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    Interferons for Hepatitis
    Interferons, Alpha

    BOXED WARNING

    Alcoholism, bipolar disorder, depression, driving or operating machinery, encephalopathy, mania, neurologic events, peripheral neuropathy, psychiatric event, psychosis, seizure disorder, seizures, substance abuse, suicidal ideation

    Alpha interferons, including peginterferon alfa-2a, may cause or aggravate a psychiatric event or disorder. Patients should be monitored closely with periodic clinical and laboratory evaluations. It is recommended to monitor and evaluate for these conditions every 3 weeks during the first 8 weeks of treatment and every 6 months thereafter and for at least 6 months after the last dose. Permanently discontinue peginterferon alfa-2a therapy for homicidal or suicidial ideation, aggressive behavior towards others, severe depression, or other severe or persistent psychiatric symptoms; institute psychiatric intervention and follow-up as appropriate. In many, but not all cases, these disorders may resolve after stopping therapy. Patients should be warned to report changes in moods or behaviors, depression, suicidal ideation or other symptoms promptly to their health care provider. Any patient with a history of substance abuse (e.g., alcoholism), encephalopathy, depression or severe psychiatric disorder (e.g., bipolar disorder, mania, psychosis) should receive peginterferon alfa-2a with extreme caution, since these conditions may worsen or relapse. Former drug addicts may fall back into drug addiction or overdose. Although dose reduction or cessation of therapy may lead to resolution of the symptoms, depression or other psychiatric symptoms may persist and suicides have occurred even after withdrawing therapy, and continued psychiatric intervention may be needed. Neurologic events have also been reported with use. Because dizziness and drowsiness are common, patients should also be warned against driving or operating machinery until they know how peginterferon alfa-2a therapy will affect them. EEG abnormalities and seizures have been reported in post-market use and peginterferon alfa-2a should be used with caution in patients with a pre-existing seizure disorder. Peripheral neuropathy has been reported when alpha interferons were given in combination with telbivudine. In one clinical trial, an increased risk and severity of peripheral neuropathy was observed with the combination use of telbivudine and peginterferon alfa-2a as compared to telbivudine alone. The safety and efficacy of telbivudine in combination with interferons for the treatment of chronic hepatitis B have not been demonstrated.

    Infection

    Alpha interferons, including peginterferon alfa-2a, may cause or aggravate fatal or life-threatening infections. Serious and severe infections (bacterial infection, viral infection, or fungal infection), some fatal, have been reported during treatment with alpha interferons, including peginterferon alfa-2a. Suppression of the bone marrow due to peginterferon alfa-2a increases the risk for serious infections, but such infections may also occur in the absence of decreased neutrophil counts. Patients should be monitored closely with baseline and periodic monitoring and clinical and laboratory evaluations. While fever may be associated with the flu-like syndrome reported commonly during interferon therapy, other causes of high or persistent fever must be ruled out, particularly in patients with reduced neutrophil counts. Appropriate anti-infective therapy should be started immediately and discontinuation of peginterferon alfa-2a therapy should be considered.

    Autoimmune disease, idiopathic thrombocytopenic purpura (ITP), psoriasis, rheumatoid arthritis, systemic lupus erythematosus (SLE), thrombotic thrombocytopenic purpura (TTP)

    Peginterferon alfa-2a should be used with caution in patients with a history of autoimmune disease. Peginterferon alfa-2a is contraindicated for use in patients with autoimmune hepatitis. Development or exacerbation of autoimmune diseases (e.g., myositis, hepatitis, thrombotic thrombocytopenic purpura (TTP), idiopathic thrombocytopenic purpura (ITP), thyroiditis, thrombocytopenia, rheumatoid arthritis, intersitial nephritis, systemic lupus erythematosus (SLE), or psoriasis) has been observed in patients receiving alpha interferons. Patients should be monitored closely with periodic clinical and laboratory evaluations. Peginterferon alfa-2a should be discontinued in patients with persistently severe or worsening signs or symptoms of these conditions. In many, but not all cases, these disorders resolve after stopping peginterferon alfa-2a.

    Angina, cardiac arrhythmias, cardiac disease, cardiomyopathy, cerebrovascular disease, coronary artery disease, hypertension, myocardial infarction or stroke

    Ischemic and other cerebrovascular and cardiovascular events (e.g., hypertension, supraventricular arrhythmias, cardiomyopathy, chest pain, unstable angina pectoris, myocardial infarction or stroke) have been observed in patients treated with peginterferon alfa-2a. Some events occurred in patients with few or no reported risk factors. The drug should be used cautiously in patients with cardiac disease (including coronary artery disease) or cerebrovascular disease. Common adverse effects of peginterferon alfa-2a such as fever and chills may exacerbate preexisting cardiac conditions. Patients with a history of myocardial infarction and cardiac arrhythmias should be closely monitored, with baseline and periodic monitoring and clinical and laboratory evaluations. An electrocardiogram (ECG) is recommended prior to initiating therapy in such patients. Ischemic and hemorrhagic cerebrovascular events (e.g., strokes) have been observed in patients treated with interferon alfa-based therapies, including peginterferon alfa-2a. Events occurred in patients with few or no reported risk factors for stroke, including patients less than 45 years of age. Because these are spontaneous reports, estimates of frequency cannot be made, and a causal relationship between interferon alfa-based therapies and these events is difficult to establish. Peginterferon alfa-2a should be discontinued in patients with persistently severe or worsening signs or symptoms of these conditions. In many, but not all cases, these disorders resolve after stopping peginterferon alfa-2a. Because cardiac disease may be worsened by ribavirin-induced hemolytic anemia, patients with a history of significant or unstable cardiac disease should not receive combination therapy with ribavirin.

    Contraception requirements, pregnancy, pregnancy testing, use with ribavirin

    There are no adequate and well-controlled studies evaluating use of peginterferon alfa-2a in pregnant women. Peginterferon alfa-2a should be assumed to have abortifacient potential based on studies in pregnant Rhesus monkeys, which showed a statistically significant increase in abortions. No teratogenic effects were seen in the offspring delivered at term. Peginterferon alfa-2a monotherapy may be administered to women of childbearing potential only after a confirmed negative pregnancy test. Advise female patients to use effective contraception requirements during therapy. Ribavirin use with peginterferon alfa-2a poses additional risks during pregnancy, and clinicians should be fully aware of the contraindications, as well as the proper use and monitoring for ribavirin therapy. Peginterferon alfa-2a use with ribavirin is contraindicated in women who are pregnant and men whose female partners are pregnant. Ribavirin may cause birth defects and death of the unborn child (intrauterine fetal death), and is genotoxic and mutagenic. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients if ribavirin is prescribed. Females drug recipients and female partners of male drug recipients must undergo pregnancy testing before starting peginterferon alfa-2a and ribavirin combination therapy, every month while being treated, and every month for the 6 months after treatment is discontinued. Contraceptive requirements exist for both males and females of childbearing potential in whom both ribavirin and peginterferon alfa-2a are prescribed. Both men and women of childbearing potential must use 2 forms of effective contraception during treatment and for 6 months after combination treatment discontinuation. If a female or the female sexual partner of a treated male becomes pregnant while taking peginterferon alfa-2a and ribavirin or within 6 months after discontinuation of treatment, the healthcare provider should be informed right away. The Ribavirin Pregnancy Registry (1-800-593-2214) should be contacted.

    DEA CLASS

    Rx

    DESCRIPTION

    Covalent conjugate of recombinant interferon alfa-2a with PEG
    Used to treat chronic HCV infections in patients 5 years and older, and chronic HBV infections in patients 3 years and older
    Improved tolerability when compared with interferon alfa-2a

    COMMON BRAND NAMES

    Pegasys, Pegasys ProClick

    HOW SUPPLIED

    Pegasys/Pegasys ProClick Subcutaneous Inj Sol: 0.5mL, 1mL, 135mcg, 180mcg

    DOSAGE & INDICATIONS

    For the treatment of chronic hepatitis C infection in patients with compensated liver disease.
    NOTE: The vials, prefilled syringes, and autoinjectors are not directly interchangeable. The same amount of drug will not be provided by equal volumes. The 1 mL vial and the 0.5 mL prefilled syringe both provide 180 mcg peginterferon alfa-2a; there are 2 autoinjector concentrations available, 180 mcg/0.5 mL and 135 mcg/0.5 mL.
    NOTE: Patients who have failed other alfa interferon treatments, must receive peginterferon alfa-2a in combination with BOTH ribavirin AND either a NS3/4A protease inhibitor or a NS5B polymerase inhibitor.
    NOTE: Safety and efficacy have not been established in patients who are liver or other organ transplant recipients, are coinfected with hepatitis B, or are coinfected with HIV with a CD4 cell count less than 100 cells/mm3.
    For the treatment of chronic hepatitis C as monotherapy.
    NOTE: Monotherapy is not recommended unless there are contraindications or substantial intolerance to other HCV antiviral therapies. The efficacy of peginterferon alfa-2a is enhanced when used in combination with other HCV therapies.
    Subcutaneous dosage
    Adults

    180 mcg subcutaneously once weekly for 48 weeks. Guidelines recommend the use of a peginterferon product plus ribavirin as part of a combination regimen depending on patient factors and genotype. There are no safety and efficacy data on treatment longer than 48 weeks. Consider treatment discontinuation if the HCV-RNA is detectable after 24 weeks or if there is not at least a 2 log10 reduction by 12 weeks. During clinical trials, only 3 of 156 patients (2%) who did not demonstrate at least a 2 log10 reduction by treatment week 12 achieved a sustained virologic response with continued treatment.

    For the treatment of chronic hepatitis C in combination with ribavirin alone.
    Subcutaneous dosage
    Adults

    180 mcg subcutaneously once weekly plus daily ribavirin for 24 or 48 weeks depending upon the viral genotype. Guidelines recommend the use of a peginterferon product plus ribavirin as part of a combination regimen depending on patient factors and genotype. For hepatitis virus C genotypes 1 or 4, a treatment duration of 48 weeks plus daily ribavirin is recommended. For HCV genotypes 2 or 3, a treatment duration of 24 weeks plus daily ribavirin is recommended. Data on genotypes 5 and 6 are insufficient for dosing recommendations. Consider treatment discontinuation if the HCV-RNA is detectable after 24 weeks or if there is not at least a 2 log10 reduction by 12 weeks.

    Children and Adolescents 5 years and older

    180 mcg/1.73 m2 x BSA subcutaneously once weekly (max: 180 mcg/week) plus ribavirin. Duration of treatment is 24 weeks for genotype 2 and 3 and 48 weeks for all other genotypes. Consider treatment discontinuation if the HCV-RNA is detectable after 24 weeks or if there is not at least a 2 log10 reduction by 12 weeks.

    For the treatment of chronic hepatitis C genotype 1 infection in combination with a nucleotide analog NS5B polymerase inhibitor or NS3/4A protease inhibitor plus ribavirin.
    Subcutaneous dosage
    Treatment-naive and prior relapse adults able to receive interferon products

    180 mcg subcutaneously once weekly with sofosbuvir and ribavirin for 12 weeks as the preferred treatment regimen; includes HIV-coinfected patients. Alternatively, 180 mcg subcutaneously once weekly with simeprevir and ribavirin for an initial 12 weeks of treatment. After the initial 3-drug regimen, give an additional 12 weeks of only peginterferon alfa and ribavirin (24 weeks for total course); includes HIV-coinfected patients without significant drug interactions. Another alternative include 180 mcg subcutaneously once weekly with boceprevir and ribavirin for 28 to 48 weeks depending on response to therapy (boceprevir added after first 4 weeks). AASLD guidelines recommend against the use of boceprevir because of inferiority compared to other regimens; however, the WHO suggests it may be an appropriate option.

    Adults failing previous peginterferon alfa and ribavirin treatment (nonresponders) without previous exposure to HCV protease inhibitors

    As an alternative for patients able to receive interferon products, peginterferon alfa 180 mcg subcutaneously once weekly in combination with one of the following: sofosbuvir and ribavirin for 12 weeks (includes HIV-coinfected patients); simeprevir and ribavirin for an initial 12 weeks, followed by an additional 36 weeks of only peginterferon alfa and ribavirin (includes HIV-coinfected patients without significant drug interactions); boceprevir and ribavirin for 36 to 48 weeks depending on response to therapy (boceprevir added after first 4 weeks). AASLD guidelines recommend against the use of boceprevir because of inferiority compared to other regimens; however, the WHO suggests it may be an appropriate option.  

    Adults failing previous treatment with peginterferon alfa, ribavirin, and a NS3/4A protease inhibitor (nonresponders)

    180 mcg subcutaneously once weekly with sofosbuvir and ribavirin for 12 weeks for genotype 1a; add an additional 12 weeks (24 weeks total) of peginterferon alfa and ribavirin for genotype 1b. This includes HIV-coinfected patients.

    For the treatment of chronic hepatitis C genotype 2 infection in combination with a nucleotide analog NS5B polymerase inhibitor plus ribavirin.
    Subcutaneous dosage
    Adults

    As alternative for nonresponders, peginterferon alfa 180 mcg subcutaneously once weekly with sofosubuvir and ribavirin for 12 weeks is recommended based on a small study.

    For the treatment of chronic hepatitis C genotype 3 infection in combination with a nucleotide analog NS5B polymerase inhibitor plus ribavirin.
    Subcutaneous dosage
    Adults

    An alternative regimen includes peginterferon alfa 180 mcg subcutaneously once weekly with sofosbuvir and ribavirin for 12 weeks; however, increased adverse effects and monitoring requirements make this a less acceptable regimen.

    For the treatment of chronic hepatitis C genotype 4 infection in combination with a nucleotide analog NS5B polymerase inhibitor or NS3/4A protease inhibitor plus ribavirin.
    Subcutaneous dosage
    Adults

    180 mcg subcutaneously once weekly with sofosbuvir and ribavirin for 12 weeks as the preferred regimen; includes HIV-coinfected patients. As an alternative in patients able to receive interferon therapy, combine with simeprevir and ribavirin for 12 weeks, then continue peginterferon alfa and ribavirin to complete 24—48 weeks total; includes HIV-coinfected patients without significant drug interactions.

    For the treatment of chronic hepatitis C genotype 5† or 6† infection in combination with a nucleotide analog NS5B polymerase inhibitor plus ribavirin.
    Subcutaneous dosage
    Adults

    180 mcg subcutaneously once weekly with sofosbuvir and ribavirin for 12 weeks is recommended based on a small number of patients; includes HIV-coinfected patients. As an alternative in treatment-naive patients, combine peginterferon alfa with ribavirin for 48 weeks; includes HIV-coinfected patients.

    For the treatment of chronic hepatitis B infection.
    Subcutaneous dosage
    Adults with compensated liver disease who have HBeAg-positive and HBeAg-negative chronic HBV infection with evidence of viral replication and liver inflammation

    180 mcg subcutaneously once weekly for 48 weeks. There are no safety and efficacy data on treatment longer than 48 weeks.

    Children and Adolescents 3 years and older who are non-cirrhotic and have HBeAg-positive chronic HBV infection with evidence of viral replication and elevated serum alanine aminotransferase (ALT)

    180 mcg/1.73 m2 x BSA subcutaneously once weekly (max: 180 mcg/week) for 48 weeks. Maintain the recommended pediatric dosage throughout the entire duration of therapy in patients who turn 18 years of age during treatment.

    MAXIMUM DOSAGE

    Adults

    180 mcg/week subcutaneously.

    Geriatric

    180 mcg/week subcutaneously.

    Adolescents

    180 mcg/1.73 m2 x BSA subcutaneously once weekly, up to a maximum of 180 mcg weekly.

    Children

    5 years and older: 180 mcg/1.73 m2 x BSA subcutaneously once weekly, up to a maximum of 180 mcg weekly.
    3 to 4 years: 180 mcg/1.73 m2 x BSA subcutaneously once weekly, up to a maximum of 180 mcg weekly for chronic hepatitis B; safety and efficacy for hepatitis C have not been established.
    Younger than 3 years: Safety and efficacy have not been established.

    Infants

    Use not recommended.

    Neonates

    Use not recommended.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Patients with decompensated hepatic disease (e.g., Child-Pugh class B or C) should not be treated with peginterferon alfa-2a. Peginterferon alfa-2a is also contraindicated for use in patients with autoimmune hepatitis. If ALT increases are progressive despite dose reduction or are accompanied by increased bilirubin or evidence of hepatic decompensation, immediately discontinue therapy.
     
    Adult patients with chronic hepatitis C: In patients with progressive ALT increases above baseline values, reduce the dose to 135 mcg SC once weekly and perform more frequent liver function monitoring. Peginterferon alfa-2a may be resumed after the ALT flare has subsided.
     
    Adult patients with chronic hepatitis B: In patients with ALT values greater than 5 times the upper limit of normal, consider dose reduction to 135 mcg SC once weekly or temporary drug discontinuation and perform more frequent liver function monitoring. Peginterferon alfa-2a may be resumed after ALT flares subside. Therapy discontinuation may be appropriate for patients with persistent ALT elevations more than 10 times the upper limit of normal.
     
    Children and Adolescents with chronic hepatitis C:
    -For alanine transaminase (ALT) > 5 but < 10 x upper limit of normal (ULN) in children and adolescents: Reduce dose to 135 mcg/1.73 m2 x BSA SC once weekly. If necessary, further modify dose until stable or ALT concentrations decrease.
    -For persistent alanine transaminase (ALT) > 10 x ULN in children and adolescents: Discontinue treatment.

    Renal Impairment

    NOTE: In all patients, estimate the creatinine clearance before peginterferon alfa-2a initiation. Due to a lack of data, dosage recommendations cannot be made for pediatric patients with renal impairment.
    CrCl >= 30 ml/min: No dosage adjustment needed.
    CrCl < 30 ml/min (Adults): Reduce dose to 135 mcg SC once weekly and closely monitor for signs and symptoms of interferon toxicity. If severe adverse reactions or laboratory abnormalities develop, the dose may be further reduced to 90 mcg SC once weekly until the adverse reactions abate. If intolerance persists after dose adjustment, discontinue peginterferon alfa-2a.
     
    Intermittent hemodialysis
    Adults: 135 mcg SC once weekly. Monitor patients closely for the potential for reduced efficacy and for signs and symptoms of interferon toxicity. If severe adverse reactions or laboratory abnormalities develop, the dose may be reduced to 90 mcg SC once weekly until the adverse reactions abate. If intolerance persists after dose adjustment, discontinue peginterferon alfa-2a.

    ADMINISTRATION

     
    NOTE: Variations in dosage and adverse reactions exist among different subtypes of interferon alfa. Therefore, do not use different brands of interferon in a single treatment regimen. Also, the vials, prefilled syringes, and autoinjectors of peginterferon alfa-2a are not directly interchangeable. The same amount of drug will not be provided by equal volumes.
     
    NOTE: Due to possible severe central nervous system reactions and severe hematologic reactions, baseline neuropsychiatric monitoring and complete blood count assessment of all patients are recommended. Pregnancy screening, liver function tests, serum creatinine, and thyroid function tests are also recommended prior to initiating therapy.
     
    NOTE: Patients should be well hydrated before drug receipt, if clinically appropriate.

    Injectable Administration

    Administer subcutaneously. Do not inject intradermally, intramuscularly, or intravenously.
    Only an individual trained in subcutaneous drug delivery should administer the injection. The initial injection should be given by a trained health care professional. A patient that is properly trained in subcutaneous injection technique may self-inject, if appropriate.
    Premedication with acetaminophen or ibuprofen may decrease the incidence of administration-related reactions (i.e., fever). Bedtime administration may increase patient tolerance of therapy.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. The solution should be clear and colorless or a light yellow. Do not use if the solution has visible particles, flakes, color, or is cloudy.

    Subcutaneous Administration

    Do not use the vials, prefilled syringes, or autoinjectors interchangeably without noting the drug concentration difference. The volume to be administered will vary based on the product. All preparations are single dose only; discard any unused solution.
    180 mcg dose: 1 ml from 180 mcg/ml vial; 0.5 ml from 180 mcg/ 0.5 ml prefilled syringe; 0.5 ml from 180 mcg/0.5 ml autoinjector; do not use 135 mcg/0.5 ml autoinjector.
    135 mcg dose: 0.75 ml from 180 mcg/ml vial; 0.375 ml from 180 mcg/0.5 ml prefilled syringe; 0.5 ml from 135 mcg/0.5 ml autoinjector; do not use 180 mcg/0.5 ml autoinjector.
    90 mcg dose: 0.5 ml from 180 mcg/ml vial; 0.25 ml from 180 mcg/ 0.5 ml prefilled syringe; do not use autoinjectors.
     
    Preparation of subcutaneous dosage immediately prior to injection:
    Gently warm the refrigerated medicine to room temperature. Accomplish this by rolling the vial in the palms of your hands for about one minute prior to injection. Warm the syringe and autoinjector by placing on clean flat surface and waiting until it reaches room temperature (approximately 20 minutes for autoinjector). Wait for any condensation on the outside of the syringe or autoinjector to disappear prior to use. Do not warm autoinjector any other way and do not remove the cap at this time.
    Do not shake the vial, prefilled syringe, or autoinjector as foaming may occur.
    If using the drug vial, flip the plastic top off the vial and clean the rubber stopper with an alcohol pad. If needed, attach the needle to the end of the syringe. Pull the plunger back to the needed dosage mark on the syringe. Insert the needle into the drug vial and inject the air into the air space of the vial. With the vial and needle inverted, withdraw the needed amount of drug solution. The vials are single use only; discard any unused portion.
    For pediatric patients, prepare dose using only the 180 mcg/mL vial. The weight based dose should be drawn from the 180 mcg/mL vial using a 1 mL tuberculin syringe.
    If using the prefilled syringe, attach the needle by removing the rubber cap from the syringe barrel and placing the needle onto the end of the syringe barrel. Do not remove the clear needle shield until immediately before injection of the product.
    With the needle in the upright position, tap the syringe barrel lightly. Press the plunger slightly to eliminate any air bubbles that may be present. If using the prefilled syringe, you may need to push some of the medicine out of the syringe to deliver the correct amount. The prefilled syringe is marked for 90 mcg, 135 mcg, and 180 mcg dosage amounts. The edge of the plunger stopper needs to be on the correct dosage line.
    If using the autoinjector, remove the blue cap and set aside.
     
    Subcutaneous (SC) injection technique (vial and syringe):
    Clean the injection area (upper thigh or abdominal area besides the navel or waistline) with an alcohol swab. Choose a new location for each subsequent injection.
    Pinch an area of skin and insert the needle with the bevel up SC as far as it will go by using a quick dart-like motion.
    Release the skin and gently pull back on the syringe before delivering the drug to ensure it is not injected into a blood vessel. If blood appears in the barrel of the syringe, remove the needle and discard the syringe. Do not reuse syringes and needles. If no blood appears, slowly push down on the plunger to deposit the medicine.
    After removal of the needle, place an alcohol swab over the injection site and press slightly.
    Do not recap the needle. If using a syringe with a needle-stick protection device, place the free end of the orange cap on a flat surface and push down until the cap covers the needle. A click will be heard. Discard the syringe and needle into a sharps container.
     
    Subcutaneous (SC) injection technique (autoinjector):
    Clean the injection area (upper thigh or abdominal area avoiding the navel or waistline) with an alcohol swab. Choose a new location for each subsequent injection.
    Pinch the injection site resting the red needle shield firmly on the skin with the autoinjector straight up and down (90 degree angle).
    Press the autoinjector firmly against the skin until the red needle shield is completely pushed in; the autoinjector is now unlocked and ready for injection.
    With the autoinjector still firmly in place against the pinched skin, press and quickly release the blue activation button with your thumb. A click will sound indicating the injection has started and the red indicator will move down the viewing window during the injection.
    To ensure the injection is complete, continuing holding the autoinjector against the skin while slowly counting to 10. At 10 seconds, lift the autoinjector straight up and away from the skin.
    A second click may sound as the blue activation button pops back up and the viewing window should be completely red.
    After removal of the autoinjector, place an alcohol swab over the injection site and press slightly. Wash hands with soap and water.
    Do not recap the autoinjector. Discard into a sharps container.

    STORAGE

    Pegasys:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Do not leave product out of the refrigerator for more than 24 hours
    - Protect from light
    - Store between 36 to 46 degrees F
    Pegasys ProClick:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Do not leave product out of the refrigerator for more than 24 hours
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Benzyl alcohol hypersensitivity, E. coli protein hypersensitivity, risk of serious hypersensitivity reactions or anaphylaxis, serious rash

    Peginterferon alfa-2a is contraindicated in patients with known hypersensitivity reactions to alpha interferons, including peginterferon alfa-2a or any of its components. There is a risk of serious hypersensitivity reactions or anaphylaxis with peginterferon alfa-2a, including angioedema, acute bronchospasm, urticaria, or other allergic-type events. Such reactions have also been observed during alpha interferon and ribavirin therapy. Serious rash, including vesiculobullous eruptions, reactions in the spectrum of Stevens-Johnson Syndrome (erythema multiforme major) with varying degrees of skin and mucosal involvement and exfoliative dermatitis (erythroderma) have been reported in patients receiving peginterferon alfa-2a with and without ribavirin. Patients developing signs or symptoms of severe skin reactions or severe hypersensitivity must discontinue therapy. Institute appropriate medical treatment. Peginterferon alfa-2a is produced using recombinant DNA technology using Escherichia coli; do not use in patients with E. coli protein hypersensitivity. Peginterferon alfa-2a injection contains benzyl alcohol and is contraindicated in any patient with benzyl alcohol hypersensitivity.

    Alcoholism, bipolar disorder, depression, driving or operating machinery, encephalopathy, mania, neurologic events, peripheral neuropathy, psychiatric event, psychosis, seizure disorder, seizures, substance abuse, suicidal ideation

    Alpha interferons, including peginterferon alfa-2a, may cause or aggravate a psychiatric event or disorder. Patients should be monitored closely with periodic clinical and laboratory evaluations. It is recommended to monitor and evaluate for these conditions every 3 weeks during the first 8 weeks of treatment and every 6 months thereafter and for at least 6 months after the last dose. Permanently discontinue peginterferon alfa-2a therapy for homicidal or suicidial ideation, aggressive behavior towards others, severe depression, or other severe or persistent psychiatric symptoms; institute psychiatric intervention and follow-up as appropriate. In many, but not all cases, these disorders may resolve after stopping therapy. Patients should be warned to report changes in moods or behaviors, depression, suicidal ideation or other symptoms promptly to their health care provider. Any patient with a history of substance abuse (e.g., alcoholism), encephalopathy, depression or severe psychiatric disorder (e.g., bipolar disorder, mania, psychosis) should receive peginterferon alfa-2a with extreme caution, since these conditions may worsen or relapse. Former drug addicts may fall back into drug addiction or overdose. Although dose reduction or cessation of therapy may lead to resolution of the symptoms, depression or other psychiatric symptoms may persist and suicides have occurred even after withdrawing therapy, and continued psychiatric intervention may be needed. Neurologic events have also been reported with use. Because dizziness and drowsiness are common, patients should also be warned against driving or operating machinery until they know how peginterferon alfa-2a therapy will affect them. EEG abnormalities and seizures have been reported in post-market use and peginterferon alfa-2a should be used with caution in patients with a pre-existing seizure disorder. Peripheral neuropathy has been reported when alpha interferons were given in combination with telbivudine. In one clinical trial, an increased risk and severity of peripheral neuropathy was observed with the combination use of telbivudine and peginterferon alfa-2a as compared to telbivudine alone. The safety and efficacy of telbivudine in combination with interferons for the treatment of chronic hepatitis B have not been demonstrated.

    Infection

    Alpha interferons, including peginterferon alfa-2a, may cause or aggravate fatal or life-threatening infections. Serious and severe infections (bacterial infection, viral infection, or fungal infection), some fatal, have been reported during treatment with alpha interferons, including peginterferon alfa-2a. Suppression of the bone marrow due to peginterferon alfa-2a increases the risk for serious infections, but such infections may also occur in the absence of decreased neutrophil counts. Patients should be monitored closely with baseline and periodic monitoring and clinical and laboratory evaluations. While fever may be associated with the flu-like syndrome reported commonly during interferon therapy, other causes of high or persistent fever must be ruled out, particularly in patients with reduced neutrophil counts. Appropriate anti-infective therapy should be started immediately and discontinuation of peginterferon alfa-2a therapy should be considered.

    Anemia, aplastic anemia, bleeding, bone marrow suppression, human immunodeficiency virus (HIV) infection, neutropenia, organ transplant, sickle cell disease, thalassemia, thrombocytopenia

    Peginterferon alfa-2a suppresses bone marrow function and may result in severe cytopenias, including anemia, neutropenia, lymphopenia, and thrombocytopenia. Peginterferon alfa-2a is associated with decreases in white cell, neutrophil, and platelet counts during the first 2 weeks of therapy. Very rarely, alpha interferons may be associated with aplastic anemia. Complete blood counts (CBC) should be obtained pretreatment and monitored routinely during therapy. Peginterferon alfa-2a should be discontinued, at least temporarily, in patients who develop severe decreases in neutrophil and/or platelet counts. Bleeding or serious infectious disorders may occur due to bone marrow suppression. In many, but not all cases, these disorders resolve after stopping peginterferon alfa-2a. Anemia from peginterferon alfa-2a may complicate the management of other blood disorders, such as thalassemia or sickle cell disease. Patients who develop neutropenia or thrombocytopenia during treatment require dosage adjustment of peginterferon alfa-2a therapy; patients that develop severe decreases in neutrophil or platelet counts should discontinue peginterferon alfa-2a treatment, at least temporarily. Severe neutropenia and thrombocytopenia occur with a greater incidence in those with human immunodeficiency virus (HIV) infection and may place them at greater infectious and bleeding risk; use cautiously if the CD4 cell count is less than 350 cells/mcL. Safety and efficacy have not been established in patients with liver or other organ transplant. Patients receiving immunosuppressive therapy due to an organ transplant may have increased risk for bone marrow suppression. As with other alpha interferons, liver and renal graft rejections have been reported in patients receiving peginterferon alfa-2a. Certain medications may increase the risk for severe bone marrow suppression. Ribavirin co-therapy may potentiate the neutropenia and lymphopenia induced by alpha interferons. Peginterferon alfa-2a/ribavirin combination therapy should be used with caution in patients with baseline neutrophil counts less than 1500/mm3, platelet counts less than 90,000/mm3, or anemia (hemoglobin less than 10 grams/dL). Pancytopenia and bone marrow suppression have been reported in the literature to occur within 3 to 7 weeks after the concomitant administration of peginterferon/ribavirin combination treatment and azathioprine. Myelotoxicity was reversible within 4 to 6 weeks upon withdrawal of both peginterferon/ribavirin therapy and concomitant azathioprine and did not recur upon reintroduction of either treatment alone. Discontinue therapy for pancytopenia, and do not re-introduce peginterferon/ribavirin treatment with azathioprine.

    Ethanol ingestion, hepatic decompensation, hepatic disease, hepatitis, hepatitis B exacerbation, hepatitis C and HIV coinfection, jaundice

    Peginterferon alfa-2a is contraindicated for use in patients with autoimmune hepatitis, in patients with hepatic decompensation due to cirrhotic hepatic disease before treatment, or those cirrhotic chronic hepatitis C and HIV coinfection with hepatic decompensation and Child-Pugh score greater than or equal to 6 before treatment. Patients with non-compensated cirrhosis may experience worsening hepatic disease including, but not limited to, jaundice, hepatic failure, and death after peginterferon alfa-2a treatment. Serum ALT concentrations should be evaluated at baseline, 2 weeks after treatment initiation, and monthly thereafter in order to determine clinical response. Any patient developing liver function test (LFT) abnormalities during peginterferon alfa-2a therapy should receive more frequent monitoring of liver function; consider dose reduction. Flares have been accompanied by other liver function test (LFT) abnormalities. Hepatitis B exacerbation (flares) during hepatitis B therapy are not uncommon and are characterized by transient and potentially severe increases in serum ALT. In patients with with chronic hepatitis B and ALT values greater than 5 times the upper limit of normal (ULN), dose reduction, temporary drug discontinuation, or permanent drug discontinuation may be appropriate. Patients with hepatitis C who experience progressive ALT increases above baseline concentrations require dosage adjustment. If ALT increases are progressive despite reduction of peginterferon alfa-2a dose or are accompanied by hyperbilirubinemia or evidence of hepatic decompensation, immediately discontinue peginterferon alfa-2a. HIV treatment guidelines recommend hepatitis C and HIV coinfected patients be treated for both viral infections concurrently. For most patients, the benefits of concurrent therapy outweighs the potential risks (i.e., drug-induced hepatic injury, complex drug interactions, overlapping toxicities); therefore, it is recommended to initiate a fully suppressive antiretroviral (ARV) therapy and a hepatitis C regimen in all coinfected patients regardless of CD4 count. However, for antiretroviral naive patients with CD4 counts greater than 500 cells/mm3, consideration may be given to deferring ARV until the hepatitis C treatment regimen has been completed. Conversely, for patients with CD4 counts less than 200 cells/mm3, consider delaying initiation of the hepatitis C treatment regimen until the patient is stable on fully suppressive ARV regimen. Instruct coinfected patients to avoid ethanol ingestion, and offer vaccinations against hepatitis A and hepatitis B as appropriate.

    Autoimmune disease, idiopathic thrombocytopenic purpura (ITP), psoriasis, rheumatoid arthritis, systemic lupus erythematosus (SLE), thrombotic thrombocytopenic purpura (TTP)

    Peginterferon alfa-2a should be used with caution in patients with a history of autoimmune disease. Peginterferon alfa-2a is contraindicated for use in patients with autoimmune hepatitis. Development or exacerbation of autoimmune diseases (e.g., myositis, hepatitis, thrombotic thrombocytopenic purpura (TTP), idiopathic thrombocytopenic purpura (ITP), thyroiditis, thrombocytopenia, rheumatoid arthritis, intersitial nephritis, systemic lupus erythematosus (SLE), or psoriasis) has been observed in patients receiving alpha interferons. Patients should be monitored closely with periodic clinical and laboratory evaluations. Peginterferon alfa-2a should be discontinued in patients with persistently severe or worsening signs or symptoms of these conditions. In many, but not all cases, these disorders resolve after stopping peginterferon alfa-2a.

    Graves' disease, hyperthyroidism, hypothyroidism, thyroid disease

    Patients with thyroid disease (e.g., hyperthyroidism or hypothyroidism) whose thyroid stimulating hormone (TSH) serum concentration cannot be maintained in the normal range by medication should not be treated with peginterferon alfa-2a. If the TSH concentration can be maintained within the normal range, TSH concentration assessment is recommended before treatment and every 3 months following initiation of peginterferon alfa-2a therapy. If the TSH concentration cannot be controlled with medications, peginterferon alfa-2a should be discontinued. Also, the development or exacerbation of autoimmune thyroid diseases (e.g., Graves' disease, thyroiditis) has been observed in patients receiving peginterferon alfa-2a. Patients should be monitored closely with periodic clinical and laboratory evaluations. Peginterferon alfa-2a should be discontinued in patients with persistently severe or worsening signs or symptoms of autoimmune thyroid disease. In many, but not all cases, autoimmune disorders resolve after stopping peginterferon alfa-2a.

    Diabetes mellitus, hyperglycemia, hypoglycemia

    Hyperglycemia, hypoglycemia, and diabetes mellitus have been observed to develop in patients treated with peginterferon alfa-2a. Patients with these conditions at baseline who cannot be effectively treated by medication should not begin peginterferon alfa-2a therapy. Patients who develop these conditions during treatment and cannot be controlled with medication may require discontinuation of peginterferon alfa-2a therapy.

    Angina, cardiac arrhythmias, cardiac disease, cardiomyopathy, cerebrovascular disease, coronary artery disease, hypertension, myocardial infarction or stroke

    Ischemic and other cerebrovascular and cardiovascular events (e.g., hypertension, supraventricular arrhythmias, cardiomyopathy, chest pain, unstable angina pectoris, myocardial infarction or stroke) have been observed in patients treated with peginterferon alfa-2a. Some events occurred in patients with few or no reported risk factors. The drug should be used cautiously in patients with cardiac disease (including coronary artery disease) or cerebrovascular disease. Common adverse effects of peginterferon alfa-2a such as fever and chills may exacerbate preexisting cardiac conditions. Patients with a history of myocardial infarction and cardiac arrhythmias should be closely monitored, with baseline and periodic monitoring and clinical and laboratory evaluations. An electrocardiogram (ECG) is recommended prior to initiating therapy in such patients. Ischemic and hemorrhagic cerebrovascular events (e.g., strokes) have been observed in patients treated with interferon alfa-based therapies, including peginterferon alfa-2a. Events occurred in patients with few or no reported risk factors for stroke, including patients less than 45 years of age. Because these are spontaneous reports, estimates of frequency cannot be made, and a causal relationship between interferon alfa-based therapies and these events is difficult to establish. Peginterferon alfa-2a should be discontinued in patients with persistently severe or worsening signs or symptoms of these conditions. In many, but not all cases, these disorders resolve after stopping peginterferon alfa-2a. Because cardiac disease may be worsened by ribavirin-induced hemolytic anemia, patients with a history of significant or unstable cardiac disease should not receive combination therapy with ribavirin.

    Pneumonitis, pulmonary disease, pulmonary hypertension, respiratory insufficiency, sarcoidosis

    Dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans, interstitial pneumonitis, pulmonary hypertension, and sarcoidosis, some resulting in respiratory failure or patient deaths, may be induced or aggravated by peginterferon alfa-2a or alpha interferon therapy. Recurrence of respiratory insufficiency and failure has been observed with interferon rechallenge. Peginterferon alfa-2a combination treatment should be suspended in patients who develop pulmonary infiltrates or pulmonary function impairment. Patients who resume interferon treatment should be closely monitored. Use with caution in patients with known pulmonary disease.

    Dialysis, renal failure, renal impairment

    Estimate the patient’s creatinine clearance (CrCl) before peginterferon alfa-2a initiation. Peginterferon alfa-2a initial dose reduction is needed for patients with renal impairment as evidenced by a CrCl less than 30 mL/min. Dose reductions are also needed for including patients patients with end-stage renal disease or renal failure who require dialysis. Closely monitor patients with moderate to severe renal impairment (e.g., CrCl less than 50 mL/min) for adverse reactions and laboratory abnormalities, especially decreased hemoglobin. If severe adverse reactions or laboratory abnormalities develop, or if adverse reactions persist after dose adjustment, discontinue peginterferon alfa-2a and/or ribavirin. Peginterferon alfa-2a was well tolerated among 25 adults with chronic hepatitis C on hemodialysis; patients were naive to interferon-based therapy. Peginterferon alfa-2a was started at the recommended dose for hemodialysis patients. During the 24-week treatment period, 3 patients had a dose reduction for a platelet count less than 50,000/mm3, but no patient had to stop treatment because of an adverse event.

    Colitis, ischemic colitis, ulcerative colitis

    Ulcerative colitis and hemorrhagic or ischemic colitis events, sometimes fatal, have been observed within 12 weeks of starting alpha interferon treatment. Abdominal pain, bloody diarrhea, and fever are the typical manifestations of colitis. Peginterferon alfa-2a therapy should be discontinued immediately if these symptoms develop. The colitis usually resolves within 1 to 3 weeks of discontinuation of alpha interferon.

    Hypertriglyceridemia, pancreatitis

    Pancreatitis, sometimes fatal, has occurred during alpha interferon and ribavirin treatment. Peginterferon alfa-2a/ribavirin combination treatment should be suspended if symptoms or signs suggestive of pancreatitis are observed. Discontinue in patients who are diagnosed with pancreatitis. Triglyceride levels are commonly elevated in subjects receiving alpha interferon therapy and were elevated in the majority of subjects participating in clinical studies receiving either peginterferon alfa-2a alone or in combination with ribavirin. Hypertriglyceridemia may occur or worsen; monitor triglycerides during therapy and watch for pancreatitis symptoms in at-risk patients.

    Diabetic retinopathy, ocular disease, optic neuritis, papilledema, retinal bleeding, retinal detachment, visual disturbance

    Decrease or loss of vision, retinopathy including macular edema, retinal artery or vein thrombosis, retinal bleeding and cotton wool spots, optic neuritis, papilledema and serous retinal detachment are induced or aggravated by treatment with peginterferon alfa-2a or other alpha interferons. All patients should receive an eye examination at baseline. Patients with pre-existing ocular disease (e.g., hypertensive or diabetic retinopathy) should receive periodic ophthalmologic exams during interferon alpha treatment. Any patient who develops ocular symptoms or visual disturbance should receive a prompt and complete eye examination. Discontinue treatment in patients who develop new or worsening ophthalmologic disorders.

    Geriatric

    Younger adult patients typically have higher virologic response rates than older patients. Clinical studies of peginterferon alfa-2a alone or in combination with ribavirin did not include sufficient numbers of subjects 65 years of age or over to determine whether they respond differently from younger adults. Adverse reactions related to alpha interferons, such as CNS, cardiac, and systemic (e.g., flu-like) effects may be more severe in the geriatric patient. Also, peginterferon alfa-2a is excreted by the kidney, and the risk of toxic reactions may be greater in patients with impaired renal function, including geriatric patients. Use with caution in geriatric patients with creatinine clearance less than or equal to 50 mL/min; reduce the dose in geriatric patients with a creatinine clearance less than 30 mL/min.

    Contraception requirements, pregnancy, pregnancy testing, use with ribavirin

    There are no adequate and well-controlled studies evaluating use of peginterferon alfa-2a in pregnant women. Peginterferon alfa-2a should be assumed to have abortifacient potential based on studies in pregnant Rhesus monkeys, which showed a statistically significant increase in abortions. No teratogenic effects were seen in the offspring delivered at term. Peginterferon alfa-2a monotherapy may be administered to women of childbearing potential only after a confirmed negative pregnancy test. Advise female patients to use effective contraception requirements during therapy. Ribavirin use with peginterferon alfa-2a poses additional risks during pregnancy, and clinicians should be fully aware of the contraindications, as well as the proper use and monitoring for ribavirin therapy. Peginterferon alfa-2a use with ribavirin is contraindicated in women who are pregnant and men whose female partners are pregnant. Ribavirin may cause birth defects and death of the unborn child (intrauterine fetal death), and is genotoxic and mutagenic. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients if ribavirin is prescribed. Females drug recipients and female partners of male drug recipients must undergo pregnancy testing before starting peginterferon alfa-2a and ribavirin combination therapy, every month while being treated, and every month for the 6 months after treatment is discontinued. Contraceptive requirements exist for both males and females of childbearing potential in whom both ribavirin and peginterferon alfa-2a are prescribed. Both men and women of childbearing potential must use 2 forms of effective contraception during treatment and for 6 months after combination treatment discontinuation. If a female or the female sexual partner of a treated male becomes pregnant while taking peginterferon alfa-2a and ribavirin or within 6 months after discontinuation of treatment, the healthcare provider should be informed right away. The Ribavirin Pregnancy Registry (1-800-593-2214) should be contacted.

    Infertility, menstrual irregularity

    Peginterferon alfa-2a may cause menstrual irregularity and infertility in women. Menstrual cycle irregularities were accompanied by both a decrease and delay in the peak 17-beta-estradiol and progesterone levels following administration of peginterferon alfa-2a at approximately 60-times the recommended human dose to female cynomolgus monkeys. A return to normal menstrual rhythm followed cessation of treatment. Every other day dosing with peginterferon alfa-2a at a dose equivalent to approximately 30 times the recommended human dose had no effects on cycle duration or reproductive hormone status. The effects of peginterferon alfa-2a on male fertility have not been studied. However, no adverse effects on fertility were observed in male Rhesus monkeys.

    Breast-feeding

    It is not known if peginterferon alfa-2a is excreted in breast milk and any effect of orally ingested interferon on a nursing infant has not been evaluated. Because of the potential for adverse reactions from the drug in a nursing infant, the manufacturer recommends that a decision be made to discontinue breast-feeding or to discontinue the drug. Patients should not do both. One case report involving two pregnant women receiving interferon alfa treatment has been published. An analysis immediately postpartum, found interferon concentrations in the breast milk (1.4 Units/mL and 6 Units/mL) to be considerably lower than the maternal serum concentrations (20.8 Units/mL and 58 Units/mL, respectively). 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.

    Children, growth inhibition, infants, neonates

    Peginterferon alfa-2a is approved for the treatment of chronic hepatitis B virus infections in children 3 years of age and older, and for the treatment of hepatitis C virus infections in children 5 years of age and older. Peginterferon alfa-2 is contraindicated in neonates and infants because it contains benzyl alcohol. Benzyl alcohol is associated with an increased incidence of neurologic and other complications which are sometimes fatal in neonates and infants. Use of peginterferon alfa-2a with ribavirin has been associated with growth inhibition in children and adolescents 5 years of age and older; monitor growth carefully in these patients. During a 48-week hepatitis C virus study, 43% of peginterferon alfa-2a and ribavirin-treated pediatric patients (5 to 17 years of age) experienced weight percentile decreases of 15 percentiles or more and 25% experienced height percentile decreases of at least 15 percentiles on normative growth curves. Of note most patients had returned to baseline normative growth curve percentiles by the end of the 2 year follow-up after treatment. At 2 years post-treatment, only 16% and 11% of patients were more than 15 percentiles below their baseline for weight and height, respectively. At 6 years post-treatment, post-treatment recovery in growth at 2 years had been maintained for most patients, although data were limited to 38 patients. The available longer term data is too limited to determine the risk of reduced adult height in some patients. Growth inhibition was also observed in a 48 week chronic hepatitis B virus study involving pediatric patients ages 3 to 17 years. At 24 weeks post-treatment, 12% of drug recipients were more than 15 percentiles below their baseline weight curve and 12% were more than 15 percentile below their baseline height curve. No data are available on longer term follow-up in these patients.

    Dental disease, dental work

    Dental disease and periodontal disorders have been reported in patients receiving peginterferon alfa and ribavirin combination therapy. Dry mouth due to peginterferon alfa/ribavirin combination therapy can impact oral health. Patients should check with their healthcare provider before having any dental work completed. Myelosuppressive effects of peginterferon alfa-2a may increase the risk of infection and bleeding during dental procedures. However, it is important for treated patients to receive regular dental care and emergency treatment when necessary. Patients should report any signs of oral infection or unusual bleeding. Patients should be instructed in proper oral hygiene, including gentle brushing and flossing of teeth and receiving regular dental exams.

    ADVERSE REACTIONS

    Severe

    neutropenia / Delayed / 5.0-12.0
    anemia / Delayed / 2.0-8.0
    eczema vaccinatum / Delayed / 1.0-5.0
    coma / Early / 0-1.0
    suicidal ideation / Delayed / 0-1.0
    peptic ulcer / Delayed / 0-1.0
    GI bleeding / Delayed / 0-1.0
    pancreatitis / Delayed / 0-1.0
    pulmonary embolism / Delayed / 0-1.0
    aplastic anemia / Delayed / 0-1.0
    thrombotic thrombocytopenic purpura (TTP) / Delayed / 0-1.0
    lupus-like symptoms / Delayed / 0-1.0
    interstitial nephritis / Delayed / 0-1.0
    stroke / Early / 0-1.0
    corneal erosion / Delayed / 0-1.0
    seizures / Delayed / Incidence not known
    bronchospasm / Rapid / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    anaphylactic shock / Rapid / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    bronchiolitis obliterans / Delayed / Incidence not known
    pulmonary hypertension / Delayed / Incidence not known
    papilledema / Delayed / Incidence not known
    retinal hemorrhage / Delayed / Incidence not known
    optic neuritis / Delayed / Incidence not known
    retinal thrombosis / Delayed / Incidence not known
    visual impairment / Early / Incidence not known
    retinopathy / Delayed / Incidence not known
    retinal detachment / Delayed / Incidence not known
    macular edema / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    red cell aplasia / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    hearing loss / Delayed / Incidence not known

    Moderate

    lymphopenia / Delayed / 3.0-81.0
    hypertriglyceridemia / Delayed / 20.0-36.0
    antibody formation / Delayed / 3.0-29.0
    elevated hepatic enzymes / Delayed / 1.0-27.0
    depression / Delayed / 18.0-18.0
    dyspnea / Early / 0-13.0
    impaired cognition / Early / 8.0-8.0
    thrombocytopenia / Delayed / 5.0-8.0
    memory impairment / Delayed / 5.0-5.0
    hypothyroidism / Delayed / 0-4.0
    blurred vision / Early / 4.0-4.0
    hyperthyroidism / Delayed / 0-3.0
    hallucinations / Early / 0-1.0
    psychosis / Early / 0-1.0
    colitis / Delayed / 0-1.0
    angina / Early / 0-1.0
    diabetes mellitus / Delayed / 0-1.0
    psoriasis / Delayed / 0-1.0
    cholangitis / Delayed / 0-1.0
    steatosis / Delayed / 0-1.0
    peripheral neuropathy / Delayed / 0-1.0
    bullous rash / Early / Incidence not known
    dehydration / Delayed / Incidence not known
    pneumonitis / Delayed / Incidence not known
    hypertension / Early / Incidence not known
    chest pain (unspecified) / Early / Incidence not known
    hyperglycemia / Delayed / Incidence not known
    hypoglycemia / Early / Incidence not known
    hyperbilirubinemia / Delayed / Incidence not known

    Mild

    asthenia / Delayed / 8.0-65.0
    fatigue / Early / 8.0-65.0
    headache / Early / 21.0-64.0
    fever / Early / 37.0-54.0
    injection site reaction / Rapid / 22.0-45.0
    myalgia / Early / 26.0-40.0
    arthralgia / Delayed / 22.0-28.0
    alopecia / Delayed / 6.0-28.0
    vomiting / Early / 15.0-25.0
    nausea / Early / 9.0-25.0
    anorexia / Delayed / 6.0-24.0
    irritability / Delayed / 19.0-19.0
    anxiety / Delayed / 19.0-19.0
    insomnia / Early / 19.0-19.0
    pruritus / Rapid / 11.0-19.0
    dizziness / Early / 6.0-16.0
    weight loss / Delayed / 4.0-16.0
    diarrhea / Early / 11.0-16.0
    rash (unspecified) / Early / 5.0-15.0
    abdominal pain / Early / 8.0-15.0
    cough / Delayed / 4.0-15.0
    infection / Delayed / 0-14.0
    influenza / Delayed / 0-14.0
    xerosis / Delayed / 4.0-10.0
    emotional lability / Early / 3.0-9.0
    epistaxis / Delayed / 9.0-9.0
    back pain / Delayed / 9.0-9.0
    diaphoresis / Early / 6.0-6.0
    pharyngitis / Delayed / 6.0-6.0
    xerostomia / Early / 4.0-6.0
    dyspepsia / Early / 0-1.0
    vesicular rash / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    tongue discoloration / Delayed / 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.
    Aldesleukin, IL-2: (Moderate) Myocardial injury, exacerbation or the initial presentation of autoimmune and inflammatory disorders, and hypersensitivity reactions appear to be increased in patients receiving aldesleukin, IL-2 and alpha interferons concurrently.
    Alemtuzumab: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Alteplase, tPA: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Altretamine: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    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) Because antithymocyte globulin is an immunosuppressant, additive affects may be seen with other immunosuppressives or antineoplastic agents. While therapy is designed to take advantage of this effect, patients may be predisposed to over-immunosuppression resulting in an increased risk of infection or other side effects.
    Antitumor antibiotics: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Arsenic Trioxide: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    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.
    Azathioprine: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Bacillus Calmette-Guerin Vaccine, BCG: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient, including those receiving Interferon therapy. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Basiliximab: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    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.
    Dexamethasone: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    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.
    Efalizumab: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    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.
    Estramustine: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    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.
    Filgrastim, G-CSF: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
    Folate analogs: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    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.
    Gefitinib: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Hydroxyurea: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Ibritumomab Tiuxetan: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Ifosfamide: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Imatinib: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    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.
    Intranasal Influenza Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient, including those receiving Interferon therapy. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    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.
    Live Vaccines: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient, including those receiving Interferon therapy. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Lomustine, CCNU: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    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.
    Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient, including those receiving Interferon therapy. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Measles/Mumps/Rubella Vaccines, MMR: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient, including those receiving Interferon therapy. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Melphalan: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Methadone: (Major) Addition of peginterferon alfa-2a 180 mcg SC once weekly to methadone maintenance therapy resulted in 10 to 15% higher mean methadone pharmacokinetic parameter values after 4 weeks of dual therapy as compared with baseline values. The pharmacokinetic parameter values of peginterferon alfa-2a were not altered by methadone. Patients received a median methadone dose of 95 mg (range, 30150 mg). If both drugs will be used concomitantly, the dosage of methadone may need to be lowered. Patients need to be cautioned to not drive or operate machinery until the effects of both drugs on them are known.
    Methotrexate: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Methoxsalen: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Methylprednisolone: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Mitoxantrone: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Natural Antineoplastics: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    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.
    Pegfilgrastim: (Major) Pegfilgrastim induces the proliferation of neutrophil-progenitor cells, and because antineoplastic agents exert toxic effects against rapidly growing cells, pegfilgrastim should not be given 14 days before or for 24 hours after cytotoxic chemotherapy.
    Pemetrexed: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Pralatrexate: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Prednisolone: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Prednisone: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    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.
    Purine analogs: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Reteplase, r-PA: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    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.
    Rotavirus Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient, including those receiving Interferon therapy. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Rubella Virus Vaccine Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient, including those receiving Interferon therapy. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    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.
    Sargramostim, GM-CSF: (Major) Sargramostim, GM-CSF, induces proliferation of hematopoietic progenitor cells, and because antineoplastic agents exert their toxic effects against rapidly growing cells, sargramostim is contraindicated during the 24 hours before or after cytotoxic chemotherapy.
    Smallpox Vaccine, Vaccinia Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient, including those receiving Interferon therapy. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    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.
    Streptokinase: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Taxanes: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Tbo-Filgrastim: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
    Telbivudine: (Severe) The use of peginterferon alfa-2a and telbivudine is contraindicated because of an increased risk of peripheral neuropathy. A clinical trial showed an increased risk and severity of peripheral neuropathy with the combination of telbivudine 600mg daily and pegylated interferon alfa-2a 180 mcg once weekly SC as compared with telbivudine or pegylated interferon alfa-2a alone. Such risk cannot be excluded for other dose regimens of pegylated interferon alfa-2a or other alfa interferons (pegylated or standard). Peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons. Advise patients to report any numbness, tingling, and/or burning sensations in the arms and/or legs with or without gait disturbance. Interrupt telbivudine receipt if peripheral neuropathy is suspected, and discontinue telbivudine if peripheral neuropathy is confirmed. Of note, the safety and efficacy of telbivudine in combination with pegylated interferons or other interferons for the treatment of chronic hepatitis B have not been demonstrated. Cautious use of peginterferon alfa-2a may be warranted with other anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs). For example, synergistic toxicity may occur with alpha interferons and zidovudine, as both can be myelosuppressive. 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.
    Tenecteplase, TNK-tPA: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Theophylline, Aminophylline: (Major) Alpha interferons, when administered systemically, may decrease the clearance of aminophylline resulting in increased plasma concentrations. Concomitant use may result in a significant increase in theophylline concentrations due to reduced aminophylline clearance. In studies, increases in theophylline levels of 25% up to 100% have occurred. Reductions in CYP1A2 activity have been noted with various alpha interferons, and likely provide a mechanism for the interaction. Monitor theophylline concentrations and for signs and symptoms of toxicity when interferons are used concomitantly; consider appropriate dose adjustments as clinically indicated. (Major) Alpha interferons, when administered systemically, may decrease the clearance of theophylline resulting in increased plasma concentrations. Concomitant use may result in a significant increase in theophylline concentrations due to reduced theophylline clearance. In studies, increases in theophylline levels of 25% up to 100% have occurred. Reductions in CYP1A2 activity have been noted with various alpha interferons, and likely provide a mechanism for the interaction. Monitor theophylline concentrations and for signs and symptoms of theophylline toxicity when interferons are used concomitantly; consider appropriate dose adjustments as clinically indicated.
    Thrombolytic Agents: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    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.
    Tositumomab: (Moderate) Use of alpha interferons are associated with myelosuppression; additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Trastuzumab: (Moderate) Use of alpha interferons are associated with myelosuppression; additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Tretinoin, ATRA: (Moderate) Use of alpha interferons are associated with myelosuppression; additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Typhoid Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient, including those receiving Interferon therapy. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Urokinase: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Varicella-Zoster Virus Vaccine, Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient, including those receiving Interferon therapy. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    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.
    Yellow Fever Vaccine, Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient, including those receiving Interferon therapy. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    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

    There are no adequate and well-controlled studies evaluating use of peginterferon alfa-2a in pregnant women. Peginterferon alfa-2a should be assumed to have abortifacient potential based on studies in pregnant Rhesus monkeys, which showed a statistically significant increase in abortions. No teratogenic effects were seen in the offspring delivered at term. Peginterferon alfa-2a monotherapy may be administered to women of childbearing potential only after a confirmed negative pregnancy test. Advise female patients to use effective contraception requirements during therapy. Ribavirin use with peginterferon alfa-2a poses additional risks during pregnancy, and clinicians should be fully aware of the contraindications, as well as the proper use and monitoring for ribavirin therapy. Peginterferon alfa-2a use with ribavirin is contraindicated in women who are pregnant and men whose female partners are pregnant. Ribavirin may cause birth defects and death of the unborn child (intrauterine fetal death), and is genotoxic and mutagenic. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients if ribavirin is prescribed. Females drug recipients and female partners of male drug recipients must undergo pregnancy testing before starting peginterferon alfa-2a and ribavirin combination therapy, every month while being treated, and every month for the 6 months after treatment is discontinued. Contraceptive requirements exist for both males and females of childbearing potential in whom both ribavirin and peginterferon alfa-2a are prescribed. Both men and women of childbearing potential must use 2 forms of effective contraception during treatment and for 6 months after combination treatment discontinuation. If a female or the female sexual partner of a treated male becomes pregnant while taking peginterferon alfa-2a and ribavirin or within 6 months after discontinuation of treatment, the healthcare provider should be informed right away. The Ribavirin Pregnancy Registry (1-800-593-2214) should be contacted.

    MECHANISM OF ACTION

    Mechanism of Action: The active component of peginterferon alfa-2a is the interferon alfa-2a moiety. Interferon alfa-2a acts similarly to native interferon alpha. Endogenous alpha-interferons (IFNs) are secreted by leukocytes (e.g., macrophages, B lymphocytes, and non-B non-T lymphocytes) in response to viral infection or various synthetic and biological inducers. All alpha-IFNs share common biologic activities generated by the binding of interferon to the cell-surface receptor. Although the exact mechanism of action is not fully understood, interferon binding to the cell surface receptor is followed by activation of tyrosine kinases, which leads to the production of several IFN-stimulated enzymes such as 2'-5'-oligoadenylate synthetase (2'-5'-OAS) and beta2-microglobulin. These and possibly other IFN-stimulated enzymes are thought to be responsible for the pleiotropic biologic effects of alpha-IFNs, which include antiviral, antiproliferative and immunomodulatory effects, cellular differentiation, regulation of cell surface major histocompatibility antigen expression (HLA class I), and cytokine induction.•Antiviral effects: Interferon exerts antiviral effects by augmenting the production and/or release of specific enzymes. Interferon-induced intracellular enzymes such as 2'5'-OAS and protein kinase contribute to inhibition of viral replication by activating endoribonucleases that cleave single-stranded viral RNA. Thus, translation of viral proteins is inhibited. The activity of IFN-induced enzymes depends on the presence of double-stranded RNA (dsRNA) formed during viral replication. It has been suggested that the antiviral activity of IFNs may be related, in part, to an effect on dsRNA. Interferon-induced enzymes may also inhibit viral penetration and uncoating, and/or viral assembly and release. Expression of major histocompatibility antigens by IFNs may also contribute to antiviral activity by enhancing the lytic effects of cytotoxic T lymphocytes.A wide range of viruses, particularly RNA viruses, are sensitive to the antiviral actions of IFN. Alpha interferons are generally active against the following viruses in vitro: adenovirus; coronavirus; encephalomyocarditis virus; hepatitis B virus; hepatitis C virus (HCV); hepatitis D virus; herpes simplex virus type 1; herpes simplex virus type 2; human immunodeficiency virus (HIV); papillomavirus; poliovirus; rhinovirus; vaccinia virus; varicella-zoster virus; vesicular stomatitis virus; human T-lymphotropic virus type I (HTLV-I). In chronic hepatitis C, INF treatment is associated with normalization of ALT and reduction of serum HCV RNA, as well as improvement in liver histopathology, in responding patients. The HCV genotype 1 is more resistant to interferon alfa treatment than other viral genotypes; 75% of persons in the United States infected with HCV carry this genotype. Many patients with a biochemical and virologic response relapse 1—2 months after stopping IFN therapy.•Effect on hepatic microsomal enzymes: Alpha interferons may inhibit microsomal enzymes involved in the hepatic cytochrome P-450 system. The effect of interferon on the CYP450 system may be related to increased enzyme degradation, suppressed enzyme synthesis, or inhibition of cytochrome P-450. Implications of this effect have not been fully evaluated, but the metabolism of certain drugs may be affected (see Drug Interactions).

    PHARMACOKINETICS

    Peginterferon alfa-2a is given subcutaneously (SC). In patients with hepatitis C infection, the mean elimination half-life of peginterferon alfa-2a (i.e., Pegasys) is 80 hours (range 50—140 hours) as compared with 5.1 hours (range 3.7—8.5 hours) for interferon alfa-2a (i.e., Roferon-A). When compared to interferon alfa-2a in healthy patients, the mean systemic clearance of peginterferon alfa-2a is approximately 100-fold lower, allowing for a reduced dosing frequency.

    Subcutaneous Route

    Following a single SC dose, the mean absorption half-life is 4.6 hours. Maximal concentrations occur between 72 and 96 hours post dose and are sustained for 168 hours. With multiple dosing there is an increase in peginterferon alfa-2a bioavailability. Steady-state serum concentrations are reached within 5—8 weeks of once weekly dosing. Mean trough concentrations (16 ng/ml) at week 48 of treatment are roughly 2-fold higher than the trough concentrations (8 ng/ml) at week 1 of treatment.