ACTIMMUNE

ACTIMMUNE (Interferon gamma-1b), an interferon gamma, is a single-chain polypeptide containing 140 amino acids. Production of ACTIMMUNE is achieved by fermentation of a genetically engineered Escherichia coli bacterium containing the DNA which encodes for the recombinant protein. Purification of the product is achieved by conventional column chromatography. ACTIMMUNE is a highly purified sterile solution consisting of non-covalent dimers of two identical 16,465 Dalton monomers; with a specific activity of 20 million International Units/mg (2 × 10 6 International Units/0.5 mL) which is equivalent to 30 million units/mg. ACTIMMUNE is a sterile, clear, colorless solution filled in a single-dose vial for subcutaneous injection. Each 0.5 mL of ACTIMMUNE contains: 100 mcg (2 million International Units) of interferon gamma-1b formulated in disodium succinate hexahydrate (0.37 mg), mannitol (20 mg), polysorbate 20 (0.05 mg), succinic acid (0.14 mg) and Sterile Water for Injection. Note that the above activity is expressed in International Units (1 million International Units/50 mcg). This is equivalent to what was previously expressed as units (1.5 million units/50 mcg).

ACTIMMUNE is indicated for reducing the frequency and severity of serious infections associated with Chronic Granulomatous Disease (CGD). ACTIMMUNE is indicated for delaying time to disease progression in patients with severe, malignant osteopetrosis (SMO). ACTIMMUNE is an interferon gamma indicated for: Reducing the frequency and severity of serious infections associated with Chronic Granulomatous Disease (CGD) ( 1 ) Delaying time to disease progression in patients with severe, malignant osteopetrosis (SMO) ( 1 )

For subcutaneous use only ( 2.1 ) The recommended dose is 50 mcg/m 2 for patients whose body surface area is greater than 0.5 m 2 and 1.5 mcg/kg/dose for patients whose body surface area is equal to or less than 0.5 m 2 three times weekly. ( 2.1 ) Monitor hematology, blood chemistries and urinalysis prior to the beginning of treatment and at 3-month intervals. ( 2.1 ) If severe reactions occur, reduce dose by 50 percent or discontinue therapy until the adverse reaction abates. ( 2.3 ) 2.1 Dosing Information The recommended dosage of ACTIMMUNE administered subcutaneously, for the treatment of patients with CGD and SMO is shown in Table 1 below: Table 1: Recommended Dosage for ACTIMMUNE for the Treatment of Patients with CGD and SMO Body Surface Area (m 2 ) Dose (mcg/m 2 ) Dose (International Units/m 2 ) Note that the above activity is expressed in International Units (1 million International Units/50 mcg). This is equivalent to what was previously expressed as units (1.5 million units/50 mcg). Frequency Greater than 0.5 m 2 50 mcg/m 2 1 million International Units/m 2 Three times weekly (For example, Monday, Wednesday and Friday) Equal to or less than 0.5 m 2 1.5 mcg/kg/dose ------------ Three times weekly (For example, Monday, Wednesday and Friday) Prior to the beginning of treatment and at three-month intervals during treatment the following laboratory tests are recommended for all patients on ACTIMMUNE (interferon gamma-1b) therapy [see Warnings and Precautions (5.3 , 5.4 , 5.6) ] : Hematologic tests – including complete blood counts, differential and platelet counts Blood chemistries – including renal and liver function tests. In patients less than 1 year of age, liver function tests should be measured monthly [see Adverse Reactions (6.2) ] . Urinalysis 2.2 Important Administration Instructions The optimum sites of subcutaneous injection are the right and left deltoid and anterior thigh. ACTIMMUNE can be administered by a physician, nurse, family member or patient when appropriately counseled in the administration of subcutaneous injections. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. ACTIMMUNE is a clear, colorless solution. ACTIMMUNE is for a single dose only. Discard any unused portion. ACTIMMUNE does not contain a preservative. ACTIMMUNE should not be mixed with other drugs in the same syringe. Administer ACTIMMUNE using either sterilized glass or plastic disposable syringes. 2.3 Dose Modification If severe reactions occur, the dosage should be reduced by 50 percent or therapy should be interrupted until the adverse reaction abates. Safety and efficacy has not been established for ACTIMMUNE given in doses greater or less than the recommended dose of 50 mcg/m 2 . Higher doses (i.e., greater than 50 mcg/m 2 ) are not recommended. The minimum effective dose of ACTIMMUNE has not been established.

ACTIMMUNE is contraindicated in patients who develop or have known hypersensitivity to interferon gamma, E. coli derived products, or any component of the product. Known hypersensitivity to interferon gamma, E. coli derived products, or any component of the product ( 4 )

The following adverse reactions are described below and elsewhere in the warnings and precautions section of the labeling: Cardiovascular Disorders [see Warnings and Precautions (5.1) ] Neurologic Disorders [see Warnings and Precautions (5.2) ] Bone Marrow Toxicity [see Warnings and Precautions (5.3) ] Hepatic Toxicity [see Warnings and Precautions (5.4) ] Hypersensitivity Reactions [see Warnings and Precautions (5.5) ] Renal Toxicity [see Warnings and Precautions (5.6) ] Common adverse reactions (incidence rate 2% or greater) for ACTIMMUNE include fever, headache, rash, chills, injection site erythema or tenderness, fatigue, diarrhea. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Amgen Inc.at 1 800 77 AMGEN (1 800 772 6436)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. The following data on adverse reactions are based on the subcutaneous administration of ACTIMMUNE at a dose of 50 mcg/m 2 , three times weekly, in patients with CGD during a clinical trial in the United States and Europe. The most common adverse reactions observed in patients with CGD are shown in the following table: Table 2: Adverse Reactions Occurring in 2% or Greater of CGD Patients Receiving ACTIMMUNE in Clinical Trials Adverse Reactions Percent of Patients ACTIMMUNE CGD (n=63) Placebo CGD (n=65) Fever 52 28 Headache 33 9 Rash 17 6 Chills 14 0 Injection site erythema or tenderness 14 2 Fatigue 14 11 Diarrhea 14 12 Vomiting 13 5 Nausea 10 2 Myalgia 6 0 Arthralgia 2 0 Similar safety data were observed in 34 patients with SMO. The clinical and laboratory toxicity associated with multiple dose studies of ACTIMMUNE is dose, route and schedule-dependent. The most common adverse reactions include constitutional symptoms such as fever, headache, chills, myalgia or fatigue which may decrease in severity as treatment continues. Less Common Adverse Reactions The following adverse reactions are assessed as potentially related to ACTIMMUNE (interferon gamma-1b) therapy: Blood and Lymphatic System — neutropenia (reversible), febrile neutropenia, leukopenia, and thrombocytopenia. Cardiovascular — angina pectoris, arrhythmia, atrial fibrillation, atrioventricular block, cardiac failure (including congestive cardiac failure), tachyarrhythmia, heart block, (acute) myocardial infarction, myocardial ischemia, syncope, and tachycardia. Gastrointestinal — abdominal pain, dyspepsia, gastrointestinal bleeding, granulomatous colitis, hepatic insufficiency, and pancreatitis, including pancreatitis with fatal outcome. General Disorders and Administration Site Conditions — asthenia, chest pain/discomfort, influenza-like illness/flu-like symptoms, injection site hemorrhage, injection site pain, malaise, rigors, and weakness. Hepatobiliary Disorders — hepatic insufficiency and hepatomegaly. Immunological — hypersensitivity, increased autoantibodies, lupus-like syndrome (including systemic lupus erythematosus-flares and drug-induced lupus erythematosus), and Stevens-Johnson syndrome. Infections and Infestations — upper respiratory tract infection. Investigations — blood alkaline phosphatase increased, liver function tests abnormal/elevation of hepatic enzymes, increased triglycerides, and weight decreased. Metabolic — hyponatremia, hypokalemia, hyperglycemia, and hypertriglyceridemia. Musculoskeletal — back pain, clubbing, and muscle spasms. Nervous System — dizziness (excluding vertigo), gait disturbance, headache, Parkinsonian symptoms, convulsion/seizure (including grand mal convulsions), and transient ischemic attacks. Psychiatric — confusion, depression, disorientation, hallucinations, mental status changes, and mental status decreased. Pulmonary — tachypnea, bronchospasm, pulmonary edema, and interstitial pneumonitis. Renal — acute renal failure (which may be reversible) and proteinuria. Skin and Subcutaneous Tissue Disorders — atopic dermatitis, (exacerbation of) dermatomyositis, transient cutaneous rash, and urticaria. Vascular Disorder — deep venous thrombosis, hypotension, pulmonary embolism. Abnormal Laboratory Test Values: Elevations of ALT and AST have been observed [see Warnings and Precautions (5.4) ] . 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of ACTIMMUNE. Because these 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. Children with CGD less than 3 years of age: Data on the safety and activity of ACTIMMUNE in 37 patients under the age of 3 years was pooled from four uncontrolled postmarketing studies. The rate of serious infections per patient-year in this uncontrolled group was similar to the rate observed in the ACTIMMUNE treatment groups in controlled trials. Developmental parameters (height, weight and endocrine maturation) for this uncontrolled group conformed to national normative scales before and during ACTIMMUNE therapy. In 6 of the 10 patients receiving ACTIMMUNE therapy before age one year 2-fold to 25-fold elevations from baseline of AST and/or ALT were observed. These elevations occurred as early as 7 days after starting treatment. Treatment with ACTIMMUNE was interrupted in all 6 of these patients and was restarted at a reduced dosage in 4. Liver transaminase values returned to baseline in all patients and transaminase elevation recurred in one patient upon ACTIMMUNE rechallenge. An 11-fold alkaline phosphatase elevation and hypokalemia in one patient and neutropenia (ANC = 525 cells/mm 3 ) in another patient resolved with interruption of ACTIMMUNE treatment and did not recur with rechallenge. In the postmarketing safety database clinically significant adverse reactions observed during ACTIMMUNE therapy in children under the age of three years (n=14) included: two cases of hepatomegaly, and one case each of Stevens-Johnson syndrome, granulomatous colitis, urticaria, and atopic dermatitis. 6.3 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. In clinical trials, 8 out of 33 ACTIMMUNE-treated patients developed non-neutralizing antibodies to interferon gamma-1b. No neutralizing antibodies to ACTIMMUNE have been detected in patients. In a Phase 1 study, none of the 38 ACTIMMUNE-treated healthy volunteers developed non-neutralizing antibodies to interferon gamma-1b. The detection of antibody formation, including neutralizing antibody, in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to ACTIMMUNE with the incidence of antibodies to other products may be misleading.

Concomitant use of drugs with neurotoxic, hematotoxic or cardiotoxic effects may increase the toxicity of interferons. ( 7.2 ) Avoid simultaneous administration of ACTIMMUNE with other heterologous serum protein or immunological preparations (e.g., vaccines). ( 7.3 ) 7.1 Myelosuppressive Agents When administering ACTIMMUNE in combination with other potentially myelosuppressive agents, monitor neutrophil and platelet counts [see Warnings and Precautions (5.3) ] . 7.2 Drugs with Neurotoxic, Hematoxic or Cardiotoxic Effects The concurrent use of drugs having neurotoxic (including effects on the central nervous system), hematotoxic, or cardiotoxic effects may increase the toxicity of interferons in these systems. It is theoretically possible that hepatotoxic and/or nephrotoxic drugs might have an effect on the clearance of ACTIMMUNE. 7.3 Immunological Preparations Simultaneous administration of ACTIMMUNE with other heterologous serum protein preparations or immunological preparations (e.g., vaccines) should be avoided due to the risk of an unexpected, or amplified, immune response. 7.4 Effects on Cytochrome P-450 Pathways Preclinical studies in rodents using species-specific interferon gamma have demonstrated a decrease in hepatic microsomal cytochrome P-450 concentrations. This could potentially lead to a depression of the hepatic metabolism of certain drugs that utilize this degradative pathway.

16.2 Storage and Handling Store vials in the refrigerator at 2 to 8 °C (36 °F – 46 °F). Do Not Freeze. Avoid excessive or vigorous agitation. Do Not Shake . An unused vial of ACTIMMUNE can be stored at room temperature up to 12 hours prior to use. Discard vials if not used within the 12 hour period. Do not return to the refrigerator.