CORTROSYN™ (cosyntropin) for Injection is a sterile Iyophilized powder in vials containing 0.25 mg of CORTROSYN™ and 10 mg of mannitol to be reconstituted with 1 mL of 0.9% Sodium Chloride Injec-tion, USP. Administration is by intravenous or intramuscular injection. Cosyntropin is α1 - 24 corticotropin, a synthetic subunit of ACTH. It is an open chain polypeptide containing, from the N terminus, the first 24 of the 39 amino acids of natural ACTH. The sequence of amino acids in the 1 - 24 compound is as follows:

CORTROSYN™ (cosyntropin) for Injection is intended for use as a diagnostic agent in the screening of patients presumed to have ad-renocortical insufficiency. Because of its rapid effect on the adrenal cortex it may be utilized to perform a 30-minute test of adrenal func-tion (plasma cortisol response) as an office or outpatient procedure, using only 2 venipunctures (see DOSAGE AND ADMINISTRATION section).

Severe hypofunction of the pituitary - adrenal axis is usually associ-ated with subnormal plasma cortisol values but a low basal level is not per se evidence of adrenal insufficiency and does not suffice to make the diagnosis. Many patients with proven insufficiency will have normal basal levels and will develop signs of insufficiency only when stressed. For this reason a criterion which should be used in estab-lishing the diagnosis is the failure to respond to adequate corticotropin stimulation. When presumptive adrenal insufficiency is diagnosed by a subnormal CORTROSYN™ test, further studies are indicated to determine if it is primary or secondary.

Primary adrenal insufficiency (Addison's disease) is the result of an intrinsic disease process, such as tuberculosis within the gland. The production of adrenocortical hormones is deficient despite high ACTH levels (feedback mechanism). Secondary or relative insufficiency arises as the result of defective production of ACTH leading in turn to disuse atrophy of the adrenal cortex. It is commonly seen, for ex-ample, as result of corticosteroid therapy, Sheehan's syndrome and pituitary tumors or ablation.

The differentiation of both types is based on the premise that a primarily defective gland cannot be stimulated by ACTH whereas a secondarily defective gland is potentially functional and will respond to adequate stimulation with ACTH. Patients selected for further study as the result of a subnormal CORTROSYN™ test should be given a 3 or 4 day course of treatment with Repository Corticotropin Injection USP and then retested. Suggested doses are 40 USP units twice daily for 4 days or 60 USP units twice daily for 3 days. Under these conditions little or no increase in plasma cortisol levels will be seen in Addison's disease whereas higher or even normal levels will be seen in cases with secondary adrenal insufficiency.

CORTROSYN™ (cosyntropin) for Injection may be administered intramuscularly or as a direct intravenous injection when used as a rapid screening test of adrenal function. It may also be given as an intravenous infusion over a 4 to 8 hour period to provide a greater stimulus to the adrenal glands. Doses of CORTROSYN™ 0.25 to 0.75 mg have been used in clinical studies and a maximal response noted with the smallest dose.

A suggested method for a rapid screening test of adrenal function has been described by Wood and Associates (1). A control blood sample of 6 to 7 mL is collected in a heparinized tube. Reconstitute 0.25 mg of CORTROSYN™ with 1mL of 0.9% Sodium Chloride Injection, USP and inject intramuscularly. The reconstituted drug product should be inspected visually for particulate matter and discoloration prior to injection. Reconstituted CORTROSYN™ should not be retained. In the pediatric population, aged 2 years or less, a dose of 0.125 mg will often suffice. A second blood sample is collected exactly 30 minutes later. Both blood samples should be refrigerated until sent to the laboratory for determination of the plasma cortisol response by some appropriate method. If it is not possible to send them to the laboratory or perform the fluorimetric procedure within 12 hours, then the plasma should be separated and refrigerated or frozen according to need.

Two alternative methods of administration are intravenous injection and infusion. CORTROSYN™ can be injected intravenously in 2 to 5 mL of saline over a 2-minute period. When given as an intravenous infusion: CORTROSYN™, 0.25 mg may be added to glucose or saline solutions and given at the rate of approximately 40 micrograms per hour over a 6-hour period. It should not be added to blood or plasma as it is apt to be inactivated by enzymes. Adrenal response may be measured in the usual manner by determining urinary steroid excre-tion before and after treatment or by measuring plasma cortisol levels before and at the end of the infusion. The latter is preferable because the urinary steroid excretion does not always accurately reflect the adrenal or plasma cortisol response to ACTH.

The usual normal response in most cases is an approximate doubling of the basal level, provided that the basal level does not exceed the normal range. Patients receiving cortisone, hydrocortisone or spirono-lactone should omit their pre-test doses on the day selected for test-ing. Patients taking inadvertent doses of cortisone or hydrocortisone on the test day and patients taking spironolactone or women taking drugs which contain estrogen may exhibit abnormally high basal plasma cortisol levels.

A paradoxical response may be noted in the cortisone or hydrocorti-sone group as seen in a decrease in plasma cortisol values following a stimulating dose of CORTROSYN™.

In the spironolactone or estrogen group only a normal incremental re-sponse is to be expected. Many patients with normal adrenal function, however, do not respond to the expected degree so that the following criteria have been established to denote a normal response:

1. The control plasma cortisol level should exceed 5 micrograms/100 mL.
2. The 30-minute level should show an increment of at least 7 micrograms/100 mL above the basal level.
3. The 30-minute level should exceed 18 micrograms/100 mL. Comparable figures have been reported by Greig and co-workers (2).

Plasma cortisol levels usually peak about 45 to 60 minutes after an injection of CORTROSYN™ and some prefer the 60-minute interval for testing for this reason. While it is true that the 60-minute values are usually higher than the 30-minute values, the difference may not be significant enough in most cases to outweigh the disadvantage of a longer testing period. If the 60-minute test period is used, the criterion for a normal response is an approximate doubling of the basal plasma cortisol value.

In patients with a raised plasma bilirubin or in patients where the plasma contains free hemoglobin, falsely high fluorescence mea-surements will result. The test may be performed at any time during the day but because of the physiological diurnal variation of plasma cortisol the criteria listed by Wood cannot apply. It has been shown that basal plasma cortisol levels and the post CORTROSYN™ incre-ment exhibit diurnal changes. However, the 30-minute plasma cortisol level remains unchanged throughout the day so that only this single criterion should be used (3).

Parenteral drug products should be inspected visually for particulate matter and discoloration whenever solution and container permit. Reconstituted CORTROSYN™ should not be retained.

Box of 10 vials of CORTROSYN™ (cosyntropin) for Injection 0.25 mg

NDC # 0548-5900-00

Storage

Store at 15-30°C (59-86°F).

CORTROSYN™ is intended as a single dose injection and contains no antimicrobial preservative. Any unused portion should be discarded.

REFERENCES

1. Wood, J.B. et al. LANCET 1.243, 1965.
2. Greig, W.R. et al. J. ENDOCR 34.411, 1966.
3. McGill, P.E. et al. ANN RHEUM DIS 26.123, 1967.

Amphastar Pharmaceuticals, Inc., Rancho Cucamonga, CA 91730 U.S.A. REV. 9-05. FDA revision date: 11/5/2002

Since CORTROSYN™ (cosyntropin) for Injection is intended for diag-nostic and not therapeutic use, adverse reactions other than a rare hypersensitivity reaction are not anticipated. A rare hypersensitivity reaction usually associated with a pre-existing allergic disease and/or a previous reaction to natural ACTH is possible. Symptoms may include slight whealing with splotchy erythema at the injection site. There have been rare reports of anaphylactic reaction. The following adverse reactions have been reported in patients after the admin-istration of CORTROSYN™ and the association has been neither confirmed nor refuted:

• bradycardia
• tachycardia
• hypertension
• peripheral edema
• rash

Corticotropin may accentuate the electrolyte loss associated with diuretic therapy.

No information provided.

General

CORTROSYN™ (cosyntropin) for Injection exhibits slight immunolog-ic activity, does not contain animal protein and is therefore less risky to use than natural ACTH. Patients known to be sensitized to natural ACTH with markedly positive skin tests will, with few exceptions, re-act negatively when tested intradermally with CORTROSYN™. Most patients with a history of a previous hypersensitivity reaction to natural ACTH or a pre-existing allergic disease will tolerate CORTROSYN™. Despite this however, CORTROSYN™ is not completely devoid of immunologic activity and hypersensitivity reactions including rare anaphylaxis are possible. Therefore, the physician should be pre-pared, prior to injection, to treat any possible acute hypersensitivity reaction.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long term studies in animals have not been performed to evaluate carcinogenic or mutagenic potential or impairment of fertility. A study in rats noted inhibition of reproductive function like natural ACTH.

Pregnancy

Pregnancy Category C. Animal reproduction studies have not been conducted with CORTROSYN™ (cosyntropin) for Injection. It is also not known whether CORTROSYN™ can cause fetal harm when ad-ministered to a pregnant woman or can affect reproduction capacity. CORTROSYN™ should be given to a pregnant woman only if clearly needed.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when CORTROSYN™ (cosyntropin) for Injection is administered to a nursing woman.

Pediatric Use

(See DOSAGE AND ADMINISTRATION section.)

No information provided.

The only contraindication to CORTROSYN™ (cosyntropin) for Injec-tion is a history of a previous adverse reaction to it.

CORTROSYN™ (cosyntropin) for Injection exhibits the full cortico-steroidogenic 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 puri-fied natural ACTH. It has been established that 0.25 mg of CORTRO-SYNTM 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.

The extra-adrenal effects which natural ACTH and CORTROSYN™ have in common include increased melanotropic activity, increased growth hormone secretion and an adipokinetic effect. These are con-sidered to be without physiological or clinical significance.

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 poly-peptides 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.

No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

COSYNTROPIN - INJECTION

(koe-sin-TROW-pin)

COMMON BRAND NAME(S): Cortrosyn

USES: Cosyntropin is a man-made portion of a certain natural substance made by the body (ACTH). It is used to diagnose adrenal gland problems (e.g., Addison's disease, insufficiency due to corticosteroid use, pituitary tumor).

HOW TO USE: This medication is given by injection into a vein or muscle by a health care professional. Health care professionals must follow all the manufacturer's instructions for properly mixing and giving this drug. Before using, check this product visually for particles or discoloration. If either is present, do not use the liquid. When this drug is given into a vein, it may be injected quickly (2 minutes) or mixed into a solution and given slowly (6 hours) as directed by your doctor.

To test for your disease, your health care professional will usually do a blood test before giving this drug and then 30 minutes after your dose. Depending on the type of test your doctor is performing, he or she may require blood or urine samples at different times to measure your response to the test. Consult your doctor for details.

SIDE EFFECTS: Minor irritation at the injection site (e.g., redness, swelling) may occur. If any of these effects persist or worsen, tell your doctor.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before using cosyntropin, tell your doctor or pharmacist if you are allergic to it; or to corticotropin; or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

It is not known whether this drug passes into breast milk. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: cortisone, estrogen, hydrocortisone, spironolactone, "water pills" (e.g., furosemide, hydrochlorothiazide).

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.

NOTES: Blood/urine tests will be done to monitor your response. Consult your doctor for more details.

MISSED DOSE: Not applicable.

STORAGE: Store at room temperature between 59-86 degrees F (15-30 degrees C) away from light and moisture. Do not store in the bathroom. Keep all medicines away from children and pets.

After mixing, this product should be used immediately. Discard any unused portion of the vial.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.