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Ribavirin (Monograph)

Brand names: Copegus, Rebetol, Ribasphere, Virazole
Drug class: Nucleosides and Nucleotides
VA class: AM800
Chemical name: 1-β-D-Ribofuranosyl-1H-1,2,4-triazole-3 carboxamide
CAS number: 36791-04-5

Medically reviewed by Drugs.com on Oct 16, 2023. Written by ASHP.

Warning

    Oral Ribavirin
  • Ribavirin not effective alone for treatment of chronic HCV infection; do not use ribavirin monotherapy for this indication.

  • Principal toxicity of oral ribavirin is hemolytic anemia which may result in worsening of cardiac disease and has resulted in fatal and nonfatal MI. Do not use ribavirin in patients with a history of clinically important or unstable cardiac disease.

  • Teratogenic and/or embryocidal effects demonstrated in all animal species exposed to ribavirin. Ribavirin has a long half-life (12 days after multiple doses) and may persist in nonplasma compartments for as long as 6 months.

  • Contraindicated in pregnant women and male partners of pregnant women. Extreme care must be used to avoid pregnancy during and for 6 months following ribavirin therapy in female patients and female partners of male patients receiving ribavirin. Must use at least 2 reliable forms of contraception during and for 6 months following completion of treatment.

    Ribavirin Nasal and Oral Inhalation
  • Aerosolized ribavirin (ribavirin for nasal and oral inhalation) should be used in patients requiring mechanical ventilator assistance only if clinicians and support staff are familiar with this mode of administration and the specific ventilator being used. Strict attention must be directed to procedures that minimize accumulation of drug precipitate, which can result in mechanical ventilator dysfunction and associated increased pulmonary pressure.

  • Initiation of aerosolized ribavirin in infants has resulted in sudden deterioration of respiratory function. Monitor respiratory function carefully during treatment. If sudden deterioration of respiratory function occurs, discontinue the drug. Reinstitute only with extreme caution and continuous monitoring; consider concomitant administration of a bronchodilator.

  • Ribavirin for nasal and oral inhalation is not indicated in adults.

Introduction

Antiviral agent; nucleoside derivative.

Uses for Ribavirin

Chronic HCV Infection

Treatment of chronic HCV infection in adults and pediatric patients with compensated liver disease.

Used in conjunction with other drugs in multiple-drug regimens for treatment of chronic HCV infection; do not use alone.

Has been used in conjunction with peginterferon alfa (peginterferon alfa-2a, peginterferon alfa-2b). Although used in conjunction with nonconjugated interferon alfa-2b in the past, such regimens no longer included in recommendations for treatment of chronic HCV infection.

Usually used in multiple-drug regimens that include one or more HCV direct-acting antivirals (DAAs) with or without peginterferon alfa. Has been used in regimens that include simeprevir (an HCV protease inhibitor), ribavirin, and peginterferon alfa; regimens that include sofosbuvir (an HCV polymerase inhibitor) and ribavirin with or without peginterferon alfa; regimens that include simeprevir (an HCV protease inhibitor), sofosbuvir (an HCV polymerase inhibitor), and ribavirin; regimens that include the fixed combination of ombitasvir (an HCV replication complex inhibitor), paritaprevir (an HCV protease inhibitor), and ritonavir (ombitasvir/paritaprevir/ritonavir) and ribavirin; or regimens that include the fixed combination ombitasvir/paritaprevir/ritonavir with dasabuvir and with ribavirin.

Safety and efficacy of oral ribavirin in conjunction with peginterferon alfa not established for treatment of chronic HCV infection in patients with decompensated liver disease, HBV coinfection, or liver or other organ transplants.

Most appropriate multiple-drug regimen depends on specific HCV genotype and patient population involved.

Treatment of chronic HCV infection is complex and rapidly evolving; consult a specialist to obtain the most up-to-date information. Information from the American Association for the Study of Liver Diseases (AASLD), Infectious Diseases Society of America (IDSA), and International Antiviral Society–USA (IAS–USA) regarding diagnosis and management of HCV infection, including recommendations for initial treatment, is available at [Web].

Acute HCV Infection

Treatment of acute HCV infection [off-label] in an attempt to prevent progression to chronic HCV infection; used in conjunction with peginterferon alfa (alfa-2a, alfa-2b).

Approximately 10–50% of patients with acute HCV infection have self-limited disease and spontaneous clearance of the virus without treatment; optimum regimen (including dosage and duration of therapy) and optimum time to initiate treatment in patients with acute HCV infection not established.

To allow for spontaneous resolution, some experts suggest delaying initiation of treatment of acute HCV infection (especially in asymptomatic individuals) for 8–12 weeks after acute onset of hepatitis, unless HCV RNA levels are high and not declining.

Consult a specialist to obtain the most up-to-date information regarding treatment of acute HCV infection.

Hepatitis E Virus (HEV) Infection

Treatment of chronic HEV infection [off-label]; has been used alone or in conjunction with peginterferon alfa.

Chronic HEV infection reported almost exclusively among immunocompromised individuals, including solid organ transplant recipients, patients receiving cancer chemotherapy, and HIV patients. Optimal treatment of chronic HEV infection not identified.

Respiratory Syncytial Virus (RSV) Infection

Ribavirin nasal and oral inhalation used for treatment of severe lower respiratory tract infections (i.e., bronchiolitis, pneumonia) caused by RSV in hospitalized infants and young children.

Manufacturer states consider use only in infants and small children with severe RSV lower respiratory tract infections; use in mechanically ventilated patients only if clinicians and support staff are familiar with the mode of administration and specific ventilator being used.

AAP states ribavirin nasal and oral inhalation therapy may be considered for selected patients with documented life-threatening RSV infection, but routine use not recommended.

Ribavirin nasal and oral inhalation has been used for treatment of RSV infection in immunocompromised adults [off-label], including bone marrow or hematopoietic cell transplant recipients; manufacturer states not indicated for treatment of RSV infection in adults.

Viral Hemorrhagic Fevers

Treatment of certain viral hemorrhagic fevers [off-label], including Lassa fever, hemorrhagic fever with renal syndrome (HFRS) caused by Hantavirus infection, infections caused by New World arenaviruses, and Crimean-Congo hemorrhagic fever.

Inactive against and not used for treatment of infections caused by Filoviridae (including Ebola hemorrhagic fever and Marburg hemorrhagic fever). Also inactive against and not used for infections by caused most Flaviviridae (including dengue hemorrhagic fever).

Treatment of Lassa fever [off-label]; considered the drug of choice. Previously recommended for postexposure prophylaxis of Lassa fever in high-risk contacts, but CDC recommends the strategy of placing exposed individuals or contacts under medical surveillance for 21 days and treating presumptively with ribavirin if clinical evidence of viral hemorrhagic fever develops.

Treatment of hemorrhagic fever with renal syndrome (HFRS); designated an orphan drug by FDA for this use. When administered IV within 4–7 days after onset of fever, has decreased viremia, renal dysfunction, vascular instability, and mortality of HFRS.

Treatment of Crimean-Congo hemorrhagic fever (CCHF). Although experience limited, CDC states use of ribavirin to treat the disease and prevent infection in high-risk contacts is reasonable based on in vitro susceptibility data for this and other Bunyaviridae.

Treatment of clinically evident viral hemorrhagic fever in the context of biologic warfare or bioterrorism when the disease is caused by Arenavirus (e.g., Lassa fever, New World hemorrhagic fever) or Bunyavirus (e.g., Rift Valley fever) or is of unknown etiology. Preemptive administration of ribavirin or postexposure prophylaxis with ribavirin not recommended following known or presumed exposure to hemorrhagic fever virus in the context of biologic warfare or bioterrorism. Those with known or presumed exposure, including high-risk contacts (i.e., individuals with mucous membrane contact with infected patient) and close contacts (i.e., individuals who live with, shake hands or hug, process laboratory specimens from, or care for infected patients [prior to initiation of appropriate precautions]) should be placed under medical surveillance for 21 days and treated presumptively with ribavirin if fever ≥38.3°C develops.

Information on diagnosis and management of viral hemorrhagic fevers is available from Special Pathogens Branch of CDC at [Web] or at 404-639-1115. Any suspected cases of viral hemorrhagic fever occurring in individuals residing in or requiring evacuation to the US should immediately be reported to local health authorities and the CDC Viral Special Pathogens Branch at 404-639-1115 or CDC Emergency Operations Center at 770-488-7100.

Adenovirus Infections

Has been used for treatment of infections caused by adenovirus in immunocompromised adults and children, including bone marrow or stem cell transplant recipients, solid organ transplant recipients (e.g., liver, kidney), and patients with leukemia or severe combined immunodeficiency.

Safety and efficacy not established; only limited experience to date.

Generally has been used in critically ill patients with severe adenovirus infections (e.g., hemorrhagic cystitis, nephritis, respiratory tract infections, GI infections, disseminated disease) who received multiple treatment modalities. Not all patients respond; unlikely to be of benefit if initiated late in the course of severe infections.

Has been used for preemptive therapy in immunocompromised patients who were asymptomatic but had clinical cultures positive for adenovirus. Possible benefits and risks in such patients not determined; asymptomatic adenovirus infections often resolve spontaneously.

Coronavirus Infections

Has been used alone or in conjunction with systemic corticosteroids for treatment of severe acute respiratory syndrome (SARS) caused by the SARS coronavirus (SARS-CoV). Clinical benefits of various anti-infective regimens used for empiric treatment of SARS, including oral ribavirin, have been disappointing. SARS first reported in Asia during early 2003 and then spread to many areas of the world, including North America, South America, and Europe. Person-to-person transmission of SARS-CoV not currently occurring anywhere in the world, but could recur and future outbreaks are possible.

Has been used in conjunction with an interferon (e.g., peginterferon alfa-2a, interferon alfa-2b) for treatment of Middle East respiratory syndrome (MERS) caused by the Middle East respiratory syndrome coronavirus (MERS-CoV). No specific treatment for MERS has been identified; some evidence that regimen of oral ribavirin and peginterferon alfa-2a may improve 14-day survival rate when used in addition to usual supportive care, but 28-day survival rate not significantly improved. MERS-CoV infections first reported in September 2012 in Saudi Arabia; as of August 28, 2015, 1,474 laboratory-confirmed cases (including 515 deaths) reported worldwide. Most reported cases to date (including 2 in the US and an outbreak in Republic of Korea) directly or indirectly linked through travel or residence to the Middle East. Information regarding evaluation, diagnosis, and management of MERS-CoV infection and guidance for individuals traveling to areas where MERS reported (e.g., the Middle East) is available at CDC website at [Web].

Ribavirin Dosage and Administration

Administration

Administer orally or by nasal and oral inhalation. Also has been administered IV.

Oral Administration

Administer ribavirin capsules, tablets, and oral solution with food.

Do not open, crush, or break capsules.

Oral solution containing 40 mg of ribavirin per mL recommended (instead of capsules) in children ≥3 years of age weighing <47 kg. The oral solution may be used in any patient ≥3 years of age, regardless of weight.

Patients should be well hydrated, especially during initial treatment.

Nasal and Oral Inhalation

Ribavirin sterile powder (Virazole) must be reconstituted and diluted and administered as a solution only via nasal and oral inhalation using the Valeant small-particle aerosol generator (SPAG) Model SPAG-2 available from the manufacturer. Do not administer using any other aerosol generator and do not administer concomitantly with other drug solutions for nebulization.

Consult the SPAG-2 manual for detailed administration instructions.

In patients not requiring mechanical ventilation, ribavirin solution for nebulization should be administered from the SPAG-2 aerosol generator via an oxygen hood. 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; because the volume and condensation area of the solution for nebulization are larger in an oxygen tent, this may alter delivery dynamics of the drug.

When ribavirin inhalation therapy is used in patients who require assisted ventilation, constantly monitor the patient and apparatus (e.g., in an intensive care setting). Use either a pressure or volume cycle ventilator in conjunction with the SPAG-2. For pressure or volume cycle ventilators, heated wire connective tubing and bacterial filters in series in the expiratory limb of the system must be used to minimize the risk of ribavirin precipitation in the system and risk of ventilator dysfunction; the filters should be changed frequently (e.g., every 4 hours). Water column pressure release valves should be used in the ventilator circuit for pressure cycle ventilators and may be used in the ventilator circuit for volume cycle ventilators. The endotracheal tube should be suctioned every 1–2 hours; monitor pulmonary pressure frequently (every 2–4 hours).

Reconstitution and Dilution

Add a minimum of 75 mL of sterile water for injection or inhalation (additive free) to the vial containing 6 g of ribavirin; shake well. Transfer reconstituted solution to the sterile 500-mL reservoir of the SPAG-2 aerosol generator; 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.

Solutions that have been placed into the SPAG-2 reservoir should be discarded at least every 24 hours and prior to the addition of freshly reconstituted solution whenever the amount of solution remaining in the reservoir is low.

Rate of Administration

When 20-mg/mL solution 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.

Administer the 20-mg/mL solution via the SPAG-2 aerosol generator at a rate of about 15 L/minute when using an oxygen hood or tent or about 12 L/minute when using a face mask.

Parenteral Administration

Although not commercially available, parenteral ribavirin is available for compassionate use protocols for treatment of viral hemorrhagic fevers such as Lassa fever, Hantavirus infections, and Congo-Crimean hemorrhagic fever. To obtain IV ribavirin for emergency use, contact FDA at 301-736-3400 for compassionate use authorization and also contact the manufacturer (Valeant Pharmaceuticals) at 800-548-5100.

Dosage

Pediatric Patients

Treatment of Chronic HCV Infection

Must be used in conjunction with other drugs as part of a multiple-drug regimen. May be used in conjunction with peginterferon alfa; although no longer recommended, has been used in conjunction with nonconjugated interferon alfa.

Concomitant Ribavirin Capsules (Rebetol, Ribasphere) or Oral Solution (Rebetol) and Peginterferon Alfa-2b (PegIntron) or Interferon Alfa-2b (Intron A)
Oral

Children 3–17 years of age: 15 mg/kg daily in 2 divided doses in conjunction with sub-Q peginterferon alfa-2b or interferon alfa-2b. (See Table 1.) Use oral solution in those weighing <47 kg. If patient reaches 18th birthday during treatment, complete treatment using pediatric dosage.

Recommended treatment duration is 24 weeks for HCV genotype 2 or 3 and 48 weeks for genotype 1.

With the exception of HCV genotypes 2 and 3, consider discontinuing HCV treatment if HCV RNA levels have not decreased ≥2 log10 from baseline at week 12 or remain detectable after 24 weeks of treatment.

Table 1. Pediatric Dosage of Ribavirin Capsules (Rebetol, Ribasphere) or Oral Solution (Rebetol) for Concomitant Use with Peginterferon Alfa-2b (PegIntron) or Nonconjugated Interferon Alfa-2b (Intron A)349403

Weight

Ribavirin Dosage (Capsules, Oral Solution)

<47 kg

15 mg/kg daily, given as oral solution in 2 divided doses

47–59 kg

400 mg in morning and 400 mg in evening

60–73 kg

400 mg in morning and 600 mg in evening

>73 kg

600 mg in morning and 600 mg in evening

Concomitant Ribavirin Tablets (Copegus) and Peginterferon Alfa-2a (Pegasys)
Oral

Children ≥5 years of age: Approximately 15 mg/kg daily in 2 divided doses in conjunction with sub-Q peginterferon alfa-2a. (See Table 2.) If patient reaches 18th birthday during treatment, complete treatment using pediatric dosage.

Recommended treatment duration is 24 weeks for HCV genotype 2 or 3 and 48 weeks for other HCV genotypes.

Table 2. Pediatric Dosage of Ribavirin Tablets (Copegus) for Concomitant Use with Peginterferon Alfa-2a (Pegasys)377

Weight

Copegus Dosage (Tablets)

23–33 kg

200 mg in morning and 200 mg in evening

34–46 kg

200 mg in morning and 400 mg in evening

47–59 kg

400 mg in morning and 400 mg in evening

60–74 kg

400 mg in morning and 600 mg in evening

>75 kg

600 mg in morning and 600 mg in evening

Dosage Modification for Toxicity
Oral

If serious adverse effects or laboratory changes occur when oral ribavirin used in conjunction with peginterferon alfa or nonconjugated interferon alfa, modify dosage of one or both drugs, if appropriate, until adverse effects abate. If intolerance persists after dosage adjustment, discontinue both drugs.

Concomitant ribavirin capsules or oral solution (Rebetol, Ribasphere) and peginterferon alfa-2b or nonconjugated interferon alfa-2b in children 3–17 years of age: If hemoglobin <10 g/dL, decrease ribavirin dosage from 15 mg/kg daily to 12 mg/kg daily and, if needed, to 8 mg/kg daily. If hemoglobin <8.5 g/dL, leukocyte count <1000/mm3, neutrophil count <500/mm3, or platelet count <50,000/mm3, permanently discontinue both drugs. In pediatric patients with preexisting cardiac conditions, closely monitor with weekly hematology evaluations if hemoglobin decreases by ≥2 g/dL during any 4-week period; discontinue if hemoglobin concentration <8.5 g/dL (or <12 g/dL after 4 weeks of reduced dosage).

Concomitant ribavirin tablets (Copegus) and peginterferon alfa-2a in children ≥5 years of age without cardiac disease: If hemoglobin <10 g/dL, decrease ribavirin dosage to 200 mg daily (200 mg in morning) in those weighing 23–33 kg, 400 mg daily (200 mg in morning and 200 mg in evening) in those weighing 34–59 kg, or 600 mg daily (200 mg in morning and 400 mg in evening) in those weighing ≥60 kg. If hemoglobin <8.5 g/dL, discontinue both drugs.

Concomitant ribavirin tablets (Copegus) and peginterferon alfa-2a in children ≥5 years of age with history of stable cardiac disease: If hemoglobin decreases by ≥2 g/dL during any 4-week period, decrease ribavirin dosage to 200 mg daily (200 mg in morning) in those weighing 23–33 kg, 400 mg daily (200 mg in morning and 200 mg in evening) in those weighing 34–59 kg, or 600 mg daily (200 mg in morning and 400 mg in evening) in those weighing ≥60 kg. If hemoglobin <12 g/dL after 4 weeks of reduced dosage, discontinue both drugs.

Consult manufacturer's information for more specific recommendations regarding dosage modification for hematologic or other adverse effects.

Treatment of Respiratory Syncytial Virus (RSV) Infection
Inhalation

Using a solution containing 20 mg/mL and SPAG-2 aerosol generator with an oxygen hood, face mask, or oxygen tent, deliver mist continuously for 12–18 hours daily for 3–7 days. Manufacturer recommends mist be delivered at a rate of about 15 L/minute when using an oxygen hood or tent or about 12 L/minute when using a face mask. The average aerosol concentration for a 12-hour delivery period is 190 mcg/L.

Dose and administration schedule for infants requiring mechanical ventilation is the same as that for infants not requiring assisted ventilation.

Viral Hemorrhagic Fevers†
Treatment of Viral Hemorrhagic Fevers in Context of Biologic Warfare or Bioterrorism†
Oral

US Army Medical Research Institute of Infectious Diseases (USAMRIID) and US Working Group on Civilian Biodefense recommend initial loading dose of 30 mg/kg, followed by 15 mg/kg daily given in 2 divided doses. Duration of treatment is 10 days.

IV regimen usually preferred. Oral regimen may be used when parenteral preparation cannot be obtained or would be impractical (e.g., when large numbers of individuals require treatment in a mass casualty setting).

IV

USAMRIID and US Working Group on Civilian Biodefense recommend initial loading dose of 30 mg/kg (maximum 2 g), followed by 16 mg/kg (maximum 1 g) every 6 hours for 4 days and then 8 mg/kg (maximum 500 mg) every 8 hours for 6 days.

IV regimen recommended for contained casualty settings if parenteral preparation can be obtained.

Treatment of Adenovirus Infections†
IV†

Severe infections in immunocompromised children: 25 mg/kg daily in 3 divided doses on day 1 followed by 15 mg/kg daily in 3 divided doses on days 2–10 has been used. Alternatively, 15 mg/kg daily for 10 days has been used.

Adults

Treatment of Chronic HCV Infection

Must be used in conjunction with other drugs as part of a multiple-drug regimen. May be used in conjunction with peginterferon alfa; although no longer recommended, has been used in conjunction with nonconjugated interferon alfa.

Usually used in multiple-drug regimens that include one or more HCV DAAs with or without peginterferon alfa. Most appropriate multiple-drug regimen depends on specific HCV genotype and patient population involved.

Concomitant Ribavirin Capsules (Rebetol, Ribasphere) and Peginterferon Alfa-2b (PegIntron)
Oral

800–1400 mg daily (based on body weight) in 2 divided doses in conjunction with sub-Q peginterferon alfa-2b. (See Table 3.) Duration of treatment depends on history of prior treatment, HCV genotype, and treatment response. (See Table 4.)

Table 3. Adult Dosage of Ribavirin Capsules (Rebetol, Ribasphere) for Concomitant Use with Peginterferon Alfa-2b (PegIntron) for Chronic HCV Infection.349403

Weight

Total Daily Dosage of Ribavirin (Capsules)

Recommended Ribavirin Dosage Regimen (Capsules)

≤65 kg

800 mg

400 mg in morning and 400 mg in evening

66–80 kg

1 g

400 mg in morning and 600 mg in evening

81–105 kg

1.2 g

600 mg in morning and 600 mg in evening

>105 kg

1.4 g

600 mg in morning and 800 mg in evening

Table 4. Duration of Treatment with Ribavirin Capsules (Rebetol, Ribasphere) and Peginterferon Alfa-2b (PegIntron) in Adults for Chronic HCV Infection.349403

Patient Type and Response

HCV Genotype

Duration

Considerations

Treatment-naive

1

48 weeks

Consider discontinuing HCV treatment if HCV RNA has not decreased ≥2 log10 by week 12 or remains detectable after 24 weeks of treatment

Treatment-naive

2,3

24 weeks

Prior failure

Any

48 weeks

Consider discontinuing HCV treatment if HCV RNA still detectable at week 12 or remains detectable after 24 weeks of treatment

Concomitant Ribavirin Capsules (Rebetol, Ribasphere) and Interferon Alfa-2b (Intron A)
Oral

Adults weighing ≤75 kg: 1 g daily (400 mg in morning and 600 mg in evening) in conjunction with sub-Q interferon alfa-2b.

Adults weighing >75 kg: 1.2 g daily (600 mg in morning and 600 mg in evening) in conjunction with sub-Q interferon alfa-2b.

Duration of treatment depends on history of prior treatment, HCV genotype, and treatment response. In treatment-naive adults, usual duration is 24–48 weeks; consider discontinuing if HCV RNA levels are not below the limit of detection at 24 weeks. If used in adults who relapsed after prior nonconjugated interferon monotherapy, manufacturers recommend treatment duration of 24 weeks.

Concomitant Ribavirin Tablets (Copegus, generic) and Peginterferon Alfa-2a (Pegasys)
Oral

Adults with HCV monoinfection (without coexisting HIV infection): 800–1200 mg daily in 2 divided doses in conjunction with sub-Q peginterferon alfa-2a. Treatment duration depends on HCV genotype. (See Table 5.)

Table 5. Adult Dosage of Ribavirin Tablets (Copegus, generic) for Concomitant Use with Peginterferon Alfa-2a (Pegasys) for Chronic HCV Monoinfection377402

HCV Genotype

Ribavirin Dosage (Tablets)

Duration

1,4

1 g daily (500 mg twice daily) in those weighing <75 kg

48 weeks

1.2 g daily (600 mg twice daily) in those weighing ≥75 kg

2,3

800 mg daily (400 mg twice daily)

24 weeks

5,6

Data insufficient to make dosage recommendations

Adults with HCV and HIV coinfection: 800 mg daily in 2 divided doses in conjunction with sub-Q peginterferon alfa-2a for 48 weeks, regardless of HCV genotype. Some experts suggest HIV-infected adults with HCV coinfection types 1, 4, 5, or 6 receive weight-based ribavirin dosage: 1 g daily (600 mg in morning and 400 mg in evening) for those weighing <75 kg or 1.2 g daily (600 mg in morning and 600 mg in evening) for those weighing ≥75 kg.

Consider discontinuing HCV treatment if HCV RNA levels have not decreased ≥2 log10 from baseline at week 12 or are still detectable after 24 weeks of treatment.

Manufacturer states safety and efficacy beyond 48 weeks of therapy not established.

Dosage Modification for Toxicity
Oral

If serious adverse effects or laboratory changes occur when oral ribavirin used in conjunction with peginterferon alfa or nonconjugated interferon alfa, modify dosage of one or both drugs, if appropriate, until adverse effects abate. If intolerance persists after dosage adjustment, discontinue both drugs.

Ribavirin capsules (Rebetol, Ribasphere) and peginterferon alfa-2b or interferon alfa-2b in adults: If hemoglobin decreases to <10 g/dL, decrease ribavirin dosage by 200 mg daily (or by 400 mg daily in those originally receiving 1.4 g daily); an additional dosage reduction of 200 mg daily may be used if needed. If hemoglobin <8.5 g/dL, leukocyte count <1000/mm3, neutrophil count <500/mm3, or platelet count <25,000/mm3, permanently discontinue both drugs. In those with history of stable cardiovascular disease, decrease ribavirin dosage by 200 mg daily if hemoglobin decreases by ≥2 g/dL during any 4-week period; discontinue if hemoglobin <8.5 g/dL (or <12 g/dL after 4 weeks of reduced dosage).

Ribavirin tablets (Copegus, generic) and peginterferon alfa-2a in adults: In those without cardiac disease, decrease ribavirin dosage to 600 mg daily (200 mg in morning and 400 mg in evening) if hemoglobin decreases to <10 g/dL; discontinue the drug if hemoglobin decreases to <8.5 g/dL. In those with history of stable cardiac disease, decrease ribavirin dosage to 600 mg daily (200 mg in morning and 400 mg in evening) if hemoglobin decreases by ≥2 g/dL during any 4-week period; discontinue the drug if hemoglobin decreases to <12 g/dL after 4 weeks of reduced dosage. If ribavirin tablets have been withheld and toxicity resolves or decreases in severity, may attempt reinitiation using ribavirin dosage of 600 mg daily; may then increase ribavirin dosage to 800 mg daily if tolerated. Do not resume usual maximum recommended adult dosage of 1–1.2 g daily (see Table 5).

Consult manufacturer's information for more specific recommendations regarding dosage modification for hematologic or other adverse effects.

Viral Hemorrhagic Fevers†
Treatment of Lassa Fever†
IV

CDC and USAMRIID recommend initial loading dose of 30 mg/kg (up to 2 g), followed by 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 total treatment duration of 10 days.

Treatment of Hantavirus Infections†
IV

Hemorrhagic fever with renal syndrome (HFRS): Initial loading dose of 33 mg/kg, followed by 16 mg/kg every 6 hours for 4 days and then 8 mg/kg every 8 hours for 3 days for a total treatment duration of 7 days has been used.

Treatment of Crimean-Congo Hemorrhagic Fever†
Oral

Initial loading dose of 30 mg/kg, followed by 15 mg/kg every 6 hours for 4 days and then 7.5 mg/kg every 8 hours for 6 days has been used.

IV

CDC and USAMRIID recommend initial loading dose of 30 mg/kg (up to 2 g), followed by 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 duration of 10 days.

Treatment of Viral Hemorrhagic Fevers in Context of Biologic Warfare or Bioterrorism†
Oral

USAMRIID and US Working Group on Civilian Biodefense recommend initial loading dose of 2 g, followed by 1.2 daily given in 2 divided doses for those weighing >75 kg or 1 g daily (400 mg in morning and 600 mg in evening) for those weighing ≤75 kg. Duration of treatment is 10 days.

IV regimen usually preferred. Oral regimen may be used when parenteral preparation cannot be obtained or would be impractical (e.g., when large numbers of individuals require treatment in a mass casualty setting).

IV

USAMRIID and US Working Group on Civilian Biodefense recommend initial loading dose of 30 mg/kg (maximum 2 g), followed by 16 mg/kg (maximum 1 g) every 6 hours for 4 days and then 8 mg/kg (maximum 500 mg) every 8 hours for 6 days.

IV regimen recommended for contained casualty settings if parenteral preparation can be obtained.

Treatment of Adenovirus Infections†
IV†

Severe infections in immunocompromised adults: Initial 33-mg/kg loading dose followed by 16 mg/kg every 6 hours for 4 days and then 8 mg/kg every 8 hours for another 3 days or longer until relevant cultures are negative for adenovirus.

Special Populations

Hepatic Impairment

Effect of hepatic impairment on pharmacokinetics of oral ribavirin not fully evaluated; peak concentrations are increased depending on severity of hepatic impairment. (See Pharmacokinetics.)

Renal Impairment

Ribavirin tablets (Copegus): Reduce dosage in adults with Clcr ≤50 mL/minute. For treatment of chronic HCV infection, use alternating doses of 200 mg and 400 mg every other day in adults with Clcr 30–50 mL/minute and use 200 mg daily in adults with Clcr <30 mL/minute or undergoing hemodialysis. Do not reduce dosage any further; if severe adverse effects or laboratory abnormalities occur, discontinue drug. Data insufficient to make dosage recommendations for pediatric patients with renal impairment.

Ribavirin capsules (Rebetol, Ribasphere), tablets (generic), oral solution (Rebetol) and peginterferon alfa-2b or interferon alfa-2b therapy: Contraindicated in adults with Clcr <50 mL/minute.

Pediatric patients with renal impairment: Discontinue ribavirin capsules or oral solution (Rebetol) and peginterferon alfa-2b or interferon alfa-2b if Scr concentrations >2 mg/dL.

Geriatric Patients

Cautious dosage selection because of age-related decreases in renal, hepatic, and/or cardiac function. Initiate therapy at the lower end of the dosing range. (See Geriatric Precautions under Cautions.)

Cautions for Ribavirin

Contraindications

Warnings/Precautions

Warnings

Precautions Related to Combination HCV Treatment Regimens

Do not use oral ribavirin alone for treatment of chronic HCV infection.

When used in conjunction with peginterferon alfa or interferon alfa, consider cautions, precautions, and contraindications associated with both oral ribavirin and peginterferon alfa or interferon alfa.

Ribavirin in conjunction with peginterferon alfa or interferon alfa is associated with substantial adverse effects including severe depression and suicidal ideation, hemolytic anemia, bone marrow suppression, autoimmune and infectious disorders, pulmonary dysfunction, pancreatitis, and diabetes. Review prescribing information and medication guide prior to initiation of therapy.

When used in multiple-drug regimen that includes one or more HCV DAAs, such as an HCV protease inhibitor (e.g., paritaprevir, simeprevir), an HCV polymerase inhibitor (e.g., dasabuvir, sofosbuvir), or an HCV replication complex inhibitor (e.g., ombitasvir), consider cautions, precautions, and contraindications associated with the HCV DAAs.

Respiratory Effects

Use of aerosolized ribavirin for treatment of RSV in infants has resulted in sudden deterioration of respiratory function. Monitor respiratory function carefully. If sudden deterioration of respiratory function occurs, discontinue therapy. Reinstitute with extreme caution and continuous monitoring; consider concomitant administration of a bronchodilator.

Optimum monitoring and attention to respiratory and fluid status needed in patients with severe lower respiratory tract infection due to RSV.

Use of oral ribavirin has been associated with adverse pulmonary effects, including dyspnea, pulmonary infiltrates, pulmonary hypertension, pneumonitis, and pneumonia (sometimes fatal). Sarcoidosis or exacerbation of sarcoidosis reported rarely with oral ribavirin.

Closely monitor patients who experience pulmonary infiltrates or deterioration in pulmonary function; if appropriate, discontinue ribavirin.

Mechanically Ventilated Patients

Administer aerosolized ribavirin under the supervision of and by qualified clinicians and support staff experienced with the specific ventilator and mode of administration. (See Nasal and Oral Inhalation under Dosage and Administration.)

Fetal/Neonatal Morbidity and Mortality

Teratogenic and/or embryocidal. Exercise extreme care to avoid pregnancy in female patients and in female partners of male patients. Women of childbearing potential and men must use 2 forms of effective contraception during therapy and for 6 months following completion of therapy.

Do not initiate therapy until a report of a negative pregnancy test has been obtained; the pregnancy test should be performed immediately prior to initiating therapy. Perform pregnancy testing monthly during therapy and for 6 months after therapy is completed.

If pregnancy occurs in a patient or in the partner of a patient during oral ribavirin therapy or during the 6 months following completion of therapy, report such cases to the pregnancy registry at 800-593-2214.

Hematologic Effects

Hemolytic anemia reported in patients receiving oral ribavirin in conjunction with interferon alfa; anemia usually occurs 1–2 weeks after initiation of therapy. Use with caution in patients with baseline risk of severe anemia (e.g., spherocytosis, history of GI bleeding).

Monitor hemoglobin or hematocrit before initiating therapy, at week 2 and 4 (or more frequently if needed), and during therapy as appropriate. Dosage modification may be necessary. (See Treatment of Chronic HCV Infection under Dosage and Administration.)

Cardiovascular Effects

Fatal and nonfatal MI reported in patients with anemia due to oral ribavirin.

Assess patient for cardiac disease before initiating therapy and monitor during therapy. Obtain an electrocardiogram in patients with known cardiac disease.

Temporarily interrupt or discontinue therapy if cardiovascular status deteriorates. Dosage modification may be necessary. (See Treatment of Chronic HCV Infection under Dosage and Administration.)

Not recommended in those with substantial or unstable cardiac disease.

Hepatic Failure

Patients with chronic HCV infection and cirrhosis may be at risk of hepatic decompensation and death during interferon alfa (including peginterferon alfa) therapy. Such patients who are coinfected with HIV and receiving highly active antiretroviral therapy (HAART) in conjunction with interferon alfa-2a therapy (with or without ribavirin) appear to be at increased risk for development of hepatic decompensation compared with patients not receiving HAART.

Closely monitor clinical status and hepatic function. Decrease dosage or immediately discontinue peginterferon alfa if decompensation (Child-Pugh score ≥6) occurs.

Sensitivity Reactions

Serious skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme, reported in patients receiving peginterferon with or without oral ribavirin.

If acute hypersensitivity reactions (urticaria, angioedema, bronchoconstriction, anaphylaxis) occur, discontinue immediately and initiate appropriate medical intervention.

General Precautions

Other Viral Infections

Safety and efficacy of oral ribavirin for treatment of HIV infection, adenovirus infection, RSV infection, parainfluenzae virus infection, or influenza virus infection not established; do not use oral ribavirin to treat these viral infections.

Pancreatitis

Temporarily interrupt oral ribavirin in patients with manifestations of pancreatitis; discontinue in patients with confirmed pancreatitis.

Dental and Periodontal Disorders

Dental and periodontal disorders reported in patients receiving oral ribavirin in conjunction with peginterferon alfa or interferon alfa; dry mouth may contribute to damage of teeth and oral mucous membranes during long-term treatment.

Advise patients to have regular dental examinations during treatment, brush their teeth thoroughly twice daily, and rinse their mouth thoroughly after vomiting.

Environmental Exposure of Health-care Personnel and Visitors

The potential risks, particularly for long-term and cumulative effects, associated with environmental exposure to aerosolized ribavirin by health-care personnel and visitors while in contact with patients undergoing inhalation therapy with the drug have not been elucidated; acute effects do not appear to be substantial. Exposure of pregnant women and possibly those who may become pregnant may represent a risk to the fetus. Consult specialized sources (e.g., National Institute for Occupational Safety and Health [NIOSH]) for recommended procedures to minimize environmental exposure.

Specific Populations

Pregnancy

Category X. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Pregnancy Registry at 800-593-2214 to monitor pregnancy outcomes of female patients and female partners of male patients exposed to ribavirin.

Lactation

Not known whether ribavirin is distributed into human milk. Discontinue nursing or delay or discontinue the drug.

Pediatric Use

Nasal and oral inhalation: Safety and efficacy established for treatment of RSV infection in infants and young children.

Ribavirin oral capsules (Rebetol, Ribasphere) and oral solution (Rebetol): Safety and efficacy in conjunction with peginterferon alfa-2b or nonconjugated interferon alfa-2b for treatment of chronic HCV infection not established in children <3 years of age. When deciding whether to use such regimens in HCV-infected children, consider evidence of disease progression (hepatic inflammation, fibrosis), prognostic factors for response, HCV genotype, and viral load. Weigh benefits against adverse effects reported in pediatric patients. Do not use concomitant ribavirin capsules or oral solution (Rebetol) and peginterferon alfa-2b or nonconjugated interferon alfa-2b in pediatric patients with Scr >2 mg/dL.

Ribavirin tablets (Copegus): Safety and efficacy in conjunction with peginterferon alfa-2b for treatment of chronic HCV infection not established in children <5 years of age.

Ribavirin tablets (generic): Safety and efficacy not established in patients <18 years of age.

Adverse effects reported with oral ribavirin in pediatric patients generally similar to those reported in adults. Suicidal ideation or attempts reported more frequently during or after oral ribavirin in pediatric patients (primarily adolescents) than in adults receiving the drug. Other adverse psychiatric effects (depression, emotional lability, somnolence), anemia, and neutropenia reported as in adults.

Decreased weight and height for age z-scores as well as percentiles of the normative population reported in pediatric patients receiving peginterferon alfa and oral ribavirin therapy. Data from an open-label trial in pediatric patients 3 through 17 years of age receiving peginterferon alfa-2b and oral ribavirin indicate that weight and height gain generally lagged behind that predicted by normative population data for entire length of treatment (48 weeks). Although general reversal of these trends noted during the 24-week posttreatment period, long-term follow-up data in pediatric patients indicate that growth inhibition induced by the regimen results in reduced final adult height in some patients.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults. Higher incidence of anemia reported in geriatric patients compared with younger adults.

Caution advised; start at the lower end of the dosing range due to greater frequency of decreased renal, hepatic, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly.

Substantially eliminated by kidneys; risk of adverse effects increased in patients with renal impairment. Monitor renal function and consider age-related decreases in renal function when selecting dosage. (See Renal Impairment under Dosage.)

Hepatic Impairment

Do not use in patients with autoimmune hepatitis or hepatic decompensation. (See Contraindications under Cautions.)

Monitor liver function before and during therapy.

Renal Impairment

Capsules (Rebetol, Ribasphere), tablets (generic), oral solution (Rebetol) : Contraindicated in patients with Clcr <50 mL/minute.

Tablets (Copegus): Use reduced dosage in adults with Clcr <50 mL/minute. (See Renal Impairment under Dosage.)

Common Adverse Effects

Oral: Fatigue/asthenia, headache, fever, rigors, nausea, myalgia, emotional lability/irritability.

Nasal and oral inhalation: Respiratory and cardiovascular effects.

Drug Interactions

Does not inhibit and is not a substrate for CYP450 isoenzymes. Interactions with drugs affecting or metabolized by CYP enzymes unlikely.

Specific Drugs

Drug

Interaction

Comments

Antacids containing magnesium, aluminum, and simethicone (Mylanta)

Decreased ribavirin concentrations

Clinical importance unknown

Antiretrovirals, HIV nucleoside reverse transcriptase inhibitors (NRTIs)

Possible increased risk of potentially fatal hepatic decompensation in cirrhotic patients with chronic HCV coinfected with HIV who are receiving peginterferon alfa (with or without ribavirin) and antiretroviral regimens that include NRTIs

Didanosine: Fatal hepatic failure, peripheral neuropathy, pancreatitis, symptomatic hyperlactatemia/lactic acidosis reported

Zidovudine: Possible increased risk of severe neutropenia (ANC <500/mm3) and severe anemia (hemoglobin <8 g/dL) if used concomitantly with peginterferon alfa and ribavirin

Ribavirin can reduce phosphorylation of lamivudine, stavudine, and zidovudine; no evidence of pharmacokinetic or pharmacodynamic interaction when ribavirin used concomitantly with these drugs in patients coinfected with HCV and HIV

Stavudine and zidovudine: In vitro evidence of antagonistic antiretroviral effects; possibility of increased risk of adverse effects

If used in patients coinfected with HIV who are receiving NRTIs, closely monitor for toxicities; if worsening toxicities are observed, consider discontinuing or reducing dosage of peginterferon and/or ribavirin; if decompensation occurs (Child-Pugh score ≥6), discontinue

Didanosine: Concomitant use contraindicated

Stavudine: Use concomitantly with caution

Zidovudine: Concomitant use not recommended; use concomitantly with caution and increased monitoring

Azathioprine

Severe pancytopenia and bone marrow suppression reported in patients receiving peginterferon alfa and oral ribavirin; may be due to interaction with ribavirin which may increase accumulation of azathioprine metabolite associated with myelotoxicity

If used concomitantly with oral ribavirin and peginterferon alfa, perform CBCs (including platelet counts) weekly for first month, twice monthly during second and third months, and then monthly or more frequently if necessary

If pancytopenia develops, discontinue all 3 drugs (azathioprine, ribavirin, peginterferon alfa) and do not reinitiate peginterferon alfa and ribavirin concomitantly with azathioprine

Daclatasvir

Clinically important interactions not expected

Interferons (interferon alfa, peginterferon alfa)

Hepatic decompensation, including some fatalities, reported in cirrhotic HCV patients coinfected with HIV receiving ribavirin, peginterferon alfa, and NRTIs

Ribavirin may potentiate hematologic effects of interferons (anemia, neutropenia, lymphocytopenia); no evidence of pharmacokinetic interaction

Ombitasvir, paritaprevir, dasabuvir fixed combination

Ombitasvir/paritaprevir/ritonavir: No in vitro evidence of antagonistic anti-HCV effects

Simeprevir

No effect on simeprevir concentrations or AUC when used with ribavirin and peginterferon alfa

In vitro evidence of additive effects against HCV; no in vitro evidence of antagonistic anti-HCV effects

Sofosbuvir

No in vitro evidence of antagonistic anti-HCV effects

Ribavirin Pharmacokinetics

Absorption

Bioavailability

Absorbed rapidly from GI tract; peak plasma concentrations achieved within 1–3 hours. Bioavailability is 64%.

Following nasal and oral inhalation, absorbed systemically from the respiratory tract. Concentrations achieved in respiratory tract secretions are likely to be substantially greater than those achieved in plasma.

Food

Administration with a high-fat meal increases oral bioavailability.

Special Populations

Mean peak plasma concentrations increased with severity of hepatic impairment; mean AUCs in individuals with mild, moderate, or severe hepatic impairment similar to AUCs in controls.

Following a single oral dose of ribavirin, AUC increased twofold or threefold in non-HCV-infected individuals with Clcr 30–60 or 10–30 mL/minute, respectively.

In HCV-infected individuals with end-stage renal disease requiring hemodialysis, ribavirin 200 mg daily (Copegus tablets) produced plasma exposures about 20% lower than exposures achieved with 1–1.2 g daily in individuals with normal renal function.

Distribution

Extent

Ribavirin and/or its metabolites accumulate in erythrocytes.

Distributes slowly into CSF. CSF concentrations approximately 70% of concurrent plasma concentrations reported in HIV-infected patients.

Not known whether ribavirin crosses the placenta or distributes into milk in humans.

Plasma Protein Binding

Not bound.

Elimination

Metabolism

Undergoes reversible phosphorylation in nucleated cells and deribosylation and amide hydrolysis.

Elimination Route

Following oral administration, eliminated in urine (61%) and feces (12%) as metabolites and unchanged drug (17%).

Half-life

Rebetol capsules: 43.6 hours (single dose) and 298 hours (multiple doses).

Copegus tablets: 120–170 hours (single dose).

Special Populations

Clearance reduced in patients with renal impairment.

Stability

Storage

Nasal and Oral Inhalation

For Inhalation Solution

25°C (may be exposed to 15–30°C). Following reconstitution, store solution under sterile conditions at 20–30°C for up to 24 hours.

After placement in SPAG-2 reservoir, discard unused solution within 24 hours and prior to adding any newly reconstituted solution (e.g., when remaining amount of solution in reservoir is low).

Oral

Capsules

25°C (may be exposed to 15–30°C).

Oral solution

2–8°C or 25°C (may be exposed to 15–30°C).

Tablets

25°C (may be exposed to 15–30°C).

Actions and Spectrum

Advice to Patients

Preparations

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.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Ribavirin

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Nasal and Oral Inhalation

For inhalation solution

6 g

Virazole

Valeant

Oral

Capsules

200 mg*

Rebetol

Merck

Ribasphere

Kadmon

Ribavirin Capsules

Solution

40 mg/mL

Rebetol

Merck

Tablets, film-coated

200 mg*

Copegus

Genentech

Ribavirin Tablets

400 mg*

Ribavirin Tablets

500 mg*

Ribavirin Tablets

600 mg*

Ribavirin Tablets

AHFS DI Essentials™. © Copyright 2024, Selected Revisions October 26, 2015. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Off-label: Use is not currently included in the labeling approved by the US Food and Drug Administration.

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