Acthrel

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Acthrel

Classes

ACTH and Analogs

Administration
Injectable Administration

Visually inspect the dissolved solution for particulate matter and discoloration prior to administration, whenever solution and container permit.

Intravenous Administration

Corticorelin, ovine is administered intravenously.
    
Reconstitution of powder for injection (Acthrel):
Dissolve 1 vial (100 mcg) of corticorelin, ovine with 2 mL of 0.9% Sodium Chloride injection, USP. Roll the vial between the hands to dissolve the corticorelin. In order to avoid bubble formation in the solution, do not shake the vial.
The resulting solution has a concentration of 50 mcg/mL and is ready for intravenous use.
 
Intravenous Administration:
 
The manufacturer does not recommend the use of a heparin solution to maintain IV cannula patency during the corticorelin test. A possible interaction between corticorelin and heparin may occur (see Drug Interactions, Adverse Reactions).
Venous blood samples for corticotropin (ACTH) should be drawn 15 minutes before and immediately prior to administration.
After reconstitution, administer by SLOW intravenous push (referred to as intravenous infusion by the manufacturer) over 30 seconds. Some adverse effects (e.g., transient tachycardia, decreased blood pressure, loss of consciousness, and asystole) associated with administration of corticorelin, ovine can be reduced by administering the drug as an infusion over 30 seconds instead of as a fast bolus injection.
Post-dose venous blood samples for corticotropin (ACTH) should be drawn at 15, 30, and 60 minutes following administration.

Adverse Reactions
Severe

asystole / Rapid / Incidence not known
angioedema / Rapid / Incidence not known

Moderate

hypotension / Rapid / Incidence not known
dyspnea / Early / Incidence not known
sinus tachycardia / Rapid / Incidence not known
wheezing / Rapid / Incidence not known

Mild

flushing / Rapid / 16.0-16.0
syncope / Early / Incidence not known
urticaria / Rapid / Incidence not known

Common Brand Names

Acthrel

Dea Class

Rx

Description

Intravenous diagnostic agent
Used after diagnosis of Cushing's syndrome, when autonomous adrenal hyperfunction is eliminated as cause
Aids in differentiation between Cushing's disease and ectopic source of excessive ACTH secretion

Dosing Considerations
Hepatic Impairment

Specific guidelines for dosage adjustment in hepatic impairment are not available; it appears that no dosage adjustments are necessary.

Renal Impairment

Renal elimination is not a primary route of elimination for corticorelin. While dose alterations for corticorelin do not appear to be necessary in renal insufficiency, hormonal responses may differ in such patients.

Drug Interactions

Dexamethasone: (Major) Patients pretreated with dexamethasone have demonstrated an inhibited or blunted response to corticotropin, ovine. Patients receiving corticotropin, ovine should not be pretreated with dexamethasone; no specific guidelines are available.
Heparin: (Major) The use of a heparin solution to maintain IV cannula patency during corticorelin stimulation tests is not recommended. A possible interaction between corticorelin and heparin may have been responsible for a major hypotensive reaction that occurred after corticorelin administration.
Vasopressin, ADH: (Major) The coadministration of corticorelin, ovine and vasopressin, ADH has resulted in a synergistic effect on the secretion of corticotropin, with a less marked synergistic response on cortisol secretion. The concomitant use of corticorelin and vasopressin should be avoided.

How Supplied

Acthrel Intravenous Inj Pwd F/Sol: 100mcg

Maximum Dosage
Adults

1 mcg/kg/dose IV or 100 mcg/dose IV.

Elderly

1 mcg/kg/dose IV or 100 mcg/dose IV.

Adolescents

1 mcg/kg/dose IV or 100 mcg/dose IV.

Children

Safety and efficacy have not been established.

Mechanism Of Action

Corticorelin, ovine is a 41-amino acid peptide isolated from ovine hypothalami. Corticorelin, ovine stimulates the release of corticotropin (ACTH) and cortisol from the anterior lobe of the pituitary gland, resulting in a rapid and sustained increase in plasma concentrations of these hormones. The administration of corticorelin, ovine also stimulates the release of related pro-opiomelanocortin peptides, beta- and gamma-lipotropins and beta-endorphin from the anterior lobe of the pituitary gland.
 
Corticorelin, ovine aids in establishing the source of excessive ACTH secretion, following the confirmation of Cushing's syndrome (i.e., pituitary-related hypercortisolism) and the ruling out of autonomous adrenal hyperfunction (i.e., ACTH-independent Cushing's syndrome). In patients with Cushing's disease (i.e., ACTH of pituitary origin), corticorelin, ovine will stimulate an increase in plasma ACTH and cortisol concentrations in the presence of already elevated plasma ACTH and cortisol levels; this hyper-response pattern indicates an impairment of the negative feedback of cortisol on the pituitary. In patients with secondary ectopic secretion of ACTH (i.e., ectopic ACTH syndrome), corticorelin, ovine will elicit little or no response in plasma ACTH and cortisol concentrations.

Pharmacokinetics

Corticorelin, ovine is usually administered via intravenous (IV) infusion. It  has also been administered by subcutaneous injection. The mean volume of distribution for corticorelin is around 6 L with an approximate metabolic clearance rate of 95 L/m2/day. Corticorelin does not appear to be bound specifically by any circulating plasma protein. Corticorelin is metabolized in the liver, other body tissues, and, to a lesser extent, the kidney; only small amounts of corticorelin are excreted in the urine.
With increasing doses of corticorelin, the subsequent rises in plasma ACTH and cortisol are more sustained and exhibit a biphasic response with a second lower peak at 2—3 hours. The ACTH and cortisol responses to corticorelin can be variable in patients with Cushing's disease; a hyper-response is typically seen despite elevated basal plasma concentrations of ACTH and cortisol. In patients with Cushing's disease, the administration of corticorelin results in a positive correlation between basal ACTH levels and maximum ACTH increments, unlike the negative correlation between basal and stimulated levels of ACTH and cortisol found in normal healthy individuals.
There are differences in basal levels and peak response levels of plasma ACTH and cortisol concentrations following AM or PM administration of corticorelin; baseline plasma ACTH and cortisol levels are usually higher in the morning. The normal unstressed person has approximately seven to ten secretory episodes of ACTH each day. Most of these episodes occur during early morning hours and are responsible for the morning plasma cortisol surge. Therefore, it is recommended that any subsequent corticorelin stimulation tests in the same patient be conducted at the same time of day as the original evaluation.

Intravenous Route

The intravenous administration of corticorelin, ovine 1 mcg/kg in normal healthy individuals results in corticorelin plasma half-lives approximately 12 minutes for the fast component and 73 minutes for the slow component. In normal healthy individuals, the intravenous administration of corticorelin, ovine 0.3 mcg/kg results in increased plasma corticotropin (ACTH) concentrations within 2 minutes, reaching peak levels after 10—15 minutes, and increased plasma cortisol concentrations within 10 minutes, reaching peak levels after 30—60 minutes.

Subcutaneous Route

Subcutaneous administration appears to be well-absorbed, although peak levels of corticorelin tend to be lower than those obtained with comparable intravenous doses. In addition, hormonal response to subcutaneous dosage remains elevated for a longer period of time, most likely because of a slow rate of absorption from the subcutaneous injection site.

Pregnancy And Lactation
Pregnancy

Corticorelin, Ovine is classified as FDA pregnancy risk Category C. No information is available regarding the use of corticorelin in pregnant humans or animals. Corticorelin should only be used during pregnancy if clearly needed.

According to the manufacturer, corticorelin should be used cautiously in breast-feeding women. It is not known if corticorelin, ovine is secreted in human milk. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.