ACTHAR

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.

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.

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.

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 )

The following clinically significant adverse reactions are described elsewhere in the labeling: Infections [see Warnings and Precautions (5.1) ] Cushing's Syndrome and Adrenal Insufficiency Upon Withdrawal [see Warnings and Precautions (5.2) ] Elevated Blood Pressure, Salt and Water Retention, and Hypokalemia [see Warnings and Precautions (5.3) ] Masking Symptoms of Other Diseases [see Warnings and Precautions (5.5) ] Gastrointestinal Perforation and Bleeding [see Warnings and Precautions (5.6) ] Behavioral and Mood Disturbances [see Warnings and Precautions (5.7) ] Ophthalmic Effects [see Warnings and Precautions (5.9) ] Immunogenicity Potential [see Warnings and Precautions (5.10) ] Negative Effects on Growth and Physical Development [see Warnings and Precautions (5.12) ] Decrease in Bone Density [see Warnings and Precautions (5.13) ] Commonly reported postmarketing adverse reactions for Acthar Gel include injection site reaction, asthenic conditions (including fatigue, malaise, asthenia and lethargy), fluid retention (including peripheral swelling), insomnia, headache, and blood glucose increased. ( 6.2 ) The most common adverse reactions (5% or greater in the recommended twice daily dosing group) for the treatment of infantile spasms are increased risk of infections, convulsions, hypertension, irritability, and pyrexia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mallinckrodt at 1-800-844-2830 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in Infants and Children Under 2 Years of Age While the types of adverse reactions seen in infants and children under age 2 treated for infantile spasms are similar to those seen in older patients, their frequency and severity may be different due to the very young age of the infant, the underlying disorder, the duration of therapy and the dosage regimen. Below is a summary of adverse reactions specifically tabulated from source data derived from retrospective chart reviews and clinical trials in children under 2 years of age treated for infantile spasms. The number of patients in controlled trials at the recommended dose was too few to provide meaningful incidence rates or to permit a meaningful comparison to the control groups. The most common adverse reactions (5% or greater in the recommended twice daily dosing group) for the treatment of infantile spasms are increased risk of infections, convulsions, hypertension, irritability, and pyrexia. TABLE: Incidence (%) of Adverse Reactions Occurring in ≥2% of Infants and Children Under 2 Years of Age Treated with Acthar Gel Adverse Reactions Recommended 75 U/m 2 twice daily n=122, (%) 150 U/m 2 once daily n=37 (%) Cardiac disorders Cardiac Hypertrophy 3 0 Endocrine disorders Cushingoid 3 22 Gastrointestinal disorders Diarrhea 3 14 Vomiting 3 5 Constipation 0 5 General disorders and administration site conditions Irritability 7 19 Pyrexia 5 8 Infections and infestations Infection Specific infections that occurred at ≥2% were candidiasis, otitis media, pneumonia and upper respiratory tract infections. 20 46 Investigations Weight gain 1 3 Metabolism and nutrition disorders Increased appetite 0 5 Decreased appetite 3 3 Nervous system disorders Convulsion In the treatment of infantile spasms, other types of seizures/convulsions may occur because some patients with infantile spasms progress to other forms of seizures (for example, Lennox-Gastaut Syndrome). Additionally, the spasms sometimes mask other seizures and once the spasms resolve after treatment, the other seizures may become visible. 12 3 Respiratory, thoracic and mediastinal disorders Nasal Congestion 1 5 Skin and subcutaneous tissue disorders Acne 0 14 Rash 0 8 Vascular disorders Hypertension 11 19 These adverse reactions may also be seen in adults and children over 2 years of age when treated for other purposes and with different doses and regimens. 6.2 Postmarketing Experience 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. 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. 6.3 Possible Additional Steroidogenic Effects Based on steroidogenic effects of Acthar Gel certain adverse events may be expected due to the pharmacological effects of corticosteroids. The adverse events that may occur but have not been reported for Acthar Gel are: Dermatologic Impaired wound healing, petechiae and ecchymoses, and suppression of skin test reactions. Metabolic Negative nitrogen balance due to protein catabolism and alteration in glucose tolerance. Musculoskeletal Loss of muscle mass and aseptic necrosis of femoral and humeral heads. Neurological Increased intracranial pressure with papilledema, (pseudo-tumor cerebri) usually after treatment, and subdural effusion. Ophthalmic Exophthalmos.

Formal drug-drug interaction studies have not been performed. Acthar Gel may accentuate the electrolyte loss associated with diuretic therapy. Acthar Gel may accentuate electrolyte loss associated with diuretics. ( 7 )

16.2 Storage and Handling Store Acthar Gel vial and Acthar Gel single-dose pre-filled SelfJect injector under refrigeration between 2°C to 8°C (36°F to 46°F) in the carton to protect from light. After removing the single-dose pre-filled SelfJect injector from the refrigerator, it can be stored at room temperature between 20°C to 25°C (68°F to 77°F) for up to 24 hours. Do not heat, freeze, or put the Acthar Gel single-dose pre-filled SelfJect injector into direct sunlight. Dispense single-dose pre-filled SelfJect injectors in the original sealed carton with the enclosed Instructions for Use.