Corticorelin

DESCRIPTION ACTHREL ® (corticorelin ovine triflutate for injection) is a sterile, nonpyrogenic, lyophilized white cake powder, containing corticorelin ovine triflutate, a trifluoroacetate salt of a synthetic peptide that is used for the determination of pituitary corticotroph responsiveness. Corticorelin ovine has an amino acid sequence identical to ovine corticotropin-releasing hormone (oCRH). Corticorelin ovine is an analogue of the naturally occurring human CRH (hCRH) peptide. Both peptides are potent stimulators of adrenocorticotropic hormone (ACTH) release from the anterior pituitary. ACTH stimulates cortisol production from the adrenal cortex. The structural formula for corticorelin ovine triflutate is described below: Ser-Gin-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Phe-His-Leu-Leu-Arg-Glu-Val-Leu-Glu-Met-Thr-Lys-Ala-Asp-Gin-Leu-Ala-Gln-Gln-Ala-His-Ser-Asn-Arg-Lys-Leu-Leu-Asp-Ile-Ala-NH 2 ∙xCF 2 COOH whereas x =4 - 8. The empirical formula of corticorelin ovine is C 205 H 339 N 59 O 63 S with a molecular weight of 4670.35 Daltons. ACTHREL ® for injection is available in vials containing 100 mcg corticorelin ovine (as the trifluoroacetate), 0.88 mg ascorbic acid, 10 mg lactose, and 26 mg cysteine hydrochloride monohydrate. Trace amounts of chloride ion may be present from the manufacturing process. The preparation is intended for intravenous administration.

INDICATIONS AND USAGE ACTHREL® is indicated for use in differentiating pituitary and ectopic production of ACTH in patients with ACTH-dependent Cushing's syndrome. Differential Diagnosis There are two forms of Cushing's syndrome: ACTH-dependent (83%), in which hypercortisolism is due either to pituitary hypersecretion of ACTH (Cushing's disease) resulting from an adenoma (40%, usually microadenomas) or nonadenomatous hyperplasia, possibly of hypothalamic origin (28%), or to hypercortisolism that is secondary to ectopic secretion of ACTH (15%) and, ACTH- independent (17%), in which hypercortisolism is due to autonomous cortisol secretion by an adrenal tumor (9% adenomas, 8% carcinomas). After the establishment of hypercortisolism consistent with the presence of Cushing's syndrome, and following the elimination of autonomous adrenal hyperfunction as its cause, the corticorelin test is used to aid in establishing the source of excessive ACTH secretion. The corticorelin stimulation test helps to differentiate between the etiologies of ACTH-dependent hypercortisolism as follows: High basal plasma ACTH plus high basal plasma cortisol (20 - 40 mcg/dL). ACTHREL ® injection (1 mcg/kg) results in: Increased plasma ACTH levels Increased plasma cortisol levels Diagnosis: Cushing's disease (ACTH of pituitary origin) High basal plasma ACTH (may be very high) plus high basal plasma cortisol (20 - 40 mcg/dL). ACTHREL ® injection (1 mcg/kg) results in: Little or no response of plasma ACTH levels Little or no response of plasma cortisol levels Diagnosis: Ectopic ACTH syndrome Test Methodology To evaluate the status of the pituitary-adrenal axis in the differentiation of a pituitary source from an ectopic source of excessive ACTH secretion, a corticorelin test procedure requires a minimum of five blood samples. Procedure Venous blood samples should be drawn 15 minutes before and immediately prior to ACTHREL ® administration. The ACTH baseline is obtained by averaging the values of the two samples. Administer ACTHREL ® as an intravenous infusion over a 30 to 60- second interval at a dose of 1 mcg/kg body weight. Higher doses are not recommended (see PRECAUTIONS and ADVERSE REACTIONS ). Draw venous blood samples at 15, 30, and 60 minutes after administration. Blood samples should be handled as recommended by the laboratory that will determine their ACTH content. It is extremely important to recognize that the reliability of the ACTHREL ® test is directly related to the inter-assay and intra-assay variability of the laboratory performing the assay. Cortisol determinations may be performed on the same blood samples for the same time points as outlined above. The blood sample handling precautions noted for ACTH should be followed for cortisol. Interpretation of Test Results The interpretation of the ACTH and cortisol responses following ACTHREL ® administration requires a knowledge of the clinical status of the individual patient, understanding of hypothalamic-pituitary-adrenal physiology, and familiarity with the normal hormonal ranges and the standards used by the laboratory that performs the ACTH and cortisol assays. Cushing's Disease The results of challenge with corticorelin injection have been reported in approximately 300 patients with Cushing's disease. Although the ACTH and cortisol responses were variable, a hyper-response to corticorelin was seen in a majority of patients, despite high basal cortisol levels. This response pattern indicates an impairment of the negative feedback of cortisol on the pituitary. Patients with pituitary-dependent Cushing's disease tested with corticorelin do not show the negative correlation between basal and stimulated levels of ACTH and cortisol that is found in normal subjects. A positive correlation between basal ACTH levels and maximum ACTH increments after corticorelin administration has been found in Cushing's disease patients. Ectopic ACTH Secretion Patients with Cushing's syndrome due to ectopic ACTH secretion (N=32) were found to have very high basal levels of ACTH and cortisol, which were not further stimulated by corticorelin. However, there have been rare instances of patients with ectopic sources of ACTH that have responded to the corticorelin test. SUMMARY OF ACTH RESPONSES IN PATIENTS WITH HIGH BASAL CORTISOL High ACTH Response Low ACTH Response High Basal ACTH Cushing's Disease Ectopic ACTH Secretion CUSHING'S DISEASE ACTH RESPONSES (mean of 181 patients) Basal ACTH 63 ± 72 pg/mL (mean ± SD) Peak ACTH 189 ± 262 pg/mL (mean ± SD) Mean of individual change from baseline + 227% ECTOPIC ACTH SECRETION RESPONSES (mean for 31 patients) Basal ACTH 266 ± 464 pg/mL (mean ± SD) Peak ACTH 276 ± 466 pg/mL (mean ± SD) Mean of individual change from baseline + 15% False negative responses to the corticorelin test in Cushing's disease patients occur approximately 5 to 10% of the time, which may lead the clinician to an incorrect diagnosis of ectopic production of ACTH at that frequency (see INDICATIONS AND USAGE, Differential Diagnosis ).

HOW SUPPLIED ACTHREL ® is supplied as a sterile, nonpyrogenic, lyophilized, white cake containing 100 mcg corticorelin ovine (as the trifluoroacetate), 0.88 mg ascorbic acid, 10 mg lactose, and 26 mg cysteine hydrochloride monohydrate. Trace amounts of chloride ion may be present from the manufacturing process. The package provides a single-dose, rubber-capped, 5 mL, brown-glass vial (NDC 55566-0302-1) containing 100 mcg corticorelin ovine (as the trifluoroacetate). ACTHREL ® is stable in the lyophilized form when stored refrigerated at 2°C to 8°C (36°F to 46°F) and protected from light. The reconstituted solution is stable up to 8 hours under refrigerated conditions. Discard unused reconstituted solution.

DOSAGE AND ADMINISTRATION Dosage A single intravenous dose of ACTHREL ® at 1 mcg/kg is recommended for the testing of pituitary corticotrophin function. A dose of 1 mcg/kg is the lowest dose that produces maximal cortisol responses and significant (though apparently sub-maximal) ACTH responses. Doses above 1 mcg/kg are not recommended (see PRECAUTIONS and ADVERSE REACTIONS ). At a dose of 1 mcg/kg, the ACTH and cortisol responses to ACTHREL ® are prolonged and remain elevated for up to 2 hours. The maximum increment in plasma ACTH occurs between 15 and 60 minutes after ACTHREL ® administration, whereas the maximum increment in plasma cortisol occurs between 30 and 120 minutes. In a clinical study of 30 normal healthy men, the peak plasma ACTH and cortisol responses to ACTHREL ® administration in the early afternoon occurred at 42 ± 29 minutes and 65 ± 26 minutes (average ±SD), respectively . If a repeated evaluation using the corticorelin stimulation test with ACTHREL ® is needed, it is recommended that the repeat test be carried out at the same time of day as the original test because there are differences in basal levels and peak response levels following a.m. or p.m. administration to normal humans. Administration ACTHREL ® is to be reconstituted aseptically with 2 mL of Sodium Chloride injection, USP (0.9% sodium chloride), at the time of use by injecting 2 mL of the saline diluent into the lyophilized drug product cake. To avoid bubble formation, DO NOT SHAKE the vial; instead, roll the vial to dissolve the product. The sterile solution containing 50 mcg corticorelin/mL is then ready for injection by the intravenous route. The dosage to be administered is determined by the patient's weight (1 mcg corticorelin/kg). Some of the adverse effects can be reduced by administering the drug as an infusion over 30 seconds instead of as a bolus injection. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

CONTRAINDICATIONS ACTHREL is contraindicated in patients with a history of a hypersensitivity reaction to ovine corticorelin or any of its excipients.

Drug Interactions The plasma ACTH response to corticorelin injection is inhibited or blunted in normal subjects pretreated with dexamethasone. The use of a heparin solution to maintain i.v. cannula patency during the corticorelin test is not recommended. A possible interaction between corticorelin and heparin may have been responsible for a major hypotensive reaction that occurred after corticorelin administration (see ADVERSE REACTIONS ).

Pregnancy Animal reproduction studies have not been conducted with corticorelin. It is also not known whether corticorelin can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. ACTHREL ® should be given to a pregnant woman only if clearly needed.

PEDIATRIC USE Only a few tests have been performed on children. Dosages were 1 mcg/kg body weight. Patient studies have involved only children with multiple hypothalamic and/or pituitary hormone deficiencies, or tumors. Only two studies with normal pediatric subjects have been conducted. No differences in response to the corticorelin test have been reported in the children studied.

ADVERSE REACTIONS Hypersensitivity reactions have been reported with 1 mcg/kg or 100 mcg/patient and include flushing of the face, neck, and upper chest; dyspnea, wheezing, urticaria, and angioedema (involving tongue, lip and facial swelling). Subjects have also reported an urge to take a deep breath, which occurs with a timing similar to, but less frequently than, that of flushing. Higher doses (>3 mcg/kg) are associated with more prolonged flushing, tachycardia, hypotension, dyspnea, and "chest compression" or tightness. In addition, at doses of >5 mcg/kg, significant increases in heart rate and decreases in blood pressure were observed. The cardiovascular effects occurred 2-3 minutes after injection and lasted for 30-60 minutes. The facial flushing was more prolonged, lasting up to 4 hours in some subjects. All signs and symptoms could be reduced by administering the drug as a 30-second infusion instead of by bolus injection. Total doses of up to 200 mcg of corticorelin were administered as a bolus injection to 60 men and women, including both healthy normal subjects and patients with endocrine disorders. In most cases, only minor adverse effects, such as transient flushing and feelings of dyspnea, were noted. However, a few patients with disorders of the pituitary-adrenal axis had major symptoms. One patient had a precipitous fall in blood pressure and pulse rate and developed asystole, which required resuscitation. In two patients with Cushing's disease and in one with secondary adrenal insufficiency, an "absence-like" loss of consciousness occurred, which started within a few seconds after injection of corticorelin and lasted from 10 seconds to 5 minutes. This was accompanied by a slight fall in blood pressure. One patient with a well documented seizure diathesis experienced a grand mal epileptic seizure following ACTHREL ® administration. The patient had discontinued anti-convulsant therapy the day of the procedure (see PRECAUTIONS - Drug Interactions ).

OVERDOSAGE Symptoms of overdose include severe facial flushing, cardiovascular changes, and dyspnea. In the event of toxic overdose (see ADVERSE REACTIONS ), adverse effects should be treated symptomatically.