ACTHAR GEL (repository corticotropin injection)

ACTHAR GEL (repository corticotropin injection)

ACTHAR GEL

Acthar Gel is a naturally sourced complex mixture of adrenocorticotropic hormone analogs and other pituitary peptides. The Acthar Gel manufacturing process converts the initial porcine pituitary extract with low ACTH content into a mixture having modified porcine ACTH and other related peptide analogs solubilized in gelatin. A major component in the formulated complex mixture is N-25 deamidated porcine ACTH (1-39).

Acthar Gel is supplied as a sterile preparation in 16% gelatin to provide a prolonged release after intramuscular or subcutaneous injection. Acthar Gel also contains 0.5% phenol, not more than 0.1% cysteine (added), sodium hydroxide and/or acetic acid to adjust pH and water for injection.

INDICATIONS AND USAGE

Infantile Spasms: Acthar Gel is indicated as monotherapy for the treatment of infantile spasms in infants and children under 2 years of age.

Multiple Sclerosis: Acthar Gel is indicated for the treatment of acute exacerbations of multiple sclerosis in adults. Controlled clinical trials have shown Acthar Gel to be effective in speeding the resolution of acute exacerbations of multiple sclerosis. However, there is no evidence that it affects the ultimate outcome or natural history of the disease.

Rheumatic Disorders: As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in: Psoriatic arthritis; Rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy); Ankylosing spondylitis.

Collagen Diseases: During an exacerbation or as maintenance therapy in selected cases of: systemic lupus erythematosus, systemic dermatomyositis (polymyositis).

Dermatologic Diseases: Severe erythema multiforme, Stevens-Johnson syndrome.

Allergic States: Serum sickness.

Ophthalmic Diseases: Severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa such as: keratitis; iritis, iridocyclitis, diffuse posterior uveitis and choroiditis, optic neuritis, chorioretinitis; anterior segment inflammation.

Respiratory Diseases: Symptomatic sarcoidosis.

Edematous State: To induce a diuresis or a remission of proteinuria in the nephrotic syndrome without uremia of the idiopathic type or that due to lupus erythematosus.

Mechanism of Action

The mechanism of action of Acthar Gel in the treatment of infantile spasms is unknown.

Acthar Gel and endogenous ACTH stimulate the adrenal cortex to secrete cortisol, corticosterone, aldosterone, and a number of weakly androgenic substances. Prolonged administration of large doses of Acthar Gel 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.

Acthar Gel is also reported to bind to melanocortin receptors.

The trophic effects of endogenous ACTH and Acthar Gel on the adrenal cortex are not well understood beyond the fact that they appear to be mediated by cyclic AMP.

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DOSAGE AND ADMINISTRATION

Specific Recommended Dosage Regimen for Infantile Spasms in Infants and Children Under 2 Years of Age: In the treatment of infantile spasms, Acthar Gel must be administered intramuscularly. The recommended regimen is a daily dose of 150 U/m2 (divided into twice daily intramuscular injections of 75 U/m2) administered over a 2-week period. Dosing with Acthar Gel should then be gradually tapered over a 2-week period to avoid adrenal insufficiency. The following is one suggested tapering schedule: 30 U/m2 in the morning for 3 days; 15 U/m2 in the morning for 3 days; 10 U/m2 in the morning for 3 days; and 10 U/m2 every other morning for 6-days.

Acthar Gel is typically dosed based on body surface area (BSA).

Recommended Dosage Regimen for the Treatment of Acute Exacerbations in Adults with Multiple Sclerosis: The recommended dose is daily intramuscular or subcutaneous doses of 80-120 units for 2-3 weeks for acute exacerbations.

Dosage should be individualized according to the medical condition of each patient. Frequency and dose of the drug should be determined by considering the severity of the disease and the initial response of the patient.

Although drug dependence does not occur, sudden withdrawal of Acthar Gel after prolonged use may lead to adrenal insufficiency or recurrent symptoms which make it difficult to stop the treatment. It may be necessary to taper the dose and increase the injection interval to gradually discontinue the medication.

Recommended Dosage Regimen for Other Indications for Adults and Children Over 2 Years of Age: Dosage should be individualized according to the disease under treatment and the general medical condition of each patient. Frequency and dose of the drug should be determined by considering severity of the disease and the initial response of the patient.

The usual dose of Acthar Gel is 40-80 units given intramuscularly or subcutaneously every 24-72 hours.

Although drug dependence does not occur, sudden withdrawal of Acthar Gel after prolonged use may lead to adrenal insufficiency or recurrent symptoms which make it difficult to stop the treatment. It may be necessary to taper the dose and increase the injection interval to gradually discontinue the medication.

CONTRAINDICATIONS

Acthar Gel is contraindicated:

  • for intravenous administration.
  • in infants under 2 years of age who have suspected congenital infections.
  • with concomitant administration of live or live attenuated vaccines in patients receiving immunosuppressive doses of Acthar Gel.
  • in patients with scleroderma, osteoporosis, systemic fungal infections, ocular herpes simplex, recent surgery, history of or the presence of a peptic ulcer, congestive heart failure, uncontrolled hypertension, primary adrenocortical insufficiency, adrenocortical hyperfunction, or sensitivity to proteins of porcine origin.

WARNINGS AND PRECAUTIONS

Infections: Acthar Gel may increase the risks related to infections with any pathogen, including viral, bacterial, fungal, protozoan or helminthic infections. Patients with latent tuberculosis or tuberculin reactivity should be observed closely, and if therapy is prolonged, chemoprophylaxis should be instituted.

Cushing’s Syndrome and Adrenal Insufficiency Upon Withdrawal: Treatment with Acthar Gel can cause hypothalamic-pituitary-adrenal (HPA) axis suppression and Cushing’s syndrome. These conditions should be monitored especially with chronic use.

Suppression of the HPA may occur following prolonged therapy with the potential for adrenal insufficiency after withdrawal of the medication. Patients should be monitored for signs of insufficiency such as weakness, hyperpigmentation, weight loss, hypotension and abdominal pain.

Elevated Blood Pressure, Salt and Water Retention, and Hypokalemia: Acthar Gel can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium and calcium. Dietary salt restriction and potassium supplementation may be necessary. Caution should be used in the treatment of patients with hypertension, congestive heart failure, or renal insufficiency.

Vaccination: Administration of live or live attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of Acthar Gel. Killed or inactivated vaccines may be administered; however, the response to such vaccines cannot be predicted. Other immunization procedures should be undertaken with caution in patients who are receiving Acthar Gel, especially when high doses are administered, because of the possible hazards of neurological complications and lack of antibody response.

Masking Symptoms of Other Diseases: Acthar Gel often acts by masking symptoms of other diseases/disorders without altering the course of the other disease/disorder. Patients should be monitored carefully during and for a period following discontinuation of therapy for signs of infection, abnormal cardiac function, hypertension, hyperglycemia, change in body weight and fecal blood loss.

Gastrointestinal Perforation and Bleeding: Acthar Gel can cause GI bleeding and gastric ulcer. There is also an increased risk for perforation in patients with certain gastrointestinal disorders. Signs of gastrointestinal perforation, such as peritoneal irritation, may be masked by the therapy. Use caution where there is the possibility of impending perforation, abscess or other pyogenic infections, diverticulitis, fresh intestinal anastomoses, and active or latent peptic ulcer.

Behavioral and Mood Disturbances: Use of Acthar Gel may be associated with central nervous system effects ranging from euphoria, insomnia, irritability (especially in infants), mood swings, personality changes, and severe depression, to frank psychotic manifestations. Also, existing emotional instability or psychotic tendencies may be aggravated. These effects are reversible once Acthar Gel therapy is stopped.

Comorbid Diseases: Patients with a comorbid disease may have that disease worsened. Caution should be used when prescribing Acthar Gel in patients with diabetes and myasthenia gravis.

Ophthalmic Effects: Prolonged use of Acthar Gel may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves and may enhance the establishment of secondary ocular infections due to fungi and viruses.

Immunogenicity Potential: Acthar Gel is immunogenic. Limited available data suggest that a patient may develop antibodies to Acthar Gel after chronic administration and loss of endogenous ACTH and Acthar Gel activity. Prolonged administration of Acthar Gel may increase the risk of hypersensitivity reactions. Cases of anaphylaxis have been reported in the postmarketing setting. Use in patients with sensitivity to porcine protein is contraindicated, and the possibility of sensitivity should be considered during the course of treatment should symptoms arise.

Use in Patients with Hypothyroidism or Liver Cirrhosis:There is an enhanced effect in patients with hypothyroidism and in those with cirrhosis of the liver.

Negative Effects on Growth and Physical Development:Long-term use of Acthar Gel may have negative effects on growth and physical development in pediatric patients. Changes in appetite are seen with Acthar Gel therapy, with the effects becoming more frequent as the dose or treatment period increases. These effects are reversible once Acthar Gel therapy is stopped. Growth and physical development of pediatric patients on prolonged therapy should be carefully monitored.

Decrease in Bone Density: Decrease in bone formation and an increase in bone resorption both through an effect on calcium regulation (i.e., decreasing absorption and increasing excretion) and inhibition of osteoblast function may occur. These, together with a decrease in the protein matrix of the bone (secondary to an increase in protein catabolism) and reduced sex hormone production, may lead to inhibition of bone growth in children and adolescents and to the development of osteoporosis at any age. Special consideration should be given to patients at increased risk of osteoporosis (i.e., postmenopausal women) before initiating therapy, and bone density should be monitored in patients on long term therapy.

Adverse reactions

The following adverse reactions have been identified during post approval use of Acthar Gel.

Because adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Allergic Reactions: Allergic responses have presented as dizziness, nausea, and anaphylaxis (anaphylactic shock, hypotension, respiratory compromise, urticaria, edema).

Cardiovascular: Necrotizing angitis (adults only), congestive heart failure, atrial fibrillation, and palpitations.

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Dermatologic: Skin thinning (adults only), facial erythema, and increased sweating (adults only).

Endocrine: Decreased carbohydrate tolerance (infants only), hirsutism, and menstrual irregularities.

Gastrointestinal: Pancreatitis (adults only), abdominal distention, and ulcerative esophagitis.

General Disorders and Administration Site Conditions: Injection site reaction and asthenic conditions (including fatigue, malaise, asthenia, and lethargy).

Infections and Infestations: Abscess.

Investigations: Blood glucose increased.

Metabolic: Hypokalemic alkalosis (infants only) and fluid retention (including peripheral swelling).

Musculoskeletal: Muscle weakness and vertebral compression fractures (infants only).

Neurological: Headache (adults only), vertigo (adults only), subdural hematoma, intracranial hemorrhage (adults only), and reversible brain shrinkage (usually secondary to hypertension) (infants only).

Psychiatric Disorders: Insomnia.

DRUG INTERACTIONS

Formal drug-drug interaction studies have not been performed.

Acthar Gel may accentuate the electrolyte loss associated with diuretic therapy.

Use in specific populations

Pregnancy: Based on Acthar Gel’s pharmacological effect of stimulating an endogenous steroid response, Acthar Gel may cause fetal harm when administered to a pregnant woman. The published literature on systemic corticosteroid use during pregnancy, which may be relevant, suggests potential concerns. Intrauterine growth restriction, decreased birth weight, and preterm birth have been reported with maternal use of corticosteroids; however, the underlying maternal condition may also contribute to these risks. Hypoadrenalism has also been reported in infants after high-dose and/or long-term use of corticosteroids during pregnancy.

Fetal-Neonatal Adverse Reactions:Hypoadrenalism has been reported in infants born to mothers treated with systemic corticosteroids during pregnancy. Infants born to mothers treated with Acthar Gel should be carefully observed for signs of hypoadrenalism, such as poor feeding, irritability, weakness, and vomiting, and managed accordingly.

Lactation: There are no available data on the presence of corticotropin in either human or animal milk, the effects on the breastfed infant, or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Acthar Gel and any potential adverse effects on the breastfed infant from Acthar Gel or from the underlying maternal condition.

Pediatric Use: Acthar Gel is indicated as monotherapy for the treatment of infantile spasms in infants and children less than 2 years of age. Both serious and other adverse reactions can occur in this population

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