ACTIMMUNE® (Interferon gamma-1b), a biologic response modifier, 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 human 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 (IU)/mg (2 × 10 6 IU per0.5 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 IU) of Interferon gamma-1b formulated in 20 mg mannitol, 0.36 mg sodium succinate, 0.05 mg polysorbate 20 and Sterile Water for Injection. Note that the above activity is expressed in International Units (1 million IU/50mcg). This is equivalent to what was previously expressed as units (1.5 million U/50mcg).


Interferons are a family of functionally related, species-specific, proteins synthesized by eukaryotic cells in response to viruses and a variety of natural and synthetic stimuli. The most striking differences between interferon-gamma and other classes of interferon concern the immunomodulatory properties of this molecule. While gamma, alpha and beta interferons share certain properties, interferon-gamma has potent phagocyte-activating effects not seen with other interferon preparations. These effects include the generation of toxic oxygen metabolites within phagocytes in vitro, which are capable of mediating the intracellular killing of selected microorganisms such as Staphylococcus aureus, Toxoplasma gondii, Leishmania donovani, Listeria monocytogenes, and Mycobacterium avium intracellulare.

Clinical studies in patients using interferon-gamma, have revealed a broad range of biological activities including the enhancement of the oxidative metabolism of tissue macrophages, enhancement of antibody-dependent cellular cytotoxicity (ADCC) and natural killer (NK) cell activity. Additionally, effects on Fc receptor expression on monocytes and major histocompatibility antigen expression have been noted. 1,2

To the extent that interferon-gamma is produced by antigen-stimulated T lymphocytes and regulates the activity of immune cells, it is appropriate to characterize interferon-gamma as a lymphokine of the interleukin type. There is growing evidence that interferon-gamma interacts functionally with other interleukin molecules such as interleukin-2 and that all of the interleukins form part of a complex, lymphokine regulatory network. 3 For example, interferon-gamma and interleukin-4 appear to reciprocally interact to regulate murine IgE levels; interferon-gamma can suppress IgE levels in humans. 4,5 Interferon-gamma also inhibits the production of collagen at the transcription level in human systems. 6

With respect to Chronic Granulomatous Disease (an inherited disorder characterized by deficient phagocyte oxidative metabolism), pilot clinical trials of the systemic administration of ACTIMMUNE® in patients with Chronic Granulomatous Disease provided evidence for a treatment-related enhancement of phagocyte function including elevation of superoxide levels and improved killing of Staphylococcus aureus. 7,8

In severe, malignant osteopetrosis (another inherited disorder characterized by an osteoclast defect leading to bone overgrowth and deficient phagocyte oxidative metabolism), 9 a treatment-related enhancement of superoxide production by phagocytes was observed in situ. 10 ACTIMMUNE was found to enhance osteoclast function in vitro. 11,12

The intravenous, intramuscular, and subcutaneous pharmacokinetics of ACTIMMUNE® have been investigated in 24 healthy male subjects following single-dose administration of 100 mcg/m 2 . 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 of100 mcg/m 2 in healthy male subjects was 38 minutes. The mean elimination half-lives for intramuscular and subcutaneous dosing with 100 mcg/m 2 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/m 2 . Pharmacokinetic studies in patients with Chronic Granulomatous Disease have not been performed.

Trace amounts of interferon-gamma were detected in the urine of squirrel monkeys following intravenous administration of 500 mcg/kg. Interferon-gamma was not detected in the urine of healthy human volunteers following administration of 100 mcg/m 2 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. Studies of the administration of interferon-gamma to nephrectomized mice and squirrel monkeys demonstrate a reduction in clearance of interferon-gamma from blood; however, prior nephrectomy did not prevent elimination.

Effects in Chronic Granulomatous Disease

A randomized, double-blind, placebo-controlled study ofACTIMMUNE® (Interferon gamma-1b) in patients with Chronic Granulomatous Disease (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 Chronic Granulomatous Disease. One hundred twenty-eight eligible patients were enrolled on this study 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 receivingACTIMMUNE (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 anACTIMMUNE 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). AnACTIMMUNE 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.

Effects in Osteopetrosis

A controlled, randomized study in patients with severe, malignant osteopetrosis 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.

ACTIMMUNE is indicated for reducing the frequency and severity of serious infections associated with Chronic Granulomatous Disease.

ACTIMMUNE is indicated for delaying time to disease progression in patients with severe, malignant osteopetrosis.


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

ACTIMMUNE should be used with caution in patients with pre-existing cardiac disease, including symptoms of ischemia, congestive heart failure or arrhythmia. No direct cardiotoxic effect has been demonstrated but it is possible that acute and transient "flu-like" or constitutional symptoms such as fever and chills frequently associated withACTIMMUNE administration at doses of 250 mcg/m 2 /day or higher may exacerbate pre-existing cardiac conditions.

Caution should be exercised when treating patients with known seizure disorders and or compromised central nervous system function. Central nervous system adverse reactions including decreased mental status, gait disturbance and dizziness have been observed, particularly in patients receiving doses greater than 250 mcg/m 2 /day. Most of these abnormalities were mild and reversible within a few days upon dose reduction or discontinuation of therapy.

Caution should be exercised when administeringACTIMMUNE to patients with myelosuppression. Reversible neutropenia and elevation of hepatic enzymes can be dose limiting above 250 mcg/m 2 /day. Thrombocytopenia and proteinuria have also been seen rarely.



Acute serious hypersensitivity reactions have not been observed in patients receiving ACTIMMUNE, however, 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 but have rarely necessitated treatment interruption.

Information for Patients

Patients being treated with ACTIMMUNE and/or their parents should be informed regarding the potential benefits and risks associated with treatment. If home use is determined to be desirable by the physician, instructions on appropriate use should be given, including review of the contents of the Patient Information Insert. This information is intended to aid in the safe and effective use of the medication. It is not a disclosure of all possible adverse or intended effects.

If home use is prescribed, a puncture resistant container for the disposal of used syringes and needles should be supplied to the patient. Patients should be thoroughly instructed in the importance of proper disposal and cautioned against any reuse of needles and syringes. The full container should be disposed of according to the directions provided by the physician (see Patient Information Insert).

The most common adverse experiences occurring withACTIMMUNE therapy are "flu-like" or constitutional symptoms such as fever, headache, chills, myalgia or fatigue (see ADVERSE REACTIONS Section) which may decrease in severity as treatment continues. Some of the "flu-like" symptoms may be minimized by bedtime administration. Acetaminophen may be used to prevent or partially alleviate the fever and headache.

The long-term effects of ACTIMMUNE therapy on growth, development or other parameters are not known.

Laboratory Tests

In addition to those tests normally required for monitoring patients with Chronic Granulomatous Disease and osteopetrosis, the following laboratory tests are recommended for all patients on ACTIMMUNE (Interferon gamma-1b) therapy prior to the beginning of and at three month intervals during treatment.

Drug Interactions

Interactions between ACTIMMUNE and other drugs have not been fully evaluated. Caution should be exercised when administering ACTIMMUNE in combination with other potentially myelosuppressive agents (see ).

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.

Carcinogenesis, Mutagenesis and Impairment of Fertility

Carcinogenesis:   ACTIMMUNE has not been tested for its carcinogenic potential.

Mutagenesis:   Ames tests using five different tester strains of bacteria with and without metabolic activation revealed no evidence of mutagenic potential. ACTIMMUNE was tested in a micronucleus assay for its ability to induce chromosomal damage in bone marrow cells of mice following two intravenous doses of 20 mg/kg. No evidence of chromosomal damage was noted.

Impairment of Fertility:   Female cynomolgus monkeys treated with daily subcutaneous doses of 30 or 150 mcg/kg ACTIMMUNE (approximately 20 and 100 times the human dose) exhibited irregular menstrual cycles or absence of cyclicity during treatment. Similar findings were not observed in animals treated with 3 mcg/kg ACTIMMUNE. No studies have been performed assessing any potential effects of ACTIMMUNE on male fertility.


Teratogenic Effects: Pregnancy Category C. ACTIMMUNE has shown an increased incidence of abortions in primates when given in doses approximately 100 × the human dose. A study in pregnant primates treated with intravenous doses, 2-100 × the human dose failed to demonstrate teratogenic activity for ACTIMMUNE. 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. In addition, studies evaluating recombinant murine interferon-gamma in pregnant mice, revealed increased incidences of uterine bleeding and abortifacient activity and decreased neonatal viability at maternally toxic doses. The clinical significance of this latter observation with recombinant murine interferon-gamma tested in a homologous system is uncertain.

Nursing Mothers

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.

Pediatric Use

Safety and effectiveness in children under the age of 1 year has not been established in patients with CGD.


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 Chronic Granulomatous Disease (CGD) during an investigational trial in the United States and Europe. The most common adverse events observed in patients with CGD are shown in the following table:

  Percent of Patients
52 28
33 9
17 6
14 0
14 2
14 11
14 12
13 5
10 2
6 0
2 0
0 2

Miscellaneous adverse events which occurred infrequently in patients with CGD and may have been related to underlying disease included back pain (2 percent versus 0 percent), abdominal pain (8 percent versus 3 percent) and depression (3 percent versus 0 percent) for ACTIMMUNE and placebo treated patients, respectively.

Similar safety data were observed in 34 patients with severe malignant osteopetrosis.

ACTIMMUNE has also been evaluated in additional disease states in studies in which patients have generally received higher doses (>100 mcg/m 2 /day) administered by intramuscular injection or intravenous infusion. All of the previously described adverse reactions which occurred in patients with Chronic Granulomatous Disease have also been observed in patients receiving higher doses. Adverse reactions not observed in patients with Chronic Granulomatous Disease receiving doses less than 100 mcg/m 2 /day but seen rarely in patients receiving ACTIMMUNE (Interferon gamma-1b) in other studies include: Cardiovascular--hypotension, syncope, tachyarrhythmia, heart block, heart failure, and myocardial infarction. Central Nervous System--confusion, disorientation, gait disturbance, Parkinsonian symptoms, seizure, hallucinations, and transient ischemic attacks. Gastrointestinal--hepatic insufficiency, gastrointestinal bleeding, and pancreatitis. Renal--reversible renal insufficiency. Hematologic--deep venous thrombosis and pulmonary embolism. Pulmonary--tachypnea, bronchospasm, and interstitial pneumonitis. Metabolic--hyponatremia and hyperglycemia. Other--exacerbation of dermatomyositis.

Abnormal Laboratory Test Values: The incidence of abnormal hematologic, coagulation, hepatic and renal laboratory tests were similar between ACTIMMUNE and placebo treatment groups in the Chronic Granulomatous Disease trial.

No neutralizing antibodies to ACTIMMUNE have been detected in any Chronic Granulomatous Disease patients receiving ACTIMMUNE.


The recommended dosage of ACTIMMUNE for the treatment of patients with Chronic Granulomatous Disease and severe, malignant osteopetrosis is 50 mcg/m 2 (1 millionIU/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 . Note that the above activity is expressed in International Units (1 millionIU/50mcg). This is equivalent to what was previously expressed as units (1.5 million U/50mcg). Injections should be administered subcutaneously three times weekly (for example, Monday, Wednesday, Friday). The optimum sites of injection are the right and left deltoid and anterior thigh. can be administered by a physician, nurse, family member or patient when trained 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.

The formulation does not contain a preservative. A vial of ACTIMMUNE is suitable for a single dose only. The unused portion of any vial should be discarded.

Higher doses are not recommended. Safety and efficacy has not been established for ACTIMMUNE given in doses greater or less than the recommended dose of 50 mcg/m 2 . The minimum effective dose of ACTIMMUNE has not been established.

If severe reactions occur, the dosage should be modified (50 percent reduction) or therapy should be discontinued until the adverse reaction abates.

ACTIMMUNE may be administered using either sterilized glass or plastic disposable syringes.


ACTIMMUNE (Interferon gamma-1b) 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 IU) of Interferon gamma-1b, formulated in 20 mg mannitol, 0.36 mg sodium succinate, 0.05 mg polysorbate 20 and Sterile Water for Injection.

Single vial (NDC 64116-011-01)

Cartons of 12 (NDC 64116-011-12)

Stability and Storage

Vials of ACTIMMUNE must be placed in a 2-8°C (36-46°F) refrigerator immediately upon receipt to insure optimal retention of physical and biochemical integrity. DO NOT FREEZE. Avoid excessive or vigorous agitation. DO NOT SHAKE. An unentered vial of ACTIMMUNE should not be left at room temperature for a total time exceeding 12 hours prior to use. Vials exceeding this time period should not be returned to the refrigerator; such vials should be discarded.

Do not use beyond the expiration date stamped on the vial.


  1. Maluish AE, Urba WJ, Longo DL, et al: The determination of an immunologically active dose of interferon gamma in patients with melanoma. J Clin Onc 6: 434-445, 1988.
  2. Nathan CF, Kaplan G, Levis W, et al: Local and systemic effects of intradermal recombinant interferon gamma in patients with lepromatous leprosy. NEJM 315: 6-11, 1986.
  3. Fauci AS, Rosenberg SA, Sherwin SA, et al: Immunomodulators in clinical medicine. Ann Internal Med 106: 421-433, 1987.
  4. Snapper CM, Paul WE: Interferon-gamma and B cell stimulatory factor-1 reciprocally regulate Ig isotype production. Science 236: 944-947, 1987.
  5. King CL, Gallin JI, Malech HL, et al: Regulation of immunoglobulin production in hyperimmunoglobulin E recurrent-infection syndrome by interferon gamma. PNAS USA 86: 10085-10089, 1989.
  6. Rosenbloom J, Feldman G, Freundlich B, Jimenez SA: Inhibition of excessive scleroderma fibroblast collagen production by recombinant gamma-interferon. Arth Rheum 29: 851-856, 1986.
  7. Ezekowitz RAB, Dinauer MC, Jaffe HS, et al: Partial correction of the phagocyte defect in patients with X-linked chronic granulomatous disease by subcutaneous interferon gamma. NEJM 319: 146-151, 1988.
  8. Sechler JMG, Malech HL, White CJ, Gallin JI: Recombinant human interferon-gamma reconstitutes defective phagocyte function in patients with chronic granulomatous disease of childhood. PNAS USA 85:4874-4878, 1988.
  9. Shapiro F: Osteopetrosis, current clinical considerations. Clin Orth & Rel Res 296: 34-44, 1993.
  10. Beard CJ, Key L, Newburger PE, Ezekowitz RAB, et al: Neutrophil defect associated with malignant infantile osteopetrosis. J Lab Clin Med 108: 498-505, 1986.
  11. Shankar L, Gerritsen EJA, and Key LL: Osteopetrosis: pathogenesis and rationale for the use of interferon-(gamma)-1b. Biodrugs 1: 23-29, 1997.
  12. Key LL, Rodriguiz RM, Willi SM: Long-term treatment of osteopetrosis with recombinant human interferon gamma. NEJM 24: 1594-1599, 1995.

Manufactured by:

InterMune Pharmaceuticals, Inc.

Burlingame, CA 94010

U.S. License No. 1267

Revised March, 2000


© 2000 InterMune Pharmaceuticals, Inc.            LB-0163


NOTE: These photos can be used only for identification by shape, color, and imprint. They do not depict actual or relative size.

The product samples shown here have been supplied by the manufacturer and reproduced in full color by PDR as a quick-reference identification aid. While every effort has been made to assure accurate reproduction, please remember that any visual identification should be considered preliminary. In cases of poisoning or suspected overdosage, the drug' identity should be verified by chemical analysis.