Ribavirin

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
Brands: Copegus, Rebetol, Ribasphere, Virazole

• 
  

  Ribavirin monotherapy is not effective for treatment of chronic hepatitis C virus (HCV) infection and should not be used alone for this indication.^{349 377 a b c}

  
  


• 
  

  The principal toxicity of oral ribavirin is hemolytic anemia which may result in worsening of cardiac disease and has resulted in fatal and nonfatal MI.^{349 377 a b c} Patients with a history of substantial or unstable cardiac disease should not be given ribavirin.^{349 377 a b c}

  
  


• 
  

  Teratogenic and/or embryocidal effects demonstrated.^{349 377 a b c} Ribavirin has a long half-life and may persist in nonplasma compartments for as long as 6 months.^{349 377 a b c} Contraindicated in pregnant women and in male partners of women who are pregnant.^{349 377 a b c} Extreme care must be taken to avoid pregnancy during and for 6 months following ribavirin therapy in female patients and in female partners of male patients receiving ribavirin.^{349 377 a b c} At least 2 reliable forms of contraception must be used during and for 6 months following completion of treatment.^{349 377 a b c}

  
  


• 
  

  Initiation of aerosolized ribavirin (given by nasal or oral inhalation) in infants has resulted in sudden deterioration of respiratory function.¹ Monitor respiratory function carefully.¹ If sudden deterioration of respiratory function occurs, discontinue therapy.¹ Reinstitute with extreme caution and continuous monitoring; consider concomitant administration of a bronchodilator.¹

  
  


• 
  

  Ribavirin for nasal or oral inhalation is not indicated in adults.¹

  
  


• 
  

  Administer aerosolized ribavirin under the supervision of and by qualified clinicians and support staff experienced with the specific ventilator and mode of administration.¹ Attention must be directed to procedures that minimize accumulation of drug precipitate, which can result in mechanical ventilator dysfunction and associated increased pulmonary pressure.¹

  
  

REMS:

FDA approved a REMS for ribavirin to ensure that the benefits of a drug outweigh the risks. However, FDA later rescinded REMS requirements. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Antiviral agent; nucleoside derivative.^{1 4 6 7 9 11 22 166}

Uses for Ribavirin

Chronic Hepatitis C Virus (HCV) Infection

Treatment of chronic HCV infection in patients with compensated liver disease.^{342 349 362 363 364 377 401 a b c} Used in conjunction with peginterferon alfa (peginterferon alfa-2a or peginterferon alfa-2b)^{342 349 362 363 364 377 401 a b c} or, less frequently, with unconjugated interferon alfa-2b.^{323 324 325 326 328 338 339 340 349 362 363 b}

Should not be used alone for treatment of chronic HCV infection.^{349 363 364 377 a b}

Peginterferon alfa in conjunction with oral ribavirin is considered the regimen of choice for treatment of chronic HCV infection in treatment-naive patients (have not previously received interferon alfa therapy) and for previously treated patients who fail to achieve a sustained virologic response following treatment with nonconjugated interferon alfa alone or in conjunction with oral ribavirin.^{349 363 364 401}

Safety and efficacy of peginterferon alfa in conjunction with oral ribavirin not established for treatment of chronic HCV infection in patients with decompensated liver disease, patients coinfected with hepatitis B virus (HBV), or in liver or other organ transplant recipients.^{349 377 a b c}

Peginterferon alfa-2a (Pegasys) alone or in conjunction with oral ribavirin (Copegus) has been effective for treatment of chronic HCV infection in certain adults coinfected with HIV (i.e., those with stable HIV infection receiving stable antiretroviral therapy or antiretroviral therapy not required).^{377 387}

Safety and efficacy of peginterferon alfa-2a (Pegasys) in conjunction with oral ribavirin not established for treatment of chronic HCV infection in patients coinfected with HIV who have CD4⁺ T-cell counts <100/mm³.^{377 387 a c} Safety and efficacy of peginterferon alfa-2b (PEG-Intron) used in conjunction with oral ribavirin not established in those with HCV and HIV coinfection.^{349 b}

Treatment of chronic HCV infection is complex and rapidly evolving; a specialist should be consulted to obtain the most up-to-date information regarding patient selection criteria and preferred regimens.³⁶³

Respiratory Syncytial Virus (RSV) Infection

Treatment of severe lower respiratory tract infections (i.e., bronchiolitis, pneumonia) caused by RSV in hospitalized infants and young children.^{1 3 4 41 75 76 89 90 91 100 101 195 196 197 202 277 295 320}

Not indicated for treatment of RSV infection in adults.¹

Viral Hemorrhagic Fevers

Treatment of viral hemorrhagic fevers†, including Lassa fever, Hantavirus infections, infections caused by New World arenaviruses, and Crimean-Congo hemorrhagic fever.^{184 337 343 344 351 389 392}

Only antiviral identified to date that exhibits potential efficacy for management of viral hemorrhagic fevers; however, ribavirin provides benefit only in some (not all) of these infections.^{343 344 351} Has some activity against Arenaviridae and Bunyaviridae, but is inactive against Filoviridae and most Flaviviridae.^{343 344 351}

Considered the drug of choice for treatment of Lassa fever†.^{59 102 104 122 123 184 191 257 258 343 351} Previously recommended for postexposure prophylaxis of Lassa fever in high-risk contacts,¹⁹¹ but CDC no longer recommends such prophylaxis.³⁹⁷ Instead, exposed individuals or contacts should be placed under medical surveillance for 21 days and treated presumptively with ribavirin if clinical evidence of viral hemorrhagic fever develops.³⁹⁷

Treatment of hemorrhagic fever with renal syndrome† (HFRS)^{184 270 271 272 276} (designated an orphan drug by FDA for this use).²⁷³

Treatment of Crimean-Congo hemorrhagic fever† (CCHF).^{184 347 389 392} 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.¹⁹¹

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.^{343 351 357} 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.³⁵¹ 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.³⁵¹

Information on diagnosis and management of viral hemorrhagic fevers is available from Special Pathogens Branch of CDC at or at 404-639-1115 or 404-639-2888.^{337 397} Clinicians should immediately notify CDC's Special Pathogens Branch of any suspected cases of viral hemorrhagic fever occurring in individuals residing in or requiring evacuation to the US.³³⁷ In addition, state health departments should notify Division of Global Migration and Quarantine (DGMQ) at CDC regarding possible travel-related exposures to ensure that prompt risk assessments, notifications, and appropriate containment measures are implemented for exposed travelers.³⁹⁷

Adenovirus Infections

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.^{393 394 395 396}

Safety and efficacy not established;^{349 377} only limited experience to date.^{393 394 395 396}

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.^{393 395 396} Not all patients respond;^{393 394 396} unlikely to be of benefit if initiated late in the course of severe infections.³⁹³

Has been used for preemptive therapy in immunocompromised patients who were asymptomatic but had clinical cultures positive for adenovirus.³⁹⁵ Possible benefits and risks in such patients not determined; asymptomatic adenovirus infections often resolve spontaneously.³⁹⁵

Severe Acute Respiratory Syndrome (SARS)

Has been used empirically in some adults and a limited number of children with severe acute respiratory syndrome† (SARS), alone or in conjunction with systemic corticosteroids; ^{367 368 369 370 371 373 380 381 382} clinical benefit of the various anti-infective regimens employed to date, including ribavirin, have been disappointing.^{368 369 373}

Ribavirin Dosage and Administration

Administration

Administer orally^{349 377 a b c} or by nasal and oral inhalation.^{1 162} Also has been administered IV†.^{184 270 271 272 276 389 393 394 395 396 397}

Oral Administration

Capsules: May be taken without regard to food, but should be taken in a consistent manner.^{349 b} Manufacturers recommend capsules be taken with food.^{349 b} Do not open, crush, or break capsules.^b

Oral solution: May be taken without regard to food, but should be taken in a consistent manner.³⁴⁹

Tablets: Should be taken with food since pivotal clinical trials involved administration with food.^{377 a c}

Patients should be well hydrated, especially during initial treatment.^{349 377 a b c}

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†.³³⁷ To obtain IV ribavirin for emergency use, contact FDA for compassionate use authorization and also contact the manufacturer (Valeant Pharmaceuticals) at 800-548-5100.³³⁷

Nasal and Oral Inhalation

Administer via nasal and oral inhalation using the Valeant small-particle aerosol generator (SPAG) Model SPAG-2 available from the manufacturer.^{1 162} Ribavirin inhalation should not be administered using any other aerosol generator and should not be administered concomitantly with other drug solutions for nebulization.¹

Consult the SPAG-2 manual for detailed administration instructions.^{1 137 162}

When ribavirin inhalation therapy is used in patients who require assisted ventilation, constantly monitor (e.g., in an intensive care setting) the patient and the apparatus.^{182 183 195} Use either a pressure or volume cycle ventilator in conjunction with the SPAG-2.¹ 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).¹ 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.¹ The endotracheal tube should be suctioned every 1–2 hours; monitor pulmonary pressure frequently (every 2–4 hours).¹

Ribavirin solution for nebulization should be administered from the SPAG-2 aerosol generator via an oxygen hood.^{1 162} 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;^{1 162} the volume of distribution and condensation area of the solution for nebulization are larger in an oxygen tent, and this may alter delivery dynamics of the drug.¹

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.^{1 4 158 162} Transfer to the sterile 500-mL reservoir for 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.^{1 4 162}

Solutions that have been placed within the SPAG-2 reservoir should be discarded at least every 24 hours and prior to the addition of freshly reconstituted solution when the amount of solution remaining in the reservoir is low.^{1 4 162}

Dosage

Pediatric Patients

Treatment of Chronic Hepatitis C Virus (HCV) Infection

Concomitant Therapy with Ribavirin and Interferon Alfa-2b (Rebetol and Intron A)

Oral

Capsules or oral solution: 15 mg/kg daily in 2 divided doses in conjunction with sub-Q interferon alfa.³⁴⁹ Use oral solution in those weighing ≤25 kg and in those who cannot swallow capsules.³⁴⁹

HCV genotype 1: Recommended duration is 48 weeks.³⁴⁹ Assess virologic response after 24 weeks of treatment;³⁴⁹ consider discontinuing if HCV RNA is not below the limits of detection.³⁴⁹

HCV genotype 2,3: Recommended duration is 24 weeks.³⁴⁹

Safety and efficacy of >48 weeks of treatment not established in pediatric patients.³⁴⁹

Pediatric Dosage of Rebetol and Intron A for Concomitant Therapy349

Weight (kg)	Rebetol Dosage (Capsules)	Intron A Dosage
25–36	200 mg in morning and 200 mg in evening	3 million units/m2 sub-Q 3 times weekly
37–49	200 mg in morning and 400 mg in evening	3 million units/m2 sub-Q 3 times weekly
50–61	400 mg in morning and 400 mg in evening	3 million units/m2 sub-Q 3 times weekly
>61	400 mg in morning and 600 mg in evening in those weighing <75 kg or 600 mg in morning and 600 mg in evening in those weighing ≥75 kg	Use usual adult dosage

Dosage modification may be necessary if adverse hematologic effects occur.³⁴⁹ (See Special Populations under Dosage and Administration.)

Treatment of Respiratory Syncytial Virus (RSV) Infection

Inhalation

Using a SPAG-2 aerosol generator and an oxygen hood, face mask, or oxygen tent, deliver mist containing 190 mcg/L at a rate of about 12.5 L of mist per minute continuously for 12–18 hours daily for 3–7 days.^{1 41 75 76 91 162}

In infants requiring mechanical ventilation, dose and administration schedule is the same as that for infants who do not require assisted ventilation.¹

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.^{343 351} Duration of treatment is 10 days.^{343 351}

IV regimen usually preferred.^{343 351} 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).^{343 351}

IV†

US Working Group on Civilian Biodefense recommends initial loading dose of 30 mg/kg (maximum 2 g), followed by 15 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.³⁵¹

IV regimen recommended for contained casualty settings if parenteral preparation can be obtained.³⁵¹

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.³⁹³ Alternatively, 15 mg/kg daily for 10 days has been used.³⁹⁶

Adults

Treatment of Chronic Hepatitis C Virus (HCV) Infection

Concomitant Therapy with Ribavirin Tablets and Peginterferon Alfa-2a (Pegasys)

Oral

Adults with HCV and HIV coinfection: 800 mg daily in 2 divided doses (regardless of HCV genotype) in conjunction with sub-Q peginterferon alfa-2a (180 mcg once weekly) for 48 weeks.^{377 387}

Adults with HCV monoinfection (without coexisting HIV infection): 800 mg–1.2 g daily in 2 divided doses (depending on HCV genotype) in conjunction with sub-Q peginterferon alfa-2a (180 mcg once weekly).^{377 a c} (See Table.)

Adult Dosage of Ribavirin Tablets and Pegasys for Patients with HCV Monoinfection377387ac

HCV Genotype	Ribavirin Tablets Dosage	Pegasys Dosage	Duration
1,4	500 mg twice daily in those weighing <75 kg or 600 mg twice daily in those weighing ≥75 kg	180 mcg sub-Q once weekly	48 weeks
2,3	400 mg twice daily	180 mcg sub-Q once weekly	24 weeks
5,6	Data insufficient to make dosage recommendations	Data insufficient to make dosage recommendations

Dosage modification may be necessary if adverse hematologic effects occur.^{377 a c} (See Special Populations under Dosage and Administration.)

Concomitant Therapy with Ribavirin Capsules and Peginterferon Alfa-2b (PEG-Intron)

Oral

800 mg daily (400 mg twice daily) in conjunction with sub-Q PEG-Intron.^{349 b} Continue regimen for 24–48 weeks in treatment-naive patients, depending on baseline disease characteristics, virologic response, and/or tolerability.^{349 b}

Dosage modification may be necessary if adverse hematologic effects occur.³⁴⁹ (See Special Populations under Dosage and Administration.)

Concomitant Therapy with Ribavirin Capsules and Interferon Alfa-2b (Intron A)

Oral

Adults weighing ≤75 kg: 1 g daily (400 mg every morning and 600 mg every evening) in conjunction with sub-Q Intron A.^{349 b}

Adults weighing >75 kg: 1.2 g daily (600 mg twice daily) in conjunction with sub-Q Intron A.^{349 b}

Continue regimen for 24–48 weeks in treatment-naive patients, depending on baseline disease characteristics, virologic response, and/or tolerability.^{349 b}

Dosage modification may be necessary if adverse hematologic effects occur.^{349 b} (See Special Populations under Dosage and Administration.)

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.^{191 343}

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.^{270 271 276}

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.³⁹²

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.^{191 343}

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 the morning and 600 mg in the evening) for those weighing ≤75 kg.^{343 351} Duration of treatment is 10 days.^{343 351}

IV regimen usually preferred.^{343 351} 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).^{343 351}

IV†

USAMRIID and US Working Group on Civilian Biodefense recommend initial loading dose of 30 mg/kg (maximum 2 g), followed by 15 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.^{343 351}

IV regimen recommended for contained casualty settings if parenteral preparation can be obtained.^{343 351}

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.^{394 396}

Special Populations

Geriatric Patients

Cautious dosage selection because of age-related decreases in renal, hepatic, and/or cardiac function.^{349 b} Initiate therapy at the lower end of the dosing range.^{349 b} (See Geriatric Precautions under Cautions.)

Patients Who Develop Hematologic Effects during Therapy

Treatment of Chronic Hepatitis C Virus (HCV) Infection

In pediatric patients with no cardiovascular disease, decrease Rebetol dosage to 7.5 mg/kg daily in 2 divided doses if hemoglobin concentration decreases to <10 g/dL; permanently discontinue the drug if concentration decreases to <8.5 g/dL.³⁴⁹ In those with history of cardiovascular disease, decrease Rebetol dosage to 7.5 mg/kg daily in 2 divided doses if hemoglobin decreases by ≥2 g/dL during any 4-week period; permanently discontinue the drug if hemoglobin is <12 g/dL after 4 weeks of a reduced ribavirin dosage.³⁴⁹

In adults with no cardiovascular disease, decrease dosage of ribavirin capsules or tablets to 600 mg daily (200 mg in morning and 400 mg in evening) if hemoglobin concentration decreases to <10 g/dL; permanently discontinue the drug if concentration decreases to <8.5 g/dL.^{349 377 a b c} In those with history of stable cardiovascular disease, decrease dosage of ribavirin capsules or tablets 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; permanently discontinue the drug if hemoglobin is <12 g/dL after 4 weeks of a reduced ribavirin dosage.^{349 377 a b c}

Cautions for Ribavirin

Contraindications

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  Hypersensitivity to ribavirin or any ingredient in the formulation.^{1 349 377 a b c}

  
  


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  Known or suspected pregnancy.^{1 349 377 a b c}

  
  


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  Male partners of pregnant women.^{349 377 a b c}

  
  


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  Patients with hemoglobinopathies (e.g., thalassemia major, sickle-cell anemia).^{349 377 a b c}

  
  


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  Use of concomitant oral ribavirin and peginterferon alfa in patients with autoimmune hepatitis.^{349 377 a b c}

  
  


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  Use of concomitant oral ribavirin and peginterferon alfa-2a (Pegasys) in cirrhotic patients with chronic HCV monoinfection (without coexisting HIV infection) who have hepatic decompensation (Child-Pugh score >6; class B and C) prior to or during treatment.^{377 387 a c}

  
  


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  Use of concomitant oral ribavirin (Copegus) and peginterferon alfa-2a (Pegasys) in cirrhotic patients with chronic HCV infection who are coinfected with HIV and have hepatic decompensation (Child-Pugh score ≥6) prior to or during treatment.^{377 387}

  
  

Warnings/Precautions

Warnings

Concomitant Peginterferon Alfa or Interferon Alfa

Ribavirin must be used in conjunction with peginterferon alfa or interferon alfa for the treatment of chronic HCV infection.^{349 377 a b c}

The usual cautions, precautions, and contraindications associated with peginterferon alfa or interferon alfa should be observed during concomitant therapy.^{349 377 a b c}

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.^{349 377 a b c} Review drug labeling and medication guide prior to initiation of therapy for safety information.^{349 377 a b c}

Respiratory Effects

Use of aerosolized ribavirin for treatment of RSV in infants has resulted in sudden deterioration of respiratory function.¹ Monitor respiratory function carefully.¹ If sudden deterioration of respiratory function occurs, discontinue therapy.¹ Reinstitute with extreme caution and continuous monitoring; consider concomitant administration of a bronchodilator.¹

Optimum monitoring and attention to respiratory and fluid status needed in patients with severe lower respiratory tract infection due to RSV.¹

Use of oral ribavirin has been associated with adverse pulmonary effects, including dyspnea, pulmonary infiltrates, pneumonitis, and pneumonia (sometimes fatal).^{349 377} Sarcoidosis or exacerbation of sarcoidosis reported rarely with oral ribavirin.^{349 377}

Closely monitor patients who experience pulmonary infiltrates or deterioration in pulmonary function; if appropriate, discontinue ribavirin.^{349 377}

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.¹ (See Nasal and Oral Inhalation under Dosage and Administration.)

Fetal/Neonatal Morbidity and Mortality

Teratogenic and/or embryocidal.^{349 377 a b c} Exercise extreme care to avoid pregnancy in female patients and in female partners of male patients.^{349 377 a b c} Women of childbearing potential and men must use 2 forms of effective contraception during therapy and for 6 months following completion of therapy.^{349 377 a b c}

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.^{349 377 a b c} Perform pregnancy testing monthly during therapy and for 6 months after therapy is completed.^{349 377 a b c}

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.^{349 377 a b c}

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.³⁴⁹

Monitor hemoglobin or hematocrit before initiating therapy, at week 2 and 4 (or more frequently if needed), and during therapy as appropriate.³⁴⁹ Dosage adjustment may be necessary.³⁴⁹ (See Special Populations under Dosage and Administration.)

Cardiovascular Effects

Fatal and nonfatal MI reported in patients with anemia due to oral ribavirin.³⁴⁹

Assess patient for cardiac disease before initiating therapy and monitor during therapy.^{349 377} Obtain an electrocardiogram in patients with known cardiac disease.³⁴⁹

Temporarily interrupt or discontinue therapy if cardiovascular status deteriorates.³⁴⁹ Dosage adjustment may be necessary.³⁴⁹ (See Special Populations under Dosage and Administration.)

Use with caution in patients with preexisting cardiac disease.³⁷⁷ Not recommended in those with substantial or unstable cardiac disease.³⁴⁹

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.³⁷⁷ 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.³⁷⁷

Closely monitor clinical status and hepatic function.³⁷⁷ Immediately discontinue peginterferon alfa if decompensation (Child-Pugh score ≥6) occurs.³⁷⁷

Sensitivity Reactions

If acute hypersensitivity reactions (urticaria, angioedema, bronchoconstriction, anaphylaxis) occur, discontinue immediately and initiate appropriate medical intervention.³⁷⁷ Interruption of therapy not usually necessary for transient rash.³⁷⁷

General Precautions

Other Viral Infections

Safety and efficacy of oral ribavirin in the treatment of HIV infection, adenovirus infection, early RSV infection, parainfluenzae virus infection, or influenza virus infection have not been established; oral ribavirin should not be used for these indications.³⁷⁷

Pancreatitis

Temporarily interrupt oral ribavirin in patients with signs and symptoms of pancreatitis; discontinue in patients with confirmed pancreatitis.^{349 377}

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 currently have not been elucidated; acute effects do not appear to be substantial.^{187 188 189 190 195 206 216 217 227 228 229 234 235 236 237 238 239 240 241 242 243 247 261 266 267} Exposure of pregnant women^{187 188 216 217 218 226 227 228 234 238 239 240 241 242 243 244 247 263 265 267} and possibly those who may be