Version May 2024
Ribavirin monotherapy is not effective for the treatment of chronic hepatitis C virus (HCV) infection and should not be used alone for this indication.
Hemolytic anemia has been reported with ribavirin therapy. The anemia associated with ribavirin therapy may result in worsening of cardiac disease that has led to fatal and nonfatal myocardial infarctions. Patients with a history of significant or unstable cardiac disease should not be treated with ribavirin
Significant teratogenic and embryocidal effects have been demonstrated in all animal species exposed to ribavirin. In addition, ribavirin has a multiple dose half-life of 12 days, and may persist in non-plasma compartments for as long as 6 months. Therefore, ribavirin therapy is contraindicated in women who are pregnant and in the male partners of women who are pregnant. Avoid pregnancy and use effective contraception during therapy and for 9 months after completion of treatment in female patients and for 6 months in female partners of male patients who are taking ribavirin therapy. Effective contraception must be utilized during treatment and during the 6-month post-treatment follow-up period.
Note: Rebetol capsule and oral solution have been discontinued in the United States for >1 year.
Chronic hepatitis C:
Note: Use as part of an appropriate combination regimen (Ref).
Weight-based ribavirin:
<75 kg: 1 g/day in 2 divided doses (Ref).
≥75 kg: 1.2 g/day in 2 divided doses (Ref).
Low initial dose ribavirin: 600 mg/day in 2 divided doses; increase as tolerated (maximum dose: 1 g/day [<75 kg] in 2 divided doses or 1.2 g/day in 2 divided doses [≥75 kg]) (Ref).
Dosing regimen, concomitant therapy, and duration is dependent on HCV genotype and treatment status (treatment-naive or treatment-experienced), as well as other factors (eg, presence and type of cirrhosis). Combination therapy with peginterferon is not recommended in HCV treatment guidelines (treatment-naive or treatment-experienced patients). Hepatitis C treatment guidelines are frequently changing with the advent of new treatment therapies and information; consult current AASLD/IDSA clinical practice guidelines for the most recent treatment recommendations (Ref).
Chronic hepatitis E infection (off-label use): Note: For immunocompromised patients (eg, solid organ transplant recipients, patients with hematologic malignancy or HIV infection), reduce immunosuppression (if possible) (Ref).
Oral: Optimal dosing has not been established: typically 600 to 800 mg/day (range: 400 mg to 1 g/day) in 1 to 2 divided doses (Ref). Optimal duration is unknown, but is typically ≥3 months based on virologic response (Ref).
Respiratory syncytial virus infection in immunocompromised patients (off-label use): Oral: Optimal dosing has not been established: 600 to 800 mg 2 to 3 times daily (Ref) or a single 10 mg/kg loading dose followed by 20 mg/kg/day in 3 divided doses (Ref). Optimal duration is unknown, but most continue until clinical resolution (Ref). Note: Consider adjunctive IVIG for patients with hypogammaglobulinemia (Ref) and corticosteroids for lung transplant recipients (Ref).
Viral hemorrhagic fever (off-label use): Note: The primary treatment is supportive care, but ribavirin may be used for patients with viral hemorrhagic fever secondary to select viruses (eg, Lassa) (Ref). Use of ribavirin for Crimean-Congo hemorrhagic fever is controversial (Ref).
Oral: 2 g loading dose followed by 1.2 g/day in 2 divided doses if weight >75 kg or 1 g/day in 2 divided doses if weight ≤75 kg (Ref) or 35 mg/kg (maximum: 2.5 g/dose) loading dose followed by 15 mg/kg (maximum: 1 g/dose) every 6 hours for 4 days, followed by 15 mg/kg (maximum: 1 g/dose) every 8 hours for 6 days (Ref).
Chronic hepatitis C: Oral:
Rebetol capsules/solution, Ribasphere capsules:
CrCl ≥50 mL/minute: No dosage adjustments necessary.
CrCl <50 mL/minute: Use is contraindicated.
Moderiba and Ribasphere tablets:
CrCl >50 mL/minute: No dosage adjustments necessary.
CrCl 30 to 50 mL/minute: Alternate 200 mg and 400 mg every other day.
CrCl <30 mL/minute: 200 mg once daily.
ESRD requiring hemodialysis: 200 mg once daily.
Note: According to the manufacturer, the dose of Moderiba and Ribasphere should not be further modified in patients with renal impairment. If severe adverse reactions or laboratory abnormalities develop, it should be discontinued, if appropriate, until the adverse reactions resolve or decrease in severity. If abnormalities persist after restarting, therapy should be discontinued. Some experts recommend a lower starting dose of ribavirin (ie, 200 mg 3 times weekly), along with close monitoring of hemoglobin and hematocrit and use of erythropoietin therapy, in patients with eGFR <30 mL/minute/1.73 m2 or those on dialysis (Ref).
Respiratory syncytial virus infection: Oral: Dose adjustment recommended, but optimal dose unknown (Ref); consider 400 mg twice daily for patients with mild renal insufficiency based on limited data (Ref).
Chronic hepatitis C:
Hepatic decompensation (Child-Pugh class B and C): Use of ribavirin in combination with interferon therapy is contraindicated (Ref). Guidelines recommend ribavirin may be considered as part of appropriate combination therapy in patients with decompensated cirrhosis who may or may not be candidates for liver transplantation. Low initial dosage (600 mg/day) with titration as tolerated is recommended in patients with Child-Pugh class C; consult current AASLD/IDSA clinical practice guidelines for the most recent treatment recommendations (Ref).
During treatment of hepatitis C:
Asymptomatic increases in ALT <10-fold: Closely monitor with repeat testing every 2 weeks. If persistent elevation remains, consider stopping therapy (Ref).
<10-fold increase in ALT from baseline with weakness, nausea, vomiting, jaundice, or significantly increased bilirubin, alkaline phosphatase, or INR: Discontinue direct-acting antiviral (DAA) (Ref).
≥10-fold increase in ALT from baseline at any time during treatment: Discontinue DAA therapy, especially with signs and symptoms of liver inflammation or increasing conjugated bilirubin, alkaline phosphatase, or INR (Ref).
Note: Once ribavirin has been withheld due to clinical adverse event or laboratory abnormality, an attempt can be made to restart ribavirin, in divided doses, at 600 mg daily, with a further ribavirin increase to 800 mg daily. Increasing the ribavirin dose to its original assigned dose (1,000 to 1,200 mg daily) is not recommended.
Patient without cardiac history:
Hemoglobin 8.5 to <10 g/dL:
Oral capsules, oral solution:
First reduction: ≤105 kg: Decrease by 200 mg daily; >105 kg: Decrease by 400 mg daily
Second reduction: Decrease by an additional 200 mg daily (not weight-based)
Oral tablets: Decrease dose to 600 mg daily (200 mg in the morning, 400 mg in the evening)
Hemoglobin <8.5 g/dL: Oral capsules, solution, tablets: Permanently discontinue treatment.
WBC <1,000 mm3, neutrophils <500 mm3: Oral capsules, solution: Permanently discontinue treatment.
Platelets <25 x 109/L: Oral capsules, solution: Permanently discontinue treatment.
Laboratory abnormalities or adverse reactions other than decreased hemoglobin: Oral tablets: Refer to dose modification guidelines in the manufacturer's labeling.
Patient with stable cardiac history:
Hemoglobin has decreased ≥2 g/dL during any 4-week period of treatment:
Oral tablets: Decrease dose to 600 mg daily (200 mg in the morning, 400 mg in the evening). If hemoglobin <8.5 g/dL any time after dose reduction or <12 g/dL after 4 weeks of dose reduction, permanently discontinue treatment.
Hemoglobin <8.5 g/dL: Oral capsules, solution, tablets: Permanently discontinue treatment.
WBC <1,000 mm3, neutrophils <500 mm3: Oral capsules, solution: Permanently discontinue treatment.
Platelets <25 x 109/L: Oral capsules, solution: Permanently discontinue treatment.
Laboratory abnormalities or adverse reactions other than decreased hemoglobin: Oral tablets: Refer to dose modification guidelines in the manufacturer's labeling.
Refer to adult dosing.
(For additional information see "Ribavirin (systemic): Pediatric drug information")
Note: Rebetol capsule and oral solution have been discontinued in the US for >1 year.
Chronic hepatitis C monoinfection:
AASLD/IDSA recommendations (Ref): Note: Use in combination with sofosbuvir in patients (treatment-naive or treatment-experienced) with genotypes 2 or 3 without cirrhosis or with compensated cirrhosis; therapy duration: genotype 2: 12 weeks; genotype 3: 24 weeks. May also be used in all genotypes in combination with direct-acting antivirals (DAAs) in DAA-experienced patients; see current guidelines for details.
Children ≥3 years and Adolescents: Oral:
<47 kg: 15 mg/kg/day in 2 divided doses.
47 to 49 kg: 600 mg/day in 2 divided doses.
50 to 65 kg: 800 mg/day in 2 divided doses.
66 to 80 kg: 1,000 mg/day in 2 divided doses.
>80 kg: 1,200 mg/day in 2 divided doses.
Manufacturer's labeling: Note: Dosing is based on product labeling and may not reflect current clinical practice. Combination therapy with interferon or peginterferon is not recommended; refer to current AASLD/IDSA clinical practice guidelines for most recent treatment recommendations (Ref).
Capsule or oral solution (Rebetol, Ribasphere) in combination with pegylated or nonpegylated interferon alfa-2b: Note: Oral solution should be used in patients unable to swallow capsules:
Children ≥3 years and Adolescents: Oral:
<47 kg: 15 mg/kg/day in 2 divided doses.
47 to 59 kg: 400 mg twice daily.
60 to 73 kg: 400 mg in the morning; 600 mg in the evening.
>73 kg: 600 mg twice daily.
Tablets (Moderiba, Ribasphere) in combination with peginterferon alfa-2a: Children ≥5 years and Adolescents able to swallow whole tablets: Oral:
23 to 33 kg: 200 mg twice daily.
34 to 46 kg: 200 mg in the morning; 400 mg in the evening.
47 to 59 kg: 400 mg twice daily.
60 to 74 kg: 400 mg in the morning; 600 mg in the evening.
≥75 kg: 600 mg twice daily.
Dosing adjustment for toxicity: Oral:
Note: Based on manufacturer's labeling, when used in combination with pegylated or nonpegylated interferon alfa-2b. Children ≥3 years and Adolescents: Once a laboratory abnormality or clinical adverse event has resolved, the ribavirin dose may be increased, based on clinical judgment, to its original assigned dose or restarted at 50% of the full dose.
Patient without cardiac history:
Hemoglobin 8.5 to <10 g/dL:
Capsules, oral solution: Children ≥3 years and Adolescents: Decrease ribavirin dose to 12 mg/kg/day; may further reduce to 8 mg/kg/day.
Tablets: Children ≥5 years and Adolescents:
23 to 33 kg: Decrease dose to 200 mg once daily in the morning.
34 to 59 kg: Decrease dose to 200 mg twice daily.
≥60 kg: Decrease dose to 200 mg in the morning and 400 mg in the evening.
Hemoglobin <8.5 g/dL: Children ≥3 years and Adolescents: Oral capsules, oral solution, tablets: Discontinue ribavirin.
WBC <1,000 mm3, neutrophils <500 mm3: Children ≥3 years and Adolescents: Oral capsules, oral solution, tablets: Discontinue treatment.
Platelets <50 x 109/L: Children ≥3 years and Adolescents: Oral capsules, oral solution, tablets: Discontinue treatment.
Patient with cardiac history:
Hemoglobin decrease ≥2 g/dL in any 4-week period of treatment:
Capsules, oral solution: Children ≥3 years and Adolescents: Decrease by 200 mg daily (regardless of the patient's initial dose); monitor and evaluate weekly.
Tablets: Children ≥5 years and Adolescents:
23 to 33 kg: Decrease dose to 200 mg once daily in the morning.
34 to 59 kg: Decrease dose to 200 mg twice daily.
≥60 kg: Decrease to 200 mg in the morning and 400 mg in the evening.
Hemoglobin <12 g/dL after 4 weeks of reduced dose: Children ≥3 years and Adolescents: Capsules, oral solution, tablets: Discontinue ribavirin.
Hemoglobin <8.5 g/dL: Children ≥3 years and Adolescents: Oral capsules, oral solution, tablets: Discontinue ribavirin.
WBC <1,000 mm3, neutrophils <500 mm3: Children ≥3 years and Adolescents: Oral capsules, oral solution, tablets: Discontinue treatment.
Platelets <50 x 109/L: Children ≥3 years and Adolescents: Oral capsules, oral solution, tablets: Discontinue treatment.
Chronic hepatitis C monoinfection:
Capsules/solution (Rebetol, Ribasphere): Children ≥3 years and Adolescents: Oral:
Baseline:
CrCl ≥50 mL/minute: No dosage adjustments are recommended.
CrCl <50 mL/minute: Use is contraindicated.
During therapy: Serum creatinine >2 mg/dL: Permanently discontinue treatment.
Tablet: There are no pediatric-specific recommendations; however, based on adult recommendations and experience with other dosage forms, dosage adjustments, and/or discontinuation of therapy may be needed in CrCl <50 mL/minute.
Chronic hepatitis C monoinfection: Hepatic decompensation in cirrhotic patients: Tablets: Children ≥5 years and Adolescents: Use is contraindicated.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Clinical trials were conducted in patients receiving peginterferon alfa-2a, peginterferon alfa-2b, and interferon alfa-2b and it is not possible to correlate frequency of adverse events with ribavirin alone. Moreover, ribavirin monotherapy is not an effective treatment for chronic hepatitis.
>10%:
Dermatologic: Alopecia (17% to 36%; children and adolescents: 17% to 23%), dermatitis (13% to 16%), dermatologic disorder (children and adolescents: 47%), diaphoresis (4% to 11%), pruritus (13% to 29%; children and adolescents: 11% to 12%), skin rash (5% to 34%; children and adolescents: 15% to 17%), xeroderma (10% to 24%)
Endocrine & metabolic: Growth retardation (children and adolescents: <3rd percentile height decrease: 70%, >15 percentile height or weight decrease: 11% to 43%, >30 percentile height decrease: ≤13%), hyperuricemia (33% to 38%), weight loss (10% to 29%; children and adolescents: 19%)
Gastrointestinal: Abdominal pain (8% to 21%), anorexia (21% to 32%; children and adolescents: 29% to 51%), decreased appetite (children and adolescents: 11% to 22%), diarrhea (10% to 22%), dyspepsia (5% to 16%; children and adolescents: <1%), gastrointestinal disease (children and adolescents: 49% to 56%), nausea (≤47%; children and adolescents: 18% to 33%), upper abdominal pain (children and adolescents: 12%), vomiting (≤29%; children and adolescents: 27% to 42%), xerostomia (4% to 12%)
Hematologic & oncologic: Anemia (11% to 35%), hemolytic anemia (10% to 13%), lymphocytopenia (12% to 14%), neutropenia (8% to 40%; severe neutropenia (children and adolescents: 1%)
Hepatic: Hyperbilirubinemia (10% to 14%)
Infection: Viral infection (12%)
Local: Erythema at injection site (children and adolescents: 29%), inflammation at injection site (13% to 25%; children and adolescents: 14%), injection site reaction (5% to 58%; children and adolescents: 19% to 45%)
Nervous system: Anxiety (≤47%), chills (23% to 39%; children and adolescents: 21%), depression (≤40%, severe depression: <1%; children and adolescents: 1% to 13%), dizziness (13% to 26%), emotional lability (≤47%; children and adolescents: 16%), fatigue (≤68%; children and adolescents: 25% to 58%), headache (41% to 69%; severe headache: children and adolescents: 1%), insomnia (26% to 41%; children and adolescents: 9% to 14%), irritability (≤47%; children and adolescents: 10% to 24%), lack of concentration (10% to 21%; children and adolescents: 5%), nervousness (≤38%; children and adolescents: 3% to 7%), pain (9% to 13%), right upper quadrant pain (6% to 12%), rigors (25% to 48%; children and adolescents: 25%)
Neuromuscular & skeletal: Arthralgia (21% to 34%; children and adolescents: 15% to 17%), asthenia (≤68%; children and adolescents: 5% to 15%), musculoskeletal pain (19% to 21%; children and adolescents: 21% to 35%), myalgia (22% to 64%; children and adolescents: 17% to 32%)
Respiratory: Cough (7% to 23%), dyspnea (13% to 26%; children and adolescents: 5%), flu-like symptoms (15% to 16%; children and adolescents: 31% to 91%), pharyngitis (12% to 13%), sinusitis (5% to 12%; children and adolescents: <1%), upper respiratory tract infection (children and adolescents: 60%)
Miscellaneous: Fever (21% to 55%; children and adolescents: 61% to 80%; high fever: children and adolescents: 4%)
1% to 10%:
Cardiovascular: Chest pain (5% to 9%), flushing (3% to 4%)
Dermatologic: Eczema (4% to 5%)
Endocrine & metabolic: Hypothyroidism (4% to 5%), menstrual disease (6% to 7%)
Gastrointestinal: Constipation (5%), decompensated liver disease (2%), dysgeusia (4% to 9%; children and adolescents: <1%)
Hematologic & oncologic: Leukopenia (5% to 10%), thrombocytopenia (≤8%)
Hepatic: Hepatomegaly (4%), increased serum alanine aminotransferase (2.1 to 5 x baseline: 1% to 5%; 5.1 x 10 x baseline: 3%; 2 x baseline: ≤1%)
Infection: Bacterial infection (3% to 5%), fungal infection (1% to 6%)
Local: Pain at injection site (children and adolescents: 1%; severe)
Nervous system: Aggressive behavior (children and adolescents: 3%), agitation (5% to 8%), hostility (children and adolescents: 2%), malaise (4% to 6%), memory impairment (5% to 6%), mood changes (5% to 9%), suicidal ideation (≤2%)
Neuromuscular & skeletal: Back pain (5%), limb pain (children and adolescents: 1%; severe)
Ophthalmic: Blurred vision (2% to 6%), conjunctivitis (4% to 5%)
Respiratory: Dyspnea on exertion (4% to 7%), rhinitis (6% to 8%)
<1%:
Cardiovascular: Angina pectoris, cardiac arrhythmia
Endocrine & metabolic: Gout
Gastrointestinal: Cholangitis, gastrointestinal hemorrhage, peptic ulcer
Hematologic & oncologic: Thrombotic thrombocytopenic purpura
Hepatic: Liver steatosis
Nervous system: Hallucination, peripheral neuropathy
Neuromuscular & skeletal: Myositis
Frequency not defined: Hematologic & oncologic: Hemolysis
Postmarketing:
Dermatologic: Exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis
Endocrine & metabolic: Dehydration, diabetes mellitus, lactic acidosis (Smith 2019)
Gastrointestinal: Colitis
Hematologic & oncologic: Aplastic anemia, bone marrow depression, pure red cell aplasia, sarcoidosis
Hypersensitivity: Anaphylaxis, angioedema, hypersensitivity reaction
Immunologic: Autoimmune disease, exacerbation of sarcoidosis
Nervous system: Cerebrovascular disease, homicidal ideation, vertigo
Ophthalmic: Retinal detachment (serous)
Otic: Auditory disturbance, hearing loss
Respiratory: Bronchoconstriction, pneumonia, pneumonitis, pulmonary disease, pulmonary hypertension, pulmonary infiltrates
Hypersensitivity to ribavirin or any component of the formulation; patients who are pregnant or may become pregnant; males with partners who are pregnant; patients with hemoglobinopathies (eg, thalassemia major, sickle cell anemia); concomitant use with didanosine.
Ribasphere capsules and Rebetol capsules/solution: Additional contraindications: Patients with a CrCl <50 mL/minute.
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Combination therapy with alfa interferons: Autoimmune hepatitis; hepatic decompensation (Child-Pugh score >6; class B and C) in cirrhotic hepatitis C with or without HIV coinfection prior to treatment (Moderiba). Also refer to individual monographs for Interferon Alfa-2b (Intron A), Peginterferon Alfa-2b, and Peginterferon Alfa-2a (Pegasys) for additional contraindication information.
Concerns related to adverse effects:
• Hemolytic anemia: [US Boxed Warning]: Hemolytic anemia has been reported with ribavirin therapy; anemia associated with ribavirin may worsen underlying cardiac disease and lead to fatal and nonfatal myocardial infarctions. Avoid use in patients with significant/unstable cardiac disease. Anemia usually occurs within 1 to 2 weeks of therapy initiation; observed in ~10% to 13% of patients when alfa interferons were combined with ribavirin. Assess cardiac function before initiation of therapy. If patient has underlying cardiac disease, assess electrocardiogram prior to and periodically during treatment. If any deterioration in cardiovascular status occurs, discontinue therapy. Use caution in patients with baseline risk of severe anemia. Assess hemoglobin and hematocrit at baseline and, at minimum, weeks 2 and 4 of therapy since initial drop may be significant (hemoglobin <10 g/dL) (AASLD/IDSA 2021). Patients with renal dysfunction and/or those >50 years of age should be carefully assessed for development of anemia.
Disease-related concerns:
• Hepatic impairment: Risk of hepatic decompensation in chronic hepatitis C patients treated with combination therapy; monitor hepatic function closely and discontinue therapy immediately if evidence of hepatic decompensation is observed.
• Hepatitis C: Appropriate use: [US Boxed Warning]: Ribavirin monotherapy is not effective for chronic hepatitis C infection and should not be used alone for hepatitis C.
• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment or discontinuation may be required.
Concurrent drug therapy issues:
Combination therapy with alfa interferons:
• Autoimmune/infectious disorders: Have occurred with combination therapy; use with caution in patients with autoimmune disease or severe infection.
• Bone marrow suppression: Pancytopenia has occurred with combination therapy and concomitant use of azathioprine; onset occurs within 3 to 7 weeks; discontinue combination therapy and azathioprine if pancytopenia occurs; may be reversible (usually within 4 to 6 weeks).
• Dental and periodontal disorders: Have been reported with combination therapy; patients should be instructed to brush teeth twice daily and have regular dental exams. Xerostomia may contribute to and/or exacerbate dental disorders.
• Dermatologic reactions: Severe cutaneous reactions, including Stevens-Johnson syndrome and exfoliative dermatitis have been reported (rarely) with combination therapy; discontinue immediately with signs or symptoms of severe skin reactions.
• Diabetes: Has occurred with combination therapy; monitor blood sugars closely.
• Hypersensitivity reactions: Acute hypersensitivity reactions (eg, anaphylaxis, angioedema, bronchoconstriction, and urticaria) have been observed with combination therapy; discontinue immediately with signs or symptoms of severe hypersensitivity reactions.
• Ophthalmologic disorders: Serious disorders (eg, retinopathy, macular edema, retinal artery/vein thrombosis, optic neuritis, retinal detachment) have occurred with combination therapy. All patients require an eye exam at baseline; those with preexisting ophthalmologic disorders (eg, diabetic or hypertensive retinopathy) require periodic follow up. Discontinue therapy in patients with new or worsening ophthalmologic disorders.
• Pancreatitis: Has occurred with combination therapy; interrupt therapy if pancreatitis is suspected and discontinue if confirmed.
• Psychiatric disorders: Severe psychiatric events have occurred including depression and suicidal/homicidal ideation during combination therapy. Suicidal ideation or attempts occurred more often in pediatric patients versus reports in adults during treatment and off-therapy follow-up (2.4% vs 1%). Avoid use in patients with a psychiatric history; discontinue if severe psychiatric symptoms occur.
• Pulmonary events: Pulmonary symptoms (eg, dyspnea, pulmonary infiltrates, pneumonitis, pulmonary hypertension, and pneumonia [rarely fatal]) have been associated with combination therapy; use with caution in patients with pulmonary disease, including sarcoidosis (exacerbation reported).
Special populations:
• Older adult: Use with caution in the elderly; may be more susceptible to adverse effects such as anemia. Monitor renal function closely.
• Pediatric: In combination therapy with alfa interferons, ribavirin may cause a reduction in growth velocity in pediatric and adolescent patients 5 to 17 years of age for the length of treatment. Delay in weight and height increases have been noted in pediatric patients treated with combination therapy. In clinical studies, decreases were noted in weight and height for age z-scores and normative growth curve percentiles. Following treatment, rebound growth and weight gain occurred in most patients; however, a small percentage did not. Long-term data indicate that combination therapy may inhibit growth resulting in reduced adult height in some patients. Growth should be closely monitored in pediatric patients during therapy and post-treatment for growth catch-up.
Dosage form specific issues:
• Benzyl alcohol and derivatives: Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity ("gasping syndrome") in neonates; the "gasping syndrome" consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggest that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer's labeling.
Other warnings/precautions:
• Appropriate use: Safety and efficacy have not been established in patients who have failed previous interferon therapy, received organ transplants, or been coinfected with hepatitis B or HIV (ribavirin tablets may be used in adult HIV-coinfected patients with clinically stable disease and CD4+ cell count >100 cells/mm3). The combination of peginterferon and ribavirin, even with additional preferred HCV antiviral agent(s), is not recommended for hepatitis C virus (HCV) (regardless of genotype) in HCV adult treatment guidelines (treatment-naive or treatment-experienced); consult current clinical practice guidelines for details on appropriate use (AASLD/IDSA 2021).
Pediatric patients treated with ribavirin in combination with alfa interferon lag behind in height and weight gains compared to normative population growth curves for the duration of treatment. Severe inhibition of growth velocity (<3rd percentile) was reported in 70% of pediatric patients during clinical trials. After therapy, 20% continued to have severely inhibited growth; however, in the majority of patients, growth velocity rates increased such that by 6 months post-treatment, weight gain stabilized to 53rd percentile (similar to predicted based on average baseline weight: 57th percentile) and height gain stabilized to 44th percentile (less than predicted based on average baseline height: 51st percentile). Post-treatment, rebound growth occurred in most patients; however, long-term data indicate that combination therapy may result in reduced adult height in some patients. Growth should be closely monitored in pediatric patients during therapy and post-treatment for growth catch-up. Guidelines recommend deferring treatment in pediatric patients until an interferon-free regimen can be prescribed (AASLD/IDSA 2018).
Some dosage forms may contain propylene glycol; in neonates large amounts of propylene glycol delivered orally, intravenously (eg, >3,000 mg/day), or topically have been associated with potentially fatal toxicities which can include metabolic acidosis, seizures, renal failure, and CNS depression; toxicities have also been reported in children and adults including hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Shehab 2009).
Rebetol capsule and oral solution have been discontinued in the United States for >1 year.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Generic: 200 mg
Tablet, Oral:
Generic: 200 mg
Yes
Capsules (Ribavirin Oral)
200 mg (per each): $9.53
Tablets (Ribavirin Oral)
200 mg (per each): $8.27
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Tablet, Oral:
Ibavyr: 200 mg, 400 mg, 600 mg [DSC]
Oral:
Capsule: Administer with food. Capsule should not be opened, crushed, or broken.
Solution: Administer with food.
Oral:
Capsule: Administer with food. Capsule should not be opened, crushed, chewed, or broken.
Solution: Administer with food.
Tablet: Administer with food.
Hazardous agent (NIOSH 2016 [group 3]).
Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage. NIOSH recommends single gloving for administration of intact tablets or capsules. NIOSH recommends double gloving, a protective gown, and (if there is a potential for vomit or spit up) eye/face protection for administration of an oral liquid/feeding tube administration (NIOSH 2016). Assess risk to determine appropriate containment strategy (USP-NF 2017).
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Moderiba: http://dailymed.nlm.nih.gov/dailymed/medguide.cfm?setid=7046ff4c-8a75-5fd4-d40f-ff0cc84eed5f
Rebetol: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/020903s057,021546s013lbl.pdf#page=26
Ribasphere: http://kadmon.com/files/ribasphere-cap-pi.pdf
Hepatitis C, chronic: Ribavirin, in combination with direct-acting antivirals, is recommended in the AASLD/IDSA guidelines as part of an antiviral regimen for certain clinical scenarios (patients at increased risk of treatment failure [eg, decompensated cirrhosis], baseline NS5A resistance-associated substitutions, or prior direct-acting antiviral treatment). Hepatitis C treatment guidelines are frequently changing with the advent of new treatment therapies and information; consult current clinical practice guidelines for the most recent treatment recommendations. The combination of peginterferon and ribavirin, even with additional preferred hepatitis C virus (HCV) antiviral agent(s), is not recommended for HCV (regardless of genotype) in HCV adult treatment guidelines (treatment-naive or treatment-experienced) (AASLD/IDSA 2021).
Hepatitis E infection, chronic; Respiratory syncytial virus infection in immunocompromised patients; Viral hemorrhagic fever
Ribavirin may be confused with riboflavin, rifAMPin, Robaxin
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
AzaTHIOprine: Ribavirin (Systemic) may increase serum concentrations of the active metabolite(s) of AzaTHIOprine. Specifically, concentrations of potentially myelotoxic methylated metabolites may be increased, while concentrations of active 6-thioguanine nucleotides may be decreased. Management: Consider using alternative agent(s) when possible. When these drugs are used in combination, monitor patients closely for signs/symptoms of myelosuppression. Risk D: Consider therapy modification
Cladribine: Agents that Undergo Intracellular Phosphorylation may diminish the therapeutic effect of Cladribine. Risk X: Avoid combination
Didanosine: Ribavirin (Systemic) may enhance the adverse/toxic effect of Didanosine. Ribavirin (Systemic) may increase serum concentrations of the active metabolite(s) of Didanosine. Risk X: Avoid combination
Influenza Virus Vaccine (Live/Attenuated): Antiviral Agents (Influenza A and B) may diminish the therapeutic effect of Influenza Virus Vaccine (Live/Attenuated). Management: Avoid administration of live influenza virus vaccine (LAIV) within 2 weeks before or 48 hours after administration of antiviral agents. Consider avoiding LAIV if peramivir was given within the last 5 days or baloxavir was given within the last 17 days. Risk D: Consider therapy modification
Interferons (Alfa): May enhance the adverse/toxic effect of Ribavirin (Systemic). Hemolytic anemia has been observed. Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): Ribavirin (Systemic) may diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
Zidovudine: May enhance the adverse/toxic effect of Ribavirin (Systemic). Specifically, the risk/severity of anemia may be increased. Management: Due to significantly increased risk of anemia, consider even closer monitoring for anemia than routinely recommended for ribavirin. Alternative therapies should be considered when clinically possible, particularly for patients with other risk factors. Risk D: Consider therapy modification
High-fat meal increases the AUC and Cmax. Management: Capsule (in combination with peginterferon alfa-2b) and tablet should be administered with food. Other dosage forms and combinations should be taken consistently in regards to food.
Patients with hepatitis C virus (HCV) infection should be treated before considering pregnancy to optimize maternal health and reduce the risk of HCV transmission. Patients who could become pregnant and their partners should not use ribavirin for at least 6 months prior to conception (AASLD/IDSA 2021).
Evaluate pregnancy status prior to use in patients who could become pregnant. A negative pregnancy test is required immediately before initiation, periodically during therapy, and during the 9 months after treatment is discontinued. Effective contraception is required during treatment and for 9 months after the last ribavirin dose. If the patient becomes pregnant during treatment, they should be counseled about potential risks of fetal exposure. Two forms of effective, reliable contraception are recommended. Contraceptive use should be evaluated periodically during ribavirin therapy and a discussion about the possible teratogenic effects of ribavirin should be conducted and documented in the patient’s medical record (AASLD/IDSA 2021).
Concentrations of ribavirin are higher in seminal fluid than serum in patients treated for HCV infection; in addition, alterations in spermatogenesis have been noted. Chronic HCV infection may also adversely affect spermatogenesis (Sinclair 2022). Use is contraindicated patients whose partners could become pregnant. Male patients and their partners who could become pregnant should both use effective contraception during treatment and for 6 months after the last ribavirin dose.
In animal reproduction studies, in utero exposure to ribavirin at doses one-twentieth of the recommended human dose caused significant teratogenic and embryocidal events.
Final data from the Ribavirin Pregnancy Registry found an increased risk of birth defects following in utero exposure to ribavirin. The registry enrolled 467 pregnant patients between 2003 and 2020. Among these, 137 cases with direct ribavirin exposure (maternal ribavirin use during the first trimester or within 6 months of conception) and 143 cases with indirect exposure via a male partner were prospectively enrolled and had medically confirmed outcome data. Among ribavirin exposures with a live birth, the rate of birth defects following direct exposure was 9.09% (8 of 88 births, 95% CI: 4.01 to 17.13) and 6.12% following indirect exposure (6 of 98 births, 95% CI: 2.28 to 12.85). This is higher than the background birth defect rate of 2.72% observed in the Metropolitan Atlanta Congenital Defects Program birth defects surveillance system, the external comparator group used by the registry. A family history of similar birth defects was observed among 2 of the 14 infants diagnosed with birth defects. A specific pattern of birth defects was not identified. The study was not designed to review the miscarriage rate; however, the rate observed was within the estimates of the US population. The pregnancy registry was closed before meeting the required sample size due to a high loss to follow-up (35%) and decreased use of ribavirin for hepatitis C virus infection (Sinclair 2022).
Ribavirin is contraindicated in patients who are pregnant and male patients whose partners are pregnant for the treatment of hepatitis C virus (HCV) infection.
Ribavirin may be used off label for the treatment of viral hemorrhagic fever (VHF) caused by select Arenaviruses and Bunyaviruses (Borio 2002). Outcome data following maternal use of ribavirin for select viral hemorrhagic diseases during pregnancy are limited (Gozel 2014; Kayem 2020; Okogbenin 2019; Pshenichnaya 2017). Although use of ribavirin is contraindicated during pregnancy for HCV infection, the risk versus benefit of ribavirin in VHF must be considered as associated mortality with VHF tends to be higher in pregnant persons (Borio 2002).
It is not known if ribavirin is present in breast milk.
Breastfeeding is not linked to the spread of hepatitis C virus; however, if nipples are cracked or bleeding, breastfeeding is not recommended (milk should be expressed and discarded) (AASLD/IDSA 2021; SMFM [Dotters-Katz 2021]). According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.
Capsules, solution, and tablets should be taken with food.
Manufacturer's labeling:
Pretreatment hematological and biochemical tests are recommended for all patients; dental exam, ECG (if preexisting cardiac abnormalities or disease) and ophthalmic exam (also periodically during treatment for those with preexisting ophthalmologic disorders) are also recommended. In adults, hematologic tests should be performed at treatment weeks 2 and 4, biochemical tests at week 4, and TSH every 12 weeks.
Pregnancy testing: Evaluate pregnancy status prior to use in patients who could become pregnant. A negative pregnancy test is required immediately before initiation, periodically during therapy, and during the 9 months after ribavirin is discontinued.
In pediatric clinical studies, hematologic and biochemical assessments were made at weeks 1, 3, 5 and 8, then every 4 weeks thereafter, and TSH every 12 weeks. Growth velocity and weight should also be monitored during and periodically after treatment discontinuation.
Serum HCV RNA (pretreatment, week 12 and week 24, and 24 weeks after completion of therapy).
Alternate recommendations for hepatitis C (AASLD/IDSA 2021):
Pretreatment assessment: Evaluate for advanced hepatic fibrosis and hepatocellular carcinoma. Confirm vaccination against hepatitis A and B (AASLD/IDSA 2021).
Laboratory tests recommended at any time before starting therapy:
Quantitative hepatitis C virus (HCV) RNA (HCV viral load), HCV genotype and subtype, HIV antigen/antibody (AASLD/IDSA 2021).
Assessment for active hepatitis B virus coinfection: Hepatitis B virus (HBV) surface antigen (HBsAg); HBV core antibody (anti-HBc) and HBV surface antibody (anti-HBs); if evidence of hepatitis B viral coinfection, HBV DNA level should be drawn. HBsAg-positive patients not already receiving HBV suppressive therapy should be either: initiated on prophylactic HBV antiviral therapy (for those with low or undetectable HBV DNA levels), which should be continued until 12 weeks after completion of HCV therapy, OR monitor HBV DNA levels monthly during and immediately after HCV therapy (AASLD/IDSA 2021).
Laboratory tests recommended 6 months prior to starting therapy: CBC, INR, hepatic function panel (serum albumin, total and direct bilirubin, ALT, AST, alkaline phosphatase), eGFR (AASLD/IDSA 2021).
Laboratory tests immediately prior to starting therapy: Serum pregnancy test for patients of childbearing potential.
On-treatment monitoring:
Periodic monitoring of LFTs and assessment for presence of symptoms of liver dysfunction (eg, weakness, nausea, vomiting, jaundice, or significantly elevated bilirubin, alkaline phosphatase, or INR) (AASLD/IDSA 2021).
In patients with diabetes, monitor blood glucose and for signs/symptoms of hypoglycemia (AASLD/IDSA 2020; Ciancio 2018; Dawood 2017; Hum 2017); in patients taking warfarin, monitor INR during and post therapy (AASLD/IDSA 2021).
Post treatment assessment of cure: Quantitative HCV viral load testing 12 or more weeks after completion of therapy to document sustained virologic response and liver transaminases (AASLD/IDSA 2021).
Rapid virological response (RVR): Absence of detectable HCV RNA after 4 weeks of treatment
Early viral response (EVR): ≥2-log decrease in HCV RNA after 12 weeks of treatment
End of treatment response (ETR): Absence of detectable HCV RNA at end of the recommended treatment period
Sustained treatment response (STR) or sustained virologic response (SVR): Absence of HCV RNA in the serum 6 months following completion of full treatment course
Inhibits replication of RNA and DNA viruses; inhibits influenza virus RNA polymerase activity and inhibits the initiation and elongation of RNA fragments resulting in inhibition of viral protein synthesis
Distribution: Oral capsule: Single dose: Vd: 2,825 L; distribution significantly prolonged in the erythrocyte (16 to 40 days), which can be used as a marker for intracellular metabolism
Protein binding: None
Metabolism: Hepatically and intracellularly (forms active metabolites); may be necessary for drug action
Bioavailability: Oral capsule: 64%
Half-life elimination, plasma: Adults:
Capsule, single dose: 24 hours in healthy adults, 44 hours with chronic hepatitis C infection (increases to ~298 hours at steady state)
Tablet, single dose: ~120 to 170 hours
Time to peak, serum: Oral capsule: Multiple doses: Children and Adolescents 3 to 16 years: ~2 hours; Adults: 3 hours; Tablet: 2 hours
Excretion: Oral capsule: Urine (61%), feces (12%)
Altered kidney function:
Capsules/Oral solution: The mean AUCtf value was 3-fold greater in subjects with CrCl values between 10 and 30 mL/minute compared with control subjects (CrCl >90 mL/minute). In subjects with CrCl values between 30 and 60 mL/minute, AUCtf was 2-fold greater compared with control subjects. Ribavirin is not effectively removed by hemodialysis.
Tablets: Clearance was reduced in patients with CrCl ≤50 mL/minute compared with patients with healthy renal function. Plasma exposure was decreased 20% in patients with ESRD on chronic hemodialysis.
Hepatic function impairment: Cmax increases with increasing severity of hepatic impairment.
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