Acthrel

Name: Acthrel

What is the most important information I should know about Acthrel (corticorelin ovine triflutate)?

Before you receive this medicine, tell your doctor about all your medical conditions and allergies.

Uses For Acthrel

Corticorelin ovine triflutate injection is used as part of a test to identify Cushing syndrome.

This medicine is to be given by or under the supervision of your doctor.

Before Using Acthrel

In deciding to use a diagnostic test, any risks of the test must be weighed against the good it will do. This is a decision you and your doctor will make. Also, other things may affect test results. For this test, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of Acthrel® in children.

Geriatric

No information is available on the relationship of age to the effects of Acthrel® in geriatric patients.

Pregnancy

Pregnancy Category Explanation
All Trimesters C Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Acthrel Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur:

Incidence not known
  • Difficult or labored breathing
  • feeling of warmth
  • hives or welts, itching, or skin rash
  • large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
  • redness of the skin
  • redness of the face, neck, arms, and occasionally, upper chest
  • tightness in the chest

Get emergency help immediately if any of the following symptoms of overdose occur:

Symptoms of overdose
  • Difficult or labored breathing
  • severe redness of the face

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

How do I store and/or throw out Acthrel?

  • If you need to store this medicine at home, talk with your doctor, nurse, or pharmacist about how to store it.

Acthrel - Clinical Pharmacology

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.

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
Basal Peak Basal Peak
a.m. 143 28 (16-65) 68 (39-114) 11 (8-13) 21 (17-25)
p.m. 70 9 (8-13) 30 (25-42) 4 (2-6) 16 (15-18)

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.

Precautions

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

(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.

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.

For the Consumer

Applies to corticorelin: intravenous powder for solution

Along with its needed effects, corticorelin (the active ingredient contained in Acthrel) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur while taking corticorelin:

Incidence not known
  • Difficult or labored breathing
  • feeling of warmth
  • hives or welts, itching, or skin rash
  • large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
  • redness of the skin
  • redness of the face, neck, arms, and occasionally, upper chest
  • tightness in the chest

Get emergency help immediately if any of the following symptoms of overdose occur while taking corticorelin:

Symptoms of overdose
  • Difficult or labored breathing
  • severe redness of the face

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