Source: FDA, National Drug Code (US) Revision Year: 2020
ACTHREL is indicated for use in differentiating pituitary and ectopic production of ACTH in patients with ACTH-dependent Cushing’s syndrome.
There are two forms of Cushing’s syndrome:
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:
Diagnosis: Cushing’s disease (ACTH of pituitary origin)
Diagnosis: Ectopic ACTH syndrome
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.
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.
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.
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.
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).
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.
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.
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.
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