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  • CLASSES

    Other Anti-Hepatitis Drugs
    Respiratory Syncytial Virus/RSV Drugs

    BOXED WARNING

    Requires an experienced clinician, respiratory depression, respiratory insufficiency

    Aerosolized ribavirin therapy requires an experienced clinician. Aerosolized ribavirin use in patients with respiratory insufficiency or respiratory depression requiring mechanical ventilation should be done only by clinicians and support staff familiar with the specific ventilator being used and the administration of aerosolized ribavirin. Ribavirin can precipitate in the respiratory apparatus which can cause additional difficulty in ventilation. Strict adherence to guidelines for minimizing accumulation of ribavirin must be followed. If worsening of respiratory function occurs, aerosolized ribavirin should be withdrawn. Aerosolized ribavirin is not for use in adults.

    Contraception requirements, male-mediated teratogenicity, pregnancy, pregnancy testing

    Ribavirin may cause birth defects and/or death of the exposed fetus (intrauterine fetal death) and must not be used during pregnancy. Ribavirin therapy may also cause male-mediated teratogenicity. The drug is contraindicated for use during pregnancy (FDA pregnancy risk category X), in females of childbearing potential who may become pregnant, or in men whose female partners are pregnant. Studies indicate teratogenic (e.g., malformations of skull, palate, eye, jaw, limbs, skeleton, and GI tract) or embryocidal properties in most of the animal species tested. The incidence and severity of these effects increased with increasing ribavirin dose. Health-care workers who are pregnant or trying to get pregnant should avoid contact with patients receiving aerosolized ribavirin. No reports of teratogenesis in babies of mothers who were exposed to aerosolized ribavirin during pregnancy have been confirmed. Ribavirin is reported to be 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 must receive pregnancy testing before starting ribavirin therapy, every month while being treated, and every month for the 6 months after treatment is discontinued. Contraception requirements exist for both males and females of childbearing potential in whom ribavirin is prescribed. Both men and women of childbearing potential must use 2 forms of effective contraception during treatment and for 6 months after treatment discontinuation. If a female or the female sexual partner of a treated male becomes pregnant while taking 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

    Ribavirin should be used with caution in males because animal studies have shown that ribavirin-induced testicular degeneration and infertility may occur. Testicular degeneration appears to be reversible after stopping ribavirin with recovery occurring within 1 or 2 spermatogenesis cycles.

    Anemia, angina, cardiac arrhythmias, cardiac disease, cerebrovascular disease, coronary artery disease, heart failure, hemolytic anemia, myocardial infarction

    Oral ribavirin should be used with caution in patients with anemia. The major clinical toxicity of ribavirin is hemolytic anemia. Decreases in hemoglobin occur within 1—2 weeks of initiating ribavirin therapy. It is recommended that a CBC be obtained in patients prior to beginning therapy, at weeks 2 and 4 of therapy and as needed. Dosage reductions are recommended for patients who experience drops in hemoglobin to < 10 g/dl; ribavirin therapy should be discontinued in patients with hemoglobin < 8.5 g/dl (see Dosage). The anemia associated with ribavirin therapy may result in deterioration in cardiac function and/or exacerbation of the symptoms of coronary artery disease or cerebrovascular disease. Patients with history of cardiac disease should be assessed before initiation of therapy and should be appropriately monitored during therapy. If there is any deterioration in cardiac status, therapy should be suspended or discontinued (see Dosage). Because cardiac disease (e.g., angina or congestive heart failure) may be worsened by drug-induced anemia, patients with a history of significant or unstable cardiac disease should not use ribavirin therapy. Those patients with a history of myocardial infarction and/or previous or current cardiac arrhythmias should be closely monitored; fatal and nonfatal myocardial infarctions have been reported in patients with ribavirin-induced anemia.

    Hepatic disease, hepatitis, hepatitis C and HIV coinfection, influenza, organ transplant, ribavirin monotherapy, viral infection

    The combination of ribavirin and peginterferon alfa-2a is contraindicated in patients with autoimmune hepatitis as this can cause a worsening of the hepatitis. Additionally, the combination of ribavirin and peginterferon alfa-2a are contraindicated in the treatment of cirrhotic chronic hepatitis C in patients who experience hepatic decompensation or hepatic disease (Child-Pugh score greater than 6; class B and C) before or during treatment, or in cirrhotic patients with hepatitis C and HIV coinfection. The safety and efficacy of oral ribavirin therapy have not been established in patients with liver or other organ transplant, decompensated hepatic disease, concurrent hepatitis B virus (HBV) or human immunodeficiency virus (HIV) infection, or in patients who are non-responders to interferon monotherapy. The safety and efficacy of oral ribavirin monotherapy for the treatment of certain viral infections including HIV infection, adenovirus, early RSV infection, parainfluenza, or influenza have not been established. Ribavirin capsules should not be used for such viral infection. In addition, monotherapy with ribavirin capsules is not effective in the treatment of hepatitis C; the safety and efficacy of ribavirin capsules have only been established when used as combination therapy with interferon alfa. 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 consuming alcohol, and offer vaccinations against hepatitis A and hepatitis B as appropriate.

    Children, growth inhibition, infants, neonates

    In infants, initiation of aerosolized ribavirin therapy has been associated with a sudden deterioration of respiratory function. Carefully monitor respiratory function. If a sudden deterioration of respiratory function occurs, treatment should be stopped and should be restarted with extreme caution; continuous monitoring is necessary and consideration should be given to concomitant administration of bronchodilators. The safety and efficacy of oral ribavirin therapy in children have only been established when used concomitantly with interferon alfa-2b for the treatment of chronic hepatitis C. In addition to other serious adverse events (generally similar in children compared to adults) that should be taken into consideration prior to initiating therapy in a pediatric patient, suicidal ideation or attempts occurred more frequently among pediatric patients, primarily adolescents, compared to adult patients (2.4% vs. 1%) during treatment and off-therapy follow-up. Monitor for the potential for growth inhibition in children and adolescents receiving peginterferon alfa-2b and ribavirin. Data from an open-label trial of patients ages 3—17 years show that weight and height gain of pediatric patients treated with peginterferon alfa-2b plus ribavirin capsules/solution lags behind predicted normal growth based on population data for the entire length of treatment. Six months after treatment, patients' weight gain rebounded to reach their predicted average; however, six months after treatment, height gain stabilized at less than the average predicted growth. Severely inhibited growth velocity (< 3rd percentile) was observed in 70% of patients while on treatment, and 20% of those patients had continued inhibited growth velocity after 6 months. Girls ages 3—11 years who were treated for 48 weeks had the largest average drop in height and weight. In another study, pediatric patients receiving 48 weeks of treatment with peginterferon alfa-2a plus ribavirin tablets also demonstrated delays in weight and height increases. At the end of treatment, 43% of peginterferon alfa-2a/ribavirin treated pediatric patients experienced weight percentile decreases of >= 15 percentiles and 25% experienced height percentile decreases of >= 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. Safety and efficacy of ribavirin capsules and solution have not been established in neonates, infants, or children < 3 years of age. Safety and efficacy of ribavirin tablets have not been established in neonates, infants, or children < 5 years or < 23 kg.

    DEA CLASS

    Rx

    DESCRIPTION

    Antiviral; synthetic guanosine analog; active against many DNA and RNA viruses.
    Used commonly in oral form in combination with interferon alfa, peginterferon alfa, or a nucleotide analog NS5B polymerase inhibitor (i.e., sofosbuvir) or NS3/4A protease inhibitor (i.e., simeprevir) for chronic hepatitis C treatment in adults and certain pediatric patients; not effective as monotherapy.
    Intravenous form is available from the US CDC for Hantaan virus infection and Lassa fever.

    COMMON BRAND NAMES

    Copegus, Moderiba, Rebetol, RibaPak, Ribasphere, Ribasphere RibaPak, RibaTab, Virazole

    HOW SUPPLIED

    Copegus/Moderiba/RibaPak/Ribasphere/Ribasphere RibaPak/RibaTab/Ribavirin Oral Tab: 200mg, 400mg, 600mg, 200-400mg, 400-600mg
    Rebetol Oral Sol: 1mL, 40mg
    Rebetol/Ribasphere/Ribavirin Oral Cap: 200mg
    Ribavirin/Virazole Respiratory (Inhalation) Pwd F/Recon: 6g

    DOSAGE & INDICATIONS

    For the treatment of respiratory syncytial virus (RSV) infection.
    Nasal and Oral Inhalation dosage
    Infants, Children, and Adolescents

    Place ribavirin 20 mg/mL solution in the drug reservoir of the SPAG-2 unit. Continuous aerosol administration for 12 to 18 hours/day for a duration of 3 to 7 days is recommended. Using a ribavirin solution of 20 mg/mL, the average aerosol dose for a 12 hour delivery period would be ribavirin 190 mcg/liter of air. Alternatively, deliver the mist at a rate of about 15 liters/minute when using an oxygen hood or tent or about 12 liters/minute when using a face mask. NOTE: Prolonged or repeated therapy may be necessary in infants with preexisting cardiac or respiratory disease or in immunocompromised infants.

    For the treatment of chronic hepatitis C infection in patients with compensated liver disease.
    NOTE: Ribavirin monotherapy is not effective for hepatitis C infection.
    NOTE: Therapy should be discontinued in patients who develop hepatic decompensation during treatment.
    For the treatment of chronic hepatitis C infection in combination with interferon alfa-2b alone.
    NOTE: Consider response prognostic factors, HCV genotype, viral load, and disease progression evidence such as hepatic inflammation and fibrosis when deciding to treat a pediatric patient. Weigh treatment benefits against potential safety risks identified in clinical trials.
    Oral dosage (capsules or oral solution)
    Adults weighing more than 75 kg

    600 mg PO twice daily (in the morning and evening) plus interferon alfa-2b. Guidelines recommend the use of a peginterferon product plus ribavirin as part of a combination regimen depending on patient factors and genotype. For interferon-alfa-naive patients, treat for 24 to 48 weeks; consider treatment discontinuation if an HCV-RNA value below the level of detection has not been achieved at 24 weeks. There are no safety or efficacy data on treatment longer than 48 weeks. For re-treatment of patients who have relapsed after interferon alfa and ribavirin therapy, treat for 24 weeks. There are no safety or efficacy data on treatment longer than 24 weeks.

    Adults weighing 75 kg or less

    400 mg PO in the morning and 600 mg PO in the evening plus interferon alfa-2b. Guidelines recommend the use of a peginterferon product plus ribavirin as part of a combination regimen depending on patient factors and genotype. For interferon-alfa-naive patients, treat for 24 to 48 weeks; consider treatment discontinuation if an HCV-RNA value below the level of detection has not been achieved at 24 weeks. There are no safety or efficacy data on treatment longer than 48 weeks. For re-treatment of patients who have relapsed after interferon alfa and ribavirin therapy, treat for 24 weeks. There are no safety or efficacy data on treatment longer than 24 weeks.

    Adolescents weighing more than 73 kg

    15 mg/kg/day or 1,200 mg/day PO given in 2 divided doses (in the morning and evening) plus interferon alfa-2b. Patients who reach their 18th birthday while on therapy should remain on the pediatric dosing regimen. The duration of treatment for genotype 1 is 48 weeks; consider treatment discontinuation if an HCV-RNA value below the level of detection has not been achieved at 24 weeks. The duration of treatment for genotype 2 or 3 is 24 weeks.

    Children and Adolescents weighing 60 to 73 kg

    15 mg/kg/day PO or 1,000 mg/day PO given in 2 divided doses (in the morning and evening) plus interferon alfa-2b. Patients who reach their 18th birthday while on therapy should remain on the pediatric dosing regimen. The duration of treatment for genotype 1 is 48 weeks; consider treatment discontinuation if an HCV-RNA value below the level of detection has not been achieved at 24 weeks. The duration of treatment for genotype 2 or 3 is 24 weeks.

    Children and Adolescents weighing 47 to 59 kg

    15 mg/kg/day PO or 800 mg/day PO given in 2 divided doses (in the morning and evening) plus interferon alfa-2b. Patients who reach their 18th birthday while on therapy should remain on the pediatric dosing regimen. The duration of treatment for genotype 1 is 48 weeks; consider treatment discontinuation if an HCV-RNA value below the level of detection has not been achieved at 24 weeks. The duration of treatment for genotype 2 or 3 is 24 weeks.

    Children and Adolescents 3 to 17 years weighing less than 47 kg

    15 mg/kg/day PO given in 2 divided doses (in the morning and evening) plus interferon alfa-2b. Patients who reach their 18th birthday while on therapy should remain on the pediatric dosing regimen. The duration of treatment for genotype 1 is 48 weeks; consider treatment discontinuation if an HCV-RNA value below the level of detection has not been achieved at 24 weeks. The duration of treatment for genotype 2 or 3 is 24 weeks.

    For the treatment of chronic hepatitis C infection in combination with a peginterferon alfa product alone.
    NOTE: Guidelines recommend the use of a peginterferon product plus ribavirin as part of a combination regimen depending on patient factors and genotype.
    Oral dosage (capsules or oral solution)
    Adults weighing more than 105 kg

    600 mg PO in the morning and 800 mg PO in the evening (1,400 mg/day) plus peginterferon alfa-2b. FDA-labeling recommends for treatment-naive patients with genotype 1, treat for 48 weeks; consider treatment discontinuation if there is not at least a 2 log10 reduction or undetectable HCV-RNA at 12 weeks or if HCV-RNA remains detectable after 24 weeks. For treatment-naive patients with genotypes 2 or 3, treat for 24 weeks. For re-treatment of prior treatment failures, treat for 48 weeks, regardless of genotype. Retreated patients who have detectable HCV-RNA at week 12 or 24 are unlikely to achieve a sustained virologic response (SVR), and treatment discontinuation should be considered.

    Adults weighing 81 to 105 kg

    600 mg PO twice daily (1,200 mg/day) plus peginterferon alfa-2b. FDA-labeling recommends treatment-naive patients with genotype 1 be treated for 48 weeks. Consider treatment discontinuation if there is not at least a 2 log10 reduction or undetectable HCV-RNA at 12 weeks or if HCV-RNA remains detectable after 24 weeks. For treatment-naive patients with genotypes 2 or 3, treat for 24 weeks. For re-treatment of prior treatment failures, treat for 48 weeks, regardless of genotype. Retreated patients who have detectable HCV-RNA at week 12 or 24 are unlikely to achieve a sustained virologic response (SVR), and treatment discontinuation should be considered.

    Adults weighing 66 to 80 kg

    400 mg PO in the morning and 600 mg PO in the evening (1,000 mg/day) plus peginterferon alfa-2b. FDA-labeling recommends treatment-naive patients with genotype 1 be treated for 48 weeks. Consider treatment discontinuation if there is not at least a 2 log10 reduction or undetectable HCV-RNA at 12 weeks or if HCV-RNA remains detectable after 24 weeks. For treatment-naive patients with genotypes 2 or 3, treat for 24 weeks. For re-treatment of prior treatment failures, treat for 48 weeks, regardless of genotype. Retreated patients who have detectable HCV-RNA at week 12 or 24 are unlikely to achieve a sustained virologic response (SVR), and treatment discontinuation should be considered.

    Adults weighing less than 66 kg

    400 mg PO twice daily (800 mg/day) plus peginterferon alfa-2b. FDA-labeling recommends treatment-naive patients with genotype 1 be treated for 48 weeks. Consider treatment discontinuation if there is not at least a 2 log10 reduction or undetectable HCV-RNA at 12 weeks or if HCV-RNA remains detectable after 24 weeks. For treatment-naive patients with genotypes 2 or 3, treat for 24 weeks. For re-treatment of prior treatment failures, treat for 48 weeks, regardless of genotype. Retreated patients who have detectable HCV-RNA at week 12 or 24 are unlikely to achieve a sustained virologic response (SVR), and treatment discontinuation should be considered.

    Adolescents weighing more than 73 kg

    15 mg/kg/day or 1,200 mg/day PO given in 2 divided doses (3 capsules in the morning and evening) plus interferon alfa-2b. Patients who reach their 18th birthday while on therapy should remain on the pediatric dosing regimen. The duration of treatment for genotype 1 is 48 weeks; consider treatment discontinuation if an HCV-RNA value below the level of detection has not been achieved at 24 weeks. The duration of treatment for genotype 2 or 3 is 24 weeks.

    Children and Adolescents weighing 60 to 73 kg

    15 mg/kg/day or 1,000 mg/day PO given in 2 divided doses (2 capsules in the morning and 3 capsules in the evening) plus interferon alfa-2b. Patients who reach their 18th birthday while on therapy should remain on the pediatric dosing regimen. The duration of treatment for genotype 1 is 48 weeks; consider treatment discontinuation if an HCV-RNA value below the level of detection has not been achieved at 24 weeks. The duration of treatment for genotype 2 or 3 is 24 weeks.

    Children and Adolescents weighing 47 to 59 kg

    15 mg/kg/day or 800 mg/day PO given in 2 divided doses (2 capsules in the morning and evening) plus interferon alfa-2b. Patients who reach their 18th birthday while on therapy should remain on the pediatric dosing regimen. The duration of treatment for genotype 1 is 48 weeks; consider treatment discontinuation if an HCV-RNA value below the level of detection has not been achieved at 24 weeks. The duration of treatment for genotype 2 or 3 is 24 weeks.

    Children and Adolescents 3 to 17 years weighing less than 47 kg

    15 mg/kg/day PO given in 2 divided doses as the oral solution (in the morning and evening) plus interferon alfa-2b. Patients who reach their 18th birthday while on therapy should remain on the pediatric dosing regimen. The duration of treatment for genotype 1 is 48 weeks; consider treatment discontinuation if an HCV-RNA value below the level of detection has not been achieved at 24 weeks. The duration of treatment for genotype 2 or 3 is 24 weeks.

    Oral dosage (tablets)
    Treatment-naive, HIV-negative adults with HCV genotype 1 or 4

    1,200 mg/day PO in 2 divided doses if weighing more than 75 kg, and 1,000 mg/day PO in 2 divided doses if weighing 75 kg or less. Give ribavirin with peginterferon alfa-2a for 48 weeks. Consider treatment discontinuation if the HCV-RNA is not undetectable after 24 weeks or if there is not at least a 2 log10 reduction by 12 weeks.

    Treatment-naive, HIV-negative adults with HCV genotype 2 or 3

    800 mg/day PO in 2 divided doses for 24 weeks with peginterferon alfa-2a. Consider treatment discontinuation if the HCV-RNA is not undetectable after 24 weeks or if there is not at least a 2 log10 reduction by 12 weeks.

    Treatment-naive, HIV-positive adults, regardless of HCV genotype

    800 mg/day PO in 2 divided doses for 48 weeks with peginterferon alfa-2a. Treatment is approved for patients with clinically stable HIV disease and a CD4 count more than 100 cells/mm3. Consider treatment discontinuation if the HCV-RNA is not undetectable after 24 weeks or if there is not at least a 2 log10 reduction by 12 weeks.

    Adolescents weighing at least 75 kg

    1,200 mg/day PO in 2 divided doses (3 tablets in the morning and evening) plus peginterferon alfa-2a. Duration of treatment is 24 weeks for genotypes 2 or 3, and is 48 weeks for all other genotypes. Maintain pediatric dosing throughout the completion of therapy if treatment is initiated prior to 18th birthday. Consider treatment discontinuation if the HCV-RNA is not undetectable after 24 weeks or if there is not at least a 2 log10 reduction by 12 weeks.

    Children and Adolescents weighing 60 to 74 kg

    1,000 mg/day PO in 2 divided doses (2 tablets in the morning and 3 tablets in the evening) plus peginterferon alfa-2a. Duration of treatment is 24 weeks for genotypes 2 or 3, and is 48 weeks for all other genotypes. Maintain pediatric dosing throughout the completion of therapy if treatment is initiated prior to 18th birthday. Consider treatment discontinuation if the HCV-RNA is not undetectable after 24 weeks or if there is not at least a 2 log10 reduction by 12 weeks.

    Children and Adolescents weighing 47 to 59 kg

    800 mg/day PO in 2 divided doses (2 tablets in the morning and evening) plus peginterferon alfa-2a. Duration of treatment is 24 weeks for genotypes 2 or 3, and is 48 weeks for all other genotypes. Maintain pediatric dosing throughout the completion of therapy if treatment is initiated prior to 18th birthday. Consider treatment discontinuation if the HCV-RNA is not undetectable after 24 weeks or if there is not at least a 2 log10 reduction by 12 weeks.

    Children and Adolescents 5 to 17 years weighing 34 to 46 kg

    600 mg/day PO in 2 divided doses (1 tablet in the morning and 2 tablets in the evening) plus peginterferon alfa-2a. Duration of treatment is 24 weeks for genotypes 2 or 3, and is 48 weeks for all other genotypes. Maintain pediatric dosing throughout the completion of therapy if treatment is initiated prior to 18th birthday. Consider treatment discontinuation if the HCV-RNA is not undetectable after 24 weeks or if there is not at least a 2 log10 reduction by 12 weeks.

    Children and Adolescents 5 to 17 years weighing 23 to 33 kg

    400 mg/day PO in 2 divided doses (1 tablet in the morning and evening) plus peginterferon alfa-2a. Duration of treatment is 24 weeks for genotypes 2 or 3, and is 48 weeks for all other genotypes. Maintain pediatric dosing throughout the completion of therapy if treatment is initiated prior to 18th birthday. Consider treatment discontinuation if the HCV-RNA is not undetectable after 24 weeks or if there is not at least a 2 log10 reduction by 12 weeks.

    For the treatment of chronic hepatitis C infection genotype 1 in combination with a nucleotide analog NS5B polymerase inhibitor or NS3/4A protease inhibitor with or without a peginterferon alfa product†.
    Oral dosage
    Treatment-naive and prior relapse adults able to receive interferon products

    Guidelines suggest weight-based dosing of 1,200 mg/day PO in 2 divided doses for patients weighing 75 kg or more and 1,000 mg/day PO in 2 divided doses for patients weighing less than 75 kg. Give ribavirin in combination with sofosbuvir and peginterferon alfa for 12 weeks as the preferred treatment regimen. Ribavirin with simeprevir and peginterferon alfa, for an initial 12 weeks of therapy, then an additional 12 weeks of only peginterferon alfa and ribavirin (24 weeks for total course) is an alternative regimen suggested by the AASLD guidelines for patients able to receive interferon products. All regimens include HIV-coinfected patients; simeprevir-containing regimens should only be used in patients without significant antiretroviral drug interactions.

    Treatment-naive and prior relapse adults unable to receive interferon products

    Guidelines suggest ribavirin weight-based dosing of 1,200 mg/day PO in 2 divided doses for patients weighing 75 kg or more and 1,000 mg/day PO in 2 divided doses for patients weighing less than 75 kg. Give ribavirin in combination with sofosbuvir and simeprevir for 12 weeks as the preferred treatment regimen. This regimen may be less desirable in patients with HIV-coinfection based on antiretroviral drug interactions. An alternative combines ribavirin with only sofosbuvir for 24 weeks. Although this regimen may be less effective, especially among patients with cirrhosis, it is the preferred regimen for patients with HIV-coinfection.

    Adults failing previous treatment with peginterferon alfa and ribavirin (nonresponders) but who have not been exposed to a NS3/4A protease inhibitor

    Guidelines suggest ribavirin weight-based dosing of 1,200 mg/day PO in 2 divided doses for patients weighing 75 kg or more and 1,000 mg/day PO in 2 divided doses for patients weighing less than 75 kg. The preferred regimen gives ribavirin in combination with sofosbuvir and simeprevir for 12 weeks. An alternative for patients able to receive interferon products combines ribavirin with sofosbuvir and peginterferon alfa for 12 weeks. Ribavirin with simeprevir and peginterferon alfa, for an initial 12 weeks of treatment, then an additional 36 weeks of only peginterferon alfa and ribavirin (48 weeks for total course) is another alternative regimen suggested by the AASLD guidelines for patients able to receive interferon products. An alternative for HIV-coinfected patients unable to receive interferon products, combines ribavirin with only sofosbuvir for 24 weeks. All regimens include HIV-coinfected patients; simeprevir-containing regimens should only be used in patients without significant antiretroviral drug interactions.

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

    Guidelines suggest ribavirin weight-based dosing of 1,200 mg/day PO in 2 divided doses for patients weighing 75 kg or more and 1,000 mg/day PO in 2 divided doses for patients weighing less than 75 kg. Give ribavirin in combination with sofosbuvir and peginterferon alfa for 12 weeks for genotype 1a; add an additional 12 weeks (24 weeks total) of peginterferon alfa and ribavirin for genotype 1b. An alternative combines ribavirin with sofosbuvir for 24 weeks. Both regimens include HIV-coinfected patients.

    For the treatment of chronic hepatitis C infections in patients with hepatocellular carcinoma awaiting liver transplant as well as patients with decompensated cirrhosis who may or may not be candidates for liver transplantation†.
    Oral dosage
    Adults

    Guidelines suggest weight-based dosing of 1,200 mg/day PO for patients more than 75 kg and 1,000 mg/day PO for patients 75 kg or less (in 2 divided doses) with consideration for renal function and hemoglobin. Ribavirin in combination with sofosbuvir for up to 48 weeks or until liver transplant, whichever occurs first, is recommended. In one open-label study, 41 patients underwent liver transplantation after receiving 48 weeks of combination therapy. Of these 41 patients, 37 had HCV RNA concentrations less than the lower limit of quantification at the time of transplantation. A 12 week post-transplant evaluation found virologic responses were maintained in 64% (n = 23 of the 36 evaluable patients) of these patients.

    For the treatment of recurrent hepatitis C infection in patients after liver transplantation†.
    Oral dosage
    Adults with HCV genotype 1

    Guidelines suggest an initial dose of 600 mg/day PO (in 2 divided doses) increased monthly by 200 mg to a weight-based dosing of 1,200 mg/day PO for patients more than 75 kg and 1,000 mg/day PO for patients 75 kg or less (in 2 divided doses) with consideration for renal function and hemoglobin. Treatment is recommended in treatment-naive patients with an allograft liver, including those with compensated and decompensated cirrhosis, in combination with sofosbuvir and simeprevir for 12 to 24 weeks. As an alternative, combine ribavirin and sofosbuvir with or without peginterferon alfa for 24 weeks.

    Adults with HCV genotypes 2 or 3

    Guidelines suggest an initial dose of 600 mg/day PO (in 2 divided doses) increased monthly by 200 mg to a weight-based dosing of 1,200 mg/day PO for patients weighing more than 75 kg and 1,000 mg/day PO for patients 75 kg or less (in 2 divided doses) with consideration for renal function and hemoglobin. Treatment is recommended in treatment-naive patients with an allograft liver, including those with compensated and decompensated cirrhosis, in combination with sofosbuvir for 24 weeks.

    For the treatment of chronic hepatitis C infection genotype 2 in combination with a nucleotide analog NS5B polymerase inhibitor with or without a peginterferon alfa product†.
    Oral dosage
    Adults weighing 75 kg or more

    1,200 mg/day PO in 2 divided doses with sofosbuvir for 12 weeks; includes HIV-coinfected patients. Patients with cirrhosis who have failed previous treatment with peginterferon alfa and ribavirin (nonresponders) may benefit from extending treatment duration to 16 weeks. An alternative for nonresponders combines ribavirin with sofosbuvir and peginterferon alfa for 12 weeks.

    Adults weighing less than 75 kg

    1,000 mg/day PO in 2 divided doses with sofosbuvir for 12 weeks; includes HIV-coinfected patients. Patients with cirrhosis who have failed previous treatment with peginterferon alfa and ribavirin (nonresponders) may benefit from extending treatment duration to 16 weeks. An alternative for nonresponders combines ribavirin with sofosbuvir and peginterferon alfa for 12 weeks.

    Adolescents weighing more than 80 kg

    1,200 mg/day PO in 2 divided doses with sofosbuvir for 12 weeks; includes HIV-coinfected patients.

    Adolescents weighing 66 to 80 kg

    1,000 mg/day PO in 2 divided doses with sofosbuvir for 12 weeks; includes HIV-coinfected patients.

    Children and Adolescents weighing 50 to 65 kg

    800 mg/day PO in 2 divided doses with sofosbuvir for 12 weeks; includes HIV-coinfected patients.

    Children and Adolescents weighing 47 to 49 kg

    600 mg/day PO in 2 divided doses with sofosbuvir for 12 weeks; includes HIV-coinfected patients.

    Children and Adolescents weighing 35 to 47 kg

    15 mg/kg/day PO in 2 divided doses with sofosbuvir for 12 weeks; includes HIV-coinfected patients.

    For the treatment of chronic hepatitis C infection genotype 3 in combination with a nucleotide analog NS5B polymerase inhibitor with or without a peginterferon alfa product†.
    Oral dosage
    Adults weighing 75 kg or more

    1,200 mg/day PO in 2 divided doses with sofosbuvir for 24 weeks; includes HIV-coinfected patients. An alternative regimen includes ribavirin with sofosbuvir and peginterferon alfa for 12 weeks; however, increased adverse effects and monitoring requirements make this a less acceptable regimen.

    Adults weighing less than 75 kg

    1,000 mg/day PO in 2 divided doses with sofosbuvir for 24 weeks; includes HIV-coinfected patients. An alternative regimen includes ribavirin with sofosbuvir and peginterferon alfa for 12 weeks; however, increased adverse effects and monitoring requirements make this a less acceptable regimen.

    Adolescents weighing more than 80 kg

    1,200 mg/day PO in 2 divided doses with sofosbuvir for 24 weeks; includes HIV-coinfected patients.

    Adolescents weighing 66 to 80 kg

    1,000 mg/day PO in 2 divided doses with sofosbuvir for 24 weeks; includes HIV-coinfected patients.

    Children and Adolescents weighing 50 to 65 kg

    800 mg/day PO in 2 divided doses with sofosbuvir for 24 weeks; includes HIV-coinfected patients.

    Children and Adolescents weighing 47 to 49 kg

    600 mg/day PO in 2 divided doses with sofosbuvir for 24 weeks; includes HIV-coinfected patients.

    Children and Adolescents weighing 35 to 47 kg

    15 mg/kg/day PO in 2 divided doses with sofosbuvir for 24 weeks; includes HIV-coinfected patients.

    For the treatment of chronic hepatitis C infection genotype 4 in combination with a nucleotide analog NS5B polymerase inhibitor or NS3/4A protease inhibitor with or without a peginterferon alfa product†.
    Oral dosage
    Adults weighing 75 kg or more

    1,200 mg/day PO in 2 divided doses with sofosbuvir and peginterferon alfa for 12 weeks as the preferred regimen. An alternative for patients able to receive interferon therapy combines ribavirin with simeprevir and peginterferon alfa for 12 weeks, then continue peginterferon alfa and ribavirin to complete 24 to 48 weeks total. An alternative for patients not able to receive interferon products combines ribavirin with sofosbuvir for 24 weeks; all regimens include HIV-coinfected patients. Administer simeprevir-containing regimen only in patients without significant drug interactions.

    Adults weighing less than 75 kg

    1,000 mg/day PO in 2 divided doses with sofosbuvir and peginterferon alfa for 12 weeks as the preferred regimen. An alternative for patients able to receive interferon therapy combines ribavirin with simeprevir and peginterferon alfa for 12 weeks, then continue peginterferon alfa and ribavirin to complete 24 to 48 weeks total. An alternative for patients not able to receive interferon products combines ribavirin with sofosbuvir for 24 weeks; all regimens include HIV-coinfected patients. Administer simeprevir-containing regimen only in patients without significant drug interactions.

    For the treatment of chronic hepatitis C infection genotypes 5 or 6 in combination with a nucleotide analog NS5B polymerase inhibitor and/or a peginterferon alfa product†.
    Oral dosage
    Adults weighing 75 kg or more

    1,200 mg/day PO in 2 divided doses with sofosbuvir and peginterferon alfa for 12 weeks is recommended based on a small number of patients. An alternative for treatment-naive patients combines ribavirin with peginterferon alfa for 48 weeks. Another alternative for nonresponders combines ribavirin with sofosbuvir for 24 weeks. All regimens include HIV-coinfected patients.

    Adults weighing less than 75 kg

    1,000 mg/day PO in 2 divided doses with sofosbuvir and peginterferon alfa for 12 weeks is recommended based on a small number of patients. An alternative for treatment-naive patients combines ribavirin with peginterferon alfa for 48 weeks. Another alternative for nonresponders combines ribavirin with sofosbuvir for 24 weeks. All regimens include HIV-coinfected patients.

    For the treatment of viral hemorrhagic fever (VHF)†, including hemorrhagic fever with renal syndrome (HFRS)† secondary to Hantaan virus infection†.
    NOTE: Ribavirin has been designated an orphan drug by the FDA for hemorrhagic fever with renal syndrome (HFRS).
    Intravenous dosage (NOTE: In the US, the IV formulation is only available through the CDC for compassionate use)†
    Adults

    A loading dose of 33 mg/kg IV, followed by 16 mg/kg IV every 6 hours for 4 days, then 8 mg/kg IV every 8 hours for 3 days (total 7 day course). Therapy may only benefit patients who have been febrile for 6 days or less.

    For Lassa fever prophylaxis†.
    Oral dosage
    Adults

    400 mg PO twice daily for 10 days OR 600 mg PO 4 times daily for 10 days OR 10 mg/kg PO 4 times daily for 5 to 8 days in high-risk contacts. The Centers for Disease Control and Prevention (CDC) supports ribavirin for treatment of Lassa fever but does not address ribavirin prophylaxis.

    Children and Adolescents 10 years and older

    600 mg PO 4 times daily for 10 days in high-risk contacts. The Centers for Disease Control and Prevention (CDC) supports ribavirin for treatment of Lassa fever but does not address ribavirin prophylaxis.

    Children 6 to 9 years

    400 mg PO 4 times daily for 10 days in high-risk contacts. The Centers for Disease Control and Prevention (CDC) supports ribavirin for treatment of Lassa fever but does not address ribavirin prophylaxis.

    For the treatment of adenovirus infection†, including pneumonitis†, hepatitis†, hemorrhagic cystitis†, and nephritis†.
    Intravenous dosage† (NOTE: In the US, the IV form is only available through the CDC for compassionate use)
    Adults, Adolescents, and Children

    Various regimens have been used. Typically the following has been given 33 mg/kg IV loading dose, followed by 16 mg/kg IV every 6 hours for 4 days, then 8 mg/kg IV every 8 hours for 3 to 6 days (total 7 to 10 day course). Other reports use a 35 mg/kg IV loading dose then 25 mg/kg IV every 8 hours or 15 mg/kg IV every 6 hours.

    For the treatment of viral encephalitis†.
    For subacute measles encephalitis† (SME).
    Intravenous dosage (NOTE: In the US, the IV form is only available through the CDC for compassionate use)
    Adults, Adolescents, and Children

    Although ribavirin is recommend by the Infectious Diseases Society of America (IDSA) for SME, a specific dose has not been suggested. The guidelines do suggest that if ribavirin is administered, it should be continued for 2 to 3 weeks. In a case report, a 20 year old patient with HIV received 30 mg/kg/day IV in 3 divided doses for 1 day followed by 20 mg/kg/day in 3 divided doses for 9 days. Although this patient ultimately succumbed to SME, this was attributed to administering therapy late into the progression of the disease. In a second case report of a 4 year old with acute leukemia, the patient received 20 mg/kg/day IV in divided doses for a 3 week course and showed clinical improvement.

    For subacute sclerosing panencephalitis† (SSPE) caused by the measles virus†.
    Intrathecal dosage (NOTE: In the US, the injectable formulation is only available through the CDC for compassionate use)
    Children and Adolescents

    Although ribavirin is recommend by the IDSA for SSPE caused by the measles virus, a specific dose has not been suggested. In a study of 5 patients (ages 3 to 15 years), intrathecal ribavirin was administered to maintain CSF concentrations between 50 to 200 mcg/ml. The initial dose administered was as 1 mg/kg diluted with saline and injected as 1 to 2 ml via the Ommaya reservoir. Doses were administered 1- to 3-times daily and ranged from 1 to 9 mg/kg/day intrathecally (max of 3 mg/kg/dose). Four of the patients showed signs of clinical improvement.

    For encephalitis† caused by the Nipah virus†.
    Oral dosage
    Adults

    Although ribavirin is recommend by the IDSA for encephalitis caused by the Nipah virus, a specific dose has not been suggested. An open label trial of 194 patients (ribavirin n=140; oral dosage n=128) received ribavirin 2 g PO on day 1, 1.2 g PO three times daily on days 2 through 4, 1.2 g PO twice daily on days 5 and 6, and 600 mg PO twice daily for another 1 to 4 days. This study suggested that ribavirin was able to reduce mortality associated with Nipah virus without serious side effects.

    Intravenous dosage (NOTE: In the US, the IV form is only available through the CDC for compassionate use)
    Adults

    Although ribavirin is recommend by the IDSA for encephalitis caused by the measles virus, a specific dose has not been suggested. An open label trial of 194 patients (ribavirin n=140; IV dosage n=12) received IV ribavirin at the end of the trial (when the IV became available) for patients unable to tolerate oral ribavirin. The dosage regimen was 30 mg/kg IV as a loading dose, then 16 mg/kg IV every 6 hours for 4 days, followed by 8 mg/kg IV every 8 hours for 3 days. The authors concluded that there were too few patients that received IV therapy to make any conclusions regarding success of therapy.

    For encephalitis† caused by the West Nile virus†.
    Intravenous dosage (NOTE: In the US, the IV form is only available through the CDC for compassionate use)
    Adults

    The IDSA recommends against using ribavirin for West Nile encephalitis due to lack of conclusive efficacy.

    For the treatment of West Nile virus infection†, including meningitis† and encephalitis†.
    NOTE: Other than supportive care, there is no established treatment for West Nile virus infection. The use of ribavirin is suggested by in vitro data only.
    Oral or Intravenous† dosage (NOTE: In the US, the IV form is only available through the CDC for compassionate use)
    Adults, Adolescents, and Children

    In one case report, a 4-year old child with lymphoma was diagnosed with West Nile virus infection based on positive IgM specific antibodies. Beginning on day 8 of admission, ribavirin 200 mg PO four times per day was given via nasogastric tube for 14 days. The WBC count gradually increased and normalized by the 12th day of admission. Slow improvement in the child's neurological status was noted at the beginning of the third week. An in vitro study has suggested that oral doses of ribavirin (2400 mg/day) are not sufficient to treat West Nile virus infection; these authors suggest using intravenous ribavirin at doses of 4 g/day in adults (e.g., 33 mg/kg IV, followed by 16 mg/kg IV every 6 hours). The Infectious Disease Society of America (IDSA) recommends against using ribavirin for West Nile encephalitis due to lack of conclusive efficacy.

    For the treatment of Severe Acute Respiratory Syndrome (SARS)†.
    Intravenous dosage or oral dosage (NOTE: In the US, IV ribavirin is only available via the CDC for compassionate use)
    Adults

    Dosage not established. 400 mg IV every 8 hours OR 1.2 g PO every 8 hours OR 2 g PO loading dose followed by 1 g (less than 75 kg) or 1.2 g (75 kg or more) PO once daily has been reported.

    For the treatment of Crimean-Congo virus hemorrhagic fever (CCVHF)† or Lassa fever infection†.
    NOTE: The use of ribavirin for hemorrhagic fever with renal syndrome (HFRS) secondary to Crimean-Congo virus is supported by in vitro data.
    Intravenous dosage (NOTE: In the US, the IV form is only available through the CDC for compassionate use)†
    Adults

    33 mg/kg IV loading dose, then 16 mg/kg IV every 6 hours for 4 days, then 8 mg/kg IV every 8 hours for 6 days.

    For Crimean-Congo virus hemorrhagic fever (CCVHF) prophylaxis†.
    Oral dosage
    Adults

    2 g PO 4 times daily for 7 days OR 2 g PO loading dose, then 2 g/day PO for 4 days, then 1.2 g/day PO for 3 days OR 2 g PO loading dose, then 4 g/day PO in 4 divided doses for 4 days, then 2 g/day PO in 4 divided doses for 6 days.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    Dependent on route of administration and indication for therapy.

    Elderly

    Dependent on route of administration and indication for therapy.

    Adolescents

    Dependent on route of administration and indication for therapy.

    Children

    Dependent on route of administration and indication for therapy.

    Infants

    Dependent on route of administration and indication for therapy.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for oral dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed. Safety and efficacy have not been established in patients with decompensated hepatic disease.

    Renal Impairment

    Rebetol:
    CrCl >= 50 ml/min: No dose adjustment needed. Closely monitor older patients (> 50 years of age) for development of anemia.
    CrCl < 50 ml/min: Use not recommended.
     
    Copegus:
    NOTE: If severe adverse reactions or laboratory abnormalities develop in patients with renal impairment, discontinue ribavirin therapy; further dose modifications are not recommended.
    CrCl > 50 ml/min: No dose adjustment needed. Closely monitor older patients (> 50 years of age) for development of anemia.
    CrCl 30—50 ml/min: Reduce to alternating doses of 400 mg and 200 mg PO every other day.
    CrCl < 30 ml/min: Reduce dose to 200 mg PO daily.
     
    Intermittent hemodialysis
    Rebetol: Use not recommended.
    Copegus: Reduce dose to 200 mg PO daily.

    ADMINISTRATION

     
    NOTE: A MedGuide is available for ribavirin and is to be dispensed with every prescription and prescription refill. The MedGuide discusses potential birth defects and use of birth control, risk of anemia, and ineffective use as monotherapy for the treatment of hepatitis C.
    Therapy in females of childbearing potential should only begin after a negative pregnancy test is confirmed. If a patient becomes pregnant during or within 6 months of completing ribavirin therapy, the prescriber or health care professional is encouraged to report the case by calling 800—727—7064.

    Oral Administration

    Monotherapy is not effective in the treatment of chronic hepatitis C.
    Administer with food.

    Oral Solid Formulations

    Capsules: Do NOT open, crush, or break the capsules.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    NOTE: Ribavirin is not approved by the FDA for intravenous administration.
    Intravenous ribavirin is available in the US only from ICN Pharmaceuticals and the Centers for Disease Control and Prevention (CDC) on a compassionate use basis under a treatment IND to treat Hantaan virus infection. For more information on obtaining intravenous ribavirin for this use call the CDC at 404—639—3311 (in New Mexico call 505—843—2111; in Arizona call 602—433—0215).
    No instructions for parenteral administration are currently available; follow the recommendations of the CDC for product preparation and administration.

    Inhalation Administration

    Only the SPAG-2 aerosol generator should be used for delivery. Read SPAG-2 operator's manual thoroughly before using.
     
    Preparation of aerosol solution:
    Using sterile technique, add sterile water for injection or inhalation (water must be preservative and additive free) to the 100 ml vial containing 6 grams of ribavirin. Transfer solution to the clean, sterilized 500 ml SPAG-2 reservoir and further dilute with sterile water for injection or inhalation to a final volume of 300 ml. The final concentration should be 20 mg/ml. Solutions placed in the reservoir should be discarded every 24 hours and prior to adding newly reconstituted solutions. Reconstituted solutions may be stored under sterile conditions, at room temperature for 24 hours.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Oral Inhalation Administration

    Mechanically ventilated infants:
    Administer using the SPAG-2 aerosol generator in conjunction with either a pressure or volume cycle ventilator. Use of heated wire connective tubing and bacteria filters in series is required in the expiratory lib of the ventilatory system to minimize the risk of ribavirin precipitation and subsequent ventilator dysfunction. Tubing and filters should be changed frequently (i.e., every hour). Water pressure release valves must be used in the ventilator circuit for pressure cycled ventilators and may be used with volume cycled ventilators.
    Patients should have their endotracheal tubes suctioned every 1—2 hours and their pulmonary pressures measured every 2—4 hours.

    Intranasal Inhalation Administration

    Non-mechanically ventilated infants:
    Administer via an infant oxygen hood using the SPAG-2 aerosol generator. If hood cannot be used, may be administered by face mask or oxygen tent, however, the oxygen tent may alter the delivery dynamics of ribavirin due to a larger volume and condensation area.

    STORAGE

    Generic:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Copegus:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Moderiba:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Rebetol:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    RibaPak:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Ribasphere:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Ribasphere RibaPak:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    RibaTab:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Virazole:
    - Reconstituted product is stable for 24 hours at room temperature
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    - Store diluted product at room temperature (68 to 77 degrees F) for up to 24 hours
    - Store in a dry place

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Ribavirin must be used in combination with either interferon alfa-2b (Intron A) or peginterferon alfa-2b (PegIntron). Alfa interferons may cause or aggravate fatal or life-threatening neuropsychiatric disorders, such as depression, suicidal ideation, suicide attempts, completed suicides, homicidal ideation, and aggression towards others. Patients with pre-existing history of substance abuse (e.g., alcoholism), depression, or severe psychiatric disorder may be at increased risk; thus, interferon therapy must be administered with extreme caution to these patients. In addition, pediatric drug recipients (primarily adolescents) are more likely to experience suicidal ideation or attempts as compared to adults (2.4% vs. 1%). Instruct all patients to immediately report any symptoms of depression or suicidal ideation to their health care provider. Closely monitor patients for depression and other psychiatric symptoms during treatment and for 6 months after the last alfa interferon dose. Patients experiencing persistent or worsening psychiatric symptoms should be immediately discontinued from combination therapy and closely followed with appropriate medical management. Although, interferon dose reduction or cessation of combination therapy may lead to resolution of the symptoms, depression may persist and suicides have occurred after withdrawing therapy. Full resolution of symptoms may take up to 3 weeks in severe cases.
     
    Ribavirin is used in combination with alpha interferons. Patients receiving interferon alpha have developed hyperglycemia, hypoglycemia, and diabetes mellitus. Patients with preexisting diabetes mellitus may experience alterations in glucose control if given combination ribavirin; interferon therapy.

    Requires an experienced clinician, respiratory depression, respiratory insufficiency

    Aerosolized ribavirin therapy requires an experienced clinician. Aerosolized ribavirin use in patients with respiratory insufficiency or respiratory depression requiring mechanical ventilation should be done only by clinicians and support staff familiar with the specific ventilator being used and the administration of aerosolized ribavirin. Ribavirin can precipitate in the respiratory apparatus which can cause additional difficulty in ventilation. Strict adherence to guidelines for minimizing accumulation of ribavirin must be followed. If worsening of respiratory function occurs, aerosolized ribavirin should be withdrawn. Aerosolized ribavirin is not for use in adults.

    Contact lenses, ocular exposure

    Health care workers or others subjected to regular ocular exposure to aerosolized ribavirin can develop ocular irritation. Eye discomfort appears to be more severe in persons wearing contact lenses; wearing eye glasses or protective eye goggles may minimize possible side effects.

    Contraception requirements, male-mediated teratogenicity, pregnancy, pregnancy testing

    Ribavirin may cause birth defects and/or death of the exposed fetus (intrauterine fetal death) and must not be used during pregnancy. Ribavirin therapy may also cause male-mediated teratogenicity. The drug is contraindicated for use during pregnancy (FDA pregnancy risk category X), in females of childbearing potential who may become pregnant, or in men whose female partners are pregnant. Studies indicate teratogenic (e.g., malformations of skull, palate, eye, jaw, limbs, skeleton, and GI tract) or embryocidal properties in most of the animal species tested. The incidence and severity of these effects increased with increasing ribavirin dose. Health-care workers who are pregnant or trying to get pregnant should avoid contact with patients receiving aerosolized ribavirin. No reports of teratogenesis in babies of mothers who were exposed to aerosolized ribavirin during pregnancy have been confirmed. Ribavirin is reported to be 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 must receive pregnancy testing before starting ribavirin therapy, every month while being treated, and every month for the 6 months after treatment is discontinued. Contraception requirements exist for both males and females of childbearing potential in whom ribavirin is prescribed. Both men and women of childbearing potential must use 2 forms of effective contraception during treatment and for 6 months after treatment discontinuation. If a female or the female sexual partner of a treated male becomes pregnant while taking 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

    Ribavirin should be used with caution in males because animal studies have shown that ribavirin-induced testicular degeneration and infertility may occur. Testicular degeneration appears to be reversible after stopping ribavirin with recovery occurring within 1 or 2 spermatogenesis cycles.

    Breast-feeding

    It is not known if ribavirin is excreted in the breast milk, although it has been shown to be toxic to nursing animals. According to the manufacturer, a decision must be made whether to discontinue nursing or discontinue treatment with ribavirin. Consider the benefits of breast-feeding, the risk of 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 ingested drug, health care providers are encouraged to report the adverse effect to the FDA.

    Anemia, angina, cardiac arrhythmias, cardiac disease, cerebrovascular disease, coronary artery disease, heart failure, hemolytic anemia, myocardial infarction

    Oral ribavirin should be used with caution in patients with anemia. The major clinical toxicity of ribavirin is hemolytic anemia. Decreases in hemoglobin occur within 1—2 weeks of initiating ribavirin therapy. It is recommended that a CBC be obtained in patients prior to beginning therapy, at weeks 2 and 4 of therapy and as needed. Dosage reductions are recommended for patients who experience drops in hemoglobin to < 10 g/dl; ribavirin therapy should be discontinued in patients with hemoglobin < 8.5 g/dl (see Dosage). The anemia associated with ribavirin therapy may result in deterioration in cardiac function and/or exacerbation of the symptoms of coronary artery disease or cerebrovascular disease. Patients with history of cardiac disease should be assessed before initiation of therapy and should be appropriately monitored during therapy. If there is any deterioration in cardiac status, therapy should be suspended or discontinued (see Dosage). Because cardiac disease (e.g., angina or congestive heart failure) may be worsened by drug-induced anemia, patients with a history of significant or unstable cardiac disease should not use ribavirin therapy. Those patients with a history of myocardial infarction and/or previous or current cardiac arrhythmias should be closely monitored; fatal and nonfatal myocardial infarctions have been reported in patients with ribavirin-induced anemia.

    Infection

    Ribavirin is used in combination with alpha interferons and should be given with caution to patients with bone marrow suppression, patients receiving other myelosuppressive therapy including radiation therapy, or patients with a history of neoplastic disease (cancer). Patients with preexisting infections should be treated prior to starting ribavirin; interferon therapy. It is recommended that a complete blood count (CBC) with differential be obtained in patients prior to beginning combination therapy, at weeks 2 and 4 of therapy and as needed. Combination therapy should be reduced or discontinued in patients who develop leukopenia, (white blood cell count < 1500/mm3), neutropenia (absolute neutrophil count < 750/mm3) or thrombocytopenia (platelet count < 80,000 or 50,000/mm3 depending upon dosage).

    Hemoglobinopathy, sickle cell disease, thalassemia

    Oral ribavirin is contraindicated in patients with any hemoglobinopathy (e.g., thalassemia major, sickle cell disease).

    Geriatric

    In general, oral ribavirin should be administered to geriatric patients cautiously, starting at the lower end of the dosing range, reflecting the greater frequency of decreased renal, hepatic and/or cardiac function, and of concomitant disease or other drug therapy. In clinical trials, elderly subjects had a higher frequency of anemia (67%) than did younger patients (28%). Aerosolized ribavirin is not indicated for use in elderly patients.

    Hepatic disease, hepatitis, hepatitis C and HIV coinfection, influenza, organ transplant, ribavirin monotherapy, viral infection

    The combination of ribavirin and peginterferon alfa-2a is contraindicated in patients with autoimmune hepatitis as this can cause a worsening of the hepatitis. Additionally, the combination of ribavirin and peginterferon alfa-2a are contraindicated in the treatment of cirrhotic chronic hepatitis C in patients who experience hepatic decompensation or hepatic disease (Child-Pugh score greater than 6; class B and C) before or during treatment, or in cirrhotic patients with hepatitis C and HIV coinfection. The safety and efficacy of oral ribavirin therapy have not been established in patients with liver or other organ transplant, decompensated hepatic disease, concurrent hepatitis B virus (HBV) or human immunodeficiency virus (HIV) infection, or in patients who are non-responders to interferon monotherapy. The safety and efficacy of oral ribavirin monotherapy for the treatment of certain viral infections including HIV infection, adenovirus, early RSV infection, parainfluenza, or influenza have not been established. Ribavirin capsules should not be used for such viral infection. In addition, monotherapy with ribavirin capsules is not effective in the treatment of hepatitis C; the safety and efficacy of ribavirin capsules have only been established when used as combination therapy with interferon alfa. 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 consuming alcohol, and offer vaccinations against hepatitis A and hepatitis B as appropriate.

    Children, growth inhibition, infants, neonates

    In infants, initiation of aerosolized ribavirin therapy has been associated with a sudden deterioration of respiratory function. Carefully monitor respiratory function. If a sudden deterioration of respiratory function occurs, treatment should be stopped and should be restarted with extreme caution; continuous monitoring is necessary and consideration should be given to concomitant administration of bronchodilators. The safety and efficacy of oral ribavirin therapy in children have only been established when used concomitantly with interferon alfa-2b for the treatment of chronic hepatitis C. In addition to other serious adverse events (generally similar in children compared to adults) that should be taken into consideration prior to initiating therapy in a pediatric patient, suicidal ideation or attempts occurred more frequently among pediatric patients, primarily adolescents, compared to adult patients (2.4% vs. 1%) during treatment and off-therapy follow-up. Monitor for the potential for growth inhibition in children and adolescents receiving peginterferon alfa-2b and ribavirin. Data from an open-label trial of patients ages 3—17 years show that weight and height gain of pediatric patients treated with peginterferon alfa-2b plus ribavirin capsules/solution lags behind predicted normal growth based on population data for the entire length of treatment. Six months after treatment, patients' weight gain rebounded to reach their predicted average; however, six months after treatment, height gain stabilized at less than the average predicted growth. Severely inhibited growth velocity (< 3rd percentile) was observed in 70% of patients while on treatment, and 20% of those patients had continued inhibited growth velocity after 6 months. Girls ages 3—11 years who were treated for 48 weeks had the largest average drop in height and weight. In another study, pediatric patients receiving 48 weeks of treatment with peginterferon alfa-2a plus ribavirin tablets also demonstrated delays in weight and height increases. At the end of treatment, 43% of peginterferon alfa-2a/ribavirin treated pediatric patients experienced weight percentile decreases of >= 15 percentiles and 25% experienced height percentile decreases of >= 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. Safety and efficacy of ribavirin capsules and solution have not been established in neonates, infants, or children < 3 years of age. Safety and efficacy of ribavirin tablets have not been established in neonates, infants, or children < 5 years or < 23 kg.

    Pancreatitis

    Oral ribavirin therapy should be suspended in patients with signs and symptoms of pancreatitis and discontinued in patients with confirmed pancreatitis. Fatal and non-fatal pancreatitis has been reported in patients treated with the combination of interferon alfa and ribavirin.

    Dialysis, renal failure, renal impairment

    Oral ribavirin therapy should not be used in patients with significant renal impairment (creatinine clearance < 50 ml/min). The mean AUC value of ribavirin was three-fold greater in patients with creatinine clearance between 10—30 ml/min than controls. Ribavirin is not removed by hemodialysis and should not be given to patients with renal failure or patients receiving dialysis.

    Thyroid disease

    Ribavirin is used in combination with alpha interferons and must not be given to patients with thyroid disease (e.g., hyperthyroidism or hypothyroidism) whose thyroid function cannot be maintained in the normal range by medication. Testing of TSH levels in these patients is recommended at baseline and every 3 months following initiation of interferon alfa-2b therapy. Also, the development or exacerbation of an autoimmune thyroid disease (e.g., Graves' disease, thyroiditis) has been observed in patients receiving alpha interferons. Interferon alfa-2b should be used with caution in these patients and only if the potential benefit justifies the risk.

    ADVERSE REACTIONS

    Severe

    hemolytic anemia / Delayed / 10.0-13.0
    eczema vaccinatum / Delayed / 4.0-5.0
    suicidal ideation / Delayed / 0-3.0
    pulmonary embolism / Delayed / 0-1.0
    aplastic anemia / Delayed / 0-1.0
    peptic ulcer / Delayed / 0-1.0
    thrombotic thrombocytopenic purpura (TTP) / Delayed / 0-1.0
    coma / Early / 0-1.0
    pancreatitis / Delayed / 0-1.0
    pulmonary hypertension / Delayed / Incidence not known
    pneumothorax / Early / Incidence not known
    cyanosis / Early / Incidence not known
    pulmonary edema / Early / Incidence not known
    apnea / Delayed / Incidence not known
    bronchospasm / Rapid / Incidence not known
    red cell aplasia / Delayed / Incidence not known
    bradycardia / Rapid / Incidence not known
    cardiac arrest / Early / Incidence not known
    retinal detachment / Delayed / Incidence not known
    teratogenesis / Delayed / Incidence not known
    hearing loss / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known

    Moderate

    anemia / Delayed / 11.0-67.0
    depression / Delayed / 1.0-36.0
    neutropenia / Delayed / 1.0-33.0
    dyspnea / Early / 5.0-26.0
    lymphopenia / Delayed / 12.0-14.0
    leukopenia / Delayed / 5.0-10.0
    chest pain (unspecified) / Early / 5.0-9.0
    blurred vision / Early / 2.0-6.0
    thrombocytopenia / Delayed / 0-5.0
    conjunctivitis / Delayed / 4.0-5.0
    hypothyroidism / Delayed / 4.0-5.0
    psychosis / Early / 0-1.0
    hallucinations / Early / 0-1.0
    angina / Early / 0-1.0
    peripheral neuropathy / Delayed / 0-1.0
    hyperthyroidism / Delayed / 0-1.0
    cholangitis / Delayed / 0-1.0
    diabetes mellitus / Delayed / 0-1.0
    constipation / Delayed / 5.0
    hepatomegaly / Delayed / 4.0
    respiratory depression / Rapid / Incidence not known
    hypoventilation / Rapid / Incidence not known
    hypotension / Rapid / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    ocular inflammation / Early / Incidence not known
    clastogenesis / Delayed / Incidence not known
    dehydration / Delayed / Incidence not known
    growth inhibition / Delayed / Incidence not known

    Mild

    fever / Early / 21.0-80.0
    fatigue / Early / 30.0-70.0
    headache / Early / 41.0-69.0
    asthenia / Delayed / 5.0-68.0
    myalgia / Early / 17.0-64.0
    injection site reaction / Rapid / 5.0-58.0
    anorexia / Delayed / 21.0-51.0
    irritability / Delayed / 3.0-47.0
    anxiety / Delayed / 3.0-47.0
    emotional lability / Early / 3.0-47.0
    nausea / Early / 18.0-47.0
    vomiting / Early / 9.0-42.0
    insomnia / Early / 14.0-41.0
    chills / Rapid / 21.0-39.0
    alopecia / Delayed / 17.0-36.0
    arthralgia / Delayed / 15.0-34.0
    weight loss / Delayed / 10.0-29.0
    pruritus / Rapid / 12.0-29.0
    rash (unspecified) / Early / 5.0-29.0
    musculoskeletal pain / Early / 19.0-28.0
    dizziness / Early / 13.0-26.0
    diarrhea / Early / 10.0-22.0
    abdominal pain / Early / 8.0-21.0
    dyspepsia / Early / 0-16.0
    pharyngitis / Delayed / 12.0-13.0
    infection / Delayed / 0-12.0
    sinusitis / Delayed / 0-12.0
    xerostomia / Early / 4.0-12.0
    dysgeusia / Early / 0-9.0
    agitation / Early / 5.0-8.0
    rhinitis / Early / 6.0-8.0
    menstrual irregularity / Delayed / 6.0-7.0
    malaise / Early / 4.0-6.0
    flushing / Rapid / 3.0-4.0
    back pain / Delayed / 5.0
    cough / Delayed / Incidence not known
    ocular irritation / Rapid / Incidence not known
    lacrimation / Early / Incidence not known
    tinnitus / Delayed / Incidence not known
    vertigo / Early / Incidence not known

    DRUG INTERACTIONS

    Abacavir: (Major) The concomitant use of ribavirin and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. The co-treatment of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) has the potential to result in complex drug interactions. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons, with or without ribavirin, 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. While ribavirin inhibits the phosphorylation reactions required to activate lamivudine, stavudine, d4T, and zidovudine, no evidence of a pharmacokinetic or pharmacodynamic interaction was seen.
    Abacavir; Dolutegravir; Lamivudine: (Major) The concomitant use of ribavirin and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. The co-treatment of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) has the potential to result in complex drug interactions. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons, with or without ribavirin, 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. While ribavirin inhibits the phosphorylation reactions required to activate lamivudine, stavudine, d4T, and zidovudine, no evidence of a pharmacokinetic or pharmacodynamic interaction was seen. (Major) While ribavirin inhibits the phosphorylation reactions required to activate lamivudine, 3TC, no evidence of a pharmacokinetic or pharmacodynamic interaction has been observed. However, the co-treatment of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) has the potential to result in complex drug interactions, and patients receiving ribavirin in combination with lamivudine should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Dose reduction or discontinuation of ribavirin should be considered if toxicities develop. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons, with or without ribavirin, appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, lamivudine has been associated with lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease.
    Abacavir; Lamivudine, 3TC: (Major) The concomitant use of ribavirin and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. The co-treatment of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) has the potential to result in complex drug interactions. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons, with or without ribavirin, 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. While ribavirin inhibits the phosphorylation reactions required to activate lamivudine, stavudine, d4T, and zidovudine, no evidence of a pharmacokinetic or pharmacodynamic interaction was seen. (Major) While ribavirin inhibits the phosphorylation reactions required to activate lamivudine, 3TC, no evidence of a pharmacokinetic or pharmacodynamic interaction has been observed. However, the co-treatment of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) has the potential to result in complex drug interactions, and patients receiving ribavirin in combination with lamivudine should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Dose reduction or discontinuation of ribavirin should be considered if toxicities develop. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons, with or without ribavirin, appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, lamivudine has been associated with lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease.
    Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Major) Ribavirin may exacerbate the hematologic toxcities of zidovudine, ZDV; concomitant use should be avoided. Ribavirin has also been found to inhibit the phosphorylation reactions required to activate zidovudine, although, no evidence of pharmacokinetic or pharmacodynamic interaction was observed. Patients receiving co-treatment of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) with these drugs should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Dose reduction or discontinuation of ribavirin should be considered if toxicities develop. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons, with or without ribavirin, appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, zidovudine has been associated with lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. (Major) The concomitant use of ribavirin and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. The co-treatment of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) has the potential to result in complex drug interactions. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons, with or without ribavirin, 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. While ribavirin inhibits the phosphorylation reactions required to activate lamivudine, stavudine, d4T, and zidovudine, no evidence of a pharmacokinetic or pharmacodynamic interaction was seen. (Major) While ribavirin inhibits the phosphorylation reactions required to activate lamivudine, 3TC, no evidence of a pharmacokinetic or pharmacodynamic interaction has been observed. However, the co-treatment of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) has the potential to result in complex drug interactions, and patients receiving ribavirin in combination with lamivudine should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Dose reduction or discontinuation of ribavirin should be considered if toxicities develop. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons, with or without ribavirin, appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, lamivudine has been associated with lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease.
    Amprenavir: (Major) The concomitant use of ribavirin 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: (Major) The concomitant use of ribavirin 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 ribavirin 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: (Major) Pancytopenia and bone marrow suppression have been reported to occur within 3 to 7 weeks after concomitant administration of peginterferon alfa-2a / ribavirin and azathioprine. Inosine monophosphate dehydrogenase (IMDH) is required for one of the metabolic pathways of azathioprine and ribavirin is known to inhibit IMDH, thereby leading to the accumulation of the azathioprine metabolite, 6-methylthioinosine monophosphate (6-MTITP). This metabolite is associated with myelotoxicity (neutropenia, thrombocytopenia, and anemia). In the limited number of cases reported (n=8), myelotoxicity was reversible within 4 to 6 weeks after withdrawal of this combination of agents and did not recur upon reintroduction of either treatment alone. All drugs should be discontinued if patients experience pancytopenia and peginterferon alfa-2a / ribavirin should NOT be reintroduced with concomitant azathioprine. Patients receiving concomitant ribavirin and azathioprine should have complete blood counts, including platelet counts, monitored weekly for the first month of treatment, twice monthly for the second and third months of treatment, and monthly thereafter. After the third month of treatment, laboratory monitoring may be increased to more than monthly if dosage or other therapy changes are necessary.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Major) The concomitant use of ribavirin and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. The co-treatment of human immunodeficiency virus (HIV) and Hepatitis C virus (HCV) has the potential to result in complex drug interactions. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons, with or without ribavirin, 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. While ribavirin inhibits the phosphorylation reactions required to activate lamivudine, stavudine, d4T, and zidovudine, no evidence of a pharmacokinetic or pharmacodynamic interaction was seen.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) The concomitant use of ribavirin and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. The co-treatment of human immunodeficiency virus (HIV) and Hepatitis C virus (HCV) has the potential to result in complex drug interactions. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons, with or without ribavirin, 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. While ribavirin inhibits the phosphorylation reactions required to activate lamivudine, stavudine, d4T, and zidovudine, no evidence of a pharmacokinetic or pharmacodynamic interaction was seen.
    Darunavir: (Major) The concomitant use of ribavirin 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 ribavirin 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 ribavirin 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 ribavirin and anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs) should be done with caution as both can cause hepatic damage. NNRTIs may cause liver damage in the context of hypersensitivity reactions or by direct toxic effects. Many studies demonstrate that nevirapine is more hepatotoxic than efavirenz. Underlying chronic HCV infection enhances the risk of developing liver enzyme elevations in patients receiving nevirapine. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Didanosine, ddI: (Severe) Ribavirin use in combination with didanosine, ddI is contraindicated. Concurrent administration increases blood concentrations of didanosine and its active metabolite, resulting in fatal hepatic failure and increased incidence of other didanosine-related clinical toxicities.
    Dolutegravir; Rilpivirine: (Major) The concomitant use of ribavirin 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: (Major) The concomitant use of ribavirin 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 ribavirin 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 ribavirin and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. The co-treatment of human immunodeficiency virus (HIV) and Hepatitis C virus (HCV) has the potential to result in complex drug interactions. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons, with or without ribavirin, 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. While ribavirin inhibits the phosphorylation reactions required to activate lamivudine, stavudine, d4T, and zidovudine, no evidence of a pharmacokinetic or pharmacodynamic interaction was seen.
    Emtricitabine: (Major) The concomitant use of ribavirin and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. The co-treatment of human immunodeficiency virus (HIV) and Hepatitis C virus (HCV) has the potential to result in complex drug interactions. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons, with or without ribavirin, 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. While ribavirin inhibits the phosphorylation reactions required to activate lamivudine, stavudine, d4T, and zidovudine, no evidence of a pharmacokinetic or pharmacodynamic interaction was seen.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) The concomitant use of ribavirin 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 ribavirin and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. The co-treatment of human immunodeficiency virus (HIV) and Hepatitis C virus (HCV) has the potential to result in complex drug interactions. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons, with or without ribavirin, 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. While ribavirin inhibits the phosphorylation reactions required to activate lamivudine, stavudine, d4T, and zidovudine, no evidence of a pharmacokinetic or pharmacodynamic interaction was seen.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) The concomitant use of ribavirin 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 ribavirin and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. The co-treatment of human immunodeficiency virus (HIV) and Hepatitis C virus (HCV) has the potential to result in complex drug interactions. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons, with or without ribavirin, 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. While ribavirin inhibits the phosphorylation reactions required to activate lamivudine, stavudine, d4T, and zidovudine, no evidence of a pharmacokinetic or pharmacodynamic interaction was seen.
    Emtricitabine; Tenofovir alafenamide: (Major) The concomitant use of ribavirin and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. The co-treatment of human immunodeficiency virus (HIV) and Hepatitis C virus (HCV) has the potential to result in complex drug interactions. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons, with or without ribavirin, 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. While ribavirin inhibits the phosphorylation reactions required to activate lamivudine, stavudine, d4T, and zidovudine, no evidence of a pharmacokinetic or pharmacodynamic interaction was seen.
    Emtricitabine; Tenofovir disoproxil fumarate: (Major) The concomitant use of ribavirin and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution. The co-treatment of human immunodeficiency virus (HIV) and Hepatitis C virus (HCV) has the potential to result in complex drug interactions. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons, with or without ribavirin, 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. While ribavirin inhibits the phosphorylation reactions required to activate lamivudine, stavudine, d4T, and zidovudine, no evidence of a pharmacokinetic or pharmacodynamic interaction was seen.
    Entecavir: (Major) The concomitant use of ribavirin and entecavir should be done with caution. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons, with or without ribavirin, 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. While ribavirin inhibits the phosphorylation reactions required to activate lamivudine, stavudine, d4T, and zidovudine, no evidence of a pharmacokinetic or pharmacodynamic interaction was seen.
    Etravirine: (Major) The concomitant use of ribavirin and anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs) should be done with caution as both can cause hepatic damage. NNRTIs may cause liver damage in the context of hypersensitivity reactions or by direct toxic effects. Many studies demonstrate that nevirapine is more hepatotoxic than efavirenz. Underlying chronic HCV infection enhances the risk of developing liver enzyme elevations in patients receiving nevirapine. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Fosamprenavir: (Major) The concomitant use of ribavirin and anti-retroviral protease inhibitors should be done with caution as both can cause hepatic damage. Most protease inhibitors have been associated with episodes of liver toxicity, with lopinavir/low-dose ritonavir, fosamprenavir/low-dose ritonavir, and nelfinavir being less hepatotoxic and tipranavir/low-dose ritonavir being the most hepatotoxic. Hyperbilirubinemia is often associated with atazanavir and/or indinavir therapy but does not reflect liver damage and is related to the inhibition of UDP glucuronosyltransferase. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Indinavir: (Major) The concomitant use of ribavirin and anti-retroviral protease inhibitors should be done with caution as both can cause hepatic damage. Most protease inhibitors have been associated with episodes of liver toxicity, with lopinavir/low-dose ritonavir, fosamprenavir/low-dose ritonavir, and nelfinavir being less hepatotoxic and tipranavir/low-dose ritonavir being the most hepatotoxic. Hyperbilirubinemia is often associated with atazanavir and/or indinavir therapy but does not reflect liver damage and is related to the inhibition of UDP glucuronosyltransferase. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Lamivudine, 3TC: (Major) While ribavirin inhibits the phosphorylation reactions required to activate lamivudine, 3TC, no evidence of a pharmacokinetic or pharmacodynamic interaction has been observed. However, the co-treatment of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) has the potential to result in complex drug interactions, and patients receiving ribavirin in combination with lamivudine should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Dose reduction or discontinuation of ribavirin should be considered if toxicities develop. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons, with or without ribavirin, appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, lamivudine has been associated with lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease.
    Lamivudine, 3TC; Zidovudine, ZDV: (Major) Ribavirin may exacerbate the hematologic toxcities of zidovudine, ZDV; concomitant use should be avoided. Ribavirin has also been found to inhibit the phosphorylation reactions required to activate zidovudine, although, no evidence of pharmacokinetic or pharmacodynamic interaction was observed. Patients receiving co-treatment of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) with these drugs should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Dose reduction or discontinuation of ribavirin should be considered if toxicities develop. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons, with or without ribavirin, appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, zidovudine has been associated with lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. (Major) While ribavirin inhibits the phosphorylation reactions required to activate lamivudine, 3TC, no evidence of a pharmacokinetic or pharmacodynamic interaction has been observed. However, the co-treatment of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) has the potential to result in complex drug interactions, and patients receiving ribavirin in combination with lamivudine should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Dose reduction or discontinuation of ribavirin should be considered if toxicities develop. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons, with or without ribavirin, appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, lamivudine has been associated with lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease.
    Lopinavir; Ritonavir: (Major) The concomitant use of ribavirin and anti-retroviral protease inhibitors should be done with caution as both can cause hepatic damage. Most protease inhibitors have been associated with episodes of liver toxicity, with lopinavir/low-dose ritonavir, fosamprenavir/low-dose ritonavir, and nelfinavir being less hepatotoxic and tipranavir/low-dose ritonavir being the most hepatotoxic. Hyperbilirubinemia is often associated with atazanavir and/or indinavir therapy but does not reflect liver damage and is related to the inhibition of UDP glucuronosyltransferase. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Nelfinavir: (Major) The concomitant use of ribavirin 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 ribavirin 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.
    Non-nucleoside reverse transcriptase inhibitors: (Major) The concomitant use of ribavirin 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 ribavirin and anti-retroviral protease inhibitors should be done with caution as both can cause hepatic damage. Most protease inhibitors have been associated with episodes of liver toxicity, with lopinavir/low-dose ritonavir, fosamprenavir/low-dose ritonavir, and nelfinavir being less hepatotoxic and tipranavir/low-dose ritonavir being the most hepatotoxic. Hyperbilirubinemia is often associated with atazanavir and/or indinavir therapy but does not reflect liver damage and is related to the inhibition of UDP glucuronosyltransferase. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Protease inhibitors: (Major) The concomitant use of ribavirin 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.
    Rilpivirine: (Major) The concomitant use of ribavirin 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.
    Ritonavir: (Major) The concomitant use of ribavirin and anti-retroviral protease inhibitors should be done with caution as both can cause hepatic damage. Most protease inhibitors have been associated with episodes of liver toxicity, with lopinavir/low-dose ritonavir, fosamprenavir/low-dose ritonavir, and nelfinavir being less hepatotoxic and tipranavir/low-dose ritonavir being the most hepatotoxic. Hyperbilirubinemia is often associated with atazanavir and/or indinavir therapy but does not reflect liver damage and is related to the inhibition of UDP glucuronosyltransferase. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Saquinavir: (Major) The concomitant use of ribavirin and anti-retroviral protease inhibitors should be done with caution as both can cause hepatic damage. Most protease inhibitors have been associated with episodes of liver toxicity, with lopinavir/low-dose ritonavir, fosamprenavir/low-dose ritonavir, and nelfinavir being less hepatotoxic and tipranavir/low-dose ritonavir being the most hepatotoxic. Hyperbilirubinemia is often associated with atazanavir and/or indinavir therapy but does not reflect liver damage and is related to the inhibition of UDP glucuronosyltransferase. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
    Stavudine, d4T: (Major) While ribavirin inhibits the phosphorylation reactions required to activate stavudine, d4T, no evidence of a pharmacokinetic or pharmacodynamic interaction has been observed. However, the co-treatment of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) has the potential to result in complex drug interactions, and patients receiving ribavirin in combination with stavudine should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Dose reduction or discontinuation of ribavirin should be considered if toxicities develop. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons, with or without ribavirin, appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, stavudine has been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease.
    Talimogene Laherparepvec: (Major) Consider the risks and benefits of treatment with talimogene laherparepvec before administering acyclovir or other antivirals to prevent or manage herpetic infection. Talimogene laherparepvec is a live, attenuated herpes simplex virus that is sensitive to acyclovir; coadministration with antiviral agents may cause a decrease in efficacy.
    Telbivudine: (Major) The concomitant use of ribavirin and telbivudine should be done with caution. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons, with or without ribavirin, 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. While ribavirin inhibits the phosphorylation reactions required to activate lamivudine, stavudine, d4T, and zidovudine, no evidence of a pharmacokinetic or pharmacodynamic interaction was seen.
    Tipranavir: (Major) The concomitant use of ribavirin 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.
    Zalcitabine, ddC: (Major) The concomitant use of ribavirin and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) should be done with caution as the combination may increase the risk for the development of hepatic decompensation. 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.
    Zidovudine, ZDV: (Major) Ribavirin may exacerbate the hematologic toxcities of zidovudine, ZDV; concomitant use should be avoided. Ribavirin has also been found to inhibit the phosphorylation reactions required to activate zidovudine, although, no evidence of pharmacokinetic or pharmacodynamic interaction was observed. Patients receiving co-treatment of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) with these drugs should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Dose reduction or discontinuation of ribavirin should be considered if toxicities develop. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons, with or without ribavirin, appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, zidovudine has been associated with lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease.

    PREGNANCY AND LACTATION

    Pregnancy

    Ribavirin may cause birth defects and/or death of the exposed fetus (intrauterine fetal death) and must not be used during pregnancy. Ribavirin therapy may also cause male-mediated teratogenicity. The drug is contraindicated for use during pregnancy (FDA pregnancy risk category X), in females of childbearing potential who may become pregnant, or in men whose female partners are pregnant. Studies indicate teratogenic (e.g., malformations of skull, palate, eye, jaw, limbs, skeleton, and GI tract) or embryocidal properties in most of the animal species tested. The incidence and severity of these effects increased with increasing ribavirin dose. Health-care workers who are pregnant or trying to get pregnant should avoid contact with patients receiving aerosolized ribavirin. No reports of teratogenesis in babies of mothers who were exposed to aerosolized ribavirin during pregnancy have been confirmed. Ribavirin is reported to be 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 must receive pregnancy testing before starting ribavirin therapy, every month while being treated, and every month for the 6 months after treatment is discontinued. Contraception requirements exist for both males and females of childbearing potential in whom ribavirin is prescribed. Both men and women of childbearing potential must use 2 forms of effective contraception during treatment and for 6 months after treatment discontinuation. If a female or the female sexual partner of a treated male becomes pregnant while taking 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

    The antiviral effect of ribavirin is not fully understood. It is phosphorylated intracellularly to mono-, di-, and triphosphate metabolites. Once phosphorylated, ribavirin disrupts cellular purine metabolism by inhibiting inosine monophosphate dehydrogenase, which leads to a decrease in guanosine triphosphate. It has been suggested that ribavirin acts as a potent RNA virus mutagen and increases the mutation rate of RNA viruses leading to 'error catastrophe.' Typically, RNA viruses have a high mutation rate that enables the virus to evolve rapidly and escape host immune mechanisms; however, the high mutation rate is also associated with the production of nonviable virions. In one virus strain, the increased mutation rate induced by ribavirin correlated with reduced formation of genomic viral RNA and decreased the infectivity of new virions. Thus, ribavirin increases the natural mutation rate beyond the limit where viable virions can be produced. Antiviral activity can be reversed by adenosine or guanosine. At high concentrations, ribavirin has some cytotoxicity within host cells.
     
    Ribavirin also increases the production of antiviral cytokines, such as interleukin (IL)—2, tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma, by Type 1 CD4 and CD8 T-cells. Type 1 T-cells are responsible for cell-mediated immunity, especially helper T-cell-mediated cytotoxic T-cell response to viral pathogens. In addition, it inhibits Type 2 T-cell-mediated immune responses. Type 2 T-cells produce IL-4, IL-5, IL-10, enhance antibody production and shift the cytokine profile from Type 1 to Type 2, which may promote viral disease progression in some cases. The ability of ribavirin to increase Type 1 and decrease Type 2 T-cell immune responses is a dose-dependent and occurs at concentrations less than those required for its antiproliferative effects.

    PHARMACOKINETICS

    Ribavirin is given by nasal/oral inhalation or orally.
     
    Ribavirin does not bind to plasma proteins. Ribavirin has a large volume of distribution (2825 L). This may be due to extensive transport of ribavirin into cells, including erythrocytes. Transport of ribavirin into non-plasma compartments appears to take place via an e(S)-type equilibrative nucleoside transporter, which is present on virtually all cell types and may explain the extensive volume of distribution of ribavirin. Concentrations in erythrocytes continue to rise for about 4 days, while plasma concentrations decline. Concentrations in CSF are approximately 70% of plasma concentrations following prolonged administration. Data are limited on whether the drug crosses the human placenta or is excreted into breast milk; however, ribavirin is teratogenic in animal models. Ribavirin undergoes metabolism by a reversible phosphorylation pathway in nucleated cells and a degradative pathway involving deribosylation and amide hydrolysis to yield a triazole carboxylic acid metabolite. Ribavirin undergoes little or no cytochrome P450 enzyme mediated metabolism. The elimination half-life of ribavirin following a single oral dose of 600 mg is 43.6 hours; following multiple doses of ribavirin 600 mg twice daily, the elimination half-life is 298 hours, which probably reflects elimination from non-plasma compartments. Ribavirin and its triazole carboxamide and triazole carboxylic acid metabolites are extensively renally eliminated.

    Oral Route

    Ribavirin is extensively and rapidly absorbed following oral administration. Tmax following oral administration is 1 hour for the oral solution following a single dose, 1.7 hours for the capsules following a single dose, and 3 hours for the capsules following multiple dosing. Pharmacokinetic parameters for ribavirin oral solution are slightly greater than for the capsules following a single dose; ribavirin Cmax is approximately 870 ng/ml for the oral solution and 780 ng/ml for the capsules; the ribavirin AUC is approximately 14,100 ng x hr/ml for the oral solution and 13,400 ng x hr/ml for the capsules. In a single dose pharmacokinetic study, the AUC and Cmax of ribavirin are increased by 70% when ribavirin capsules are administered with a high-fat meal. There are insufficient data to address the clinical relevance of this study; however, in clinical trials with interferon alfa-2b, ribavirin was administered without regard to meals. Ribavirin undergoes extensive first-pass metabolism resulting in an absolute bioavailability of 64%. Steady state plasma levels are reached in approximately 4 weeks following oral doses of 600 mg twice daily.

    Inhalation Route

    Following nasal and oral inhalation the amount of ribavirin absorbed into respiratory tract secretions vary depending on method of delivery, concentration of drug in solution, and length of time of delivery. Peak concentrations in respiratory tract secretions are generally achieved at the end of the inhalation period and are greater than plasma concentrations. A small amount of systemic absorption occurs following nasal inhalation. Following inhalation, the elimination half-life is about 9.5 hours and appears to take place in a biphasic manner.