Interferon Gamma-1b

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 )

Injection: 100 mcg (2 million International Units) per 0.5 mL solution in a single-dose vial. ACTIMMUNE (interferon gamma-1b) is a sterile, clear, colorless solution filled in a single-dose vial for subcutaneous injection. Injection : 100 mcg (2 million International Units) of Interferon gamma-1b in 0.5 mL solution in a single dose vial. ( 3 )

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 )

Cardiovascular Disorders : Pre-existing cardiac conditions may be exacerbated. ( 5.1 ) Neurologic Disorders : Reduce dose or discontinue if decreased mental status, gait disturbance, dizziness occur. ( 5.2 ) Bone Marrow Toxicity : Monitor for neutropenia and thrombocytopenia particularly when administering ACTIMMUNE in combination with other potentially myelosuppressive agents. ( 5.3 ) Hepatic Toxicity : Reduce dose or discontinue to reverse severe elevations of aspartate transaminase (AST) and/or alanine transaminase (ALT); monitor liver function monthly in patients less than 1 year old. ( 5.4 ) Hypersensitivity Reactions: If serious hypersensitivity reactions occur, discontinue and institute appropriate medical therapy. ( 5.5 ) Renal Toxicity : Monitor renal function regularly when administering ACTIMMUNE to patients with severe renal insufficiency ( 5.6 )

5.1 Cardiovascular Disorders Acute and transient "flu-like" symptoms such as fever and chills induced by ACTIMMUNE at doses of 250 mcg/m 2 /day (greater than 10 times the weekly recommended dose) or higher may exacerbate pre-existing cardiac conditions. Patients with pre-existing cardiac conditions, including ischemia, congestive heart failure or arrhythmia on ACTIMMUNE should be monitored for signs/symptoms of exacerbation. Some of the "flu-like" symptoms may be minimized by bedtime administration of ACTIMMUNE. Acetaminophen may also be used to ameliorate these effects.

5.2 Neurologic Disorders Decreased mental status, gait disturbance and dizziness have been observed, particularly in patients receiving ACTIMMUNE doses greater than 250 mcg/m 2 /day (greater than 10 times the weekly recommended dose). Most of these abnormalities were reversible within a few days upon dose reduction or discontinuation of therapy. Monitor patients when administering ACTIMMUNE to patients with seizure disorders or compromised central nervous system function.

5.3 Bone Marrow Toxicity Reversible neutropenia and thrombocytopenia that can be severe and may be dose related have been observed during ACTIMMUNE therapy. Monitor neutrophil and platelet counts in patients with myelosuppression during treatment with ACTIMMUNE.

5.4 Hepatic Toxicity Repeated administration of ACTIMMUNE to patients with advanced hepatic disease may result in accumulation of interferon gamma-1b. Frequent assessment of liver function in these patients is recommended. Elevations of aspartate transaminase (AST) and/or alanine transaminase (ALT) (up to 25-fold) have been observed during ACTIMMUNE therapy. The incidence appeared to be higher in patients less than 1 year of age compared to older children. The transaminase elevations were reversible with reduction in dosage or interruption of ACTIMMUNE treatment. Patients begun on ACTIMMUNE before age one year should receive monthly assessments of liver function. If severe hepatic enzyme elevations develop, ACTIMMUNE dosage should be modified [see Dosage and Administration (2.3) ] .

5.5 Hypersensitivity Reactions Isolated cases of acute serious hypersensitivity reactions have been observed in patients receiving ACTIMMUNE. If such an acute reaction develops the drug should be discontinued immediately and appropriate medical therapy instituted. Transient cutaneous rashes have occurred in some patients following injection of ACTIMMUNE that have necessitated treatment interruption.

5.6 Renal Toxicity Monitor renal function regularly when administering ACTIMMUNE in patients with severe renal insufficiency because the possibility exists that with repeated administration, accumulation of interferon gamma-1b may occur. Renal toxicity has been reported in patients receiving ACTIMMUNE.

5.7 Allergic Reactions to Natural Rubber The stopper of the glass vial for ACTIMMUNE contains natural rubber (a derivative of latex) which may cause allergic reactions.

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.

Based on animal data, may cause fetal harm. ( 8.1 )

8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies in pregnant women. ACTIMMUNE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal Data ACTIMMUNE has shown an increased incidence of abortions in primates when given from gestation day 20 to 80 in doses approximately 100 times the human dose. A study in pregnant primates treated with subcutaneous doses 2 – 100 times the human dose failed to demonstrate teratogenic activity for ACTIMMUNE. Female mice treated subcutaneously with recombinant murine IFN-interferon gamma (rmuIFN-gamma) at 280 times the maximum recommended clinical dose of ACTIMMUNE from shortly after birth through puberty but not during pregnancy had offspring which exhibited decreased body weight during the lactation period. The clinical significance of this finding observed following treatment of mice with rmuIFN-gamma is uncertain. For lower doses, there is no evidence of maternal toxicity, embryotoxicity, fetotoxicity or teratogenicity in preclinical studies.

8.2 Lactation Risk Summary It is not known whether ACTIMMUNE is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ACTIMMUNE, a decision should be made whether to discontinue nursing or to discontinue the drug, dependent upon the importance of the drug to the mother.

8.3 Females and Males of Reproductive Potential Infertility Based on the information available, it cannot be excluded that the presence of higher levels of interferon gamma may impair male fertility and that in certain cases of female infertility increased levels of interferon gamma may have played a role [ see Nonclinical Toxicology (13.1) ]. In younger patients, the long-term effect on fertility is also not known.

8.4 Pediatric Use The safety and effectiveness of ACTIMMUNE has been established in pediatric patients aged 1 year and older in CGD patients and 1 month and older in SMO patients [see Clinical Studies (14) ]. There are no data available for pediatric patients below the age of 1 month.

8.5 Geriatric Use Clinical studies of ACTIMMUNE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Interferons bind to specific cell surface receptors and initiate a sequence of intracellular events that lead to the transcription of interferon-stimulated genes. The three major groups of interferons (alpha, beta, gamma) have partially overlapping biological activities that include immunoregulation such as increased resistance to microbial pathogens and inhibition of cell proliferation. Type 1 interferons (alpha and beta) bind to the alpha/ beta receptor. Interferon gamma binds to a different cell surface receptor and is classified as Type 2 interferon. Specific effects of interferon gamma include the enhancement of the oxidative metabolism of macrophages, antibody dependent cellular cytotoxicity (ADCC), activation of natural killer (NK) cells, and the expression of Fc receptors and major histocompatibility antigens. CGD is an inherited disorder of leukocyte function caused by defects in the enzyme complex responsible for phagocyte superoxide generation. ACTIMMUNE does not increase phagocyte superoxide production even in treatment responders. In SMO (an inherited disorder characterized by an osteoclast defect, leading to bone overgrowth, and by deficient phagocyte oxidative metabolism), a treatment-related enhancement of superoxide production by phagocytes was observed. ACTIMMUNE was found to enhance osteoclast function in vivo. In both disorders, the exact mechanism(s) by which ACTIMMUNE has a treatment effect has not been established. Changes in superoxide levels during ACTIMMUNE therapy do not predict efficacy and should not be used to assess patient response to therapy.