CLASSES

Interferons, Gamma

DEA CLASS

Rx

DESCRIPTION

Recombinant gamma interferon
Used for reducing frequency and severity of infections in chronic granulomatous disease (CGD) and for delaying time to disease progression in severe, malignant osteopetrosis
Premedicate with acetaminophen and administer at bedtime to minimize flu-like symptoms

COMMON BRAND NAMES

Actimmune

HOW SUPPLIED

Actimmune Subcutaneous Inj Sol: 0.5mL, 100mcg

DOSAGE & INDICATIONS

†Indicates off-label use

MAXIMUM DOSAGE

50 mcg/m2/dose subcutaneously.

50 mcg/m2/dose subcutaneously.

50 mcg/m2/dose subcutaneously.

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

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

DOSING CONSIDERATIONS

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.

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.

STORAGE

Actimmune:
- Discard product if it contains particulate matter, is cloudy, or discolored
- Discard product if stored at room temperature for more than 12 hours
- Discard unused portion. Do not store for later use.
- Do not freeze
- Product stored at controlled room temperature should not be returned to a refrigerator
- Refrigerate (between 36 and 46 degrees F)

CONTRAINDICATIONS / PRECAUTIONS

A clinical trial comparing interferon gamma-1b to placebo in the treatment of idiopathic pulmonary fibrosis (IPF) was terminated early as an interim analysis showed that patients who received interferon gamma-1b did not benefit. At a median duration of 64 weeks (range: 41 to 84 weeks), 15% of patients treated with interferon gamma-1b died, compared to 13% of patients treated with placebo.

Monitor neutrophil and platelet counts in patients with with preexisting bone marrow suppression, such as patients with immunosuppression, during treatment with interferon gamma-1b. Severe, reversible neutropenia and thrombocytopenia that may be dose-related have been observed with interferon gamma-1b therapy. All patients are recommended to have a complete blood count with differential at baseline and every 3 months during treatment.

Monitor liver function at baseline and monthly in all infants who receive interferon gamma-1b. In clinical trials, the incidence of elevated hepatic enzyme concentrations (2- to 25-fold increase) appeared to be higher in patients less than 1 year of age compared to older children. The elevations occurred as early as 7 days after initiation of treatment and were reversible with interruption of treatment and dosage reduction. The safety and effectiveness of interferon gamma-1b in neonates and infants for the treatment of chronic granulomatous disease (CGD) have not been established.

Monitor patients with preexisting cardiac disease including ischemia (i.e., angina or myocardial infarction), congestive heart failure, or cardiac arrhythmias, for signs or symptoms of exacerbation. 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 of 250 mcg/m2/day or more may exacerbate the cardiac condition. Some of the flu-like symptoms may be minimized by administration of interferon gamma-1b at bedtime and concomitant use of acetaminophen.

Monitor patients with seizure disorder or compromised central nervous system function when administering interferon gamma-1b. Adverse CNS reactions such as decreased mental status, gait disturbance, and dizziness have been reported with interferon gamma-1b, particularly in patients receiving doses of 250 mcg/m2/day or more. Most events were mild and reversible within a few days of either dose reduction or therapy discontinuation. Advise all patients to use caution when driving or operating machinery until they are aware of how this medication affects them.

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. Additionally, the stopper of the glass vial contains natural rubber, a derivative of latex, which may cause allergic reactions in patients with latex hypersensitivity.

Monitor liver function frequently in patients with advanced hepatic disease as repeated administration of interferon gamma-1b may result in accumulation of the drug. Elevated hepatic enzymes have been reported. The transaminase elevations were reversible with treatment interruption and/or dosage reduction. If severe hepatic enzyme elevations occur, modify the interferon gamma-1b dosage. Monitor liver function tests at baseline and at least every 3 months in all patients.

Monitor renal function regularly in patients with severe renal impairment or renal failure when administering interferon gamma-1b as repeated administration may result in accumulation of the drug. Renal toxicity has been reported in patients receiving interferon gamma-1b. Monitor renal function tests and urinalysis at baseline and at least every 3 months in all patients.

Use interferon gamma-1b during pregnancy only if the potential benefit justifies the potential risk to the fetus. There are no adequate and well-controlled studies of interferon gamma-1b use in pregnant women. In animal studies, an increased incidence of spontaneous abortion was observed at interferon gamma-1b doses approximately 100 times the recommended human dose. No teratogenicity was observed with subcutaneous doses of 2 to 100 times the human dose.

It is unknown if interferon gamma-1b is excreted into breast milk. Because many drugs are excreted in breast milk and due to the potential for serious adverse reactions in the nursing infant from interferon gamma-1b, discontinue breast-feeding or discontinue interferon gamma-1b, taking into consideration the importance of the drug to the mother.

Based on available data, it cannot be excluded that the presence of higher concentrations of interferon gamma-1b may pose a reproductive risk and impair male fertility, and that in certain cases of female infertility, higher concentrations of interferon gamma-1b may have contributed. In younger patients, the long-term effects of interferon gamma-1b on fertility are unknown. In female animal studies, irregular menstrual cycles or absence of cyclicity during treatment was observed at interferon gamma-1b doses approximately 20 and 100 times the human dose; similar findings were not seen with doses of 3 mcg/kg. Increased incidence of atretic ovarian follicles was observed at interferon gamma-1b doses 32 times the maximum recommended clinical dose for 4 weeks. In male animal studies, decreased spermatogenesis was observed at 8 times the maximum recommended clinical dose for 4 weeks; reversible decreases in sperm counts and fertility and an increase in the number of abnormal sperm were also observed in animals treated with interferon gamma-1b from shortly after birth through puberty with doses 280 times the maximum recommended clinical dose. The impact and clinical significance of these findings on fertility are unknown.

Vaccination with live vaccines should be avoided due to the risk of neutropenia during interferon gamma-1b therapy.

ADVERSE REACTIONS

GI bleeding / Delayed / Incidence not known
pancreatitis / Delayed / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
lupus-like symptoms / Delayed / Incidence not known
proteinuria / Delayed / Incidence not known
renal failure (unspecified) / Delayed / Incidence not known
seizures / Delayed / Incidence not known
myocardial infarction / Delayed / Incidence not known
pulmonary embolism / Delayed / Incidence not known
heart failure / Delayed / Incidence not known
AV block / Early / Incidence not known
atrial fibrillation / Early / Incidence not known
thrombosis / Delayed / Incidence not known
arrhythmia exacerbation / Early / Incidence not known
bronchospasm / Rapid / Incidence not known
pulmonary edema / Early / Incidence not known

chest pain (unspecified) / Early / Incidence not known
colitis / Delayed / Incidence not known
atopic dermatitis / Delayed / Incidence not known
erythema / Early / Incidence not known
leukopenia / Delayed / Incidence not known
neutropenia / Delayed / Incidence not known
thrombocytopenia / Delayed / Incidence not known
hyponatremia / Delayed / Incidence not known
hyperglycemia / Delayed / Incidence not known
hypertriglyceridemia / Delayed / Incidence not known
hypokalemia / Delayed / Incidence not known
elevated hepatic enzymes / Delayed / Incidence not known
hepatomegaly / Delayed / Incidence not known
depression / Delayed / Incidence not known
ataxia / Delayed / Incidence not known
hallucinations / Early / Incidence not known
confusion / Early / Incidence not known
angina / Early / Incidence not known
hypotension / Rapid / Incidence not known
sinus tachycardia / Rapid / Incidence not known
antibody formation / Delayed / Incidence not known
tachypnea / Early / Incidence not known
pneumonitis / Delayed / Incidence not known

fever / Early / 52.0-52.0
headache / Early / 33.0-33.0
rash / Early / 17.0-17.0
chills / Rapid / 14.0-14.0
fatigue / Early / 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
malaise / Early / Incidence not known
asthenia / Delayed / Incidence not known
weakness / Early / Incidence not known
abdominal pain / Early / Incidence not known
dyspepsia / Early / Incidence not known
urticaria / Rapid / Incidence not known
weight loss / Delayed / Incidence not known
dizziness / Early / Incidence not known
back pain / Delayed / Incidence not known
syncope / Early / Incidence not known
infection / Delayed / Incidence not known

DRUG INTERACTIONS

Abacavir: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Abacavir; Dolutegravir; Lamivudine: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6). (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Abacavir; Lamivudine, 3TC: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6). (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Major) Use interferons and zidovudine together with caution. Closely monitor patients for treatment-associated toxicities, especially hematologic effects and hepatic decompensation, and manage as recommended for the individual therapies. Coadministration of alpha interferons may increase the hematologic toxicity of zidovudine. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) are also associated with hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. Interferon therapy may also reduce zidovudine clearance. (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6). (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
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: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. 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.
Atazanavir; Cobicistat: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. 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.
Bacillus Calmette-Guerin Vaccine, BCG: (Major) Avoid the concomitant use of interferon gamma-1b with other immunological preparations such as live vaccines due to the risk of an unpredictable or amplified, immune response.
Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Cabotegravir; Rilpivirine: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Chloroquine: (Moderate) Concurrent use of chloroquine and interferons is not recommended as there is an increased risk of retinal toxicity.
Darunavir: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. 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.
Darunavir; Cobicistat: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. 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.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. 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. (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. 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.
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.
Dolutegravir; Lamivudine: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
Dolutegravir; Rilpivirine: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
Efavirenz: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and efavirenz can both cause hepatotoxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and efavirenz can both cause hepatotoxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6). (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and efavirenz can both cause hepatotoxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Emtricitabine: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Emtricitabine; Tenofovir alafenamide: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Entecavir: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Fosamprenavir: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. 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.
Indinavir: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. 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.
Intranasal Influenza Vaccine: (Major) Avoid the concomitant use of interferon gamma-1b with other immunological preparations such as live vaccines due to the risk of an unpredictable or amplified, immune response.
Lamivudine, 3TC: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
Lamivudine, 3TC; Zidovudine, ZDV: (Major) Use interferons and zidovudine together with caution. Closely monitor patients for treatment-associated toxicities, especially hematologic effects and hepatic decompensation, and manage as recommended for the individual therapies. Coadministration of alpha interferons may increase the hematologic toxicity of zidovudine. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) are also associated with hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. Interferon therapy may also reduce zidovudine clearance. (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
Live Vaccines: (Major) Avoid the concomitant use of interferon gamma-1b with other immunological preparations such as live vaccines due to the risk of an unpredictable or amplified, immune response.
Lopinavir; Ritonavir: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. 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.
Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Major) Avoid the concomitant use of interferon gamma-1b with other immunological preparations such as live vaccines due to the risk of an unpredictable or amplified, immune response.
Measles/Mumps/Rubella Vaccines, MMR: (Major) Avoid the concomitant use of interferon gamma-1b with other immunological preparations such as live vaccines due to the risk of an unpredictable or amplified, immune response.
Nelfinavir: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. 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.
Nevirapine: (Major) The concomitant use of interferons and nevirapine should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Nevirapine may cause liver damage in the context of hypersensitivity reactions or by direct toxic effects. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. Patients with signs or symptoms of hepatitis, or with increased transaminases combined with rash or other systemic symptoms, must discontinue nevirapine and seek medical evaluation immediately.
Nirmatrelvir; Ritonavir: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. 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.
Ombitasvir; Paritaprevir; Ritonavir: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. 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.
Protease inhibitors: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. 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.
Rilpivirine: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Ritonavir: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. 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.
Rotavirus Vaccine: (Major) Avoid the concomitant use of interferon gamma-1b with other immunological preparations such as live vaccines due to the risk of an unpredictable or amplified, immune response.
Rubella Virus Vaccine Live: (Major) Avoid the concomitant use of interferon gamma-1b with other immunological preparations such as live vaccines due to the risk of an unpredictable or amplified, immune response.
Saquinavir: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. 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.
Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (Major) Avoid the concomitant use of interferon gamma-1b with other immunological preparations such as live vaccines due to the risk of an unpredictable or amplified, immune response.
Smallpox Vaccine, Vaccinia Vaccine: (Major) Avoid the concomitant use of interferon gamma-1b with other immunological preparations such as live vaccines due to the risk of an unpredictable or amplified, immune response.
Stavudine, d4T: (Major) Patients receiving stavudine with interferons (with or without ribavirin) should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation compared to patients not receiving HAART. Additionally, stavudine has been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Discontinuation of stavudine should be considered as medically appropriate. Dose reduction or discontinuation of interferon, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
Telbivudine: (Major) An increased risk and severity of peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons. Patients should be advised to report any numbness, tingling, and/or burning sensations in the arms and/or legs, with or without gait disturbance. Interrupt telbivudine if peripheral neuropathy is suspected, and discontinue the drug if peripheral neuropathy is confirmed. Since both interferons and telbivudine may cause hepatotoxicity, hepatic function should also be closely monitored.
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: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. 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.
Typhoid Vaccine: (Major) Avoid the concomitant use of interferon gamma-1b with other immunological preparations such as live vaccines due to the risk of an unpredictable or amplified, immune response.
Varicella-Zoster Virus Vaccine, Live: (Major) Avoid the concomitant use of interferon gamma-1b with other immunological preparations such as live vaccines due to the risk of an unpredictable or amplified, immune response.
Vigabatrin: (Major) Vigabatrin is associated with vision loss. The drug should not be used with interferons, which are associated with a potential for serious ophthalmic effects (e.g., retinopathy, optic neuritis, visual impairment), unless the benefit of treatment clearly outweighs the risks.
Yellow Fever Vaccine, Live: (Major) Avoid the concomitant use of interferon gamma-1b with other immunological preparations such as live vaccines due to the risk of an unpredictable or amplified, immune response.
Zidovudine, ZDV: (Major) Use interferons and zidovudine together with caution. Closely monitor patients for treatment-associated toxicities, especially hematologic effects and hepatic decompensation, and manage as recommended for the individual therapies. Coadministration of alpha interferons may increase the hematologic toxicity of zidovudine. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) are also associated with hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. Interferon therapy may also reduce zidovudine clearance.

PREGNANCY AND LACTATION

Use interferon gamma-1b during pregnancy only if the potential benefit justifies the potential risk to the fetus. There are no adequate and well-controlled studies of interferon gamma-1b use in pregnant women. In animal studies, an increased incidence of spontaneous abortion was observed at interferon gamma-1b doses approximately 100 times the recommended human dose. No teratogenicity was observed with subcutaneous doses of 2 to 100 times the human dose.

It is unknown if interferon gamma-1b is excreted into breast milk. Because many drugs are excreted in breast milk and due to the potential for serious adverse reactions in the nursing infant from interferon gamma-1b, discontinue breast-feeding or discontinue interferon gamma-1b, taking into consideration the importance of the drug to the mother.

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.