CLASSES

ACTH and Analogs

DEA CLASS

Rx

DESCRIPTION

Parenteral adrenocorticotropic hormone (ACTH); highly purified and extracted from porcine pituitary glands
Repository injection primarily used in adults for multiple sclerosis; other corticosteroids usually preferred for other indications
In pediatric patients, repository injection primarily used for infantile spasms in infants and children less than 2 years

COMMON BRAND NAMES

Acthar, CORTROPHIN

HOW SUPPLIED

Corticotropin (Porcine)/H.P. Acthar Intramuscular Inj Sol: 1mL, 80U
Corticotropin (Porcine)/H.P. Acthar Subcutaneous Inj Sol: 1mL, 80U

DOSAGE & INDICATIONS

MAXIMUM DOSAGE

80 units/day subcutaneous or IM for most conditions; up to 120 units/day IM for multiple sclerosis exacerbations.

80 units/day subcutaneous or IM for most conditions; up to 120 units/day IM for multiple sclerosis exacerbations.

80 units/day subcutaneous or IM.

2 years and older: 80 units/day subcutaneously or IM.
Less than 2 years: 150 units/m2/day IM.

150 units/m2/day IM.

Safety and efficacy have not been established.

DOSING CONSIDERATIONS

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

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

ADMINISTRATION

The repository corticotropin (ACTH) gel injection is not for intravenous use; administer by intramuscular or subcutaneous routes only.
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

STORAGE

Acthar:
- Refrigerated product should reach room temperature before administration
- Store in refrigerator at 2 to 8 degrees C (36 to 46 degrees F)
CORTROPHIN:
- Discard product if it contains particulate matter, is cloudy, or discolored
- Protect from direct sunlight
- Store in a cool, well ventilated, dry place
- Store in original container
- Store in refrigerator at 2 to 8 degrees C (36 to 46 degrees F)
- Store upright
H.P. Acthar:
- Refrigerate (between 36 and 46 degrees F)

CONTRAINDICATIONS / PRECAUTIONS

The use of corticotropin is contraindicated in patients with previous hypersensitivity to corticotropin therapy and those with porcine protein hypersensitivity. Prolonged administration of corticotropin may increase the risk of hypersensitivity reactions; consider hypersensitivity if symptoms arise during therapy. Anaphylaxis has been reported with postmarketing use of corticotropin. Limited data suggest the potential for the development of antibodies to corticotropin with chronic administration along with a loss of both endogenous ACTH and corticotropin activity. Although true corticosteroid hypersensitivity is rare, patients who have demonstrated a prior hypersensitivity reaction to corticotropin should not receive any form of corticotropin. It is possible, though also rare, that such patients will display cross-hypersensitivity to other corticosteroids. It is advisable that patients who have a hypersensitivity reaction to any corticosteroid undergo skin testing, which, although not a conclusive predictor, may help to determine if hypersensitivity to another corticosteroid exists. Such patients should be carefully monitored during and following the administration of any corticosteroid.

Corticotropin repository gel is contraindicated for intravenous administration.

Due to suppression of the immune system, corticotropin should not be used in patients with infection caused by bacteria, viruses, or fungi that is not controlled by antimicrobials, unless it is a life-threatening situation. The use of corticotropin is contraindicated in patients with a systemic fungal infection, ocular herpes infection, or in very young pediatric patients with a suspected congenital infection. The use of corticotropin in patients with herpes simplex ocular infection can increase the risk of corneal perforation. Those patients with latent tuberculosis or a positive tuberculin skin test should be observed closely during therapy with corticotropin; if therapy is prolonged, initiate chemoprophylaxis.

Vaccination with live or live attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticotropin. Killed or inactivated vaccines should be given with caution during therapy with corticotropin because corticotropin inhibits antibody response after vaccination and neurologic reactions may be aggravated.

Corticotropin is contraindicated in patients with uncontrolled hypertension or congestive heart failure and should be used with caution in patients any degree of hypertension or heart failure. Corticotropin should be used cautiously in patients with other types of cardiac disease due to its propensity to cause water retention and hypertension and to lower serum potassium concentrations. Patients may require potassium supplementation while receiving corticotropin.

Since corticotropin stimulates the production of endogenous corticosteroids, the drug should be used with caution in patients with GI disease, including diverticulitis, ulcerative colitis, or intestinal anastomosis due to a risk of perforation. The use of corticotropin is contraindicated in patients with peptic ulcer disease.

The use of corticotropin is contraindicated in patients with scleroderma or in patients that have had recent surgery.

Corticotropin is contraindicated in patients with primary adrenal insufficiency, hypercortisolism, or any condition associated with these disorders. Prolonged therapy with corticotropin causes hypothalamic-pituitary-adrenal (HPA) suppression due to inhibition of corticotropin release from the pituitary. Patients on long-term therapy may require additional doses of corticosteroids when subjected to stress such as illness, infection, surgery, or trauma. Abrupt discontinuation of corticotropin, especially after prolonged therapy, can lead to adrenal insufficiency. Patients should be monitored for symptoms of adrenal insufficiency after corticotropin therapy is discontinued; these symptoms include fatigue, anorexia, weakness, hyperpigmentation, weight loss, hypotension, and abdominal pain. Parents and caregivers of pediatric patients receiving corticotropin for the treatment of infantile spasms should be informed of the possibility of adrenal insufficiency when the drug is discontinued and instructed to monitor for these symptoms. Adrenal insufficiency can be minimized by tapering of the corticotropin dose prior to discontinuation. Glucocorticoids can also cause or aggravate Cushing's syndrome and therefore should be avoided in patients with Cushing's disease.

Corticotropin should be used with extreme caution in patients with certain chronic or comorbid conditions because the drug may exacerbate these conditions. These include behavioral disorders such as psychosis or emotional instability and neurologic diseases such as myasthenia gravis or seizure disorder.

Corticotropin should be used with caution in patients with certain endocrine conditions such as diabetes mellitus and hypothyroidism. Corticotropin may exacerbate diabetes mellitus; diabetic patients may have an increased requirement for insulin or oral hypoglycemics. Monitor patients for hyperglycemia during and for a period of time after corticotropin therapy. Patients with hypothyroidism can have an exaggerated response to corticotropin or exogenous corticosteroids; any corticosteroid should be used with caution in these patients.

Due to the sodium-retaining, fluid-retaining, and potassium-wasting properties of the drug, corticotropin should be used with caution in patients with renal impairment, hypokalemia, hypernatremia, or other patients who may be sensitive to fluid/electrolyte disturbances.

Use corticotropin cautiously in patients with thromboembolic disease because this drug rarely has been reported to increase blood coagulability and to precipitate intravascular thrombosis, thrombophlebitis, and thromboembolism.

Prolonged therapy with corticotropin can cause atrophy of the bone protein matrix due to protein catabolism. This atrophy can cause osteoporosis, fractures, aseptic necrosis of femoral and humoral heads, and pathologic fractures of long bones. Corticotropin is contraindicated in patients with pre-existing osteoporosis. Use cautiously in geriatric, debilitated, and postmenopausal females.

The use of corticotropin (ACTH) is contraindicated in neonates, infants and children less than 2 years of age with a suspected congenital infection. Specific data regarding use of this drug in neonates are not available. Infants and children less than 2 years experience a high rate of infections while receiving corticotropin therapy for infantile spasms; monitor patients carefully for signs and symptoms of infection. Long-term use of corticotropin may have negative effects on growth and physical development in pediatric patients, resulting in growth inhibition. Changes in appetite are seen with corticotropin therapy, with the effects becoming more frequent as the dose or treatment period increases. These effects are reversible once corticotropin use is stopped. Growth and physical development of pediatric patients on prolonged therapy should be carefully monitored.

Corticotropin, ACTH may cause fetal harm when administered to a patient during pregnancy due to stimulation of an endogenous steroid response. Use of corticosteroids during pregnancy has been associated with intrauterine growth restriction, decreased birth weight and preterm birth; thus there is potential concern regarding use of corticotropin in pregnancy. Hypoadrenalism has also been reported in infants born to patients who received high-dose and/or long-term corticosteroid therapy during pregnancy. Corticotropin has not been adequately studied in animals to determine risk of therapy during pregnancy. Closely monitor infants exposed to corticotropin during pregnancy for signs of hypoadrenalism, such as poor feeding, irritability, weakness, and vomiting. Adrenocortical disease during pregnancy is relatively rare as most cases are diagnosed before a woman becomes pregnant, but ACTH stimulated normal cortisol values have been established for each trimester. Adrenal disease may cause significant maternal and fetal morbidity, so accurate and rapid diagnosis is important. The use of cosyntropin to confirm the diagnosis of adrenal insufficiency during pregnancy, when suspected, is described in the literature.

There are no available data on the presence of corticotropin, ACTH in human milk, the effects on the breastfed infant, or on milk production. Because many drugs are excreted in human milk and due to the potential for serious adverse reactions in nursing infants, the manufacturer states that a decision should be made whether to discontinue breast-feeding or to discontinue the drug, taking into account the importance of the drug to the mother and the indication for use. However, due to its large molecular weight and short half-life of only 10 to 15 minutes, corticotropin, ACTH is unlikely to appear in human milk. It is also unlikely that corticotropin, ACTH would be absorbed by the infant because it would probably be degraded in the infant's gastrointestinal tract. Animal data suggests an increase in breast milk cortisol levels might be expected after administration of corticotropin to a nursing mother. However, if corticotropin is required in the mother, it is not a reason to discontinue breast-feeding. Alternative therapies to consider include other corticosteroids, such as prednisone and methylprednisolone. Prednisone concentrations in breast milk are low, and no adverse effects have been reported in the breast-fed infant with maternal use of any corticosteroid during breast-feeding; prednisone is generally considered compatible to use during lactation.

ADVERSE REACTIONS

seizures / Delayed / 3.0-12.0
skin atrophy / Delayed / Incidence not known
esophageal ulceration / Delayed / Incidence not known
GI perforation / Delayed / Incidence not known
GI bleeding / Delayed / Incidence not known
pancreatitis / Delayed / Incidence not known
scarlatiniform exanthema / Rapid / Incidence not known
anaphylactic shock / Rapid / Incidence not known
ocular hypertension / Delayed / Incidence not known
heart failure / Delayed / Incidence not known
atrial fibrillation / Early / Incidence not known
vasculitis / Delayed / Incidence not known
papilledema / Delayed / Incidence not known
intracranial bleeding / Delayed / Incidence not known
avascular necrosis / Delayed / Incidence not known
bone fractures / Delayed / Incidence not known

Cushing's syndrome / Delayed / 3.0-22.0
hypertension / Early / 11.0-19.0
constipation / Delayed / 0-5.0
candidiasis / Delayed / 2.0
erythema / Early / Incidence not known
impaired wound healing / Delayed / Incidence not known
esophagitis / Delayed / Incidence not known
hypotension / Rapid / Incidence not known
wheezing / Rapid / Incidence not known
exophthalmos / Delayed / Incidence not known
ocular infection / Delayed / Incidence not known
cataracts / Delayed / Incidence not known
sodium retention / Delayed / Incidence not known
peripheral edema / Delayed / Incidence not known
hypokalemia / Delayed / Incidence not known
edema / Delayed / Incidence not known
metabolic alkalosis / Delayed / Incidence not known
fluid retention / Delayed / Incidence not known
palpitations / Early / Incidence not known
euphoria / Early / Incidence not known
depression / Delayed / Incidence not known
psychosis / Early / Incidence not known
subdural hematoma / Early / Incidence not known
pseudotumor cerebri / Delayed / Incidence not known
EEG changes / Delayed / Incidence not known
hyperglycemia / Delayed / Incidence not known
hypothalamic-pituitary-adrenal (HPA) suppression / Delayed / Incidence not known
withdrawal / Early / Incidence not known
osteoporosis / Delayed / Incidence not known
osteopenia / Delayed / Incidence not known
myasthenia / Delayed / Incidence not known
growth inhibition / Delayed / Incidence not known

infection / Delayed / 20.0-46.0
irritability / Delayed / 7.0-19.0
acne vulgaris / Delayed / 14.0-14.0
diarrhea / Early / 3.0-14.0
rash / Early / 8.0-8.0
fever / Early / 5.0-8.0
vomiting / Early / 3.0-5.0
nasal congestion / Early / 1.0-5.0
injection site reaction / Rapid / Incidence not known
ecchymosis / Delayed / Incidence not known
hyperhidrosis / Delayed / Incidence not known
petechiae / Delayed / Incidence not known
nausea / Early / Incidence not known
urticaria / Rapid / Incidence not known
pruritus / Rapid / Incidence not known
dizziness / Early / Incidence not known
emotional lability / Early / Incidence not known
fatigue / Early / Incidence not known
insomnia / Early / Incidence not known
malaise / Early / Incidence not known
lethargy / Early / Incidence not known
asthenia / Delayed / Incidence not known
headache / Early / Incidence not known
vertigo / Early / Incidence not known
menstrual irregularity / Delayed / Incidence not known
hirsutism / Delayed / Incidence not known

DRUG INTERACTIONS

Calcium Carbonate: (Moderate) Calcium absorption is reduced when calcium carbonate is taken concomitantly with systemic corticosteroids. Systemic corticosteroids induce a negative calcium balance by inhibiting intestinal calcium absorption as well as by increasing renal calcium losses. The mechanism by which these drugs inhibit calcium absorption in the intestine is likely to involve a direct inhibition of absorptive cell function. Patients taking systemic corticosteroids should ensure proper intake of calcium as directed by their health care provider.
Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Moderate) Calcium absorption is reduced when calcium carbonate is taken concomitantly with systemic corticosteroids. Systemic corticosteroids induce a negative calcium balance by inhibiting intestinal calcium absorption as well as by increasing renal calcium losses. The mechanism by which these drugs inhibit calcium absorption in the intestine is likely to involve a direct inhibition of absorptive cell function. Patients taking systemic corticosteroids should ensure proper intake of calcium as directed by their health care provider.
Calcium Carbonate; Magnesium Hydroxide: (Moderate) Calcium absorption is reduced when calcium carbonate is taken concomitantly with systemic corticosteroids. Systemic corticosteroids induce a negative calcium balance by inhibiting intestinal calcium absorption as well as by increasing renal calcium losses. The mechanism by which these drugs inhibit calcium absorption in the intestine is likely to involve a direct inhibition of absorptive cell function. Patients taking systemic corticosteroids should ensure proper intake of calcium as directed by their health care provider.
Calcium Carbonate; Magnesium Hydroxide; Simethicone: (Moderate) Calcium absorption is reduced when calcium carbonate is taken concomitantly with systemic corticosteroids. Systemic corticosteroids induce a negative calcium balance by inhibiting intestinal calcium absorption as well as by increasing renal calcium losses. The mechanism by which these drugs inhibit calcium absorption in the intestine is likely to involve a direct inhibition of absorptive cell function. Patients taking systemic corticosteroids should ensure proper intake of calcium as directed by their health care provider.
Calcium Carbonate; Risedronate: (Moderate) Calcium absorption is reduced when calcium carbonate is taken concomitantly with systemic corticosteroids. Systemic corticosteroids induce a negative calcium balance by inhibiting intestinal calcium absorption as well as by increasing renal calcium losses. The mechanism by which these drugs inhibit calcium absorption in the intestine is likely to involve a direct inhibition of absorptive cell function. Patients taking systemic corticosteroids should ensure proper intake of calcium as directed by their health care provider.
Calcium Carbonate; Simethicone: (Moderate) Calcium absorption is reduced when calcium carbonate is taken concomitantly with systemic corticosteroids. Systemic corticosteroids induce a negative calcium balance by inhibiting intestinal calcium absorption as well as by increasing renal calcium losses. The mechanism by which these drugs inhibit calcium absorption in the intestine is likely to involve a direct inhibition of absorptive cell function. Patients taking systemic corticosteroids should ensure proper intake of calcium as directed by their health care provider.
Calcium; Vitamin D: (Moderate) Calcium absorption is reduced when calcium carbonate is taken concomitantly with systemic corticosteroids. Systemic corticosteroids induce a negative calcium balance by inhibiting intestinal calcium absorption as well as by increasing renal calcium losses. The mechanism by which these drugs inhibit calcium absorption in the intestine is likely to involve a direct inhibition of absorptive cell function. Patients taking systemic corticosteroids should ensure proper intake of calcium as directed by their health care provider.
Daratumumab; Hyaluronidase: (Minor) Corticosteroids (e.g., cortisone, corticotropin, ACTH), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Hyaluronidase, Recombinant; Immune Globulin: (Minor) Corticosteroids (e.g., cortisone, corticotropin, ACTH), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Hyaluronidase: (Minor) Corticosteroids (e.g., cortisone, corticotropin, ACTH), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Pertuzumab; Trastuzumab; Hyaluronidase: (Minor) Corticosteroids (e.g., cortisone, corticotropin, ACTH), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Rituximab; Hyaluronidase: (Minor) Corticosteroids (e.g., cortisone, corticotropin, ACTH), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
Trastuzumab; Hyaluronidase: (Minor) Corticosteroids (e.g., cortisone, corticotropin, ACTH), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.

PREGNANCY AND LACTATION

Corticotropin, ACTH may cause fetal harm when administered to a patient during pregnancy due to stimulation of an endogenous steroid response. Use of corticosteroids during pregnancy has been associated with intrauterine growth restriction, decreased birth weight and preterm birth; thus there is potential concern regarding use of corticotropin in pregnancy. Hypoadrenalism has also been reported in infants born to patients who received high-dose and/or long-term corticosteroid therapy during pregnancy. Corticotropin has not been adequately studied in animals to determine risk of therapy during pregnancy. Closely monitor infants exposed to corticotropin during pregnancy for signs of hypoadrenalism, such as poor feeding, irritability, weakness, and vomiting. Adrenocortical disease during pregnancy is relatively rare as most cases are diagnosed before a woman becomes pregnant, but ACTH stimulated normal cortisol values have been established for each trimester. Adrenal disease may cause significant maternal and fetal morbidity, so accurate and rapid diagnosis is important. The use of cosyntropin to confirm the diagnosis of adrenal insufficiency during pregnancy, when suspected, is described in the literature.

There are no available data on the presence of corticotropin, ACTH in human milk, the effects on the breastfed infant, or on milk production. Because many drugs are excreted in human milk and due to the potential for serious adverse reactions in nursing infants, the manufacturer states that a decision should be made whether to discontinue breast-feeding or to discontinue the drug, taking into account the importance of the drug to the mother and the indication for use. However, due to its large molecular weight and short half-life of only 10 to 15 minutes, corticotropin, ACTH is unlikely to appear in human milk. It is also unlikely that corticotropin, ACTH would be absorbed by the infant because it would probably be degraded in the infant's gastrointestinal tract. Animal data suggests an increase in breast milk cortisol levels might be expected after administration of corticotropin to a nursing mother. However, if corticotropin is required in the mother, it is not a reason to discontinue breast-feeding. Alternative therapies to consider include other corticosteroids, such as prednisone and methylprednisolone. Prednisone concentrations in breast milk are low, and no adverse effects have been reported in the breast-fed infant with maternal use of any corticosteroid during breast-feeding; prednisone is generally considered compatible to use during lactation.

MECHANISM OF ACTION

Corticotropin and endogenous ACTH stimulates steroidogenesis and the release of cortisol (hydrocortisone), corticosterone, and weak androgens from the adrenal cortex. The physiologic and pharmacologic effects of corticotropin are due primarily to the glucocorticoid cortisol, which also has some mineralocorticoid activity. Prolonged administration of large doses of corticotropin induces hyperplasia and hypertrophy of the adrenal cortex and continuous high output of cortisol, corticosterone and weak androgens. The release of endogenous ACTH is under the influence of the nervous system via the regulatory hormone released from the hypothalamus and by a negative corticosteroid feedback mechanism. Elevated plasma cortisol suppresses ACTH release. The antiinflammatory actions of corticosteroids are thought to involve phospholipase A2 inhibitory proteins, collectively called lipocortins; lipocortins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of the precursor molecule arachidonic acid. Other effects of corticotropin include extra-adrenal effects such as binding to melanocortin receptors.
 
Although oral glucocorticoids do not depend on adrenal function for effectiveness, have a more predictable profile, and have easily regulated doses for patient-specific therapy, corticotropin therapy is preferred by some clinicians in certain conditions.
 
The mechanism of action of corticotropin for the treatment of infantile spasms is unknown.

PHARMACOKINETICS

Corticotropin (ACTH) is administered subcutaneously and intramuscularly. Corticotropin is available as a repository corticotropin injection (RCI). ACTH rapidly disappears from the circulation following its intravenous administration; in humans, the plasma half-life is about 15 minutes. The pharmacokinetics of the repository corticotropin injection have not been adequately characterized. The maximal effects of a trophic hormone on a target organ are achieved when optimal amounts of hormone are acting continuously. Thus, a fixed dose of the repository corticotropin injection will demonstrate a linear increase in adrenocortical secretion with increasing duration of an infusion.
 
Affected cytochrome P450 isoenzymes and drug transporters: None known