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: Molecular Formula: C136H210N40O31SMolecular Weight: 2933 g/mol.Cosyntropin for injection is sterile lyophilized powder in single-dose vials containing 0.25 mg of cosyntropin and 10 mg of mannitol.. chemical-strucure.

PHARMACODYNAMICS SECTION.

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 cosyntropin assumes added importance in view of the known antigenicity of natural ACTH.

PREGNANCY SECTION.

8.1 Pregnancy Risk SummaryAvailable data from case reports over decades of use with cosyntropin during pregnancy have not identified an increasedrisk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Unidentified adrenal insufficiency can resultin 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 riskUnidentified 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.

SPL UNCLASSIFIED SECTION.

2.1 Important Information Before Conducting Cosyntropin for Injection Testing oIn general, stop glucocorticoids and spironolactone on the day of cosyntropin for injection testing. However, long-acting glucocorticoids may need to be stopped for longer period before cosyntropin for injection testing [seeWarnings and Precautions (5.2), Drug Interactions (7)].oStop estrogen-containing drugs four to six weeks before cosyntropin for injection testing [see Warnings andPrecautions (5.2), Drug Interactions (7)].. oIn general, stop glucocorticoids and spironolactone on the day of cosyntropin for injection testing. However, long-acting glucocorticoids may need to be stopped for longer period before cosyntropin for injection testing [seeWarnings and Precautions (5.2), Drug Interactions (7)].. oStop estrogen-containing drugs four to six weeks before cosyntropin for injection testing [see Warnings andPrecautions (5.2), Drug Interactions (7)].

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 cosyntropin for injection:oanaphylactic reactionobradycardiaotachycardiaohypertensionoperipheral edemaorash. oanaphylactic reaction. obradycardia. otachycardia. ohypertension. operipheral edema. orash. 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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

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.

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 cosyntropin is similar to that of purified natural ACTH. It has been established that 0.25 mg of cosyntropin will stimulate the adrenal cortex maximally and to the same extent as 25 units of natural ACTH. This dose of cosyntropin 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 cosyntropin assumes added importance in view of the known antigenicity of natural ACTH.

CONTRAINDICATIONS SECTION.

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

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION oIn general, stop glucocorticoids and spironolactone on the day of cosyntropin for injection testing. For long-acting glucocorticoids, stop for longer period before cosyntropin for injection testing. (2.1)oFor adults, the recommended dose is 0.25 mg to be administered by intravenous or intramuscular injection. (2.2)oFor pediatric patients, the recommended dose to be administered by intravenous or intramuscular injection is (2.3):o0.125 mg for patients birth to less than years of ageo0.25 mg for patients to 17 years of ageoObtain blood samples for serum cortisol level at baseline and exactly 30 and 60 minutes after cosyntropin for injection administration. (2.5)oSee Full Prescribing Information for reconstitution and interpretation of cortisol levels information. (2.4, 2.6). oIn general, stop glucocorticoids and spironolactone on the day of cosyntropin for injection testing. For long-acting glucocorticoids, stop for longer period before cosyntropin for injection testing. (2.1). oFor adults, the recommended dose is 0.25 mg to be administered by intravenous or intramuscular injection. (2.2). oFor pediatric patients, the recommended dose to be administered by intravenous or intramuscular injection is (2.3):. o0.125 mg for patients birth to less than years of age. o0.25 mg for patients to 17 years of age. oObtain blood samples for serum cortisol level at baseline and exactly 30 and 60 minutes after cosyntropin for injection administration. (2.5). oSee 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 oIn general, stop glucocorticoids and spironolactone on the day of cosyntropin for injection testing. However, long-acting glucocorticoids may need to be stopped for longer period before cosyntropin for injection testing [seeWarnings and Precautions (5.2), Drug Interactions (7)].oStop estrogen-containing drugs four to six weeks before cosyntropin for injection testing [see Warnings andPrecautions (5.2), Drug Interactions (7)].. oIn general, stop glucocorticoids and spironolactone on the day of cosyntropin for injection testing. However, long-acting glucocorticoids may need to be stopped for longer period before cosyntropin for injection testing [seeWarnings and Precautions (5.2), Drug Interactions (7)].. oStop estrogen-containing drugs four to six weeks before cosyntropin for injection testing [see Warnings andPrecautions (5.2), Drug Interactions (7)].. 2.2 Recommended Dose for Adults oThe recommended dose of cosyntropin for injection in adults is 0.25 mg to be administered by intravenous or intramuscular injection.. oThe 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 oThe 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 PatientsAge Recommended Dose Volume of Reconstituted Solution Birth to less than years 0.125 mg 0.5 mL to 17 years 0.25 mg mL oThe 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.. 2.4 Reconstitution Instructions oAseptically reconstitute the lyophilized powder in the vial using mL of 0.9% Sodium Chloride Injection, USP and gently swirl.oAfter reconstitution, the final concentration of cosyntropin for injection reconstituted solution is 0.25 mg/mL.oParenteral 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.oIf the cosyntropin for injection reconstituted solution is not used immediately, discard the unused cosyntropin for injection reconstituted solution.. oAseptically reconstitute the lyophilized powder in the vial using mL of 0.9% Sodium Chloride Injection, USP and gently swirl.. oAfter reconstitution, the final concentration of cosyntropin for injection reconstituted solution is 0.25 mg/mL.. oParenteral 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.. oIf the cosyntropin for injection reconstituted solution is not used immediately, discard the unused cosyntropin for injection reconstituted solution.. 2.5 Administration Information oCosyntropin for injection may be administered by intramuscular or intravenous injection.oObtain 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.. oCosyntropin for injection may be administered by intramuscular or intravenous injection.. oObtain 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 oStimulated 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)].. oStimulated 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)].

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.. oFor injection: 0.25 mg of cosyntropin as lyophilized powder in single-dose vial for reconstitution (3). oFor injection: 0.25 mg of cosyntropin as lyophilized powder in single-dose vial for reconstitution (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS oDrug effects on plasma cortisol levels:oAccuracy of the test results can be affected by concomitant medications.oGlucocorticoids 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 longer period before cosyntropin for injection testing. (7)oEstrogen: May elevate plasma total cortisol levels. Stop estrogen containing drugs to weeks before cosyntropin for injection testing. (7). oDrug effects on plasma cortisol levels:. oAccuracy of the test results can be affected by concomitant medications.. oGlucocorticoids 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 longer period before cosyntropin for injection testing. (7). oEstrogen: May elevate plasma total cortisol levels. Stop estrogen containing drugs to weeks before cosyntropin for injection testing. (7). 7.1 Drug Effects on Plasma Cortisol Levels oAccuracy 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)].oGlucocorticoids 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 longer period before cosyntropin for injection testing.oEstrogen: May elevate plasma total cortisol levels. Stop estrogen containing drugs to 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.. oAccuracy 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)].. oGlucocorticoids 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 longer period before cosyntropin for injection testing.. oEstrogen: May elevate plasma total cortisol levels. Stop estrogen containing drugs to 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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING How SuppliedCosyntropin for injection 0.25 mg, in single-dose vial for reconstitution.Box contains 10 single-dose vials NDC 0781-3440-95Storage and HandlingStore at 20o to 25oC (68o to 77oF); excursions permitted between 15 to 30C (59 to 86F) [see USP Controlled RoomTemperature].Cosyntropin for injection is intended as single-dose injection and contains no antimicrobial preservative. Any unusedportion should be discarded.

INDICATIONS & USAGE SECTION.

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

INFORMATION FOR PATIENTS SECTION.

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, facialswelling, tightness of the chest, and wheezing [see Contraindications (4), Warnings and Precautions (5.1)].Drug Interference with Cosyntropin for Injection TestingAdvise patients and/or caregivers to stop taking glucocorticoids and spironolactone on the day of cosyntropin for injection testing. However, for patients taking long-acting glucocorticoids, advise them to stop for longer periods before cosyntropin for injection testing. Advise patients to stop taking estrogen-containing drugs four to six weeks before cosyntropin for injection testing [see Dosage and Administration (2.1), Warnings and Precautions (5.2), and Drug Interactions (7)].Manufactured by Oakwood Labs, forSandoz Inc., Princeton, NJ 08540.

LACTATION SECTION.

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 cosyntropin for injection and any potential adverse effects on the breastfed infant from cosyntropin for injection or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

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 cosyntropin is similar to that of purified natural ACTH. It has been established that 0.25 mg of cosyntropin will stimulate the adrenal cortex maximally and to the same extent as 25 units of natural ACTH. This dose of cosyntropin will produce maximal secretion of 17-OH corticosteroids, 17-ketosteroids and/or 17-ketogenic steroids.

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.

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL NDC 0781-3440-95Cosyntropin for Injection0.25 mg/vialRx OnlyFOR DIAGNOSTIC USE ONLYFor IV or IM UseLyophilized and Must be dilutedDiscard unused portion10 0.25 mg Single Dose VialSANDOZ. carton.

PEDIATRIC USE SECTION.

8.4 Pediatric Use Cosyntropin for injection is approved for use in pediatric patients [see Dosage and Administration (2.3)].

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 increasedrisk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Unidentified adrenal insufficiency can resultin 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 riskUnidentified 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 cosyntropin for injection and any potential adverse effects on the breastfed infant from cosyntropin for injection or from the underlying maternal condition.. 8.4 Pediatric Use Cosyntropin for injection is approved for use in pediatric patients [see Dosage and Administration (2.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oHypersensitivity: reactions including anaphylaxis have been reported. Monitor patients for hypersensitivity reactions and treat as needed. (5.1)oDiagnostic Inaccuracies: 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. Any condition that elevates or lowers cortisol binding globulin levels may increase or decrease plasma total cortisol levels, respectively. (2.1, 5.2, 7). oHypersensitivity: reactions including anaphylaxis have been reported. Monitor patients for hypersensitivity reactions and treat as needed. (5.1). oDiagnostic Inaccuracies: 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. 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 Cosyntropin for Injection Cosyntropin for 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 cosyntropin for injection 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 cosyntropin for injection testing. Long-acting glucocorticoids may need to be stopped for longer period before cosyntropin for injection 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 cosyntropin for injection 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.