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  • CLASSES

    Interferons, Gamma

    DEA CLASS

    Rx

    DESCRIPTION

    Recombinant form of gamma interferon; chemically and pharmacologically distinct from interferon alpha or interferon beta; specific activity of 20 million International Units (IU)/mg.

    COMMON BRAND NAMES

    Actimmune

    HOW SUPPLIED

    Actimmune Subcutaneous Inj Sol: 0.5mL, 100mcg

    DOSAGE & INDICATIONS

    For the treatment of chronic granulomatous disease to reduce the frequency and severity of serious infections.
    NOTE: Interferon gamma-1b has been designated an orphan drug by the FDA for this indication.
    Subcutaneous dosage
    Adults, Adolescents, and Children with body surface area (BSA) > 0.5 m2

    50 mcg/m2 subcutaneously 3 times weekly. If severe reactions occur, the dosage should be reduced by 50%, or therapy should be held until the reaction resolves.

    Adults, Adolescents, and Children with body surface area (BSA) <= 0.5 m2

    1.5 mcg/kg subcutaneously 3 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 m2

    50 mcg/m2 subcutaneously 3 times weekly. If severe reactions occur, the dosage should be reduced by 50%, or therapy should be held until the reaction resolves.

    Infants and Children with body surface area (BSA) <= 0.5 m2

    1.5 mcg/kg subcutaneously 3 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†.
    Subcutaneous dosage
    Adults

    In a placebo-controlled study, receipt of interferon gamma-1b 200 mcg subcutaneously 3 times weekly did not significantly affect the time to progression-free survival (disease progression or death) as compared with placebo. All 330 adults studied had a lack of disease improvement with a total prednisone dose of least 1,800 mg over the preceding 2 years. Patients could continue taking a stable prednisone dose of 15 mg/day or less. Of patients with a baseline FVC of 62% or greater, 3 of the 86 who received interferon gamma-1b and 11 of the 88 who received placebo died. In comparison, of patients with a baseline FVC less than 62%, 13 of 76 patients who got interferon gamma-1b and 17 of 80 patients who got placebo died. As most patients in the study had disease progression rather than mortality, further data on the impact of interferon gamma1-b on patient survival are needed. According to the manufacturer, a phase 3 trial was stopped early due to an absence of a statistically significant difference in overall mortality between the interferon gamma-1b group (14.5%) and the placebo group (12.7%); the primary endpoint was survival, and patients had mild to moderate lung function impairment. In a previous preliminary study, 18 patients treated with interferon gamma-1b 180 to 200 mcg subcutaneously 3 times weekly plus prednisone for 12 months had significant improvement in pulmonary ventilation (lung capacity and forced vital capacity) and gas exchange as compared with patients who received prednisone alone.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    50 mcg/m2/dose subcutaneously.

    Geriatric

    50 mcg/m2/dose subcutaneously.

    Adolescents

    50 mcg/m2/dose subcutaneously.

    Children

    50 mcg/m2/dose subcutaneously or 1.5 mcg/kg/dose subcutaneously for a BSA <= 0.5 m2.

    Infants

    50 mcg/m2/dose subcutaneously or 1.5 mcg/kg/dose subcutaneously for a BSA <= 0.5 m2.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; if severe hepatic reactions occur, reduce the dose by 50% or interrupt therapy until the adverse reaction abates.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    For storage information, see specific product information within the How Supplied section.

    Injectable Administration

    The activity of interferon gamma-1b is expressed as International Units (1 million International Units/50 mcg); each 0.5 mL vial contains 100 mcg (2 million International Units).
    Premedication with acetaminophen or ibuprofen may decrease the incidence of fever and headache. Administer at bedtime to minimize some of the flu-like symptoms.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Subcutaneous Administration

    No dilution necessary. Use either sterilized glass or plastic disposable syringes. Do not mix with other drugs in the same syringe.
    Inject subcutaneously into the right or left deltoid or anterior thigh. Care should be taken to avoid intradermal or intravascular injection. Rotate injection sites.

    STORAGE

    Actimmune:
    - Do not freeze
    - Refrigerate (between 36 and 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Pulmonary fibrosis

    A clinical trial comparing interferon gamma-1b to placebo in the treatment of idiopathic pulmonary fibrosis (IPF), the INSPIRE trial, was terminated early as an interim analysis showed that patients who received interferon gamma-1b did not benefit. The analysis showed that 14.5% of patients treated with interferon gamma-1b died, compared to 12.7% of patients treated with placebo.

    Bone marrow suppression, immunosuppression

    Interferon gamma-1b may cause neutropenia and thrombocytopenia. Severe, reversible neutropenia and thrombocytopenia that may be dose-related have been observed. Administer with caution to patients with preexisting bone marrow suppression such as patients with immunosuppression.

    Pregnancy

    Interferon gamma-1b is classified as FDA pregnancy risk category C. No adequate and well-controlled studies have been conducted in pregnant women, and its ability to cause fetal harm or affect reproductive capacity is unknown. In primate studies, an increased incidence of spontaneous abortion were observed at doses approximately 100-times the recommended human dose. The manufacturer advises use during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

    Breast-feeding

    Data are limited regarding use of interferon gamma-1b during breast-feeding, and its excretion into breast milk is unknown. According to the manufacturer, either the drug or breast-feeding should be discontinued because of the potential for serious adverse reactions in a nursing infant. However, because the drug is a protein and likely to be digested by the infants gastrointestinal tract, the risk of systemic exposure and toxicity in a nursing infant may be limited. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, health care providers are encouraged to report the adverse effect to the FDA.

    Infants, neonates

    The safe and effective use of interferon gamma-1b in neonates and infants (< 1 year of age) for the treatment of chronic granulomatous disease have 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. Also, the incidence of elevated hepatic enzyme concentrations appeared to be higher among patients less than 1 year of age as compared with older children. Monitor liver function monthly in all infants who receive interferon gamma-1b.

    Angina, cardiac arrhythmias, cardiac disease, heart failure, myocardial infarction

    Interferon gamma-1b should be used cautiously in patients with preexisting 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 mcg/m2 may exacerbate the cardiac condition.

    Seizure disorder

    Interferon gamma-1b should be used with caution in patients with seizure disorder 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 mcg/m2. Most events were mild and reversible within a few days of either dose reduction or therapy discontinuation.

    E. coli protein hypersensitivity, mannitol hypersensitivity

    Interferon gamma-1b is contraindicated in patients with a prior history of E. coli protein hypersensitivity or known hypersensitivity to interferon gamma or any product component. Patients with mannitol hypersensitivity may not be appropriate candidates for interferon gamma-1b, as the drug formulation contains mannitol.

    Hepatic disease

    Cautious use of interferon gamma-1b may be warranted in patients with hepatic disease. The drug may cause elevated hepatic enzyme concentrations (see Adverse Reactions).

    ADVERSE REACTIONS

    Severe

    pancreatitis / Delayed / Incidence not known
    GI bleeding / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    proteinuria / Delayed / Incidence not known
    seizures / Delayed / Incidence not known
    heart failure / Delayed / Incidence not known
    pulmonary embolism / Delayed / Incidence not known
    thrombosis / Delayed / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    bronchospasm / Rapid / Incidence not known

    Moderate

    atopic dermatitis / Delayed / Incidence not known
    erythema / Early / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    neutropenia / Delayed / Incidence not known
    hypokalemia / Delayed / Incidence not known
    hepatomegaly / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    confusion / Early / Incidence not known
    hallucinations / Early / Incidence not known
    ataxia / Delayed / Incidence not known
    colitis / Delayed / Incidence not known
    hypertriglyceridemia / Delayed / Incidence not known
    hyponatremia / Delayed / Incidence not known
    hypotension / Rapid / Incidence not known
    tachypnea / Early / Incidence not known
    hyperglycemia / Delayed / Incidence not known
    pneumonitis / Delayed / Incidence not known

    Mild

    fever / Early / 52.0-52.0
    headache / Early / 33.0-33.0
    rash (unspecified) / Early / 17.0-17.0
    fatigue / Early / 14.0-14.0
    chills / Rapid / 14.0-14.0
    diarrhea / Early / 14.0-14.0
    injection site reaction / Rapid / 14.0-14.0
    vomiting / Early / 13.0-13.0
    nausea / Early / 10.0-10.0
    myalgia / Early / 6.0-6.0
    arthralgia / Delayed / 2.0-2.0
    urticaria / Rapid / Incidence not known
    maculopapular rash / Early / Incidence not known
    dizziness / Early / Incidence not known
    syncope / Early / Incidence not known

    DRUG INTERACTIONS

    Abacavir: (Major) The concomitant use of interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. Interferon beta-1b has been shown to reduce zidovudine, ZDV, clearance by as much as 93% as interferon beta may interfere with the glucuronidation of zidovudine. Dosage reduction of zidovudine may be necessary when interferon beta and zidovudine are coadministered. Synergistic toxicity may occur with alpha interferons and zidovudine, as both can be myelosuppressive. Peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons; however a clinical trial showed an increased risk and severity of peripheral neuropathy with the combination of telbivudine and pegylated interferon alfa-2a compared to telbivudine alone. Interferons and NRTIs can both cause hepatic damage. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Abacavir; Dolutegravir; Lamivudine: (Major) Caution is advised with coadministration of lamivudine and interferons as hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa, with or without ribavirin. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Patients receiving interferon alfa, with or without ribavirin, and lamivudine should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Discontinuation of lamivudine should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). (Major) The concomitant use of interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. Interferon beta-1b has been shown to reduce zidovudine, ZDV, clearance by as much as 93% as interferon beta may interfere with the glucuronidation of zidovudine. Dosage reduction of zidovudine may be necessary when interferon beta and zidovudine are coadministered. Synergistic toxicity may occur with alpha interferons and zidovudine, as both can be myelosuppressive. Peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons; however a clinical trial showed an increased risk and severity of peripheral neuropathy with the combination of telbivudine and pegylated interferon alfa-2a compared to telbivudine alone. Interferons and NRTIs can both cause hepatic damage. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Abacavir; Lamivudine, 3TC: (Major) Caution is advised with coadministration of lamivudine and interferons as hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa, with or without ribavirin. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Patients receiving interferon alfa, with or without ribavirin, and lamivudine should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Discontinuation of lamivudine should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). (Major) The concomitant use of interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. Interferon beta-1b has been shown to reduce zidovudine, ZDV, clearance by as much as 93% as interferon beta may interfere with the glucuronidation of zidovudine. Dosage reduction of zidovudine may be necessary when interferon beta and zidovudine are coadministered. Synergistic toxicity may occur with alpha interferons and zidovudine, as both can be myelosuppressive. Peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons; however a clinical trial showed an increased risk and severity of peripheral neuropathy with the combination of telbivudine and pegylated interferon alfa-2a compared to telbivudine alone. Interferons and NRTIs can both cause hepatic damage. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Major) Caution is advised with coadministration of lamivudine and interferons as hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa, with or without ribavirin. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Patients receiving interferon alfa, with or without ribavirin, and lamivudine should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Discontinuation of lamivudine should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). (Major) The concomitant use of interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. Interferon beta-1b has been shown to reduce zidovudine, ZDV, clearance by as much as 93% as interferon beta may interfere with the glucuronidation of zidovudine. Dosage reduction of zidovudine may be necessary when interferon beta and zidovudine are coadministered. Synergistic toxicity may occur with alpha interferons and zidovudine, as both can be myelosuppressive. Peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons; however a clinical trial showed an increased risk and severity of peripheral neuropathy with the combination of telbivudine and pegylated interferon alfa-2a compared to telbivudine alone. Interferons and NRTIs can both cause hepatic damage. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. (Major) The concomitant use of interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. Interferon beta-1b has been shown to reduce zidovudine, ZDV, clearance by as much as 93% as interferon beta may interfere with the glucuronidation of zidovudine. Dosage reduction of zidovudine may be necessary when interferon beta and zidovudine are coadministered. Synergistic toxicity may occur with alpha interferons and zidovudine, as both can be myelosuppressive. Peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons; however a clinical trial showed an increased risk and severity of peripheral neuropathy with the combination of telbivudine and pegylated interferon alfa-2a compared to telbivudine alone. Interferons and NRTIs can both cause hepatic damage. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Amprenavir: (Major) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatic damage. Most protease inhibitors have been associated with episodes of liver toxicity, with lopinavir/low-dose ritonavir, fosamprenavir/low-dose ritonavir, and nelfinavir being less hepatotoxic and tipranavir/low-dose ritonavir being the most hepatotoxic. Hyperbilirubinemia is often associated with atazanavir and/or indinavir therapy but does not reflect liver damage and is related to the inhibition of UDP glucuronosyltransferase. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Antithymocyte Globulin: (Moderate) Caution is advised with the concomitant use of antithymocyte globulin and interferon gamma-1b as an additive risk of bleeding may occur. Interferon gamma-1b can cause severe, reversible neutropenia and thrombocytopenia that may be dose-related.
    Atazanavir: (Major) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatic damage. Most protease inhibitors have been associated with episodes of liver toxicity, with lopinavir/low-dose ritonavir, fosamprenavir/low-dose ritonavir, and nelfinavir being less hepatotoxic and tipranavir/low-dose ritonavir being the most hepatotoxic. Hyperbilirubinemia is often associated with atazanavir and/or indinavir therapy but does not reflect liver damage and is related to the inhibition of UDP glucuronosyltransferase. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Atazanavir; Cobicistat: (Major) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatic damage. Most protease inhibitors have been associated with episodes of liver toxicity, with lopinavir/low-dose ritonavir, fosamprenavir/low-dose ritonavir, and nelfinavir being less hepatotoxic and tipranavir/low-dose ritonavir being the most hepatotoxic. Hyperbilirubinemia is often associated with atazanavir and/or indinavir therapy but does not reflect liver damage and is related to the inhibition of UDP glucuronosyltransferase. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Chloroquine: (Moderate) Concurrent use of chloroquine and interferons is not recommended as there is an increased risk of retinal toxicity.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Major) The concomitant use of interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. Interferon beta-1b has been shown to reduce zidovudine, ZDV, clearance by as much as 93% as interferon beta may interfere with the glucuronidation of zidovudine. Dosage reduction of zidovudine may be necessary when interferon beta and zidovudine are coadministered. Synergistic toxicity may occur with alpha interferons and zidovudine, as both can be myelosuppressive. Peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons; however a clinical trial showed an increased risk and severity of peripheral neuropathy with the combination of telbivudine and pegylated interferon alfa-2a compared to telbivudine alone. Interferons and NRTIs can both cause hepatic damage. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) The concomitant use of interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. Interferon beta-1b has been shown to reduce zidovudine, ZDV, clearance by as much as 93% as interferon beta may interfere with the glucuronidation of zidovudine. Dosage reduction of zidovudine may be necessary when interferon beta and zidovudine are coadministered. Synergistic toxicity may occur with alpha interferons and zidovudine, as both can be myelosuppressive. Peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons; however a clinical trial showed an increased risk and severity of peripheral neuropathy with the combination of telbivudine and pegylated interferon alfa-2a compared to telbivudine alone. Interferons and NRTIs can both cause hepatic damage. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Darunavir: (Major) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatic damage. Most protease inhibitors have been associated with episodes of liver toxicity, with lopinavir/low-dose ritonavir, fosamprenavir/low-dose ritonavir, and nelfinavir being less hepatotoxic and tipranavir/low-dose ritonavir being the most hepatotoxic. Hyperbilirubinemia is often associated with atazanavir and/or indinavir therapy but does not reflect liver damage and is related to the inhibition of UDP glucuronosyltransferase. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Darunavir; Cobicistat: (Major) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatic damage. Most protease inhibitors have been associated with episodes of liver toxicity, with lopinavir/low-dose ritonavir, fosamprenavir/low-dose ritonavir, and nelfinavir being less hepatotoxic and tipranavir/low-dose ritonavir being the most hepatotoxic. Hyperbilirubinemia is often associated with atazanavir and/or indinavir therapy but does not reflect liver damage and is related to the inhibition of UDP glucuronosyltransferase. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatic damage. Most protease inhibitors have been associated with episodes of liver toxicity, with lopinavir/low-dose ritonavir, fosamprenavir/low-dose ritonavir, and nelfinavir being less hepatotoxic and tipranavir/low-dose ritonavir being the most hepatotoxic. Hyperbilirubinemia is often associated with atazanavir and/or indinavir therapy but does not reflect liver damage and is related to the inhibition of UDP glucuronosyltransferase. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Delavirdine: (Major) The concomitant use of interferons and anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs) should be done with caution as both can cause hepatic damage. NNRTIs may cause liver damage in the context of hypersensitivity reactions or by direct toxic effects. Many studies demonstrate that nevirapine is more hepatotoxic than efavirenz. Underlying chronic HCV infection enhances the risk of developing liver enzyme elevations in patients receiving nevirapine. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Didanosine, ddI: (Major) The concomitant use of interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. Interferon beta-1b has been shown to reduce zidovudine, ZDV, clearance by as much as 93% as interferon beta may interfere with the glucuronidation of zidovudine. Dosage reduction of zidovudine may be necessary when interferon beta and zidovudine are coadministered. Synergistic toxicity may occur with alpha interferons and zidovudine, as both can be myelosuppressive. Peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons; however a clinical trial showed an increased risk and severity of peripheral neuropathy with the combination of telbivudine and pegylated interferon alfa-2a compared to telbivudine alone. Interferons and NRTIs can both cause hepatic damage. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Efavirenz: (Major) The concomitant use of interferons and anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs) should be done with caution as both can cause hepatic damage. NNRTIs may cause liver damage in the context of hypersensitivity reactions or by direct toxic effects. Many studies demonstrate that nevirapine is more hepatotoxic than efavirenz. Underlying chronic HCV infection enhances the risk of developing liver enzyme elevations in patients receiving nevirapine. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Efavirenz; Emtricitabine; Tenofovir: (Major) The concomitant use of interferons and anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs) should be done with caution as both can cause hepatic damage. NNRTIs may cause liver damage in the context of hypersensitivity reactions or by direct toxic effects. Many studies demonstrate that nevirapine is more hepatotoxic than efavirenz. Underlying chronic HCV infection enhances the risk of developing liver enzyme elevations in patients receiving nevirapine. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. (Major) The concomitant use of interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. Interferon beta-1b has been shown to reduce zidovudine, ZDV, clearance by as much as 93% as interferon beta may interfere with the glucuronidation of zidovudine. Dosage reduction of zidovudine may be necessary when interferon beta and zidovudine are coadministered. Synergistic toxicity may occur with alpha interferons and zidovudine, as both can be myelosuppressive. Peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons; however a clinical trial showed an increased risk and severity of peripheral neuropathy with the combination of telbivudine and pegylated interferon alfa-2a compared to telbivudine alone. Interferons and NRTIs can both cause hepatic damage. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Emtricitabine: (Major) The concomitant use of interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. Interferon beta-1b has been shown to reduce zidovudine, ZDV, clearance by as much as 93% as interferon beta may interfere with the glucuronidation of zidovudine. Dosage reduction of zidovudine may be necessary when interferon beta and zidovudine are coadministered. Synergistic toxicity may occur with alpha interferons and zidovudine, as both can be myelosuppressive. Peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons; however a clinical trial showed an increased risk and severity of peripheral neuropathy with the combination of telbivudine and pegylated interferon alfa-2a compared to telbivudine alone. Interferons and NRTIs can both cause hepatic damage. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) The concomitant use of interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. Interferon beta-1b has been shown to reduce zidovudine, ZDV, clearance by as much as 93% as interferon beta may interfere with the glucuronidation of zidovudine. Dosage reduction of zidovudine may be necessary when interferon beta and zidovudine are coadministered. Synergistic toxicity may occur with alpha interferons and zidovudine, as both can be myelosuppressive. Peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons; however a clinical trial showed an increased risk and severity of peripheral neuropathy with the combination of telbivudine and pegylated interferon alfa-2a compared to telbivudine alone. Interferons and NRTIs can both cause hepatic damage. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) The concomitant use of interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. Interferon beta-1b has been shown to reduce zidovudine, ZDV, clearance by as much as 93% as interferon beta may interfere with the glucuronidation of zidovudine. Dosage reduction of zidovudine may be necessary when interferon beta and zidovudine are coadministered. Synergistic toxicity may occur with alpha interferons and zidovudine, as both can be myelosuppressive. Peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons; however a clinical trial showed an increased risk and severity of peripheral neuropathy with the combination of telbivudine and pegylated interferon alfa-2a compared to telbivudine alone. Interferons and NRTIs can both cause hepatic damage. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Emtricitabine; Tenofovir alafenamide: (Major) The concomitant use of interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. Interferon beta-1b has been shown to reduce zidovudine, ZDV, clearance by as much as 93% as interferon beta may interfere with the glucuronidation of zidovudine. Dosage reduction of zidovudine may be necessary when interferon beta and zidovudine are coadministered. Synergistic toxicity may occur with alpha interferons and zidovudine, as both can be myelosuppressive. Peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons; however a clinical trial showed an increased risk and severity of peripheral neuropathy with the combination of telbivudine and pegylated interferon alfa-2a compared to telbivudine alone. Interferons and NRTIs can both cause hepatic damage. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Emtricitabine; Tenofovir disoproxil fumarate: (Major) The concomitant use of interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. Interferon beta-1b has been shown to reduce zidovudine, ZDV, clearance by as much as 93% as interferon beta may interfere with the glucuronidation of zidovudine. Dosage reduction of zidovudine may be necessary when interferon beta and zidovudine are coadministered. Synergistic toxicity may occur with alpha interferons and zidovudine, as both can be myelosuppressive. Peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons; however a clinical trial showed an increased risk and severity of peripheral neuropathy with the combination of telbivudine and pegylated interferon alfa-2a compared to telbivudine alone. Interferons and NRTIs can both cause hepatic damage. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Entecavir: (Major) The concomitant use of interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. Interferon beta-1b has been shown to reduce zidovudine, ZDV, clearance by as much as 93% as interferon beta may interfere with the glucuronidation of zidovudine. Dosage reduction of zidovudine may be necessary when interferon beta and zidovudine are coadministered. Synergistic toxicity may occur with alpha interferons and zidovudine, as both can be myelosuppressive. Peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons; however a clinical trial showed an increased risk and severity of peripheral neuropathy with the combination of telbivudine and pegylated interferon alfa-2a compared to telbivudine alone. Interferons and NRTIs can both cause hepatic damage. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Etravirine: (Major) The concomitant use of interferons and anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs) should be done with caution as both can cause hepatic damage. NNRTIs may cause liver damage in the context of hypersensitivity reactions or by direct toxic effects. Many studies demonstrate that nevirapine is more hepatotoxic than efavirenz. Underlying chronic HCV infection enhances the risk of developing liver enzyme elevations in patients receiving nevirapine. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Fosamprenavir: (Major) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatic damage. Most protease inhibitors have been associated with episodes of liver toxicity, with lopinavir/low-dose ritonavir, fosamprenavir/low-dose ritonavir, and nelfinavir being less hepatotoxic and tipranavir/low-dose ritonavir being the most hepatotoxic. Hyperbilirubinemia is often associated with atazanavir and/or indinavir therapy but does not reflect liver damage and is related to the inhibition of UDP glucuronosyltransferase. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Indinavir: (Major) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatic damage. Most protease inhibitors have been associated with episodes of liver toxicity, with lopinavir/low-dose ritonavir, fosamprenavir/low-dose ritonavir, and nelfinavir being less hepatotoxic and tipranavir/low-dose ritonavir being the most hepatotoxic. Hyperbilirubinemia is often associated with atazanavir and/or indinavir therapy but does not reflect liver damage and is related to the inhibition of UDP glucuronosyltransferase. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Lamivudine, 3TC: (Major) Caution is advised with coadministration of lamivudine and interferons as hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa, with or without ribavirin. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Patients receiving interferon alfa, with or without ribavirin, and lamivudine should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Discontinuation of lamivudine should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6).
    Lamivudine, 3TC; Zidovudine, ZDV: (Major) Caution is advised with coadministration of lamivudine and interferons as hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa, with or without ribavirin. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Patients receiving interferon alfa, with or without ribavirin, and lamivudine should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Discontinuation of lamivudine should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). (Major) The concomitant use of interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. Interferon beta-1b has been shown to reduce zidovudine, ZDV, clearance by as much as 93% as interferon beta may interfere with the glucuronidation of zidovudine. Dosage reduction of zidovudine may be necessary when interferon beta and zidovudine are coadministered. Synergistic toxicity may occur with alpha interferons and zidovudine, as both can be myelosuppressive. Peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons; however a clinical trial showed an increased risk and severity of peripheral neuropathy with the combination of telbivudine and pegylated interferon alfa-2a compared to telbivudine alone. Interferons and NRTIs can both cause hepatic damage. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Lopinavir; Ritonavir: (Major) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatic damage. Most protease inhibitors have been associated with episodes of liver toxicity, with lopinavir/low-dose ritonavir, fosamprenavir/low-dose ritonavir, and nelfinavir being less hepatotoxic and tipranavir/low-dose ritonavir being the most hepatotoxic. Hyperbilirubinemia is often associated with atazanavir and/or indinavir therapy but does not reflect liver damage and is related to the inhibition of UDP glucuronosyltransferase. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Nelfinavir: (Major) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatic damage. Most protease inhibitors have been associated with episodes of liver toxicity, with lopinavir/low-dose ritonavir, fosamprenavir/low-dose ritonavir, and nelfinavir being less hepatotoxic and tipranavir/low-dose ritonavir being the most hepatotoxic. Hyperbilirubinemia is often associated with atazanavir and/or indinavir therapy but does not reflect liver damage and is related to the inhibition of UDP glucuronosyltransferase. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Nevirapine: (Major) The concomitant use of interferons and anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs) should be done with caution as both can cause hepatic damage. NNRTIs may cause liver damage in the context of hypersensitivity reactions or by direct toxic effects. Many studies demonstrate that nevirapine is more hepatotoxic than efavirenz. Underlying chronic HCV infection enhances the risk of developing liver enzyme elevations in patients receiving nevirapine. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatic damage. Most protease inhibitors have been associated with episodes of liver toxicity, with lopinavir/low-dose ritonavir, fosamprenavir/low-dose ritonavir, and nelfinavir being less hepatotoxic and tipranavir/low-dose ritonavir being the most hepatotoxic. Hyperbilirubinemia is often associated with atazanavir and/or indinavir therapy but does not reflect liver damage and is related to the inhibition of UDP glucuronosyltransferase. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Protease inhibitors: (Major) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatic damage. Most protease inhibitors have been associated with episodes of liver toxicity, with lopinavir/low-dose ritonavir, fosamprenavir/low-dose ritonavir, and nelfinavir being less hepatotoxic and tipranavir/low-dose ritonavir being the most hepatotoxic. Hyperbilirubinemia is often associated with atazanavir and/or indinavir therapy but does not reflect liver damage and is related to the inhibition of UDP glucuronosyltransferase. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Ritonavir: (Major) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatic damage. Most protease inhibitors have been associated with episodes of liver toxicity, with lopinavir/low-dose ritonavir, fosamprenavir/low-dose ritonavir, and nelfinavir being less hepatotoxic and tipranavir/low-dose ritonavir being the most hepatotoxic. Hyperbilirubinemia is often associated with atazanavir and/or indinavir therapy but does not reflect liver damage and is related to the inhibition of UDP glucuronosyltransferase. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Saquinavir: (Major) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatic damage. Most protease inhibitors have been associated with episodes of liver toxicity, with lopinavir/low-dose ritonavir, fosamprenavir/low-dose ritonavir, and nelfinavir being less hepatotoxic and tipranavir/low-dose ritonavir being the most hepatotoxic. Hyperbilirubinemia is often associated with atazanavir and/or indinavir therapy but does not reflect liver damage and is related to the inhibition of UDP glucuronosyltransferase. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Stavudine, d4T: (Major) The concomitant use of interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. Interferon beta-1b has been shown to reduce zidovudine, ZDV, clearance by as much as 93% as interferon beta may interfere with the glucuronidation of zidovudine. Dosage reduction of zidovudine may be necessary when interferon beta and zidovudine are coadministered. Synergistic toxicity may occur with alpha interferons and zidovudine, as both can be myelosuppressive. Peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons; however a clinical trial showed an increased risk and severity of peripheral neuropathy with the combination of telbivudine and pegylated interferon alfa-2a compared to telbivudine alone. Interferons and NRTIs can both cause hepatic damage. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Telbivudine: (Major) The concomitant use of interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. Interferon beta-1b has been shown to reduce zidovudine, ZDV, clearance by as much as 93% as interferon beta may interfere with the glucuronidation of zidovudine. Dosage reduction of zidovudine may be necessary when interferon beta and zidovudine are coadministered. Synergistic toxicity may occur with alpha interferons and zidovudine, as both can be myelosuppressive. Peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons; however a clinical trial showed an increased risk and severity of peripheral neuropathy with the combination of telbivudine and pegylated interferon alfa-2a compared to telbivudine alone. Interferons and NRTIs can both cause hepatic damage. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Theophylline, Aminophylline: (Major) Interferons, when administered systemically, may decrease the clearance of aminophylline resulting in increased plasma levels. Until additional information is available,interferons should be used cautiously in patients receiving aminophylline. Monitor theophylline concentrations and for signs and symptoms of toxicity. (Major) Interferons, when administered systemically, may decrease the clearance of theophylline resulting in increased plasma levels. Until additional information is available,interferons should be used cautiously in patients receiving theophylline. Monitor theophylline concentrations and for signs and symptoms of toxicity.
    Tipranavir: (Major) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatic damage. Most protease inhibitors have been associated with episodes of liver toxicity, with lopinavir/low-dose ritonavir, fosamprenavir/low-dose ritonavir, and nelfinavir being less hepatotoxic and tipranavir/low-dose ritonavir being the most hepatotoxic. Hyperbilirubinemia is often associated with atazanavir and/or indinavir therapy but does not reflect liver damage and is related to the inhibition of UDP glucuronosyltransferase. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Vigabatrin: (Major) Vigabatrin should not be used with interferons, which are associated with serious ophthalmic effects (e.g., retinopathy or glaucoma) unless the benefit of treatment clearly outweighs the risks.
    Zalcitabine, ddC: (Major) The concomitant use of interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. Interferon beta-1b has been shown to reduce zidovudine, ZDV, clearance by as much as 93% as interferon beta may interfere with the glucuronidation of zidovudine. Dosage reduction of zidovudine may be necessary when interferon beta and zidovudine are coadministered. Synergistic toxicity may occur with alpha interferons and zidovudine, as both can be myelosuppressive. Peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons; however a clinical trial showed an increased risk and severity of peripheral neuropathy with the combination of telbivudine and pegylated interferon alfa-2a compared to telbivudine alone. Interferons and NRTIs can both cause hepatic damage. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Zidovudine, ZDV: (Major) The concomitant use of interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. Interferon beta-1b has been shown to reduce zidovudine, ZDV, clearance by as much as 93% as interferon beta may interfere with the glucuronidation of zidovudine. Dosage reduction of zidovudine may be necessary when interferon beta and zidovudine are coadministered. Synergistic toxicity may occur with alpha interferons and zidovudine, as both can be myelosuppressive. Peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons; however a clinical trial showed an increased risk and severity of peripheral neuropathy with the combination of telbivudine and pegylated interferon alfa-2a compared to telbivudine alone. Interferons and NRTIs can both cause hepatic damage. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.

    PREGNANCY AND LACTATION

    Pregnancy

    Interferon gamma-1b is classified as FDA pregnancy risk category C. No adequate and well-controlled studies have been conducted in pregnant women, and its ability to cause fetal harm or affect reproductive capacity is unknown. In primate studies, an increased incidence of spontaneous abortion were observed at doses approximately 100-times the recommended human dose. The manufacturer advises use during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

    Data are limited regarding use of interferon gamma-1b during breast-feeding, and its excretion into breast milk is unknown. According to the manufacturer, either the drug or breast-feeding should be discontinued because of the potential for serious adverse reactions in a nursing infant. However, because the drug is a protein and likely to be digested by the infants gastrointestinal tract, the risk of systemic exposure and toxicity in a nursing infant may be limited. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, health care providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Interferon gamma-1b acts similarly to native interferon gamma. Interferons, including interferon gamma, are species-specific proteins produced in response to viruses as well as a variety of other natural and synthetic stimuli. Interferon gamma is a Type II interferon or immune interferon, which is produced by T-cells and natural killer (NK) cells after activation with immune or inflammatory stimuli as opposed to viral infection. CD8+ T-cells and CD4+ T-helper -0 and -1 subsets express interferon gamma in certain conditions. Following activation of T-cells, interferon gamma transcripts and proteins may be noted within hours. Interleukin (IL)-12 and IL-18 act synergistically to induce interferon gamma production by T-cells through mechanisms involving transcription factors and not activation of T-cell receptors. Interleukin-12 and tumor necrosis factor (TNF)-alpha, secreted by macrophages following contact with bacterial products, stimulate NK cells to secrete interferon gamma. Interferon gamma in turn stimulates macrophages to increase IL-12 and TNF-alpha production, which enhances interferon gamma synthesis by NK cells. Interleukin-10 downregulates interferon gamma production by NK and T-cells by preventing macrophage secretion of IL-12 and TNF-alpha.
    •Antiviral Effects: Interferon gamma has direct and indirect antiviral activities. Indirect actions are due to the effect of interferon gamma on immune responses including antigen processing and presentation and induction of antiviral cellular and humoral immune responses. All interferons can induce a direct 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 induces cellular resistance to cytomegalovirus, herpes simplex virus, and adenovirus in vitro.
    •Macrophage Activation: Interferon gamma is the primary factor for macrophage activation. Interferon gamma can induce the ability of macrophages to kill a variety of intracellular and extracellular parasites and neoplastic cells. Interferon gamma reduces the susceptibility of macrophages to microbial infection and enhances the recognition of targets during the innate phase of immunity through the regulation of certain cell-surface proteins. Interferon gamma upregulates TNF-alpha, interferon-beta, and IL-1, which enhance macrophage activity, while downregulating the production of macrophage inhibitory cytokines IL-4 and IL-10. Interferon gamma enhances oxidative metabolism due to nitric oxide (NO) or NADPH oxidase products (e.g., superoxide, hydrogen peroxide, and hypohalous acid). Enhanced oxidative metabolism 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. Patients with chronic granulomatous disease lack components of NADPH oxidase leading to an inability to produce reactive oxygen species resulting in severe recurrent infections. 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.
    •Antigen Processing and Presentation: Interferon gamma enhances antigen processing and signaling by increasing the expression of MHC class I and II proteins on the membranes of B-cells, dendritic cells, and macrophages. Interferon gamma also enhances antigen processing by regulating proteins required for antigenic peptide generation and increasing the expression of peptide transporters associated with antigen processing.
    •Humoral Immunity: Interferon gamma increases the expression of high-affinity Fc receptors for IgG on monocytes and macrophages. Additionally, interferon gamma is an important regulator of Ig class receptor switching. Interferon gamma facilitates the interaction between humoral and cellular immune responses and thus, enhances host defense against viral and bacterial organisms.
    •Antitumor Effects: Proposed mechanisms for interferon gamma include increasing expression of tumor suppressor genes such as IRF-1 and PKR and the ability to activate macrophages to nonspecifically lysis tumor cells through oxygen and nitrogen reactive intermediates and production of TNF. Interferon gamma can increase the antigenicity of tumors by increasing the expression of MHC class I and II proteins. However, trials of interferon gamma in many solid tumors have been disappointing.
    •Other Effects: Interferon gamma enhances recruitment of leukocytes to sites of infection or inflammation and increases intracellular concentrations of certain antimicrobials, including macrolides and quinolones. This activity is important in the ability of interferon gamma to clear infections.

    PHARMACOKINETICS

    Interferon gamma-1b is administered subcutaneously. Available pharmacokinetic data were obtained through study of healthy males. Interferon gamma-1b is not detected in the urine following administration to healthy adult males.
     
    Affected cytochrome P-450 isoenzymes: none
    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 the CYP450 system may be susceptible to drug interactions with interferon gamma-1b. Until additional human data are available, interferon gamma-1b should be used cautiously in patients receiving drugs that are metabolized by the CYP system, especially drugs with a narrow therapeutic index.
     

    Intravenous Route

    Following intravenous bolus administration, the half-life of interferon gamma-1b is 25—35 minutes, which is similar to endogenous interferon gamma.

    Subcutaneous Route

    Following subcutaneous administration of interferon gamma-1b, 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. Accumulation does not occur following multiple subcutaneous doses.