corticotropin 80 UNT/ML Injectable Solution [Acthar]

INDICATIONS AND USAGE Acthar Gel is indicated as monotherapy for the treatment of infantile spasms in infants and children under 2 years of age. ( 1.1 ) Acthar Gel is indicated for the treatment of exacerbations of multiple sclerosis in adults. ( 1.2 ) Acthar Gel may be used for the following disorders and diseases: rheumatic ( 1.3 ); collagen ( 1.4 ); dermatologic ( 1.5 ); allergic states ( 1.6 ); ophthalmic ( 1.7 ); respiratory ( 1.8 ); and edematous state. ( 1.9 ) 1.1 Infantile Spasms Acthar Gel is indicated as monotherapy for the treatment of infantile spasms in infants and children under 2 years of age. 1.2 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. 1.3 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. 1.4 Collagen Diseases During an exacerbation or as maintenance therapy in selected cases of: systemic lupus erythematosus, systemic dermatomyositis (polymyositis). 1.5 Dermatologic Diseases Severe erythema multiforme, Stevens-Johnson syndrome. 1.6 Allergic States Serum sickness. 1.7 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. 1.8 Respiratory Diseases Symptomatic sarcoidosis. 1.9 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.

DOSAGE AND ADMINISTRATION Acthar Gel vial is for either intramuscular or subcutaneous injection. ( 2.1 ) Acthar Gel single-dose pre-filled SelfJect injector: is for subcutaneous administration by adults only. ( 2.1 ) used to administer single doses of 40 units or 80 units only. ( 2.1 ) Infantile spasms: doses must be administered intramuscularly using the Acthar gel vial. The recommended dose is 150 U/m 2 divided into twice daily injections of 75 U/m 2 . After 2 weeks of treatment dosing should be gradually tapered and discontinued over a 2-week period. Acthar Gel single-dose pre-filled SelfJect injector is not to be used for the treatment of infantile spasms ( 2.2 ) Acute exacerbations of multiple sclerosis: daily intramuscular or subcutaneous doses of 80 to 120 units for 2-3 weeks may be administered. It may be necessary to taper the dose. ( 2.3 ) Other disorders and diseases: individualize dosing depending on the disease and patient. The usual dose is 40 to 80 units given intramuscularly or subcutaneously every 24 to 72 hours. It may be necessary to taper the dose. ( 2.4 ) 2.1 Important Information Acthar Gel vial is intended for either intramuscular or subcutaneous injection. Acthar Gel single-dose pre-filled SelfJect injector is for subcutaneous administration by adults (18 years of age and older) only. The single-dose pre-filled SelfJect injector should only be used to administer single doses of either 40 units or 80 units. For administration of doses other than 40 units or 80 units, use the Acthar Gel multi-dose vial. 2.2 Recommended Dosage for Infantile Spasms in Infants and Children Under 2 Years of Age In the treatment of infantile spasms, Acthar Gel must be administered intramuscularly using the Acthar gel vial. Do not use the Acthar Gel single-dose pre-filled SelfJect injector for the treatment of infantile spasms. The recommended regimen is a daily dose of 150 U/m 2 (divided into twice daily intramuscular (IM) injections of 75 U/m 2 ) 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/m 2 in the morning for 3 days; 15 U/m 2 in the morning for 3 days; 10 U/m 2 in the morning for 3 days; and 10 U/m 2 every other morning for 6 days. Acthar Gel is typically dosed based on body surface area (BSA). For calculation of body surface area, use the following formula: Equation Formula 2.3 Recommended Dosage for the Treatment of Acute Exacerbations in Adults with Multiple Sclerosis The recommended dose is daily intramuscular or subcutaneous doses of 80 to 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. 2.4 Recommended Dosage 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 to 80 units given intramuscularly or subcutaneously every 24 to 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. 2.5 Preparation and Administration Visually inspect the liquid for particulate matter and discoloration prior to administration. Acthar Gel must not be injected if the solution is cloudy or contains particulate matter. Acthar Gel Multi-Dose Vial Warm to room temperature before using. Take caution to not over-pressurize the vial prior to withdrawing the product. Acthar Gel Single-Dose Pre-filled SelfJect Injector Preparation Prior to injection, remove from the refrigerator and sealed tray and allow to sit for 45 minutes to warm to room temperature. Administration Read the FDA-approved Instructions for Use carefully before administering. Administer by subcutaneous injection only. Acthar Gel single-dose pre-filled SelfJect injector is not for intramuscular injection. Inject in the upper thigh, abdomen, or back of arm. Avoid injecting within 1 inch of navel, knee, or groin area. Avoid areas with scars, tattoos, warts, birthmarks, or stretch marks, or where the skin is irritated. Rotate injection sites. Do not use the same site more than one time per week.

WARNINGS AND PRECAUTIONS The adverse effects of Acthar Gel are related primarily to its steroidogenic effects. Not all of the adverse events described below have been seen after treatment with Acthar Gel, but they might be expected to occur because they are steroidogenic effects [see Adverse Reactions (6.3) ] . Infections: Increased susceptibility to new infection and increased risk of exacerbation, dissemination or reactivation of latent infections. Signs and symptoms of infection may be masked. ( 5.1 ) Adrenal Insufficiency after Prolonged Therapy: Monitor for effects of hypothalamic-pituitary-adrenal axis suppression after stopping treatment. ( 5.2 ) Cushing's Syndrome: May occur after prolonged therapy. Monitor for signs and symptoms. ( 5.2 ) Elevated Blood Pressure, Salt and Water Retention, and Hypokalemia: Monitor blood pressure and sodium and potassium levels. ( 5.3 ) Masking of Symptoms of Other Underlying Disease/Disorders: Monitor patients for signs of other underlying disease/disorders that may be masked. ( 5.5 ) Gastrointestinal Perforation and Bleeding: There is a risk for gastric ulcers and bleeding. There is an increased risk of perforation in patients with certain GI disorders. Signs and symptoms may be masked. Monitor for signs of perforation and bleeding. ( 5.6 ) Behavioral and Mood Disturbances: May include euphoria, insomnia, mood swings, personality changes, severe depression and psychosis. Existing conditions may be aggravated. ( 5.7 ) Comorbid Diseases: Symptoms of diabetes and myasthenia gravis may be worsened with treatment. ( 5.8 ) Ophthalmic Effects: Monitor for cataracts, infections and glaucoma. ( 5.9 ) Immunogenicity Potential: Neutralizing antibodies with chronic administration may lead to a loss of endogenous ACTH activity. ( 5.10 ) Use in Patients with Hypothyroidism or Liver Cirrhosis: May result in an enhanced effect. ( 5.11 ) Negative Effects on Growth and Physical Development: Monitor pediatric patients on long term therapy. ( 5.12 ) Decrease in Bone Density: Monitor for osteoporosis in patients on long term therapy. ( 5.13 ) 5.1 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. 5.2 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. The symptoms of adrenal insufficiency in infants treated for infantile spasms can be difficult to identify. The symptoms are non-specific and may include anorexia, fatigue, lethargy, weakness, excessive weight loss, hypotension and abdominal pain. It is critical that parents and caregivers be made aware of the possibility of adrenal insufficiency when discontinuing Acthar Gel and should be instructed to observe for, and be able to recognize, these symptoms [see Patient Counseling Information (17) ] . The recovery of the adrenal gland may take from days to months so patients should be protected from the stress (e.g., trauma or surgery) by the use of corticosteroids during the period of stress. The adrenal insufficiency may be minimized by tapering of the dose when discontinuing treatment. Signs or symptoms of Cushing's syndrome may occur during therapy but generally resolve after therapy is stopped. Patients should be monitored for these signs and symptoms such as deposition of adipose tissue in characteristics sites (e.g., moon face, truncal obesity), cutaneous striae, easy bruisability, decreased bone mineralization, weight gain, muscle weakness, hyperglycemia, and hypertension. 5.3 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 or renal insufficiency. Acthar Gel is contraindicated in patients with congestive heart failure [see Contraindications (4) ] . 5.4 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 can not 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. 5.5 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. 5.6 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. 5.7 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. 5.8 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. 5.9 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. 5.10 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. 5.11 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. 5.12 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 th

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. Acthar Gel is contraindicated: for intravenous administration ( 4 ) in infants under 2 years of age who have suspected congenital infections ( 4 ) with concomitant administration of live or live attenuated vaccines in patients receiving immunosuppressive doses of Acthar Gel ( 4 ) 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 ( 4 )

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.