2.1 Important Information Before Conducting
CORTROSYN TESTING

• In general, stop glucocorticoids and spironolactone on the day of CORTROSYN testing. However, long-acting glucocorticoids may need to be stopped for a 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.

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.

2.4 Reconstitution Instructions

• Aseptically reconstitute the lyophilized powder in the vial using 1 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.

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)].

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 a 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.

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 a longer period before CORTROSYN testing.
• Estrogen: May elevate plasma total cortisol levels. Stop estrogen containing drugs 4 to 6 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.

8.1 Pregnancy

Risk Summary
Available 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 a 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 Considerations
Disease-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 Summary
There 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 mother’s 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)].

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 a 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.

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.