Cortrosyn (Cosyntropin)

CORTROSYN®

Organon

Cosyntropin

Adrenocorticotropic Hormone

Action And Clinical Pharmacology: The pharmacologic profile of cosyntropin is similar to that of purified natural ACTH, it has been established that 250 µg of cosyntropin will stimulate the adrenal cortex maximally and to the same extent as 25 units of natural ACTH. These clinical observations confirm earlier animal and assay studies establishing the 1:100 ratio. This dose of cosyntropin will produce maximal secretion of 17-OH corticosteroids, 17-ketosteroids and/or 17-ketogenic steroids. Aldosterone secretion is increased also to some degree.

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

Severe hypofunction of the pituitary-adrenal axis is usually associated with subnormal plasma cortisol values but a low basal concentration is not per se evidence of adrenal insufficiency and dose not suffice to make the diagnosis. Many patients with proven insufficiency, will have normal basal concentrations and will develop signs of insufficiency only when stressed. For this reason, the only criterion which should be used in establishing the diagnosis is the failure to respond to adequate corticotropin stimulation as provided by 250 µg of cosyntropin. When presumptive adrenal insufficiency is diagnosed by a negative cosyntropin 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 concentrations (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 example, as a 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 negative cosyntropin test should be given a 3 or 4 day course of treatment with purified cortrophin gel 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 concentrations will be seen in Addison’s disease whereas higher or even normal concentrations will be seen in cases with secondary adrenal insufficiency.

Indications And Clinical Uses: A diagnostic agent in the screening of patients presumed to have adrenocortical insufficiency. Because of its rapid effect on the adrenal cortex it is now possible to perform a 30 minute test of adrenal function (plasma cortisol response) as an office or outpatient procedure, using only 2 venipunctures (see Dosage).

Contra-Indications: A history of a previous adverse reaction to cosyntropin. Precautions

Precautions: Pregnancy: When pregnancy is present or suspected, weigh the benefits of using cosyntropin against the possible hazards to the fetus.

It is not advisable to add cosyntropin, a synthetic polypeptide, to blood and plasma transfusions, because prolonged interaction with enzymes present in these fluids may cause breakdown of the polypeptide.

Allergic reactions may occur in response to cosyntropin. Marked redness and pain at the injection site, urticaria, pruritus, severe malaise or dyspnea may occur.

Severe anaphylactic reactions usually can be avoided by discontinuing the use of the drug at the earliest sign of local or systemic hypersensitivity. In the rare event of a serious incident occurring despite these precautions, initiate the following emergency measures as treatment for shock: i.v. injection of epinephrine HCl 100 to 800 g and high doses of an i.v. corticosteroid, should be administered immediately. Because of the possibility of an allergic reaction occurring the injections should be given under medical supervision and the patient kept under observation for about 1 hour. Self-injection by patients is not recommended. Should prodromal signs occur, further use of cosyntropin should be stopped. Repeat administration may increase the risk of hypersensitivity. Patients should be instructed to inform subsequent physicians of previous use of corticotropic hormones.

Adverse Reactions: Cosyntropin is intended for short-term use. Adverse reactions other than a rare hypersensitivity reaction are not anticipated. To date, only 9 such reactions have been reported in the literature and in each instance the patient had a pre-existing allergic disease and/or a previous reaction to natural ACTH.

Dosage And Administration: Cosyntropin may be administered i.m. or as a direct i.v. injection when used as a rapid screening test of adrenal function. It may also be given as an i.v. infusion over a 4 to 8 hour period to provide a greater stimulus to the adrenal glands. Doses of 250 to 750 g 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 is as follows: A control blood sample is taken and 250 g of cosyntropin, dissolved in sterile saline, is then injected intramuscularly. A second blood sample is collected exactly 30 minutes later and the plasma cortisol response is then determined. In children, aged 2 years or less, a dose of 125 g will often suffice.

The usual normal response in most cases is an approximate doubling of the basal concentration, provided that this does not exceed the normal range. Patients taking inadvertent doses of hydrocortisone on the test day and women taking estrogen containing drugs may exhibit abnormally high basal plasma cortisol concentrations. A paradoxical response may be noted in the former group as seen in a decrease in plasma cortisol values following a stimulating dose of cosyntropin. In the latter group only a normal incremental response 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 concentration should exceed 5 g/100 mL. 2. The 30 minute concentration should show an increment of at least 7 g/100 mL above the basal concentration. 3. The 30 minute concentration should exceed 18 g/100 mL.

These criteria also apply when the drug is injected i.v. in 2 to 5 mL of saline over a 2 minute period.

Plasma cortisol concentrations usually peak about 45 to 60 minutes after an injection of cosyntropin 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.

When given as an i.v. infusion, 250 g may be added to glucose or saline solutions and given at the rate of approximately 40 g/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 steriod excretion before and after treatment or by measuring plasma cortisol concentrations before and at the end of the infusion. The latter is preferable because urinary steroid excretion does not always accurately reflect the adrenal or plasma cortisol response to ACTH.

Patients receiving hydrocortisone should omit their pretest doses on the day selected for testing. The test may be performed at anytime during the day but, because of the physiological diurnal variation of plasma cortisol, the criteria listed above cannot apply. It has been shown that basal plasma cortisol concentrations and the post-cosyntropin increment exhibit diurnal changes. However, the 30 minute plasma cortisol concentration remains unchanged throughout the day so that only this single criterion should be used.

Availability And Storage: Each vial contains: cosyntropin 250 g (as a lyophilized powder). Nonmedicinal ingredients: glacial acetic acid, mannitol and sodium chloride. Each ampul of diluent contains: 1 mL of sodium chloride 0.9 % injection. Boxes of 10 vials and 10 ampuls.

CORTROSYN® Organon Cosyntropin Adrenocorticotropic Hormone

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