Label: ACTHREL- corticorelin ovine triflutate injection, powder, lyophilized, for solution

Pharmacodynamics

In normal subjects, intravenous administration of corticorelin results in a rapid and sustained increase of plasma ACTH levels and a near parallel increase of plasma cortisol.  In addition, intravenous administration of corticorelin to normal subjects causes a concomitant and prolonged release of the related proopiomelanocortin peptides β- and γ-lipotropins (β -and γ-LPH) and β-endorphin (β -END).  A number of dose-response studies have been performed on normal subjects using a range of corticorelin doses.  In one study, doses of corticorelin ranging from 0.001 to 30 mcg/kg body weight were administered to 29 healthy volunteers.  Blood samples were taken over a 2-hour period for determination of plasma ACTH and cortisol concentrations.  There was a direct dose-dependent relationship that was more pronounced for ACTH than for cortisol.  The threshold dose was 0.03 mcg/kg, the half-maximal dose was 0.3-1.0 mcg/kg and the maximally effective dose was 3-10 mcg/kg.

Plasma ACTH levels in normal subjects increased 2 minutes after injection of corticorelin doses of ≥0.3 mcg/kg and reached peak levels after 10-15 minutes.  Plasma cortisol levels increased within 10 minutes and reached peak levels at 30 to 60 minutes.  As the dose of corticorelin was increased, the rises in plasma ACTH and cortisol were more sustained, showing a biphasic response with a second lower peak at 2-3 hours after injection.  Similar results were found in another study using 0.3, 3.0, and 30 mcg/kg doses.  The duration of mean plasma ACTH increase after injection of 0.3, 3.0, and 30 mcg/kg was 4, 7, and 8 hours, respectively.  The effect on plasma cortisol was similar, but more prolonged.  Because there are differences in basal levels and peak response levels following a.m. or p.m. administration, it is recommended that subsequent evaluations in the same patient using the corticorelin stimulation test be carried out at the same time of day as the original evaluation.

Baseline ACTH and cortisol levels are usually higher in the morning.  Pooled ACTH values from normal unstressed subjects (n=119) were 25 ± 7 pg/mL in the a.m. and 10 ± 3 in the p.m.; similar pooled cortisol values (n=170) were 11 ± 3 mcg/dL in the a.m. and 4 ± 2 mcg/dL in the p.m.  The normal unstressed person has about seven to ten secretory episodes of ACTH each day.  Most of them occur in the early morning hours and are responsible for the morning plasma cortisol surge.  The following figure shows the daily circadian rhythm of ACTH and cortisol secretions in a normal unstressed person. Insulin, plasma renin activity, prolactin, and growth hormone release are not affected by corticorelin administration in humans.

Continuous 24-hour infusion of corticorelin (0.5, 1.0, and 3.0 mcg/kg/hr) increased plasma ACTH concentrations to a plateau of 15-20 pg/mL by the third hour and urinary-free cortisol reaches 173 ± 43 mcg/dL by 24 hours, comparable to those levels observed in patients with major depression, but less than levels noted in Cushing's disease. Continuous infusion did not abolish the circadian rhythm of plasma ACTH and cortisol, but did appear to desensitize the corticotroph. Intermittent doses of corticorelin (25 mcg every 4 hours for 72 hours), however, continued to elicit the expected ACTH and cortisol responses.

Intravenous administration of 1 mcg/kg corticorelin in combination with 10 pressor units intramuscular vasopressin had a synergistic effect on ACTH and a less marked synergistic effect on cortisol secretion.

The basal and peak response levels of ACTH and cortisol to a 1 mcg/kg or 100 mcg dose of corticorelin administered to normal volunteers in the morning and the evening are given below. These values were obtained by combining the results from 9 clinical trials conducted in the a.m. and 4 clinical trials conducted in the p.m.

The following table is to be used only as a general guide.

Pharmacokinetics

Following a single intravenous injection of 1 mcg/kg of corticorelin to normal men, the disappearance of immunoreactive corticorelin (IR-corticorelin) from plasma follows a biexponential decay curve. Plasma half-lives for IR-corticorelin are 11.6 ± 1.5 minutes (mean ± SE) for the fast component and 73 ± 8 minutes for the slow component. The mean volume of distribution for IR-corticorelin is 6.2 ± 0.5 L with an approximate metabolic clearance rate of 95 ± 11 L/m2/day. Graded intravenous doses of corticorelin (0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30 mcg/kg) produced a linear increase in plasma IR-corticorelin. Corticorelin does not appear to be bound specifically by a circulating plasma protein.

Differential Diagnosis

There are two forms of Cushing's syndrome:

1. 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,

2. 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:
  1. Increased plasma ACTH levels
  2. 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:
  1. Little or no response of plasma ACTH levels
  2. 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.

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.

General

The severity of adverse effects to a corticorelin injection appear to be dose-dependent. Dosages above 1 mcg/kg are not recommended. While few adverse effects have been observed at the 1 mcg/kg or 100 mcg dose, higher doses have been associated with transient tachycardia, decreased blood pressure, loss of consciousness, and asystole (see ADVERSE REACTIONS). These symptoms can be substantially reduced by administering the drug as a 30-second intravenous infusion instead of a bolus injection. At a dose of 200 mcg corticorelin, 4 of 60 volunteers and patients with disturbances of the hypothalamic-pituitary-adrenal (HPA) axis were reported to have had decreased blood pressures. One patient had a severe hypotensive reaction with asystole. Three other patients had an "absence-like" loss of consciousness lasting approximately 5 minutes. In subsequent investigations by the same researchers over a 3-year period using 100 mcg of corticorelin, one patient in approximately 150 to 200 experienced a severe drop in blood pressure and loss of sinus rhythm after receiving 55 mcg of corticorelin, which may have been due to interaction with heparin (see PRECAUTIONS - Drug Interactions).

Hypersensitivity

Hypersensitivity reactions have been reported in patients receiving ACTHREL. Reactions included urticaria, flushing of the face, neck and upper chest; dyspnea, wheezing, urticaria and angioedema involving tongue, lip and facial swelling (see ADVERSE REACTIONS). Should a hypersensitivity reaction occur, discontinue ACTHREL, monitor and treat if indicated.

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).

Carcinogenesis, Mutagenesis, Impairment of Fertility

Animal studies have not been conducted with corticorelin to evaluate carcinogenic potential, mutagenicity, or effect on fertility.

Pregnancy

Nursing Mothers

It is not known whether corticorelin is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ACTHREL® is administered to a nursing woman.

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.

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.