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Clinical trials with REBETOL (ribavirin) in combination with Peglntron or INTRON A have been conducted in over 7800 subjects from 3 to 76 years of age.

The primary toxicity of ribavirin is hemolytic anemia. Reductions in hemoglobin levels occurred within the first 1 to 2 weeks of oral therapy. Cardiac and pulmonary reactions associated with anemia occurred in approximately 10% of patients [see WARNINGS AND PRECAUTIONS].

Greater than 96% of all subjects in clinical trials experienced one or more adverse reactions. The most commonly reported adverse reactions in adult subjects receiving Peglntron or INTRON A in combination with REBETOL (ribavirin) were injection site inflammation/reaction, fatigue/asthenia, headache, rigors, fevers, nausea, myalgia and anxiety/emotional lability/irritability. The most common adverse reactions in pediatric subjects, ages 3 and older, receiving REBETOL (ribavirin) in combination with Peglntron or INTRON A were pyrexia, headache, neutropenia, fatigue, anorexia, injection site erythema, and vomiting.

The Adverse Reactions section references the following clinical studies:

• REBETOL (ribavirin) /Peglntron Combination therapy studies:
  • Clinical Study 1 - evaluated Peglntron monotherapy (not further described in this label; see Peglntron Powder for Injection Package Insert for information about this study).
  • Study 2 - evaluated REBETOL (ribavirin) 800 mg/day flat dose in combination with 1.5 mcg/kg/week Peglntron or with INTRON A.
  • Study 3 - evaluated Peglntron/weight-based REBETOL (ribavirin) in combination with Peglntron/flat dose REBETOL (ribavirin) regimen.
  • Study 4- compared two Peglntron (1.5 mcg/kg/week and 1 mcg/kg/week) doses in combination with REBETOL (ribavirin) and a third treatment group receiving Pegasys® (180 mcg/week)/Copegus (1000-1200 mg/day).
  • Study 5 - evaluated Peglntron (1.5 mcg/kg/week) in combination with weight-based REBETOL (ribavirin) in prior treatment failure subjects.
• Peglntron/REBETOL (ribavirin) Combination Therapy in Pediatric Patients
• REBETOL (ribavirin) /INTRON A Combination Therapy studies for adults and pediatrics

Serious adverse reactions have occurred in approximately 12% of subjects in clinical trials with Peglntron with or without REBETOL [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. The most common serious events occurring in subjects treated with Peglntron and REBETOL (ribavirin) were depression and suicidal ideation [see WARNINGS AND PRECAUTIONS], each occurring at a frequency of less than 1%. Suicidal ideation or attempts occurred more frequently among pediatric patients, primarily adolescents, compared to adult patients (2.4% versus 1%) during treatment and off-therapy follow-up [see WARNINGS AND PRECAUTIONS]. The most common fatal reaction occurring in subjects treated with Peglntron and REBETOL (ribavirin) was cardiac arrest, suicide ideation, and suicide attempt [see WARNINGS AND PRECAUTIONS], all occurring in less than 1 % of subjects.

Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rated in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Clinical Studies Experience - REBETOL (ribavirin) /Peglntron Combination Therapy

Adult Subjects

Adverse reactions that occurred in the clinical trial at > 5% incidence are provided by treatment group from the REBETOL (ribavirin) /Peglntron Combination Therapy (Study 2) in Table 6.

Table 6: Adverse Reactions Occurring in > 5% of Adult Subjects

Table 7 summarizes the treatment related adverse reactions in Study 4 that occurred at a 510% incidence.

Table 7: Summary of Treatment-Related Adverse Reactions (210% Incidence) By Descending Frequency

The incidence of serious adverse reactions was comparable in all studies. In Study 3, there was a similar incidence of serious adverse reactions reported for the weight-based REBETOL (ribavirin) group (12%) and with the flat-dose REBETOL (ribavirin) regimen. In Study 2, the incidence of serious adverse reactions was 17% in the Peglntron/REBETOL (ribavirin) groups compared to 14% in the INTRON A/REBETOL (ribavirin) group.

In many but not all cases, adverse reactions resolved after dose reduction or discontinuation of therapy. Some subjects experienced ongoing or new serious adverse reactions during the 6-month follow-up period. In Study 2, many subjects continued to experience adverse reactions several months after discontinuation of therapy. By the end of the 6-month follow-up period, the Incidence of ongoing adverse reactions by body class In the Peglntron 1.5/REBETOL (ribavirin) group was 33% (psychiatric), 20% (musculoskeletal), and 10% (for endocrine and for Gl). In approximately 10 to 15% of subjects'weight loss, fatigue, and headache had not resolved.

There have been 31 subject deaths which occurred during treatment or during follow-up in these clinical trials. In Study 1, there was 1 suicide in a subject receiving Peglntron monotherapy and 2 deaths among subjects receiving INTRON A monotherapy (1 murder/suicide and 1 sudden death). In Study 2, there was 1 suicide in a subject receiving Peglntron/REBETOL (ribavirin) combination therapy; and 1 subject death in the INTRON A/REBETOL (ribavirin) group (motor vehicle accident). There have been 31 subject deaths which occurred during treatment or during follow-up in the three clinical trials. In Study 3, there were 14 deaths, 2 of which were probable suicides and 1 was an unexplained death in a person with a relevant medical history of depression. In Study 4, there were 12 deaths, 6 of which occurred in subjects who received Peglntron/REBETOL (ribavirin) combination therapy, 5 in the Peglntron 1.5 mcg/REBETOL (ribavirin) arm (N=1019) and 1 in the Peglntron 1 mcg/REBETOL (ribavirin) arm (N=1016), and 6 of which occurred in subjects receiving Pegasys/Copegus (N=1035). There were 3 suicides which occurred during the off treatment follow-up period in subjects who received Peglntron (1.5 mcg/kg)/REBETOL (ribavirin) combination therapy.

In studies 1 and 2,10 to 14% of subjects receiving Peglntron, alone or in combination with REBETOL (ribavirin) , discontinued therapy compared with 6% treated with INTRON A alone and 13% treated with INTRON A in combination with REBETOL (ribavirin) . Similarly in Study 3,15% of subjects receiving Peglntron in combination with weight-based REBETOL (ribavirin) and 14% of subjects receiving Peglntron and flat dose REBETOL (ribavirin) discontinued therapy due to an adverse reaction. The most common reasons for discontinuation of therapy were related to known interferon effects of psychiatric, systemic (e.g., fatigue, headache), or gastrointestinal adverse reactions. In study 4,13% of subjects in the Peglntron 1.5 mcg/REBETOL (ribavirin) arm, 10% in the Peglntron 1 mcg/REBETOL (ribavirin) arm and 13% in the Pegasys 180 mcg/Copegus arm discontinued due to adverse events.

In Study 2, dose reductions due to adverse reactions occurred in 42% of subjects receiving Peglntron (1.5 mcg/kg)/REBETOL (ribavirin) and in 34% of those receiving INTRON A/REBETOL (ribavirin) . The majority of subjects (57%) weighing 60 kg or less receiving Peglntron (1.5 mcg/kg)/REBETOL (ribavirin) required dose reduction. Reduction of interferon was dose related (Peglntron 1.5 meg/kg > Peglntron 0.5 meg/kg or INTRON A), 40%, 27%, 28%, respectively. Dose reduction for REBETOL (ribavirin) was similar across all three groups, 33 to 35%. The most common reasons for dose modifications were neutropenia (18%), or anemia (9%) (see Laboratory Values). Other common reasons included depression, fatigue, nausea, and thrombocytopenia. In Study 3, dose modifications due to adverse reactions occurred more frequently with WBD compared to flat dosing (29% and 23%, respectively). In Study 4, 16% of subjects had a dose reduction of Peglntron to 1 meg/kg in combination with REBETOL (ribavirin) , with an additional 4% requiring the second dose reduction of Peglntron to 0.5 meg/kg due to adverse events compared to 15% of subjects in the Pegasys/Copegus arm, who required a dose reduction to 135 meg/week with Pegasys, with an additional 7% in the Pegasys/Copegus arm requiring second dose reduction to 90 meg/week with Pegasys.

In the Peglntron/REBETOL (ribavirin) combination trials the most common adverse reactions were psychiatric which occurred among 77% of subjects in Study 2 and 68% to 69% of subjects in Study 3. These psychiatric adverse reactions included most commonly depression, irritability, and insomnia, each reported by approximately 30% to 40% of subjects in all treatment groups. Suicidal behavior (ideation, attempts, and suicides) occurred in 2% of all subjects during treatment or during follow-up after treatment cessation [see WARNINGS AND PRECAUTIONS]. In study 4 psychiatric adverse reactions occurred in 58 % of subjects in the Peglntron 1.5 mcg/REBETOL (ribavirin) arm, 55% of subjects in the Peglntron 1 mcg/REBETOL (ribavirin) arm, 57% of subjects in the Pegasys 180 mcg/Copegus arm.

Peglntron induced fatigue or headache in approximately two-thirds of subjects, with fever or rigors in approximately half of the subjects. The severity of some of these systemic symptoms (e.g., fever and headache) tends to decrease as treatment continues. In Studies 1 and 2, application site inflammation and reaction (e.g., bruise, itchiness, and irritation) occurred at approximately twice the incidence with Peglntron therapies (in up to 75% of subjects) compared with INTRON A. However, injection site pain was infrequent (2 to 3%) in all groups. In Study 3 there was a 23 to 24% incidence overall for injection site reactions or inflammation.

Subjects receiving REBETOL (ribavirin) /Peglntron as retreatment after failing a previous interferon combination regimen reported adverse reactions similar to those previously associated with this regimen during clinical trials of treatment-naTve subjects.

Pediatric Subjects

In general, the adverse-reaction profile in the pediatric population was similar to that observed in adults. In the pediatric study, the most prevalent adverse reactions in all subjects were pyrexia (80%), headache (62%), neutropenia (33%), fatigue (30%), anorexia (29%), injection-site erythema (29%) and vomiting (27%). The majority of adverse reactions reported in the study were mild or moderate in severity. Severe adverse reactions were reported in 7% (8/107) of all subjects and included injection site pain (1%), pain in extremity (1%), headache (1%), neutropenia (1%), and pyrexia (4%). Important adverse reactions that occurred in this subject population were nervousness (7%; 7/107), aggression (3%; 3/107), anger (2%; 2/107), and depression (1%; 1/107). Five subjects received levothyroxine treatment, 3 with clinical hypothyroidism and 2 with asymptomatic TSH elevations.

Dose modifications of Peglntron and/or ribavirin were required in 25% of subjects due to treatment-related adverse reactions, most commonly for anemia, neutropenia and weight loss. Two subjects (2%; 2/107) discontinued therapy as the result of an adverse reaction.

Adverse reactions that occurred with ≥ 5 10% incidence in the pediatric trial subjects are provided in Table 8.

Table 8: Percentage (%) of Pediatric Subjects With Treatment-Related Adverse Reactions (in at Least 10% of All Subjects)

Laboratory Values

Adult and Pediatric Subjects

The adverse reaction profile in Study 3, which compared Peglntron/weight-based REBETOL (ribavirin) combination to a Peglntron/flat dose REBETOL (ribavirin) regimen, revealed an increased rate of anemia with weight-based dosing (29% vs. 19% for weight-based vs. flat dose regimens, respectively). However, the majority of cases of anemia were mild and responded to dose reductions.

Changes in selected laboratory values during treatment in combination with REBETOL (ribavirin) treatment are described below. Decreases in hemoglobin, leukocytes, neutrophils, and platelets may require dose reduction or permanent discontinuation from therapy [see DOSAGE AND ADMINISTRATION]. Changes in selected laboratory values during therapy are described in Table 9. Most of the changes in laboratory values in the Peglntron/REBETOL (ribavirin) study with pediatric were mild or moderate.

Table 9: Selected Laboratory Values During Treatment With REBETOL (ribavirin) Plus Peglntron or REBETOL (ribavirin) Plus INTRON A in Previously Untreated Subjects

Hemoglobin. Hemoglobin levels decreased to < 11 g/dL in about 30% of subjects in Study 2. In Study 3, 47% of subjects receiving WBD REBETOL (ribavirin) and 33% on flat dose REBETOL (ribavirin) had decreases in hemoglobin levels < 11 g/dl. Reductions in hemoglobin to < 9 g/dL occurred more frequently in subjects receiving WBD compared to flat dosing (4% and 2%, respectively). In Study 2, dose modification was required in 9% and 13% of subjects in the Peglntron/REBETOL (ribavirin) and INTRON A/REBETOL (ribavirin) groups. In Study 4, patients receiving Peglntron (1.5 meg/kg)/REBETOL (ribavirin) had decreases in hemoglobin levels to between 8.5 to < 10 g/dL (28%) and to < 8.5 g/dL (3%), whereas in patients receiving Pegasys 180 mcg/Copegus these decreases occurred in 26% and 4% of subjects respectively. Hemoglobin levels become stable by treatment Weeks 4-6 on average. The typical pattern observed was a decrease in hemoglobin levels by treatment Week 4 followed by stabilization and a plateau, which was maintained to the end of treatment. In the Peglntron monotherapy trial, hemoglobin decreases were generally mild and dose modifications were rarely necessary [see DOSAGE AND ADMINISTRATION].

Neutrophils. Decreases in neutrophil counts were observed in a majority of adult subjects treated with combination therapy with REBETOL (ribavirin) in Study 2 (85%) and INTRON A/REBETOL (ribavirin) (60%). Severe potentially life-threatening neutropenia ( < 0.5 x 10⁹/L) occurred in 2% of subjects treated with INTRON A/REBETOL (ribavirin) and in approximately 4% of subjects treated with Peglntron/REBETOL (ribavirin) in Study 2. Eighteen percent of subjects receiving Peglntron/REBETOL (ribavirin) in Study 2 required modification of interferon dosage. Few subjects ( < 1%) required permanent discontinuation of treatment. Neutrophil counts generally return to pre-treatment levels 4 weeks after cessation of therapy [see DOSAGE AND ADMINISTRATION].

Platelets. Platelet counts decreased to < 100,000/mm³ in approximately 20% of subjects treated with Peglntron alone or with REBETOL (ribavirin) and in 6% of adult subjects treated with INTRON A/REBETOL (ribavirin) . Severe decreases in platelet counts ( < 50,000/mm³) occur in < 4% of adult subjects. Subjects may require discontinuation or dose modification as a result of platelet decreases [see DOSAGE AND ADMINISTRATION]. In Study 2,1 % or 3% of subjects required dose modification of INTRON A or Peglntron, respectively. Platelet counts generally returned to pretreatment levels 4 weeks after the cessation of therapy.

Thyroid Function. Development of TSH abnormalities, with and without clinical manifestations, are associated with interferon therapies. In Study 2, clinically apparent thyroid disorders occur among subjects treated with either INTRON A or Peglntron (with or without REBETOL (ribavirin) ) at a similar incidence (5% for hypothyroidism and 3% for hyperthyroidism). Subjects developed new onset TSH abnormalities while on treatment and during the follow-up period. At the end of the follow-up period 7% of subjects still had abnormal TSH values.

Bilirubin and uric acid. In Study 2,10 to 14% of subjects developed hyperbilirubinemia and 33 to 38% developed hyperuricemia in association with hemolysis. Six subjects developed mild to moderate gout.

Clinical Studies Experience - REBETOL (ribavirin) /INTRON A Combination Therapy

Adult Subjects

In clinical trials, 19% and 6% of previously untreated and relapse subjects, respectively, discontinued therapy due to adverse reactions in the combination arms compared to 13% and 3% in the interferon arms. Selected treatment-related adverse reactions that occurred in the US studies with ≥ 5% incidence are provided by treatment group (see Table 10). In general, the selected treatment-related adverse reactions 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 Subjects

In clinical trials of 118 pediatric subjects 3 to 16 years of age, 6% discontinued therapy due to adverse reactions. Dose modifications were required in 30% of subjects, most commonly for anemia and neutropenia. In general, the adverse-reaction 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 subjects compared to adult subjects. Conversely, pediatric subjects experienced less fatigue, dyspepsia, arthralgia, insomnia, irritability, impaired concentration, dyspnea, and pruritus compared to adult subjects. Selected treatment-related adverse reactions that occurred with ≥ 5% incidence among all pediatric subjects who received the recommended dose of REBETOL (ribavirin) /INTRON A combination therapy are provided in Table 10.

Table 10: Selected Treatment-Related Adverse Reactions: Previously Untreated and Relapse Adult Subjects and Previously Untreated Pediatric Subjects

Subjects reporting one or more adverse reactions. A patient may have reported more than one adverse reaction within a body system/organ class category.

Laboratory Values

Changes in selected hematologic values (hemoglobin, white blood cells, neutrophils, and platelets) during therapy are described below (see Table 11).

Hemoglobin. Hemoglobin decreases among subjects receiving REBETOL (ribavirin) therapy began at Week 1, with stabilization by Week 4. In previously untreated subjects 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 subjects 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 to 8 weeks of cessation of therapy in most subjects.

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 subjects with a previous diagnosis of Gilbert's syndrome. This has not been associated with hepatic dysfunction or clinical morbidity.

Table 11: Selected Hematologic Abnormalities During Treatment With REBETOL (ribavirin) Plus INTRON A: Previously Untreated and Relapse Adult Subjects and Previously Untreated Pediatric Subjects

Postmarketing Experiences

The following adverse reactions have been identified and reported during post approval use of REBETOL (ribavirin) in combination with INTRON A or Peglntron. 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.

Blood and Lymphatic System disorders

Pure red cell aplasia, aplastic anemia

Ear and Labyrinth disorders

Hearing disorder, vertigo

Respiratory, Thoracic and mediastinal disorders

Pulmonary hypertension

Eye disorders

Serous retinal detachment

Endocrine disorders

Diabetes

Didanosine

Exposure to didanosine or its active metabolite (dideoxyadenosine 5'-triphosphate) is increased when didanosine is coadministered with ribavirin, which could cause or worsen clinical toxicities; therefore, coadministration of REBETOL (ribavirin) Capsules or Oral Solution and didanosine is contraindicated. Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactactemia/lactic acidosis have been reported in clinical trials.

Nucleoside Analogues

Hepatic decompensation (some fatal) has occurred in cirrhotic HIV/HCV co-infected patients receiving combination antiretroviral therapy for HIV and interferon alpha and ribavirin. Adding treatment with alpha interferons alone or in combination with ribavirin may increase the risk in this patient subset. Patients receiving interferon with ribavirin and nucleoside reverse transcriptase inhibitors (NRTIs) should be closely monitored for treatment- associated toxicities, especially hepatic decompensation and anemia. Discontinuation of NRTIs should be considered as medically appropriate (see Individual NRTI Product Information). Dose reduction or discontinuation of interferon, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh > 6).

Ribavirin may antagonize the cell culture antiviral activity of stavudine and zidovudine against HIV. Ribavirin has been shown in cell culture to inhibit phosphorylation of lamivudine, stavudine, and zidovudine, which could lead to decreased antiretroviral activity. However, in a study with another pegylated interferon in combination with ribavirin, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV/HCV virologic suppress) interaction was observed when ribavirin and lamivudine (n=18), stavudine (n=10), or zidovudine (n=6) were coadministered as part of a multidrug regimen to HIV/HCV co-infected subjects. Therefore, concomitant use of ribavirin with either of these drugs should be used with caution.

Drugs Metabolized by Cytochrome P-450

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 for Injection and REBETOL (ribavirin) Capsules In a multiple-dose pharmacoklnetlc study.

Azathioprine

The use of ribavirin for the treatment of chronic hepatitis C in patients receiving azathioprine has been reported to induce severe pancytopenia and may increase the risk of azathioprine-related myelotoxicity. Inosine monophosphate dehydrogenase (IMDH) is required for one of the metabolic pathways of azathioprine. Ribavirin is known to inhibit IMDH, thereby leading to accumulation of an azathioprine metabolite, 6-methylthioinosine monophosphate (6-MTITP), which is associated with myelotoxicity (neutropenia, thrombocytopenia, and anemia). Patients receiving azathioprine with ribavirin should have complete blood counts, including platelet counts, monitored weekly for the first month, twice monthly for the second and third months of treatment, then monthly or more frequently if dosage or other therapy changes are necessary [See WARNINGS AND PRECAUTIONS]

Last reviewed on RxList: 12/3/2010
This monograph has been modified to include the generic and brand name in many instances.