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  • 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

    CORTROPHIN, H.P. Acthar

    HOW SUPPLIED

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

    DOSAGE & INDICATIONS

    For the treatment of infantile spasms.
    Intramuscular dosage (repository corticotropin injection)
    Infants and Children less than 2 years

    75 units/m2/dose intramuscularly twice daily for 2 weeks is the FDA-approved regimen. The dose should then be tapered over a 2 week period to avoid adrenal insufficiency. The manufacturer suggests the following tapering schedule: 30 units/m2/dose intramuscularly every morning for 3 days, 15 units/m2/dose intramuscularly every morning for 3 days, 10 units/m2/dose intramuscularly every morning for 3 days, and 10 units/m2/dose intramuscularly every other morning for 6 days. Body surface area should be calculated with the following formula: BSA (m2) = the square root of ([height (cm) x weight (kg)]/3600). Various other non-FDA-approved regimens have been used off label. Low doses of 5 to 40 units/day intramuscularly for 1 to 6 weeks have been recommended by some neurologists, whereas others recommend larger doses of 40 to 160 units/day intramuscularly for 3 to 12 months. In 1 study, no major difference in efficacy was found between low doses for short periods and large doses for longer periods of time; however, hypertension was more common with the larger doses. In this study, the low-dose regimen was 20 units/day intramuscularly for 2 weeks. If the patient responded, the dose was tapered and discontinued over a 1-week period. If the patient did not respond, the dose was increased to 30 units/day intramuscularly for 4 weeks, then tapered and discontinued over a 1-week period. The high-dose regimen was 150 units/m2/day intramuscularly for 3 weeks; the dose was then tapered and discontinued over 9 weeks.

    For the treatment of acute exacerbations of multiple sclerosis.
    Intramuscular or Subcutaneous dosage (repository corticotropin injection)
    Adults

    80 to 120 units/day IM or subcutaneously for 2 to 3 weeks. It may be necessary to taper the dose.

    For the adjunctive treatment of an acute episode or exacerbation of rheumatoid arthritis, juvenile rheumatoid arthritis (JRA)/juvenile idiopathic arthritis (JIA), or ankylosing spondylitis.
    Intramuscular or Subcutaneous dosage (repository corticotropin injection)
    Adults, Adolescents, and Children 2 years and older

    40 to 80 units subcutaneously or IM every 24 to 72 hours. Individualize the dose and dosing frequency after considering the disease severity, patient response, and plasma and urine corticosteroid concentrations. After prolonged use, a gradual taper may be necessary in order to avoid adrenal insufficiency or recurrent symptoms. Selected cases may require low-dose maintenance therapy.

    For the treatment of symptomatic sarcoidosis.
    Intramuscular or Subcutaneous dosage (repository corticotropin injection)
    Adults, Adolescents, and Children greater than 2 years

    40 to 80 units IM or subcutaneously every 24 to 72 hours. Individualize the dose and dosing frequency after considering the disease severity, patient response, and plasma and urine corticosteroid concentrations. After prolonged use, a gradual taper may be necessary in order to avoid adrenal insufficiency or recurrent symptoms.

    For the treatment of ophthalmic diseases, such as keratitis, iritis, iridocyclitis, diffuse posterior uveitis, choroiditis, optic neuritis, chorioretinitis, and anterior segment inflammation.
    Intramuscular or Subcutaneous dosage (repository corticotropin injection)
    Adults, Adolescents, and Children greater than 2 years

    40 to 80 units IM or subcutaneously every 24 to 72 hours. Individualize the dose and dosing frequency after considering the disease severity, patient response, and plasma and urine corticosteroid concentrations. After prolonged use, a gradual taper may be necessary in order to avoid adrenal insufficiency or recurrent symptoms.

    For the induction of diuresis or remission of proteinuria in the nephrotic syndrome.
    Intramuscular or subcutaneous dosage (repository corticotropin injection)
    Adults, Adolescents, and Children greater than 2 years

    40 to 80 units IM or subcutaneously every 24 to 72 hours. Individualize the dose and dosing frequency after considering the disease severity, patient response, and plasma and urine corticosteroid concentrations. After prolonged use, a gradual taper may be necessary in order to avoid adrenal insufficiency or recurrent symptoms.

    For the treatment of dermatologic and allergic states, including severe erythema multiforme, Stevens-Johnson syndrome, or serum sickness, or for collagen diseases such as systemic lupus erythematosus (SLE) or systemic dermatomyositis (polymyositis).
    Intramuscular or Subcutaneous dosage (repository corticotropin injection)
    Adults, Adolescents, and Children greater than 2 years

    40 to 80 units IM or subcutaneously every 24 to 72 hours. Individualize the dose and dosing frequency after considering the disease severity, patient response, and plasma and urine corticosteroid concentrations. After prolonged use, a gradual taper may be necessary in order to avoid adrenal insufficiency or recurrent symptoms.

    For the adjunctive treatment of an acute episode or exacerbation of psoriatic arthritis (PsA).
    Subcutaneous or Intramuscular dosage (repository corticotropin injection)
    Adults, Adolescents, and Children 2 years and older

    The usual dose is 40 to 80 units given subcutaneously or IM every 24 to 72 hours. Individualize the dose and dosing frequency after considering the disease severity, patient response, and plasma and urine corticosteroid concentrations. After prolonged use, a gradual taper may be necessary in order to avoid adrenal insufficiency or recurrent symptoms. Selected cases may require low-dose maintenance therapy. Guidelines support use for symptomatic relief and acute symptoms.

    MAXIMUM DOSAGE

    Adults

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

    Geriatric

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

    Adolescents

    80 units/day subcutaneous or IM.

    Children

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

    Infants

    150 units/m2/day IM.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

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

    Renal Impairment

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

    ADMINISTRATION

    Injectable 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.

    Intramuscular Administration

    Allow the repository gel injection to reach room temperature before administration. Caution should be taken not to over-pressurize the vial prior to withdrawing the product.
    Inject deeply into a large muscle mass. Rotate sites of injection.

    Subcutaneous Administration

    Allow the repository gel injection to reach room temperature before administration. Caution should be taken not to over-pressurize the vial prior to withdrawing the product.
    Inject subcutaneously, taking care not to inject intradermally. Rotate injection sites.

    STORAGE

    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:
    - Store in refrigerator at 2 to 8 degrees C (36 to 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Corticosteroid hypersensitivity, porcine protein hypersensitivity

    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.

    Intravenous administration

    Corticotropin repository gel is contraindicated for intravenous administration.

    Fungal infection, herpes infection, infection, ocular infection, tuberculosis

    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


    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.

    Cardiac disease, heart failure, hypertension

    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.

    Diverticulitis, peptic ulcer disease, ulcerative colitis

    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.

    Scleroderma, surgery

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

    Adrenal insufficiency, Cushing's syndrome, hypercortisolism, hypothalamic-pituitary-adrenal (HPA) suppression

    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.

    Myasthenia gravis, psychosis, seizure disorder

    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.

    Diabetes mellitus, hypothyroidism

    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.

    Hypernatremia, hypokalemia, renal impairment

    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.

    Thromboembolic disease

    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.

    Geriatric, osteoporosis, postmenopausal females

    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.

    Children, growth inhibition, infants, neonates

    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.

    Pregnancy

    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.

    Breast-feeding

    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

    Severe

    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

    Moderate

    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

    Mild

    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

    Pregnancy

    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