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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
The empirical formula of
corticorelin ovine is C205H339N59O63S
with a molecular weight of 4670.35 Daltons. Â 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.
ACTHREL® is indicated for use in differentiating
pituitary and ectopic production of ACTH in patients with ACTH-dependent
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%
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:
High basal plasma ACTH (may be very high) plus high
basal plasma cortisol (20 -40 mcg/dL). ACTHREL® injection (1 mcg/kg)
Little or no response of plasma ACTH levels
Little or no response of plasma cortisol levels 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.
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
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.
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
High ACTH Response
Low ACTH Response
High Basal ACTH
Ectopic ACTH Secretion
CUSHING'S DISEASE ACTH
RESPONSES (mean of 181 patients)
Basal ACTH 63 ± 72 pg/mL (mean
Peak ACTH 189 ± 262 pg/mL (mean
Mean of individual change from
baseline + 227%
ECTOPIC ACTH SECRETION RESPONSES (mean for 31
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 Differential Diagnosis above).
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DOSAGE AND ADMINISTRATION
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.
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.
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
and 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).
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Warnings & Precautions
No information provided. Please refer to PRECAUTIONS below.
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 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.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Animal studies have not been conducted with corticorelin
to evaluate carcinogenic potential, mutagenicity, or effect on fertility.
Pregnancy Category C
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.
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.
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
Overdosage & Contraindications
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.
ACTHREL is contraindicated in patients with a history of
a hypersensitivity reaction to ovine corticorelin or any of its excipients.
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
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 resin 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.
Basal Concentrations and Peak Responses of ACTH and
Cortisol in Normal Subjects after 1 mcg/kg or 100 mcg of ACTHREL®
Time of Day
No. of Subjects
ACTH Concentration mean (range) pg/mL
Cortisol Concentration mean (range) mcg/dL
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.
No information provided. Please refer to the WARNINGS AND PRECAUTIONS section.