Ribavirin: Package Insert and Label Information

RIBAVIRIN — ribavirin capsule
Aurobindo Pharma Limited

WARNING: EMBRYO-FETAL TOXICITY, HEMOLYTIC ANEMIA, and MONOTHERAPY NOT RECOMMENDED

  • 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 may persist in non-plasma 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. Avoid pregnancy and use effective contraception during therapy and for 9 months after completion of treatment in female patients and for 6 months in female partners of male patients who are taking ribavirin therapy. [see Contraindications (4), Warnings and Precautions (5.1), Use in Specific Populations (8.1,8.3), and Nonclinical Toxicology (13.1)].
  • Hemolytic anemia has been reported with ribavirin therapy. 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 (2.5), Warnings and Precautions (5.2), and Adverse Reactions (6.1)].
  • 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)].

1 INDICATIONS AND USAGE

1.1 Chronic Hepatitis C (CHC)

Ribavirin capsules in combination with interferon alfa-2b (pegylated and nonpegylated) are 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 (5.9, 5.10), and Use in Specific Populations (8.4)].

The following points should be considered when initiating ribavirin capsules combination therapy with PegIntron® or INTRON A®:

  • Combination therapy with ribavirin capsules/PegIntron is preferred over ribavirin capsules/INTRON A as this combination provides substantially better response rates [see Clinical Studies (14)].
  • 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 duration lasting longer than one year.

2 DOSAGE AND ADMINISTRATION

2.1 General Dosing Information

Do not open, crush or break ribavirin capsules. Ribavirin capsules should be taken with food [see Clinical Pharmacology (12.3) ].

2.2 Ribavirin capsules/PegIntron Combination Therapy

Adult Patients

The recommended dose of ribavirin capsules when used in combination with PegIntron is 800 mg to 1,400 mg based on patient body weight in two divided doses (see Table 1). Refer to PegIntron labeling for PegIntron dosing information.

Duration of Treatment – Interferon Alpha-naïve Patients

The treatment duration for patients with genotype 1 is 48 weeks. Discontinuation of therapy should be considered in patients who do not achieve at least a 2 log10 drop or loss of hepatitis C virus (HCV)-RNA at 12 weeks, or if HCV-RNA remains detectable after 24 weeks of therapy. Patients with genotype 2 and 3 should be treated for 24 weeks.

Duration of Treatment – Re-treatment with PegIntron/Ribavirin capsules of Prior Treatment Failures
The treatment duration for patients who previously failed therapy is 48 weeks, regardless of HCV genotype. Re-treated patients who fail to achieve undetectable HCV-RNA at Week 12 of therapy, or whose HCV-RNA remains detectable after 24 weeks of therapy, are highly unlikely to achieve SVR and discontinuation of therapy should be considered [see Clinical Studies (14.1)].

Table 1: Recommended Adult Dosing for Ribavirin capsules in Combination with PegIntron
Body Weight (kg) Ribavirin capsules Daily Dose Ribavirin Number of Capsules
Less than 66 800 mg/day 2 x 200 mg capsules AM2 x 200 mg capsules PM
66 to 80 1,000 mg/day 2 x 200 mg capsules AM3 x 200 mg capsules PM
81 to 105 1,200 mg/day 3 x 200 mg capsules AM3 x 200 mg capsules PM
Greater than 105 1,400 mg/day 3 x 200 mg capsules AM4 x 200 mg capsules PM

Pediatric Patients
Dosing of ribavirin capsules in pediatric patients is determined by body weight. The recommended dose of ribavirin capsules when used in combination with PegIntron in pediatric patients ages 3 to 17 years is 15 mg/kg/day in two divided doses (see Table 2). Refer to PegIntron labeling for PegIntron dosing information. The treatment duration for patients with genotype 1 is 48 weeks. Patients with genotype 2 and 3 should be treated for 24 weeks.

Table 2: Recommended Pediatric Ribavirin capsules Dosing in Combination with PegIntron
* Ribavirin Oral Solution may be used in any patient regardless of body weight.
Body Weight (kg) Ribavirin capsules Daily Dose Ribavirin Number of Capsules
Less than 47 15 mg/kg/day Use Ribavirin Oral Solution*
47 to 59 800 mg/day 2 x 200 mg capsules AM2 x 200 mg capsules PM
60 to 73 1,000 mg/day 2 x 200 mg capsules AM3 x 200 mg capsules PM
Greater than 73 1,200 mg/day 3 x 200 mg capsules AM3 x 200 mg capsules PM

2.3 Ribavirin capsules/INTRON A Combination Therapy

Adults

Duration of Treatment – Interferon Alpha-naïve Patients

The recommended dose of ribavirin capsules when used in combination with INTRON A depends on the patient’s body weight (see Table 3). Refer to Intron A labeling for interferon dosing information. 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),Adverse Reactions (6.1), 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 for treatment duration lasting longer than 48 weeks in the previously untreated patient population.

Duration of Treatment – Re-treatment with INTRON A/Ribavirin capsules in Relapse Patients
In patients who relapse following nonpegylated interferon monotherapy, the recommended duration of treatment is 24 weeks.

Table 3: Recommended Ribavirin capsules Dosing in Combination with INTRON A
Body Weight Ribavirin Capsules
At least 75 kg 2 x 200 mg capsules AM 3 x 200 mg capsules PM daily orally
Greater than 75 kg 3 x 200 mg capsules AM 3 x 200 mg capsules PM daily orally

Pediatrics The recommended dose of ribavirin capsules when used in combination with INTRON A is 15 mg/kg per day orally in two divided doses (see Table 2). Refer to Intron A labeling for interferon dosing information.

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 and 3 is 24 weeks.

2.4 Testing Prior to Initiation of Ribavirin capsules

The following laboratory tests are recommended in all patients treated with ribavirin capsules prior to initiation of treatment and 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, 5.6)], complete and differential white blood cell counts, and platelet count.
  • Blood chemistries — liver function tests and TSH.
  • Pregnancy — in women of childbearing potential.
  • ECG [see Warnings and Precautions (5.2)].

2.5 Dose Modifications

If severe adverse reactions or laboratory abnormalities develop during ribavirin capsules combination therapy, modify or discontinue the dose until the adverse reaction abates or decreases in severity (see Table 4) [see Warnings and Precautions (5)]. If intolerance persists after dose adjustment, combination therapy should be discontinued. Refer to PegIntron labeling for additional information regarding dose reduction of PegIntron.

Dose reduction in pediatric patients is accomplished by modifying the recommended ribavirin capsules dose from the original starting dose of 15 mg/kg daily in a two-step process to 12 mg/kg/day, then to 8 mg/kg/day, if needed (see Table 4).

Ribavirin capsules are contraindicated in patients with creatinine clearance less than 50 mL/min [see Contraindications (4)]. Patients 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 capsules should be administered with caution to patients with pre-existing cardiac disease. Assess cardiovascular status before initiation of treatment and during therapy. If there is any deterioration of cardiovascular status, discontinue combination therapy [see Warnings and Precautions (5.2)].

In patients with a history of stable cardiovascular disease, a permanent dose reduction is required if the hemoglobin decreases by 2 g/dL or more during any 4-week period. If the hemoglobin level remains below 12 g/dL after 4 weeks on a reduced dose, discontinue combination therapy.

Modify or discontinue ribavirin capsules dosing in any patient whose hemoglobin level falls below 10 g/dL (see Table 4) [see Warnings and Precautions (5.2)].

Table 4: Guidelines for Dose Modification and Discontinuation of Ribavirin capsules in combination with PegIntron or INTRON A Based on Laboratory Parameters in Adults and Pediatrics
Laboratory Parameters Reduce Ribavirin capsules Daily Dose (see note 1) if: Reduce PegIntron or INTRON A Dose (see note 2) if: Discontinue Therapy if:
Note 1: Adult patients: 1st dose reduction of ribavirin is by 200 mg/day (except in patients receiving the 1,400 mg, dose reduction should be by 400 mg/day). If needed, 2nd dose reduction of ribavirin is by an additional 200 mg/day. Patients whose dose of ribavirin is reduced to 600 mg daily receive one 200 mg capsule in the morning and two 200 mg capsules in the evening. Pediatric patients: 1st dose reduction of ribavirin is to 12 mg/kg/day, 2nd dose reduction of ribavirin is to 8 mg/kg/day.Note 2: Adult patients treated with ribavirin capsules and PegIntron: 1st dose reduction of PegIntron is to 1 mcg/kg/week. If needed, 2nd dose reduction of PegIntron is to 0.5 mcg/kg/week.Pediatric patients treated with ribavirin capsules and PegIntron: 1st dose reduction of PegIntron is to 40 mcg/m2 /week, 2nd dose reduction of PegIntron is to 20 mcg/m2 /week. For patients on ribavirin capsules /INTRON A combination therapy: reduce INTRON A dose by 50%.* Pediatric patients who have pre-existing cardiac conditions and experience a hemoglobin decrease greater than or equal to 2 g/dL during any 4-week period during treatment should have weekly evaluations and hematology testing. These guidelines are for patients with stable cardiac disease. Patients with a history of significant or unstable cardiac disease should not be treated with PegIntron/ribavirin capsules combination therapy [see Warnings and Precautions (5.2)].
WBC N/A 1.0 to <1.5 x 109 /L <1.0 x 109 /L
Neutrophils N/A 0.5 to <0.75 x 109 /L <0.5 x 109 /L
Platelets N/A 25 to < 50 x 109 /L (adults) <25 x 109 /L (adults)
N/A 50 to <70 x 109 /L (pediatrics) <50 x 109 /L (pediatrics)
Creatinine N/A N/A >2 mg/dL (pediatrics)
Hemoglobin in patients without history of cardiac disease 8.5 to <10 g/dL N/A <8.5 g/dL
Reduce Ribavirin capsules Dose by 200 mg/day and PegIntron or INTRON A Dose by Half if:
Hemoglobin in patients with history of stable cardiac disease*† ≥2 g/dL decrease in hemoglobin during any four-week period during treatment <8.5 g/dL or <12 g/dL after four weeks of dose reduction

Refer to labeling for INTRON A or PegIntron for additional information about how to reduce an INTRON A or PegIntron dose.

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