Ribavirin, usp capsules

Ribavirin   Single- and multiple-dose pharmacokinetic properties in adults with chronic hepatitis C are summarized in TABLE 1 . Ribavirin was rapidly and extensively absorbed following oral administration. However, due to first-pass metabolism, the absolute bioavailability averaged 64% (44%). There was a linear relationship between dose and AUC tf (AUC from time zero to last measurable concentration) following single doses of 200-1200 mg ribavirin. The relationship between dose and C max was curvilinear, tending to asymptote above single doses of 400-600 mg.

Upon multiple oral dosing, based on AUC12 hr , a sixfold accumulation of ribavirin was observed in plasma. Following oral dosing with 600 mg BID, steady-state was reached by approximately 4 weeks, with mean steady-state plasma concentrations of 2200 (37%) ng/mL. Upon discontinuation of dosing, the mean half-life was 298 (30%) hours, which probably reflects slow elimination from nonplasma compartments.

Effect of Food on Absorption of Ribavirin   Both AUC tf and C max increased by 70% when Ribavirin Capsules were administered with a high-fat meal (841 kcal, 53.8 g fat, 31.6 g protein, and 57.4 g carbohydrate) in a single-dose pharmacokinetic study. There are insufficient data to address the clinical relevance of these results. Clinical efficacy studies with Ribavirin/INTRON A were conducted without instructions with respect to food consumption. During clinical studies with Ribavirin/PEG-INTRON, all subjects were instructed to take Ribavirin Capsules with food. (See DOSAGE AND ADMINISTRATION .)

Effect of Antacid on Absorption of Ribavirin   Coadministration with an antacid containing magnesium, aluminum, and simethicone (Mylanta 1 ) resulted in a 14% decrease in mean ribavirin AUC tf . The clinical relevance of results from this single-dose study is unknown.

Ribavirin transport into nonplasma compartments has been most extensively studied in red blood cells, and has been identified to be primarily via an e s -type equilibrative nucleoside transporter. This type of transporter is present on virtually all cell types and may account for the extensive volume of distribution. Ribavirin does not bind to plasma proteins.

Ribavirin has two pathways of metabolism: (i) a reversible phosphorylation pathway in nucleated cells; and (ii) a degradative pathway involving deribosylation and amide hydrolysis to yield a triazole carboxylic acid metabolite. Ribavirin and its triazole carboxamide and triazole carboxylic acid metabolites are excreted renally. After oral administration of 600 mg of 14 C-ribavirin, approximately 61% and 12% of the radioactivity was eliminated in the urine and feces, respectively, in 336 hours. Unchanged ribavirin accounted for 17% of the administered dose.

Results of in vitro studies using both human and rat liver microsome preparations indicated little or no cytochrome P450 enzyme-mediated metabolism of ribavirin, with minimal potential for P450 enzyme-based drug interactions.

No pharmacokinetic interactions were noted between INTRON A Injection and Ribavirin Capsules in a multiple-dose pharmacokinetic study.

Special Populations

Renal Dysfunction   The pharmacokinetics of ribavirin were assessed after administration of a single oral dose (400 mg) of ribavirin to non HCV-infected subjects with varying degrees of renal dysfunction. The mean AUC tf value was threefold greater in subjects with creatinine clearance values between 10 to 30 mL/min when compared to control subjects (creatinine clearance >90 mL/min). In subjects with creatinine clearance values between 30 to 60 mL/min, AUC tf was twofold greater when compared to control subjects. The increased AUC tf appears to be due to reduction of renal and non-renal clearance in these patients. Phase III efficacy trials included subjects with creatinine clearance values >50 mL/min. The multiple dose pharmacokinetics of ribavirin cannot be accurately predicted in patients with renal dysfunction. Ribavirin is not effectively removed by hemodialysis. Patients with creatinine clearance <50 mL/min should not be treated with ribavirin (See WARNINGS .)

Hepatic Dysfunction   The effect of hepatic dysfunction was assessed after a single oral dose of ribavirin (600 mg). The mean AUC tf values were not significantly different in subjects with mild, moderate, or severe hepatic dysfunction (Child-Pugh Classification A, B, or C) when compared to control subjects. However, the mean C max values increased with severity of hepatic dysfunction and was twofold greater in subjects with severe hepatic dysfunction when compared to control subjects.

Pediatric Patients   Pharmacokinetic evaluations in pediatric subjects have not been performed.

Elderly Patients   Pharmacokinetic evaluations in elderly subjects have not been performed.

Gender   There were no clinically significant pharmacokinetic differences noted in a single-dose study of eighteen male and eighteen female subjects.

Pregnancy

Ribavirin Capsules may cause birth defects and/or death of the exposed fetus. Ribavirin therapy is contraindicated for use in women who are pregnant or in men whose female partners are pregnant. (See WARNINGS , PRECAUTIONS - Information for Patients and Pregnancy Category X .) Ribavirin Capsules are contraindicated in patients with a history of hypersensitivity to ribavirin or any component of the capsule.

Patients with autoimmune hepatitis must not be treated with combination Ribavirin/INTRON A therapy because using these medicines can make the hepatitis worse.

Patients with hemoglobinopathies (eg, thalassemia major, sickle-cell anemia) should not be treated with Ribavirin Capsules.

There is limited experience with overdosage. Acute ingestion of up to 20 grams of Ribavirin Capsules, INTRON A ingestion of up to 120 million units, and subcutaneous doses of INTRON A up to 10 times the recommended doses have been reported. Primary effects that have been observed are increased incidence and severity of the adverse events related to the therapeutic use of INTRON A and ribavirin. However, hepatic enzyme abnormalities, renal failure, hemorrhage, and myocardial infarction have been reported with administration of single subcutaneous doses of INTRON A that exceed dosing recommendations.

There is no specific antidote for INTRON A or ribavirin, and hemodialysis and peritoneal dialysis are not effective for treatment of overdose of either agent.

DOSAGE AND ADMINISTRATION (see CLINICAL PHARMACOLOGY , Special Populations ; see WARNINGS )

Ribavirin/INTRON A Combination Therapy

The recommended dose of Ribavirin Capsules depends on the patient's body weight. The recommended dose of ribavirin is provided in TABLE 9 .

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 Description of Clinical Studies and ADVERSE REACTIONS .) 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.

In patients who relapse following interferon therapy, the recommended duration of treatment is 24 weeks. There are no safety and efficacy data on treatment for longer than 24 weeks in the relapse patient population.

Ribavirin may be administered without regard to food, but should be administered in a consistent manner with respect to food intake. (See CLINICAL PHARMACOLOGY .)

Ribavirin/PEG-INTRON Combination Therapy

The recommended dose of Ribavirin Capsules is 800 mg/day in 2 divided doses: two capsules (400 mg) in the morning with food and two capsules (400 mg) in the evening with food.

Dose Modifications (TABLE 10)

If severe adverse reactions or laboratory abnormalities develop during combination Ribavirin/INTRON A therapy the dose should be modified, or discontinued if appropriate, until the adverse reactions abate. If intolerance persists after dose adjustment, Ribavirin/INTRON A therapy should be discontinued.

Ribavirin should not be used in patients with creatinine clearance <50 mL/min. (See WARNINGS and CLINICAL PHARMACOLOGY , Special Populations .)

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 .)

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 Ribavirin/INTRON A therapy.

It is recommended that a patient whose hemoglobin level falls below 10 g/dL have his/her ribavirin dose reduced to 600 mg daily (1 × 200-mg capsule AM, 2 × 200 mg capsules PM). A patient whose hemoglobin level falls below 8.5 g/dL should be permanently discontinued from ribavirin therapy. (See WARNINGS .)

Ribavirin 200-mg Capsules are white, opaque capsules with 200 mg and W-1523 imprinted on the capsule shell; the capsules are packaged in a bottle containing 42 capsules (NDC-59930-1523-4), 56 capsules (NDC 59930-1523-3), 70 capsules (NDC 59930-1523-2), and 84 capsules (NDC 59930-1523-1).

Storage Conditions

The bottle of Ribavirin Capsules should be stored at 25°C (77°F); excursions are permitted between 15° and 30°C (59° and 86°F).

Warrick Pharmaceuticals Corporation

Reno, NV 89506 USA

B-26964210  3/03