ACTHREL Powder for solution for injection Ref.[10025] Active ingredients: Corticorelin

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 – 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.

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).

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).

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 studied.