Usual Adult Dose for Chronic Hepatitis C

CAPSULES, ORAL SOLUTION:
In combination with peginterferon alfa-2b:
Less than 66 kg: 400 mg orally twice a day
66 to 80 kg: 400 mg orally in the morning and 600 mg in the evening
81 to 105 kg: 600 mg orally twice a day
Greater than 105 kg: 600 mg orally in the morning and 800 mg in the evening

Duration of therapy:

• Interferon alpha-naive patients with genotype 1: 48 weeks
• Interferon alpha-naive patients with genotype 2 and 3: 24 weeks
• Retreatment with peginterferon alfa-2b/ribavirin of prior treatment failures: 48 weeks, regardless of HCV genotype

In combination with interferon alfa-2b:
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 of therapy:

• Interferon alpha-naive patients: 24 to 48 weeks
• Retreatment with interferon alfa-2b/ribavirin in patients who relapse after nonpegylated interferon monotherapy: 24 weeks

Comments:

• The manufacturer's product information for peginterferon alfa-2b or interferon alfa-2b should be consulted.
• Combination therapy with peginterferon alfa-2b is preferred; provides substantially better response rates than combination therapy with interferon alfa-2b.
• 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 a failing course of therapy.

Approved indication: In combination with peginterferon alfa-2b or interferon alfa-2b, for treatment of chronic hepatitis C in patients with compensated liver disease

TABLETS:
In combination with peginterferon alfa-2a:

• Genotypes 1 and 4 in patients less than 75 kg: 1000 mg/day orally in 2 divided doses for 48 weeks
• Genotypes 1 and 4 in patients 75 kg or more: 1200 mg/day orally in 2 divided doses for 48 weeks
• Genotypes 2 and 3: 800 mg/day orally in 2 divided doses for 24 weeks
• Genotypes 5 and 6: Insufficient data to make a recommendation
• In patients coinfected with HIV: 800 mg/day orally in 2 divided doses for 48 weeks, regardless of HCV genotype

Comments:

• The manufacturer's product information for peginterferon alfa-2a should be consulted.

Approved indication: In combination with peginterferon alfa-2a, for treatment of patients with chronic hepatitis C who have compensated liver disease and have not been previously treated with interferon alfa

Usual Adult Dose for Respiratory Syncytial Virus

(Not approved by FDA)

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 per day for 3 to 7 days

Comments:

• The operator's manual for the SPAG-2 should be consulted.
• Using 20 mg/mL, the aerosol concentration for a 12-hour delivery period averages 190 mcg/L of air.
• Ribavirin should not be administered simultaneously or combined with any other aerosolized medications.
• Sudden deterioration of respiratory function has been associated with initiation of ribavirin inhalation therapy in infants; careful monitoring of respiratory function during therapy 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 coadministration of bronchodilators should be considered.

Approved indication: For treatment of hospitalized infants and young children with severe lower respiratory tract infections due to respiratory syncytial virus

Usual Pediatric Dose for Chronic Hepatitis C

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

Ribavirin dosages according to weight:
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

Duration of therapy:

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

Comments:

• The manufacturer's product information for peginterferon alfa-2b or interferon alfa-2b should be consulted.
• Combination therapy with peginterferon alfa-2b is preferred; provides substantially better response rates than combination therapy with interferon alfa-2b.
• Patients who reach their 18th birthday while receiving peginterferon alfa-2b plus ribavirin should remain on the pediatric dosing regimen.
• 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 a failing course of therapy.

Approved indication: In combination with peginterferon alfa-2b or interferon alfa-2b, for treatment of chronic hepatitis C in patients with compensated liver disease

TABLETS:
5 years or older:
In combination with peginterferon alfa-2a:
23 to 33 kg: 200 mg orally twice a day
34 to 46 kg: 200 mg orally in the morning and 400 mg in the evening
47 to 59 kg: 400 mg orally twice a day
60 to 74 kg: 400 mg orally in the morning and 600 mg in the evening
75 kg or more: 600 mg orally twice a day

Duration of therapy:

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

Comments:

• The manufacturer's product information for peginterferon alfa-2a should be consulted.
• Patients who reach their 18th birthday while receiving peginterferon alfa-2a plus ribavirin should remain on the pediatric dosing regimen.

Approved indication: In combination with peginterferon alfa-2a, for treatment of patients with chronic hepatitis C who have compensated liver disease and have not been previously treated with interferon alfa

Renal Dose Adjustments

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

TABLETS:
Adults:
In combination with peginterferon alfa-2a:
CrCl 30 to 50 mL/min: Alternating doses, 200 mg and 400 mg orally every other day
CrCl less than 30 mL/min: 200 mg orally once a day

Comments:

• The dose of ribavirin tablets should not be further modified in patients with renal dysfunction. If severe side effects or laboratory abnormalities develop, ribavirin should be discontinued, if appropriate, until side effects abate or decrease in severity. If intolerance persists after restarting ribavirin, peginterferon alfa-2a/ribavirin should be discontinued.

Pediatrics: Data not available

Liver Dose Adjustments

Data not available

Dose Adjustments

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

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

ADULTS (with normal renal function):
CAPSULES, ORAL SOLUTION:
Hemoglobin (Hgb) 8.5 to less than 10 g/dL in patients without history of cardiac disease:
First dose reduction: Dose should be reduced by 200 mg/day (except in 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.

2 g/dL or greater decrease in Hgb during any 4 week period during therapy in patients with history of stable cardiac disease: Dose should be permanently reduced by 200 mg/day.

Interferon alfa-2b (pegylated or nonpegylated) plus ribavirin should be discontinued if:

• Hgb less than 8.5 g/dL
• Hgb less than 12 g/dL after 4 weeks of dose reduction (in patients with history of stable cardiac disease)
• 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

Discontinuation of therapy:

• In HCV genotype 1, interferon alpha-naive patients receiving peginterferon alfa-2b/ribavirin should discontinue therapy 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 alpha-naive patient receiving interferon alfa-2b/ribavirin whose HCV-RNA levels remain detectable after 24 weeks of therapy.

TABLETS:
Patients with no cardiac disease:
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:
2 g/dL or greater 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.

Comments:

• These guidelines also apply to laboratory abnormalities or side effects other than decreases in Hgb values.
• Once ribavirin has been withheld due to a laboratory abnormality or clinical side effect, restarting at 600 mg/day and further increase to 800 mg/day may be attempted; increasing ribavirin to the original dose is not recommended.

Discontinuation of therapy:

• Discontinuation of peginterferon alfa-2a/ribavirin should be considered if 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.
• Peginterferon alfa-2a/ribavirin should be discontinued if hepatic decompensation occurs during therapy.

PEDIATRICS (with normal renal function):
CAPSULES, ORAL SOLUTION:
Hgb 8.5 to less than 10 g/dL in patients without history of cardiac disease:
First dose reduction: Dose should be reduced to 12 mg/kg/day orally in 2 divided doses.
Second dose reduction (if needed): Dose should be reduced to 8 mg/kg/day orally in 2 divided doses.

2 g/dL or greater decrease in Hgb during any 4 week period during therapy in pediatric patients with preexisting cardiac conditions: Weekly evaluations and hematology testing are recommended.

Interferon alfa-2b (pegylated or nonpegylated) plus ribavirin should be discontinued if:

• Hgb less than 8.5 g/dL
• Hgb less than 12 g/dL after 4 weeks of dose reduction (in patients with history of stable cardiac disease)
• 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

Discontinuation of therapy:

• Pediatric patients receiving peginterferon alfa-2b/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 therapy compared to pretreatment or if they have detectable HCV-RNA after 24 weeks of therapy.
• Treatment discontinuation should be considered in any patient receiving interferon alfa-2b/ribavirin whose HCV-RNA levels remain detectable after 24 weeks of therapy.

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 59 kg: 200 mg orally twice a day
60 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.

Comments:

• These guidelines also apply to laboratory abnormalities or side effects other than decreases in Hgb values.
• An increase to the original dose may be attempted upon resolution of a laboratory abnormality or clinical side effect, depending on physician's judgment; if ribavirin was withheld due to a laboratory abnormality or clinical side effect, restarting at one-half the full dose may be attempted.

Discontinuation of therapy:

• Discontinuation of peginterferon alfa-2a/ribavirin should be considered if 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.
• Peginterferon alfa-2a/ribavirin should be discontinued if hepatic decompensation occurs during therapy.

Precautions

US BOXED WARNINGS: Risk of Serious Disorders and Ribavirin-Associated Effects; Teratogenic and Embryocidal Effects; Sudden Deterioration of Respiratory Function with Inhalation Solution:
CAPSULES, ORAL SOLUTION, TABLETS:

• MONOTHERAPY: Ribavirin monotherapy is not effective for treatment of chronic hepatitis C (CHC) virus infection and should not be used alone for this indication.
• HEMOLYTIC ANEMIA: Hemolytic anemia is the primary clinical toxicity of ribavirin. Anemia due to ribavirin may worsen cardiac disease and lead to fatal and nonfatal myocardial infarctions. Patients with history of significant or unstable cardiac disease should not be treated with ribavirin.
• TERATOGENIC AND/OR EMBRYOCIDAL EFFECTS: All animal species exposed to ribavirin have shown significant teratogenic and/or embryocidal effects. In addition, ribavirin has a multiple-dose half-life of 12 days and may persist in nonplasma compartments for as long as 6 months. Ribavirin is contraindicated in women who are 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..

INHALATION THERAPY: This formulation is not indicated for use in adults.

• Use of aerosolized drug for inhalation in patients requiring mechanical ventilator assistance should be undertaken only by physicians and support staff familiar with this mode of administration and specific ventilator being used; strict attention must be paid to procedures that have been shown to minimize the accumulation of drug precipitate, which can result in mechanical ventilator dysfunction and associated increased pulmonary pressures.
• Sudden deterioration of respiratory function has been associated with initiation in infants; respiratory function should be carefully monitored; if initiation appears to produce sudden deterioration of respiratory function, treatment should be stopped and reinstituted only with extreme caution, continuous monitoring, and consideration of concomitant administration of bronchodilators.
• Physicians and patients should be aware that ribavirin has been shown to produce testicular lesions in rodents and to be teratogenic in all animal species in which adequate studies have been conducted (rodents and rabbits).

Oral: Safety and efficacy have not been established in patients younger than 3 years.
Inhalation: Safety and efficacy have only been established in hospitalized infants and young children; not for use in adults

Consult WARNINGS section for additional precautions.

Dialysis

Oral ribavirin is not effectively removed by hemodialysis.

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

TABLETS:
Adults:
In combination with peginterferon alfa-2a:
Hemodialysis: 200 mg orally once a day

Comments:

• The dose of ribavirin tablets should not be further modified in patients with renal dysfunction. If severe side effects or laboratory abnormalities develop, ribavirin should be discontinued, if appropriate, until side effects abate or decrease in severity. If intolerance persists after restarting ribavirin, peginterferon alfa-2a/ribavirin should be discontinued.

Pediatrics: Data not available

Other Comments

Administration advice:

• Use the Small Particle Aerosol Generator Model-2 (SPAG-2) for administration of inhaled ribavirin; no other aerosol generation device recommended. Consult the manufacturer's product information for further information regarding administration of the inhalation solution.
• Do not give oral ribavirin as monotherapy.
• Take oral ribavirin with food.
• Do not open, crush, or break ribavirin oral capsules.

Storage requirements:

• Inhalation solution: Lyophilized drug powder should be stored in a dry area at room temperature; reconstituted solutions may be stored (under sterile conditions) at room temperature for 24 hours; solutions in SPAG-2 unit should be discarded at least every 24 hours.
• Oral solution: May be stored at room temperature or in the refrigerator
• Tablets and capsules: Should be stored at room temperature

Reconstitution/preparation techniques:
Inhalation solution: The manufacturer's product information should be consulted.

General:

• Only physicians and support staff familiar with the specific ventilator used and this method of drug administration should use aerosolized ribavirin in patients requiring mechanical ventilator assistance. 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.
• Safety and efficacy of ribavirin capsules/oral solution have not been established for treatment beyond 1 year; when used with interferon alfa-2b in previously untreated patients, safety and efficacy have not been established beyond 48 weeks.
• Safety and efficacy of ribavirin tablets have not been established for treatment beyond 48 weeks.

Monitoring:

• Cardiovascular: ECG (prior to therapy) and cardiovascular status (prior to and during therapy) in patients with preexisting cardiac disease
• Endocrine: Blood chemistries, including TSH (prior to therapy and periodically thereafter)
• General: Pregnancy testing in women of childbearing potential (prior to therapy and monthly thereafter)
• Hematologic: Standard hematologic tests (prior to therapy and periodically thereafter) including Hgb (pretreatment, weeks 2 and 4 of therapy, and as clinically appropriate), complete and differential white blood cell counts, platelet count; signs/symptoms of anemia in patients with renal dysfunction and those older than 50 years
• Hepatic: Blood chemistries, including liver function tests (prior to therapy and periodically thereafter); clinical status and hepatic function (during therapy); signs/symptoms of hepatic decompensation

Patient advice:

• Patients should be well hydrated, especially during initial stages of oral therapy.