Ribavirin

RIBAVIRIN- ribavirin capsule
Sandoz Inc

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)].

1 INDICATIONS AND USAGE

1.1 Chronic Hepatitis C (CHC)

Ribavirin capsules USP in combination with interferon alfa-2b (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 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 retreatment 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 should be taken with food [see Clinical Pharmacology (12.3)]. Ribavirin should not be used in patients with creatinine clearance less than 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 – Retreatment 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 AM3 x 200 mg capsules PMdaily orally

>75 kg

3 x 200 mg capsules AM3 x 200 mg capsules PMdaily orally

Pediatrics

The recommended dose of ribavirin is 15 mg/kg per day orally (divided dose AM and PM). INTRON A for Injection by body weight of 25 kg to 61 kg is 3 million IU/m2 three times weekly subcutaneously.

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 less than 50 mL/min. 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 should be administered with caution to patients with pre-existing 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 greater than or equal to 2 g/dL during any 4-week period. In addition, for these cardiac history patients, if the hemoglobin remains less than 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 4 [see Warnings and Precautions (5.2)].

Table 4. Guidelines for Dose Modification and Discontinuation of INTRON A Based on Laboratory Parameters in Adults and Pediatrics
*
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 [see Warnings and Precautions (5.2)].

LaboratoryParameters

ReduceRibavirinDaily Dose(see note 1) if:

ReduceINTRON ADose(see note 2) if:

DiscontinueTherapy if:

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 Dose by200 mg/day andINTRON 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

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: For patients on ribavirin/INTRON A combination therapy: reduce INTRON A dose by 50%.

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

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