Ribavirin is a synthetic nucleoside antiviral agent that has a broad spectrum of antiviral activity against both RNA and DNA viruses.1, 2, 3, 4
Chronic Hepatitis C Virus Infection
Ribavirin capsules are used in combination with interferon alfa-2b (Intron® A; no longer available in the US) or peginterferon alfa-2b (PegIntron®; no longer available in the US) for the treatment of chronic hepatitis C virus (HCV) infection in adults and pediatric patients ≥3 years of age with compensated liver disease.2 According to the manufacturer, when initiating treatment with ribavirin capsules, it is important to consider that combination therapy with peginterferon alfa-2b is preferred over combination therapy with interferon alfa-2b since the former combination provides substantially better response rates.2 Additionally, patients with the following characteristics are less likely to benefit from retreatment after failing a treatment course: previous nonresponse, previous pegylated interferon treatment, significant bridging fibrosis or cirrhosis, and genotype 1 infection.2 Efficacy and safety data for the combination are not available for treatment duration lasting longer than 1 year.2
Ribavirin tablets are used in combination with peginterferon alfa-2a (Pegasys®) for the treatment of chronic HCV infection in adults and pediatric patients ≥5 years of age with compensated liver disease who have not been previously treated with interferon alpha.3 According to the manufacturer, this indication is based on clinical trials of combination therapy in patients with chronic HCV and compensated liver disease, some of whom had histological evidence of cirrhosis (Child-Pugh class A), and in adults with clinically stable human immunodeficiency virus (HIV) and CD4+ count >100 cells/mm3.3 The indication is based on the achievement of undetectable HCV RNA after 24 or 48 weeks of treatment, based on HCV genotype, and the maintenance of sustained virologic response (SVR) 24 weeks after the final dose.3 Efficacy and safety data are not available for treatment duration longer than 48 weeks.3 Efficacy and safety of the combination have not been established for treatment of chronic HCV infection in previous nonresponders to interferon therapy, patients with decompensated liver disease, or in liver or other organ transplant recipients.3 Safety and efficacy of ribavirin tablets for the treatment of adenovirus, respiratory syncytial virus (RSV), parainfluenza, or influenza virus have not been established; this agent should not be used for these indications according to the manufacturer.3
Oral ribavirin is designated an orphan drug by the US Food and Drug Administration (FDA) for treatment of chronic HCV infection in pediatric patients.273
Effectiveness and safety of ribavirin capsules in combination with peginterferon alfa-2b for the treatment of chronic HCV infection in adults were established based on 2 randomized studies, 1 large US community-based trial, and 1 noncomparative trial; the noncomparative trial involved patients who failed previous combination interferon alpha plus ribavirin treatment.2 These studies showed that the ribavirin plus peginterferon alfa-2b combination resulted in adequate treatment response as indicated by SVR rates.2 Effectiveness and safety of ribavirin capsules in combination with interferon alfa-2b for the treatment of chronic HCV infection in adults were established based on virologic and histological response rates observed in 2 multicenter, double-blind studies (US and international) involving previously untreated patients and patients with relapse.2
Effectiveness and safety of ribavirin tablets in combination with peginterferon alfa-2a for the treatment of chronic HCV infection were established based on 2 randomized controlled trials in adults with compensated liver disease who were previously untreated with interferon, and 1 randomized trial in patients with patients with HCV/HIV coinfection.3 In these studies, efficacy was demonstrated based on achievement of undetectable HCV RNA after 24 or 48 weeks of treatment, based on HCV genotype, and the maintenance of SVR 24 weeks after the final dose.3 In the 2 randomized controlled trials, treatment response rates were lower in patients with poor prognostic factors (>40 years of age, cirrhosis, weight >85 kg, HCV genotype 1 with high versus low viral load, and African-American patients compared to Caucasians).3 In patients with HCV/HIV coinfection, treatment response rates were lower in those with poor prognostic factors (including HCV genotype 1, HCV RNA >800,000 IU/mL, and cirrhosis) receiving pegylated interferon alpha therapy.3
Current HCV treatment guidelines do not recommend the combination of ribavirin and peginterferon/interferon, even with additional preferred HCV antiviral agent(s), for adults with HCV, regardless of genotype or treatment history.119
Similar to data in adults, SVR rates in those receiving a regimen or oral ribavirin and peginterferon alfa have been lower in children infected with HCV genotype 1 than in those infected with other genotypes.2, 3, 426, 428
In a multicenter study in 107 children 3-17 years of age with compensated chronic HCV infection who were previously untreated (52% female, 89% Caucasian, 67% infected with HCV genotype 1), a regimen of ribavirin capsules (15 mg/kg daily) and peginterferon alfa-2b was given for 24 weeks (genotype 2, genotype 3 with baseline HCV RNA level <600,000 IU/mL) or 48 weeks (HCV genotypes 1 and 4, genotype 3 with baseline HCV RNA level of ≥600,000 IU/mL).2, 426 The overall SVR (defined as undetectable plasma HCV RNA at 24 weeks after treatment) rate was 65%.426 In children who received a 24-week regimen, the SVR rate was 93% in those with genotype 2 infections and 100% in those with genotype 3 infections and baseline HCV RNA level <600,000 IU/mL.2 In children who received a 48-week regimen, the SVR rate was 53% in those with genotype 1 infections, 80% in those with genotype 4 infections, and 67% in those with genotype 3 infections and baseline HCV RNA level of ≥600,000 IU/mL.2
In a study of 118 children 3-16 years of age with compensated chronic HCV infection who were previously untreated (57% male, 80% Caucasian, 78% infected with HCV genotype 1), a regimen of ribavirin capsules (15 mg/kg daily) and interferon alfa-2b was given for 48 weeks.2 The overall response (HCV RNA below limit of detection) was 46%; the response rate in children with genotype 1 and non-genotype-1 was 36 and 81%, respectively.2
In a study in 114 children 5-17 years of age with chronic HCV infection, compensated liver disease, and detectable HCV RNA who were previously untreated, patients were randomized to receive a 48-week regimen of ribavirin tablets 15 mg/kg daily plus peginterferon alfa-2a or monotherapy with peginterferon alfa-2a.3 Overall, SVR (defined as undetectable plasma HCV RNA [<50 IU/mL] on or after week 68) was attained in 53% of those treated with peginterferon alfa-2a and oral ribavirin compared with 20% of those treated with peginterferon alfa-2a monotherapy.3 In those treated with the combination regimen, the SVR rate was 47% in those with genotype 1 infections and 80% in those with non-genotype-1 infections.3
Current HCV treatment guidelines do not recommend the combination of ribavirin and peginterferon/interferon, even with additional preferred HCV antiviral agent(s), for pediatric patients with HCV.119
Overall, the use of ribavirin in combination with interferon or peginterferon is no longer recommended for the treatment of chronic HCV due to poor efficacy and a high rate of adverse effects with the regimen.8 The current standard of care now consists of all-oral direct-acting antiviral (DAA) agents, which are more effective, have fewer adverse effects, and have a shorter duration of therapy.8 Treatment with DAA agents are recommended essentially for all patients with HCV, including those coinfected with human immunodeficiency virus (HIV).8, 119
Because the treatment of chronic HCV infection is complex and rapidly evolving, it is recommended that treatment be directed by clinicians who are familiar with the disease and that a specialist be consulted to obtain the most up-to-date information.119 Information from the American Association for the Study of Liver Diseases (AASLD) and Infectious Diseases Society of America (IDSA) regarding diagnosis and management of HCV infection, including recommendations for initial treatment and treatment in patients from HIV/HCV coinfection, is available at [Web].119
Respiratory Syncytial Virus Infection
Ribavirin is used via nasal and oral inhalation (Virazole®) for treatment of severe lower respiratory tract infections caused by RSV in hospitalized infants and young children.1 Efficacy of ribavirin therapy in RSV infection may depend on treatment early in the course of severe lower respiratory tract infection.1
The manufacturer states that use of ribavirin nasal and oral inhalation therapy should be considered only for infants and small children with severe RSV lower respiratory tract infections.1 The manufacturer states that ribavirin inhalation therapy may be used in patients requiring mechanical ventilator assistance; however, such therapy should be undertaken only by clinicians and support staff familiar with this mode of administration and with the specific ventilator being used, and strict attention must be paid to procedures that have been shown to minimize accumulation of drug precipitate in the equipment.1
Most infants and children with RSV infection only exhibit manifestations of mild, self-limited infection that does not require hospitalization or antiviral therapy (e.g., ribavirin).1 In children with mild RSV lower respiratory tract infections, if hospitalization is required, it usually is of shorter duration than that required for a complete course of ribavirin inhalation therapy (i.e., 3-7 days).1 These patients should not be treated with the drug.1 The manufacturer states that the decision to treat with ribavirin nasal and oral inhalation therapy is based on RSV infection severity.1 The severity of RSV respiratory tract infection and its attendant risk to the patient may be increased in infants and young children with an underlying compromising condition (e.g., prematurity, cardiopulmonary disease, immunodeficiency).1
When indicated, ribavirin nasal and oral inhalation therapy may be started pending results of definitive diagnostic tests, but the drug should be discontinued if RSV lower respiratory tract infection is not documented.1 Appropriate specimens (i.e., respiratory tract secretions) for rapid identification of RSV should be obtained prior to initiating or during the first 24 hours of ribavirin therapy.1 Rapid diagnostic methods for identification of RSV include demonstration of RSV viral antigen in respiratory tract secretions using immunofluorescence or enzyme-linked immunosorbent assay (ELISA).1 The fact that false-positive or false-negative test results may occur with these rapid diagnostic methods should be considered.1
Ribavirin has been used for the treatment of RSV infection in immunocompromised adults†.9, 10 According to guidelines from the American Society of Transplantation and Cellular Therapy and the Transplant Infectious Disease Special Interest Group, oral ribavirin may be used for the treatment of RSV infection in hematopoietic cell transplant recipients† with upper respiratory tract infection and an Immunodeficiency Scoring Index (ISI) score of ≥3 and a high-risk condition, and for any patient with lower respiratory tract infection regardless of ISI score.9 According to guidelines from the American Society of Transplantation Infectious Diseases Community of Practice, oral or aerosolized ribavirin is recommended for lung transplant recipients† with upper or lower respiratory tract RSV infection and can be considered in non-lung solid organ transplant recipients† with lower respiratory tract disease.10
Findings from 2 placebo-controlled studies in hospitalized, nonmechanically ventilated infants with lower respiratory tract infection have indicated that ribavirin inhalation therapy can improve clinical manifestations of disease, especially when therapy was initiated within the first 3 days following onset of infection.1 In one of these studies, virus titers in respiratory secretions were also substantially reduced.1 These findings are supported by data from additional controlled studies conducted since the initial trials of aerosolized ribavirin in the treatment of RSV infection.1
In one randomized, double-blind, controlled study in infants (mean age 1.4 months) requiring mechanical ventilation for respiratory failure caused by RSV, ribavirin inhalation therapy at the recommended dosage resulted in decreases compared with placebo in the duration of mechanical ventilation required from 9.9 to 4.9 days and in the duration of required supplemental oxygen from 13.5 to 8.7 days.1, 299 Intensive patient management and monitoring techniques were used during the study, including endotracheal tube suctioning every 1-2 hours, arterial blood gas monitoring every 2-6 hours, and recording of proximal airway pressure, ventilatory rate, and FI O2 every hour.1, 299 In addition, certain procedures were performed to reduce the risk of precipitation of ribavirin and possible ventilator malfunction (e.g., heated wire tubing, 2 bacterial filters connected in series in the expiratory limb of the ventilator with filter changes every 4 hours, water column pressure release valves to monitor internal ventilator pressures installed when connecting ventilator circuits to the small-particle aerosol generator [SPAG-2®]).1
The American Academy of Pediatrics (AAP) states that while ribavirin inhalation therapy demonstrated a small increase in oxygen saturation in small clinical trials, there was no decrease in the need for mechanical ventilation or in the length of stay.105 Due to limited evidence for a clinically important benefit and the risk of adverse effects, the AAP does not recommend the routine use of the drug.105
Ribavirin is used orally and/or IV† for treatment of certain viral hemorrhagic fevers†, including Lassa fever†, hemorrhagic fever with renal syndrome (HFRS) caused by Hantavirus infection†, some infections caused by New World arenaviruses†, and Crimean-Congo hemorrhagic fever†.1000 Although parenteral ribavirin is not commercially available in the US, it is available for compassionate use protocols for treatment of viral hemorrhagic fevers.1000 Ribavirin has been designated an orphan drug by FDA for treatment of HFRS†.273
Information on diagnosis and management of viral hemorrhagic fevers is available from the Viral Special Pathogens Branch of the Centers for Disease Control and Prevention (CDC).1001 If a diagnosis of viral hemorrhagic fever is considered, public health officials should coordinate with the CDC to ensure appropriate precautions, and can consult with the CDC Viral Special Pathogens Branch by calling the CDC Emergency Operations Center at 770-488-7100.1001
Ribavirin has been used for treatment of infections caused by adenovirus†.6 However, safety and efficacy of oral ribavirin for treatment of adenovirus infections have not been established.2, 3 Evidence is limited, and there is heterogeneity among studies regarding the virus serotypes treated patient characteristics, the syndromes produced, disease progression time, and use in combination with other drugs.6
Ribavirin has been used alone or in combination with other agents for the treatment of severe acute respiratory syndrome† (SARS), Middle East respiratory syndrome† (MERS), and coronavirus disease 2019† (COVID-19).5 However, findings from studies on the efficacy of ribavirin for the treatment of these coronaviruses have been contradictory.5
Oral ribavirin has been used for the treatment of chronic hepatitis E virus infection†.1002 According to guidelines from the American Society of Transplant Infectious Diseases Community of Practice, oral ribavirin monotherapy may be used after reduction in immunosuppression in patients with chronic hepatitis E infection.1002 The optimal treatment of chronic hepatitis E virus has not been established.1002
Dispensing and Administration Precautions
Ribavirin is administered orally or by inhalation.1, 2, 3 Ribavirin has been administered IV†.1000
When oral ribavirin is used in conjunction with peginterferon or interferon, the cautions, precautions, and contraindications associated with both oral ribavirin and the interferon should be considered.2, 3 Refer to the full prescribing information for warnings and precautions of peginterferon alfa-2a (Pegasys®), peginterferon alfa-2b (PegIntron®), or interferon alfa-2b (Intron® A).20, 388, 500
Ribavirin is available as capsules or tablets containing 200 mg of the drug.2, 3
Take ribavirin capsules or tablets with food.2, 3 Do not crush, open, or break ribavirin capsules .2
According to the manufacturer, administer ribavirin capsules in combination with peginterferon alfa-2b (PegIntron®; no longer available in the US) or interferon alfa-2b (Intron® A; no longer available in the US).2
According to the manufacturer, administer ribavirin tablets in combination with Pegasys® (peginterferon alfa-2a); do not administer ribavirin tablets as monotherapy.3
If use of ribavirin tablets is considered in children ≥5 years of age, clinicians should ensure that the child can reliably swallow the tablets.3
Patients should be well hydrated during oral ribavirin therapy, especially during initial treatment.2, 3
Store ribavirin capsules or tablets at 20-25°C (excursions permitted to 15-30°C).2, 3 Keep the tablet bottle tightly closed.3
Ribavirin for inhalation is supplied as 6 grams of lyophilized powder per 100 mL vial for aerosol administration only.1
Ribavirin powder for inhalation is intended for administration only using the small-particle aerosol generator (SPAG) model 2 (SPAG-2®).1 Aerosolized ribavirin for inhalation has not been tested with any other aerosol generating device.1 Prior to administration of ribavirin inhalation, review the SPAG-2 instructions for use to assure thorough familiarity with the use and operation of the SPAG-2 aerosol generator.1
Do not administer ribavirin in a mixture for combined aerosolization or simultaneously with other aerosolized medications.1
In infants not requiring mechanical ventilation, administer ribavirin solution for nebulization from the SPAG-2 aerosol generator via an oxygen hood.1 If an oxygen hood cannot be used, the solution may be administered from the SPAG-2 aerosol generator via a face mask or oxygen tent; however, the volume and condensation area of the solution for nebulization are larger in an oxygen tent, and this may alter delivery dynamics of the drug.1 Refer to the SPAG-2 instructions for use.1
When ribavirin inhalation therapy is used in patients who require mechanical ventilation, either a pressure or volume cycle ventilator may be used in conjunction with the SPAG-2.1
Administration of ribavirin inhalation therapy in infants requiring mechanical ventilator assistance should be undertaken only by physicians and support staff who are familiar with this mode of administration of the drug and with the specific ventilator being used.1 In addition, strict attention must be paid to procedures that have been shown to minimize accumulation of ribavirin precipitate in the ventilator.1
Suction the endotracheal tubes of mechanically ventilated patients every 1-2 hours and monitor pulmonary pressure frequently (every 2-4 hours).1 In order to minimize the risk of ribavirin precipitation in either pressure or volume cycle ventilators, use heated wire connective tubing and place bacterial filters in series in the expiratory limb of the system; change the filters frequently (e.g., every 4 hours).1 In addition, to indicate presence of elevated ventilator pressures, water column pressure release valves should be used in the ventilator circuit for pressure cycle ventilators and also may be used in the ventilator circuit for volume cycle ventilators.1
Store ribavirin vials containing the lyophilized drug powder in a dry place at 25°C (excursions permitted to 15-30°C).1 Reconstituted solutions may be stored, under sterile conditions, at room temperature (20-30°C) for 24 hours.1 Solutions placed in the SPAG-2 unit should be discarded at least every 24 hours and prior to adding any newly reconstituted solution (e.g., when the remaining amount of solution in the reservoir is low).1
To prepare ribavirin sterile powder for inhalation, initially reconstitute the drug with a minimum of 75 mL of sterile water for injection or inhalation (additive free) in the original 100 mL glass vial.1 Shake well.1 Then, transfer this initial solution to a sterile 500-mL reservoir for the SPAG-2 aerosol generator, and further dilute with sterile water for injection or inhalation (additive free) to a final volume of 300 mL to provide a solution containing 20 mg/mL.1 This water should not have had any antimicrobial agent or other substance added.1
Visually inspect the solution for particulate matter and discoloration prior to administration.1 After the solution has been placed in the SPAG-2 reservoir, discard any unused solution remaining in the reservoir within 24 hours and prior to adding any newly reconstituted solution (e.g., when remaining amount of solution in reservoir is low).1
When reconstituted and diluted ribavirin solution containing 20-mg/mL is delivered using the SPAG-2 aerosol generator according to the manufacturer's instructions, the average aerosol concentration for a 12-hour delivery period is 190 mcg/L.1
Ribavirin has been administered IV† .1000
A parenteral preparation of ribavirin is not commercially available in the US, but is available for compassionate use protocols for treatment of viral hemorrhagic fevers†.1000 Compassionate use of IV ribavirin can be obtained from Bausch Health; clinicians may initiate requests by contacting the Viral Special Pathogens Branch of the Centers for Disease Control and Prevention (770-488-7100).1000
Chronic Hepatitis C Virus Infection
When ribavirin capsules are used in conjunction with peginterferon alfa-2b (PegIntron®, no longer available in the US) for treatment of chronic HCV infection, the usual adult dosage is 800-1400 mg daily based on body weight in 2 divided doses.2 (See Table 1.) Refer to the PegIntron® prescribing information for dosing information of this drug.388 The recommended duration of concomitant peginterferon alfa-2b and ribavirin (capsule) treatment depends on HCV genotype, history of prior treatment, and response to treatment.2 (See Table 2.)
Weight | Total Daily Dosage of Ribavirin (Capsules) | Recommended Ribavirin Dosage Regimen (Capsules) |
|---|---|---|
65 kg or less | 800 mg | 400 mg in the morning and 400 mg in the evening |
66-80 kg | 1 g | 400 mg in the morning and 600 mg in the evening |
81-105 kg | 1.2 g | 600 mg in the morning and 600 mg in the evening |
>105 kg | 1.4 g | 600 mg in the morning and 800 mg in the evening |
Patient and Response | HCV Genotype | Duration | Considerations |
|---|---|---|---|
Treatment-naïve | 1 | 48 weeks | Consider discontinuing HCV treatment if HCV RNA has not decreased by at least 2 log10 by week 12 or remains detectable after 24 weeks of treatment |
Treatment-naïve | 2,3 | 24 weeks | |
Prior treatment failure | Any | 48 weeks | Consider discontinuing HCV treatment if HCV RNA still detectable at week 12 or remains detectable after 24 weeks of treatment |
If oral ribavirin capsules are used in conjunction with nonconjugated interferon alfa-2b (Intron® A; no longer available in the US) for treatment of chronic HCV infection, the manufacturers recommend a ribavirin dosage of 1 g daily (400 mg in morning and 600 mg in evening) for adults weighing 75 kg or less and 1.2 g daily (600 mg in morning and 600 mg in evening) for adults weighing more than 75 kg.2 Refer to the Intron A® prescribing information for dosing information of this drug.500 The duration of treatment should be individualized depending on baseline disease characteristics, response to therapy, and tolerability of the regimen.2 The manufacturers state that concomitant nonconjugated interferon alfa-2b and ribavirin capsule therapy should be continued for 24-48 weeks in treatment-naive patients, but discontinuance of treatment should be considered in patients who have not achieved HCV RNA levels below the limit of detection at 24 weeks.2 If concomitant therapy is used in patients who relapsed after prior nonconjugated interferon monotherapy, the manufacturers recommend a treatment duration of 24 weeks.2
When ribavirin tablets are used in conjunction with peginterferon alfa-2a (Pegasys®) for initial treatment of chronic HCV infection in adults with HCV monoinfection (without coexisting HIV infection), the usual dosage is 800-1200 mg daily, administered in 2 divided doses.3 (See Table 3). Refer to the Pegasys® prescribing information for dosing information of this drug, including dosage modifications in patients with renal impairment.20 The recommended duration of concomitant peginterferon alfa-2a and ribavirin (tablet) treatment depends on HCV genotype.3 (See Table 3).
HCV Genotype | Ribavirin Dosage (Tablets) | Duration |
|---|---|---|
1,4 | 1 g daily (400 mg in the morning and 600 mg in the evening) in those weighing <75 kg or 1.2 g daily (600 mg twice daily) in those weighing ≥75 kg | 48 weeks |
2,3 | 800 mg daily (400 mg twice daily) | 24 weeks |
5,6 | Data insufficient to make dosage recommendations |
When ribavirin tablets are used in conjunction with peginterferon alfa-2a (Pegasys®) for initial treatment of chronic HCV infection in adults with HCV and HIV coinfection, the usual dosage is 800 mg daily for a duration of 48 weeks, regardless of HCV genotype.3 Refer to the Pegasys® prescribing information for dosing information of this drug.20
For the treatment of viral hemorrhagic fevers† in adults, the US Army Medical Research Institute of Infectious Diseases (USAMRIID) recommends IV† ribavirin given in a regimen consisting of an initial loading dose of 30 mg/kg (up to 2 g), followed by a dosage of 16 mg/kg (up to 1 g) every 6 hours for 4 days and then 8 mg/kg (up to 500 mg) every 8 hours for 6 days for a total treatment course of 10 days.343
Alternatively, a 10-day regimen of oral ribavirin should be used for treatment of viral hemorrhagic fevers when the parenteral ribavirin preparation cannot be obtained or would be impractical (e.g., when large numbers of individuals require treatment in a mass casualty setting).343 When an oral ribavirin regimen is used, the USAMRIID recommends that adults receive an initial loading dose of 2000 mg followed by 1200 mg daily given in 2 divided doses for those weighing more than 75 kg, or 1000 mg daily (400 mg in morning and 600 mg in evening) for those weighing 75 kg or less.343
Chronic Hepatitis C Virus Infection
When ribavirin capsules are used in conjunction with peginterferon alfa-2b (PegIntron®; no longer available in the US) or nonconjugated interferon alfa-2b (Intron® A; no longer available in the US) for treatment of chronic HCV infection in children 3-17 years of age, the manufacturer recommends a ribavirin dosage of 15 mg/kg daily in 2 divided doses.2 (See Table 4). Refer to the PegIntron® or Intron® A prescribing information for dosing information of these drugs.388, 500 The recommended duration of treatment is 24 weeks in those with HCV genotype 2 or 3, or 48 weeks in those with HCV genotype 1.2 In patients treated with ribavirin and interferon alfa-2b combination therapy, assess virologic response at 24 weeks, and consider discontinuance of therapy in patients who have not achieved HCV RNA levels below the limit of detection at 24 weeks.2 In patients treated with ribavirin and peginterferon alfa-2b combination therapy (excluding HCV genotypes 2 and 3), discontinue therapy at 12 weeks if HCV RNA has dropped less than 2 log10 compared to pretreatment level, or at 24 weeks if HCV RNA is still detectable.2
Weight | Ribavirin Dosage |
|---|---|
47-59 kg | 400 mg in the morning and 400 mg in the evening |
60-73 kg | 400 mg in the morning and 600 mg in the evening |
>73 kg | 600 mg in the morning and 600 mg in the evening |
When ribavirin tablets are used in conjunction with peginterferon alfa-2a (Pegasys®) for treatment of chronic HCV infection in children 5 years of age or older capable of swallowing tablets, the manufacturers recommend a ribavirin dosage of approximately 15 mg/kg daily in divided doses.3 (See Table 5). Patients who reach their 18th birthday during treatment should continue receiving the pediatric dosage regimen for the remaining duration of treatment.3 Refer to the Pegasys® prescribing information for dosing information of this drug.20 The recommended duration of treatment is 24 weeks for HCV genotype 2 or 3, and 48 weeks for other HCV genotypes.3
Weight | Ribavirin Dosage |
|---|---|
23-33 kg | 200 mg in the morning and 200 mg in the evening |
34-46 kg | 200 mg in the morning and 400 mg in the evening |
47-59 kg | 400 mg in the morning and 400 mg in the evening |
60-74 kg | 400 mg in the morning and 600 mg in the evening |
≥75 kg | 600 mg in the morning and 600 mg in the evening |
Respiratory Syncytial Virus Infection
When ribavirin is used via nasal and oral inhalation for treatment of severe lower respiratory tract infections caused by respiratory syncytial virus (RSV) in hospitalized infants and young children, the drug should be initiated as soon as possible following the onset of signs and symptoms of infection.1
For treatment of severe RSV infection, a SPAG-2 aerosol generator with an oxygen hood, face mask, or oxygen tent should be used to deliver the reconstituted and diluted ribavirin solution containing 20 mg/mL continuously for 12-18 hours daily for 3-7 days.1 The average aerosol concentration for a 12-hour delivery period is 190 mcg/L of air.1 Dose and administration schedule of ribavirin inhalation therapy for infants who require mechanical ventilation is the same as that for infants who do not require assisted ventilation.1
For the treatment of viral hemorrhagic fevers† in children, the USAMRIID recommends IV† ribavirin given in a regimen consisting of an initial loading dose of 30 mg/kg (up to 2 g), followed by a dosage of 16 mg/kg (up to 1 g) every 6 hours for 4 days and then 8 mg/kg (up to 500 mg) every 8 hours for 6 days for a total treatment course of 10 days.343
If an oral ribavirin regimen is used in children, USAMRIID recommends an initial loading dose of 30 mg/kg followed by 15 mg/kg daily given in 2 divided doses for 10 days.343
Dosage Modification for Toxicity
Administer oral ribavirin with caution to patients with pre-existing cardiac disease.2, 3 Evaluate patients before commencement of therapy and monitor patients appropriately during therapy.2, 3 If there is any deterioration of cardiovascular status, discontinue therapy.2, 3
If severe adverse effects or laboratory changes occur when ribavirin capsules are used in combination with interferon alfa-2b (Intron® A) or peginterferon alfa-2b (PegIntron®), dosage should be modified or the agent(s) should be discontinued, if appropriate, until the adverse reactions abate or decrease in severity.2 If intolerance persists after dosage adjustment, discontinue combination therapy.2 Refer to Table 6 for recommendations for dosage modification or treatment discontinuation based on laboratory parameters.2
In pediatric patients, dosage reduction is accomplished by modifying the recommended ribavirin capsules dose from the original starting dosage of 15 mg/kg daily in a 2-step process to 12 mg/kg daily, then to 8 mg/kg daily, if needed (see Table 6).2
In patients with a history of stable cardiovascular disease, permanently reduce dosage if the hemoglobin decreases by ≥2 g/dL during any 4-week period.2 If hemoglobin remains <12 g/dL after 4 weeks on a reduced dosage, discontinue combination therapy.2
Modify or discontinue ribavirin capsules dosing in any patient whose hemoglobin level falls below 10 g/dL.2
Laboratory Parameters | Recommendationa |
|---|---|
WBC | Discontinue combination therapy if <1000/mm3 |
Neutrophils | Discontinue combination therapy if <500/mm3 |
Platelets | Discontinue combination therapy if <25,000/mm3 (adults) or <50,000/mm3 (pediatrics) |
Creatinine | Discontinue combination therapy if >2 mg/dL (pediatrics) |
Hemoglobin in patients without history of cardiac disease | Reduce ribavirin capsule daily dosage if 8.5 to <10 g/dLb; Discontinue combination therapy if <8.5 g/dL |
Hemoglobin in patients with history of stable cardiac diseasec d | Reduce ribavirin capsule daily dosage by 200 mg/day if ≥2 g/dL decrease in hemoglobin during any 4-week period during treatment Discontinue combination therapy <8.5 g/dL or <12 g/dL after 4 weeks of dosage reduction |
aRefer to labeling for interferon alfa-2b (Intron® A) or peginterferon alfa-2b (PegIntron®) for information on how and when to reduce dosage of these agents for specific laboratory parameters.
bIn adults, 1st dosage reduction of ribavirin is by 200 mg/day (except in patients receiving 1400 mg, for whom dosage reduction should be by 400 mg/day).2 If needed, 2nd dosage reduction of ribavirin is by an additional 200 mg/day.2 Patients whose dosage of ribavirin is reduced to 600 mg daily receive 200 mg in the morning and 400 mg in the evening.2 In pediatric patients, 1st dosage reduction of ribavirin is to 12 mg/kg daily, and 2nd dosage reduction of ribavirin is to 8 mg/kg daily.2
cPediatric patients who have pre-existing cardiac conditions and experience a hemoglobin decrease ≥2 g/dL during any 4-week period during therapy should undergo weekly evaluations and hematology testing.2
dPatients with a history of significant or unstable cardiac disease should not be treated with peginterferon alfa-2b/ribavirin capsules combination therapy.2
If serious adverse effects or laboratory changes occur when ribavirin tablets are used in conjunction with peginterferon alfa-2a (Pegasys®), dosage should be modified or the agent(s) should be discontinued, if appropriate, until the adverse reactions abate or decrease in severity.3 If intolerance persists after dosage adjustment, discontinue combination therapy.3 Refer to Table 7 for recommendations for dosage modifications and treatment discontinuation based on the patient's hemoglobin concentration and cardiac status.3
In adults, once ribavirin tablets have been withheld due to either a laboratory abnormality or clinical adverse reaction, an attempt may be made to restart ribavirin tablets at 600 mg daily and further increase the dosage to 800 mg daily.3 However, do not increase the dosage to the original assigned dosage (1-1.2 g).3
In pediatric patients, upon resolution of a laboratory abnormality or clinical adverse reaction, an attempt may be made (based on physician judgment) to increase the ribavirin tablet dosage to the original dosage.3 If ribavirin tablets have been withheld due to a laboratory abnormality or clinical adverse reaction, an attempt may be made to restart ribavirin tablets at one-half the full dosage.3
Recommendations Regarding Ribavirin Therapya | Recommendations Regarding Ribavirin Therapy a | |
|---|---|---|
Laboratory Values | Hemoglobin <10 g/dL in patients with no cardiac disease, or Decrease in hemoglobin of ≥2 g/dL during any 4-week period in patients with history of stable cardiac disease | Hemoglobin <8.5 g/dL in patients with no cardiac disease, or Hemoglobin <12 g/dL despite 4 weeks at reduced dose in patients with history of stable cardiac disease |
Adults (any weight) | Reduce ribavirin dosage to 200 mg in the morning and 400 mg in the evening | Discontinue ribavirin |
Pediatric patients 5-18 years of age | ||
23-33 kg | Reduce ribavirin dosage to 200 mg in the morning | Discontinue ribavirin |
34-46 kg | Reduce ribavirin dosage to 200 mg in the morning and 200 mg in the evening | Discontinue ribavirin |
47-59 kg | Reduce ribavirin dosage to 200 mg in the morning and 200 mg in the evening | Discontinue ribavirin |
60-74 kg | Reduce ribavirin dosage to 200 mg in the morning and 400 mg in the evening | Discontinue ribavirin |
≥75 kg | Reduce ribavirin dosage to 200 mg in the morning and 400 mg in the evening | Discontinue ribavirin |
aThe recommendations in this table also apply to laboratory abnormalities or adverse reactions other than decreases in hemoglobin values.3
The manufacturers make no specific dosage recommendations for patients with hepatic impairment.1, 2, 3
The manufacturer of ribavirin tablets states that dosage should be reduced in adults with creatinine clearance of 50 mL/minute or less.3 When ribavirin tablets are used for treatment of chronic HCV infection, adults with creatinine clearance of 30-50 mL/minute should receive alternating doses of 200 mg and 400 mg every other day, and adults with creatinine clearance less than 30 mL/minute or undergoing hemodialysis should receive 200 mg daily.3 Dosage should not be reduced any further; if severe adverse effects or laboratory abnormalities occur, the drug should be discontinued, if appropriate, until the adverse reactions abate or decrease in severity.3 If intolerance persists after restarting ribavirin tablets, discontinue ribavirin and peginterferon alfa-2a combination therapy.3
Data are insufficient to make dosage recommendations for use of ribavirin tablets in pediatric patients with renal impairment.3
Ribavirin capsules are contraindicated in patients with creatinine clearance less than 50 mL/minute.2
The manufacturers makes no specific dosage recommendations for geriatric patients.1, 2, 3
Since ribavirin is substantially excreted by the kidney and geriatric patients frequently have decreased renal function, renal function should be monitored closely and dosage adjusted accordingly.2, 3
Ribavirin capsules should be used with caution in geriatric patients, usually initiating therapy at the lower end of the usual dosage range to reflect the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in this population.2
Fetal/Neonatal Morbidity and Mortality
Oral ribavirin has a boxed warning regarding the risk of birth defects and/or fetal death.2, 3 Ribavirin has demonstrated significant teratogenic and/or embryocidal effects in all animal species studied.1, 2, 3 These effects occurred at doses as low as one-twentieth of the recommended human dosage.2, 3 Ribavirin may impair male fertility based on animal data.2, 3 Oral and aerosolized ribavirin are contraindicated in women who are or may become pregnant;1, 2, 3 oral ribavirin is also contraindicated in male partners of pregnant women.2, 3 Do not start ribavirin therapy until a report of a negative pregnancy test has been obtained immediately prior to planned initiation of therapy.2, 3 Exercise extreme care to avoid pregnancy in female patients and in female partners of male patients.2, 3
Inform patients of the potential hazard to a fetus.2, 3 Advise female patients of reproductive potential to use effective contraception and to have periodic monitoring with pregnancy tests during treatment with ribavirin capsules and during the 9-month period after treatment discontinuation.2 Advise male patients and their female partners of reproductive potential to use effective contraception during treatment with ribavirin capsules and during the 6-month period after treatment discontinuation.2 Advise female patients of reproductive potential, and male patients and their female partners of reproductive potential, to use ≥2 forms of effective contraception during treatment with ribavirin tablets and for 6 months after treatment discontinuation.3 Pregnancy testing should occur monthly during therapy with ribavirin tablets and for 6 months after treatment discontinuation.3
Oral ribavirin includes a boxed warning regarding the risk of hemolytic anemia.2, 3 In clinical trials, hemolytic anemia was observed in approximately 10% of patients treated with ribavirin capsules plus interferon alfa-2b (Intron® A), and in 13% of patients treated with ribavirin tablets plus peginterferon alfa-2a (Pegasys®).2, 3 Since ribavirin-associated anemia usually occurs within 1-2 weeks after initiation of oral ribavirin therapy, hemoglobin or hematocrit should be determined before initiating therapy, at weeks 2 and 4 of therapy, or more frequently if clinically indicated.2, 3 Follow patients as clinically appropriate.2, 3 Ribavirin tablets should be used with caution in patients with baseline risk of severe anemia (e.g., spherocytosis, history of GI bleeding).3 Because ribavirin-induced anemia may exacerbate preexisting cardiac disease and fatal and nonfatal myocardial infarctions have been reported in patients with ribavirin-associated anemia, patients should be assessed for underlying cardiac disease before initiation of ribavirin therapy.2, 3 Those with preexisting cardiac disease should have ECGs before the drug is initiated and should be appropriately monitored during therapy.2, 3 If there is any deterioration of cardiovascular status, oral ribavirin should be suspended or discontinued.2, 3 Oral ribavirin should not be used in patients with a history of substantial or unstable cardiac disease.2, 3
Lack of Effectiveness with Monotherapy
Oral ribavirin has a boxed warning regarding the lack of effectiveness with monotherapy of chronic hepatitis C virus infection.2, 3 Oral ribavirin monotherapy is not effective, and should not be used for treatment of chronic HCV infection.2, 3 The safety and efficacy of ribavirin capsules have only been established when used together with peginterferon alfa-2b (PegIntron®) or interferon alfa-2b (Intron® A) as combination therapy.2 Ribavirin tablets should be administered in combination with peginterferon alfa-2a (Pegasys®).3
Use of Aerosolized Ribavirin with Mechanical Ventilators
Use of ribavirin inhalation therapy in patients requiring mechanical ventilator assistance should be undertaken only by physicians and support staff familiar with this mode of administration and the specific ventilator being used.1 Because ribavirin may precipitate in the respiratory apparatus in patients requiring mechanical ventilation and can cause mechanical ventilator dysfunction and associated increased pulmonary pressures, strict attention should be given to procedures that have been shown to minimize the accumulation of ribavirin precipitates in the apparatus.1 These procedures include use of bacterial filters in series in the expiratory limb of the ventilator circuit with frequent changes (every 4 hours), water column pressure release valves to indicate elevated ventilator pressures, frequent monitoring of these devices and verification that ribavirin crystals have not accumulated within the ventilator circuitry, and frequent suctioning and monitoring of the patient.1 Those administering ribavirin inhalation therapy in conjunction with mechanical ventilator use should be thoroughly familiar with detailed descriptions of these procedures as outlined in the SPAG-2 instructions for use.1
Deterioration of Respiratory Function
Initiation of ribavirin inhalation therapy in infants has been associated with sudden deterioration of respiratory function.1 Monitor respiratory function carefully during treatment.1 Ribavirin should be discontinued if sudden worsening of respiratory function occurs following initiation of therapy with the drug; ribavirin should be reintroduced only with extreme caution and continuous monitoring, and consideration should be given to concomitant administration of bronchodilators.1 Optimum monitoring and attention to respiratory and fluid status are required in patients with severe lower respiratory tract infection due to respiratory syncytial virus (RSV).1
Aerosolized Ribavirin Use in Adults
Ribavirin inhalation is not indicated for use in adults.1 Patients and clinicians should be aware that the drug is teratogenic in animals and ribavirin therapy should not be initiated in women of childbearing potential.1
Oral ribavirin in conjunction with peginterferon or interferon should be suspended in patients with manifestations of pancreatitis and discontinued in those with confirmed pancreatitis.2, 3
Pulmonary symptoms (e.g., dyspnea, pulmonary infiltrates, pneumonitis, pulmonary hypertension, pneumonia) have been reported during oral ribavirin plus interferon combination therapy; occasional cases of fatal pneumonia have occurred.2, 3 Sarcoidosis or the exacerbation of sarcoidosis has also been reported.2, 3
Patients who experience pulmonary infiltrates or a deterioration in pulmonary function while receiving oral ribavirin with peginterferon or interferon should be closely monitored and, if appropriate, combination therapy should be discontinued.2, 3
New or worsening ophthalmologic disorders may occur.2 Perform an eye exam before initiating treatment with oral ribavirin.2, 3
Ribavirin plus peginterferon alfa-2b (PegIntron®) combination therapy may cause severe decreases in neutrophil and platelet counts, as well as hematologic, endocrine (e.g., thyroid-stimulating hormone [TSH]), and hepatic abnormalities.2, 3
Complete hematology and blood chemistry testing before initiating treatment with oral ribavirin plus interferon combination therapy and then periodically thereafter.2, 3
After initiation of therapy with ribavirin capsules, assess standard hematologic tests, including hemoglobin (at weeks 2 and 4 of therapy and as clinically indicated), CBC, differential WBC count, and platelet count, periodically during treatment.2 Assess blood chemistries (liver function tests and TSH) periodically during treatment.2 In the clinical trial evaluating ribavirin capsules in adults, CBCs (including hemoglobin, neutrophil, and platelet counts) and chemistries (including AST, ALT, bilirubin, and uric acid) were measured during the treatment period at 2, 4, 8, and 12 weeks, and then at 6-week intervals, or more frequently if abnormalities developed.2 In pediatric patients, the same laboratory parameters were evaluated with additional assessment of hemoglobin at treatment week 6.2 TSH levels were measured every 12 weeks during treatment.2 HCV-RNA should be measured periodically during treatment.2
After initiation of therapy with ribavirin tablets, perform hematologic tests at 2 and 4 weeks and perform biochemical tests at 4 weeks; perform additional testing periodically during therapy.3 In the clinical trial evaluating ribavirin tablets in adults, CBC (including hemoglobin, WBC, and platelet counts) and chemistries (including liver function tests and uric acid) were measured at 1, 2, 4, 6, and 8 weeks, and then every 4—6 weeks or more frequently if abnormalities developed.3 In the pediatric clinical trial, hematologic and chemistry assessments were at 1, 3, 5, and 8 weeks, then every 4 weeks.3 TSH was measured every 12 weeks.3
The manufacturer states that the entry criteria used in clinical studies evaluating safety and efficacy of ribavirin tablets and peginterferon alfa-2a for treatment of chronic HCV infection can be considered a guideline for acceptable baseline values for initiation of therapy.3 These studies required that hemoglobin be ≥12 g/dL in women and ≥13 g/dL in men with HCV monoinfection (without concomitant HIV infection) or ≥11 g/dL in women and ≥12 g/dL in men coinfected with HCV and HIV.3 In addition, these studies required that platelet counts be ≥90,000/mm3 (as low as 75,000/mm3 in those with cirrhosis or 70,000/mm3 in those coinfected with HCV and HIV) and that absolute neutrophil counts (ANCs) be ≥1500/mm3.3 These studies also required that thyrotropin (TSH) and thyroxine (T4) concentrations be within normal limits or that patients have adequately controlled thyroid function; additionally, it was required that CD4+ cell count be ≥200 cells/mm3, or CD4+ cell count be ≥100 cells/mm3 but <200 cells/mm3 and HIV-1 RNA be <5000 copies/mL, in patients coinfected with HIV.2
Dental and Periodontal Disorders
Dental and periodontal disorders have been reported in patients treated with ribavirin capsules and interferon/peginterferon combination therapy.2 Additionally, dry mouth (which was reported in 8% and 12% of patients receiving ribavirin capsules and interferon or peginterferon, respectively) could have a damaging effect on teeth and mucous membranes of the mouth during long-term therapy with these combinations.2
Patients should be advised to have regular dental examinations during treatment, brush their teeth thoroughly twice daily, and rinse their mouth thoroughly after vomiting.2
Bone Marrow Suppression and Concomitant Use of Azathioprine
Pancytopenia and bone marrow suppression have been reported in a limited number of patients within 3—7 weeks after the concomitant administration of pegylated interferon/ribavirin and azathioprine.2, 3 Myelotoxicity was reversible within 4—6 weeks upon withdrawal of both HCV antiviral therapy and concomitant azathioprine and did not recur upon reintroduction of either treatment alone.2, 3
Discontinue pegylated interferon, ribavirin, and azathioprine if pancytopenia occurs, and do not reintroduce pegylated interferon/ribavirin with concomitant azathioprine.2, 3
Impact on Growth in Pediatric Patients
Data from an open-label study found that weight and height gain of pediatric patients 3—17 years of age treated with ribavirin capsules and peginterferon alfa-2b (PegIntron®) combination therapy lagged behind that predicted by normative population data for the entire length of treatment.2 Following treatment, rebound growth and weight gain occurred in most patients.2 However, long-term follow-up data in pediatric patients indicate that combination therapy with ribavirin capsules plus peginterferon alfa-2b may induce growth inhibition that causes reduced adult height in some patients.2 Similarly, an impact on growth was observed in patients treated with ribavirin capsules and interferon alfa-2b (Intron® A) for 1 year.2 In a long-term follow-up trial of a limited number of these patients, reduced final adult height was observed in some patients.2
During combination therapy with ribavirin tablets and peginterferon alfa-2a (Pegasys®) for up to 48 weeks, growth inhibition was observed in pediatric patients 5—17 years of age.3 The available longer term data on patients who were followed up to 6 years after treatment are too limited to determine the risk of reduced adult height in some patients.3
Patients with chronic HCV with cirrhosis may be at risk of hepatic decompensation and death when treated with alpha interferons such as peginterferon alfa-2a (Pegasys®).3 Cirrhotic patients with chronic HCV coinfected with HIV receiving highly active antiretroviral therapy (HAART) and interferon alfa-2a with or without ribavirin appear to be at increased risk for the development of hepatic decompensation compared to those not receiving HAART.3 In a study of 129 cirrhotic patients with chronic HCV coinfected with HIV who were receiving HAART, 14 patients developed hepatic decompensation, of whom 6 patients died.3 All 14 patients were on nucleoside reverse transcriptase inhibitors (NRTIs); the small number of patients do not allow discrimination between specific NRTIs or the associated risk.3
Monitor patient clinical status and hepatic function closely during treatment for signs and symptoms of hepatic decompensation.3 Discontinue ribavirin tablets plus peginterferon alfa-2a combination therapy immediately in patients with hepatic decompensation.3
Severe acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) have been reported with ribavirin plus alpha interferon combination therapy.3 If such a reaction occurs, discontinue combination therapy immediately and institute appropriate medical therapy.3
Serious dermatologic reactions, including vesiculobullous eruptions, reactions in the spectrum of Stevens-Johnson syndrome with varying degrees of skin and mucosal involvement, and exfoliative dermatitis, have been reported in patients receiving peginterferon alfa-2a (Pegasys®) with and without ribavirin.3 If signs or symptoms of severe skin reactions occur, discontinue therapy.3
Ribavirin may cause fetal toxicity and/or death based on findings from animal studies.1, 2, 3 The drug has been shown to be teratogenic and/or embryocidal in almost all animal species tested to date at dosages well below the recommended human dosage.1, 2, 3 Malformations of the skull, palate, eye, jaw, limbs, skeleton, and GI tract have been reported in animal studies.1, 2, 3 The incidence and severity of teratogenic effects increase with increasing dosage.1, 2, 3 Survival of fetuses and offspring was reduced.1, 2, 3
Data from the ribavirin pregnancy registry are insufficient to identify a drug-associated risk of birth defects, miscarriage, or adverse maternal or fetal outcomes in humans.2
Oral ribavirin is contraindicated in women who are or may become pregnant and also is contraindicated in male partners of such women.2, 3 Extreme care should be exercised to avoid pregnancy in female patients receiving ribavirin and in female partners of male patients receiving ribavirin.2, 3 Based on a multiple-dose ribavirin half-life of 12 days, the drug may persist in nonplasma compartments for as long as 6 months (e.g., 15 half-lives of clearance for ribavirin).2, 3 If ribavirin is inadvertently administered during pregnancy or pregnancy occurs, inform the patient of the potential hazard to the fetus.2, 3
Oral ribavirin should not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiating therapy.2, 3 Perform periodic pregnancy testing during treatment with ribavirin capsules and during the 9-month period after treatment discontinuation.2 Perform pregnancy testing monthly during therapy with ribavirin tablets and for 6 months after treatment discontinuation.3
Advise female patients of reproductive potential to use effective contraception during treatment with ribavirin capsules and for 9 months after treatment discontinuation.2 Advise male patients and their female partners of reproductive potential to use effective contraception during treatment with ribavirin capsules and for 6 months after treatment discontinuation.2
Advise female patients of reproductive potential and male patients and their female partners of reproductive potential to use ≥2 forms of effective contraception during treatment with ribavirin tablets and for 6 months after treatment discontinuation.3
Ribavirin nasal and oral inhalation is contraindicated in women who are or may become pregnant.1 Because of animal evidence of the drug's teratogenic potential, hospitals are encouraged to perform training programs to minimize potential occupational exposure to ribavirin.1 Health-care personnel who are pregnant should consider avoiding direct care of patients being treated with aerosolized ribavirin.1 If close patient contact cannot be avoided, precautions to limit exposure should be taken.1 Refer to the National Institute for Occupational Safety and Health (NIOSH) recommendations for hazardous drugs for additional information to minimize environmental exposures.7
Ribavirin has been shown to be toxic to lactating animals and their offspring.1 It is not known whether ribavirin is distributed into human milk following nasal/oral inhalation or oral administration.1, 2, 3 There are no data on the effects of ribavirin on the breast-fed infant or on milk production.2
Because of the potential for serious adverse reactions to oral ribavirin in nursing infants, a decision should be made whether to discontinue nursing or discontinue ribavirin therapy, taking into account the importance of the drug to the woman.3 The benefits of breast-feeding should be considered along with the mother's clinical need for ribavirin and any potential adverse effects on the breast-fed child from the drug or from the underlying maternal condition.2
Females and Males of Reproductive Potential
Ribavirin may cause fetal harm when administered during pregnancy.2, 3
The effect of ribavirin on fertility in male or female animals has not been fully investigated.1 In studies in mice, ribavirin dosages of 35-150 mg/kg daily (estimated human equivalent of 2.92-12.5 mg/kg daily based on body surface area adjustment for the adult) resulted in seminiferous tubule atrophy, decreased sperm concentrations, and increased numbers of sperm with abnormal morphology; partial recovery of sperm production was apparent 3-6 months after the drug was discontinued.1 Ribavirin has been shown to produce testicular lesions (e.g., tubular atrophy) in adult rats receiving oral dosages of 16 mg/kg daily (estimated human equivalent of 2.29 mg/kg daily based on body surface area adjustment for the adult); lower dosages were not tested.1 In addition, sperm abnormalities have occurred in mice following oral ribavirin doses of 15-150 mg/kg daily (approximately 0.1-0.8 times the maximum human 24-hour dose of ribavirin) administered for 3 or 6 months.2, 3 Essentially total recovery from ribavirin-induced testicular toxicity was apparent within 1 or 2 spermatogenesis cycles following discontinuance of the drug.2, 3 However, ribavirin is known to accumulate in intracellular components from which the drug is cleared very slowly, and it is not yet known whether ribavirin contained in sperm will exert a potential teratogenic effect upon fertilization of the ova.2, 3
Females of reproductive potential must have a negative pregnancy test prior to initiating treatment with ribavirin capsules and should have pregnancy tests performed periodically during therapy and for 9 months post therapy.2 Females of reproductive potential must have a negative pregnancy test prior to initiating treatment with ribavirin tablets and must perform a pregnancy test monthly during therapy and for 6 months post therapy.3
Advise female patients of reproductive potential to use effective contraception during treatment with ribavirin capsules and for 9 months post therapy.2 Advise male patients and their female partners of reproductive potential to use effective contraception during treatment with ribavirin capsules and for 6 months post therapy.2
Advise female patients of reproductive potential, and male patients and their female partners of reproductive potential, to use effective contraception (2 reliable forms) during treatment with ribavirin tablets and for 6 months post therapy.3
Safety and efficacy of aerosolized ribavirin (ribavirin nasal and oral inhalation) have been established for treatment of RSV infection in infants and young children.1
Safety and efficacy of ribavirin tablets have not been established for treatment of chronic HCV infection in children younger than 5 years of age.3 Pharmacokinetic evaluations in pediatric patients have not been performed.3
Safety and efficacy of ribavirin capsules in conjunction with peginterferon alfa-2b (PegIntron®) have not been established for treatment of chronic HCV infection in children younger than 3 years of age.2 When deciding whether to use ribavirin capsules in conjunction with interferon alfa-2b (Intron® A) in HCV-infected children, evidence of disease progression (e.g., hepatic inflammation, fibrosis), prognostic factors for response, HCV genotype, and viral load should be considered.2 The benefits of such treatment should be weighed against adverse effects reported in pediatric patients.2
Suicidal ideation or attempts occurred more frequently in pediatric patients (2.4%) than in adults (1%) during or after therapy; most of these children were adolescents.2 Like adults, other adverse psychiatric effects (e.g., depression, emotional lability, somnolence), anemia, and neutropenia were also reported in pediatric patients.2
Clinical studies of oral ribavirin used in conjunction with interferon therapy did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients.2, 3 In clinical trials, geriatric patients had a higher frequency of anemia (67%) than did younger patients (28%).2 Pharmacokinetic evaluations for ribavirin in geriatric patients have not been performed.3
Because ribavirin is known to be substantially excreted by the kidney, patients with renal impairment are at increased risk of ribavirin-induced toxicity; geriatric patients frequently have decreased renal function, and renal function should be monitored closely and dosage adjusted accordingly.2, 3
Ribavirin capsules should be used with caution in geriatric patients, usually initiating therapy at the lower end of the usual dosage range to reflect the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in this population.2
The effect of hepatic impairment was assessed after a single dose (600 mg) of ribavirin capsules.2 The mean AUC of ribavirin was not altered in individuals with mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, or C) compared to controls.2 However, mean peak plasma concentration increased with severity of hepatic impairment and was increased twofold in those with severe hepatic impairment compared to controls.2
The effect of hepatic impairment on the pharmacokinetics of ribavirin tablets has not been evaluated.3 Clinical trials of ribavirin tablets were restricted to patients with Child-Pugh class A disease.3
Because ribavirin is known to be substantially excreted by the kidney, and because patients with renal impairment are at increased risk of ribavirin-induced toxicity, renal function should be monitored closely and dosage adjusted accordingly.2, 3
The pharmacokinetics of ribavirin capsules were assessed after administration of a single oral dose (400 mg) of ribavirin to non-HCV-infected patients with varying degrees of renal impairment.2 The AUC was twofold or threefold greater in those with creatinine clearances of 30-60 or 10-30 mL/minute, respectively, compared with individuals with normal renal function.2 The increased AUC may be because of reduction of renal and nonrenal clearance in these patients.2 The multiple-dose pharmacokinetics of ribavirin cannot be accurately predicted in patients with renal impairment.2 Ribavirin is not effectively removed by hemodialysis.2 Patients with creatinine clearance <50 mL/minute should not be treated with ribavirin capsules.2
The pharmacokinetics of ribavirin tablets have been evaluated in patients with chronic HCV infection and varying degrees of renal impairment (moderate, severe, or requiring hemodialysis).3 Among those with creatinine clearances of 50 mL/minute or less, the apparent clearance of ribavirin was approximately 30% of values observed in patients with normal renal function.3 Based on these results, pharmacokinetic modeling has provided a basis for dosage adjustments of ribavirin tablets in such patients.3 Dosage of ribavirin tablets should be adjusted for patients with creatinine clearance <50 mL/minute.3 Carefully monitor clinical and hematologic status of patients with creatinine clearance ≤50 mL/minute receiving ribavirin tablets.3 Withdraw therapy in patients with clinically important laboratory abnormalities or adverse reactions that are persistently severe or worsening.3 No data are available for pediatric patients with renal impairment.3 Plasma ribavirin is removed by hemodialysis with an extraction ratio of approximately 50%; however, plasma exposure of the drug is not expected to change with hemodialysis due to the large volume of distribution of the drug.3 In a small number of individuals with end-stage renal disease receiving hemodialysis, a ribavirin dosage (as tablets) of 200 mg daily provided plasma ribavirin exposures approximately 20% lower than those observed in individuals with normal renal function receiving recommended dosages.3
Safety and efficacy of oral ribavirin in conjunction with interferon or peginterferon for the treatment of HCV have not been established in patients with liver or other transplantations.2, 3
HIV or Hepatitis B Virus Co-Infection
Safety and efficacy of ribavirin capsules in conjunction with peginterferon alfa-2b or interferon alfa-2b have not been established in chronic HCV patients coinfected with HIV or hepatitis B virus (HBV).2
The most common adverse effects in adults (≥40%) receiving ribavirin capsule plus peginterferon alfa-2b (PegIntron®) or interferon alfa-2b (Intron® A) combination therapy were injection site reaction, fatigue/asthenia, headache, rigors, fevers, nausea, myalgia and anxiety/emotional lability/irritability.2 Hemolytic anemia occurred in >10% of adults receiving ribavirin capsule plus peginterferon alfa-2b or interferon alfa-2b combination therapy.2 The most common adverse effects (greater than 25%) in pediatric patients receiving ribavirin capsule plus peginterferon alfa-2b or interferon alfa-2b combination therapy were pyrexia, headache, neutropenia, fatigue, anorexia, injection site erythema, and vomiting.2
The most common adverse effects (frequency >40%) in adults receiving ribavirin tablet plus peginterferon alfa-2a (Pegasys®) combination therapy were fatigue/asthenia, pyrexia, myalgia, and headache.3 The most common adverse effects in pediatric patients were similar to those seen in adults.3
Information on adverse effects of ribavirin inhalation therapy has been obtained principally from clinical studies conducted prior to 1986, from a controlled study conducted in 1989-1990, and from postmarketing surveillance reports.1 The most common adverse effects associated with inhalation of the drug appear to include respiratory and cardiovascular effects.1
The following drug interactions are based on studies using oral ribavirin.2, 3 When oral ribavirin is used in combination with peginterferon alfa-2a, peginterferon alfa-2b (no longer available in the US), or interferon alfa-2b (no longer available in the US), consider the interactions associated with the interferon; refer to the full prescribing information for the interferon drug interactions.2, 3, 20, 388, 500
In vitro studies indicate that ribavirin does not inhibit cytochrome P-450 (CYP) isoenzymes 2C9, 2C19, 2D6, or 3A4, and is not a substrate of CYP enzymes.3
Studies have not been performed to evaluate potential drug interactions in infants receiving ribavirin inhalation concomitantly with other drugs used to treat RSV infections (e.g., digoxin, bronchodilators, anti-infectives, antimetabolites, other antiviral agents).1 The manufacturer states that the effect of ribavirin inhalation on laboratory tests has not been evaluated.1
Drugs Affecting or Affected by Hepatic Microsomal Enzymes
In vitro studies indicate that ribavirin does not inhibit and is not a substrate for CYP enzymes.3 Therefore, there is little potential for drug interactions with drugs metabolized by CYP enzymes.2
Although the clinical importance is unknown, concomitant administration of a single dose of ribavirin capsules and a single dose of an antacid containing magnesium, aluminum, and simethicone decreased the mean AUC of ribavirin by 14%.2
HIV Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
Ribavirin may antagonize the cell culture antiretroviral activity of zidovudine.2 In vitro data indicate ribavirin reduces/inhibits phosphorylation of lamivudine and zidovudine.2, 3 However, concomitant use of oral ribavirin and lamivudine or zidovudine in patients coinfected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) did not result in pharmacokinetic (e.g., alterations in plasma concentrations of active metabolites) or pharmacodynamic (e.g., loss of HIV/HCV virologic suppression) interactions.2, 3 Use ribavirin concomitantly with any of these drugs with caution.2
Cases of hepatic decompensation (some fatal) were observed in cirrhotic patients with chronic HCV infection who were coinfected with HIV and receiving NRTIs and ribavirin therapy.2, 3
Patients receiving oral ribavirin and interferon alfa or peginterferon alfa concomitantly with NRTIs should be closely monitored for treatment-associated toxicities, particularly hepatic decompensation and anemia.2, 3 Consider discontinuance of the NRTI as medically appropriate;2 consult the prescribing information for the specific NRTI for guidance regarding toxicity management.2, 3 Dosage reduction or discontinuance of peginterferon alfa (or interferon alfa) and/or oral ribavirin should be considered if worsening toxicities, including hepatic decompensation (e.g., Child-Pugh score greater than 6), occur.2, 3
An increased incidence of severe neutropenia (absolute neutrophil count [ANC] less than 500/mm3) and severe anemia (hemoglobin less than 8 g/dL) was reported in patients coinfected with HCV and HIV who were receiving zidovudine in conjunction with peginterferon alfa-2a and ribavirin tablets compared with those not receiving zidovudine.3 Consider discontinuing zidovudine as medically appropriate.3
Severe pancytopenia (marked decreases in erythrocytes, neutrophils, and platelets) and bone marrow suppression have been reported in some patients receiving azathioprine concomitantly with peginterferon alfa and oral ribavirin.2, 3 Such effects generally occurred within 3-7 weeks after initiation of concomitant therapy, reversed within 4-6 weeks after all 3 drugs were discontinued, and did not recur when either azathioprine or the regimen of peginterferon alfa plus oral ribavirin was reinitiated alone.2, 3
These adverse effects may occur because ribavirin inhibits inosine monophosphate dehydrogenase, which may result in accumulation of 6-methylthioinosine monophosphate, an azathioprine metabolite associated with myelotoxicity.2, 3
If azathioprine and oral ribavirin are used concomitantly, monitor CBCs, including platelet counts, weekly for the first month, twice monthly during the second and third months of treatment, and then monthly or more frequently if dosage or other therapy changes are necessary.2, 3 If pancytopenia develops, discontinue all 3 drugs (azathioprine, ribavirin, peginterferon alfa); do not restart peginterferon alfa and oral ribavirin therapy with concomitant azathioprine.2, 3
No pharmacokinetic interactions were observed between interferon alfa-2b and ribavirin capsules in a multiple-dose pharmacokinetic study.2
There is no evidence of a pharmacokinetic interaction between ribavirin and peginterferon alfa-2a.3
Ribavirin is a synthetic nucleoside antiviral agent (purine analogue).2, 3 The exact mechanism of action of the antiviral activity of ribavirin against hepatitis C virus (HCV) has not been fully elucidated.2, 3 Ribavirin has direct antiviral activity against many RNA viruses.2, 3 Ribavirin increases the mutation frequency in the genomes of several RNA viruses and ribavirin triphosphate inhibits HCV polymerase.2, 3
The antiviral activity of ribavirin in the HCV replicon is not fully understood and has not been defined due to the cellular toxicity of ribavirin.2 The anti-HCV activity of interferon was demonstrated in cell culture using self-replicating HCV RNA or HCV infection.2 In a cell culture model system, ribavirin inhibited autonomous HCV RNA replication with a 50% effective concentration (EC50) value of 11—21 mcM.3 Peginterferon alfa-2a also inhibited HCV RNA replication in the same model.3 The combination of ribavirin plus peginterferon alfa-2a was more effective at inhibiting HCV RNA replication compared to either agent alone.3
Ribavirin has demonstrated antiviral activity against respiratory syncytial virus (RSV).1 The inhibitory activity of ribavirin for RSV is selective, and the precise mechanism of action is unknown.1 Reversal of the antiviral activity of ribavirin by guanosine or xanthosine suggests that ribavirin may act as an analogue of these cellular metabolites.1
Neutralizing antibody responses to RSV were decreased in infants treated with aerosolized ribavirin compared to those treated with placebo.1 In one study, RSV-specific immune globulin E antibody in bronchial secretions was decreased in patients treated with aerosolized ribavirin.1 In animals, ribavirin has produced lymphoid atrophy of the thymus, spleen, and lymph nodes.1 The drug has also decreased humoral immune responses in animals.1 Cellular immunity was also mildly depressed in animal studies.1 The clinical importance of these findings is unknown.1
Ribavirin is absorbed systemically from the respiratory tract following nasal and oral inhalation.1 Following nasal and oral inhalation (via face mask) of ribavirin for 2.5 hours daily for 3 days in a limited number of pediatric patients, plasma ribavirin concentrations averaged 0.76 (range: 0.44-1.55) µM, and the plasma half-life of ribavirin was 9.5 hours.1 Plasma ribavirin concentrations averaged 6.8 (range: 1.5-14.3) µM in a limited number of pediatric patients inhaling aerosolized ribavirin via face mask or mist tent for 20 hours daily for 5 days.1
The bioavailability of ribavirin administered via nasal and oral inhalation has not been determined but may depend on the method of drug delivery during nebulization (i.e., oxygen hood, face mask, oxygen tent).1 Peak plasma ribavirin concentrations achieved with nasal and oral inhalation of usual dosages of the drug are less than concentrations that reportedly reduce RSV plaque formation by 85-98%.1 Concentrations of ribavirin achieved in respiratory tract secretions via nasal and oral inhalation are likely to be substantially greater than concentrations necessary to inhibit plaque formation of susceptible strains of RSV in vitro.1 However, RSV is found within virus-infected cells in the respiratory tract, and it is not known whether ribavirin concentrations in plasma or respiratory tract secretions better reflect the intracellular concentrations of the drug.1
Studies in animals and humans have shown that ribavirin and/or its metabolites accumulate in erythrocytes, plateauing in erythrocytes in about 4 days in humans and then declining with a half-life of about 40 days (the half-life of erythrocytes).1 The extent of accumulation of ribavirin and/or its metabolites in erythrocytes following inhalation of the drug has not been established.1
Ribavirin is rapidly and extensively absorbed following oral administration, with peak plasma concentrations of the drug occurring 1.7 hours and 3 hours, respectively, following single-dose or multiple-dose (twice daily) administration of ribavirin 600 mg capsules.2 However, the absolute bioavailability of ribavirin averages only 64% following oral administration because the drug undergoes first-pass metabolism.2 In adults with chronic HCV infection, the plasma half-life of ribavirin averages 43.6 hours after a single 600-mg oral dose and averages 298 hours at steady state (reached by approximately 4 weeks) in those receiving a dosage of 600 mg twice daily.2
Multiple dose ribavirin pharmacokinetic data are available for patients with HCV who received ribavirin tablets in combination with peginterferon alfa-2a.3 Following oral administration of ribavirin, the time to reach peak plasma concentration was 2 hours.3 The terminal half-life of ribavirin following administration of a single oral dose of ribavirin is approximately 120—170 hours.3 There is extensive accumulation of ribavirin following multiple (twice daily) doses of the drug, such that peak plasma ribavirin concentrations at steady state are fourfold higher than those following a single dose.3 The contribution of renal and hepatic pathways to ribavirin elimination is unknown.3
Oral bioavailability of ribavirin appears to be increased when the drug is administered with a high-fat meal.3 Concomitant administration of oral ribavirin (as capsules or tablets) with a high-fat meal increases the peak ribavirin plasma concentration and AUC.2, 3 Results of a single-dose study indicate that peak plasma concentration and AUC of ribavirin reportedly increase by 70% when ribavirin capsules are administered with a high-fat meal (31.6 g protein, 57.4 g carbohydrate, 53.8 g fat; 841 kcal).2 Peak plasma concentration and AUC of ribavirin reportedly increase by 66 and 42%, respectively, when ribavirin tablets are administered with a high-fat meal; drug absorption is slowed.3
Results of in vitro studies using both human and rat liver microsome preparations indicated little or no cytochrome P-450 (CYP) enzyme-mediated metabolism of ribavirin;2 ribavirin is not a substrate of CYP isoenzymes.3 Ribavirin does not bind to plasma proteins.2 Ribavirin has 2 pathways of metabolism: a) a reversible phosphorylation pathway in nucleated cells; and b) a degradative pathway involving deribosylation and amide hydrolysis to produce a triazole carboxylic acid metabolite.2 Ribavirin and its triazole carboxamide and triazole carboxylic acid metabolites are excreted via the kidneys.2 After oral administration of a 600-mg radiolabeled dose of ribavirin, approximately 61 and 12% of the dose was eliminated in the urine and feces, respectively, in 336 hours; unchanged drug accounted for 17% of the administered dose.2
Ribavirin is a broad spectrum antiviral nucleoside that demonstrates activity against a variety of RNA and DNA viruses.4
Ribavirin has demonstrated antiviral activity against respiratory syncytial virus (RSV).1 Several clinical isolates of RSV were assessed for ribavirin susceptibility by plaque reduction in tissue culture.1 Plaques of susceptible strains of RSV were reduced 85-98% by ribavirin concentrations of 16 mcg/mL; however, plaque reduction may vary with the test method.1 In addition to antiviral activity against RSV, ribavirin is also active in vitro against influenza A and B viruses and herpes simplex virus; however, the clinical importance of these findings is unknown.1
Development of in vitro or in vivo resistance to the antiviral activity of ribavirin has not been fully evaluated.1
Variable response to combination ribavirin-pegylated interferon therapy has been noted with differing HCV genotypes.2, 3 However, no specific correlations have been identified for particular viral genetic determinants;3 genetic changes associated with the variable response have not been identified.2 Cross-resistance has not been reported between ribavirin and interferons.2, 3
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Nasal and Oral Inhalation | For inhalation solution | 6 g* | Ribavirin for inhalation solution | |
Bausch Health | ||||
Oral | Capsules | 200 mg* | Ribavirin Capsules | |
Tablets, film-coated | 200 mg* | Ribavirin Tablets |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
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2. Aurobindo Pharma USA, Inc. Ribavirin capsules prescribing information. East Windsor, NJ; 2023 Jul.
3. Aurobindo Pharma USA, Inc. Ribavirin tablets prescribing information. East Windsor, NJ; 2023 May.
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105. American Academy of Pediatrics. Red Book: 2024 Report of the Committee on Infectious Diseases. 33rd ed. Itasca, IL: American Academy of Pediatrics; 2024.
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426. Wirth S, Ribes-Koninckx C, Calzado MA et al. High sustained virologic response rates in children with chronic hepatitis C receiving peginterferon alfa-2b plus ribavirin. J Hepatol . 2010; 52:501-7. [PubMed 20189674]
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500. Merck Sharp & Dohme Corp. Intron® A (interferon alfa-2b) injection prescribing information. Whitehouse Station, NJ; 2021 Nov.
1000. Centers for Disease Control and Prevention (CDC) Yellow Book 2024. Viral Hemorrhagic Fevers. Accessed 2024 Nov 11. [Web]
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