The primary toxicity of ribavirin is hemolytic anemia. Reductions in hemoglobin levels occurred within the first 1-2 weeks of oral therapy. (See WARNINGS.) Cardiac and pulmonary events associated with anemia occurred in approximately 10% of patients. (See WARNINGS.)

REBETOL/INTRON A Combination Therapy

In clinical trials, 19% and 6% of previously untreated and relapse patients, respectively, discontinued therapy due to adverse events in the combination arms compared to 13% and 3% in the interferon arms. Selected treatment-emergent adverse events that occurred in the US studies with ≥ 5% incidence are provided in TABLE 7 by treatment group. In general, the selected treatment-emergent adverse events were reported with lower incidence in the international studies as compared to the US studies with the exception of asthenia, influenza-like symptoms, nervousness, and pruritus.

Pediatric Patients

In clinical trials of 118 pediatric patients 3 to 16 years of age, 6% discontinued therapy due to adverse events. Dose modifications were required in 30% of patients, most commonly for anemia and neutropenia. In general, the adverse event profile in the pediatric population was similar to that observed in adults. Injection site disorders, fever, anorexia, vomiting, and emotional lability occurred more frequently in pediatric patients compared to adult patients. Conversely, pediatric patients experienced less fatigue, dyspepsia, arthralgia, insomnia, irritability, impaired concentration, dyspnea, and pruritus compared to adult patients. Selected treatment-emergent adverse events that occurred with ≥ 5% incidence among all pediatric patients who received the recommended dose of REBETOL/INTRON A combination therapy are provided in TABLE 7.

TABLE 7. Selected Treatment-Emergent Adverse Events: Previously Untreated and Relapse Adult Patients and Previously Untreated Pediatric Patients

In addition, the following spontaneous adverse events have been reported during the marketing surveillance of REBETOL/INTRON A therapy: hearing disorder and vertigo.

REBETOL/PegIntron Combination Therapy

Overall, in clinical trials, 14% of patients receiving REBETOL in combination with PegIntron, discontinued therapy compared with 13% treated with REBETOL in combination with INTRON A. The most common reasons for discontinuation of therapy were related to psychiatric, systemic (e.g., fatigue, headache), or gastrointestinal adverse events. Adverse events that occurred in clinical trial at > 5% incidence are provided in TABLE 8 by treatment group. Safety and effectiveness of REBETOL in combination with PegIntron has not been established in pediatric patients.

TABLE 8. Adverse Events Occurring in > 5% of Patients

Laboratory Values

REBETOL/INTRON A Combination Therapy

Changes in selected hematologic values (hemoglobin, white blood cells, neutrophils, and platelets) during therapy are described below. (See TABLE 9.)

Hemoglobin. Hemoglobin decreases among patients receiving REBETOL therapy began at Week 1, with stabilization by Week 4. In previously untreated patients treated for 48 weeks the mean maximum decrease from baseline was 3.1 g/dL in the US study and 2.9 g/dL in the International study. In relapse patients the mean maximum decrease from baseline was 2.8 g/dL in the US study and 2.6 g/dL in the International study. Hemoglobin values returned to pretreatment levels within 4-8 weeks of cessation of therapy in most patients.

Bilirubin and Uric Acid. Increases in both bilirubin and uric acid, associated with hemolysis, were noted in clinical trials. Most were moderate biochemical changes and were reversed within 4 weeks after treatment discontinuation. This observation occurs most frequently in patients with a previous diagnosis of Gilbert's syndrome. This has not been associated with hepatic dysfunction or clinical morbidity.

TABLE 9. Selected Hematologic Values During Treatment With REBETOL Plus INTRON A: Previously Untreated and Relapse Adult Patients and Previously Untreated Pediatric Patients

REBETOL/PegIntron Combination Therapy

Changes in selected hematologic values (hemoglobin, white blood cells, neutrophils, and platelets) during therapy are described below. (See TABLE 10.)

Hemoglobin

REBETOL induced a decrease in hemoglobin levels in approximately two thirds of patients. Hemoglobin levels decreased to < 11g/dL in about 30% of patients. Severe anemia ( < 8 g/dL) occurred in < 1% of patients. Dose modification was required in 9 and 13% of patients in the PegIntron/REBETOL and INTRON A/REBETOL groups.

Bilirubin and Uric Acid

In the REBETOL/PegIntron combination trial 10-14% of patients developed hyperbilirubinemia and 33-38% developed hyperuricemia in association with hemolysis. Six patients developed mild to moderate gout.

TABLE 10. Selected Hematologic Values During Treatment With REBETOL Plus PegIntron

Postmarketing Experiences

The following adverse reactions have been identified during postapproval use of REBETOL in combination with INTRON A or PegIntron therapy: hearing disorder, vertigo, aplastic anemia, pure red cell aplasia. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Didanosine: Coadministration of REBETOL Capsules or Oral Solution and didanosine is not recommended. Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactactemia/lactic acidosis have been reported in clinical trials (see CLINICAL PHARMACOLOGY: Drug Interactions).

Stavudine and Zidovudine: Ribavirin may antagonize the in vitro antiviral activity of stavudine and zidovudine against HIV. Therefore, concomitant use of ribavirin with either of these drugs should be used with caution (see CLINICAL PHARMACOLOGY: Drug Interactions).

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