Ribavirin

RIBAVIRIN — ribavirin capsule
AvKARE, Inc.

label

WARNING: RISK OF SERIOUS DISORDERS AND RIBAVIRIN-ASSOCIATED EFFECTS

  • Ribavirin monotherapy is not effective for the treatment of chronic hepatitis C virus infection and should not be used alone for this indication [see Warnings and Precautions ( 5.10 )].
  • The primary toxicity of ribavirin is hemolytic anemia. The anemia associated with ribavirin therapy may result in worsening of cardiac disease that has led to fatal and nonfatal myocardial infarctions. Patients with a history of significant or unstable cardiac disease should not be treated with ribavirin [see Dosage and Administration ( 2.4) and Warnings and Precautions ( 5.2 )].
  • Significant teratogenic and embryocidal effects have been demonstrated in all animal species exposed to ribavirin. In addition, ribavirin has a multiple-dose half-life of 12 days, and so 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 both female patients and in female partners of male patients who are taking ribavirin therapy. At least two reliable forms of effective contraception must be utilized during treatment and during the 6 month posttreatment follow-up period [see Contraindications ( 4), Warnings and Precautions ( 5.1), Use in Specific Populations ( 8.1), Nonclinical Toxicology ( 13.1), and Patient Counseling Information ( 17.2 )].

1 INDICATIONS AND USAGE

1.1 Chronic Hepatitis C (CHC)

Ribavirin capsules in combination with interferon alfa-2b (nonpegylated) is indicated for the treatment of Chronic Hepatitis C (CHC) in patients 3 years of age and older with compensated liver disease [see Warnings and Precautions (5.10) and Use in Specific Populations (8.4)].

The following points should be considered when initiating ribavirin capsule combination therapy with INTRON A:

  • These indications are based on achieving undetectable HCV-RNA after treatment for 24 or 48 weeks and maintaining a Sustained Virologic Response (SVR) 24 weeks after the last dose.
  • Patients with the following characteristics are less likely to benefit from re-treatment after failing a course of therapy: previous nonresponse, previous pegylated interferon treatment, significant bridging fibrosis or cirrhosis, and genotype 1 infection [see Clinical Studies (14) ].
  • No safety and efficacy data are available for treatment of longer than one year.

2 DOSAGE AND ADMINISTRATION

Under no circumstances should ribavirin capsules be opened, crushed, or broken. Ribavirin capsules should be taken with food [see Clinical Pharmacology (12.3) ]. Ribavirin capsules should not be used in patients with creatinine clearance < 50 mL/min.

2.2 Ribavirin/INTRON A Combination Therapy

Adults

Duration of Treatment – Interferon Alpha-naïve Patients

The recommended dose of INTRON A is 3 million IU three times weekly subcutaneously. The recommended dose of ribavirin capsules depends on the patient’s body weight (refer to Table 3). The recommended duration of treatment for patients previously untreated with interferon is 24 to 48 weeks. The duration of treatment should be individualized to the patient depending on baseline disease characteristics, response to therapy, and tolerability of the regimen [see Indications and Usage (1.1) and Clinical Studies (14)]. After 24 weeks of treatment, virologic response should be assessed. Treatment discontinuation should be considered in any patient who has not achieved an HCV-RNA below the limit of detection of the assay by 24 weeks. There are no safety and efficacy data on treatment for longer than 48 weeks in the previously untreated patient population.

Duration of Treatment – Re-treatment with INTRON A/Ribavirin in Relapse Patients
In patients who relapse following nonpegylated interferon monotherapy, the recommended duration of treatment is 24 weeks.
Table 3: Recommended Dosing
Body Weight Ribavirin Capsules
≤ 75 kg

2 x 200 mg capsules AM

> 75 kg

3 x 200 mg capsules AM

Pediatrics

The recommended dose of ribavirin is 15 mg/kg per day orally (divided dose AM and PM). Refer to Table 5 for Pediatric Dosing of ribavirin in combination with INTRON A. INTRON A for injection by body weight of 25 kg to 61 kg is 3 million IU/m2 three times weekly subcutaneously. Refer to adult dosing table for > 61 kg body weight.

The recommended duration of treatment is 48 weeks for pediatric patients with genotype 1. After 24 weeks of treatment, virologic response should be assessed. Treatment discontinuation should be considered in any patient who has not achieved an HCV-RNA below the limit of detection of the assay by this time. The recommended duration of treatment for pediatric patients with genotype 2/3 is 24 weeks.

2.3 Laboratory Tests

The following laboratory tests are recommended for all patients treated with ribavirin, prior to beginning treatment and then periodically thereafter.

  • Standard hematologic tests — including hemoglobin (pretreatment, Week 2 and Week 4 of therapy, and as clinically appropriate [see Warnings and Precautions (5.2, 5.7)], complete and differential white blood cell counts, and platelet count.
  • Blood chemistries — liver function tests and TSH.
  • Pregnancy — including monthly monitoring for women of childbearing potential.
  • ECG [see Warnings and Precautions (5.2) ].

2.4 Dose Modifications

If severe adverse reactions or laboratory abnormalities develop during combination ribavirin/INTRON A therapy, modify or discontinue the dose until the adverse reaction abates or decreases in severity [see Warnings and Precautions (5) ]. If intolerance persists after dose adjustment, combination therapy should be discontinued.

Ribavirin should not be used in patients with creatinine clearance < 50 mL/min. Subjects with impaired renal function and those over the age of 50 should be carefully monitored with respect to development of anemia [see Warnings and Precautions (5.2), Use in Specific Populations (8.5), and Clinical Pharmacology (12.3)].

Ribavirin should be administered with caution to patients with preexisting cardiac disease. Patients should be assessed before commencement of therapy and should be appropriately monitored during therapy. If there is any deterioration of cardiovascular status, therapy should be stopped [see Warnings and Precautions (5.2) ].

For patients with a history of stable cardiovascular disease, a permanent dose reduction is required if the hemoglobin decreases by ≥ 2 g/dL during any 4 week period. In addition, for these cardiac history patients, if the hemoglobin remains < 12 g/dL after 4 weeks on a reduced dose, the patient should discontinue combination therapy.

It is recommended that a patient whose hemoglobin level falls below 10 g/dL have his/her ribavirin dose modified or discontinued per Table 5 [see Warnings and Precautions (5.2) ].

Table 5: Guidelines for Dose Modification and Discontinuation of INTRON A/Ribavirin Based on Laboratory Parameters in Adults and Pediatrics
*
For adult patients with a history of stable cardiac disease receiving INTRON A in combination with ribavirin, the INTRON A dose should be reduced by half and the ribavirin dose by 200 mg/day if a > 2 g/dL decrease in hemoglobin is observed during any 4 week period. INTRON A and ribavirin should be permanently discontinued if patients have hemoglobin levels < 12 g/dL after this ribavirin dose reduction. Pediatric patients who have preexisting cardiac conditions and experience a hemoglobin decrease ≥ 2 g/dL during any 4 week period during treatment should have weekly evaluations and hematology testing.
1st dose reduction of ribavirin is by 200 mg/day, except in patients receiving the 1400 mg dose it is by 400 mg/day; 2nd dose reduction of ribavirin (if needed) is by an additional 200 mg/day.
For patients on ribavirin/INTRON A combination therapy, reduce INTRON A dose by 50%.
Laboratory Values Adults Pediatrics Adults Pediatrics
INTRON A Ribavirin
Hgb < 10 g/dL For patients with cardiac disease, reduce by 50%* See footnote * Adjust Dose

1st reduction to 12 mg/kg/day

2nd reduction to 8 mg/kg/day

WBC < 1.5 x 109 /L Adjust Dose Reduce by 50% No Dose Change No Dose Change
Neutrophils < 0.75 x 109 /L
Platelets
< 50 x 109 /L (Adults)
< 70 x 109 /L (Pediatrics)
Hgb < 8.5 g/dL Permanently Discontinue Permanently Discontinue Permanently Discontinue Permanently Discontinue
WBC < 1 x 109 /L
Neutrophils < 0.5 x 109 /L
Creatinine > 2 mg/dL (Pediatrics)
Platelets < 25 x 109 /L (Adults)
< 50 x 109 /L (Pediatrics)

Refer to the INTRON A Package Insert for additional information about how to reduce an INTRON A dose.

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