Description:

Interferon gamma-1b (rINFgamma-1b) is a recombinant form of gamma interferon containing 140 amino acids. Interferon gamma-1b is derived from genetically engineered Escherichia coli and is supplied as a highly purified solution with a specific activity of 20 million International Units (IU)/mg. A unit of activity is based on antiviral activity against encephalomyocarditis virus. Recombinant gamma interferons are identified by a number indicating the sequence at position 1 and a letter characterizing position 139. Interferon gamma-1b has a hydrogen and methionine at position 1 and a hydroxyl group at position 139. Endogenous interferon gamma is a heterogeneous protein of 166 amino acids encoded on chromosome 12 and is chemically and pharmacologically distinct from interferon alpha or beta. Interferon gamma-1b is used to decrease the frequency and severity of infections associated with chronic granulomatous disease (CGD). Prior to the availability of interferon gamma-1b, the standard treatment for these patients included surgical drainage of abcesses, extended use of systemic antimicrobial prophylaxis, and transfusion of white blood cells. Clinical trials with interferon gamma-1b in the treatment of CGD were terminated prematurely due to significant benefit over placebo. In the treatment of osteopetrosis, interferon gamma-1b significantly prolongs the time to disease progression as compared with treatment with calcitriol (165 days vs. 65 days, respectively). Interferon gamma-1b is currently under investigation for the treatment of cryptococcal meningitis, multiple-drug resistant tuberculosis, systemic fungal disease, other mycobacterium infections, and pulmonary fibrosis. An inhaled formulation is undergoing safety and efficacy testing in the treatment of cystic fibrosis. Interferon gamma-1b is no longer under investigation for treatment of atopic dermatitis or renal cell carcinoma due to lack of benefit. The FDA approved interferon gamma-1b in December 1990 for the treatment of granulomatous disease. In February 2000, under fast track review, the FDA approved interferon gamma-1b for delaying the time to disease progression in patients with severe, malignant osteopetrosis. InterMune distributes Actimmune� in North America while Boehringer Ingelheim distributes the product outside of North America (Imukin�).

Mechanism of Action: Interferon gamma belongs to the class of interferons, which are species-specific proteins produced in response to viruses as well as a variety of other natural and synthetic stimuli. Interferons regulate immune response. Interferon gamma is a Type II interferon or immune interferon. As compared to the other interferons (alpha and beta), interferon gamma is acid labile, encoded on a different chromosome, and binds to different cell surface receptors. Similar to interferons alpha and beta, interferon gamma increases the expression of class I major histocompatibility complex (MHC), enhances the activity of NK cells, interferes with viral replication, and decreases cell proliferation. In addition, interferon gamma activates macrophages, increases expression of MHC class II, and stimulates formation of cytotoxic T lymphocytes. There are two types of interferon gamma receptors that differ in molecular weight, acid stability, and regulation of receptor expression. These receptor differences may explain the various effects of interferon gamma. Interferon gamma receptors have been found on epithelial and hematopoietic cells and fibroblasts.[2747] Since interferon gamma is produced by activated T lymphocytes and regulates the activity of immune cells, it may be more appropriate to describe interferon gamma as a lymphokine of the interleukin type. There is evidence that interferon gamma interacts functionally with other interleukin molecules such as interleukin (IL)-2 and that all of the interleukins form part of a complex, lymphokine regulatory network. The interaction of interferon gamma with IL-4 results in suppression of IgE levels as well as inhibition of collagen production in humans. Interferon gamma also stimulates the release of IL-1, which is important in the activation of T lymphocytes. All interferons can induce an antiviral activity in host cells by affecting attachment, penetration, uncoating, transcription, assembly, and maturation of viruses. Interferons inhibit viral translation through induction and activation of 2,5-olgoadenylate synthetase pathway and the eukaryotic protein synthesis pathway. Induction of 2,5-olgoadenylate synthetase leads to degradation of viral messenger RNA and activation of protein synthesis initiation factor inhibits viral translation. Interferon gamma is produced only after T lymphocytes become activated and is more important in stimulating immune reactions rather than direct antiviral actions. Interferon gamma induces cellular resistance to cytomegalovirus, herpes simplex virus, and adenovirus in vitro.[2747] Interferon gamma is required for macrophage activation. The exact mechanism by which interferon gamma mediates this is unknown but seems to result from enhancement of oxidative metabolism in tissue macrophages, as well as, enhancement of antibody-dependent cellular cytotoxicity and natural killer cell activity. Enhanced oxidative metabolism results in the production of toxic oxygen metabolites within phagocytes which allows more efficient killing of certain fungi, bacteria, and protozoal microbes, including Staphylococcus aureus, Aspergillus fumigatus, Chlamydia psittaci, Plasmodium falciparum, Leishmania donovani, Toxoplasma gondii, and Listeria monocytogenes. Interferon gamma also enhances antigen processing and signaling by antigen-presenting cells by increasing the expression of MHC class II on the membranes of macrophages. Use of interferon gamma in patients with chronic granulomatous disease results in a reduced risk of developing a serious infection. In osteopetrosis, a disorder characterized by an osteoclast defect leading to bone overgrowth and deficient macrophage oxidative metabolism, interferon gamma enhancement of superoxide production by phagocytes has been observed in vitro. Interferon gamma also has been shown to enhance osteoclast function in vitro. Pharmacokinetics: Interferon gamma-1b is administered subcutaneously. Available pharmacokinetic data has been obtained through study of healthy males. Following administration, approximately 90% of the dose is absorbed. Peak serum concentrations occur 7 hours after subcutaneous administration with an elimination half-life of about 5.9 hours. Following intravenous bolus administration, the half-life of interferon gamma-1b is 25�35 minutes, which is similar to endogenous interferon gamma.[2748] Accumulation does not occur following multiple subcutaneous doses. Interferon gamma-1b is not detected in the urine following administration to healthy adult males.

Indications...Dosage For the treatment of chronic granulomatous disease: NOTE: Interferon gamma-1b has been designated an orphan drug by the FDA for this indication. Subcutaneous dosage: Adults and children with body surface area (BSA) > 0.5 m 2 : 50 �g/m2 SC three times weekly. If severe reactions occur, the dosage should be reduced by 50%, or therapy should be held until the reaction resolves. Adults and children with body surface area (BSA) <= 0.5 m 2 : 1.5 �g/kg SC three times weekly. If severe reactions occur, the dosage should be reduced by 50%, or therapy should be held until the reaction resolves. For the treatment of severe, malignant osteopetrosis to delay the time to disease progression: NOTE: Interferon gamma-1b has been designated an orphan drug by the FDA for this indication. Subcutaneous dosage: Children with body surface area (BSA) > 0.5 m 2 : 50 �g/m2 SC three times weekly. If severe reactions occur, the dosage should be reduced by 50%, or therapy should be held until the reaction resolves. Children with body surface area (BSA) <= 0.5 m 2 : 1.5 �g/kg SC three times weekly. If severe reactions occur, the dosage should be reduced by 50%, or therapy should be held until the reaction resolves. For the treatment of idiopathic pulmonary fibrosis� in patients refractory to corticosteroid therapy: Subcutaneous dosage: Adults: In a small, preliminary study, patients were treated with 200 �g interferon gamma-1b SC three times weekly plus prednisone for 12 months. Results of this study indicated that patients treated with interferon gamma-1b in combination with prednisone had significant improvement in pulmonary ventilation (lung capacity and force vital capacity) and gas exchange as compared to those patients receiving prednisone alone.[2749] For the adjuvant treatment of refractory mycobacterium infection due to Mycobacterium avium complex (MAC)� in conjunction with traditional antimycobacterial agents: Subcutaneous dosage: Adults and Children >= 5 years: In a small series of patients with refractory non-tuberculous mycobacterium infection, the addition of interferon gamma 50 �g SC three times per week (reduced by 50% if patients experienced intolerable adverse effects) to traditional antimycobacterial therapy produced both subjective and clinical responses in 7 of 7 patients. The dose was administered for 4�19 months in these 7 patients.[1222] Patients with renal impairment: Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed. Patients with hepatic impairment: Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed. �non-FDA-approved indication

Administration Subcutaneous Administration �No dilution necessary. �The activity of interferon gamma-1b is now expressed as International Units (1 million IU/50 �g). �Premedication with acetaminophen or ibuprofen may decrease the incidence of fever and headache. Administer at bedtime to minimize some of the flu-like symptoms. �Store in a refrigerator between 2 and 8 degrees C (36 and 46 degrees F); do not freeze. Do not shake vial. Discard any unused portions or any vial left at room temperature for > 12 hours. �Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Subcutaneous injection: �Inject subcutaneously into the right or left deltoid or anterior thigh. Care should be taken to avoid intradermal or intravascular injection. Rotate injection sites.

Contraindications Interferon gamma-1b dosage >= 250 �g/m2 may cause neutropenia. Interferon gamma-1b should be administered with caution to patients with pre-existing bone marrow suppression. At doses listed in the package insert, interferon gamma-1b is not usually myelosuppressive. Interferon gamma-1b is classified as FDA pregnancy category C. It is recommended that the drug not be used in pregnant women because the safety of interferon gamma-1b during pregnancy has not been established. Females of childbearing age should use effective methods of birth control while receiving interferon gamma-1b. It is unknown whether interferon gamma-1b is excreted into breast milk, therefore, it is recommended that breast-feeding be discontinued while the mother is receiving interferon gamma-1b. The safe and effective use of interferon gamma-1b in infants (< 1 year of age) for the treatment of chronic granulomatous disease has not been established, therefore, use in these patients is not recommended by the manufacturer. In clinical trials for osteopetrosis, children aged 1 month to 8 years (mean age 1.5 years) were treated safely. The long-term effects of interferon gamma-1b therapy on growth, development, or other parameters are not known. Interferon gamma-1b should be used cautiously in patients with pre-existing cardiac disease including ischemia (i.e., angina or myocardial infarction), congestive heart failure, or cardiac arrhythmias. No direct cardiotoxic effects have been noted, but it is possible that the transient, acute flu-like symptoms (i.e., fever and chills) associated with interferon gamma-1b doses >= 250 �g/m2 may exacerbate the cardiac condition. Interferon gamma-1b should be used with caution in patients with seizure disorders or compromised CNS function. Adverse CNS reactions such as decreased mental status, gait disturbance, and dizziness have been reported with interferon gamma-1b, particularly in patients receiving doses >= 250 �g/m2. Interferon gamma-1b is contraindicated in patients with a prior history of E. coli protein hypersensitivity.

Interactions The interaction of interferon gamma-1b with other drugs has not been fully determined. Studies in rodents have demonstrated alterations in the levels of the hepatic cytochrome P450 concentrations. Drugs metabolized by this system, including warfarin, theophylline, and phenytoin, may be susceptible to drug interactions with interferon gamma-1b. Until additional human data is available, interferon gamma-1b should be used cautiously in patients receiving phenytoin or fosphenytoin, theophylline, or warfarin.

Adverse Reactions The most common adverse reactions with interferon gamma-1b involve flu-like symptoms. The symptoms may include fever (52%), headache (33%), chills (14%), and fatigue (14%). Arthralgia, myalgia, and night time diaphoresis may also occur. Premedication with acetaminophen or ibuprofen may prevent or partially alleviate the fever and headache. Nausea/vomiting (10%/13%) and diarrhea (14%) have also been reported. In patients receiving interferon gamma-1b for indications other than chronic granulomatous disease, pancreatitis and GI bleeding have been recorded. Rash (unspecified) may develop (17%) or patients may develop an injection site reaction with erythema and tenderness around the injection site (14%). Maculopapular rash or urticaria has been reported. Acute hypersensitivity reactions have not been reported with interferon gamma-1b. In interferon gamma-1b doses >= 250 �g/m2/day, reversible neutropenia and elevated hepatic enzymes can be dose limiting. Thrombocytopenia and proteinuria have also been seen rarely at these doses. Interferon gamma-1b-induced central nervous system toxicity including altered mental status, ataxia, confusion, and dizziness has been observed, particularly in patients receiving dosages >= 250 �g/m2/day. Parkinsonian symptoms, disorientation, seizures, and hallucinations have also been reported. Neurotoxic effects are usually reversible after withdrawal of interferon gamma-1b. Additional adverse reactions have been reported in patients receiving interferon gamma-1b at dosages > 100 �g/m2/day for indications other than chronic granulomatous disease. These reactions include bronchospasm, deep vein thrombosis, heart block, heart failure, hypotension, interstitial pneumonitis, myocardial infarction, pulmonary embolism, reversible renal insufficiency, syncope, tachyarrhythmia, and tachypnea. Neutralizing antibodies to interferon gamma-1b have not been reported in patients treated for chronic granulomatous disease.

Interferon Gamma-1b Actimmune�

2747. Bolinger AM, Taeubel MA. Recombinant gamma interferon for the treatment of chronic granulomatous disease and other disorders. Clin Pharm 1992;11:834�50.

2748. Kurzrock R, Rosenblum MG, Sherwin SA, et al. Pharmacokinetics, single-dose tolerance, and biologic activity of recombinant gamma-interferon in cancer patients. Cancer Res 1985;45:2866�72.

2749. Zieche R, Hofbauer E, Wittmann K, et al. A preliminary study of long-term treatment with interferon gamma-1b and low-dose prednisone in patients with idiopathic pulmonary fibrosis. N Engl J Med 1999;341;1264�9.

1222. Holland SM, Eisenstein EM, Kuhns DB et al. Treatment of refractory disseminated nontuberculous mycobacterial infection with interferon gamma. N Engl J Med 1994;330:1348�55.