ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Because adverse reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. The following adverse reactions have been identified during post approval use of CORTROSYN:anaphylactic reactionbradycardiatachycardiahypertensionperipheral edemarash. anaphylactic reaction. bradycardia. tachycardia. hypertension. peripheral edema. rash. Most common adverse reactions are: anaphylactic reaction, bradycardia, tachycardia, hypertension, peripheral edema, and rashTo report SUSPECTED ADVERSE REACTIONS, contact Amphastar Pharmaceuticals, Inc. at 1-800-423-4136 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Cosyntropin exhibits the full corticosteroidogenic activity of natural ACTH. Various studies have shown that the biologic activity of ACTH resides in the N-terminal portion of the molecule and that the 1-20 amino acid residue is the minimal sequence retaining full activity. Partial or complete loss of activity is noted with progressive shortening of the chain beyond 20 amino acid residues. For example, the decrement from 20 to 19 results in 70% loss of potency.The pharmacologic profile of CORTROSYN is similar to that of purified natural ACTH. It has been established that 0.25 mg of CORTROSYN will stimulate the adrenal cortex maximally and to the same extent as 25 units of natural ACTH. This dose of CORTROSYN will produce maximal secretion of 17-OH corticosteroids, 17-ketosteroids and/or 17-ketogenic steroids.. 12.2 Pharmacodynamics. Animal, human and synthetic ACTH (1-39) which all contain 39 amino acids exhibit similar immunologic activity. This activity resides in the C-terminal portion of the molecule and the 22-39 amino acid residues exhibit the greatest degree of antigenicity. In contrast, synthetic polypeptides containing 1-19 or fewer amino acids have no detectable immunologic activity. Those containing 1-26, 1-24 or 1-23 amino acids have very little immunologic although full biologic activity. This property of CORTROSYN assumes added importance in view of the known antigenicity of natural ACTH.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. CORTROSYN is contraindicated in patients with history of hypersensitivity to cosyntropin or to any excipients of CORTROSYN. Reactions have included anaphylaxis [see Warnings and Precautions (5.1)]. CORTROSYN is contraindicated in patients with history of hypersensitivity to cosyntropin or to any excipients of CORTROSYN. Reactions have included anaphylaxis. (4, 5.1). CORTROSYN is contraindicated in patients with history of hypersensitivity to cosyntropin or to any excipients of CORTROSYN. Reactions have included anaphylaxis. (4, 5.1).

DESCRIPTION SECTION.

11 DESCRIPTION. Cosyntropin is an adrenocorticotropic hormone (ACTH). Cosyntropin is synthetic beta - 24 corticotropin, synthetic subunit of ACTH. It is an open chain polypeptide containing, the first 24 of the 39 amino acids of natural ACTH in sequence from terminal. The sequence of amino acids in the - 24 compound is as follows:The empirical formula is C136H210N40O31S with molecular weight of 2934 g/mol.CORTROSYN (cosyntropin) for Injection is sterile lyophilized powder in single-dose vials containing 0.25 mg of cosyntropin and 10 mg of mannitol. Sodium Hydroxide and Glacial acetic acid may be used to adjust pH.. amino.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. In general, stop glucocorticoids and spironolactone on the day of CORTROSYN testing. For long-acting glucocorticoids, stop for longer period before CORTROSYN testing. (2.1)For adults, the recommended dose is 0.25 mg to be administered by intravenous or intramuscular injection. (2.2)For pediatric patients, the recommended dose to be administered by intravenous or intramuscular injection is (2.3):o 0.125 mg for patients birth to less than years of ageo 0.25 mg for patients to 17 years of age Obtain blood samples for serum cortisol level at baseline and exactly 30 and 60 minutes after CORTROSYN administration. (2.5)See Full Prescribing Information for reconstitution and interpretation of cortisol levels information. (2.4, 2.6). In general, stop glucocorticoids and spironolactone on the day of CORTROSYN testing. For long-acting glucocorticoids, stop for longer period before CORTROSYN testing. (2.1). For adults, the recommended dose is 0.25 mg to be administered by intravenous or intramuscular injection. (2.2). For pediatric patients, the recommended dose to be administered by intravenous or intramuscular injection is (2.3):o 0.125 mg for patients birth to less than years of ageo 0.25 mg for patients to 17 years of age Obtain blood samples for serum cortisol level at baseline and exactly 30 and 60 minutes after CORTROSYN administration. (2.5). See Full Prescribing Information for reconstitution and interpretation of cortisol levels information. (2.4, 2.6). 2.1 Important Information Before ConductingCORTROSYN TESTING. In general, stop glucocorticoids and spironolactone on the day of CORTROSYN testing. However, long-acting glucocorticoids may need to be stopped for longer period before CORTROSYN testing [see Warnings and Precautions (5.2), Drug Interactions (7)]. Stop estrogen-containing drugs four to six weeks before CORTROSYN testing [see Warnings and Precautions (5.2), Drug Interactions (7)]. In general, stop glucocorticoids and spironolactone on the day of CORTROSYN testing. However, long-acting glucocorticoids may need to be stopped for longer period before CORTROSYN testing [see Warnings and Precautions (5.2), Drug Interactions (7)]. Stop estrogen-containing drugs four to six weeks before CORTROSYN testing [see Warnings and Precautions (5.2), Drug Interactions (7)]. 2.2 Recommended Dose for Adults. The recommended dose of CORTROSYN in adults is 0.25 mg to be administered by intravenous or intramuscular injection.. The recommended dose of CORTROSYN in adults is 0.25 mg to be administered by intravenous or intramuscular injection.. 2.3 Recommended Dose for Pediatric Patients. The recommended dose of CORTROSYN in pediatric patients, aged birth to 17 years, to be administered by intravenous or intramuscular injection is presented in Table 1. Table 1. Recommended CORTROSYN Dose for Pediatric Patients AgeRecommended Dose Volume of Reconstituted Solution Birth to less than years 0.125 mg 0.5 mL to 17 years 0.25 mg mL. 2.4 Reconstitution Instructions. Aseptically reconstitute the lyophilized powder in the vial using mL of 0.9% Sodium Chloride Injection, USP and gently swirl.After reconstitution, the final concentration of CORTROSYN reconstituted solution is 0.25 mg/mL.Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The reconstituted CORTROSYN solution should be clear and colorless, and free of particulates. If CORTROSYN solution is cloudy or contains particulates, do not administer.If the CORTROSYN reconstituted solution is not used immediately, discard the unused CORTROSYN reconstituted solution.. Aseptically reconstitute the lyophilized powder in the vial using mL of 0.9% Sodium Chloride Injection, USP and gently swirl.. After reconstitution, the final concentration of CORTROSYN reconstituted solution is 0.25 mg/mL.. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The reconstituted CORTROSYN solution should be clear and colorless, and free of particulates. If CORTROSYN solution is cloudy or contains particulates, do not administer.. If the CORTROSYN reconstituted solution is not used immediately, discard the unused CORTROSYN reconstituted solution.. 2.5 Administration Information. CORTROSYN may be administered by intramuscular or intravenous injection.Obtain blood sample for baseline serum cortisol. Obtain blood samples again for assessment of cortisol levels exactly 30 minutes and 60 minutes after administration of CORTROSYN.. CORTROSYN may be administered by intramuscular or intravenous injection.. Obtain blood sample for baseline serum cortisol. Obtain blood samples again for assessment of cortisol levels exactly 30 minutes and 60 minutes after administration of CORTROSYN.. 2.6 Interpretation of Plasma Cortisol Levels after CORTROSYN Injection. Stimulated plasma cortisol levels of less than 18 mcg/dL at 30- or 60-minutes post CORTROSYN injection are suggestive of adrenocortical insufficiency. Cutoff values for exclusion of adrenocortical insufficiency may vary according to the assay used. Test results can be affected by concomitant medications and certain medical conditions [see Warnings and Precautions (5.2)]. Stimulated plasma cortisol levels of less than 18 mcg/dL at 30- or 60-minutes post CORTROSYN injection are suggestive of adrenocortical insufficiency. Cutoff values for exclusion of adrenocortical insufficiency may vary according to the assay used. Test results can be affected by concomitant medications and certain medical conditions [see Warnings and Precautions (5.2)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. For Injection: 0.25 mg of cosyntropin as lyophilized powder in single-dose vial for reconstitution.. For injection: 0.25 mg of cosyntropin as lyophilized powder in single-dose vial for reconstitution (3). For injection: 0.25 mg of cosyntropin as lyophilized powder in single-dose vial for reconstitution (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Drug effects on plasma cortisol levels:o Accuracy of the test results can be affected by concomitant medications.o Glucocorticoids and spironolactone: May falsely elevate plasma cortisol levels. Stop these drugs on day of CORTROSYN testing. Long-acting glucocorticoids may need to be stopped for longer period before CORTROSYN testing. (7)o Estrogen: May elevate plasma total cortisol levels. Stop estrogen containing drugs to weeks before CORTROSYN testing. (7) Drug effects on plasma cortisol levels:o Accuracy of the test results can be affected by concomitant medications.o Glucocorticoids and spironolactone: May falsely elevate plasma cortisol levels. Stop these drugs on day of CORTROSYN testing. Long-acting glucocorticoids may need to be stopped for longer period before CORTROSYN testing. (7)o Estrogen: May elevate plasma total cortisol levels. Stop estrogen containing drugs to weeks before CORTROSYN testing. (7) 7.1 Drug Effects on Plasma Cortisol Levels. Accuracy of the test results can be affected by concomitant medications. Plasma cortisol levels and subsequent diagnosis of adrenocortical insufficiency following CORTROSYN administration may be inaccurate if patients are on certain medications because of their effect on cortisol or cortisol binding globulin levels [see Dosage and Administration (2.1) and Warnings and Precautions (5.2)]. Glucocorticoids and spironolactone: May falsely elevate plasma cortisol levels. Stop these drugs on the day of CORTROSYN testing. Long-acting glucocorticoids may need to be stopped for longer period before CORTROSYN testing.Estrogen: May elevate plasma total cortisol levels. Stop estrogen containing drugs to weeks before CORTROSYN testing to allow cortisol binding globulin levels to return to levels within the reference range. Alternatively, concomitant measurement of cortisol binding globulin at the time of testing can be done; if cortisol binding globulin levels are elevated, plasma total cortisol levels are considered inaccurate.. Accuracy of the test results can be affected by concomitant medications. Plasma cortisol levels and subsequent diagnosis of adrenocortical insufficiency following CORTROSYN administration may be inaccurate if patients are on certain medications because of their effect on cortisol or cortisol binding globulin levels [see Dosage and Administration (2.1) and Warnings and Precautions (5.2)]. Glucocorticoids and spironolactone: May falsely elevate plasma cortisol levels. Stop these drugs on the day of CORTROSYN testing. Long-acting glucocorticoids may need to be stopped for longer period before CORTROSYN testing.. Estrogen: May elevate plasma total cortisol levels. Stop estrogen containing drugs to weeks before CORTROSYN testing to allow cortisol binding globulin levels to return to levels within the reference range. Alternatively, concomitant measurement of cortisol binding globulin at the time of testing can be done; if cortisol binding globulin levels are elevated, plasma total cortisol levels are considered inaccurate.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. How SuppliedCORTROSYN (cosyntropin) for injection 0.25 mg, in single-dose vial for reconstitution.Box contains 10 single-dose vials NDC 0548-5900-00Storage and HandlingStore at 20o to 25oC (68o to 77oF); excursions permitted between 15 to 30C (59 to 86F) [see USP Controlled Room Temperature].CORTROSYN injection is intended as single-dose injection and contains no antimicrobial preservative. Any unused portion should be discarded.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. CORTROSYN is indicated, in combination with other diagnostic tests, for use as diagnostic agent in the screening of adrenocortical insufficiency in adults and pediatric patients.. CORTROSYN is an adrenocorticotropin hormone indicated, in combination with other diagnostic tests, for use as diagnostic agent in the screening of adrenocortical insufficiency in adults and pediatric patients.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term carcinogenicity studies in animals to evaluate the carcinogenic potential of cosyntropin have not been conducted. Studies to evaluate mutagenic potential or impairment of fertility in animals have not been conducted.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPLE DISPLAY PANEL: Carton. For Diagnostic Use OnlyCORTROSYN(R) consyntrosin for Injection 0.25 mgFor IM or IV useRx onlyNDC 0548-5900-00Stock No. 59005259006K/8-24Single Dose VialsContains 10 VialsAmphastar Pharmaceuticals, Inc.Rancho Cucamonga, CA 91730 U.S.A.. carton.

PATIENT COUNSELING INFORMATION.

17 PATIENT COUNSELING INFORMATION. Advise the patient and/or caregiver to read the FDA-approved patient labeling (Patient Information).Hypersensitivity Reactions, Including AnaphylaxisInform patients and/or caregivers of the early signs of hypersensitivity reactions including rash, hives, itching, facial swelling, tightness of the chest, and wheezing [see Contraindications (4), Warnings and Precautions (5.1)].Drug Interference with CORTROSYN TestingAdvise patients and/or caregivers to stop taking glucocorticoids and spironolactone on the day of CORTROSYN testing. However, for patients taking long-acting glucocorticoids, advise them to stop for longer periods before CORTROSYN testing. Advise patients to stop taking estrogen-containing drugs four to six weeks before CORTROSYN testing [see Dosage and Administration (2.1), Warnings and Precautions (5.2), and Drug Interactions (7)].Manufactured by:Amphastar Pharmaceuticals, Inc.Rancho Cucamonga, CA 91730 U.S.A.Rev. 12-23.

SPL UNCLASSIFIED SECTION.

2.1 Important Information Before ConductingCORTROSYN TESTING. In general, stop glucocorticoids and spironolactone on the day of CORTROSYN testing. However, long-acting glucocorticoids may need to be stopped for longer period before CORTROSYN testing [see Warnings and Precautions (5.2), Drug Interactions (7)]. Stop estrogen-containing drugs four to six weeks before CORTROSYN testing [see Warnings and Precautions (5.2), Drug Interactions (7)]. In general, stop glucocorticoids and spironolactone on the day of CORTROSYN testing. However, long-acting glucocorticoids may need to be stopped for longer period before CORTROSYN testing [see Warnings and Precautions (5.2), Drug Interactions (7)]. Stop estrogen-containing drugs four to six weeks before CORTROSYN testing [see Warnings and Precautions (5.2), Drug Interactions (7)].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryAvailable data from case reports over decades of use with cosyntropin during pregnancy have not identified an increased risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Unidentified adrenal insufficiency can result in adverse maternal or fetal outcomes (see Clinical Considerations).The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk for major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.Clinical ConsiderationsDisease-associated maternal and/or embryo/fetal risk Unidentified adrenal insufficiency during pregnancy can result in maternal and/or fetal death; therefore, the diagnosis of suspected adrenal insufficiency during pregnancy should not be delayed.. 8.2 Lactation. Risk SummaryThere are no data on the presence of cosyntropin in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for CORTROSYN and any potential adverse effects on the breastfed infant from CORTROSYN or from the underlying maternal condition.. 8.4 Pediatric Use. CORTROSYN is approved for use in pediatric patients [see Dosage and Administration (2.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hypersensitivity: reactions including anaphylaxis have been reported. Monitor patients for hypersensitivity reactions and treat as needed. (5.1)Diagnostic Inaccuracies: Cortisol levels and subsequent diagnosis of adrenocortical insufficiency following CORTROSYN administration may be inaccurate if patients are on certain medications because of their effect on cortisol or cortisol binding globulin levels. Any condition that elevates or lowers cortisol binding globulin levels may increase or decrease plasma total cortisol levels, respectively. (2.1, 5.2, 7). Hypersensitivity: reactions including anaphylaxis have been reported. Monitor patients for hypersensitivity reactions and treat as needed. (5.1). Diagnostic Inaccuracies: Cortisol levels and subsequent diagnosis of adrenocortical insufficiency following CORTROSYN administration may be inaccurate if patients are on certain medications because of their effect on cortisol or cortisol binding globulin levels. Any condition that elevates or lowers cortisol binding globulin levels may increase or decrease plasma total cortisol levels, respectively. (2.1, 5.2, 7). 5.1 Hypersensitivity to CORTROSYN Injection. CORTROSYN injection hypersensitivity reactions including anaphylaxis have been reported. Monitor patients for hypersensitivity reactions and treat as needed.. 5.2 Diagnostic Inaccuracies. Cortisol levels and subsequent diagnosis of adrenocortical insufficiency following CORTROSYN administration may be inaccurate if patients are on certain medications because of their effect on cortisol or cortisol binding globulin levels.Glucocorticoids and spironolactone may result in falsely elevated cortisol levels. Stop these drugs on the day of CORTROSYN testing. Long-acting glucocorticoids may need to be stopped for longer period before CORTROSYN testing [see Dosage and Administration (2.1) and Drug Interactions (7)]. Estrogen-containing drugs increase cortisol binding globulin levels which can increase plasma total cortisol levels. To obtain accurate plasma total cortisol levels, stop estrogen containing drugs four to six weeks before CORTROSYN testing to allow cortisol binding globulin levels to return to levels within the reference range [see Dosage and Administration (2.1) and Drug Interactions (7)]. Alternatively, concomitant measurement of cortisol binding globulin at the time of testing can be done; if cortisol binding globulin levels are elevated, plasma total cortisol levels are considered inaccurate.Any condition that elevates or lowers cortisol binding globulin levels may increase or decrease plasma total cortisol levels, respectively. Cortisol binding globulin levels can be low in cirrhosis or nephrotic syndrome. Measure cortisol binding globulin levels as necessary to ensure accuracy of interpretation of plasma total cortisol levels.