COSYNTROPIN

Cosyntropin is an adrenocorticotropic hormone (ACTH). Cosyntropin is synthetic beta 1 - 24 corticotropin, a 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 N terminal. The sequence of amino acids in the 1 - 24 compound is as follows: Molecular Formula: C 136 H 210 N 40 O 31 S Molecular Weight: 2933 g/mol. Cosyntropin for injection is a sterile lyophilized powder in single-dose vials containing 0.25 mg of cosyntropin and 10 mg of mannitol. chemical-strucure

Cosyntropin for injection is indicated, in combination with other diagnostic tests, for use as a diagnostic agent in the screening of adrenocortical insufficiency in adults and pediatric patients. Cosyntropin for injection is an adrenocorticotropin hormone indicated, in combination with other diagnostic tests, for use as a diagnostic agent in the screening of adrenocortical insufficiency in adults and pediatric patients. ( 1 )

• In general, stop glucocorticoids and spironolactone on the day of cosyntropin for injection testing. For long-acting glucocorticoids, stop for a longer period before cosyntropin for injection 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 2 years of age o 0.25 mg for patients 2 to 17 years of age • Obtain blood samples for serum cortisol level at baseline and exactly 30 and 60 minutes after cosyntropin for injection administration. ( 2.5 ) • See Full Prescribing Information for reconstitution and interpretation of cortisol levels information. ( 2.4 , 2.6 ) 2.1 Important Information Before Conducting Cosyntropin for Injection Testing • In general, stop glucocorticoids and spironolactone on the day of cosyntropin for injection testing. However, long-acting glucocorticoids may need to be stopped for a longer period before cosyntropin for injection testing [see Warnings and Precautions ( 5.2 ), Drug Interactions ( 7 )] . • Stop estrogen-containing drugs four to six weeks before cosyntropin for injection testing [see Warnings and Precautions ( 5.2 ), Drug Interactions ( 7 )] . 2.2 Recommended Dose for Adults • The recommended dose of cosyntropin for injection 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 cosyntropin for injection in pediatric patients, aged birth to 17 years, to be administered by intravenous or intramuscular injection is presented in Table 1 . Table 1. Recommended Cosyntropin for Injection Dose for Pediatric Patients Age Recommended Dose Volume of Reconstituted Solution Birth to less than 2 years 0.125 mg 0.5 mL 2 to 17 years 0.25 mg 1 mL 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 cosyntropin for injection 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 cosyntropin for injection solution should be clear and colorless, and free of particulates. If cosyntropin for injection solution is cloudy or contains particulates, do not administer. • If the cosyntropin for injection reconstituted solution is not used immediately, discard the unused cosyntropin for injection reconstituted solution. 2.5 Administration Information • Cosyntropin for injection 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 cosyntropin for injection. 2.6 Interpretation of Plasma Cortisol Levels after Cosyntropin for Injection • Stimulated plasma cortisol levels of less than 18 mcg/dL at 30- or 60-minutes post cosyntropin for 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 )] .

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

Because adverse reactions are 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. The following adverse reactions have been identified during post approval use of cosyntropin for injection: • anaphylactic reaction • bradycardia • tachycardia • hypertension • peripheral edema • rash Most common adverse reactions are: anaphylactic reaction, bradycardia, tachycardia, hypertension, peripheral edema, and rash ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

• 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 cosyntropin for injection testing. Long-acting glucocorticoids may need to be stopped for a longer period before cosyntropin for injection testing. ( 7 ) o Estrogen: May elevate plasma total cortisol levels. Stop estrogen containing drugs 4 to 6 weeks before cosyntropin for injection 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 cosyntropin for injection 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 cosyntropin for injection testing. Long-acting glucocorticoids may need to be stopped for a longer period before cosyntropin for injection testing. • Estrogen: May elevate plasma total cortisol levels. Stop estrogen containing drugs 4 to 6 weeks before cosyntropin for injection 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. 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 cosyntropin for injection 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 cosyntropin for injection testing. Long-acting glucocorticoids may need to be stopped for a longer period before cosyntropin for injection testing. • Estrogen: May elevate plasma total cortisol levels. Stop estrogen containing drugs 4 to 6 weeks before cosyntropin for injection 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.