Ribavirin Dosage

Usual Adult Dose for Chronic Hepatitis C

TABLETS:
In combination with peginterferon alfa-2a 180 mcg subcutaneously once a week:
Genotypes 1, 4:
Less than 75 kg: 1000 mg/day orally in 2 divided doses for 48 weeks
75 kg or more: 1200 mg/day orally in 2 divided doses for 48 weeks

Genotypes 2, 3: 800 mg/day orally in 2 divided doses for 24 weeks
Genotypes 5, 6: Insufficient data to make a recommendation

Chronic hepatitis C with HIV coinfection: Ribavirin 800 mg/day orally in 2 divided doses plus peginterferon alfa-2a 180 mcg subcutaneously once a week for 48 weeks, regardless of genotype

CAPSULES, ORAL SOLUTION:
In combination with peginterferon alfa-2b 1.5 mcg/kg subcutaneously once a week: 800 to 1400 mg orally per day in 2 divided doses

Dosages according to weight:
Less than 40 kg: Ribavirin 400 mg orally twice a day plus peginterferon alfa-2b 50 mcg subcutaneously once a week

40 to 50 kg: Ribavirin 400 mg orally twice a day plus peginterferon alfa-2b 64 mcg subcutaneously once a week

51 to 60 kg: Ribavirin 400 mg orally twice a day plus peginterferon alfa-2b 80 mcg subcutaneously once a week

61 to 65 kg: Ribavirin 400 mg orally twice a day plus peginterferon alfa-2b 96 mcg subcutaneously once a week

66 to 75 kg: Ribavirin 400 mg orally in the morning and 600 mg in the evening plus peginterferon alfa-2b 96 mcg subcutaneously once a week

76 to 80 kg: Ribavirin 400 mg orally in the morning and 600 mg in the evening plus peginterferon alfa-2b 120 mcg subcutaneously once a week

81 to 85 kg: Ribavirin 600 mg orally twice a day plus peginterferon alfa-2b 120 mcg subcutaneously once a week

86 to 105 kg: Ribavirin 600 mg orally twice a day plus peginterferon alfa-2b 150 mcg subcutaneously once a week

Greater than 105 kg: Ribavirin 600 mg orally in the morning and 800 mg in the evening plus peginterferon alfa-2b 1.5 mcg/kg subcutaneously once a week

Duration:
Interferon alpha-naive patients:
Genotype 1: 48 weeks
Genotypes 2 and 3: 24 weeks

Retreatment with peginterferon alfa-2b plus ribavirin of prior treatment failures: 48 weeks, regardless of HCV genotype

In combination with interferon alfa-2b 3 million international units subcutaneously 3 times a week:
75 kg or less: 400 mg orally in the morning and 600 mg in the evening
Greater than 75 kg: 600 mg orally twice a day

Duration:
Interferon-naive patients: 24 to 48 weeks
Retreatment with interferon alfa-2b plus ribavirin in patients who relapse following nonpegylated interferon monotherapy: 24 weeks

Usual Adult Dose for Respiratory Syncytial Virus

Case Review: One vial (6 g) dissolved and delivered through a Small Particle Aerosol Generator (SPAG-2) over a continuous 22-hour period, daily for 5 consecutive days

Usual Pediatric Dose for Respiratory Syncytial Virus

20 mg/mL as the starting solution in the drug reservoir of the SPAG-2 unit, with continuous aerosol administration for 12 to 18 hours/day for 3 to 7 days

Usual Pediatric Dose for Chronic Hepatitis C

TABLETS:
5 years or older:
In combination with peginterferon alfa-2a 180 mcg/1.73 m2 x body surface area (BSA) subcutaneously once a week (maximum dose: 180 mcg):
23 to 33 kg: 400 mg/day orally in 2 divided doses
34 to 46 kg: 600 mg/day orally in 2 divided doses
47 to 59 kg: 800 mg/day orally in 2 divided doses
60 to 74 kg: 1000 mg/day orally in 2 divided doses
75 kg or more: 1200 mg/day orally in 2 divided doses

Duration:
Genotype 2 and 3: 24 weeks
Other genotypes: 48 weeks

CAPSULES, ORAL SOLUTION:
3 years or older: 15 mg/kg orally per day in 2 divided doses in combination with peginterferon alfa-2b or interferon alfa-2b

Duration:
Genotype 1: 48 weeks
Genotypes 2 and 3: 24 weeks

Ribavirin dosages according to weight:
In combination with peginterferon alfa-2b 60 mcg/m2/week subcutaneously:
Less than 47 kg: 15 mg/kg (oral solution) orally per day in 2 divided doses
47 to 59 kg: 400 mg orally twice a day
60 to 73 kg: 400 mg orally in the morning and 600 mg in the evening
Greater than 73 kg: 600 mg orally twice a day

In combination with interferon alfa-2b three times a week therapy:
Less than 47 kg: 15 mg/kg (oral solution) orally per day in 2 divided doses
47 to 59 kg: 400 mg orally twice a day
60 to 75 kg: 400 mg orally in the morning and 600 mg in the evening
Greater than 75 kg: 600 mg orally twice a day

Interferon alfa-2b dosages according to weight:
25 to 61 kg: 3 million international units/m2 subcutaneously 3 times a week
Greater than 61 kg: Use adult dosage.

Renal Dose Adjustments

TABLETS:
Adults:
CrCl 30 to 50 mL/min: Alternating doses, 200 mg and 400 mg orally every other day (in combination with peginterferon alfa-2a 180 mcg subcutaneously once a week)
CrCl less than 30 mL/min: 200 mg orally once a day (in combination with peginterferon alfa-2a 135 mcg subcutaneously once a week)

The dose of ribavirin tablets should not be further modified in patients with renal impairment. If severe adverse reactions or laboratory abnormalities develop, ribavirin tablets should be discontinued, if appropriate, until the adverse reactions abate or decrease in severity. If intolerance persists after restarting ribavirin tablets, peginterferon alfa-2a plus ribavirin combination therapy should be discontinued.

Pediatrics: Data not available

CAPSULES, ORAL SOLUTION:
CrCl less than 50 mL/min: Contraindicated

Liver Dose Adjustments

Data not available

Dose Adjustments

Dosage must be individualized to the patient's specific disease characteristics (e.g., genotype), preexisting cardiac disease, and development of adverse reactions or laboratory abnormalities.

If severe adverse reactions or laboratory abnormalities develop during combination treatment, the dose should be modified or discontinued, if appropriate, until the adverse reactions abate or decrease in severity. Combination therapy should be discontinued if intolerance persists after dose adjustment.

ADULTS (with normal renal function):
TABLETS:
Patients with no cardiac disease:
Hemoglobin (Hgb) less than 10 g/dL: 200 mg orally in the morning and 400 mg in the evening
Hgb less than 8.5 g/dL: Discontinue.

Patients with history of stable cardiac disease:
Greater than or equal to 2 g/dL decrease in Hgb during any 4-week period: 200 mg orally in the morning and 400 mg in the evening
Hgb less than 12 g/dL despite 4 weeks at reduced dose: Discontinue.

These guidelines also apply to laboratory abnormalities or adverse reactions other than decreases in Hgb values.

Once ribavirin has been withheld due to a laboratory abnormality or clinical manifestation, restarting at 600 mg/day and a further increase to 800 mg/day may be attempted. Increasing ribavirin to the original dose is not recommended.

Discontinuation of peginterferon alfa-2a plus ribavirin should be considered if the patient has not shown at least a 2 log10 reduction from baseline in HCV RNA by 12 weeks of therapy, or if HCV RNA levels remain detectable after 24 weeks of therapy.

CAPSULES, ORAL SOLUTION:
Hgb less than 10 g/dL:
First dose reduction:
Patients receiving 1200 mg/day or less: Dose should be reduced by 200 mg/day.
Patients receiving 1400 mg/day: Dose should be reduced by 400 mg/day.

Second dose reduction (if needed): Dose should be reduced by an additional 200 mg/day.

In patients with history of stable cardiac disease:
Hgb 2 g/dL or greater decrease during any 4-week interval: Permanently reduce by 200 mg/day.
Hgb less than 12 g/dL following 4 weeks of reduced dosage: Discontinue permanently.

Interferon alfa-2b (pegylated or nonpegylated) plus ribavirin should be permanently discontinued if any of the following occurs:
Hgb less than 8.5 g/dL
WBC less than 1 x 10(9)/L
Neutrophils less than 0.5 x 10(9)/L
Platelets less than 25 x 10(9)/L

HCV genotype 1 interferon-alfa-naive patients receiving peginterferon alfa-2b plus ribavirin should discontinue treatment if there is not at least a 2 log10 drop or loss of HCV RNA at 12 weeks of therapy, or whose HCV RNA levels remain detectable after 24 weeks of therapy. Regardless of genotype, previously treated patients who have detectable HCV RNA at week 12 or 24, are highly unlikely to achieve sustained virologic response and discontinuation of therapy should be considered. Treatment discontinuation should be considered in any interferon-alfa-naive patient receiving interferon alfa-2b plus ribavirin whose HCV RNA levels remain detectable after 24 weeks of therapy.

PEDIATRICS (with normal renal function):
TABLETS:
Hgb less than 10 g/dL in patients with no cardiac disease or decrease in Hgb of 2 g/dL or more during any 4-week period in patients with history of stable cardiac disease:
23 to 33 kg: 200 mg orally in the morning
34 to 46 kg: 200 mg orally twice a day (morning and evening)
47 to 59 kg: 200 mg orally twice a day (morning and evening)
60 to 74 kg: 200 mg orally in the morning and 400 mg in the evening
75 kg or more: 200 mg orally in the morning and 400 mg in the evening

Hgb less than 8.5 g/dL in patients with no cardiac disease or Hgb less than 12 g/dL despite 4 weeks at reduced dose in patients with history of stable cardiac disease: Discontinue.

These guidelines also apply to laboratory abnormalities or adverse reactions other than decreases in Hgb values.

An increase to the original dose may be attempted upon resolution of a laboratory abnormality or clinical adverse reaction, depending on physician's judgment. If ribavirin has been withheld due to a laboratory abnormality or clinical adverse reaction, restarting at one-half the full dose may be attempted.

Discontinuation of peginterferon alfa-2a plus ribavirin should be considered if the patient has not shown at least a 2 log10 reduction from baseline in HCV RNA by 12 weeks of therapy, or if HCV RNA levels remain detectable after 24 weeks of therapy.

CAPSULES, ORAL SOLUTION:
Hgb less than 10 g/dL:
First dose reduction: 12 mg/kg/day orally in 2 divided doses
Second dose reduction (if needed): 8 mg/kg/day orally in 2 divided doses

Hgb 2 g/dL or greater decrease during any 4-week interval in patients with preexisting cardiac conditions should have weekly evaluations and hematology testing.

Interferon alfa-2b (pegylated or nonpegylated) plus ribavirin should be permanently discontinued if any of the following occurs:
Hgb less than 8.5 g/dL
WBC less than 1 x 10(9)/L
Neutrophils less than 0.5 x 10(9)/L
Platelets less than 50 x 10(9)/L
Creatinine greater than 2 mg/dL

Pediatric patients receiving peginterferon alfa-2b plus ribavirin (excluding those with HCV Genotype 2 and 3) should discontinue therapy if their HCV RNA dropped less than 2 log10 after 12 weeks of treatment compared to pretreatment or if they have detectable HCV RNA after 24 weeks of treatment. Treatment discontinuation should be considered in any patient receiving interferon alfa-2b plus ribavirin whose HCV RNA levels remain detectable after 24 weeks of therapy.

Precautions

Ribavirin is contraindicated in women who are or may become pregnant and men whose female partners are pregnant. During therapy and for 6 months after discontinuation, extreme care must be taken to avoid pregnancy in female patients and female partners of male patients, including the use of at least 2 reliable forms of effective birth control. A negative pregnancy test should be obtained immediately before initiation of therapy, monthly during therapy, and for 6 months after discontinuation.

Capsules and oral solution: Ribavirin combination therapy is contraindicated in patients with hemoglobinopathies (e.g., thalassemia major, sickle cell anemia), autoimmune hepatitis, and CrCl less than 50 mL/min.

Tablets: Ribavirin is contraindicated in patients with hemoglobinopathies. Ribavirin and peginterferon alfa-2a combination therapy is contraindicated in patients with autoimmune hepatitis and in cirrhotic chronic hepatitis C (CHC) monoinfected patients with hepatic decompensation (Child-Pugh score greater than 6; class B and C) before therapy. Combination therapy is also contraindicated in cirrhotic CHC patients coinfected with HIV with hepatic decompensation (Child-Pugh score greater than or equal to 6) before treatment. During treatment, patients' clinical status and hepatic function should be closely monitored for signs and symptoms of hepatic decompensation. Ribavirin tablets and peginterferon alfa-2a should be discontinued at once if hepatic decompensation occurs.

Ribavirin coadministration with didanosine is contraindicated.

Ribavirin monotherapy is not effective for the treatment of chronic hepatitis C (CHC) and should not be used alone for this indication. Combination therapy with ribavirin capsules/oral solution plus peginterferon alfa-2b is preferred over ribavirin capsules/oral solution plus interferon alfa-2b as this combination provides substantially better response rates.

Ribavirin combination therapy (combined with peginterferon alfa-2a, peginterferon alfa-2b, or interferon alfa-2b) has been associated with severe depression, suicidal ideation, hemolytic anemia, bone marrow suppression, autoimmune and infectious disorders, ophthalmologic disorders, cerebrovascular disorders, pulmonary dysfunction, pancreatitis, colitis, and diabetes. Treatment interruption, dose reduction, or discontinuation may be required to manage adverse effects.

Pulmonary symptoms (including dyspnea, pulmonary infiltrates, pneumonitis, pulmonary hypertension, pneumonia, and fatal pneumonia), sarcoidosis, and exacerbation of sarcoidosis have occurred during treatment with ribavirin and interferon. Patients should be closely monitored if pulmonary infiltrates or pulmonary dysfunction occur, and treatment stopped if necessary.

Sudden deterioration of respiratory function has been associated with initiation of ribavirin inhalation therapy in infants. Careful monitoring of respiratory function during therapy is recommended. If initiation of inhaled ribavirin produces sudden deterioration of respiratory function, therapy should be discontinued and restarted only with extreme caution, continuous monitoring, and the coadministration of bronchodilators should be considered.

Use of aerosolized ribavirin in patients requiring mechanical ventilator assistance is recommended only by physicians and support staff familiar with the specific ventilator used and this method of administration of ribavirin. Strict attention must be paid to procedures that minimize accumulation of drug precipitate, which can result in mechanical ventilator dysfunction and associated increased pulmonary pressures.

Hemolytic anemia (Hgb less than 10 g/dL) is the primary clinical toxicity of ribavirin. It occurs within the first 1 to 2 weeks of treatment. Hemoglobin (Hgb) or hematocrit should be obtained before starting treatment, at Week 2 and Week 4 of therapy, or more often if clinically necessary. Patients should then be monitored as clinically appropriate. Caution is recommended if initiating therapy in any patient with baseline risk of severe anemia (e.g., spherocytosis, history of gastrointestinal bleeding). Patients with renal dysfunction and/or greater than 50 years of age should be monitored for anemia development. Patients should be well hydrated, especially during initial stages of therapy.

Anemia due to ribavirin has resulted in worsening of cardiac disease and has led to fatal and nonfatal myocardial infarctions. Patients should be assessed for underlying cardiac disease prior to initiation of ribavirin therapy. Patients with preexisting cardiac disease should have electrocardiograms prior to therapy and should be properly monitored during therapy. Patients with a history of significant or unstable cardiac disease should not be treated with ribavirin. Ribavirin should be suspended or discontinued if cardiovascular status deteriorates.

Standard hematologic tests (including Hgb, complete and differential white blood cell counts, and platelet count), blood chemistries (liver function tests, uric acid, and thyroid stimulating hormone), and an electrocardiogram are recommended for all patients prior to starting ribavirin. Following the start of therapy, hematological tests should be performed at 2 weeks and 4 weeks and biochemical tests should be performed at 4 weeks. Additional testing is recommended periodically throughout therapy.

Renal function should be evaluated in all patients prior to initiation of ribavirin tablets by estimating the patient's CrCl. The dose of ribavirin tablets should be reduced in patients with CrCl 50 mL/min or less and the peginterferon alfa-2a dose should be reduced in patients with CrCl less than 30 mL/min. The clinical and hematologic status of patients with CrCl 50 mL/min or less receiving ribavirin tablets should be carefully monitored. Therapy should be discontinued in patients with clinically significant laboratory abnormalities or adverse reactions which are persistently severe or worsening.

Pancytopenia (marked decreases in red blood cells, neutrophils, and platelets) and bone marrow suppression have been reported within 3 to 7 weeks following concomitant administration of pegylated interferon plus ribavirin and azathioprine. Pegylated interferon, ribavirin, and azathioprine should be discontinued for pancytopenia, and pegylated interferon plus ribavirin should not be reintroduced with concomitant azathioprine.

The use of ribavirin for CHC treatment in patients receiving azathioprine has been reported to induce severe pancytopenia and may increase the risk of azathioprine-related myelotoxicity. Patients receiving azathioprine with ribavirin should have complete blood counts (including platelet counts) monitored weekly for the first month, twice monthly for the second and third months of therapy, then monthly or more frequently if dosage or other therapy changes are needed.

Severe acute hypersensitivity reactions such as urticaria, angioedema, bronchoconstriction, and anaphylaxis have been reported in patients treated with alfa interferon and ribavirin. Therapy should be discontinued immediately and appropriate medical therapy instituted if such a reaction develops. Severe skin reactions (including vesiculobullous eruptions, Stevens-Johnson syndrome, erythema multiforme, and exfoliative dermatitis/erythroderma) have been reported in patients treated with peginterferon alfa-2a alone and with ribavirin. Therapy should be discontinued immediately in patients developing serious skin reactions. Transient rashes do not necessitate interruption of therapy.

Ribavirin therapy should be suspended in patients with signs and symptoms of pancreatitis, and discontinued in patients with confirmed pancreatitis.

Decrease or loss of vision, retinopathy including macular edema, retinal artery or vein, thrombosis, retinal hemorrhages and cotton wool spots, optic neuritis, papilledema, and serous retinal detachment are induced or aggravated by alpha interferon therapy. Since ribavirin is used in combination with alpha interferons, all patients should have an eye examination at baseline. Periodic ophthalmologic exams during combination therapy are recommended in patients with preexisting ophthalmologic disorders (e.g., diabetic or hypertensive retinopathy). Any patient developing ocular symptoms should get a complete eye examination at once. Combination therapy with alpha interferons should be discontinued in patients developing new or worsening ophthalmologic disorders.

Dental and periodontal disorders have been reported in patients receiving ribavirin and interferon or peginterferon combination therapy. In addition, dry mouth during long-term treatment with the combination of ribavirin and interferon alfa-2b or pegylated interferon alfa-2b could have damaging effects on teeth and mucous membranes of the mouth. Patients should brush their teeth thoroughly twice daily and have regular dental examinations. If vomiting occurs, patients should be advised to rinse out their mouth thoroughly afterwards.

Immune reconstitution syndrome has occurred during combination antiretroviral therapy. Patients responding to therapy may develop an inflammatory response to indolent or residual opportunistic infections and require evaluation and treatment.

Patients with previous nonresponse, previous pegylated interferon treatment, significant bridging fibrosis or cirrhosis, and/or genotype 1 infection are less likely to benefit from retreatment after failing a course of therapy.

Safety and efficacy data are not available for therapy duration over 1 year.

Safety and efficacy of ribavirin combination therapy (combined with peginterferon alfa-2a, peginterferon alfa-2b, or interferon alfa-2b) have not been established for the treatment of adenovirus, RSV, parainfluenza, or influenza infections, in liver or other organ transplant patients, in decompensated liver disease due to hepatitis C, nonresponders to interferon therapy, or in patients coinfected with hepatitis B or HIV and CD4+ counts less than 100 cells/mm3.

Inhaled ribavirin is not indicated for use in adults.

Safety and efficacy for the treatment of hepatitis C have not been established beyond 48 weeks in previously untreated patients and beyond 24 weeks in relapse patients. Safety and efficacy for the treatment of hepatitis C have not been established beyond 48 weeks in pediatric patients.

Safety and efficacy of ribavirin capsules and oral solution have not been established in pediatric patients less than 3 years of age. Safety and efficacy of ribavirin tablets have not been established in pediatric patients less than 5 years of age.

Dialysis

TABLETS:
Adults:
Hemodialysis: 200 mg orally once a day (in combination with peginterferon alfa-2a 135 mcg subcutaneously once a week)

The dose of ribavirin tablets should not be further modified in patients with renal impairment. If severe adverse reactions or laboratory abnormalities develop, ribavirin tablets should be discontinued, if appropriate, until the adverse reactions abate or decrease in severity. If intolerance persists after restarting ribavirin tablets, peginterferon alfa-2a plus ribavirin combination therapy should be discontinued.

Pediatrics: Data not available

CAPSULES, ORAL SOLUTION:
CrCl less than 50 mL/min: Contraindicated

Ribavirin oral is not removed by hemodialysis.

Other Comments

The Small Particle Aerosol Generator Model-2 (SPAG-2) should be used for administration of inhaled ribavirin. No other aerosol generation device is recommended.

Oral ribavirin should be taken with food. Patients should be well hydrated.

Oral ribavirin capsules should not be opened, crushed, or broken.

Patients who reach their eighteenth birthday while receiving peginterferon alfa-2a plus ribavirin tablets or peginterferon alfa-2b plus ribavirin capsules/oral solution should remain on the pediatric dosing regimen.

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