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Ribavirin (Systemic)

Pronunciation

Pronunciation

(rye ba VYE rin)

Index Terms

  • RTCA
  • Tribavirin

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule, Oral:

Rebetol: 200 mg

Ribasphere: 200 mg

Generic: 200 mg

Miscellaneous, Oral:

Moderiba: 400 mg & 600 mg (56 ea) [contains fd&c blue #1 aluminum lake]

Moderiba: 200 mg & 400 mg (56 ea) [contains fd&c blue #1 aluminum lake, fd&c blue #2 aluminum lake]

RibaTab: 400 mg & 600 mg (56 ea [DSC]) [contains fd&c blue #1 aluminum lake]

Solution, Oral:

Rebetol: 40 mg/mL (100 mL) [contains propylene glycol, sodium benzoate; bubble-gum flavor]

Tablet, Oral:

Copegus: 200 mg

Moderiba: 200 mg [contains fd&c blue #2 aluminum lake]

Moderiba 1200 Dose Pack: 600 mg [contains fd&c blue #1 aluminum lake]

Moderiba 800 Dose Pack: 400 mg [contains fd&c blue #1 aluminum lake]

Ribasphere: 200 mg [contains fd&c blue #2 aluminum lake]

Ribasphere: 400 mg, 600 mg [contains fd&c blue #1 aluminum lake]

Ribasphere RibaPak: Ribasphere RibaPak 800: 400 mg AM dose, 400 mg PM dose, Ribasphere RibaPak 1200: 600 mg AM dose, 600 mg PM dose, Ribasphere RibaPak 1000: 600 mg AM dose, 400 mg PM dose [contains fd&c blue #1 aluminum lake]

Ribasphere RibaPak: Ribasphere RibaPak 600: 200 mg AM dose, 400 mg PM dose [contains fd&c blue #1 aluminum lake, fd&c blue #2 aluminum lake]

RibaTab: 400 mg [DSC], 600 mg [DSC] [contains fd&c blue #1 aluminum lake]

Generic: 200 mg

Brand Names: U.S.

  • Copegus
  • Moderiba
  • Moderiba 1200 Dose Pack
  • Moderiba 800 Dose Pack
  • Rebetol
  • Ribasphere
  • Ribasphere RibaPak
  • RibaTab [DSC]

Pharmacologic Category

  • Antihepaciviral, Nucleoside (Anti-HCV)

Pharmacology

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

Metabolism

Hepatically and intracellularly (forms active metabolites); may be necessary for drug action

Excretion

Oral capsule: Urine (61%), feces (12%)

Time to Peak

Serum: Oral capsule: Multiple doses: Children and Adolescents 3 to 16 years: ~2 hours; Adults: 3 hours; Tablet: 2 hours

Half-Life Elimination

Plasma: Adults: Oral:

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

Protein Binding

Oral: None

Special Populations: Renal Function Impairment

Capsules/Oral solution

The mean AUCtf value was threefold greater in subjects with creatinine clearance (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 twofold greater compared with control subjects. Ribavirin is not effectively removed by hemodialysis.

Tablets

Copegus, Moderiba

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.

Ribasphere

In clinical trials with ribavirin, clearance was reduced in patients with CrCl <50 mL/minute compared with patients with healthy renal function.

Special Populations: Hepatic Function Impairment

Cmax increases with increasing severity of hepatic impairment.

Use: Labeled Indications

Oral capsule: In combination with interferon alfa 2b (pegylated or nonpegylated) injection for the treatment of chronic hepatitis C in interferon alfa-naive or experienced patients ≥3 years of age with compensated liver disease. Patients likely to fail re-treatment after a prior failed course include previous nonresponders, those who received previous pegylated interferon treatment, patients who have significant bridging fibrosis or cirrhosis, or those with genotype 1 infection.

Oral solution: In combination with interferon alfa-2b (pegylated or nonpegylated) injection for the treatment of chronic hepatitis C in interferon alfa-naive or experienced patients ≥3 years of age with compensated liver disease. Patients likely to fail re-treatment after a prior failed course include previous nonresponders, those who received previous pegylated interferon treatment, patients who have significant bridging fibrosis or cirrhosis, or those with genotype 1 infection.

Oral tablet: In combination with peginterferon alfa-2a for the treatment of adults (Copegus, Moderiba, Ribasphere) and patients ≥5 years of age (Copegus and Moderiba) with chronic HCV infection who have compensated liver disease and have not previously been treated with interferon alpha, and in adult chronic hepatitis C patients coinfected with HIV

Guideline recommendations: Peginterferon and ribavirin, without 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). In addition, nonpegylated interferons are not included in any recommended HCV treatment regimens. Current AASLD/IDSA recommendations do not specify a particular peginterferon (eg, 2a or 2b) to combine with oral ribavirin and additional preferred HCV antiviral agent(s); however, guideline recommendations are based on clinical trials that used peginterferon alfa-2a (AASLD/IDSA 2015). Hepatitis C treatment guidelines are constantly changing with the advent of new treatment therapies and information; consult current clinical practice guidelines for the most recent treatment recommendations.

Contraindications

Oral formulations: Hypersensitivity to ribavirin or any component of the formulation; women who are pregnant or may become pregnant; males whose female partners 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

Oral combination therapy with alfa interferons: Autoimmune hepatitis, hepatic decompensation (Child-Pugh score >6; class B and C) in cirrhotic chronic hepatitis C monoinfected patients prior to treatment, hepatic decompensation (Child-Pugh score ≥6) in cirrhotic chronic hepatitis C patients coinfected with HIV prior to treatment. Also refer to individual monographs for Interferon Alfa-2b (Intron A), Peginterferon Alfa-2b, and Peginterferon Alfa-2a (Pegasys) for additional contraindication information.

Dosing: Adult

Manufacturer’s labeling:

Chronic hepatitis C monoinfection (in combination with peginterferon alfa-2b): Note: Combination therapy with peginterferon alone is not recommended in HCV treatment guidelines (treatment-naive or treatment-experienced patients) (AASLD/IDSA 2015).

Oral capsule, oral solution (Rebetol, Ribasphere):

<66 kg: 800 mg daily (400 mg in the morning and evening)

66 to 80 kg: 1,000 mg daily (400 mg in the morning, 600 mg in the evening)

81 to 105 kg: 1,200 mg daily (600 mg in the morning, 600 mg in the evening)

>105 kg: 1,400 mg daily (600 mg in the morning, 800 mg in the evening)

Duration of therapy: Manufacturer’s labeling: Genotype 1: 48 weeks; Genotypes 2, 3: 24 weeks; patients who previously failed therapy: 48 weeks (regardless of genotype).

Chronic hepatitis C monoinfection (in combination with interferon alfa-2b): Note: Nonpegylated interferons are not included in any recommended treatment regimens in HCV treatment guidelines (treatment-naive or treatment-experienced patients) (AASLD/IDSA 2015).

Oral capsule (Rebetol, Ribasphere):

≤75 kg: 1,000 mg daily (400 mg in the morning, 600 mg in the evening)

>75 kg: 1,200 mg daily (600 mg in the morning, 600 mg in the evening)

Duration of therapy: Manufacturer’s labeling: Individualized therapy duration of 24 to 48 weeks

Chronic hepatitis C monoinfection (in combination with peginterferon alfa-2a): Note: Combination therapy with peginterferon alone is not recommended in HCV treatment guidelines (treatment-naive or treatment-experienced patients) (AASLD/IDSA 2015).

Oral tablet (Copegus, Moderiba, Ribasphere):

Genotype 1, 4:

<75 kg: 1,000 mg daily in 2 divided doses for 48 weeks

≥75 kg: 1,200 mg daily in 2 divided doses for 48 weeks

Genotype 2, 3: 800 mg daily in 2 divided doses for 24 weeks

Chronic hepatitis C coinfection with HIV (in combination with peginterferon alfa-2a): Oral tablet (Copegus, Moderiba, Ribasphere): 800 mg daily in 2 divided doses for 48 weeks (regardless of genotype). Note: Combination therapy with peginterferon alone is not recommended in clinical practice guidelines for HCV treatment treatment-naive or treatment-experienced patients, including those with HIV coinfection (AASLD/IDSA 2015).

Alternate recommendations:

Chronic hepatitis C monoinfection (off-label regimens; AASLD/IDSA 2015):

Weight-based ribavirin:

<75 kg: 1,000 mg daily in 2 divided doses

≥75 kg: 1,200 mg daily in 2 divided doses

Treatment regimens and durations are dependent on HCV genotype, treatment status (treatment-naive or treatment-experienced), as well as other factors (eg, presence of cirrhosis, interferon eligibility). Regimens presented are limited to those where ribavirin is a required component; regimens in which ribavirin use is optional have not been included; consult current AASLD/IDSA guidelines for further guidance:

Treatment-naive patients:

Genotype 1a: Weight-based ribavirin in combination with dasabuvir and fixed dose paritaprevir/ritonavir/ombitasvir for 12 weeks (without cirrhosis) or 24 weeks (with cirrhosis)

Genotype 2: Weight-based ribavirin in combination with sofosbuvir for 12 weeks (without cirrhosis) or 16 weeks (with cirrhosis)

Genotype 3:

Weight-based ribavirin in combination with sofosbuvir and peginterferon (interferon-eligible patients) for 12 weeks

Weight-based ribavirin in combination with sofosbuvir (interferon-ineligible patients) for 24 weeks

Genotype 4:

Weight-based ribavirin in combination with fixed dose paritaprevir/ritonavir/ombitasvir for 12 weeks

Weight-based ribavirin in combination with sofosbuvir for 24 weeks

Weight-based ribavirin in combination with sofosbuvir and peginterferon for 12 weeks

Genotype 5 or 6: Weight-based ribavirin in combination with sofosbuvir and peginterferon for 12 weeks

Treatment-experienced patients:

Genotype 1a:

In whom a previous regimen of ribavirin and peginterferon has failed: Weight-based ribavirin in combination with dasabuvir and fixed dose paritaprevir/ritonavir/ombitasvir for 12 weeks (without cirrhosis) or 24 weeks (with compensated cirrhosis)

Genotype 1a or 1b:

In whom a previous regimen of ribavirin and peginterferon has failed: Weight-based ribavirin in combination with ledipasvir/sofosbuvir for 12 weeks (with compensated cirrhosis)

In whom a previous sofosbuvir-containing regimen (with or without peginterferon) has failed: Weight-based ribavirin in combination with ledipasvir/sofosbuvir for 12 weeks (without cirrhosis) or 24 weeks (with cirrhosis)

In whom a previous regimen of an HCV protease inhibitor (telaprevir, boceprevir, or simeprevir) plus ribavirin/peginterferon has failed: Weight-based ribavirin in combination with ledipasvir/sofosbuvir for 12 weeks (with cirrhosis)

Genotype 2:

In whom a previous regimen of ribavirin and peginterferon has failed:

Weight-based ribavirin in combination with sofosbuvir for 16 or 24 weeks

Weight-based ribavirin in combination with sofosbuvir and peginterferon (interferon-eligible patients) for 12 weeks

In whom a previous regimen of sofosbuvir and ribavirin has failed: Retreatment with weight-based ribavirin in combination with sofosbuvir and peginterferon (interferon-eligible patients) for 12 weeks

Genotype 3:

In whom a previous regimen of ribavirin and peginterferon has failed:

Weight-based ribavirin in combination with sofosbuvir and peginterferon (interferon-eligible patients) for 12 weeks (with or without cirrhosis)

Weight-based ribavirin in combination with daclatasvir and sofosbuvir for 12 weeks (without cirrhosis) or 24 weeks (with cirrhosis; interferon-ineligible patients)

In whom a previous regimen of sofosbuvir and ribavirin has failed:

Weight-based ribavirin in combination with daclatasvir and sofosbuvir (interferon-ineligible patients) for 24 weeks

Weight-based ribavirin in combination with sofosbuvir and peginterferon (interferon-eligible patients) for 12 weeks

Genotype 4:

In whom a previous regimen of ribavirin and peginterferon has failed:

Weight-based ribavirin in combination with fixed dose paritaprevir/ritonavir/ombitasvir for 12 weeks

Weight-based ribavirin in combination with sofosbuvir and peginterferon (interferon-eligible) for 12 weeks

Weight-based ribavirin in combination with sofosbuvir for 24 weeks

Genotype 5 or 6:

In whom prior treatment has failed: Weight-based ribavirin in combination with sofosbuvir and peginterferon (interferon-eligible) for 12 weeks

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Chronic hepatitis C monoinfection (in combination with pegylated or nonpegylated interferon alfa-2b): Manufacturer’s labeling:

Children ≥3 years: Oral capsule or solution (Rebetol, Ribasphere): Note: Oral solution should be used in children <47 kg, or those unable to swallow capsules. Children who start treatment prior to age 18 years should continue on pediatric dosing regimen through therapy completion. Recommended therapy duration (manufacturer labeling): Genotypes 2, 3: 24 weeks; all other genotypes: 48 weeks

Oral capsule, oral solution dosing recommendations:

<47 kg: 15 mg/kg/day in 2 divided doses (morning and evening) as oral solution

47 to 59 kg: 800 mg daily (400 mg in morning and evening)

60 to 73 kg: 1,000 mg daily (400 mg in morning and 600 mg in the evening)

>73 kg: 1,200 mg daily (600 mg in morning and evening)

Chronic hepatitis C monoinfection (in combination with peginterferon alfa-2a): Manufacturer’s labeling:

Children ≥5 years and Adolescents: Oral tablet (Copegus, Moderiba): Note: Assess child’s ability to swallow tablet; children who start treatment prior to age 18 years should continue on pediatric dosing regimen through therapy completion. Recommended therapy duration (manufacturer labeling): Genotypes 2, 3: 24 weeks; all other genotypes: 48 weeks

23 to 33 kg: 400 mg daily (200 mg in the morning and evening)

34 to 46 kg: 600 mg daily (200 mg in the morning and 400 mg in the evening)

47 to 59 kg: 800 mg daily (400 mg in the morning and evening)

60 to 74 kg: 1,000 mg daily (400 mg in the morning and 600 mg in the evening)

≥75 kg: 1,200 mg daily (600 mg in the morning and evening)

Dosing: Renal Impairment

CHC infection: Oral:

Rebetol capsules/solution, Ribasphere capsules:

Adults:

CrCl ≥50 mL/minute: No dosage adjustments necessary.

CrCl <50 mL/minute: Use is contraindicated.

Children: Serum creatinine >2 mg/dL: Permanently discontinue treatment.

Ribasphere tablets: Adults:

CrCl ≥50 mL/minute: No dosage adjustments necessary.

CrCl <50 mL/minute: Use is not recommended.

Copegus and Moderiba tablets: Adults:

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: The dose of Copegus and Moderiba 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.

Dosing: Hepatic Impairment

CHC infection: Hepatic decompensation (Child-Pugh class B and C): Manufacturer’s labeling: Oral tablets: Use contraindicated.

Dosing: Adjustment for Toxicity

Notes:

Children 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. Initiate restart at 50% of the full dose.

Adults: 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:

Children ≥3 years: Oral capsules, oral solution:

First reduction: Decrease to 12 mg/kg/day

Second reduction: Decrease to 8 mg/kg/day

Children ≥5 years and Adolescents: Oral tablets (Copegus, Moderiba):

23 to 33 kg: Decrease dose to 200 mg daily (in the morning)

34 to 59 kg: Decrease dose to 400 mg daily (200 mg in the morning and evening)

≥60 kg: Decrease dose to 600 mg daily (200 mg in the morning and 400 mg in the evening)

Adults:

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: Children, Adolescents, and Adults: Oral capsules, solution, tablets: Permanently discontinue treatment.

WBC <1,000 mm3, neutrophils <500 mm3: Children and Adults: Oral capsules, solution: Permanently discontinue treatment.

Platelets <50 x 109/L: Children: Oral capsules, solution: Permanently discontinue treatment.

Platelets <25 x 109/L: Adults: Oral capsules, solution: Permanently discontinue treatment.

Laboratory abnormalities or adverse reactions other than decreased hemoglobin: Children ≥5 years, Adolescents, and Adults: Oral tablets (Moderiba): 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:

Children and Adolescents: Oral capsules, solution: Decrease ribavirin by 200 mg daily (regardless of the patient’s initial dose); decrease peginterferon alfa-2b dose by 50%; monitor and evaluate weekly. If hemoglobin <8.5 g/dL any time after dose reduction or <12 g/dL after 4 weeks of dose reduction, permanently discontinue treatment.

Children ≥5 years and Adolescents: Oral tablets (Copegus, Moderiba):

23 to 33 kg: Decrease dose to 200 mg daily (in the morning)

34 to 59 kg: Decrease dose to 400 mg daily (200 mg in the morning and evening)

≥60 kg: 600 mg daily (200 mg in the morning, 400 mg in the evening)

Note: 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 has decreased ≥2 g/dL during any 4-week period of treatment: Adults:

Oral capsules, solution: Decrease dose by 200 mg daily; decrease peginterferon alfa-2b dose by 50%. If hemoglobin <8.5 g/dL any time after dose reduction or <12 g/dL after 4 weeks of dose reduction, permanently discontinue 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: Children, Adolescents, and Adults: Oral capsules, solution, tablets: Permanently discontinue treatment.

WBC <1,000 mm3, neutrophils <500 mm3: Children and Adults: Oral capsules, solution: Permanently discontinue treatment.

Platelets <50 x 109/L: Children: Oral capsules, solution: Permanently discontinue treatment.

Platelets <25 x 109/L: Adults: Oral capsules, solution: Permanently discontinue treatment.

Laboratory abnormalities or adverse reactions other than decreased hemoglobin: Children ≥5 years, Adolescents, and Adults: Oral tablets (Moderiba): Refer to dose modification guidelines in the manufacturer’s labeling.

Administration

Oral:

Capsule: Administer with food. Capsule should not be opened, crushed, chewed, or broken.

Solution: Administer with food. Use oral solution for children <47 kg, or those who cannot swallow capsules.

Tablet: Administer with food.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 3]).

Dietary Considerations

Capsules, solution, and tablets should be taken with food.

Storage

Oral: Store at 25°C (77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). Solution may also be refrigerated at 2°C to 8°C (36°F to 46°F).

Drug Interactions

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. Consider therapy modification

Didanosine: Ribavirin (Systemic) may enhance the adverse/toxic effect of Didanosine. Ribavirin (Systemic) may increase serum concentrations of the active metabolite(s) of Didanosine. 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 anti-influenza antivirals during the period beginning 48 hours prior to and ending 2 weeks after vaccine administration. Persons receiving these agents within 2 weeks of the live intranasal spray vaccine should receive a repeat vaccine dose. Consider therapy modification

Interferons (Alfa): May enhance the adverse/toxic effect of Ribavirin (Systemic). Hemolytic anemia has been observed. Monitor therapy

Vitamin K Antagonists (eg, warfarin): Ribavirin (Systemic) may diminish the anticoagulant effect of Vitamin K Antagonists. 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. Consider therapy modification

Adverse Reactions

All adverse reactions are documented while receiving combination therapy with alfa interferons; percentages as reported in adults unless noted, most common pediatric adverse reactions were similar to adults; asterisked (*) percentages are those similar to interferon therapy alone:

>10%:

Central nervous system: Fatigue (60% to 70% [30% in pediatric patients])*, headache (43% to 66%)*, fever (32% to 55%)*, insomnia (26% to 41% [9% in pediatric patients]), depression (20% to 36%)*, irritability (23% to 33%), dizziness (14% to 26%), impaired concentration (10% to 21%)*, pain (≤13%), emotional lability (7% to 12%)*, anxiety (11%)

Dermatologic: Alopecia (27% to 36% [17% in pediatric patients]), pruritus (13% to 29% [11% in pediatric patients]), rash (5% to 28%), dry skin (10% to 24%), dermatitis (≤16%)

Endocrine and metabolic: Growth suppression (pediatric) percentile decrease (≥15 percentiles: weight 43%; height 25%), hyperuricemia (33% to 38%)

Gastrointestinal: Nausea (25% to 47% [18% in pediatric patients]), anorexia (21% to 32%), weight decrease (10% to 29%), vomiting (9% to 25%)*, diarrhea (10% to 22%), dyspepsia (6% to 16%), abdominal pain (8% to 13% [21% in pediatric patients]), xerostomia (≤12%), RUQ pain (≤12%)

Hematologic: Leukopenia (6% to 45%), neutropenia (8% to 42%; grade 4: 2% to 11%; 40% with HIV coinfection), hemoglobin decreased (11% to 35%), anemia (11% to 17%), thrombocytopenia (<1% to 15%), lymphopenia (12% to 14%), hemolytic anemia (10% to 13%)

Hepatic: Bilirubin increase (10% to 32%)

Local: Injection site reaction (36% to 58%), inflammation at injection site (18% to 25%)

Neuromuscular & skeletal: Decreased linear skeletal growth (including lagging weight gain; 70% in pediatric patients), myalgia (40% to 64% [17% in pediatric patients])*, rigors (25% to 48%), arthralgia (21% to 34%)*, musculoskeletal pain (19% to 28% [35% in pediatric patients])

Respiratory: Upper respiratory tract infection (60% in pediatric patients), dyspnea (13% to 26%), cough (7% to 23%), pharyngitis (≤13%), sinusitis (≤12%)*

Miscellaneous: Flu-like syndrome (13% to 18% [up to 91% in pediatric patients])*, viral infection (≤12%), diaphoresis (≤11%)

1% to 10%:

Cardiovascular: Chest pain (5% to 9%)*, flushing (≤4%)

Central nervous system: Mood alteration (≤6%; 9% with HIV coinfection), agitation (5% to 8%), nervousness (6%)*, memory impairment (≤6%), malaise (≤6%), suicidal ideation (adolescents: 2%; adults: 1%)

Dermatologic: Eczema (4% to 5%)

Endocrine & metabolic: Menstrual disorder (≤7%), hypothyroidism (≤5%)

Gastrointestinal: Taste perversion (4% to 9%), constipation (5%)

Hepatic: Hepatomegaly (4%), transaminases increased (1% to 3%), hepatic decompensation (2% with HIV coinfection)

Neuromuscular & skeletal: Weakness (9% to 10%), back pain (5%)

Ocular: Blurred vision (≤6%), conjunctivitis (≤5%)

Respiratory: Rhinitis (≤8%), exertional dyspnea (≤7%)

Miscellaneous: Fungal infection (≤6%), bacterial infection (3% to 5%)

<1% (Limited to important or life-threatening): Aggression, angina, aplastic anemia, arrhythmia; autoimmune disorders (systemic lupus erythematosus, rheumatoid arthritis, sarcoidosis); bone marrow suppression, cerebral hemorrhage, cholangitis, colitis, coma, corneal ulcer, dehydration, diabetes mellitus, drug abuse relapse/overdose, exfoliative dermatitis, fatty liver, hearing impairment/loss, gastrointestinal bleeding, gout, hallucination, hepatic dysfunction, hyper-/hypothyroidism, hypersensitivity (including anaphylaxis, angioedema, bronchoconstriction, and urticaria), macular edema, myositis, optic neuritis, papilledema, pancreatitis, peptic ulcer, peripheral neuropathy, pneumonitis, psychosis, psychotic disorder, pulmonary dysfunction, pulmonary embolism, pulmonary infiltrates, pure red cell aplasia, retinal artery/vein thrombosis, retinal detachment, retinal hemorrhage, retinopathy, sarcoidosis exacerbation; skin reactions (erythema multiforme, exfoliative dermatitis, urticaria, vesiculobullous eruptions); Stevens-Johnson syndrome, suicide, thrombotic thrombocytopenic purpura, thyroid function test abnormalities; transplant rejection (kidney, liver); vision loss

Note: Incidence of headache, fever, suicidal ideation, and vomiting are higher in children.

ALERT: U.S. Boxed Warning

Appropriate use (oral):

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 (oral):

The primary clinical toxicity of ribavirin is hemolytic anemia, which may result in worsening of cardiac disease and lead to fatal and nonfatal myocardial infarctions (MIs). Do not treat patients with a history of significant or unstable cardiac disease with ribavirin.

Pregnancy (oral):

Significant teratogenic and/or 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 it may persist in nonplasma 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. Extreme care must be taken to avoid pregnancy during therapy and for 6 months after completion of treatment in women receiving ribavirin therapy and female partners of men who are taking ribavirin therapy. At least 2 reliable forms of effective contraception must be used during treatment and during the 6-month posttreatment follow-up period.

Warnings/Precautions

Concerns related to adverse effects:

• Hemolytic anemia: [US Boxed Warning]: Hemolytic anemia is the primary clinical toxicity of oral 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. 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, pneumonia [rarely fatal]) have been associated with combination therapy; use with caution in patients with pulmonary disease, including sarcoidosis (exacerbation reported).

Special populations:

• Elderly: 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 patients for the length of treatment. Delay in weight and height increases have been noted in children 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. Growth should be closely monitored in pediatric patients during therapy and post-treatment for growth catch-up.

• Pregnancy: [US Boxed Warning]: Significant teratogenic and/or embryocidal effects have been observed in all animal studies. Use is contraindicated in pregnant women or male partners of pregnant women. Avoid pregnancy in female patients and female partners of male patients during therapy by using two effective forms of contraception; continue contraceptive measures for at least 6 months after completion of therapy. The manufacturer recommends that pregnant health care workers take precautions to limit exposure to ribavirin aerosol.

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 suggests 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.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 3]).

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 unless CD4+ cell count is ≤100 cells/mm3 and HIV-1 RNA <5,000 cells/mm3). Hemoglobin at initiation must be ≥12 g/dL (women) or ≥13 g/dL (men) in CHC monoinfected patients and ≥11 g/dL (women) or ≥12 g/dL (men) in CHC and HIV coinfected patients. Oral ribavirin should not be used for adenovirus, RSV, influenza or parainfluenza infections. Combination therapy of peginterferon and ribavirin, without additional HCV antiviral agent(s), is not recommended for the treatment of hepatitis C virus (AASLD/IDSA 2015).

Monitoring Parameters

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 at treatment weeks 2 and 4, biochemical tests at week 4, and TSH at week 12. In pediatric patients, monitor growth closely during and after treatment.

Pregnancy screening (in woman of childbearing age) and pregnancy tests monthly during and for 6 months after treatment discontinuation.

In pediatric clinical studies, hematologic and biochemical assessments were made at weeks 1, 3, 5 and 8, then every 4 weeks thereafter. Growth velocity and weight should also be monitored during and periodically after treatment discontinuation.

Baseline values used in adult clinical trials in combination with alfa interferons:

Platelet count ≥90,000/mm3 (75,000/mm3 for cirrhosis or 70,000/mm3 for coinfection with HIV)

ANC ≥1,500/mm3

Hemoglobin ≥12 g/dL for women and ≥13 g/dL for men (11 g/dL for HIV coinfected women and 12 g/dL for HIV coinfected men)

TSH and T4 within normal limits or adequately controlled

CD4+ cell count ≥200 cells/microL or CD4+ cell count 100 to 200 cells/microL and HIV-1 RNA <5,000 copies/mL for coinfection with HIV

Serum HCV RNA (pretreatment, week 12 and week 24, and 24 weeks after completion of therapy).

Alternate recommendations (AASLD/IDSA 2015):

Baseline (within 12 weeks prior to starting antiviral therapy): CBC, INR, hepatic function panel (albumin, total and direct bilirubin, ALT, AST, and alkaline phosphatase), calculated GFR

Baseline (at any time prior to starting antiviral therapy): HCV genotype and subtype, quantitative HCV viral load

During therapy: CBC, serum creatinine, calculated GFR, hepatic function panel (after 4 weeks of therapy and as clinically indicated); quantitative HCV viral load testing (after 4 weeks of therapy and at 12 weeks after completion of therapy). If quantitative HCV viral load is detectable at treatment week 4, repeat testing is recommended after 2 additional weeks of treatment (treatment week 6).

Pregnancy Risk Factor

X

Pregnancy Considerations

[US Boxed Warning]: Use is contraindicated in pregnant women or male partners of pregnant women. Significant teratogenic and/or embryocidal effects have been observed in all animal species with adequate studies. Avoid pregnancy in female patients and female partners of male patients during therapy by using two effective forms of contraception; continue contraceptive measures for at least 6 months after completion of therapy. A negative pregnancy test is required immediately before initiation, monthly during therapy, and for 6 months after treatment is discontinued. If patient or female partner becomes pregnant during treatment, she should be counseled about potential risks of exposure.

Mother-to-child transmission of HCV does not occur if the woman is not viremic, therefore, HCV-infected women of childbearing potential should postpone pregnancy until therapy is complete. Treatment of HCV is not recommended for women who are already pregnant (AASLD/IDSA 2015).

Health care providers and patients are encouraged to enroll women exposed to ribavirin during pregnancy or within 6 months after treatment in the Ribavirin Pregnancy Registry (800-593-2214).

Patient Education

• Discuss specific use of vaccine and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, insomnia, nausea, vomiting, diarrhea, lack of appetite, hair loss, loss of strength and energy, joint pain, dry skin, or dry mouth. Have patient report immediately to prescriber signs of pancreatitis (severe abdominal pain, severe back pain, severe nausea, or vomiting), signs of depression (suicidal ideation, anxiety, emotional instability, or confusion), signs of infection, tachycardia, severe dizziness, passing out, excessive weight loss, vision changes, blindness, urinary retention, change in amount of urine passed, severe muscle pain, severe muscle weakness, pale skin, signs of hemolytic anemia (severe loss of strength and energy, dark urine, or jaundice), signs of a severe pulmonary disorder (lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse), signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes), bleeding, or bruising (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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