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:

• 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/m2. Higher doses (i.e., greater than 50 mcg/m2) are not recommended. The minimum effective dose of ACTIMMUNE has not been established.

5.1 Cardiovascular Disorders

Acute and transient "flu-like" symptoms such as fever and chills induced by ACTIMMUNE at doses of 250 mcg/m2/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/m2/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.

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/m2, 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:

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.

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.

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.

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.

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

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.

12.1 Mechanism of Action

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.

12.3 Pharmacokinetics

Pharmacokinetic studies in patients with CGD have not been performed. The intravenous, intramuscular, and subcutaneous pharmacokinetics of ACTIMMUNE have been investigated in 24 healthy male subjects following single-dose administration of 100 mcg/m2 (twice the recommended dose for CGD and SMO patients). ACTIMMUNE is rapidly cleared after intravenous administration (1.4 Liters/minute) and slowly absorbed after intramuscular or subcutaneous injection. After intramuscular or subcutaneous injection, the apparent fraction of dose absorbed was greater than 89%. The mean elimination half-life after intravenous administration of 100 mcg/m2 in healthy male subjects was 38 minutes. The mean elimination half-lives for intramuscular and subcutaneous dosing with 100 mcg/m2 were 2.9 and 5.9 hours, respectively. Peak plasma concentrations, determined by ELISA, occurred approximately 4 hours (1.5 ng/mL) after intramuscular dosing and 7 hours (0.6 ng/mL) after subcutaneous dosing. Multiple dose subcutaneous pharmacokinetic studies were conducted in 38 healthy male subjects. There was no accumulation of ACTIMMUNE after 12 consecutive daily injections of 100 mcg/m2.

Interferon gamma was not detected in the urine of healthy human volunteers following administration of 100 mcg/m2 of ACTIMMUNE by the intravenous, intramuscular and subcutaneous routes. In vitro perfusion studies utilizing rabbit livers and kidneys demonstrate that these organs are capable of clearing interferon gamma from perfusate.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14.1 Effects in Chronic Granulomatous Disease (CGD)

A randomized, double-blind, placebo-controlled trial of ACTIMMUNE (interferon gamma-1b) in patients with CGD, was performed to determine whether ACTIMMUNE administered subcutaneously on a three times weekly schedule could decrease the incidence of serious infectious episodes and improve existing infectious and inflammatory conditions in patients with CGD. One hundred twenty-eight eligible patients were enrolled in this trial including patients with different patterns of inheritance. Most patients received prophylactic antibiotics. Patients ranged in age from 1 to 44 years with the mean age being 14.6 years. The study was terminated early following demonstration of a highly statistically significant benefit of ACTIMMUNE therapy compared to placebo with respect to time to serious infection (p=0.0036), the primary endpoint of the investigation. Serious infection was defined as a clinical event requiring hospitalization and the use of parenteral antibiotics. The final analysis provided further support for the primary endpoint (p=0.0006). There was a 67 percent reduction in relative risk of serious infection in patients receiving ACTIMMUNE (n=63) compared to placebo (n=65). Additional supportive evidence of treatment benefit included a twofold reduction in the number of primary serious infections in the ACTIMMUNE group (30 on placebo versus 14 on ACTIMMUNE, p=0.002) and the total number and rate of serious infections including recurrent events (56 on placebo versus 20 on ACTIMMUNE, p=<0.0001). Moreover, the length of hospitalization for the treatment of all clinical events provided evidence highly supportive of an ACTIMMUNE treatment benefit. Placebo patients required three times as many inpatient hospitalization days for treatment of clinical events compared to patients receiving ACTIMMUNE (1493 versus 497 total days, p=0.02). An ACTIMMUNE treatment benefit with respect to time to serious infection was consistently demonstrated in all subgroup analyses according to stratification factors, including pattern of inheritance, use of prophylactic antibiotics, as well as age. There was a 67 percent reduction in relative risk of serious infection in patients receiving ACTIMMUNE compared to placebo across all groups. The beneficial effect of ACTIMMUNE therapy was observed throughout the entire study, in which the mean duration of ACTIMMUNE administration was 8.9 months/patient.

14.2 Effects in Severe, Malignant Osteopetrosis (SMO)

A controlled, randomized trial in patients with SMO was conducted with ACTIMMUNE administered subcutaneously three times weekly. Sixteen patients were randomized to receive either ACTIMMUNE plus calcitriol (n=11), or calcitriol alone (n=5). Patients ranged in age from 1 month to 8 years, mean 1.5 years. Treatment failure was considered to be disease progression as defined by 1) death, 2) significant reduction in hemoglobin or platelet counts, 3) a serious bacterial infection requiring antibiotics, or 4) a 50 dB decrease in hearing or progressive optic atrophy. The median time to disease progression was significantly delayed in the ACTIMMUNE plus calcitriol arm versus calcitriol alone. In the treatment arm, the median was not reached. Based on the observed data, however, the median time to progression in this arm was at least 165 days versus a median of 65 days in the calcitriol alone arm. In an analysis which combined data from a second study, 19 of 24 patients treated with ACTIMMUNE plus or minus calcitriol for at least 6 months had reduced trabecular bone volume compared to baseline.

16.1 How Supplied

ACTIMMUNE (interferon gamma-1b) is a sterile, clear, colorless solution filled in a single-dose vial for subcutaneous injection. Each vial permits the extraction of up to 0.5 mL of ACTIMMUNE with additional volume to facilitate solution withdrawal. Each 0.5 mL of ACTIMMUNE contains: 100 mcg (2 million International Units) of interferon gamma-1b.

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.