ACTHAR

6 ADVERSE REACTIONS 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.

7 DRUG INTERACTIONS 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 )