Copegus

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Copegus

Classes

Nucleoside RNA Synthesis Inhibitor Antivirals
Respiratory Antivirals
Respiratory Syncytial Virus (RSV) Antivirals

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.
A negative pregnancy test must be obtained immediately prior to starting therapy in females of childbearing potential. Periodic pregnancy testing should be done during treatment and for the 9-month period after stopping treatment.
Use of effective contraception is required during treatment and for 9 months post-therapy in females of reproductive potential.
Use of effective contraception is required during treatment and for 6 months post-therapy in male patients and their female partners.
Hazardous Drugs Classification
NIOSH 2016 List: Group 3
NIOSH (Draft) 2020 List: Table 2
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
INJECTABLE/Inhalation Drugs: Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
ORAL TABLETS/CAPSULES/ORAL LIQUID: Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure and require additional protective equipment. Eye/face and respiratory protection may be needed during preparation and administration.

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 included in the WHO Model List of Essential Medicine for the treatment of viral hemorrhagic fevers. For more information on obtaining intravenous ribavirin on a compassionate use basis contact the FDA at 301-796-3400.
No instructions for parenteral administration are currently available; follow the recommendations of the CDC/FDA 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.
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
 
Preparation of 20 mg/mL aerosol solution
Using sterile technique, add a minimum of 75 mL of Sterile Water for Injection or inhalation (water must be preservative and additive-free) to the 100 mL vial containing 6 g of ribavirin and shake well. Alternatively, may dilute with 0.9% Sodium Chloride Injection to achieve a near isotonic solution.
Transfer the reconstituted 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.
 
Preparation of 60 mg/mL aerosol solution†
Using sterile technique, add a minimum of 100 mL of Sterile Water for Injection or inhalation (water must be preservative and additive-free) to the 100 mL vial containing 6 g of ribavirin and shake well. Alternatively, may dilute with 0.9% Sodium Chloride Injection to achieve a near isotonic solution.
Transfer the reconstituted solution to the clean, sterilized 500 mL SPAG-2 reservoir. The final concentration should be 60 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.

Oral Inhalation Administration

Mechanically ventilated patients
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 limb 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 4 hours). Water column 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 to 2 hours, and their pulmonary pressures measured every 2 to 4 hours.

Intranasal Inhalation Administration

Non-mechanically ventilated patients
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.[42030]

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 / 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

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.

Male-mediated teratogenicity, pregnancy

Ribavirin is contraindicated for use during pregnancy, in females of childbearing potential who may become pregnant, or in males whose female partners are pregnant. The drug has been associated with birth defects (including male-mediated teratogenicity) and death of the exposed fetus (intrauterine fetal death). Available data from the Ribavirin Pregnancy Registry, show a higher rate of birth defects among live birth from directly exposed mother (9.09%, n = 88) and indirectly exposed mother (by a male partner; 6.12%, n = 98) compared to a background birth defect rate of 2.72%. Animal studies indicate teratogenic (e.g., malformations of skull, palate, eye, jaw, limbs, skeleton, and gastrointestinal tract) or embryocidal properties in all 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; however, no reports of teratogenesis in babies of mothers who were exposed to aerosolized ribavirin during pregnancy have been confirmed. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients if ribavirin is prescribed. The health care provider must be informed right away if a female patient becomes pregnant while taking ribavirin or within 9 months after discontinuing treatment. Similarly, the provider must be notified if the sexual partner of a male patient becomes pregnant during or within 6 months of treatment with ribavirin. The drug recipient or the sexual partner of the drug recipient that becomes pregnant should be apprised of the potential hazard to the fetus.[29161]

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 all adult and adolescent patients presenting with HIV infection undergo routine screening for hepatitis C virus (HCV). Additionally, perform HCV screening in any child whose mother is known to have HCV infection. For HCV seronegative individuals who are at continued high risk of acquiring hepatitis C, specifically men who have sex with men (MSM) or persons who inject drugs, additional HCV screening is recommended annually or as indicated by clinical presentation (e.g., unexplained ALT elevation), risk activities, or exposure. Similarly, the AASLD/IDSA HCV guidelines and the CDC preexposure prophylaxis (PrEP) guidelines recommend HCV serologic testing at baseline and every 12 months for MSM, transgender women, and persons who inject drugs. Use an FDA-approved immunoassay licensed for detection of HCV antibodies (anti-HCV); in settings where acute HCV infection is suspected or in persons with known prior infection that cleared spontaneously or after treatment, use of nucleic acid testing for HCV RNA is recommended. If hepatitis C and HIV coinfection is identified, consider treating both viral infections concurrently. It is recommended to use a fully suppressive antiretroviral therapy and an HCV regimen in all patients with coinfection regardless of CD4 count, as lower CD4 counts do not appear to compromise the efficacy of HCV treatment. In most patients, a simplified pangenotypic HCV regimen (i.e., glecaprevir; pibrentasvir or sofosbuvir; velpatasvir) may be an appropriate choice; however, these regimens are NOT recommended for use in persons with HCV and HIV coinfection who: are treatment-experience with HCV relapse (reinfection after successful therapy is not an exclusion); have decompensated cirrhosis; on a tenofovir disoproxil fumarate containing regimen with eGFR less than 60 mL/minute; on efavirenz, etravirine, nevirapine, or boosted protease inhibitor; have untreated chronic hepatitis B; are pregnant. Patients with HCV and HIV coinfection who meet these exclusion criteria should be treated for HCV following standard approaches as described in the AASLD/IDSA HCV guidelines. Treatment of HCV infection in children younger than 3 years is not usually recommended; however, treatment should be considered for all children 3 years and older with HCV and HIV coinfection who have no contraindications to treatment. Instruct patients with coinfection to avoid consuming alcohol, limit ingestion of potentially hepatotoxic medications, avoid iron supplementation in the absence of documented iron deficiency, and receive vaccinations against hepatitis A and hepatitis B as appropriate.

Common Brand Names

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

Dea Class

Rx

Description

Antiviral; synthetic guanosine analog; active against many DNA and RNA viruses.
Used in oral form with interferon alfa, peginterferon alfa, or a direct acting antiviral (DAA) for chronic hepatitis C treatment in adults and certain pediatric patients; not effective as monotherapy; aerosolized and oral ribavirin used for RSV treatment
Intravenous form is available from the US CDC for Hantaan virus infection and Lassa fever

Dosage And Indications
For the treatment of respiratory syncytial virus (RSV) infection. For the treatment of respiratory syncytial virus (RSV) infection in high-risk immunocompromised adult patients (i.e., hematologic malignancies, HSCT recipients, solid organ transplant patients)†.
NOTE: Guidelines recommend treatment with aerosolized or systemic ribavirin and IVIG for patients with RSV upper respiratory tract infection disease (URTID) undergoing allogeneic HSCT or recipients of allogeneic HSCT with lower respiratory tract infection disease (LRTID) or risk factors for progression to RSV LRTID and death. For solid organ transplant patients, treatment with aerosolized or oral ribavirin with or without IVIG and corticosteroids is recommended for lung transplant recipients with URTID or LRTID. Treatment with aerosolized or oral ribavirin for non-lung solid organ recipients with LRTID can be considered.
NOTE: Efficacy data for treatment of RSV in adults is limited to use in immunocompromised patients, particularly HSCT recipients. For other adult patients, treatment for RSV infection is generally supportive, consisting of therapy with bronchodilators, supplemental oxygen, intravenous fluid, and antipyretics.
Nasal and Oral Inhalation dosage (continuous aerosolization) Adults

6 g (as 20 mg/mL solution) aerosolized over 12 to 18 hours daily for 3 to 7 days. Longer treatment may be needed for those with severe infections. 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.

Nasal and Oral Inhalation dosage (intermittent aerosolization) Adults

2 g (as 60 mg/mL solution) aerosolized over 2 to 4 hours given every 8 hours for 3 to 7 days. Longer treatment may be needed for those with severe infections.

Oral dosage Adults weighing 75 kg or more

Optimal dosing has not been established and variable dosage regimens are reported. Most common dosage regimens are a fixed dose of 800 mg PO twice daily or 600 mg PO 3 times daily or a weight-based dose of 10 mg/kg loading dose (Max: 600 mg/dose) PO on day 1, followed by 10 to 30 mg/kg/day (Usual Max: 1,800 mg/day) PO divided every 8 hours. Treatment duration is usually 5 to 10 days; however, longer treatment may be needed for those with severe infections.

Adults weighing less than 75 kg

Optimal dosing has not been established and variable dosage regimens are reported. Most common dosage regimens are a fixed dose of 600 mg PO 2 to 3 times daily or a weight-based dose of 10 mg/kg loading dose (Max: 600 mg/dose) PO on day 1, followed by 10 to 30 mg/kg/day (Usual Max: 1,800 mg/day) PO divided every 8 hours. Treatment duration is usually 5 to 10 days; however, longer treatment may be needed for those with severe infections.

For the treatment of respiratory syncytial virus (RSV) infection in pediatric patients.
NOTE: Because of limited evidence for a clinically relevant benefit, potential toxic effects, and high cost, the American Academy of Pediatrics (AAP) does not recommend routine use of aerosolized ribavirin in pediatric patients.
NOTE: Guidelines recommend treatment with aerosolized or systemic ribavirin and IVIG for patients with RSV upper respiratory tract infection disease (URTID) undergoing allogeneic HSCT or recipients of allogeneic HSCT with lower respiratory tract infection disease (LRTID) or risk factors for progression to RSV LRTID and death. For solid organ transplant patients, treatment with aerosolized or oral ribavirin with or without IVIG and corticosteroids is recommended for lung transplant recipients with URTID or LRTID. Treatment with aerosolized or oral ribavirin of non-lung solid organ recipients with LRTID can be considered.
Nasal and Oral Inhalation dosage (continuous aerosolization) Adolescents†

6 g (as 20 mg/mL solution) aerosolized over 12 to 18 hours daily for 3 to 7 days. Longer treatment may be needed for those with severe infections. 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.

Infants and Children

6 g (as 20 mg/mL solution) aerosolized over 12 to 18 hours daily for 3 to 7 days. Longer treatment may be needed for those with severe infections. 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.

Neonates

6 g (as 20 mg/mL solution) aerosolized over 12 to 18 hours daily for 3 to 7 days. Longer treatment may be needed for those with severe infections. 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.

Nasal and Oral Inhalation dosage (intermittent aerosolization)† Infants, Children, and Adolescents

2 g (as 60 mg/mL solution) aerosolized over 2 to 4 hours given every 8 hours for 3 to 7 days. Longer treatment may be needed for those with severe infections.

Neonates

2 g (as 60 mg/mL solution) aerosolized over 2 to 4 hours given every 8 hours for 3 to 7 days. Longer treatment may be needed for those with severe infections.

Oral dosage† Infants, Children, and Adolescents

15 to 25 mg/kg/day (Usual Max: 1,800 mg/day) PO divided every 8 to 12 hours has been used in high-risk pediatric oncology patients; however, data are very limited and dosing is not well established. Treatment duration is usually 7 to 10 days or until symptoms have resolved.

For the treatment of chronic hepatitis C infection.
NOTE: Ribavirin monotherapy is not effective for hepatitis C infection.
For the treatment of chronic hepatitis C infection in patients with compensated hepatic disease (Child-Pugh A) when used in combination with interferon alfa-2b alone.
NOTE: Dose reduction or treatment discontinuation should be considered in patients who develop worsening clinical toxicities, including hepatic decompensation (Child-Pugh score greater than 6).
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. 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. 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 patients with compensated hepatic disease (Child-Pugh A) when used in combination with a peginterferon alfa product alone.
NOTE: Dose reduction or treatment discontinuation should be considered in patients who develop worsening clinical toxicities, including hepatic decompensation (Child-Pugh score greater than 6).
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 hepatitis C infection in patients with or without compensated cirrhosis (Child-Pugh A) when used in combination with a direct-acting antiviral (DAA)†. Oral dosage Treatment-naive Adults with genotype 3, compensated cirrhosis, AND baseline RAS Y93H

Guidelines recommend weight-based dosing of 1,200 mg/day PO for patients 75 kg or more and 1,000 mg/day PO for patients less than 75 kg (in 2 divided doses) given in combination with sofosbuvir; velpatasvir for 12 weeks as an alternative regimen.

Treatment-experienced Adults with genotype 3, compensated cirrhosis, AND prior exposure to a sofosbuvir containing regimen

Guidelines recommend weight-based dosing of 1,200 mg/day PO for patients 75 kg or more and 1,000 mg/day PO for patients less than 75 kg (in 2 divided doses) given in combination with sofosbuvir; velpatasvir; voxilaprevir for 12 weeks.

Treatment-experienced Adults with genotypes 1, 2, 3, 4, 5, or 6 AND prior exposure to glecaprevir; pibrentasvir

Guidelines recommend weight-based dosing of 1,200 mg/day PO for patients 75 kg or more and 1,000 mg/day PO for patients less than 75 kg (in 2 divided doses) given with glecaprevir; pibrentasvir plus sofosbuvir for 16 weeks. Alternatively, in patients with compensated cirrhosis, weight-based ribavirin may be given with sofosbuvir; velpatasvir; voxilaprevir for 12 weeks.

Treatment-experienced Adults with genotypes 1, 2, 3, 4, 5, or 6 AND multiple DAA treatment failures

Guidelines recommend weight-based dosing of 1,200 mg/day PO for patients 75 kg or more and 1,000 mg/day PO for patients less than 75 kg (in 2 divided doses) given with sofosbuvir; velpatasvir; voxilaprevir for 24 weeks. Alternatively, weight-based ribavirin may be given with glecaprevir; pibrentasvir plus sofosbuvir for 16 weeks (increase to 24 weeks for genotype 3 with cirrhosis or prior failure on glecaprevir; pibrentasvir plus sofosbuvir).

For the treatment of hepatitis C infection in patients with decompensated cirrhosis (Child-Pugh B or C) when used in combination with DAA†. Oral dosage Adults with genotypes 1, 4, 5, or 6

Guidelines recommend an initial dose of 600 mg PO once daily with either ledipasvir; sofosbuvir or sofosbuvir; velpatasvir for 12 weeks. If tolerated, the ribavirin dose may be increased as follows: if less than 75 kg give 500 mg PO twice daily; if 75 kg or more give 600 mg PO twice daily. Recommendation includes patients who may or may not be candidates for liver transplant, including those with hepatocellular carcinoma.

Adults with genotypes 2 or 3

Guidelines recommend an initial dose of 600 mg PO once daily with sofosbuvir; velpatasvir for 12 weeks. If tolerated, the ribavirin dose may be increased as follows: if less than 75 kg give 500 mg PO twice daily; if 75 kg or more give 600 mg PO twice daily. Recommendation includes patients who may or may not be candidates for liver transplant, including those with hepatocellular carcinoma.

Adults with genotypes 1, 4, 5, or 6 in whom prior sofosbuvir-based treatment failed

Guidelines recommend an initial dose of 600 mg PO once daily with either ledipasvir; sofosbuvir or sofosbuvir; velpatasvir for 24 weeks. If tolerated, the ribavirin dose may be increased as follows: if less than 75 kg give 500 mg PO twice daily; if 75 kg or more give 600 mg PO twice daily. Recommendation includes patients who may or may not be candidates for liver transplant, including those with hepatocellular carcinoma.

Adults with genotypes 2 or 3 in whom prior sofosbuvir-based treatment failed

Guidelines recommend an initial dose of 600 mg PO once daily with sofosbuvir; velpatasvir for 24 weeks. If tolerated, the ribavirin dose may be increased as follows: if less than 75 kg give 500 mg PO twice daily; if 75 kg or more give 600 mg PO twice daily. Recommendation includes patients who may or may not be candidates for liver transplant, including those with hepatocellular carcinoma.

Adults with genotypes 1, 2, 3, 4, 5, or 6 in whom prior NS5A inhibitor-based treatment failed

Guidelines recommend an initial dose of 600 mg PO once daily with sofosbuvir; velpatasvir for 24 weeks. If tolerated, the ribavirin dose may be increased as follows: if less than 75 kg give 500 mg PO twice daily; if 75 kg or more give 600 mg PO twice daily. Recommendation includes patients who may or may not be candidates for liver transplant, including those with hepatocellular carcinoma.

For the treatment of hepatitis C infection in patients who have undergone a liver or kidney transplant†. Oral dosage Adults with decompensated cirrhosis (Child-Pugh B or C) who have undergone liver transplantation and have genotypes 1, 4, 5, or 6

Guidelines recommend an initial dose of 600 mg PO once daily with either ledipasvir; sofosbuvir or sofosbuvir; velpatasvir for 12 weeks (for treatment-naive) or 24 weeks (for treatment-experienced). If tolerated, the ribavirin dose may be increased as follows: if less than 75 kg give 500 mg PO twice daily; if 75 kg or more give 600 mg PO twice daily.

Adults with decompensated cirrhosis (Child-Pugh B or C) who have undergone liver transplantation and have genotypes 2 or 3

Guidelines recommend an initial dose of 600 mg PO once daily with sofosbuvir; velpatasvir for 12 weeks (for treatment-naive) or 24 weeks (for treatment-experienced). If tolerated, the ribavirin dose may be increased as follows: if less than 75 kg give 500 mg PO twice daily; if 75 kg or more give 600 mg PO twice daily.

DAA-experienced Adults with genotype 1, 2, 3, 4, 5, or 6 who have undergone a liver or kidney transplantation, with compensated cirrhosis (Child-Pugh A) and multiple negative baseline characteristics

Guidelines recommend an initial dose of 600 mg PO once daily with sofosbuvir; velpatasvir; voxilaprevir for 12 weeks. If tolerated, the ribavirin dose may be increased as follows: if less than 75 kg give 500 mg PO twice daily; if 75 kg or more give 600 mg PO twice daily.

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

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

Treatment of chronic HCV infection
Oral capsule (Rebetol):
CrCl 50 mL/minute or more: No dose adjustment needed. Closely monitor older patients (older than 50 years of age) for development of anemia.
CrCl less than 50 mL/minute: Use is contraindicated.
 
Oral tablet:
NOTE: If severe adverse reactions or laboratory abnormalities develop in patients with renal impairment, discontinue ribavirin therapy; further dose modifications are not recommended.
CrCl more than 50 mL/minute: No dose adjustment needed. Closely monitor older patients (older than 50 years of age) for development of anemia.
CrCl 30 to 50 mL/minute: Reduce to alternating doses of 400 mg and 200 mg PO every other day.
CrCl less than 30 mL/minute: Reduce dose to 200 mg PO daily.
 
Treatment of respiratory syncytial virus (RSV) infection†
Oral capsule or tablet:
NOTE: Ribavirin dosage should be adjusted for renal impairment; however, optimal dosing has not been established and variable dosage regimens are reported. One study reported a dose reduction to 400 mg PO twice daily (from 600 mg or 800 mg PO twice daily) for patients with mild renal impairment. Another protocol recommends the following dose adjustments based on a dose of 10 mg/kg/dose (Max: 600 mg/dose) PO every 8 hours.
CrCl 30 to 50 mL/minute: Maximum dose of 200 mg PO every 8 hours.
CrCl 10 to 29 mL/minute: Recommendations unavailable; some experts use 200 mg PO once daily under close clinical and laboratory monitoring.
If severe adverse reactions or laboratory abnormalities develop in patients with renal impairment, discontinue ribavirin therapy; further dose modifications are not recommended.
 
Intermittent hemodialysis
Oral capsule (Rebetol): Use is contraindicated.
Oral tablet: Reduce dose to 200 mg PO daily.

Drug Interactions

Abacavir: (Moderate) Use abacavir with ribavirin and interferon with caution and closely monitor for hepatic decompensation and anemia. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Hepatic decompensation (some fatal) has occurred in HCV/HIV coinfected patients who received both ribavirin/interferon and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) therapies.
Abacavir; Dolutegravir; Lamivudine: (Moderate) Use abacavir with ribavirin and interferon with caution and closely monitor for hepatic decompensation and anemia. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Hepatic decompensation (some fatal) has occurred in HCV/HIV coinfected patients who received both ribavirin/interferon and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) therapies. (Moderate) Use lamivudine with ribavirin and interferon with caution and closely monitor for hepatic decompensation and anemia. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Hepatic decompensation (some fatal) has occurred in HCV/HIV coinfected patients who received both ribavirin/interferon and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) therapies. In addition, ribavirin has been shown in cell culture to inhibit phosphorylation of lamivudine, which could lead to decreased antiretroviral activity; however, while ribavirin inhibits the phosphorylation reactions required to activate lamivudine, no evidence of a pharmacokinetic or pharmacodynamic interaction has been observed.
Abacavir; Lamivudine, 3TC: (Moderate) Use abacavir with ribavirin and interferon with caution and closely monitor for hepatic decompensation and anemia. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Hepatic decompensation (some fatal) has occurred in HCV/HIV coinfected patients who received both ribavirin/interferon and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) therapies. (Moderate) Use lamivudine with ribavirin and interferon with caution and closely monitor for hepatic decompensation and anemia. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Hepatic decompensation (some fatal) has occurred in HCV/HIV coinfected patients who received both ribavirin/interferon and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) therapies. In addition, ribavirin has been shown in cell culture to inhibit phosphorylation of lamivudine, which could lead to decreased antiretroviral activity; however, while ribavirin inhibits the phosphorylation reactions required to activate lamivudine, no evidence of a pharmacokinetic or pharmacodynamic interaction has been observed.
Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Moderate) Use abacavir with ribavirin and interferon with caution and closely monitor for hepatic decompensation and anemia. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Hepatic decompensation (some fatal) has occurred in HCV/HIV coinfected patients who received both ribavirin/interferon and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) therapies. (Moderate) Use lamivudine with ribavirin and interferon with caution and closely monitor for hepatic decompensation and anemia. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Hepatic decompensation (some fatal) has occurred in HCV/HIV coinfected patients who received both ribavirin/interferon and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) therapies. In addition, ribavirin has been shown in cell culture to inhibit phosphorylation of lamivudine, which could lead to decreased antiretroviral activity; however, while ribavirin inhibits the phosphorylation reactions required to activate lamivudine, no evidence of a pharmacokinetic or pharmacodynamic interaction has been observed. (Moderate) Use zidovudine with ribavirin and interferon with caution and closely monitor for hepatic decompensation and anemia. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Hepatic decompensation (some fatal) has occurred in HCV/HIV coinfected patients who received both ribavirin/interferon and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) therapies. In addition, ribavirin may antagonize the cell culture antiviral activity of zidovudine against HIV; however, no evidence of a pharmacokinetic or pharmacodynamic interaction has been observed.
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.
Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Use emtricitabine with ribavirin and interferon with caution and closely monitor for hepatic decompensation and anemia. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Hepatic decompensation (some fatal) has occurred in HCV/HIV coinfected patients who received both ribavirin/interferon and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) therapies.
Cabotegravir; 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.
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.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (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. (Moderate) Use emtricitabine with ribavirin and interferon with caution and closely monitor for hepatic decompensation and anemia. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Hepatic decompensation (some fatal) has occurred in HCV/HIV coinfected patients who received both ribavirin/interferon and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) therapies.
Delavirdine: (Moderate) The concomitant use of ribavirin and antiretroviral 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: (Contraindicated) Use of ribavirin 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; Lamivudine: (Moderate) Use lamivudine with ribavirin and interferon with caution and closely monitor for hepatic decompensation and anemia. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Hepatic decompensation (some fatal) has occurred in HCV/HIV coinfected patients who received both ribavirin/interferon and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) therapies. In addition, ribavirin has been shown in cell culture to inhibit phosphorylation of lamivudine, which could lead to decreased antiretroviral activity; however, while ribavirin inhibits the phosphorylation reactions required to activate lamivudine, no evidence of a pharmacokinetic or pharmacodynamic interaction has been observed.
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.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Use lamivudine with ribavirin and interferon with caution and closely monitor for hepatic decompensation and anemia. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Hepatic decompensation (some fatal) has occurred in HCV/HIV coinfected patients who received both ribavirin/interferon and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) therapies. In addition, ribavirin has been shown in cell culture to inhibit phosphorylation of lamivudine, which could lead to decreased antiretroviral activity; however, while ribavirin inhibits the phosphorylation reactions required to activate lamivudine, no evidence of a pharmacokinetic or pharmacodynamic interaction has been observed.
Efavirenz: (Moderate) The concomitant use of ribavirin and antiretroviral 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 Disoproxil Fumarate: (Moderate) The concomitant use of ribavirin and antiretroviral 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. (Moderate) Use emtricitabine with ribavirin and interferon with caution and closely monitor for hepatic decompensation and anemia. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Hepatic decompensation (some fatal) has occurred in HCV/HIV coinfected patients who received both ribavirin/interferon and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) therapies.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) The concomitant use of ribavirin and antiretroviral 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. (Moderate) Use lamivudine with ribavirin and interferon with caution and closely monitor for hepatic decompensation and anemia. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Hepatic decompensation (some fatal) has occurred in HCV/HIV coinfected patients who received both ribavirin/interferon and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) therapies. In addition, ribavirin has been shown in cell culture to inhibit phosphorylation of lamivudine, which could lead to decreased antiretroviral activity; however, while ribavirin inhibits the phosphorylation reactions required to activate lamivudine, no evidence of a pharmacokinetic or pharmacodynamic interaction has been observed.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Use emtricitabine with ribavirin and interferon with caution and closely monitor for hepatic decompensation and anemia. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Hepatic decompensation (some fatal) has occurred in HCV/HIV coinfected patients who received both ribavirin/interferon and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) therapies.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Use emtricitabine with ribavirin and interferon with caution and closely monitor for hepatic decompensation and anemia. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Hepatic decompensation (some fatal) has occurred in HCV/HIV coinfected patients who received both ribavirin/interferon and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) therapies.
Emtricitabine: (Moderate) Use emtricitabine with ribavirin and interferon with caution and closely monitor for hepatic decompensation and anemia. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Hepatic decompensation (some fatal) has occurred in HCV/HIV coinfected patients who received both ribavirin/interferon and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) therapies.
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. (Moderate) Use emtricitabine with ribavirin and interferon with caution and closely monitor for hepatic decompensation and anemia. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Hepatic decompensation (some fatal) has occurred in HCV/HIV coinfected patients who received both ribavirin/interferon and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) therapies.
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. (Moderate) Use emtricitabine with ribavirin and interferon with caution and closely monitor for hepatic decompensation and anemia. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Hepatic decompensation (some fatal) has occurred in HCV/HIV coinfected patients who received both ribavirin/interferon and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) therapies.
Emtricitabine; Tenofovir alafenamide: (Moderate) Use emtricitabine with ribavirin and interferon with caution and closely monitor for hepatic decompensation and anemia. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Hepatic decompensation (some fatal) has occurred in HCV/HIV coinfected patients who received both ribavirin/interferon and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) therapies.
Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Use emtricitabine with ribavirin and interferon with caution and closely monitor for hepatic decompensation and anemia. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Hepatic decompensation (some fatal) has occurred in HCV/HIV coinfected patients who received both ribavirin/interferon and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) therapies.
Etravirine: (Moderate) The concomitant use of ribavirin and antiretroviral 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: (Moderate) Use lamivudine with ribavirin and interferon with caution and closely monitor for hepatic decompensation and anemia. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Hepatic decompensation (some fatal) has occurred in HCV/HIV coinfected patients who received both ribavirin/interferon and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) therapies. In addition, ribavirin has been shown in cell culture to inhibit phosphorylation of lamivudine, which could lead to decreased antiretroviral activity; however, while ribavirin inhibits the phosphorylation reactions required to activate lamivudine, no evidence of a pharmacokinetic or pharmacodynamic interaction has been observed.
Lamivudine, 3TC; Zidovudine, ZDV: (Moderate) Use lamivudine with ribavirin and interferon with caution and closely monitor for hepatic decompensation and anemia. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Hepatic decompensation (some fatal) has occurred in HCV/HIV coinfected patients who received both ribavirin/interferon and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) therapies. In addition, ribavirin has been shown in cell culture to inhibit phosphorylation of lamivudine, which could lead to decreased antiretroviral activity; however, while ribavirin inhibits the phosphorylation reactions required to activate lamivudine, no evidence of a pharmacokinetic or pharmacodynamic interaction has been observed. (Moderate) Use zidovudine with ribavirin and interferon with caution and closely monitor for hepatic decompensation and anemia. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Hepatic decompensation (some fatal) has occurred in HCV/HIV coinfected patients who received both ribavirin/interferon and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) therapies. In addition, ribavirin may antagonize the cell culture antiviral activity of zidovudine against HIV; however, no evidence of a pharmacokinetic or pharmacodynamic interaction has been observed.
Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Use lamivudine with ribavirin and interferon with caution and closely monitor for hepatic decompensation and anemia. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Hepatic decompensation (some fatal) has occurred in HCV/HIV coinfected patients who received both ribavirin/interferon and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) therapies. In addition, ribavirin has been shown in cell culture to inhibit phosphorylation of lamivudine, which could lead to decreased antiretroviral activity; however, while ribavirin inhibits the phosphorylation reactions required to activate lamivudine, no evidence of a pharmacokinetic or pharmacodynamic interaction has been observed.
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: (Moderate) The concomitant use of ribavirin and antiretroviral 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.
Nirmatrelvir; 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.
Non-nucleoside reverse transcriptase inhibitors: (Moderate) The concomitant use of ribavirin and antiretroviral 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.
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: (Moderate) Use stavudine with ribavirin and interferon together with caution and closely monitor for hepatic decompensation and anemia. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Hepatic decompensation (some fatal) has occurred in HCV/HIV coinfected patients who received both ribavirin/interferon and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) therapies. In addition, ribavirin may antagonize the cell culture antiviral activity of stavudine against HIV; however, no evidence of a pharmacokinetic or pharmacodynamic interaction has been observed.
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.
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.
Zidovudine, ZDV: (Moderate) Use zidovudine with ribavirin and interferon with caution and closely monitor for hepatic decompensation and anemia. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Hepatic decompensation (some fatal) has occurred in HCV/HIV coinfected patients who received both ribavirin/interferon and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) therapies. In addition, ribavirin may antagonize the cell culture antiviral activity of zidovudine against HIV; however, no evidence of a pharmacokinetic or pharmacodynamic interaction has been observed.

How Supplied

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

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.

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.

Pregnancy And Lactation
Pregnancy

Females of childbearing potential must undergo pregnancy testing immediately prior to starting ribavirin therapy and periodically while being treated and for 9 months after treatment is discontinued. Due to the reproductive risk, contraception requirements exist for males and females of childbearing potential in whom ribavirin is prescribed. For females of reproductive potential, effective contraception is required during treatment and for 9 months post-therapy. For male patients and their female partners, effective contraception is required during treatment and for 6 months post-therapy.