness, sedation, allergic rash, leukopenia, anemia, and/or thrombocytopenia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Direct Success Inc. at 844-597-6373 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Metopirone Drug Interactions
Information about and practical guidance on preventing clinically significant drug/drug and drug/food interactions that may occur in people taking the drug.7 DRUG INTERACTIONS Anticonvulsants, psychotropic, hormone preparations, corticosteroids, antithyroid agents, cyproheptadine: may affect the results of the metyrapone test. ( 7.1 ) Acetaminophen: Avoid concomitant use with Metopirone. ( 7.2 ) 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 Acetaminophen Metopirone inhibits the glucuronidation of acetaminophen, which may decrease elimination of acetaminophen and lead to increased risk of adverse reactions related to acetaminophen. Avoid concomitant use of Metopirone with acetaminophen.
Clinical pharmacology
Information about the clinical pharmacology and actions of the drug in humans.12 CLINICAL PHARMACOLOGY 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 max of metyrapone following a single 750 mg is 3.7 mcg/mL falling to 0.5 mcg/mL 4 hours after administration. Absorption The time to peak plasma concentration of metyrapone is approximately 1 hour after oral administration. Elimination The mean (± SD) terminal elimination half‑lives of metyrapone and its active metabolite metyrapol are 1.9 (± 0.7) hours and approximately 4 hours, respectively. Metabolism Metyrapone is reduced to metyrapol, an active alcohol metabolite. Both metyrapone and metyrapol are conjugated with glucuronide. Eight hours after a single oral dose, the ratio of metyrapone to its active metabolite metyrapol in plasma is 1:1.5. Excretion Following administration of metyrapone 750 mg every 4 hours, approximately 5.3% of the dose was excreted in urine as unchanged and 38.5% as its active metabolite metyrapol within 72 hours after the first dose.
Mechanism of action
Information about the established mechanism(s) of the drugÕs action in humans at various levels (for example receptor, membrane, tissue, organ, whole body). If the mechanism of action is not known, this field contains a statement about the lack of information.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.
Pharmacodynamics
Information about any biochemical or physiologic pharmacologic effects of the drug or active metabolites related to the drugÕs clinical effect in preventing, diagnosing, mitigating, curing, or treating disease, or those related to adverse effects or toxicity.12.2 Pharmacodynamics Metopirone exposure-response relationships and the time course of pharmacodynamic response are unknown.
Pharmacokinetics
Information about the clinically significant pharmacokinetics of a drug or active metabolites, for instance pertinent absorption, distribution, metabolism, and excretion parameters.12.3 Pharmacokinetics The mean C max of metyrapone following a single 750 mg is 3.7 mcg/mL falling to 0.5 mcg/mL 4 hours after administration. Absorption The time to peak plasma concentration of metyrapone is approximately 1 hour after oral administration. Elimination The mean (± SD) terminal elimination half‑lives of metyrapone and its active metabolite metyrapol are 1.9 (± 0.7) hours and approximately 4 hours, respectively. Metabolism Metyrapone is reduced to metyrapol, an active alcohol metabolite. Both metyrapone and metyrapol are conjugated with glucuronide. Eight hours after a single oral dose, the ratio of metyrapone to its active metabolite metyrapol in plasma is 1:1.5. Excretion Following administration of metyrapone 750 mg every 4 hours, approximately 5.3% of the dose was excreted in urine as unchanged and 38.5% as its active metabolite metyrapol within 72 hours after the first dose.
Contraindications
Information about situations in which the drug product is contraindicated or should not be used because the risk of use clearly outweighs any possible benefit, including the type and nature of reactions that have been reported.4 CONTRAINDICATIONS Metopirone is contraindicated in patients with adrenal cortical insufficiency or hypersensitivity to Metopirone or to any of its excipients. In patients with adrenal cortical insufficiency ( 4 ) Hypersensitivity to Metopirone or to any of its excipients ( 4 )
Description
General information about the drug product, including the proprietary and established name of the drug, the type of dosage form and route of administration to which the label applies, qualitative and quantitative ingredient information, the pharmacologic or therapeutic class of the drug, and the chemical name and structural formula of the drug.11 DESCRIPTION Metopirone (metyrapone capsules) is an adrenal steroid synthesis inhibitor, available as 250‑mg capsules for oral administration. Its chemical name is 2‑methyl‑1, 2‑di‑3‑pyridyl‑1‑propanone, and its structural formula is Metyrapone is a white to light amber, fine, crystalline powder, having a characteristic odor. It is sparingly soluble in water, and soluble in methanol and in chloroform. It forms water‑soluble salts with acids. Its molecular weight is 226.27. Inactive Ingredients : Ethyl vanillin, gelatin, glycerol, macrogol 400, macrogol 4000, paramethoxy acetophenone, purified water, sodium ethyl parahydroxybenzoate, sodium propyl parahydroxybenzoate, titanium dioxide, + red ink (aluminum chloride hexahydrate, carminic acid, hypromellose, propylene glycol, sodium hydroxide). Chemical Structure
Dosage and administration
Information about the drug product’s dosage and administration recommendations, including starting dose, dose range, titration regimens, and any other clinically sigificant information that affects dosing recommendations.2 DOSAGE AND ADMINISTRATION Single-Dose Short Test: 30 mg/kg at midnight ( 2.2 ) 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) ). Recommended Dose In adult and pediatric patients, the recommended single dose is 30 mg/kg (maximum 3 grams of Metopirone) administered at midnight with milk/yogurt or snack. The blood sample for the assay is taken early the following morning (7:30-8:00 a.m.). After the blood sample is collected, a prophylactic dose of glucocorticoid may be considered for patients with high risk for acute adrenal insufficiency. Interpretation of 11‑desoxycortisol and ACTH Levels After Metopirone Administration Approximately 8 hours after administration of Metopirone, evaluate the values of ACTH and 11-desoxycortisol. Normal values will depend on the method used to determine ACTH and 11‑desoxycortisol levels. An intact HPA axis function is generally indicated by an increase in 11‑desoxycortisol to over 70 mcg/L. Because of an overlap between a normal ACTH response and an abnormal ACTH response, the ACTH response alone cannot be used to distinguish between healthy individuals and those with adrenal insufficiency.
Dosage forms and strengths
Information about all available dosage forms and strengths for the drug product to which the labeling applies. This field may contain descriptions of product appearance.3 DOSAGE FORMS AND STRENGTHS Capsules: Metopirone 250 mg soft gelatin, white to yellowish‑white, oblong, opaque, imprinted with "HRA" on one side in red ink. Capsules: 250 mg ( 3 )
Indications and usage
A statement of each of the drug products indications for use, such as for the treatment, prevention, mitigation, cure, or diagnosis of a disease or condition, or of a manifestation of a recognized disease or condition, or for the relief of symptoms associated with a recognized disease or condition. This field may also describe any relevant limitations of use.1 INDICATIONS AND USAGE Metopirone is indicated, in combination with other diagnostic tests, for the diagnosis of adrenal insufficiency in adult and pediatric patients. Metopirone is indicated, in combination with other diagnostic tests, for the diagnosis of adrenal insufficiency in adult and pediatric patients. ( 1 )
Spl product data elements
Usually a list of ingredients in a drug product.Metopirone Metyrapone METYRAPONE METYRAPONE POLYETHYLENE GLYCOL 400 POLYETHYLENE GLYCOL 4000 GLYCERIN ETHYLPARABEN SODIUM 4-ACETYLANISOLE GELATIN, UNSPECIFIED PROPYLPARABEN SODIUM ETHYL VANILLIN TITANIUM DIOXIDE WATER white to yellowish-white soft gelatin; oblong; opaque HRA
Carcinogenesis and mutagenesis and impairment of fertility
Information about carcinogenic, mutagenic, or fertility impairment potential revealed by studies in animals. Information from human data about such potential is part of the warnings field.13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long‑term animal carcinogenicity studies have not been conducted with Metopirone. Mutagenesis Metyrapone was not mutagenic with or without metabolic activation in bacterial mutagenicity tests. Impairment of Fertility No studies have been conducted to assess the effect of Metopirone on fertility.
Nonclinical toxicology
Information about toxicology in non-human subjects.13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long‑term animal carcinogenicity studies have not been conducted with Metopirone. Mutagenesis Metyrapone was not mutagenic with or without metabolic activation in bacterial mutagenicity tests. Impairment of Fertility No studies have been conducted to assess the effect of Metopirone on fertility.
Package label principal display panel
The content of the principal display panel of the product package, usually including the product’s name, dosage forms, and other key information about the drug product.PRINCIPAL DISPLAY PANEL - 250 mg Bottle Carton NDC 76336-455-18 Metopirone ® (Metyrapone Capsules) 250 mg 18 capsules Rx only HRA Pharma Rare Diseases PRINCIPAL DISPLAY PANEL - 250 mg Bottle Carton
Recent major changes
A list of the section(s) that contain substantive changes that have been approved by FDA in the product labeling. The headings and subheadings, if appropriate, affected by the change are listed together with each section’s identifying number and the month and year on which the change was incorporated in the labeling.Indications and Usage ( 1 ) 09/2022 Dosage and Administration, Single-Dose Short Test ( 2.2 ) 09/2022
| Indications and Usage ( | 09/2022 |
| Dosage and Administration, Single-Dose Short Test ( | 09/2022 |
Spl unclassified section
Information not classified as belonging to one of the other fields. Approximately 40% of labeling with effective_time between June 2009 and August 2014 have information in this field.Manufactured by: Catalent Germany Eberbach GmbH Eberbach, Germany For: HRA Pharma Rare Diseases CHATILLON, France © 2022 HRA Pharma Rare Diseases | Metopirone is a registered trademark of HRA Pharma Rare Diseases Address medical inquiries to: Direct Success Inc. 1710 Hwy 34 Farmingdale, NJ 07727 1-844-597-6373 Fax: 1-855-674-6767
Metopirone: Information for patients
Information necessary for patients to use the drug safely and effectively, such as precautions concerning driving or the concomitant use of other substances that may have harmful additive effects.17 PATIENT COUNSELING INFORMATION Advise patient to read the FDA-approved labeling (Patient Information). Advise patient that Metopirone may induce acute adrenal insufficiency (nausea, vomiting, abdominal pain, hypotension) [see Warnings and Precautions (5.1) ] . Advise patient that Metopirone may cause dizziness and sedation. Advise patients not to drive or operate machinery until these effects have passed [see Warnings and Precautions (5.2) ] .
Geriatric use
Information about any limitations on any geriatric indications, needs for specific monitoring, hazards associated with use of the drug in the geriatric population.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.
Pediatric use
Information about any limitations on any pediatric indications, needs for specific monitoring, hazards associated with use of the drug in any subsets of the pediatric population (such as neonates, infants, children, or adolescents), differences between pediatric and adult responses to the drug, and other information related to the safe and effective pediatric use of the drug.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) ].
Pregnancy
Information about effects the drug may have on pregnant women or on a fetus. This field may be ommitted if the drug is not absorbed systemically and the drug is not known to have a potential for indirect harm to the fetus. It may contain information about the established pregnancy category classification for the drug. (That information is nominally listed in the teratogenic_effects field, but may be listed here instead.)8.1 Pregnancy Risk Summary Available data from published case series and reports on Metopirone use in pregnant females are insufficient to identify a drug-associated risk of major birth defects or miscarriage. Metyrapone crosses the placenta and may decrease fetal cortisol production (see Data ) . Animal reproductive studies have not been conducted with metyrapone. Metyrapone can decrease reproductive hormones by targeting adrenal androgenesis. Data Human Data The Metopirone test was administered to pregnant women in their second and third trimester of pregnancy and evidence was found that the fetal pituitary responded to the enzymatic block. Transplacental transfer of Metopirone has been shown in humans and the drug can impair the biosynthesis of fetal and placental steroids. There are a few published reports of low cortisol levels at birth in infants exposed in utero following chronic use of metyrapone in pregnant females.
Use in specific populations
Information about use of the drug by patients in specific populations, including pregnant women and nursing mothers, pediatric patients, and geriatric patients.8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data from published case series and reports on Metopirone use in pregnant females are insufficient to identify a drug-associated risk of major birth defects or miscarriage. Metyrapone crosses the placenta and may decrease fetal cortisol production (see Data ) . Animal reproductive studies have not been conducted with metyrapone. Metyrapone can decrease reproductive hormones by targeting adrenal androgenesis. Data Human Data The Metopirone test was administered to pregnant women in their second and third trimester of pregnancy and evidence was found that the fetal pituitary responded to the enzymatic block. Transplacental transfer of Metopirone has been shown in humans and the drug can impair the biosynthesis of fetal and placental steroids. There are a few published reports of low cortisol levels at birth in infants exposed in utero following chronic use of metyrapone in pregnant females. 8.2 Lactation Risk Summary Metyrapone and its active metabolite, metyrapol, are present in human milk. There are no available data on the effects of metyrapone on the breastfed infant or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Metopirone and any potential adverse effects on the breastfed infant from Metopirone or from the underlying maternal condition. 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.
How supplied
Information about the available dosage forms to which the labeling applies, and for which the manufacturer or distributor is responsible. This field ordinarily includes the strength of the dosage form (in metric units), the units in which the dosage form is available for prescribing, appropriate information to facilitate identification of the dosage forms (such as shape, color, coating, scoring, and National Drug Code), and special handling and storage condition information.16 HOW SUPPLIED/STORAGE AND HANDLING 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.
Storage and handling
Information about safe storage and handling of the drug product.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.
Disclaimer: Do not rely on openFDA or Phanrmacy Near Me to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. Source: OpenFDA, Healthporta Drugs API