Inhalation: Treatment of patients with respiratory syncytial virus (RSV) infections; specially indicated for treatment of severe lower respiratory tract RSV infections in patients with an underlying compromising condition (prematurity, bronchopulmonary dysplasia and other chronic lung conditions, congenital heart disease, immunodeficiency, immunosuppression), and recent transplant recipients

Oral capsule:

In combination with interferon alfa-2b (Intron® A) injection for the treatment of chronic hepatitis C in patients with compensated liver disease who have relapsed after alpha interferon therapy or were previously untreated with alpha interferons

In combination with peginterferon alfa-2b (PEG-Intron®) injection for the treatment of chronic hepatitis C in patients with compensated liver disease who were previously untreated with alpha interferons

Oral solution: In combination with interferon alfa 2b (Intron® A) injection for the treatment of chronic hepatitis C in patients 3 years of age with compensated liver disease who were previously untreated with alpha interferons or patients 18 years of age who have relapsed after alpha interferon therapy

Oral tablet: In combination with peginterferon alfa-2a (Pegasys®) injection for the treatment of chronic hepatitis C in patients with compensated liver disease who were previously untreated with alpha interferons

Additional contraindications for oral formulation: Male partners of pregnant women; Clcr< 50 mL/minute; hemoglobinopathies (eg, thalassemia major, sickle cell anemia); as monotherapy for treatment of chronic hepatitis C; patients with autoimmune hepatitis, anemia, severe heart disease

Inhalation: Use with caution in patients requiring assisted ventilation because precipitation of the drug in the respiratory equipment may interfere with safe and effective patient ventilation; monitor carefully in patients with COPD and asthma for deterioration of respiratory function. Ribavirin is potentially mutagenic, tumor-promoting, and gonadotoxic. Although anemia has not been reported with inhalation therapy, consider monitoring for anemia 1-2 weeks post-treatment. Pregnant healthcare workers may consider unnecessary occupational exposure; ribavirin has been detected in healthcare workers' urine. Healthcare professionals or family members who are pregnant (or may become pregnant) should be counseled about potential risks of exposure and counseled about risk reduction strategies.

Oral: Anemia has been observed in patients receiving the interferon/ribavirin combination. Severe psychiatric events have also occurred including depression and suicidal behavior during combination therapy; avoid use in patients with a psychiatric history. Hemolytic anemia is a significant toxicity; usually occurring within 1-2 weeks. Assess cardiac disease before initiation. Anemia may worsen underlying cardiac disease; use caution. If any deterioration in cardiovascular status occurs, discontinue therapy. Use caution in pulmonary disease; pulmonary symptoms have been associated with administration. Use caution in patients with sarcoidosis (exacerbation reported). Negative pregnancy test is required before initiation and monthly thereafter. Avoid pregnancy in female patients and female partners of male patients during therapy. Discontinue therapy in suspected/confirmed pancreatitis. Use caution in elderly patients; higher frequency of anemia; take renal function into consideration before initiating. Safety and efficacy have not been established in organ transplant patients, decompensated liver disease, concurrent hepatitis B virus or HIV exposure, or pediatric patients <3 years of age.

Inhalation:

1% to 10%:

Central nervous system: Fatigue, headache, insomnia

Gastrointestinal: Nausea, anorexia

Hematologic: Anemia

<1% Hypotension, cardiac arrest, digitalis toxicity, conjunctivitis, mild bronchospasm, worsening of respiratory function, apnea

Note: Incidence of adverse effects (approximate) in healthcare workers: Headache (51%); conjunctivitis (32%); rhinitis, nausea, rash, dizziness, pharyngitis, and lacrimation (10% to 20%)

Oral (all adverse reactions are documented while receiving combination therapy with interferon alpha-2b; percentages as reported in adults):

>10%:

Central nervous system: Dizziness (17% to 26%), headache (63% to 66%)*, fatigue (60% to 70%)*, fever (32% to 41%)*, insomnia (26% to 39%), irritability (23% to 32%), depression (23% to 36%)*, emotional lability (7% to 12%)*, impaired concentration (10% to 14%)*

Dermatologic: Alopecia (27% to 32%), rash (20% to 28%), pruritus (13% to 21%)

Gastrointestinal: Nausea (38% to 47%), anorexia (21% to 27%), dyspepsia (14% to 16%), vomiting (9% to 12%)*

Hematologic: Decreased hemoglobin (25% to 36%), decreased WBC, absolute neutrophil count <0.5 x 10⁹/L (5% to 11%), thrombocytopenia (6% to 14%), hyperbilirubinemia (24% to 34%), hemolysis

Neuromuscular & skeletal: Myalgia (61% to 64%)*, arthralgia (29% to 33%)*, musculoskeletal pain (20% to 28%), rigors (40% to 43%)

Respiratory: Dyspnea (17% to 19%), sinusitis (9% to 12%)*, nasal congestion

Miscellaneous: Flu-like syndrome (13% to 18%)*

*Similar to interferon alone

1% to 10%:

Cardiovascular: Chest pain (5% to 9%)*

Central nervous system: Nervousness (~5%)*

Gastrointestinal: Taste perversion (6% to 8%)

Hematologic: Hemolytic anemia (~10%)

Neuromuscular & skeletal: Weakness (9% to 10%)

*Similar to interferon alone

<1%: Diabetes mellitus, gout, pancreatitis, pulmonary dysfunction, suicidal ideation, thyroid function test abnormalities

Postmarketing and/or case reports: Hearing disorder, vertigo, sarcoidosis (including exacerbations of sarcoidosis)

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

Antiretroviral (nucleoside): Concomitant use of ribavirin and nucleoside analogues may increase the risk of developing lactic acidosis (includes adefovir, didanosine, lamivudine, stavudine, zalcitabine, zidovudine). Concurrent use with didanosine has been noted to increase the risk of pancreatitis, peripheral neuropathy in addition to lactic acidosis. Suspend therapy if signs/symptoms of toxicity are present.

Stavudine: Antagonistic in vitro; use with caution (per manufacturer)

Zidovudine: Antagonistic in vitro; use with caution (per manufacturer)

Inhalation: Store vials in a dry place at 15°C to 25°C (59°F to 78°F). Do not use any water containing an antimicrobial agent to reconstitute drug; reconstituted solution is stable for 24 hours at room temperature. Should not be mixed with other aerosolized medication.

Oral: Store at 15°C to 30°C (59°F to 86°F). Solution may also be refrigerated at 2°C to 8°C (36°F to 46°F).

Absorption: Inhalation: Systemic; dependent upon respiratory factors and method of drug delivery; maximal absorption occurs with the use of aerosol generator via endotracheal tube; highest concentrations in respiratory tract and erythrocytes

Distribution: Oral capsule: Single dose: Vd 2825 L; distribution significantly prolonged in the erythrocyte (16-40 days), which can be used as a marker for intracellular metabolism

Protein binding: Oral: None

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

Bioavailability: Oral: 64%

Half-life elimination, plasma:

Children: Inhalation: 6.5-11 hours

Adults: Oral capsule, single dose: 24 hours in healthy adults, 44 hours with chronic hepatitis C infection (increases to ~298 hours at steady state)

Time to peak, serum: Inhalation: At end of inhalation period; Oral capsule: Multiple doses: 3 hours

Excretion: Inhalation: Urine (40% as unchanged drug and metabolites); Oral capsule: Urine (61%), feces (12%)

Aerosol inhalation: Infants and children: Use with Viratek® small particle aerosol generator (SPAG-2) at a concentration of 20 mg/mL (6 g reconstituted with 300 mL of sterile water without preservatives). Continuous aerosol administration: 12-18 hours/day for 3 days, up to 7 days in length

Oral capsule or solution: Children 3 years: Chronic hepatitis C (in combination with interferon alfa-2b):

Rebetol®: Oral: Note: Oral solution should be used in children 3-5 years of age, children 25 kg, or those unable to swallow capsules.

Capsule/solution: 15 mg/kg/day in 2 divided doses (morning and evening)

Capsule dosing recommendations:

25-36 kg: 400 mg/day (200 mg morning and evening)

37-49 kg: 600 mg/day (200 mg in the morning and two 200 mg capsules in the evening)

50-61 kg: 800 mg/day (two 200 mg capsules morning and evening)

>61 kg: Refer to Adults dosing

Note: Duration of therapy is 48 weeks in pediatric patients with genotype 1 and 24 weeks in patients with genotype 2,3. Discontinue treatment in any patient if HCV-RNA is not below the limit of detection of the assay after 24 weeks of therapy.

Note: Also refer to Interferon Alfa-2b/Ribavirin combination pack monograph.

Oral capsule:

Adults:

Chronic hepatitis C (in combination with interferon alfa-2b):

75 kg: 400 mg in the morning, then 600 mg in the evening

>75 kg: 600 mg in the morning, then 600 mg in the evening

Note: If HCV-RNA is undetectable at 24 weeks, duration of therapy is 48 weeks. In patients who relapse following interferon therapy, duration of dual therapy is 24 weeks.

Note: Also refer to Interferon Alfa-2b/Ribavirin combination pack monograph.

Chronic hepatitis C (in combination with peginterferon alfa-2b): 400 mg twice daily; duration of therapy is 1 year; after 24 weeks of treatment, if serum HCV-RNA is not below the limit of detection of the assay, consider discontinuation.

Oral tablet: Adults:

Chronic hepatitis C, genotype 1,4 (in combination with peginterferon alfa-2a):

<75kg: 1000 mg/day in 2 divided doses for 48 weeks

75kg: 1200 mg/day in 2 divided doses for 48 weeks

Chronic hepatitis C, genotype 2,3 (in combination with peginterferon alfa-2a): 800 mg/day in 2 divided doses for 24 weeks

Note: Also refer to Peginterferon Alfa-2a monograph.

Dosage adjustment in renal impairment: Clcr<50 mL/minute: Oral route is contraindicated

Dosage adjustment for toxicity: Oral: Capsule, solution, tablet:

Patient without cardiac history:

Hemoglobin <10 g/dL:

Children: 7.5 mg/kg/day

Adults: Decrease dose to 600 mg/day

Hemoglobin <8.5 g/dL: Children and Adults: Permanently discontinue treatment

Patient with cardiac history:

Hemoglobin has 2 g/dL decrease during any 4-week period of treatment:

Children: 7.5 mg/kg/day

Adults: Decrease dose to 600 mg/day

Hemoglobin <12 g/dL after 4 weeks of reduced dose: Children and Adults: Permanently discontinue treatment

Inhalation: Ribavirin should be administered in well-ventilated rooms (at least 6 air changes/hour). In mechanically-ventilated patients, ribavirin can potentially be deposited in the ventilator delivery system depending on temperature, humidity, and electrostatic forces; this deposition can lead to malfunction or obstruction of the expiratory valve, resulting in inadvertently high positive end-expiratory pressures. The use of one-way valves in the inspiratory lines, a breathing circuit filter in the expiratory line, and frequent monitoring and filter replacement have been effective in preventing these problems. Solutions in SPAG-2 unit should be discarded at least every 24 hours and when the liquid level is low before adding newly reconstituted solution. Should not be mixed with other aerosolized medication.

Oral: Administer concurrently with interferon alfa injection. Capsule should not be opened, crushed, chewed, or broken. Capsules are not for use in children <5 years of age. Use oral solution for children 3-5 years, those 25 kg, or those who cannot swallow capsules.

Capsule, in combination with interferon alfa-2b: May be administered with or without food, but always in a consistent manner in regard to food intake.

Capsule, in combination with peginterferon alfa 2b: Administer with food.

Solution, in combination with interferon alfa-2b: May be administered with or without food, but always in a consistent manner in regard to food intake.

Tablet: Should be administered with food.

Inhalation: Respiratory function, hemoglobin, reticulocyte count, CBC, I & O

Oral: CBC with differential (pretreatment, 2- and 4 weeks after initiation); pretreatment and monthly pregnancy test for women of childbearing age; LFTs, TSH, HCV-RNA after 24 weeks of therapy; ECG in patients with pre-existing cardiac disease

Capsule (Rebetol®, Ribasphere™): 200 mg

Powder for aerosol (Virazole®): 6 g

Solution, oral (Rebetol®): 40 mg/mL (100 mL) [contains sodium benzoate; bubble gum flavor]

Tablet (Copegus®): 200 mg

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