VA Class:AM800

AHFS Class:

• Nucleosides and Nucleotides 8:18.32

Generic Name(s):

• Ribavirin

Chemical Name:

• 1-β-D-Ribofuranosyl-1 H -1,2,4-triazole-3 carboxamide

Ribavirin is a synthetic nucleoside antiviral agent that has a broad spectrum of antiviral activity against both RNA and DNA viruses.1,6,9,11,22,166

Hepatitis C Virus Infection

Chronic Hepatitis C Virus Infection

For treatment of chronic HCV infection, oral ribavirin must be used as part of a multiple-drug regimen and should not be used alone.119,349,377,402,403

Oral ribavirin has been used in conjunction with peginterferon alfa-2a (Pegasys^®) or peginterferon alfa-2b (PegIntron^®) for treatment of chronic hepatitis C virus (HCV) infection in adults and pediatric patients with compensated liver disease.20,119,342,349,377,388,402,403,419,420,421,422,423 Safety and efficacy of oral ribavirin in conjunction with peginterferon alfa or interferon alfa have not been established for treatment of chronic HCV infection in patients with decompensated liver disease,349,377,402,403 patients with hepatitis B virus (HBV) coinfection,349,403 or in liver or other organ transplant recipients.349,377,402,403 Although oral ribavirin was used in conjunction with nonconjugated interferon alfa-2b in the past for the treatment of chronic HCV infection,323,324,331,332,333,338,339,340,349,362,403,428 regimens that include nonconjugated interferon are associated with lower response rates than regimens that include peginterferon alfa342 and such regimens are no longer included in recommendations for the treatment of chronic HCV infection.119

Oral ribavirin usually is used in multiple-drug regimens that include one or more HCV direct-acting antivirals (DAAs) with or without peginterferon alfa.119,179,180,187,188 Ribavirin has been used in regimens that include simeprevir (an HCV protease inhibitor), ribavirin, and peginterferon alfa;187 regimens that include sofosbuvir (an HCV polymerase inhibitor) and ribavirin with or without peginterferon alfa;119,188 regimens that include simeprevir (an HCV protease inhibitor), sofosbuvir (an HCV polymerase inhibitor), and ribavirin;119 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;119,179 or regimens that include the fixed combination ombitasvir/paritaprevir/ritonavir with dasabuvir and with ribavirin.119,180 The most appropriate multiple-drug regimen depends on the specific HCV genotype and patient population involved.119

Because treatment of chronic HCV 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), 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].119

Pediatric Patients

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 Ribavirin oral capsules (Rebetol^®, Ribasphere^®) and oral solution (Rebetol^®) are used in conjunction with peginterferon alfa-2b (PegIntron^®) or nonconjugated interferon alfa-2b for treatment of chronic HCV infection in children 3 years of age or older with compensated liver disease.349,403 Oral ribavirin tablets (Copegus^®) are used in conjunction with peginterferon alfa-2a (Pegasys^®) for initial treatment of chronic HCV infection in children 5 years of age or older with compensated liver disease.377 Similar to data in adults, sustained virologic response (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.349,377,426,428

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 oral ribavirin (Rebetol^® 15 mg/kg daily) and peginterferon alfa-2b (60 mcg/m² once weekly) was given for 24 weeks (genotype 2, genotype 3 with baseline HCV RNA level less than 600,000 IU/mL) or 48 weeks (HCV genotypes 1 and 4, genotype 3 with baseline HCV RNA level of 600,000 IU/mL or greater).349,426 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 less than 600,000 IU/mL.349 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 or greater.349

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 oral ribavirin (Copegus^® 15 mg/kg daily) and peginterferon alfa-2a (180 mcg/1.73 m² × body surface area [BSA] once weekly) or monotherapy with peginterferon alfa-2a (180 mcg/1.73 m² × BSA once weekly).377,427 Overall, SVR (defined as undetectable plasma HCV RNA [less than 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.377 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.377

Individuals Coinfected with HCV and HIV

Because HCV infection tends to progress more rapidly in patients coinfected with human immunodeficiency virus (HIV), the AASLD, US Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), HIV Medicine Association of the Infectious Diseases Society of America (IDSA), and other experts state that all HIV-infected patients should be periodically screened for HCV and those diagnosed with HCV should be offered HCV treatment, provided there are no contraindications to such therapy.119,120,121,190,191,200 Optimal timing of initiation of HCV treatment relative to antiretroviral therapy has not been established.120,121,190 There is some evidence that HIV-infected patients with CD4⁺ T-cell counts less than 200 cells/mm³ receiving an HCV treatment regimen of ribavirin used in conjunction with peginterferon alfa have lower HCV treatment response rates and increased rates of toxicity compared to HIV-infected patients with CD4⁺ T-cell counts exceeding 350 cells/mm³.200 Some experts recommend that HCV treatment in patients with HCV and HIV coinfection should not be initiated until after at least 6 months of antiretroviral therapy,190 and state that initiation of HCV treatment is not usually recommended in HIV-infected patients with CD4⁺ T-cell counts less than 200 cells/mm³.190 The US Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents states that antiretroviral therapy should be initiated in all patients coinfected with HCV and HIV, including those with high CD4⁺ T-cell counts and cirrhosis.200 In patients with HCV and HIV coinfection who have low CD4⁺ T-cell counts (e.g., less than 200 cells/mm³), the HHS panel recommends prompt initiation of antiretroviral therapy and states that initiation of HCV treatment may be delayed until the patient is stable on the HIV treatment regimen.200

Oral ribavirin has been used in conjunction with peginterferon alfa for treatment of chronic HCV infection in adults with compensated liver disease who are coinfected with HIV.120,121,190,191,423 Although some ribavirin manufacturers state that safety and efficacy of oral ribavirin used in conjunction with peginterferon alfa-2b (PegIntron^®) or interferon alfa-2b (Intron^® A) have not been established in patients with HCV and HIV coinfection,349,403 other ribavirin manufacturers state that initial studies evaluating safety and efficacy of oral ribavirin used in conjunction with peginterferon alfa-2a for treatment of chronic HCV infection included clinically stable HIV-infected adults with CD4⁺ T-cell counts greater than 100 cells/mm³.377,402 There is evidence that HCV treatment regimens that only include ribavirin and peginterferon alfa are associated with poor SVR rates, especially in patients with HCV and HIV coinfection.200

Various multiple-drug regimens that include one or more HCV DAAs (e.g., sofosbuvir and ribavirin with or without peginterferon alfa; sofosbuvir and simeprevir with ribavirin) have been used for treatment of chronic HCV infection in patients coinfected with HIV.112,119,188 The most appropriate regimen depends on the HCV genotype and whether the patient is treatment naive or has relapsed after prior HCV treatment.119 Some experts state that multiple-drug regimens recommended for treatment of chronic HCV infection in patients coinfected with HIV are the same as those recommended for individuals without HIV infection, provided that potential drug interactions and overlapping toxicities between drugs in the HCV treatment regimen and drugs in the antiretroviral regimen are taken into consideration.119

If ribavirin is included in the HCV multiple-drug treatment regimen in HIV-infected patients, potential drug interactions with HIV nucleoside reverse transcriptase inhibitors (e.g., didanosine, lamivudine, stavudine, zidovudine) should be considered.83,119 (See HIV Nucleoside Reverse Transcriptase Inhibitors under Drug Interactions: Antiretroviral Agents.)

Treatment of chronic HCV infection in patients coinfected with HIV can by complicated because of high pill burden, overlapping toxicities, and drug interactions.119,190,200 Because treatment in patients coinfected with HCV and HIV is complex and rapidly evolving, current recommendations regarding management of HCV infection ([Web]) and management of HIV infection ([Web]) should be considered and expert consultation is recommended.119

Acute Hepatitis C Virus Infection

Oral ribavirin has been used in conjunction with peginterferon alfa (alfa-2a, alfa-2b) for treatment of acute HCV infection† in an attempt to prevent progression to chronic HCV infection.96,120,121,126,128,129,190

There is evidence that patients with acute HCV infection have higher treatment response rates than those with chronic HCV infection and that treatment of the acute infection can reduce the risk that the disease will evolve to chronic infection.120,190 SVR rates of 62-90% or higher have been reported when peginterferon alfa or nonconjugated interferon alfa monotherapy or peginterferon alfa in conjunction with oral ribavirin was used for treatment of acute HCV infection.120,122,123,124,128,129 However, approximately 10-50% of patients with acute HCV infection have self-limited disease and spontaneous clearance of the virus without treatment;120 the spontaneous resolution rate varies depending on whether the acute infection is asymptomatic or symptomatic, the route of HCV transmission, and age at which the infection was acquired.120

The optimum regimen (including dosage and duration of therapy) and optimum time to initiate treatment in patients with acute HCV infection have not been established.120,190 To allow for spontaneous resolution, some experts suggest that it might be reasonable to delay initiation of treatment of acute HCV infection (especially in symptomatic patients) for 8-12 weeks after acute onset of hepatitis, unless HCV RNA levels are high and not declining;120 others suggest monitoring for 8-20 weeks after initial exposure.121

Although some experts recommend that treatment be offered to all HIV-infected patients with acute HCV infection, others recommend observing HIV-infected patients for 3-6 months before initiating HCV treatment, especially patients more likely to have spontaneous clearance after acute HCV infection (e.g., those with C/C IL28B genotype).190

Consultation with a specialist is advised to obtain the most up-to-date information regarding treatment of acute HCV infection.120,121

Hepatitis E Virus Infection

Oral ribavirin has been used alone or in conjunction with peginterferon alfa for treatment of chronic hepatitis E virus (HEV) infection†.430,431,432,433

Chronic HEV infection has been reported almost exclusively among immunocompromised individuals, including solid organ transplant recipients, patients receiving cancer chemotherapy, and HIV-infected patients.430,431,432,433 Although optimal treatment of chronic HEV infection has not been identified, there is evidence that ribavirin monotherapy is associated with a sustained virologic response in some solid organ transplant recipients.431,432

Respiratory Syncytial Virus Infection

Ribavirin is used via nasal and oral inhalation (Virazole^®) for treatment of severe lower respiratory tract infections (i.e., bronchiolitis and/or pneumonia) caused by respiratory syncytial virus (RSV) in hospitalized infants and young children.1,16,41,59,60,75,76,89,90,91,100,101,105,162,196,197,202,277,278,405,410,411,412,413,414,415,416,417,418

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 and that use in mechanically ventilated patients should be undertaken only by clinicians and support staff familiar with the mode of administration and the specific ventilator being used.1 The American Academy of Pediatrics (AAP) states that ribavirin nasal and oral inhalation therapy may be considered for selected patients with documented, potentially life-threatening RSV infection, but routine use of the drug is not recommended.105

Efficacy of ribavirin therapy in RSV infection depends on prompt initiation of the drug following the onset of signs and symptoms.1,137 Ribavirin inhalation therapy is not a substitute for usual supportive respiratory therapy and fluid management in patients with severe respiratory tract infection.1,89

When indicated, ribavirin nasal and oral inhalation therapy may be started pending results of definitive diagnostic tests, particularly when the clinical diagnosis is compatible with RSV infection during the RSV season (usually November to April),137 but the drug generally 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).1,8,60,87,105 The fact that false-positive or false-negative test results may occur with these rapid diagnostic methods should be considered.1,105 Test results from other diagnostic procedures that use culture techniques generally are not available for 1-5 days.105

High-risk Infants and Children

Ribavirin nasal and oral inhalation therapy is used for treatment of severe lower respiratory tract infections caused by RSV in hospitalized infants and young children.1,16,41,45,75,76,89,90,91,100,101,105,196,197,202,277,278,405,410,411,412,413,414,415,416,417,418

Outbreaks of RSV infection usually occur annually during the winter and early spring.105 RSV is one of the most common diseases of early childhood.105 Most infants are infected during the first year of life, and essentially all children have been infected with RSV at least once by their second birthday.105 Most previously healthy infants and young children with RSV infection do not exhibit signs and/or symptoms of lower respiratory tract infection or only exhibit manifestations of mild, self-limited infection that does not require hospitalization or antiviral therapy (e.g., ribavirin).1,105 Mild RSV lower respiratory tract infections in previously healthy patients in this age group generally improve within a few days with supportive care and do not require treatment with ribavirin nasal and oral inhalation therapy; 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).1,105

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).1,60,75,91,92,100,105,196,216,405 In infants with preexisting cardiac and respiratory disease (i.e., bronchopulmonary dysplasia and/or congenital heart disease), ribavirin inhalation therapy may increase the rate of improvement in clinical manifestations of the infection,75,196 especially during the first 24 hours after initiating therapy.75 The drug has also been effective in treatment of pneumonia associated with severe RSV and/or parainfluenza infections in immunocompromised infants (e.g., infants with severe combined immunodeficiency disease [ SCID]),9,16,60,90,100 decreasing viral shedding in respiratory tract secretions and promoting improvement in clinical manifestations of pneumonia, including arterial blood gases, cough, fever, and respiratory rate.9,16,60,90 However, complete recovery occurred only after bone marrow transplantation in these immunocompromised infants,90,100 suggesting that a healthy, intact host immune system is necessary for complete recovery from RSV infection in immunocompromised patients, even following ribavirin inhalation therapy.9,60

Clinical Experience

Results of some placebo-controlled studies have indicated that ribavirin inhalation therapy can improve clinical manifestations of RSV lower respiratory tract infection in hospitalized infants with severe infection,1,3,9,16,41,60,75,76,91,101,197 especially when therapy was initiated within the first 3 days following onset of infection.1,41,75,137,197 The effect of such therapy on short- and long-term morbidity and on mortality remains to be more fully elucidated.106,137,197,199,201,202,203,204,205,206,207,216,224,400

In some studies, ribavirin-treated infants generally experienced a more rapid improvement in cough, respiratory rate, rales, chest recession, and/or heart rate compared with infants receiving the placebo,41,75,91 but the duration of wheezing did not appear to be substantially affected by the drug.4,76,91,197,201 Ribavirin inhalation therapy has also decreased the duration and amount of viral shedding in respiratory tract secretions,1,4,9,16,76 although reported effects on viral shedding have been inconsistent,3,41,76,91,101,196,197,202,205,206 in part because such effects generally do not seem to become apparent until several days after initiation of therapy (e.g., after 3 days).74,75,76,197 Clinical manifestations of RSV infection, including arterial oxygen saturation, lethargy, cough, and rales, have improved as early as 3 days following initiation of inhalation therapy with the drug in some infants.1,3,4,9,16,41,75,76,197 In addition, in a limited number of infants with severe pneumonia associated with RSV infection, prolonged inhalation therapy (e.g., 7-22 days) reportedly has been effective in promoting recovery in most children76 and has decreased viral shedding in respiratory tract secretions.76

In some of the initial studies, the use of sterile water instead of saline for the placebo control has been criticized because of the potential for sterile water to cause bronchospasm and potentially affect outcomes.416 Subsequent randomized studies performed using a saline control have produced inconsistent results.405,410,411,412,413,414,416,417 Studies that assessed outcomes such as length of hospitalization, length of intensive care stay, and duration of illness have not generally revealed differences between patients receiving ribavirin and those receiving placebo.41,411,412,414,416 Studies that evaluated the effects of aerosolized ribavirin treatment on outcomes such as symptoms and clinical severity have also yielded inconsistent results.41,76,91,197,411,413 Some studies reported improved clinical scores on days 1-4 of ribavirin treatment,41,75,76 quicker improvement of some symptoms (e.g., cough and crepitation),91,197 reduced nasal viral shedding at end of treatment,75 and greater improvements in blood gas values.75 Other studies did not indicate a benefit from ribavirin treatment for such outcomes.411,413 In a study in children with mild RSV illness and underlying disease (bronchopulmonary dysplasia, congenital heart disease), early treatment with aerosolized ribavirin resulted in a greater rate of improvement of clinical scores, reduced oxygen requirements, and greater oxygen saturation.418

Results of long-term follow-up studies have been inconsistent.410,415,417 One study indicated a decreased incidence of 2 or more wheezing episodes during the 6 years following ribavirin treatment for RSV infection versus placebo, but no differences in overall respiratory illness or symptoms during the same period.415 A 1-year follow-up study of patients who received aerosolized ribavirin in conjunction with usual treatment versus usual treatment alone for RSV infection indicated a decreased incidence of reactive airway disease and respiratory tract infections in those who received ribavirin.410 A follow-up study of 5 years' duration found no differences in annual rates, timing, or severity of lower respiratory tract illness, nor were there differences observed in pulmonary function.417

Mechanically Ventilated Patients

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 (See Nasal and Oral Inhalation under Cautions: Precautions and Contraindications and see Nasal and Oral Inhalation under Dosage and Administration: Reconstitution and Administration.)

Clinical Experience

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; there were no technical difficulties with ribavirin inhalation therapy during the study.1,299,300,301,302 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 F_IO₂ 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 SPAG-2).1

Adults

Although the manufacturer states that ribavirin nasal and oral inhalation therapy is not indicated for use in adults,1 aerosolized ribavirin has been used alone or in conjunction with IV† ribavirin for the treatment of severe RSV infection in previously healthy adults†.283 Aerosolized ribavirin also has been used alone or in conjunction with immune globulin IV (IGIV) for treatment of RSV infection in immunocompromised adults†, including bone marrow or hematopoietic cell transplant recipients.213,407,409,429,434 In addition, IV† ribavirin has been used for treatment of RSV infection in a limited number of adult lung transplant recipients†.406

Viral Hemorrhagic Fevers

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†.105,337,343,344,351,389,392 Although parenteral ribavirin is not commercially available in the US, it is available for compassionate use protocols for treatment of viral hemorrhagic fevers.337,343 (See Parenteral Administration under Dosage and Administration: Administration.)

Viral hemorrhagic fevers are a diverse group of infections caused by RNA viruses from 5 viral families, including Arenaviridae (e.g., Lassa virus [ Lassa fever], Junin virus [ Argentine hemorrhagic fever], Lujo virus, Machupo virus [Bolivian hemorrhagic fever], Guanarito virus [Venezuelan hemorrhagic fever], Sabia virus [Brazilian hemorrhagic fever]), Bunyaviridae (e.g., Hantavirus infections, Crimean-Congo hemorrhagic fever, Rift Valley fever), Filoviridae (e.g., Ebola hemorrhagic fever, Marburg hemorrhagic fever), Flaviviridae (e.g., dengue hemorrhagic fever, yellow fever, Kyasanur Forest disease, Omsk hemorrhagic fever, Alkhurma viruses), and Paramyxoviridae.105,337,343,344,351 Ribavirin has been used for the management of various viral hemorrhagic fevers; however, the drug provides benefit only in some (not all) of these infections.343,344,351 Ribavirin has some activity against Arenaviridae and Bunyaviridae, but is inactive against Filoviridae (including Ebola and Marburg viruses) and most Flaviviridae.343,344,351

The principal clinical features of viral hemorrhagic fevers usually result from microvascular damage and changes in vascular permeability.337,343,344 Although certain types of hemorrhagic fever viruses can cause relatively mild illnesses, many of these viruses cause severe, life-threatening disease.337,343,344,351 Specific clinical manifestations vary by the type of viral hemorrhagic fever, but initially often include fever, fatigue, dizziness, myalgia, prostration, loss of strength, and exhaustion.337,343,344 Severe cases often exhibit signs of bleeding under the skin, in internal organs, and from body orifices (e.g., mouth, eyes, ears), but death rarely results from blood loss per se.343,344 Severely ill patients may exhibit shock and neurologic (e.g., nervous system abnormalities, coma, seizures, delirium), pulmonary, and hematopoietic involvement.343,344 Some viral hemorrhagic fevers may result in renal failure, which is proportional in many cases to the degree of cardiovascular compromise but integral to the disease process in hemorrhagic fever with renal syndrome.343,344

Risks of Exposure and Infection

The viruses that cause viral hemorrhagic fevers are principally zoonotic (i.e., they reside naturally in and depend on an animal reservoir host or arthropod vector for replication and survival) and are distributed worldwide.337,343,344,351 Because each virus is associated with one or more particular host species, the virus and associated disease usually occur only in areas where the host species lives and the risk of contracting naturally occurring viral hemorrhagic fevers usually is restricted geographically to these respective areas.337,344 However, humans occasionally become infected by a host that has been exported from its native habitat.344 Naturally occurring viral hemorrhagic fevers can be transmitted to humans when human activities overlap with activities of infected reservoir hosts or vectors.337,344,351 Transmission can occur through contact with the urine, feces, saliva, or other body excretions of rodent reservoirs or through the bites of arthropod vectors (e.g., mosquitoes, ticks).337,344,351 Transmission also can occur through the care and slaughter of infected livestock or consumption of raw meat from infected animals.337,344,351 Some of these viruses (e.g., those associated with Ebola, Marburg, Lassa fever, and Crimean-Congo hemorrhagic fevers) can be spread from person to person.337,344,351

Person-to-person transmission of viral hemorrhagic fevers can occur directly via close contact with infected individuals or their body fluids or cadavers or indirectly via contact with objects contaminated with infected body fluids.343,344,351 In addition, some of the viruses (including Lassa fever virus, Crimean-Congo hemorrhagic fever virus and Ebola and Marburg viruses) are associated with aerosol nosocomial spread.343 Although humans are not a natural reservoir for the viruses, patients with viral hemorrhagic fever often harbor significant quantities of virus in blood and other body fluids and secretions.343 Therefore, nosocomial transmission and secondary infections in contacts and health-care personnel have been reported, especially if infection control procedures are inadequate.337,343,344,351

The US Army Medical Research Institute of Infectious Diseases (USAMRIID)343 and US Working Group on Civilian Biodefense351 state that there is a risk that human infection with viruses that cause hemorrhagic fevers could occur as the result of biologic warfare or bioterrorism since most hemorrhagic fever viruses can be transmitted by aerosols.343,344,351 (See Viral Hemorrhagic Fevers in the Context of Biologic Warfare or Bioterrorism under Uses: Viral Hemorrhagic Fevers.)

Information on diagnosis and management of viral hemorrhagic fevers is available from the Viral Special Pathogens Branch of CDC at [Web] or at 404-639-1115.345 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 the CDC Emergency Operations Center at 770-488-7100.337

Travelers

Although the risk for travelers is considered to be low, travelers to endemic areas are at increased risk of exposure to viral hemorrhagic fevers if they are engaging in animal research or are healthcare workers or others providing care for patients in the community, particularly when an outbreak of viral hemorrhagic fever is occurring.337 Healthcare workers should observe standard precautions, including contact and droplet precautions, when working with patients if viral hemorrhagic fever is suspected.337 In addition, direct contact with corpses of patients suspected of having died of Ebola, Marburg, or Old World arenavirus infection should be avoided.337

Travelers should avoid contact with host or vector species (e.g., rodents, bats, livestock) and should not visit locations where an outbreak of viral hemorrhagic fever is occurring.337 Travelers to areas where Rift Valley fever or Crimean-Congo hemorrhagic fever is endemic are at increased risk and should avoid direct contact with livestock and should minimize their exposure to mosquito bites by using insecticide-treated bed nets and insect repellants.337 Contact with or consumption of primates, bats, and other bushmeat should be avoided.337 In addition, direct contact with corpses of patients suspected of having died of Ebola, Marburg, or Old World arenavirus infection should be avoided.337

Lassa Fever

Ribavirin has been effective when used orally and/or IV† for treatment of Lassa fever†, and is considered the drug of choice for treatment of the disease.59,104,105,146,177,257,258,343,351

Lassa fever is a severe, often fatal, hemorrhagic fever caused by Lassa virus, an Arenavirus that can be transmitted to humans from asymptomatically infected rodents (multimammate rats).337,344 Transmission to humans can occur via inhalation of primary aerosols from rodent urine, by ingestion of contaminated food, or by direct contact of broken skin with rodent excreta.337,344 Rodent infestation and inappropriate food storage increase the risk of human infection.337 Person-to-person transmission of Lassa fever has been reported (including transmission to health-care workers) and usually occurs because of contact with blood, tissue, secretions, or excretions from an infected individual; transmission via aerosols also has been reported.337,343,344 Lassa fever is endemic in portions of West Africa (including areas in Sierra Leone, Guinea, Liberia, and Nigeria).337,343,344

Ribavirin treatment has been associated with decreased morbidity and mortality in patients with Lassa fever,104,105,146,343,351 and appears to be more effective than Lassa immune plasma therapy (convalescent plasma obtained from survivors of the disease) or no therapy.104,146 Ribavirin is most effective when initiated early in the course of the infection (within 6-7 days of onset of symptoms).105,146,343 Patients need intensive supportive care, including maintenance of appropriate fluid and electrolyte balance, oxygenation, and blood pressure, as well as treatment of any complicating infections.344

When treating patients with Lassa fever, strict barrier precautions (use of gloves, gowns, masks, goggles) should be used to minimize exposure to patient blood and other body fluids.105,343 Although use of oral ribavirin for postexposure prophylaxis of Lassa fever† in high-risk contacts of patients with Lassa fever (i.e., individuals who, within 3 weeks of diagnosis of Lassa fever in a patient, have mucous membrane contact [e.g., kissing, sexual intercourse] with the infected patient, or who have had a needle stick or other penetrating injury involving contact with the patient's secretions, excretions, blood, tissue, or other body fluids during this period) has been suggested,219 efficacy of the drug for such prophylaxis has never been studied in humans.343,351 Therefore, oral ribavirin prophylaxis is not usually recommended for exposed individuals.397 Instead, the CDC recommends that a treatment regimen of IV† ribavirin be used in contacts with clinical evidence of the infection during the incubation period.397

Hantavirus Infections

Hemorrhagic Fever with Renal Syndrome (HFRS)

Ribavirin has been used IV† for treatment of hemorrhagic fever with renal syndrome† (HFRS),105,270,271,272,276 and has been designated an orphan drug by FDA for treatment of this condition.273 HFRS is caused by Hantaan virus (a Hantavirus) and related Bunyaviridae and is characterized by hemorrhagic fever associated with vascular instability, shock, and severe renal insufficiency resulting from acute interstitial nephritis; a subsequent diuretic phase is then observed105,270,271,272

When administered IV† within 4-7 days after the onset of fever, ribavirin has been shown to be effective in decreasing the viremia, renal dysfunction, vascular instability, and mortality of HFRS.105,270,271,272,276 Patients also need intensive supportive care, including avoidance of transporting patients, supportive care for shock, prevention of overhydration (particularly with crystalloid solution), dialysis for complications of renal failure, control of hypertension during the oliguric phase, and early recognition of possible myocardial failure with appropriate therapy.105

Hantavirus Pulmonary Syndrome (HPS)

A Hantavirus infection named Hantavirus pulmonary syndrome (HPS) was recognized in the US, principally among residents of the Southwest.285,286,287,288,289,290,291,292,294,297,303,304,305 HPS is mainly produced by a strain of Hantavirus named Sin Nombre (Muerto Canyon) virus,315,317 most closely related to the Prospect Hill strain of Hantavirus.305,319 Available data strongly suggest that the deer mouse ( Peromyscus maniculatus ) is the principal reservoir of Sin Nombre virus.287,288,289,290,291,292,304,305,309,313,314 Although the overall incidence of HPS is unknown,317 the syndrome appears to be widespread geographically since HPS has been reported in areas outside of the Southwest.305,310,311,313 Humans are thought to be at risk for infection after exposure to rodent excreta or saliva, either through aerosols or direct inoculation.285,291 There currently is no evidence of arthropod vectors of hantavirus transmission.291,309,314 Manifestations of HPS, while sharing some clinical manifestations of other Hantavirus infections (e.g., HFRS), do not include the prominent renal involvement and hemorrhagic manifestations285,286,287,288,289,290,291,292,308 previously described with Hantavirus infections.105,270,271,272,276 Instead, HPS is characterized by abrupt onset of fever or hypothermia and myalgias, variably accompanied by headache, chills, cough, dyspnea, nausea, vomiting, diarrhea, hypotension, tachycardia, tachypnea, and abdominal distress, followed by a precipitous onset of rapidly progressive bilateral interstitial infiltrates resembling radiographic changes of adult respiratory distress syndrome (ARDS) and frequently by shock; most cases to date have been fatal.285,286,287,288,289,290,291,292,294,297,298,304,305,306,307,308,309,310,311,312,313,314,317

Optimum therapy for treatment of HPS remains to be established,105,270,271,272,276,285,286,292,329 but is principally symptomatic and supportive.304,308,317,329,330,344 Prompt supportive management of pulmonary edema, severe hypoxemia, and hypotension during the first 24-48 hours, including avoidance of excessive fluid administration and early use of inotropic and vasopressor agents, appears particularly important.105,304,308,317,344 Based on in vitro antiviral activity and limited experience in treating other Hantavirus infections (e.g., HFRS) and various hemorrhagic fevers (e.g., Lassa fever),105,270,271,272,276,285,286,292,297 IV† ribavirin had been used for treatment of HPS†.105,285,286,292,297,298,304,308,314 From June 1993 through August 1994, IV ribavirin† (administered as a 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) was available under an open-label investigational new drug (IND) protocol from CDC for treatment of HPS.286,292,297,358 However, in July 1994, experts from outside CDC reviewed the results of this open-label IND protocol and concluded that, while ribavirin generally was well tolerated in patients with HPS, the drug had no clear positive influence on the outcome of such infection.315 Therefore, enrollment under the IND protocol was closed in September 1994.317 A total of 140 patients were enrolled in the study and 37 completed a 7- to 10-day regimen of ribavirin; reasons for early termination of treatment included death, alternate diagnosis, adverse effects, negative HPS testing, clinical improvement, and drug shortage.358 Placebo-controlled, randomized clinical studies have been initiated to evaluate ribavirin for treatment of HPS.329,330 Clinicians and public health officials should remain alert for individuals with unexplained bilateral interstitial infiltrates accompanied by fever; appropriate specimens should be collected for serologic and diagnostic tests from these individuals.317 Suspected cases of HPS should be reported to CDC through corresponding state health departments.317

Crimean-Congo Hemorrhagic Fever

Ribavirin has been used orally or IV† with some success in a limited number of patients for treatment of Crimean-Congo hemorrhagic fever† (CCHF).105,347,389,392 Although experience with ribavirin in the treatment and prevention of CCHF is substantially more limited than that with Lassa fever,153,154,219 CDC states that use of ribavirin to treat the disease and to prevent infection in high-risk contacts seems reasonable based on in vitro susceptibility data for this and other Bunyaviridae.219 CDC recommends that similar procedures for care, including isolation and body fluid precautions and therapy, recommended for Lassa fever be followed for patients with Crimean-Congo hemorrhagic fever and their contacts; however, additional study and experience are necessary.219

Viral Hemorrhagic Fevers caused by Filoviridae and Flaviviridae

Ribavirin is inactive in vitro against Filoviridae, including Ebola and Marburg viruses, and is not effective for treatment of Ebola hemorrhagic fever or Marburg hemorrhagic fever.219,343,344,351 Ribavirin also is inactive against most Flaviviridae.343,344,351

Viral Hemorrhagic Fevers in the Context of Biologic Warfare or Bioterrorism

Because of the potential risk that viruses that cause hemorrhagic fever might be used in the context of biologic warfare or bioterrorism, the Working Group on Civilian Biodefense and other experts (e.g., USAMRIID) have made recommendations for treatment of viral hemorrhagic fevers in such a setting.343,351 Ribavirin is recommended for the treatment of clinically evident viral hemorrhagic fever in the context of biologic warfare or bioterrorism† when the disease is caused by an Arenavirus (e.g., Lassa fever, New World hemorrhagic fever) or Bunyavirus (e.g., Rift Valley fever) or is of unknown etiology.343,351,357 Although safety and efficacy of oral or IV† ribavirin have not been established in children or in pregnant women, experts (i.e., the Working Group on Civilian Biodefense) recommend that children or pregnant women with clinically evident viral hemorrhagic fever caused by an Arenavirus or Bunyavirus or of unknown etiology should receive ribavirin since the benefits are likely to outweigh the risks of such therapy.351 In addition to use of ribavirin when indicated, treatment of patients with viral hemorrhagic virus infection requires intensive supportive care with careful maintenance of fluid and electrolyte balance, circulatory volume, and blood pressure.343,351

Preemptive administration of ribavirin or postexposure prophylaxis with the drug in the absence of clinical signs of infection in individuals with known or presumed exposure to a hemorrhagic fever virus in the context of biologic warfare or bioterrorism is not currently recommended.351 Individuals with known or presumed exposure to a hemorrhagic fever virus and all known high-risk contacts (i.e., individuals who have mucous membrane contact with an infected patient) and close contacts (i.e., individuals who live with, shake hands or hug, process laboratory specimens, or care for an infected patient [prior to initiation of appropriate precautions]) should be placed under medical surveillance for 21 days after the potential exposure or last contact with the infected patient.351 Exposed individuals and contacts who develop a temperature of 38.3°C or higher should receive ribavirin for the presumptive treatment of viral hemorrhagic fever† unless there is an alternative diagnosis or the etiologic agent is a filovirus or flavivirus.351 Only high-risk or close contacts of patients with Rift Valley fever or Flavivirus infection who processed laboratory specimens from an infected patient prior to initiation of appropriate precautions require medical surveillance since these viruses are not transmitted from person to person.351

Adenovirus Infections

Ribavirin has been used IV† with some success 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.393,394,395,396 However, safety and efficacy of the drug for treatment of adenovirus infections have not been established.349,377 Experience is limited to date393,394,395,396 and further study is needed to determine the role of ribavirin in the treatment of adenovirus infections.394,395,396

In most reported cases, ribavirin was used in critically ill patients with severe adenovirus infections (e.g., hemorrhagic cystitis, nephritis, respiratory tract infections, GI infections, disseminated disease); these patients received multiple treatment modalities and it is difficult to determine whether the drug contributed to a favorable outcome.393,395,396 In some patients, IV† ribavirin was used in conjunction with IV cidofovir.393,394 There is evidence that not all patients respond to ribavirin therapy393,394,396 and that the drug is unlikely to be of benefit if initiated late in the course of severe infections.393

In addition to being used in patients with severe adenovirus infections, ribavirin has been used for preemptive therapy in several immunocompromised patients who were asymptomatic, but had clinical cultures positive for adenovirus.395 However, the possible benefits and risks of the drug in such patients have not been determined since asymptomatic adenovirus infections often resolve spontaneously.395

Coronavirus Infections

Severe Acute Respiratory Syndrome (SARS)

IV† and/or oral ribavirin 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 SARS was first reported in Asia during early 2003 and then spread to many other areas of the world, including North America, South America, and Europe.346,367,368,369,370,371,372,373,376,380,381 By July 2003, more than 8000 SARS cases and 780 deaths were reported from 29 countries worldwide.386 A new human pathogen, a member of the coronavirus family, was identified as the causative agent and was named the SARS coronavirus (SARS-CoV).346,374,385 Although person-to-person transmission of SARS-CoV does not appear to be occurring anywhere in the world at the present time, it could recur and future outbreaks of SARS-CoV are possible.386

Because SARS can be fatal (overall case-fatality rate 10%, which can increase to more than 50% in patients older than 60 years of age),386 various empiric therapies were attempted.367,368,369,370,371,373,380,381,382 SARS may be difficult to differentiate from influenza or bacterial pneumonia early in the course of the infection, and patients were treated with multiple anti-infective regimens aimed at presumptively treating known bacterial pathogens of atypical pneumonia.367,368,369,370,371,373,380,381,382 In addition, because some early evidence suggested that a paramyxovirus might be the causative pathogen,368 ribavirin therapy (with or without corticosteroids) was used for empiric therapy in some patients.367,368,369,370,371,373,380,381,382

The clinical benefits of the various anti-infective regimens employed in the treatment of SARS, including ribavirin, were disappointing.368,369,373 Results from several in vitro studies using isolates obtained from infected patients indicated that ribavirin concentrations that inhibit ribavirin-susceptible viruses do not inhibit replication or cell-to-cell transmission of SARS-CoV.373,384,390 In a retrospective analysis of SARS patients in Toronto, ribavirin was used for empiric therapy in 88% of patients but was temporally associated with clinically important toxicity and was discontinued in 18%.380 Because the most efficacious therapeutic regimen, if any, remains to be established,367,368,369,370,371,372,373 suspected cases should be reported to local health departments and managed according to the most recent recommendations of the WHO ([Web]) and US Centers for Disease Control and Prevention (CDC; [Web]).346,367,370,372,373,386

Middle East Respiratory Syndrome (MERS)

Ribavirin has been used in conjunction with an interferon (e.g., peginterferon alfa-2a, interferon alfa-2b) for the treatment of Middle East respiratory syndrome† (MERS) caused by the Middle East respiratory syndrome coronavirus (MERS-CoV).440,441,442,443,445

MERS was first reported in September 2012 in patients in Saudi Arabia.435,436,439,441,444 Most cases of MERS-CoV infection have involved severe respiratory illness requiring hospitalization, although some cases involved only mild or asymptomatic disease.435,436,444,445 The case-fatality rate for MERS has been reported to range from 36-50%.441,444 Human cases generally have been attributed to human-to-human transmission of MERS-CoV, but the virus does not appear to pass easily from person to person unless there is close contact (e.g., providing unprotected care to a MERS patient) and sustained human-to-human transmission has not been reported to date.444,445,446 Although MERS-CoV is a zoonotic virus that is transmitted to humans from contact with infected animals, the route of transmission from animals to humans has not been fully identified.444,445,446 Dromedary camels appear to be a major reservoir host for MERS-CoV and an animal source for human infections, but the exact role of camels in direct or indirect transmission of the virus to humans is unknown.444,446

MERS-CoV appears to be circulating throughout the Arabian Peninsula, primarily in Saudi Arabia, and the majority of MERS cases reported since 2012 have occurred in Saudi Arabia.444,446 As of August 28 2015, there were 1,474 laboratory-confirmed cases of MERS reported to the World Health Organization (WHO), including 515 deaths.444 MERS cases have been reported in the Middle East (Iran, Jordan, Kuwait, Lebanon, Oman, Qatar, Saudi Arabia, United Arab Emirates, Yemen), Europe (Austria, France, Germany, Greece, Italy, Netherlands, Turkey, United Kingdom), Africa (Algeria, Egypt, Tunisia), Asia (China, Malaysia, Philippines, Republic of Korea, Thailand), and North America (US).446 The majority of MERS cases that have occurred outside the Middle East have been directly or indirectly linked through travel or residence to the Middle East.436,444,446 Although an outbreak of MERS was reported in the Republic of Korea (South Korea) beginning in May 2015 and has involved at least 185 cases and 36 deaths, these were related to a traveler from the Middle East and linked to healthcare facilities where MERS patients were treated.439,444,446 There were 2 confirmed cases reported in the US in 2014; both individuals had recently lived and worked in Saudi Arabia before arriving in the US.436,439

No specific treatment for MERS-CoV infection has been identified.436,444,445 Because there is some evidence that ribavirin and interferon are active against the MERS-CoV virus in vitro and in animal studies437,438,443,445 and because of prior experience using ribavirin in patients with SARS, a regimen of oral ribavirin in conjunction with an interferon (e.g., peginterferon alfa-2a, interferon alfa-2b) has been used in some patients with MERS-CoV infection.440,441,442,443,445 In a retrospective, observational study of 5 patients who received oral ribavirin and interferon in conjunction with systemic corticosteroids, no patients survived; however, it is unclear whether this outcome was because the regimen was ineffective or because treatment was initiated late in the course of the disease (range 10-22 days after hospital admission).441 In a retrospective, cohort study that included 44 patients with laboratory-confirmed MERS, the 14-day survival rate from the date of diagnosis was 70% in patients who were treated with a regimen of oral ribavirin and peginterferon alfa-2a (initiated within a median of 3 days from time of diagnosis; range 0-8 days) in addition to usual supportive care compared with a 14-day survival rate of 29% in the comparator group that only received usual supportive care.443 However, the 28-day survival rate was only 30% in patients who received the ribavirin and peginterferon alfa-2a treatment regimen compared with 17% in the comparator group.443

CDC states that MERS-CoV infection should be considered in the differential diagnosis of individuals who develop respiratory symptoms within 14 days after traveling from countries in or near the Arabian peninsula and all suspected cases should be reported to state or local health departments.436 Information regarding evaluation, diagnosis, and management of MERS-CoV infection and guidance for individuals traveling to areas where MERS has been reported (e.g., the Middle East) is available at the CDC website at [Web].436,439

Reconstitution and Administration

Oral Administration

Ribavirin capsules,349,403 tablets,377,402 and oral solution349 are administered orally with food.

Ribavirin capsules should not be opened, crushed, or broken.349,403

If use of Copegus^® 200-mg tablets is considered in children 5 years of age or older, clinicians should ensure that the child can reliably swallow the tablets.377

Ribavirin oral solution containing 40 mg of ribavirin per mL is recommended (instead of capsules) in children 3 years of age or older weighing less than 47 kg.349 The oral solution may be used in any patient 3 years of age or older, regardless of weight.349

Patients should be well hydrated during oral ribavirin therapy, especially during initial treatment.349,377,402,403

Nasal and Oral Inhalation

Commercially available ribavirin sterile powder (Virazole^®) is intended for administration only as a solution via nasal and oral inhalation using the Valeant small-particle aerosol generator (SPAG) Model SPAG-2 available from the manufacturer.1,162 The SPAG-2 aerosol generator is intended for administration of ribavirin inhalation only and should not be used for the administration of other drugs.162 Prior to administration of ribavirin inhalation, the operator's manual provided by the manufacturer should be reviewed to assure thorough familiarity with the use and operation of the SPAG-2 aerosol generator.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

In patients not requiring mechanical ventilation, 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 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

When ribavirin inhalation therapy is used in patients who require assisted ventilation, either a pressure or volume cycle ventilator may be used in conjunction with the SPAG-2.1 Administration of ribavirin inhalation therapy in patients 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 The endotracheal tubes of mechanically ventilated patients should be suctioned every 1-2 hours and pulmonary pressure should be monitored frequently (every 2-4 hours).1 In order to minimize the risk of ribavirin precipitation in either pressure or volume cycle ventilators, heated wire connective tubing should be used and bacterial filters should be placed in series in the expiratory limb of the system; the filters should be changed 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 Some clinicians have inserted a one-way valve in the inspiratory line of the ventilator (a pressure-limited, Healthdyne 102 infant ventilator) circuit proximal to the T-shaped connector to prevent the ribavirin solution from entering the humidifier or the ventilator, another one-way valve between the SPAG-2 aerosol generator and this T-shaped connector to prevent loss of volume from the SPAG-2 apparatus, and a disposable exhalation valve in the expiratory line to prevent the ribavirin from entering the ventilator.182 This entire system was inspected every 2 hours, temperature was maintained at 36-37°C to minimize drug precipitation, a high- and low-pressure alarm (in addition to the ventilator alarm) was connected to the inspiratory line of the circuit to warn of occlusion of the ventilator alarm tubing or any inadvertent circuit disruption, and the drying-chamber flow was reduced or stopped to avoid delivering excess pressure.182 In addition, the one-way valves and exhalation valve were changed every 4 hours regardless of the amount of precipitate present, the endotracheal tube was instilled with a 0.9% sodium chloride solution and cleared at least every 2 hours, the tubing was changed every 8 hours, and the patient was monitored continuously by pulse oximetry.182 Regardless of the method used, constant monitoring (e.g., in an intensive care setting) of the patient and the apparatus is necessary.182,183 The SPAG-2 manual should be consulted for detailed administration instructions.1,162

Reconstitution and Dilution

Ribavirin sterile powder (Virazole^®) is initially reconstituted by adding a minimum of 75 mL of sterile water for injection or inhalation (additive free) to a vial labeled as containing 6 g of ribavirin and shaking well.1,162 This initial solution should then be transferred to a sterile 500-mL reservoir for the SPAG-2 aerosol generator, and further diluted with sterile water for injection or inhalation (additive free) to a final volume of 300 mL to provide a solution containing 20 mg/mL.1,162

Diluents containing any additive should not be used for reconstitution of ribavirin.1

Ribavirin solutions should be inspected visually for particulate matter and discoloration prior to administration.1,162 After the solution has been placed in the SPAG-2 reservoir, any unused solution remaining in the reservoir should be discarded within 24 hours and prior to adding any newly reconstituted solution (e.g., when remaining amount of solution in reservoir is low).1

Rate of Administration

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

The manufacturer recommends that the 20-mg/mL solution be administered 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.162

Parenteral Administration

Ribavirin has been administered IV†.105,146,177,219,270,271,272,276,347,380,381,382

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† such as Lassa fever†, Hantavirus infections†, and Crimean-Congo hemorrhagic fever†.337 To obtain IV† ribavirin for emergency use, clinicians should contact the US Food and Drug Administration (FDA) at 301-736-3400 for compassionate use authorization and also contact the manufacturer (Valeant Pharmaceuticals) at 800-548-5100.337

Dosage

Chronic Hepatitis C Virus Infection

For treatment of chronic hepatitis C virus (HCV) infection, oral ribavirin must be used in conjunction with other drugs as part of a multiple-drug regimen.119,349,377,402,403

Oral ribavirin may be used in conjunction with peginterferon alfa for the treatment of chronic HCV infection;119,349,377,402,403 although no longer recommended,119 ribavirin was used in the past in conjunction with nonconjugated interferon alfa.349,403

For treatment of chronic HCV infection, oral ribavirin usually is used in multiple-drug regimens that include one or more HCV direct-acting antivirals (DAAs) with or without peginterferon alfa.119,179,180,187,188 Ribavirin has been used in regimens that include simeprevir (an HCV protease inhibitor), ribavirin, and peginterferon alfa;187 regimens that include sofosbuvir (an HCV polymerase inhibitor) and ribavirin with or without peginterferon alfa;119,188 regimens that include simeprevir (an HCV protease inhibitor), sofosbuvir (an HCV polymerase inhibitor), and ribavirin;119 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;119,179 or regimens that include the fixed combination ombitasvir/paritaprevir/ritonavir with dasabuvir and with ribavirin.119,180 The most appropriate multiple-drug regimen depends on the specific HCV genotype and patient population involved.119

Dosage and duration of oral ribavirin treatment in patients with chronic HCV infection depend on body weight, HCV genotype, specific treatment regimen used, response to treatment, and tolerability of the regimen.119,349,377,402,403 Modification of ribavirin dosage may be necessary if adverse effects occur.349,377,402,403

For information on dosage of peginterferon alfa or interferon alfa used in conjunction with oral ribavirin for treatment of chronic HCV infection, see Dosage and Administration: Dosage, in Peginterferon Alfa 8:18.20 and see Dosage and Administration: Dosage in Interferon Alfa 8:18.20.

For information on dosage of HCV DAAs used in conjunction with oral ribavirin (with or without peginterferon alfa) for treatment of chronic HCV infection, see the individual monographs in HCV Antivirals 8:18.40.

Adult Dosage

When oral ribavirin capsules (Rebetol^®, Ribasphere^®) are used in conjunction with peginterferon alfa-2b (PegIntron^®) for treatment of chronic HCV infection, the usual adult dosage is 800-1400 mg daily based on body weight.349,403 (See Table 1.) The recommended duration of concomitant peginterferon alfa-2b and oral ribavirin treatment depends on HCV genotype, history of prior treatment, and response to treatment.349,403 (See Table 2.)

When oral ribavirin tablets (Copegus^®, generic) 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.377,402 The recommended duration of concomitant peginterferon alfa-2a and oral ribavirin treatment depends on HCV genotype.377,402 (See Table 3.)

When oral ribavirin tablets (Copegus^®, generic) 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 in 2 divided doses for a duration of 48 weeks, regardless of HCV genotype.377,402 However, some experts suggest that HIV-infected adults with HCV genotypes 1, 4, 5, or 6 receive a weight-based ribavirin dosage of 1 g daily (i.e., 600 mg in morning and 400 mg in evening) if they weigh less than 75 kg or 1.2 g daily (i.e., 600 mg in morning and 600 mg in evening) if they weigh 75 kg or more.190

If oral ribavirin capsules (Rebetol^®, Ribasphere^®) are used in conjunction with nonconjugated interferon alfa-2b (Intron A^®) 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.349,403 The duration of treatment depends on prior treatment, HCV genotype, and treatment response.349,403 The manufacturers state that concomitant nonconjugated interferon alfa-2b and oral ribavirin 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.349,403 If concomitant therapy is used in patients who relapsed after prior nonconjugated interferon monotherapy, the manufacturers recommend a treatment duration of 24 weeks.349,403

Pediatric Dosage

When ribavirin capsules (Rebetol^®, Ribasphere^®) or oral solution (Rebetol^®) is used in conjunction with peginterferon alfa-2b (PegIntron^®) or nonconjugated interferon alfa-2b (Intron^® A) for treatment of chronic HCV infection in children 3-17 years of age, the manufacturers recommend a ribavirin dosage of 15 mg/kg daily in 2 divided doses.349,403 (See Table 4.) The recommended duration of treatment is 24 weeks in those with HCV genotype 2 or 3 or 48 weeks in those with HCV genotype 1.349,403 Discontinuance of HCV treatment should be considered if HCV RNA has not decreased by at least 2 log₁₀ from baseline at treatment week 12 or if HCV RNA is detectable at treatment week 24.349 Patients who reach their 18th birthday during treatment should continue receiving the pediatric dosage regimen for the remaining duration of treatment.349

When ribavirin tablets (Copegus^®) 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.377 (See Table 5.) Patients who reach their 18th birthday during treatment should continue receiving the pediatric dosage regimen for the remaining duration of treatment.377 The recommended duration of treatment is 24 weeks for HCV genotype 2 or 3 and 48 weeks for other HCV genotypes.377

Dosage Modification for Toxicity (Adult Dosage)

If serious adverse effects or laboratory changes occur when oral ribavirin is used in conjunction with peginterferon alfa or nonconjugated interferon alfa in adults with chronic HCV infection, dosage of one or both drugs should be modified, if appropriate, until the adverse reactions abate.349,377,402,403 If intolerance persists after dosage adjustments, both drugs should be discontinued.349,377,402,403

When ribavirin capsules (Rebetol^®, Ribasphere^®) are used in adults, ribavirin dosage should be decreased by 200 mg daily (or by 400 mg daily in those originally receiving 1.4 g daily) if hemoglobin decreases to 8.5 to less than 10 g/dL; an additional dosage reduction of 200 mg daily may be used if needed.349,403 Both ribavirin and peginterferon alfa or nonconjugated interferon alfa should be permanently discontinued in adults with hemoglobin concentrations less than 8.5 g/dL, leukocyte counts less than 1000/mm³, neutrophil counts less than 500/mm³, or platelet counts less than 25,000/mm³.349,403 In adults receiving ribavirin capsules concomitantly with peginterferon alfa or nonconjugated interferon alfa who have a history of stable cardiovascular disease, ribavirin dosage should be decreased by 200 mg daily if hemoglobin decreases by 2 g/dL or more during any 4-week period and treatment should be discontinued if hemoglobin concentrations are less than 8.5 g/dL (or less than 12 g/dL after 4 weeks of reduced dosage).349

When ribavirin tablets (Copegus^®, generic) are used in adults without cardiac disease, ribavirin dosage should be decreased to 600 mg daily (200 mg in morning and 400 mg in evening) if hemoglobin decreases to less that 10 g/dL; the drug should be discontinued if hemoglobin decreases to less than 8.5 g/dL.377,402 When ribavirin tablets are used in adults with a history of stable cardiac disease, ribavirin dosage should be decreased to 600 mg daily (200 mg in morning and 400 mg in evening) if hemoglobin decreases by 2 g/dL or more during any 4-week period; the drug should be discontinued if hemoglobin decreases to less than 12 g/dL after 4 weeks of reduced dosage.377,402 In patients who have had ribavirin tablets withheld, an attempt may be made to reinitiate the drug at a dosage of 600 mg daily after the toxicity has resolved or decreased in severity; dosage may then be increased to 800 mg daily if tolerated.377,402 The usual maximum recommended adult dosage of 1-1.2 g daily (see Table 3) should not be resumed.377,402

The manufacturer's information should be consulted for more specific recommendations regarding dosage modification for hematologic or other adverse effects.349,377,402,403

Dosage Modification for Toxicity (Pediatric Dosage)

If serious adverse effects or laboratory changes occur when oral ribavirin is used in conjunction with peginterferon alfa or nonconjugated interferon alfa in pediatric patients with chronic HCV infection, dosage of one or both drugs should be modified, if appropriate, until the adverse reactions abate.349,377,403 If intolerance persists after dosage adjustments, both drugs should be discontinued.349,377,403

When ribavirin capsules (Rebetol^®, Ribasphere^®) or oral solution (Rebetol^®) is used in children 3-17 years of age, ribavirin dosage should be decreased from 15 mg/kg daily to 12 mg/kg daily and, if needed, to 8 mg/kg daily if hemoglobin decreases to less than 10 g/dL.349,403 Both ribavirin and peginterferon alfa or nonconjugated interferon alfa should be permanently discontinued in pediatric patients with hemoglobin concentrations less than 8.5 g/dL, leukocyte counts less than 1000/mm³, neutrophil counts less than 500/mm³, or platelet counts less than 50,000/mm³.349,403 Pediatric patients with preexisting cardiac conditions receiving ribavirin capsules concomitantly with peginterferon alfa or nonconjugated interferon alfa should be closely monitored with weekly hematology evaluations if hemoglobin concentration decreases by 2 g/dL or more during any 4-week period and treatment should be discontinued if hemoglobin concentration is less than 8.5 g/dL (or less than 12 g/dL after 4 weeks of reduced dosage).349

When ribavirin tablets (Copegus^®) are used in children 5 years of age or older without cardiac disease, ribavirin dosage should be decreased if hemoglobin decreases to less than 10 g/dL and should be discontinued if hemoglobin decreases to less than 8.5 g/dL.377 When ribavirin tablets are used in children 5 years of age or older with a history of stable cardiac disease, ribavirin dosage should be decreased if hemoglobin decreases by 2 g/dL or more during any 4-week period and the drug should be discontinued if hemoglobin decreases to less than 12 g/dL after 4 weeks of reduced dosage.377 In children requiring dosage reduction, a decreased ribavirin dosage of 200 mg daily (200 mg in morning) should be used in those weighing 23-33 kg, 400 mg daily (200 mg in morning and 200 mg in evening) should be used in those weighing 34-59 kg, or 600 mg daily (200 mg in morning and 400 mg in evening) should be used in those weighing 60 kg or more.377

The manufacturer's information should be consulted for more specific recommendations regarding dosage modification for hematologic or other adverse effects.349,377,402,403

Respiratory Syncytial Virus Infection

When 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, the drug should be initiated as soon as possible following the onset of signs and symptoms of infection.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 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.1,162 The manufacturer recommends that the 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.162 The average aerosol concentration for a 12-hour delivery period is 190 mcg/L.1

When administered as recommended, the dose of ribavirin delivered to the respiratory tract via the small-particle aerosol generator can be estimated using the following equation:41,61,93,95,97

dose delivered to respiratory tract = minute volume (liters) × duration of inhalation (minutes) × 0.19 mg/L (nebulized ribavirin concentration) × 0.7 (fraction of inhaled dose deposited in respiratory tract)

The manufacturer states that the duration of a course of ribavirin inhalation therapy for RSV infection should be a minimum of 3 days but should not exceed 7 days.1 Some clinicians indicate that more prolonged and/or repeated therapy with the drug may be necessary in infants with preexisting cardiac and/or respiratory disease75 or immunocompromised infants (e.g., infants with severe combined immunodeficiency disease [SCID])60,76,90,100 with severe lower respiratory tract infection caused by RSV. Therapy with ribavirin inhalation is intended as an adjunct to usual supportive respiratory therapy and fluid management in patients with RSV infection.1 (See Nasal and Oral Inhalation under Cautions: Precautions and Contraindications.)

Viral Hemorrhagic Fevers

Lassa Fever

For the treatment of Lassa fever†, the US Centers for Disease Control and Prevention (CDC), US Army Medical Research Institute of Infectious Diseases (USAMRIID), and other experts recommend 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.219,343

Hantavirus Infections

For treatment of hemorrhagic fever with renal syndrome† (HFRS) caused by Hantaan (a Hantavirus) and related Bunyaviridae, IV† ribavirin has been administered in a limited number of patients as an initial loading dose of 33 mg/kg followed by a dosage of 16 mg/kg every 6 hours for 4 days and then 8 mg/kg every 8 hours for 3 days for a total treatment course of 7 days270,271,276

Crimean-Congo Hemorrhagic Fever

For treatment of Crimean-Congo hemorrhagic fever†, the CDC, USAMRIID, and other experts recommend an adult IV† ribavirin 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.219,343 Alternatively, a 10-day regimen of oral ribavirin consisting of an 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 effective for treatment of Crimean-Congo hemorrhagic fever† in some patients.392

For the prevention of Crimean-Congo hemorrhagic fever† in high-risk contacts, the CDC has recommended an oral ribavirin dosage of 500-600 mg every 6 hours for 7-10 days for adults and children older than 9 years of age and an oral dosage of 400 mg every 6 hours for children 6-9 years of age.219,257 Dosage for children younger than 6 years of age has not been established.257 The prophylactic efficacy of various dosages of oral ribavirin remains to be established,257,258 and the CDC continues to periodically reassess its recommendations based on accumulating experience.258 Some clinicians suggest that, based on dose-response experience in the treatment of active disease with low degrees of viremia, oral dosages lower than those recommended by CDC may prove effective for prophylaxis and that pediatric dosages adjusted by body weight or surface area would be more appropriate, especially for prepubertal children.258 Because of the prolonged elimination half-life of the drug, consideration may be given to administering an initial IV† loading dose in high-risk contacts if the interval between exposure and initiation of prophylaxis is several days.216,258

Viral Hemorrhagic Fevers in the Context of Biologic Warfare or Bioterrorism

For the treatment of clinically evident viral hemorrhagic fever in the context of biologic warfare or bioterrorism† when the disease is caused by an Arenavirus or Bunyavirus or is of unknown etiology, some experts (e.g., the US Working Group on Civilian Biodefense, USAMRIID) recommend that adults or children receive an IV† ribavirin regimen consisting of an initial loading dose of 30 mg/kg (maximum 2 g), followed by a dosage of 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.343,351 The IV regimen is recommended for contained casualty settings.343,351

Alternatively, a 10-day regimen of oral ribavirin should be used for treatment of these 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).343,351 When an oral ribavirin regimen is used, the US Working Group on Civilian Biodefense and USAMRIID recommend 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.343,351 If an oral ribavirin regimen is used in children, these experts recommend an initial loading dose of 30 mg/kg followed by 15 mg/kg daily given in 2 divided doses.343,351

Preemptive administration of ribavirin or postexposure prophylaxis in the absence of clinical signs of infection in individuals with known or presumed exposure to a hemorrhagic fever virus in the context of biologic warfare or bioterrorism is not recommended.351 However, individuals with known or presumed exposure to a hemorrhagic fever virus and all known high-risk contacts (i.e., individuals who have mucous membrane contact with an infected patient) and close contacts (i.e., individuals who live with, shake hands or hug, process laboratory specimens, or care for an infected patient [prior to initiation of appropriate precautions]) should be placed under medical surveillance for 21 days after the potential exposure or last contact with the infected patient.351 Exposed individuals and contacts who develop a temperature of 38.3°C or higher should receive presumptive treatment of viral hemorrhagic fever† using the ribavirin regimens recommended for treatment of clinically evident viral hemorrhagic fever, unless there is an alternative diagnosis or the etiologic agent is found to be a filovirus or a flavivirus.351 Although medical surveillance is not necessary for close or high risk contacts of patients diagnosed with Rift Valley fever or a flavivirus since these specific viruses are not transmitted person to person, surveillance is recommended for individuals who processed laboratory specimens from these patients prior to initiation of appropriate precautions since these viruses can be transmitted in the laboratory setting.351

Adenovirus Infections

For treatment of severe infections caused by adenovirus† in immunocompromised adults, IV† ribavirin has been given in a regimen consisting of an initial loading dose of 33 mg/kg, followed by a dosage of 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 were negative for adenovirus.394,396

For treatment of severe infections caused by adenovirus† in immunocompromised children, IV† ribavirin has been given in a dosage of 25 mg/kg daily in 3 divided doses on day 1, followed by 15 mg/kg daily given in 3 divided doses on days 2-10.393 Alternatively, a dosage of 15 mg/kg daily for 10 days has been used for treatment of adenovirus infections in children.396

Dosage in Renal and Hepatic Impairment

Renal Impairment

The manufacturer states that dosage of ribavirin tablets (Copegus^®) should be reduced in adults with creatinine clearance of 50 mL/minute or less.377 When Copegus^® is 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.377 Dosage should not be reduced any further; if severe adverse effects or laboratory abnormalities occur, the drug should be discontinued.377 Data are insufficient to make dosage recommendations for use of Copegus^® in pediatric patients with renal impairment.377

Ribavirin capsules (Rebetol^®, Ribasphere^®),349,403 tablets (Ribasphere^®),402 and oral solution (Rebetol^®)349 are contraindicated in patients with creatinine clearance less than 50 mL/minute.349,402,403 In pediatric patients receiving ribavirin capsules or oral solution (Rebetol^®) with peginterferon alfa-2b or nonconjugated interferon alfa-2b, both drugs should be discontinued if serum creatinine concentrations exceed 2 mg/dL.349

Hepatic Impairment

Although the effect of hepatic impairment on the pharmacokinetics of oral ribavirin has not been fully evaluated,349,377,402,403 peak plasma concentrations are increased depending on the severity of hepatic impairment.349,403 (See Oral Administration under Pharmacokinetics: Absorption.)

Oral Administration

Oral ribavirin used in conjunction with peginterferon alfa or nonconjugated interferon alfa usually is well tolerated, but the combination can cause a variety of serious adverse reactions that may require dosage reduction or discontinuance.349,377 Important adverse effects reported with concomitant oral ribavirin and peginterferon alfa or interferon alfa therapy include severe depression and suicidal ideation, hemolytic anemia, suppression of bone marrow function, autoimmune and infectious disorders, ophthalmologic disorders, cerebrovascular disorders, pulmonary dysfunction, colitis, pancreatitis, and diabetes.349,377 In clinical studies, 6-19% of patients receiving combination therapy in clinical studies discontinued therapy because of adverse effects.322,323,324,325,326,327,349,377 The most common reasons for discontinuance were psychiatric symptoms, flu-like syndrome (lethargy, fatigue, headache), adverse dermatologic effects, adverse GI effects, and adverse hematologic effects (anemia, neutropenia, thrombocytopenia).349,377

Adverse effects reported with oral ribavirin in conjunction with peginterferon alfa-2a in patients coinfected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) generally are similar to those reported in patients with HCV monoinfection (without HIV infection).377 However, adverse hematologic effects (anemia, neutropenia, thrombocytopenia), weight decrease, and mood alteration have been reported more frequently in those coinfected with HCV and HIV.377 In addition, there is an increased risk of hepatic decompensation in cirrhotic HCV patients coinfected with HIV receiving antiretroviral therapy and interferon alfa with or without oral ribavirin.377

For information on the adverse effects associated with peginterferon alfa or interferon alfa, see Cautions in Peginterferon Alfa 8:18.20 and see Cautions in Interferon Alfa 8:18.20.

Hematologic Effects

The primary toxicity or oral ribavirin is hemolytic anemia (hemoglobin less than 10 g/dL).349,377 Ribavirin appears to produce a dose-3,4,132,133,138,297 and time-dependent,3,4,133,138 reversible anemia,3,4,9,16,22,31,79,108,132,138,140,149,175,297 especially during oral1,4,13,108,113,133,175,252,253,254 or IV†1,4,19,79,113,154,297 use of the drug in dosages of 1.2 g or higher daily (about 15-17 mg/kg daily) for more than 10 days.3,4,9,22,31,79,108,140,149,158 (See Effects on Erythrocytes under Cautions: Nasal and Oral Inhalation.)

Anemia has been reported in 10-13% of patients receiving oral ribavirin in conjunction with peginterferon alfa or interferon alfa in clinical studies evaluating this regimen for treatment of HCV infection.349,377 Anemia also has been reported in patients receiving oral or IV† ribavirin for treatment146 or prevention257 of Lassa fever or Hantavirus infections;175,252,253,254,297

Ribavirin-associated anemia generally occurs within 1-2 weeks following initiation of oral ribavirin therapy,349,377 and the maximum hemoglobin decrease usually occurs during the first 8 weeks of therapy.377 Anemia may be mild and reversible within 2-4 weeks after discontinuance of the drug,146,175,252,253,254,257 although severe anemia which may require transfusion can occur, and complete reversal occasionally may be delayed for several months after discontinuance of ribavirin.175,253,297

Reversible increases in bilirubin and uric acid concentrations may occur as the result of hemolytic anemia.349,403 In clinical studies, these alterations occurred most frequently in patients previously diagnosed with Gilbert's syndrome and were generally moderate and reversed within 4 weeks of treatment discontinuance.349,403 An association with hepatic dysfunction or clinical morbidity has not been established.349,403

Ribavirin-induced anemia may result in deterioration in cardiac function and/or exacerbation of the symptoms of coronary disease; fatal and nonfatal myocardial infarctions have been reported in patients with ribavirin-associated anemia.349,377

Hepatic Effects

Transient increases in serum bilirubin,3,4,9,13,22,31,108,140,149 AST (SGOT),31,140,149 and ALT (SGPT)31 concentrations have occurred during use of oral9,13,22,108 or IV†9 ribavirin.

Patients with chronic HCV infection and cirrhosis may be at risk of hepatic decompensation and death during peginterferon alfa or interferon 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

Respiratory Effects

Adverse pulmonary effects, including dyspnea,349,377,402,403 pulmonary infiltrates,349,377,402,403 pneumonitis,349,377,402,403 pulmonary hypertension,349,377,402,403 pneumonia (including some fatalities),349,377,402,403 coughing, pharyngitis, rhinitis, and sinusitis, have occurred in patients receiving oral ribavirin in clinical studies. In addition, sarcoidosis or exacerbation of sarcoidosis has been reported.349,377,402,403

Nervous System Effects

Psychiatric events including insomnia, irritability, and depression have occurred in 26-39, 23-32, and 23-25% of patients, respectively, receiving oral ribavirin in conjunction with interferon alfa-2b in clinical studies.349 Suicidal ideation or attempts has been reported in about 1% of adults receiving such therapy in clinical studies; these events were more common in adolescents than adults.349

Other Adverse Effects

Serious skin reactions, including vesiculobullous eruptions, reactions in the spectrum of Stevens-Johnson syndrome with varying degrees of skin and mucosal involvement, and erythroderma, have been reported in patients receiving peginterferon alfa-2a with or without ribavirin.377

Dental and periodontal disorders have been reported in patients receiving ribavirin in conjunction with peginterferon alfa or interferon alfa.349,403 Dry mouth may result in damage to teeth and oral mucous membranes during long-term treatment.349,403

Hearing disorder,349 vertigo,349 and pancreatitis349 have been reported in patients receiving oral ribavirin in conjunction with peginterferon alfa or interferon alfa.

Nasal and Oral Inhalation

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 respiratory1 and cardiovascular effects;1 these effects generally occur infrequently.3,74,75,76,95,99,101,103

Although a definite causal relationship to the drug has not been established, serious adverse effects have occasionally occurred during ribavirin inhalation therapy in severely ill infants with underlying life-threatening conditions, many of whom required assisted respiration.1 Death has occurred in 20 patients during or shortly after discontinuance of ribavirin inhalation therapy, but a causal relationship to the drug was not clearly established.1,4,101 The long-term toxic potential of the drug in children has not been fully elucidated.201,202,203,205,207

Respiratory Effects

Worsening of respiratory function has occurred, sometimes suddenly, during ribavirin inhalation therapy in infants with RSV infections or in adults† with chronic obstructive pulmonary disease (COPD) or asthma.1,4 In infants with underlying life-threatening conditions, inhalation of the drug has been associated with aggravation and worsening of respiratory function, apnea, and physical dependence on assisted respiration.1,4 In adults with COPD or asthma, therapy with the drug frequently has been associated with deterioration in pulmonary function, and dyspnea and chest soreness have occurred in several adults with asthma.1,4,134 Minor pulmonary function abnormalities have also been observed in healthy adults receiving ribavirin inhalation.1,4 Bronchospasm, pulmonary edema, hypoventilation, cyanosis, dyspnea, bacterial pneumonia, pneumothorax, apnea, atelectasis, and ventilator dependence also have been associated with ribavirin inhalation therapy.1,4 Several deaths that were characterized as possibly related to ribavirin inhalation therapy by the treating physician occurred in infants who experienced worsening respiratory status related to bronchospasm while receiving the drug.1

Ribavirin inhalation therapy in patients who require assisted respiration137,182,183,196 has resulted in mechanical problems caused by precipitation of the drug in the respiratory apparatus, including the endotracheal tube and other tubing, and may result in inadequate assisted respiration and gas exchange in these patients.1,4,137,162 Increases in positive inspiratory and end-expiratory pressures have occurred in these patients as a result of drug precipitation and subsequent malfunction or obstruction of valves in the respiratory apparatus, and pneumothorax can result from such alterations in the pressures of the apparatus.1,4,137,196 Accumulation of fluid in tubing of the apparatus (“rain out”) has also occurred.1,4,137 There have been several deaths reported in infants with RSV who were undergoing assisted respiration while receiving ribavirin inhalation therapy.1 In these cases, death was attributed to mechanical ventilator malfunction caused by precipitation of the drug within the ventilator apparatus that led to excessively high pulmonary pressures and diminished oxygenation.1 Whenever ribavirin inhalation therapy is used in a patient requiring mechanical ventilator assistance, strict attention must be paid to procedures that have been shown to minimize the accumulation of drug precipitate.1,137,182,183,196,277,278 (See Nasal and Oral Inhalation under Cautions: Precautions and Contraindications and see Nasal and Oral Inhalation under Dosage and Administration: Reconstitution and Administration.)

Additional study is needed to determine the safety of prolonged and multiple courses of ribavirin inhalation therapy.61,159 In a study in developing ferrets, inhalation of ribavirin dosages of 60 mg/kg for 10 or 30 days resulted in inflammatory and possible emphysematous changes in the lungs,1 and proliferative changes were observed following dosages of 131 mg/kg for 30 days;1 however, the relevance of these findings to humans is not known.1,159 The manufacturer states that prolonged courses of ribavirin inhalation therapy are not recommended;1 some clinicians caution that prolonged or multiple courses of ribavirin inhalation therapy could potentially affect respiratory tract physiology secondary to biochemical changes and that high concentrations of the drug could affect respiratory membranes.

Cardiovascular Effects

Adverse cardiovascular effects, including cardiac arrest, hypotension, bradycardia, and cardiac glycoside intoxication, have been reported in patients receiving ribavirin inhalation therapy.1,4 In addition, bigeminy, bradycardia, and tachycardia have occurred with ribavirin inhalation in patients with underlying congenital heart disease.1 Cardiac lesions were observed in mice and rats receiving ribavirin inhalation dosages of 30 and 36 mg/kg daily, respectively, for 4 weeks, and in monkeys and rats receiving oral dosages of 120 and 154-200 mg/kg daily, respectively, for 1-6 months; however, the relevance of this finding to humans is not known.1

Effects on Erythrocytes

Although anemia was not reported with ribavirin inhalation therapy in several controlled clinical trials,1,4,9,101 most of these infants and young children who received the drug via inhalation were not evaluated 1-2 weeks following discontinuance of the drug, when evidence of ribavirin-induced anemia is most likely.1,4 Reversible anemia, reticulocytosis, and hemolytic anemia have been reported in postmarketing experience of patients receiving the drug via inhalation.1,4

Studies in animals and humans have shown that ribavirin and/or its metabolites accumulate in erythrocytes1,4,16,22,80,132,133,138,169 and persist for prolonged periods (e.g., weeks or longer) following administration of the drug,1,4 possibly because of minimal phosphatase activity in these cells.6,9 (See Pharmacokinetics: Distribution and Elimination.)

Ribavirin appears to produce a dose-3,4,132,133,138,297 and time-dependent,3,4,133,138 reversible anemia,3,4,9,16,22,31,79,108,132,138,140,149,175,297 especially during oral1,4,13,108,113,133,175,252,253,254 or IV1,4,19,79,113,154,297 use of the drug in dosages of 1.2 g or higher daily (about 15-17 mg/kg daily) for more than 10 days.3,4,9,22,31,79,108,140,149,158 Ribavirin-induced anemia appears to result from hemolysis of erythrocytes16,22,132,133,138,146,297 and inhibition of late stages of erythrocyte maturation in bone marrow.16,22,132,133,138,297 The drug does not appear to affect erythrocyte stem cells.22,132,133,138 Ribavirin also does not appear to affect the maturation of leukocyte precursors or leukocytes16,132 and may increase the production of megakaryocytes and thrombocytes.132

Other Adverse Effects

Rash,1,4 erythema of the eyelids,91 and conjunctivitis1,4,94 have occurred in patients receiving ribavirin inhalation therapy. These effects usually resolve within hours after ribavirin therapy is discontinued.1

Adverse hepatic effects, including increased transaminase concentrations, have not been observed during ribavirin inhalation therapy.9,74,75,76,91,93,94,95,158,159

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 but acute effects do not appear to be substantial.171,172,189,192,195,206,216,217,227,228,229,234,235,236,237,238,239,240,241,242,243,247,261,266,267 However, because of animal evidence of ribavirin's teratogenic potential and absence of data defining safe levels of aerosol exposure to the drug, some experts and clinicians state that such exposure of pregnant women171,172,216,217,218,226,227,228,234,238,239,240,241,242,243,244,247,263,265,267 and possibly those who may become pregnant171,172,216,265 may represent a risk to the fetus. Evidence from several studies in which health-care personnel were exposed to ribavirin while in contact with patients undergoing ribavirin inhalation therapy revealed minimal concentrations of the drug in urine284 or erythrocytes (in only a single sample)171,172,244,249 and undetectable concentrations in plasma or serum, and no adverse effects attributable to the drug in these personnel.171,172,189,236,238 However, only a limited number of personnel were studied.172,189,236,238,284 In one study, urinary concentrations of ribavirin were measurable in 65% of nurses caring for children receiving aerosolized ribavirin via a variety of administration methods and in 15% of respiratory therapists, with creatinine-corrected urinary concentrations of the drug averaging 4.25 (range: less than 0.25 up to 35) ng of ribavirin per mg of creatinine.284

The most frequent adverse effects reported to date in health-care personnel exposed to aerosolized ribavirin include eye irritation (which may be more likely in contact lens wearers) and headache, which usually were mild and reversible following discontinuance of exposure.1,231,232,234,235,265 Nasal and/or throat irritation, pharyngitis, lacrimation, nausea, dizziness, fatigue, rash, bronchospasm, rhinitis, chest pain, and nasal congestion also have been reported in health-care personnel in contact with patients undergoing ribavirin inhalation therapy.1,232,235,265 A causal relationship between many of these adverse effects and ribavirin exposure has not been established.1,216,235,265 In most cases, these adverse effects resolved within minutes to hours of discontinuing close exposure to aerosolized ribavirin1 and few of the personnel exposed to aerosolized drug required medical attention.234,235 Ribavirin can precipitate on contact lenses of health-care personnel exposed to aerosolized drug,231,232 and such precipitation may be associated with conjunctivitis.231,265 Therefore, it has been suggested that contact lens wearers use eyeglasses rather than contact lenses or, alternatively, use protective goggles while potentially in contact with aerosolized ribavirin.231,265,284,318

Evidence from several studies indicates that measurable exposure of health-care personnel to the drug can occur, the level of which depends on the method of drug administration to the patient1,171,172,218,225,226,236,237,238,239,240,241,246,247,248,249,284 and probably other factors including length of exposure, number of patients treated in a room simultaneously, room ventilation, administration schedule, integrity of the small-particle aerosol generator, and variations in work practices (e.g., turning off the small-particle aerosol generator before manipulating the delivery apparatus).218,235,236,238,239,240,241,248,284 In a few of these studies in which personal-breathing-zone area air samples from health-care personnel (nurses and respiratory therapists) and bedside area air samples were collected, the highest levels of exposure occurred during contact with patients receiving the drug via a tracheostomy tube,218,241,249 followed by those receiving the drug via an oxygen hood218,236,238 or tent,171,172,249 and the lowest level occurred during contact with those receiving the drug via a ventilator1,171,172,236,248,249,284 that included an in-line filter in the expiratory line.171,172 An exposure level intermediate to the tent/hood and the ventilator was observed during contact with a patient receiving the drug via a face mask,171,172,249 and exposure levels higher than those with a ventilator but lower than those with a face mask were observed with an aerosol delivery hood that included a vacuum exhaust filtration system (available from Valeant) or with a croup tent (croupette).236,239,284 Exposure levels observed with an aerosol delivery hood combined with a scavenging tent were lower than those with an aerosol delivery hood alone and similar to those with a ventilator.284 Ribavirin concentrations in personal area air samples reportedly averaged 579 mcg/m³ (range: 390-828 mcg/m³) for personnel in contact with patients receiving the drug via a tracheostomy tube,218 485 mcg/m³ (range: 26-1692 mcg/m³) for those in contact with patients receiving the drug via an oxygen hood,236 161 mcg/m³ (range: 69-316 mcg/m³) for those in contact with patients receiving the drug via an oxygen tent,171,172,249 25-34 mcg/m³ (range: 1-91 mcg/m³) for those in contact with patients receiving the drug via an aerosol delivery hood with a vacuum exhaust filtration system,236,284 23 mcg/m³ (range: 12-28 mcg/m³ for those in contact with patients receiving the drug via a croup tent,284 6 mcg/m³ (range: undetectable to 12 mcg/m³) for those in contact with patients receiving the drug via an aerosol delivery hood combined with a scavenging tent,284 and 6 or less mcg/m³ for those in contact with patients receiving the drug via a ventilator;171,172,236,248,249,284 concentrations in bedside area air samples generally substantially exceeded those in personal area air samples171,172,218,241,249 In a pilot study involving one patient receiving ribavirin via a double-tent system (consisting of an oxygen tent canopy over an oxygen hood), undetectable concentrations of ribavirin were found in personal-breathing-zone area air samples from health-care personnel and in bedside area samples.246 However, further studies are needed to evaluate the double-tent system.246 In addition, theoretical estimates based on exposure data from these studies indicate that the amount of ribavirin that potentially could be absorbed systemically by personnel receiving relatively high-level exposure (e.g., during contact with patients receiving the drug via an oxygen tent) could potentially represent a risk to the fetus.171,172,225,249

Until potential risks of exposure are more clearly delineated, health-care personnel who provide direct care to patients receiving aerosolized ribavirin and are pregnant, lactating, or in relationships of likely reproductive potential should be counseled about risk-reduction strategies, including alternative job responsibilities.171,172,216,217,218,226,227,238,239,240,241,247,266,267,318 Visitors (including family members) of patients receiving aerosolized ribavirin also should be advised of the potential risks associated with exposure to the drug since they may spend considerable time in close proximity to the patient's bedside.171,172,218,238,239,241,247,266,284,318 Data currently available cannot be extrapolated reliably to assess possible risks to individuals working elsewhere in a room or ward where ribavirin is being administered via aerosolization.171 However, measurable concentrations of ribavirin have been detected in the air at nurses' stations located near the rooms of patients receiving ribavirin inhalation therapy via an oxygen hood, an aerosol delivery hood, a croup tent, or an aerosol delivery hood in combination with a scavenging tent.238,284 Such measurable exposure may have resulted from positive pressure or inadequate negative pressure in patient rooms.284

Because of uncertainties about potential risk, procedures to minimize environmental exposure to aerosolized ribavirin generally should be developed.1,171,172,216,217,218,225,226,227,228,229,230,236,237,238,239,240,241,243,247,249,267 Whenever possible, patients receiving ribavirin inhalation therapy should be located in rooms where potential exposure of personnel and other patients is minimized (e.g., private rooms with adequate ventilation or, preferably, the National Institute for Occupational Safety and Health [NIOSH] recommends isolation rooms that are under negative pressure and have adequate air exchange and exhaust to the outside).1,172,216,217,218,225,226,227,230,238,239,241,244,247,249,266,284,318 Use of gowns, gloves, goggles, and masks, which already may be part of the usual procedures for minimizing nosocomial spread of RSV when in contact with infected patients, has been suggested, although the level of protection provided is not known.216,217,225,226,227,235,237,238,239,240,244,245,247,249,266,284 Some experts, including NIOSH, state that use of surgical masks by health-care personnel caring for ribavirin-treated patients probably is unlikely to provide an effective means for reducing environmental exposure to the drug,1,171,172,194,217,218,238,239,240,241,244,249,284 and therefore currently is not recommended by these experts as a primary protective measure.171,172,218,238,239,240,241,249,284 However, use of alternative, appropriately designed (e.g., for adequate particle-size filtration) and well-fitted face masks (e.g., 3M Company model 9970)216,217,225,226,235,237,284 or powered air-purifying respirators237 may provide protection. In deciding the method of administration of ribavirin inhalation therapy, current data on associated exposure levels should be considered, and, whenever possible, methods associated with the lowest levels of exposure employed.171,172,216,218,236,237,238,239,240,241,247,284 Except when immediate care is necessary, the small-particle aerosol generator should be turned off (using a remote switch) temporarily, but for at least 5-10 minutes before entering the room, when attending to the patient and when handling the respiratory apparatus.1,217,218,226,235,236,238,239,240,241,244,267,284 In addition, the air pressure of the ribavirin treatment room should be evaluated (e.g., using tissue paper at the ajar doorway) and ideally be negative relative to the hallway prior to initiation of a treatment session.284 An aerosol delivery hood intended for use in administering oxygen and aerosolized ribavirin and that includes a vacuum exhaust filtration system has recently become available from the manufacturer of ribavirin (Valeant) and reportedly can substantially reduce the risk of aerosol emission into the environment during ribavirin inhalation therapy.216,217,226,230,236,248,250 Other devices, procedures, and precautions to minimize environmental exposure to aerosolized ribavirin have been suggested, and occupational safety or other experts should be consulted for additional information.172,217,218,225,226,235,237,238,239,240,241,244,245,246,247,248,249,250,262,264,284 NIOSH currently is gathering additional information on potential risks associated with environmental exposure to aerosolized ribavirin by health-care personnel; results of these evaluations will be made available by NIOSH upon completion.238,239,240,241,247

Precautions and Contraindications

Oral Administration

Oral ribavirin is contraindicated in patients with known hypersensitivity to ribavirin or any component of the formulations.349,377,402,403 The drug should be discontinued immediately and appropriate therapy initiated if an acute hypersensitivity reaction (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) occurs.377 The drug should also be discontinued in patients with manifestations of severe skin reactions (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme).377

Oral ribavirin is contraindicated in women who are or may become pregnant and also is contraindicated in male partners of pregnant women.349,377,402,403 (See Pregnancy under Cautions: Pregnancy, Fertility, and Lactation.)

Oral ribavirin is contraindicated in patients with hemoglobinopathies (e.g., thalassemia, sickle cell anemia).349,377,402,403

Concomitant use of oral ribavirin and didanosine is contraindicated.349,377,402,403 (See Increased Risk of Adverse Effects under Antiretroviral Agents: HIV Nucleoside Reverse Transcriptase Inhibitors, in Drug Interactions.)

Oral ribavirin capsules (Rebetol^®, Ribasphere^®), tablets (generic), and oral solution (Rebetol^®) are contraindicated in patients with creatinine clearance less than 50 mL/minute.349,402,403

Use of oral ribavirin and peginterferon alfa or interferon alfa is contraindicated in patients with autoimmune hepatitis.349,377,402,403

Use of ribavirin tablets (Copegus^®, generic) in conjunction with peginterferon alfa-2a is contraindicated in cirrhotic patients with chronic HCV monoinfection (without coexisting HIV infection) who have hepatic decompensation (Child-Pugh score greater than 6; class B and C) prior to or during treatment.377,402

Use of ribavirin tablets (Copegus^®, generic) in conjunction with peginterferon alfa-2a is contraindicated in cirrhotic patients with chronic HCV infection who are coinfected with HIV and have hepatic decompensation (Child-Pugh score 6 or greater) prior to or during treatment.377,402

Hematologic and Cardiac Precautions

Patients receiving oral ribavirin should be monitored for the development of anemia.349,377,402,403 (See Hematologic Effects under Cautions: Oral Administration.) 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 (or more frequently if needed), and then as clinically appropriate.349,377,402,403 Other standard hematologic tests, including complete and differential white blood cell counts and platelet counts, also should be performed prior to and periodically during oral ribavirin therapy.349,377,402,403 Ribavirin should be used with caution in patients with baseline risk of severe anemia (e.g., spherocytosis, history of GI bleeding).377,402

The manufacturers state that the entry criteria used in clinical studies evaluating safety and efficacy of oral ribavirin (Copegus^®) and peginterferon alfa-2a for treatment of chronic HCV infection can be considered a guideline for acceptable baseline values for initiation of therapy.377,402 These studies required that hemoglobin be at least 12 g/dL in women and at least 13 g/dL in men with HCV monoinfection (without concomitant HIV infection) or at least 11 g/dL in women and at least 12 g/dL in men coinfected with HCV and HIV.377,402 In addition, these studies required that platelet counts be at least 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 at least 1500/mm³.377,402

If use of IV† ribavirin therapy is being considered, some clinicians recommend that baseline hemoglobin concentrations of 8 g/dL or less should be corrected prior to initiation of the drug and patients monitored closely throughout the course of treatment.297

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.349,377,402,403 Those with preexisting cardiac disease should have ECGs before the drug is initiated and should be appropriately monitored during therapy.349,377,402,403 If there is any deterioration of cardiovascular status, oral ribavirin should be suspended or discontinued.349,377,402,403 Oral ribavirin should not be used in patients with a history of substantial or unstable cardiac disease.349,377,402,403

Precautions Related to Combination HCV Treatment Regimens

Oral ribavirin monotherapy is not effective349,377 and should not be used for treatment of chronic HCV infection.119,349,377

When oral ribavirin is used in conjunction with peginterferon alfa or interferon alfa, the cautions, precautions, and contraindications associated with both oral ribavirin and peginterferon alfa or interferon alfa should be considered.20,349,377,388 (See Cautions in Peginterferon Alfa 8:18.20 and in Interferon Alfa 8:18.20.)

Safety and efficacy of oral ribavirin in conjunction with peginterferon alfa or interferon alfa have not been established in liver or other organ transplant recipients,349,377,402,403 patients coinfected with HCV and hepatitis B virus (HBV),349,403 or patients with HCV infection and decompensated liver disease.349,377,402,403

Safety and efficacy of ribavirin capsules (Rebetol^®, Ribasphere^®) in conjunction with peginterferon alfa or nonconjugated interferon alfa-2b have not been established in chronic HCV patients coinfected with HIV.349,403

Some manufacturers state that safety and efficacy of ribavirin tablets (Copegus^®, generic) in conjunction with peginterferon alfa-2a have not been established in chronic HCV patients who have not responded to interferon therapy377,402 or are coinfected with HIV and have CD4⁺ T-cell counts less than 100/mm³.377

Safety and efficacy of oral ribavirin in conjunction with peginterferon alfa or interferon alfa for treatment of infections caused by HIV, adenovirus, RSV, parainfluenza, or influenza virus have not been established and this regimen should not be used for these indications.349,377

Patients receiving oral ribavirin in conjunction with peginterferon alfa or interferon alfa for treatment of chronic HCV infection should be advised that the effect of such treatment on transmission of the virus is not known and that appropriate precautions should be taken to prevent transmission.349,377

Patients who experience pulmonary infiltrates or a deterioration in pulmonary function while receiving oral ribavirin with peginterferon alfa or interferon alfa should be closely monitored and, if appropriate, the drugs should be discontinued.349,377

Oral ribavirin in conjunction with peginterferon alfa or interferon alfa should be suspended in patients with manifestations of pancreatitis and discontinued in those with confirmed pancreatitis.349,377

When oral ribavirin is used in a multiple-drug regimen that includes one or more HCV direct-acting antivirals (DAAs), including those classified as HCV protease inhibitors (e.g., paritaprevir, simeprevir), HCV polymerase inhibitors (e.g., dasabuvir, sofosbuvir), or HCV replication complex inhibitors (e.g., ombitasvir), the cautions, precautions, and contraindications associated with the HCV DAAs also should be considered.179,180,187,188 (See Cautions in the individual monographs in HCV Antivirals 8:18.40.)

Other Precautions

Thyroid function should be assessed prior to and periodically during oral ribavirin therapy.349,377 In clinical studies evaluating use of oral ribavirin (Copegus^®) and peginterferon alfa-2a for treatment of chronic HCV infection, study entry criteria required thyrotropin (thyroid-stimulating hormone, TSH) and thyroxine (T₄) concentrations within normal limits or adequately controlled thyroid function.377

Patients should be advised to have regular dental examinations during treatment, brush their teeth thoroughly twice daily, and rinse their mouth thoroughly after vomiting.349,403

Nasal and Oral Inhalation

Ribavirin inhalation therapy is contraindicated in patients with known hypersensitivity to the drug or any ingredient in the formulation and also is contraindicated in women who are or may become pregnant.1

Ribavirin nasal and oral inhalation therapy is not a substitute for usual supportive respiratory therapy and fluid management in infants and young children with severe lower respiratory tract infection caused by respiratory syncytial virus (RSV),1,4,89 and careful monitoring of respiratory function and fluid balance in these patients is necessary.1 Although the manufacturer states that use of ribavirin inhalation currently is recommended only for pediatric patients with severe RSV lower respiratory tract infection,1 if the inhalation is used in other patients†, careful monitoring of respiratory function is necessary during inhalation therapy.1,137 Because initiation of ribavirin inhalation therapy in infants has been associated with sudden deterioration of respiratory function, the drug 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

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.1,137,159,182,183,196 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.1,137,159,162,182,183,196 These procedures include use of bacterial filters in series in the expiratory limb of the ventilator circuit with frequent changes (e.g., 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 (See Nasal and Oral Inhalation under Dosage and Administration: Reconstitution and Administration.)

Patients receiving ribavirin inhalation therapy for longer than 1-2 weeks should be monitored for the development of anemia (see Effects on Erythrocytes under Cautions: Nasal and Oral Inhalation);158,159 monitoring for this adverse effect generally is not considered necessary in patients receiving the inhalation for 7 days or less.158,159 The risk of developing anemia and need for close monitoring are increased in patients receiving systemic (e.g., oral, IV) ribavirin therapy.1,4,9,13,19,22,79,108,113,133,146,154,175,252,253,254,297

The manufacturer states that although ribavirin inhalation currently is not intended for use in adults, clinicians should be aware that the drug is teratogenic in animals and ribavirin therapy should not be initiated in women of childbearing potential.1 (See Pregnancy under Cautions: Pregnancy, Fertility, and Lactation.) Some experts state that potential risk of environmental exposure to aerosolized ribavirin by pregnant health-care personnel or visitors should be considered.171,172,216,217,218,226,227,238,239,240,241,247 (See Environmental Exposure of Health-care Personnel and Visitors under Cautions: Nasal and Oral Inhalation.)

Pediatric Precautions

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 oral capsules (Rebetol^®, Ribasphere^®) or ribavirin oral solution (Rebetol^®) in conjunction with peginterferon alfa-2b or nonconjugated interferon alfa-2b have not been established for treatment of chronic HCV infection in children younger than 3 years of age.349,403 When deciding whether to use such regimens in HCV-infected children, evidence of disease progression (hepatic inflammation, fibrosis), prognostic factors for response, HCV genotype, and viral load should be considered.349,403 The benefits of such treatment should be weighed against adverse effects reported in pediatric patients.349,403,349 Concomitant therapy with ribavirin capsules or oral solution (Rebetol^®) and peginterferon alfa-2b or nonconjugated interferon alfa-2b should not be used in pediatric patients with serum creatinine concentrations greater than 2 mg/dL.349

Safety and efficacy of ribavirin tablets (Copegus^®) in conjunction with peginterferon alfa-2b have not been established for treatment of chronic HCV infection in children younger than 5 years of age.377 Some manufacturers state that safety and efficacy of ribavirin tablets have not been established in patients younger than 18 years of age.402

Adverse effects reported with oral ribavirin in conjunction with peginterferon alfa or interferon alfa in pediatric patients generally are similar to those reported in adults.349,377 In clinical studies in children, 2-13% of patients discontinued oral ribavirin and interferon alfa therapy because of adverse effects; dosage modifications were required in 25-30%, usually because of anemia, neutropenia, or weight loss.349,377 Among patients receiving concomitant therapy with ribavirin capsules and interferon alfa-2b, injection site disorders, fever, anorexia, vomiting, and emotional lability were reported more frequently in pediatric patients than in adults; however, fatigue, dyspepsia, arthralgia, insomnia, irritability, impaired concentrations, dyspnea, and pruritus were reported less frequently in pediatric patients than in adults.349 Overall, 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.349 Like adults, other adverse psychiatric effects (depression, emotional lability, somnolence), anemia, and neutropenia were also reported in pediatric patients.349

Delays in weight and height gain compared with baseline have been reported in pediatric patients receiving peginterferon alfa and oral ribavirin therapy.349,377,403 Decreased weight and height for age z-scores as well as percentiles of the normative population have been reported.349,377,403 Data from pediatric patients receiving peginterferon alfa-2a and oral ribavirin indicate that at the end of treatment 43% experienced a weight percentile decrease of 15 percentiles or more and 25% experienced a height percentile decrease of 15 percentiles or more on the normative growth curves.377 Most children had returned to baseline normative growth curve percentiles for weight and height at the end of 2-year follow-up after completion of treatment (mean weight for age percentile was 64% at baseline and 60% at 2 years posttreatment, mean height percentile was 54% at baseline and 56% at 2 years posttreatment).377

Data from an open-label trial in pediatric patients 3 through 17 years of age receiving peginterferon alfa-2b and oral ribavirin indicated that weight and height gain generally lagged behind that predicted by normative population data for the entire length of treatment.349 During a 48-week treatment course, there was a decrease in the rate of linear growth (mean percentile assignment decrease of 7%) and a decrease in the rate of weight gain (mean percentile assignment decrease of 9%).349 Although a general reversal of these trends was noted during the 24-week posttreatment period, long-term follow-up data in pediatric patients indicate that oral ribavirin and peginterferon alfa-2b treatment may induce a growth inhibition that results in reduced final adult height in some patients.349

Geriatric Precautions

Clinical studies of oral ribavirin used in conjunction with peginterferon alfa or interferon alfa did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients.349,377 In clinical trials, geriatric patients had a higher frequency of anemia (67%) than did younger patients (28%).349

Oral ribavirin 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.349 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.349,377 Oral ribavirin capsules (Rebetol^®, Ribasphere^®)349,403 , tablets (generic),402 and oral solution (Rebetol^®)349 should not be used in geriatric patients with creatinine clearance less than 50 mL/minute;349 dosage of ribavirin tablets (Copegus^®) should be adjusted for patients with creatinine clearance less than 50 mL/minute.377 (See Renal Impairment under Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Mutagenicity and Carcinogenicity

Ribavirin increased the incidence of cell transformations and mutations in mouse Balb/c 3T3 fibroblasts at concentrations of 0.015 mg/mL and in L5178Y lymphoma cells at concentrations of 0.03-5 mg/mL (without metabolic activation).1 In vitro, in L5178Y cells with the addition of a metabolic activation fraction, there were modest increases in mutation rates (3-4 times higher) at ribavirin concentrations of 3.75-10 mg/mL.1 In the mouse micronucleus assay, ribavirin was clastogenic at IV doses of 20-200 mg/kg (estimated human equivalent of 1.67-16.7 mg/kg based on body surface area adjustment for a 60-kg adult); however, the drug was not mutagenic in a dominant lethal assay in rats at intraperitoneal doses of 50-200 mg/kg administered for 5 days (estimated human equivalent of 7.14-28.6 mg/kg based on body surface area adjustment for the adult).1

The carcinogenic potential of ribavirin has not been fully determined.1,4,349,377 Results of a chronic feeding study in rats receiving 16-100 mg/kg daily (estimated human equivalent of 2.3-14.3 mg/kg daily based on body surface area adjustment for the adult) suggest that ribavirin may induce benign mammary, pancreatic, pituitary, and adrenal tumors.1 Preliminary results of 2 oral gavage oncogenicity studies in mice and rats receiving 18-24 months of ribavirin are inconclusive as to the carcinogenic potential of the drug but demonstrate a relationship between chronic ribavirin exposure and increased incidences of vascular lesions (microscopic hemorrhages) in mice and retinal degeneration in rats.1 The mice and rats in these studies received 20-75 and 10-40 mg/kg, respectively, of ribavirin daily (estimated human equivalent of 1.67-6.25 and 1.43-5.71 mg/kg, respectively, daily based on body surface area adjustment for the adult).1

Pregnancy, Fertility, and Lactation

Pregnancy

Ribavirin may cause fetal toxicity and/or death.1,349,377 The drug has been shown to be teratogenic and/or embryocidal in almost all animal species tested to date.1,3,4,13,16,131,135,140,149,171,172,259,349,377 Malformations of the skull, palate, eye, jaw, limbs, skeleton, and GI tract have been reported in animal studies.1,4,131,135,136,139,349,377 The incidence and severity of teratogenic effects increase with increasing dosage.1,377

Oral ribavirin is contraindicated in women who are or may become pregnant and also is contraindicated in male partners of such women.349,377

Extreme care should be exercised to avoid pregnancy in female patients receiving ribavirin and in female partners of male patients receiving ribavirin.349,377 In addition, based on a multiple-dose ribavirin half-life of 12 days, pregnancy also should be avoided in female patients and in female partners of male patients for 6 months after oral ribavirin is discontinued (e.g., 15 half-lives of clearance for ribavirin).349,377 Oral ribavirin should not be initiated until a report of a negative pregnancy test has been obtained; the pregnancy test should be performed immediately prior to initiating therapy.349,377 Women of childbearing potential and men with female partners of childbearing potential should be counseled about effective contraception and must use 2 reliable forms of contraception during and, because of the long half-life of the drug, for 6 months following completion of therapy.349,377 Pregnancy tests should be performed monthly during and for 6 months after the drug is discontinued.349,377 If ribavirin is inadvertently administered during pregnancy or if the patient becomes pregnant while receiving the drug or up to 6 months after discontinuance, the patient should be informed of the potential hazard to the fetus.145,158,159,349,377 If pregnancy occurs in a patient or in the partner of a patient receiving oral ribavirin or during the 6 months following completion of therapy, clinicians and patients are encouraged to report such cases to the ribavirin pregnancy registry at 800-593-2214.349,377,402,403

Ribavirin nasal and oral inhalation is contraindicated in women who are or may become pregnant.1,4 In addition, because of animal evidence of the drug's teratogenic potential, some experts state that environmental exposure to aerosolized ribavirin by pregnant health-care personnel or visitors may represent a risk to the fetus.171,172,216,217,218,226,227,234,238,239,240,241,242,243,244,247 Whether a potential risk exists for women exposed to aerosolized ribavirin in the environment who may become pregnant remains controversial,171,172,217,218,238,239,241,247 but some experts and clinicians state that such women at least should be advised of the drug's teratogenic potential.171,172,216,218,226,227,234 (See Environmental Exposure of Health-care Personnel and Visitors under Cautions: Nasal and Oral Inhalation.)

Evidence of teratogenicity was observed following a single oral ribavirin dose of 2.5 mg/kg in hamsters and following oral dosages of 1 mg/kg daily in rats.1,4,16,135,172,259 Abnormalities of the skull, brain, skin, palate, eye, jaw, skeleton, and GI tract1,4,131,135,136,139,349,377 were observed in rats receiving oral ribavirin dosages of 10, 30, 60, or 90 mg/kg daily on days 6-15 of gestation131,139 and in hamsters receiving oral and/or parenteral dosages of 2.5-5 or 25 mg/kg on days 7-9 or 12-15 of gestation, respectively.135,136,139 Reproduction studies in rats using oral ribavirin dosages of 60 and 90 mg/kg daily have shown decreases in the number of live births131,259 and in fetal survival (first and second generation).1,4,131 Reproduction studies in hamsters using an IV ribavirin dose of 5 mg/kg on day 8 of gestation have shown an increased rate of resorption.135 Ribavirin has been shown to produce skeletal malformations in rabbits receiving oral dosages of 0.3 mg/kg daily and was embryocidal in rabbits receiving oral dosages of 1 mg/kg daily.1,4,16,172,259 When administered orally in dosages of 120 mg/kg daily in baboons, however, ribavirin showed no evidence of teratogenic or embryocidal effects.3,4,16,131,140,149,172

Fertility

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 daily1,16,131 (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 (estimated human equivalent of 1.25-12.5 mg/kg/day, based on body surface area adjustment for a 60-kg adult; 0.1-0.8 times the maximum human 24-hour dose of ribavirin) administered for 3 or 6 months.349 Essentially total recovery from ribavirin-induced testicular toxicity was apparent within 1 or 2 spermatogenesis cycles following discontinuance of the drug.349 However, ribavirin is known to accumulate in intracellular components of cells 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.349

Oral ribavirin should be used with caution in fertile men.349 Men receiving oral ribavirin are advised to take every precaution (i.e., effective contraception using 2 reliable forms) to avoid risk of pregnancy in their female partners during and for 6 months following completion of therapy.349,377

Lactation

Ribavirin has been shown to be toxic to lactating animals and their offspring.1 It is not known whether ribavirin is distributed into milk following nasal or oral inhalation or oral administration in humans.1,349,377

Because of the potential for serious adverse reactions to oral ribavirin in nursing infants, a decision should be made whether to discontinue nursing or to delay or discontinue oral ribavirin therapy taking into account the importance of the drug to the woman.349,377

The following drug interactions are based on studies using oral ribavirin.349,377,402,403 Studies have not been performed to evaluate potential drug interactions in infants receiving ribavirin nasal and oral inhalation concomitantly with other drugs (e.g., digoxin, diuretics, respiratory smooth muscle relaxants such as theophylline, anti-infectives, antimetabolites, other antiviral agents).1,4,214

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

In vitro studies indicate that ribavirin does not inhibit and is not a substrate for cytochrome P-450 (CYP) enzymes.349,377 Therefore, there is little potential for drug interactions with drugs affecting or metabolized by CYP enzymes;349 no effect on the pharmacokinetics of representative drugs metabolized by CYP2C9, 2C19, 2D6, or 3A4 have been reported.377

Antacids

Although the clinical importance is unknown, concomitant administration of a single dose of oral ribavirin and a single dose of antacid containing magnesium, aluminum, and simethicone (Mylanta^®) decreased the mean area under the plasma concentration-time curve (AUC) of ribavirin by 14%.349

Antiretroviral Agents

HIV Nucleoside Reverse Transcriptase Inhibitors

There is evidence that concomitant use of ribavirin and human immunodeficiency virus (HIV) nucleoside reverse transcriptase inhibitors (NRTIs) may increase the risk of certain adverse effects associated with mitochondrial dysfunction (e.g., potentially fatal hepatic failure, peripheral neuropathy, pancreatitis, symptomatic hyperlactatemia/lactic acidosis).349,352,353,354

Although there have been some reports that ribavirin may potentiate the antiretroviral activity of didanosine,280,281,282,353,354 there is evidence from in vitro studies that ribavirin may antagonize the antiretroviral activity of some other NRTIs (e.g., lamivudine, stavudine, zidovudine).173,222,279,349,377

Concomitant use of oral ribavirin and lamivudine, stavudine, or zidovudine in patients coinfected with hepatitis C virus (HCV) and 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.377

Increased Risk of Adverse Effects

Concomitant use of oral ribavirin and didanosine is contraindicated because there have been reports of fatal hepatic failure, peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis in patients receiving the drugs concomitantly.200,349,377,402,403

Concomitant use of oral ribavirin and zidovudine is not recommended because of the potential for worsening anemia.200 If ribavirin and zidovudine are used concomitantly, caution is advised and patients should be closely monitored for virologic response and toxicities, particularly anemia, hepatic decompensation, and neutropenia.200,222,349,377,402,403 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 oral ribavirin compared with those not receiving zidovudine.377 In patients receiving zidovudine concomitantly with interferon alfa and ribavirin, consideration should be given to discontinuing zidovudine, as medically appropriate.222 In patients receiving established HIV and HCV treatment, consideration should be given to replacing zidovudine.222,190

Oral ribavirin should be used concomitantly with stavudine with caution.349,377,402,403

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.349,377 Dosage reduction or discontinuance of peginterferon alfa (or interferon alfa) and/or oral ribavirin should be considered if worsening toxicities occur.349,377 The concomitant regimen should be discontinued if hepatic decompensation occurs.377 Prescribing information for the specific NRTI should be consulted for guidance regarding toxicity management.349,377

Cirrhotic patients with chronic HCV infection who are coinfected with HIV and receiving antiretroviral therapy concomitantly with a regimen of interferon alfa or peginterferon alfa and oral ribavirin may be at increased risk of potentially fatal hepatic decompensation compared with those not receiving highly active antiretroviral therapy (HAART).349,377 There have been several reports of lactic acidosis or pancreatitis occurring in HIV-infected patients coinfected with HCV who received antiretroviral therapy concomitantly with ribavirin and interferon alfa therapy.352,354 These patients had been receiving long-term therapy with antiretroviral regimens that included one or more NRTIs (abacavir, didanosine, lamivudine, stavudine, zidovudine) and were clinically stable until lactic acidosis or pancreatitis developed 4-6 months after a regimen of ribavirin and interferon alfa was initiated for treatment of chronic HCV infection.352,354 In addition, hepatic decompensation (including some fatalities) were reported in a study evaluating a regimen of peginterferon alfa-2a and oral ribavirin in patients coinfected with HCV and HIV; all those who developed hepatic decompensation were cirrhotic at baseline and were receiving NRTIs (e.g., abacavir, didanosine, lamivudine, stavudine, zidovudine).377

Because ribavirin also is a nucleoside analog, it has been suggested that concomitant use of ribavirin and NRTIs may result in an adverse additive effect on mitochondrial function; however, it also has been suggested that ribavirin may have potentiated the adverse effects of the NRTIs through some other mechanism or that the viral diseases themselves may have been partly responsible for mitochondrial dysfunction in these patients.352,353,354,355

Synergism and/or Antagonism

Results of in vitro tests in various cell cultures and peripheral blood lymphocytes indicate that ribavirin may potentiate the antiretroviral effects of didanosine against HIV by promoting formation of didanosine-5'-triphosphate (ddA-TP), the metabolically active metabolite of didanosine.280,281,282,353,354 Conversely, there is some evidence from in vitro studies that ribavirin antagonizes the antiretroviral activity of some other NRTIs (e.g., stavudine, zidovudine).173,220,222,279,349,377 The mechanism by which ribavirin antagonizes the antiretroviral effects of these NRTIs has not been elucidated but it has been suggested that ribavirin may interfere with phosphorylation steps that convert the drugs to their active triphosphate metabolite, deoxythymidine triphosphate (dT-TP) or dideoxycytidine-5'-triphosphate (ddC-TP), respectively. 173,279,349,352,377 Despite this in vitro antagonism, antiretroviral regimens that include zidovudine or stavudine have been used concomitantly with ribavirin (with or without interferon alfa or peginterferon alfa) in some HIV-infected patients coinfected with HCV without evidence of an increase in HIV viral load.349,350,377

Azathioprine

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.349,377,402,403 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 and oral ribavirin was reinitiated alone.349,377,402,403 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.349,377,402,403

If azathioprine and a regimen of peginterferon alfa and oral ribavirin are used concomitantly, complete blood counts (CBCs), including platelet counts, should be monitored weekly for the first month, twice monthly during the second and third months of treatment, and then monthly or more frequently if necessary.349,377,402,403 If pancytopenia develops, all 3 drugs (azathioprine, ribavirin, peginterferon alfa) should be discontinued and peginterferon alfa and oral ribavirin therapy should not be restarted with concomitant azathioprine.349,377,402,403

HCV Antivirals

HCV Polymerase Inhibitors

Dasabuvir

There is no in vitro evidence of antagonism between the fixed combination of ombitasvir, paritaprevir, and dasabuvir (ombitasvir/paritaprevir/dasabuvir) and ribavirin against HCV.180

Sofosbuvir

There is no in vitro evidence of antagonism between sofosbuvir and ribavirin against HCV.188

HCV Protease Inhibitors

Paritaprevir

There is no in vitro evidence of antagonism between the fixed combination ombitasvir/paritaprevir/dasabuvir and ribavirin against HCV.180

Simeprevir

Concomitant use of simeprevir with ribavirin and peginterferon alfa does not affect simeprevir concentrations or AUC compared with use of simeprevir alone.187

In vitro, simeprevir and ribavirin have additive effects against HCV;114 there is no in vitro evidence of antagonism between simeprevir and ribavirin against HCV.114,187

HCV Replication Complex Inhibitors

Daclatasvir

Concomitant use of daclatasvir with ribavirin is not expected to result in any clinically important interactions.178

Ombitasvir

There is no in vitro evidence of antagonism between the fixed combination ombitasvir/paritaprevir/dasabuvir and ribavirin against HCV.180

Interferons

Concomitant use of ribavirin, peginterferon alfa, and HIV NRTIs in cirrhotic patients with HCV and HIV coinfection has been associated with hepatic decompensation, including some fatalities.349,377,402,403 (See HIV Nucleoside Reverse Transcriptase Inhibitors under Drug Interactions: Antiretroviral Agents.)

Ribavirin may potentiate the hematologic effects (anemia, neutropenia, lymphopenia) induced by interferon alfas, including peginterferon alfa.20,388

There is no evidence of a pharmacokinetic interaction between ribavirin and peginterferon alfa-2a.377

Laboratory Test Interferences

The manufacturer states that the effect of ribavirin on laboratory tests has not been evaluated.1,4

Acute Toxicity

Pathogenesis

The oral LD₅₀ of ribavirin has been reported to be 2 g (estimated human equivalent dose of 0.17 g/kg, based on body surface area)1,131 and 5.3 g/kg5,22,50,131 in mice and rats, respectively, and the intraperitoneal LD₅₀ has been reported to be 0.9-1.35,22,50,131 and 2 g/kg,22,131 respectively.

Ribavirin accumulates in human erythrocytes and remains in the body for weeks or longer after administration of the drug.1,4,16,132,133,138

Manifestations

In animals, overdosage of ribavirin produces anorexia;131 lethargy;1,131 muscle weakness;131 prostration;131 GI effects, including hemorrhage, diarrhea, and vomiting;1,131 and death.131

In humans, acute ingestion of up to 20 g of ribavirin as capsules (Rebetol^®) has been reported and was associated with an increased incidence and severity of the usual adverse effects of the drug.349 The manufacturers state that overdosage of ribavirin inhalation solution1 or ribavirin tablets (Copegus^®)377 has not been reported to date. However, hypocalcemia and hypomagnesemia have been observed when dosages up to and exceeding 4 times the recommended maximum dosage of oral ribavirin were administered IV†.377

Treatment

There is no specific antidote for ribavirin, and hemodialysis and peritoneal dialysis are not effective for treatment of ribavirin overdosage.349 While ribavirin is removed by hemodialysis with an extraction ratio of 50%, because of the large volume of distribution of the drug, plasma exposure is not expected to change with hemodialysis.377

Mechanism of Action

Antiviral Effect

The exact mechanism of action of the antiviral activity of ribavirin has not been fully elucidated,1,3,4 but the drug appears to exert its antiviral activity by interfering with RNA3,7,21,28,34,35,140,149,166 and DNA synthesis3,7,35,38,39,140,149,166 and subsequently inhibiting protein synthesis21,28 and viral replication.3,15,18,28,33,148,157 The antiviral activity of the drug results principally in an intracellular virustatic effect in cells infected with ribavirin-sensitive RNA or DNA viruses;3,4,7 however, specific mechanisms of action of the drug may vary depending on the virus.7,23,31,140,149 In virus-infected cells in vitro, ribavirin generally exhibits a greater affinity for inhibition of viral DNA and RNA synthesis than cellular (host cell) DNA and RNA synthesis.6,12,15,21,40 However, in vesicular stomatitis virus-infected cells in vitro, the drug appeared to exhibit a greater affinity for inhibition of cellular than viral RNA synthesis.28 Inhibition of cellular RNA synthesis usually occurs only at in vitro concentrations higher than those necessary for inhibition of cellular DNA synthesis.35 Ribavirin is reportedly cytotoxic in some viral-infected cells (e.g., cells infected with the polycythemia-inducing strain of Friend virus, herpes simplex type 1 virus, or enterovirus 72 [formerly hepatitis A virus])27,82,148 and in uninfected cells,7,12,35,140,149 resulting in inhibition of cell division,7 DNA and RNA synthesis,35,140,149 and subsequent protein synthesis.35 The cytotoxic effect of the drug usually occurs only at concentrations 100-200 times those necessary to inhibit viral DNA synthesis or viral replication.12,82 The antiviral and cytotoxic activities of ribavirin appear to be reversible following removal of the drug.7,15,35,72,82,140,149,166

The antiviral activity of ribavirin appears to depend principally on intracellular conversion of the drug to ribavirin-5'triphosphate3,4,6,7,16,22,24,83,140,149,161 and -monophosphate.3,4,7,16,24,29,140,149,161 Ribavirin-5'diphosphate exhibits minimal antiviral activity compared with the monophosphate or triphosphate.150,159 Ribavirin is readily absorbed across the cellular plasma membrane, probably via a nucleoside transport mechanism.3,4,7 The drug is then converted via cellular enzymes to deribosylated ribavirin (the 1,2,4-triazole-3-carboxamide)3,4,11,31,72 and phosphorylated to ribavirin-5'monophosphate, -diphosphate, and -triphosphate.3,4,7,9,17,31,32,47,72,140,149,156,161 Phosphorylation of ribavirin occurs principally in virus-infected cells,158,161 but also occurs in uninfected cells.161 Ribavirin is converted to ribavirin-5'monophosphate via adenosine kinase;6,11,22,24,156 the monophosphate is phosphorylated to the diphosphate and triphosphate via other cellular enzymes,72,161 including adenosine kinase.24,161 The enzyme deoxyadenosine kinase may also participate in the phosphorylation of ribavirin.26 Formation of ribavirin-5'monophosphate appears to be the rate-limiting step in the formation of ribavirin-5'triphosphate.158,159 The extent of phosphorylation of ribavirin by both uninfected and virus-infected cells in vitro is directly related to the extracellular (e.g., in the culture medium) concentration of the drug.158,159,161 Ribavirin-5'triphosphate is the principal intracellular form of the drug,6,9,11,22,156,161 with only approximately 4 and 12% of the phosphorylated metabolites present as ribavirin-5'diphosphate and -monophosphate, respectively.161 Transit of the drug out of cells appears to occur only after dephosphorylation via phosphatases.6,9,140,149

Reversal of the antiviral activity of ribavirin by guanosine,1,6,7,9,18,21,22,29,33,34,38,67,152,157,166 adenosine,38,161 or xanthosine1,7,22,29,38,67,152,157,166 suggests that the pharmacologic activity of ribavirin, which is structurally similar to these cellular metabolites,1,7,72,166 involves guanosine nucleotides.3,4,6,7,9,11,18,22,29,161,166 Guanosine nucleotides and phosphorylated ribavirin are substrates for many of the same enzyme systems, but guanosine and its nucleotides are not substrates for adenosine kinase.9,159

In vitro studies with influenza virus indicate that ribavirin 5'triphosphate functions as a preferential inhibitor of viral RNA polymerase.3,4,6,7,9,11,25,31,34,83,140,149 Ribavirin-5'triphosphate competes with adenosine-5'triphosphate and guanosine-5'triphosphate for viral RNA polymerase.22,83 Inhibition of cellular (host cell) RNA polymerase3,4,11,22 reportedly is minimal and reversible.25,31 In vitro studies with influenza virus have shown that ribavirin-5'triphosphate also inhibits viral replication by inhibiting guanylyltransferase and methyltransferase, enzymes necessary for the addition of guanosine triphosphate to the 5' terminus (“cap”) of viral messenger RNA (mRNA),3,4,6,7,9,11,16,22,23 and by competing with guanosine for incorporation into the 5' terminus of viral mRNA.3,4,9,11,23,160 Although the rate of synthesis of mRNA does not appear to be affected,3,4 the efficiency of translation of mRNA in viral replication is decreased by about 80%.3,4,22,28 Viruses in which the 5' mRNA terminus is naturally absent (e.g., poliovirus) are generally not substantially inhibited by ribavirin.3,4,23,69

Ribavirin-5'monophosphate appears to exhibit minimal antiviral activity relative to ribavirin-5'triphosphate;3,4 however, the monophosphate does function as a competitive inhibitor of IMP dehydrogenase (inosine monophosphate dehydrogenase),3,4,6,7,9,11,21,22,24,29,30,31,140,149,150,166 the enzyme necessary for synthesis of guanosine monophosphate.6,7,11,166 Compared with the monophosphate of the drug, the diphosphate only minimally inhibits this enzyme.150 Inhibition of IMP dehydrogenase results in depletion of intracellular nucleotide pools of guanosine triphosphate,3,4,7,9,11,17,21,22,23,156,161 but has only minimal effects on the rates of RNA and DNA synthesis.3,4,29,31 Further study is necessary to determine the importance of ribavirin-5'monophosphate and the inhibition of IMP dehydrogenase and subsequent depletion of intracellular nucleotide pools in the regulation of other cellular enzyme activity.3,4

In vitro studies indicate that ribavirin inhibits phosphorylation of thymidine at drug concentrations of 2 µmol/L (0.5 mcg/mL) and that DNA synthesis is inhibited only at drug concentrations of 200 µmol/L (50 mcg/mL).6,11 Unlike acyclovir, ribavirin appears to be incorporated minimally, if at all, into growing chains of DNA and RNA.11,149,156 In vitro studies with vaccinia virus have shown that the virus DNA fails to coat in the presence of ribavirin, resulting in incomplete viral particles.140,149

Ribavirin reportedly does not induce interferon production.4,7,10,11,36,166,168

Effects on Host Immune Responses

Ribavirin reportedly has only minimal inhibitory effects on host immune responses;10,19 however, evidence regarding specific effects of the drug on these responses is conflicting,4,10,37,77,95,103 and the effects appear to depend on cellular drug concentrations, with low and high ribavirin concentrations producing stimulation and inhibition of immune responses, respectively.4,10,37,42,77,140,149 The clinical importance of these effects is not known,1 however, and additional study is necessary.13 The manufacturer states that stimulation of cellular and/or humoral immune responses may not contribute to the virustatic activity of ribavirin in humans.4

In animals, ribavirin has produced lymphoid atrophy of the thymus, spleen, and lymph nodes.1 The drug has also decreased cellular and humoral (e.g., antibody formation against some viruses) immune responses in animals at dosages approximately 10-20 times the usual human dosage.1,4,10,37,140,149 At lower dosages, stimulation of antibody formation against some viruses has been reported.4,10 The drug has been shown to stimulate T cells (T-lymphocytes) indirectly by inhibiting splenic suppressor cells10 and to produce a dose-dependent inhibition of antigen- and mitogen-induced proliferation of lymphocytes without affecting cell survival.38 In human infants, antibody formation against respiratory syncytial virus (RSV) has decreased during therapy with ribavirin,1,16,41 but the clinical importance of this finding is not known.1 The drug has been shown to have little, if any, effect on antibody formation against influenza A13,95,103 or B4,97 or measles virus141 in infected patients. Decreases in antibody formation during viral infections may result from decreases in antigenic stimulation secondary to ribavirin-induced inhibition of viral replication16,37,41 or from a direct inhibition of antibody formation by the drug.41 Ribavirin may indirectly inhibit RSV-specific immunoglobulin E and histamine, which are increased in infants who have wheezing in association with RSV infection, by decreasing RSV and attendant antigenic stimulation.41

Ribavirin has also been reported to have some antitumor activity, which may in part depend on the drug's immunologic effects.37 The drug has inhibited tumor growth in animals infected with transplanted adenovirus tumors, possibly by simultaneously inhibiting humoral immune responses and stimulating cellular immune responses, thereby enhancing tumor cell rejection.37 The apparent antitumor activity of ribavirin may also result, in part, from interference with RNA synthesis in virus-infected cells or interference with cellular enzymes necessary for cell transformation rather than from direct antitumor activity.140,149

Spectrum

Ribavirin has a spectrum of antiviral activity that is broader than that of other currently available antiviral agents.7,17,45,82,158,166 Ribavirin is active in vitro against many RNA viruses,16,17,40,43,50,82,140,149 including various Arenaviridae,68,81 Bunyaviridae,68,219 Orthomyxoviridae,7,16,17,22,31,40,44,50,55,56,58,61,66,69,70 Paramyxoviridae,7,16,18,22,31,40,44,46,50,60,61,62,64,65,69,82,141 Picornaviridae,7,16,22,40,69,82,148 Reoviridae,7,40,46,57,61,69 Retroviridae,15,16,48 and Togaviridae.68 The drug also is active in vitro against many DNA viruses,16,17,40,43,50,82,140,149 including various Adenoviridae,7,16,22,40,50,67,69,82 Herpesviridae,7,16,17,22,31,40,46,50,52,61,63,67,69,82 and Poxviridae.7,16,22,31,39,40,50,67,69,82 However, some viruses inhibited by ribavirin in vitro appear to be less susceptible to the drug in vivo.7,31,40,68,71,144

In Vitro Susceptibility Testing

Various methods (e.g., cytopathic effect inhibition, immunofluorescence, plaque inhibition, reverse transcriptase activity, solid phase radioimmunoassay, virus titer reduction, viral hemagglutinin inhibition) have been used to test in vitro susceptibility of viruses to ribavirin.1,31,46,48,50,58,62,64,65,66,69,82,140,148,149 Results and interpretations of these tests are method dependent1,7,52,140,149 and results may be substantially affected by the cell type used for the in vitro culture.7,67,69,140,149,166 In addition, the relationship between in vitro susceptibility of viruses to ribavirin and clinical response has not been determined.1 In viral susceptibility testing, 1 mcg of ribavirin per mL is approximately equivalent to 4 µmol/L.61,140,149

RNA Viruses

Ribavirin is active in vitro against many RNA viruses including respiratory syncytial virus (RSV);1,44,60,61,64 many strains of influenza A1,7,16,22,31,40,44,50,55,56,58,61,66,69,70,166 and B1,7,16,22,31,40,44,50,55,56,61,66,69,166 viruses; measles virus;7,16,18,22,31,44,46,69,82,141,166 subacute sclerosing panencephalitis virus;16,18,22,31,61,69,82,166 parainfluenza viruses;7,16,22,31,44,46,50,61,62,69,82,166 mumps virus;7,40,61,65,69 enterovirus 72 (formerly hepatitis A virus);43,148 human rhinoviruses;7,16,22,31,40,69,82,166 human reovirus 1,7,40,46 2,40 and 3;40 human rotavirus;7 Colorado tick fever virus;57,61 human immunodeficiency virus (HIV);15,48,49,54,175 Crimean-Congo hemorrhagic fever virus;219 Junin virus (causes Argentine hemorrhagic fever);68,186,195 various hantaviruses (including those causing Korean hemorrhagic fever and hantavirus pulmonary syndrome);164,165 yellow fever virus;68 Lassa fever virus;81 and Machupo virus (causes Bolivian hemorrhagic fever).68 The drug also has antiviral activity in vivo against hantavirus,51,68,163 Lassa fever virus,16,22,40,51,61,71,81 and Rift Valley fever virus.40,51,68,71 Some viruses, including arboviruses,7,31,40,68,71,144 rhinoviruses,7 and rotaviruses,7,40,144 that are inhibited in vitro by ribavirin may not be inhibited in vivo.

In cell culture, ribavirin preferentially affects RSV-infected rather than uninfected cells.1,158 In studies using a plaque inhibition assay, plaques of susceptible strains of RSV were reduced by 50-98% by ribavirin concentrations of 3-30 mcg/mL,1,60,61,64,161 but plaque reduction appears to be method dependent, and the clinical importance of this in vitro effect is not known.1 The MIC of ribavirin reported for susceptible strains of influenza A has ranged from 0.01-3.2 mcg/mL using cytopathic effect (CPE) inhibition, virus titer reduction, or viral hemagglutinin inhibition.7,31,55,56,61,140,149 The IC₅₀ (concentration of drug required to produce 50% inhibition of plaque formation) for H0N1, H1N1, H_SW1N1, H2N2, and H3N2 strains of influenza A has ranged from 2.8-8.5 mcg/mL.58,66

The MIC of ribavirin for susceptible strains of influenza B has been reported to range from 0.01-3.2 mcg/mL using CPE inhibition, virus titer reduction, or viral hemagglutinin inhibition.7,31,55,56,140,149 The IC₅₀ for susceptible strains of influenza B ranged from 2.6-6.3 mcg/mL using a plaque inhibition assay.66 The MIC for strains of subacute sclerosing panencephalitis virus has ranged from 10-50 mcg/mL using CPE inhibition,31,61,82 and the MIC reported for susceptible strains of measles virus has ranged from 0.003-10 mcg/mL using CPE or plaque inhibition or virus titer reduction.7,31,46,69,82

The MIC of ribavirin reported for susceptible strains of parainfluenza virus (1, 2, or 3) has ranged from 3.2-32 mcg/mL using CPE or plaque inhibition, virus titer reduction, or viral hemagglutinin inhibition.31,46,61,62,82 The MIC for susceptible strains of mumps virus is 0.1-10 mcg/mL,7,61 and that for susceptible strains of human rhinoviruses has ranged from 10-32 mcg/mL,31,82,140,149 although some strains of human rhinoviruses have been reported to have MICs up to 100 mcg/mL.7,69,82,140,149 The MIC of ribavirin reported for susceptible strains of human reovirus has ranged from 0.32-10 mcg/mL,7,46,69 and has been reported to be 0.1-1 mcg/mL for susceptible strains of human rotavirus7 and 3.2 mcg/mL for susceptible strains of Colorado tick fever virus.57,61

In studies using immunofluorescence or reverse transcriptase activity, human immunodeficiency virus (HIV) was inhibited by ribavirin concentrations of 10-100 mcg/mL;15,48 however, in a study using CPE inhibition, the cytopathic effect of HIV against ATH8 cells was not inhibited by concentrations up to 100 mcg/mL.143,167

In a study using solid phase radioimmunoassay, enterovirus 72 (formerly hepatitis A virus) was partially inhibited by ribavirin concentrations of 25 mcg/mL and was substantially inhibited by concentrations of 62.5 or 125 mcg/mL;148 however, the latter concentrations were also cytotoxic to infected cells.148

The ED₅₀ (dose required to produce 50% inhibition of plaque formation) of ribavirin for Hantaan virus has been reported to be 15-16 mcg/mL.164,165

Although the clinical importance is unclear, ribavirin has some activity against West Nile virus (WNV) in vitro.365,366,391 In one in vitro study in human neural cells, high doses of ribavirin inhibited replication and cytopathogenicity of WNV.365 In another study using a primate cell system infected with WNV, high doses of ribavirin were protective against the virus and a cytotoxic effect occurred with very high doses.366 Further study is needed to determine whether ribavirin has in vivo activity against WNV and to determine whether the drug might provide any benefits in the treatment of clinical infection caused by the virus.366 However, based on these preliminary in vitro studies, it has been suggested that very high IV dosages of ribavirin would be required to attain serum concentrations of the drug that might be potentially effective.366

Results from several in vitro studies using isolates obtained from patients with severe acute respiratory syndrome (SARS) indicate that ribavirin concentrations that inhibit ribavirin-susceptible viruses do not inhibit replication or cell-to-cell transmission of the coronavirus that has been identified as the causative agent of SARS (SARS-CoV).373,384 There is some evidence that ribavirin is active in vitro against the coronavirus identified as the causative agent of Middle East respiratory syndrome (MERS-CoV).437,438

Ribavirin generally is inactive against poliovirus,3,4,23,31,40,51,59,69,82,140,149 Ebola virus (causes Ebola hemorrhagic fever),219 Marburg virus (causes Marburg hemorrhagic fever),219 and coxsackieviruses.31,40,51,140,149 In one study, however, ribavirin was active against group B coxsackievirus 3 in vitro and in vivo in mice.208

DNA Viruses

Ribavirin has antiviral activity in vitro against many DNA viruses including herpes simplex types 1 (HSV-1)16,22,31,40,46,50,61,63,67,69,82,166 and 2 (HSV-2);7,16,22,31,40,50,52,61,67,69,82,166 human cytomegalovirus;7,16,22,31,40,67,69,166 and human adenovirus.7,16,22,31,40,50,67,69,82,166 However, cytomegalovirus may not be susceptible to the drug in vivo.7,31,40,144 In vitro, ribavirin has some activity against variola virus,383 vaccinia virus7,16,22,31,39,40,50,67,69,82,85,166,142,383 and other orthopoxviruses including camelpox,85 cowpox,85,383 and monkeypox.85,383 Although ribavirin was active against cowpox virus in a mouse model, the in vivo activity of the drug against poxvirus infections (including smallpox) in humans has not been evaluated to date.176

Using CPE or plaque inhibition or virus titer reduction, the MIC of ribavirin reported for susceptible strains of HSV-131,46,63,67,82,140,149 or -27,31,67,82,140,149 has generally ranged from 0.32-3.2 mcg/mL; however, MICs up to 100 mcg/mL have been reported for some strains of these viruses.7,52,61,67,69,82,140,149 The MIC for susceptible strains of human cytomegalovirus has ranged from 10-32 mcg/mL using CPE inhibition or virus titer reduction,7,31,67,69 and that for susceptible strains of vaccinia virus has ranged from 0.1-3.2 mcg/mL using CPE or plaque inhibition or virus titer reduction.7,31 However, MICs up to 50 mcg/mL have been reported for some strains of vaccinia.67,82 The MIC for susceptible strains of human adenovirus has ranged from 10-32 mcg/mL,7,31,82 although the MIC has ranged up to 200 mcg/mL for some strains.7,69

In cell culture using a plaque inhibition assay, plaques of simian varicella-zoster virus were reduced 50% by ribavirin concentrations of 50 mcg/mL;158 however, the drug appears to have little, if any, activity against human varicella-zoster virus.7,158 Ribavirin has been reported to produce a dose-related inhibition of hepatitis B surface antigen (HBsAg) production in vitro;53 however, the importance of this in vitro effect has not been determined53 and the drug has failed to alter production of hepatitis B antigens in several in vivo studies in animals7,31,140,147,149 and in humans.107,116

Other Organisms

Ribavirin is slightly active in vitro against some gram-negative aerobic bacteria and some fungi.31,140,149 Brucella suis , Pseudomonas aeruginosa , and Phialophora verrucosa are reportedly inhibited by ribavirin concentrations of 5.25-12.5 mcg/mL.31,140,149 Ribavirin concentrations of 500 mcg/mL or greater may be necessary to inhibit other bacteria and fungi.31,140,149

Resistance

Development of in vitro or in vivo resistance to the antiviral activity of ribavirin has not been fully evaluated.1,4 Unlike some other currently available antiviral agents (e.g., acyclovir, amantadine),3,4,63,69,73 resistance to ribavirin does not appear to develop during repeated exposure of most susceptible viruses to the drug.3,4,39,40,60,63,64,69,73,74,75,76,140,149 The lack of development of resistance in susceptible viruses may result from ribavirin's multiple mechanisms of antiviral action.3,4 (See Mechanism of Action: Antiviral Effect.)

Pharmacokinetics

In the Pharmacokinetics section, 1 mcg of ribavirin per mL is approximately equivalent to 4 µmol/L.61

Absorption

Nasal and Oral Inhalation

Ribavirin is absorbed systemically from the respiratory tract following nasal and oral inhalation.1,4,16,61,79 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).1,4,61 At a constant flow rate, the amount of drug delivered to the respiratory tract theoretically is directly related to the concentration of nebulized drug solution and the duration of inhalation therapy.61,97 In addition, alterations in the method of aerosol delivery can affect the amount of drug reaching the respiratory tract.61 The fraction of an inhaled dose of ribavirin that is deposited in the respiratory tract during oral and nasal inhalation of a nebulized solution containing 190 mcg/L using a small-particle aerosol generator has been estimated to average about 70%,9,41,61,97,98,158 but the actual amount deposited depends on several factors including respiratory rate and tidal volume.93,97,98,159 The fraction of a nasally and orally inhaled dose of ribavirin that is swallowed and absorbed from the GI tract has not been determined.158

Peak plasma ribavirin concentrations generally appear to occur at the end of the inhalation period when the drug is inhaled orally and nasally using a small-particle aerosol generator,61 and increase with increasing duration of the inhalation period.16,61 Following nasal and oral inhalation (via face mask) of 0.82 mg/kg per hour for 2.5 hours daily for 3 days in a limited number of pediatric patients, peak plasma ribavirin concentrations averaged 0.19 (range: 0.11-0.388) mcg/mL.1,4,16,61,79 Peak plasma ribavirin concentrations averaged 0.275 (range: 0.21-0.35) or 1.1 (range: 0.45-2.18) mcg/mL in a limited number of patients inhaling 0.82 mg/kg per hour for 5 or 8 hours daily, respectively, for 3 days,4,16,61 and averaged 1.7 (range: 0.38-3.58) mcg/mL in a limited number of pediatric patients inhaling 0.82 mg/kg per hour via face mask, mist tent, or respirator for 20 hours daily for 5 days.1,4,16,61 Highest plasma concentrations for a given dosage of ribavirin appear to be achieved in patients receiving the drug from the aerosol generator via an endotracheal tube.61 The manufacturer states that peak plasma ribavirin concentrations achieved with nasal and oral inhalation of usual dosages of the drug are less than concentrations that reportedly reduce respiratory syncytial virus (RSV) plaque formation by 85-98%.1 (See Spectrum: RNA Viruses.)

Concentrations of ribavirin achieved in respiratory tract secretions in patients inhaling the drug nasally and orally are likely to be substantially greater than those achieved in plasma.1,4,16,61 In a limited number of pediatric patients who received a nasally and orally inhaled ribavirin dose of 0.82 mg/kg per hour for 8 hours daily for 3 days, peak concentrations of the drug in respiratory tract secretions (from endotracheal tube) ranged from 250-1925 mcg/mL.4,16,61 In pediatric patients who received 0.82 mg/kg per hour via nasal and oral inhalation for 20 hours daily for 5 days, ribavirin concentrations in respiratory tract secretions (from endotracheal tube) ranged from 313-28,250 mcg/mL during therapy, with peak concentrations averaging 3075 (range: 313-7050) mcg/mL at the end of therapy.4,16,61 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.1,4 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

Oral Administration

Ribavirin is rapidly absorbed following oral administration,13,16,80,193,349 with peak plasma concentrations of the drug occurring within 1-3 hours after multiple doses.3,16,31,80,193,349 However, the absolute bioavailability of ribavirin averages only 64% following oral administration because the drug undergoes first-pass metabolism.349

Oral bioavailability of ribavirin appears to be increased when the drug is administered with a high-fat meal.377 Concomitant administration of oral ribavirin (as capsules or tablets) with a high-fat meal increases the peak ribavirin plasma concentration and area under the plasma concentration-time curve (AUC).349,377 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).349 Peak plasma concentration and AUC of ribavirin reportedly increase by 66 and 42%, respectively, when ribavirin tablets are administered with a high-fat meal.377

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.377 Following oral administration of single or multiple 600-mg doses of ribavirin (as capsules), mean peak plasma concentrations in adults average 0.782 or 3.7 mcg/mL, respectively.349 In patients weighing more than 75 kg, ribavirin 1.2 g daily (as tablets) given with food for 12 weeks resulted in peak plasma ribavirin concentrations of 2.7 mcg/mL.377

In children 5-16 years of age, mean peak plasma concentrations average 3.3 mcg/mL following ribavirin dosages of 15 mg/kg twice daily (as capsules).349

Following oral administration of a single 400-mg dose of ribavirin (as capsules), 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.349

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.377

Following oral administration of a single 600-mg dose of ribavirin (as capsules), the AUC of ribavirin was not altered in individuals with mild, moderate, or severe hepatic dysfunction compared to controls.349 However, mean peak plasma concentration was increased twofold in those with severe hepatic impairment (Child-Pugh class C) compared to controls.349

Distribution

Following nasal and oral inhalation, highest ribavirin concentrations are found in the respiratory tract2 and erythrocytes.2,3,16,22,80 Following parenteral administration of single doses in monkeys and baboons, ribavirin and/or its metabolites are distributed in highest concentrations into skeletal muscle; blood cells, principally erythrocytes; and liver.80,169

Studies in animals and humans have shown that ribavirin and/or its metabolites accumulate in erythrocytes.1,4,16,22,61,132,133,138,149,193 The extent of accumulation of ribavirin and/or its metabolites in erythrocytes following inhalation of the drug has not been established,1 but, following oral administration of a single 3-mg/kg dose, erythrocyte concentrations of the drug have been reported to peak within approximately 4 days,1,4,16,80,149 exceeding concurrent plasma concentrations at 4 days by about 100-fold,80 and then declining with a half-life of about 40 days (the half-life of erythrocytes).1,16,80,149 During the initial 1-2 hours following oral administration of a single dose of the drug, erythrocyte concentrations increase at a rate similar to plasma concentrations; thereafter, erythrocyte concentrations continue to increase for about 4 days as plasma drug concentrations decline.80 Approximately 3% of a single ribavirin dose is present in erythrocytes 72 hours after oral administration.6,80

Ribavirin appears to distribute slowly into CSF.78,169 Following chronic (4-7 weeks) oral administration of ribavirin in patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC), CSF concentrations of the drug were approximately 70% of concurrent plasma concentrations.78 It is not known whether ribavirin crosses the placenta158 or distributes into milk in humans.1,158 The drug appears to be only minimally bound to plasma proteins.193

Elimination

Plasma concentrations of ribavirin appear to decline in a manner dependent on the route of drug administration.3,40,80,193 Following nasal and oral inhalation in a limited number of pediatric patients, the plasma half-life of ribavirin averaged about 9.5 (range: 6.5-11) hours.1,3,4,16,61,79 Following oral administration of a single dose of the drug in a limited number of healthy adults, plasma ribavirin concentrations declined in a multiphasic manner, with half-lives averaging 24 hours 10-80 hours after the dose3,40,80,149 and 48 hours or longer in the terminal phase.80 In adults with chronic hepatitis C infection, 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.349 The terminal half-life of ribavirin following a single oral 800-, 1000-, or 1200-mg dose of ribavirin capsules is about 120-170 hours.377,379

Based on limited data, the half-life of ribavirin in respiratory tract secretions following nasal and oral inhalation for 3 days reportedly is approximately 1.4-2.5 hours.9,61 Elimination of the drug from the respiratory tract may result from distribution across respiratory membranes, clearance by macrophages in the respiratory tract, and/or upward ciliary activity.61

Ribavirin is metabolized principally to deribosylated ribavirin (the 1,2,4-triazole-3-carboxamide),2,4,6,16,31,32,79,80 probably in the liver;2 the antiviral activity of 1,2,4-triazole-3-carboxamide against various RNA and DNA viruses is reportedly similar to ribavirin.47,149,166 The drug is also metabolized to 1,2,4-triazole-3-carboxylic acid.32,79,80 In vitro, ribavirin has been shown to be metabolized to ribavirin-5'monophosphate, -diphosphate, and -triphosphate,3,4,7,9,17,31,32,47,72,140,149,156,161 principally by intracellular phosphorylation of the drug via adenosine kinase6,11,22,24 and other cellular enzymes.72,161 It is likely that phosphorylation in vivo is necessary for the antiviral activity of the drug.3,4,6,7,16,22,24,29,83,140,149 (See Mechanism of Action: Antiviral Effect.) Ribavirin also undergoes phosphorylation in erythrocytes, principally to ribavirin-5'-triphosphate;6,156 approximately 81, 16, and 3% of drug metabolized in erythrocytes is present as ribavirin-5'triphosphate, -diphosphate, and -monophosphate, respectively.6 It has been suggested that prolonged distribution of the drug in erythrocytes may result from minimal phosphatase activity in these cells, with transit of the drug out of cells dependent on dephosphorylation via phosphatases.6,9,140,149,193

Results of in vitro studies using both human and rat livers microsome preparations indicated little or no cytochrome P-450 (CYP) enzyme-mediated metabolism of ribavirin;349 ribavirin is not a substrate of CYP isoenzymes.377

Ribavirin is excreted principally in urine.2,40,80,149 In healthy adults with normal renal function, approximately 53% of a single oral dose is excreted in urine within 72-80 hours,2,4,16,80 with about 33% excreted within the first 24 hours.80 Approximately 37, 30, and 30% of the fraction excreted in urine appears as unchanged drug, 1,2,4-triazole-3-carboxamide, and 1,2,4-triazole-3-carboxylic acid, respectively, within 1.5-2 hours, and approximately 17, 50, and 22%, respectively, within 24 hours.80 About 15% of a single oral dose is excreted in feces within 72 hours.2,4,16 Little, if any, ribavirin appears to be eliminated in expired CO₂.158,169

The pharmacokinetics of ribavirin tablets (Copegus^®) have been evaluated in patients with chronic HCV infection and varying degrees of renal impairment (moderate, severe, or requiring hemodialysis).377 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.377 Based on these results, pharmacokinetic modeling has provided a basis for dosage adjustments of Copegus^® in such patients.377 (See Renal Impairment under Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Chemistry and Stability

Chemistry

Ribavirin is a synthetic nucleoside antiviral agent.1,4,6,7,9,11,22,166 Ribavirin is structurally similar to guanosine,2,4,6,7,9,11,22 xanthosine,2 and pyrazofurin (pyrazomycin).7,47,50,140,149 The drug differs structurally from guanosine in that the D-ribose of the nucleoside is attached to a 1,2,4-triazole-3-carboxamide moiety7 rather than a purine ring.158 The ribavirin structure is necessary to maintain the drug's antiviral activity;6,7,9,47,151,155 alterations in either the D-ribose moiety or the triazole or carboxamide moieties result in a substantial loss of antiviral activity.7,9,11,31,47,149,151,155,160 However, acetylation or phosphorylation of the ribosyl hydroxyl groups9,31 or conversion of the carboxamide group of the triazole carboxamide moiety to a carboxamidine moiety does not affect the drug's antiviral activity, since conversion of these compounds back to ribavirin occurs intracellularly.6,9,166

Ribavirin occurs as a white,1,2,4 crystalline powder1,4,31,140,149 that is tasteless and odorless.31,140,149 At 25°C, the maximum aqueous solubility of ribavirin is 142 mg/mL and the drug is slightly soluble in alcohol.1,2

Ribavirin is commercially available for nasal or oral inhalation as a powder for inhalation solution (Virazole^®).1 For oral administration, ribavirin is commercially available as capsules (Rebetol^®, Ribasphere^®, generic),349,403 oral solution (Rebetol^®),349 or tablets (Copegus^®, generic).377,402

Commercially available ribavirin powder for inhalation solution occurs as a white, sterile, lyophilized powder.1,2,158 When reconstituted and diluted in sterile water for injection or inhalation (additive free) as directed, ribavirin solutions containing 20 mg/mL are clear and colorless,158 have an osmolarity of 82 mOsm/L,158 and have a pH of 5-6.9.1,2,251 When these solutions are administered as directed using the Valeant small-particle aerosol generator (SPAG) Model SPAG-2, the SPAG-2 delivers a mist containing about 190 mcg of ribavirin per L1,4,41,61,75,93,94,95,97,98,162 as nebulized particles having a median mass diameter of 1.3 µm,41,61,75,76,94,95,97,98,162 with 95% of the particles having a mass diameter less than 5 µm.41,61,93,94,95,97,98

Stability

Commercially available ribavirin powder for inhalation solution should be stored in tight containers251 in a dry place1,162,251 at 25°C, but may be exposed to temperatures ranging from 15-30°C.1,2,162,251 Ribavirin inhalation solutions contain no preservatives and are stable for 24 hours when stored under sterile conditions at a room temperature of 20-30°C.1,2,162 Following addition of the reconstituted solution to the reservoir of the SPAG-2, any unused solution remaining in the reservoir should be discarded within 24 hours and prior to adding any newly reconstituted solution (e.g., when remaining amount of solution in reservoir is low).1

Ribavirin capsules349,403 or tablets377,402 should be stored at 25°C, but may be exposed to temperatures ranging from 15-30°C.349,377,403

Ribavirin oral solution should be stored at 2-8°C or at 25°C, but may be exposed to temperatures ranging from 15-30°C.349

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