Ribavirin adverse reactions

# Adverse Reactions
Clinical trials with REBETOL in combination with PegIntron 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 .
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 PegIntron or INTRON A in combination with REBETOL 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 in combination with PegIntron or INTRON A were pyrexia, headache, neutropenia, fatigue, anorexia, injection site erythema, and vomiting.
The Adverse Reactions section references the following clinical trials:
- REBETOL/PegIntron Combination therapy trials:
Clinical Study 1  evaluated PegIntron monotherapy (not further described in this label; see labeling for PegIntron for information about this trial).
Study 2  evaluated REBETOL 800 mg/day flat dose in combination with 1.5 mcg/kg/week PegIntron or with INTRON A.
Study 3  evaluated PegIntron/weight-based REBETOL in combination with PegIntron/flat dose REBETOL regimen.
Study 4  compared two PegIntron (1.5 mcg/kg/week and 1 mcg/kg/week) doses in combination with REBETOL and a third treatment group receiving Pegasys(180 mcg/week)/Copegus (1000-1200 mg/day).
Study 5  evaluated PegIntron (1.5 mcg/kg/week) in combination with weight-based REBETOL in prior treatment failure subjects.
- Clinical Study 1  evaluated PegIntron monotherapy (not further described in this label; see labeling for PegIntron for information about this trial).
- Study 2  evaluated REBETOL 800 mg/day flat dose in combination with 1.5 mcg/kg/week PegIntron or with INTRON A.
- Study 3  evaluated PegIntron/weight-based REBETOL in combination with PegIntron/flat dose REBETOL regimen.
- Study 4  compared two PegIntron (1.5 mcg/kg/week and 1 mcg/kg/week) doses in combination with REBETOL and a third treatment group receiving Pegasys(180 mcg/week)/Copegus (1000-1200 mg/day).
- Study 5  evaluated PegIntron (1.5 mcg/kg/week) in combination with weight-based REBETOL in prior treatment failure subjects.
- PegIntron/REBETOL Combination Therapy in Pediatric Patients
- REBETOL/INTRON A Combination Therapy trials for adults and pediatrics
Serious adverse reactions have occurred in approximately 12% of subjects in clinical trials with PegIntron with or without REBETOL . The most common serious events occurring in subjects treated with PegIntron and REBETOL were depression and suicidal ideation , 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 . The most common fatal reaction occurring in subjects treated with PegIntron and REBETOL was cardiac arrest, suicide ideation, and suicide attempt , 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 rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

## Clinical Trials Experience  REBETOL/PegIntron Combination Therapy

### Adult Subjects
Adverse reactions that occurred in the clinical trial at greater than 5% incidence are provided by treatment group from the REBETOL/PegIntron Combination Therapy (Study 2) in Table 5.
Table 6 summarizes the treatment-related adverse reactions in Study 4 that occurred at a greater than or equal to 10% incidence.
The incidence of serious adverse reactions was comparable in all trials. In Study 3, there was a similar incidence of serious adverse reactions reported for the weight-based REBETOL group (12%) and for the flat-dose REBETOL regimen. In Study 2, the incidence of serious adverse reactions was 17% in the PegIntron/REBETOL groups compared to 14% in the INTRON A/REBETOL 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 PegIntron 1.5/REBETOL group was 33% (psychiatric), 20% (musculoskeletal), and 10% (for endocrine and for GI). In approximately 10 to 15% of subjects, weight loss, fatigue, and headache had not resolved.
There have been 31 subject deaths that occurred during treatment or during follow-up in these clinical trials. In Study 1, there was 1 suicide in a subject receiving PegIntron 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 PegIntron/REBETOL combination therapy; and 1 subject death in the INTRON A/REBETOL group (motor vehicle accident). 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 PegIntron/REBETOL combination therapy, 5 in the PegIntron 1.5 mcg/REBETOL arm (N=1019) and 1 in the PegIntron 1 mcg/REBETOL arm (N=1016), and 6 of which occurred in subjects receiving Pegasys/Copegus (N=1035); there were 3 suicides that occurred during the off treatment follow-up period in subjects who received PegIntron (1.5 mcg/kg)/REBETOL combination therapy.
In Studies 1 and 2, 10 to 14% of subjects receiving PegIntron, alone or in combination with REBETOL, discontinued therapy compared with 6% treated with INTRON A alone and 13% treated with INTRON A in combination with REBETOL. Similarly in Study 3, 15% of subjects receiving PegIntron in combination with weight-based REBETOL and 14% of subjects receiving PegIntron and flat dose REBETOL 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 PegIntron 1.5 mcg/REBETOL arm, 10% in the PegIntron 1 mcg/REBETOL 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 PegIntron (1.5 mcg/kg)/REBETOL and in 34% of those receiving INTRON A/REBETOL. The majority of subjects (57%) weighing 60 kg or less receiving PegIntron (1.5 mcg/kg)/REBETOL required dose reduction. Reduction of interferon was dose-related (PegIntron 1.5 mcg/kg greater than PegIntron 0.5 mcg/kg or INTRON A), 40%, 27%, 28%, respectively. Dose reduction for REBETOL 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 weight-based dosing (WBD) compared to flat dosing (29% and 23%, respectively). In Study 4, 16% of subjects had a dose reduction of PegIntron to 1 mcg/kg in combination with REBETOL, with an additional 4% requiring the second dose reduction of PegIntron to 0.5 mcg/kg due to adverse events compared to 15% of subjects in the Pegasys/Copegus arm, who required a dose reduction to 135 mcg/week with Pegasys, with an additional 7% in the Pegasys/Copegus arm requiring second dose reduction to 90 mcg/week with Pegasys.
In the PegIntron/REBETOL 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 . In Study 4, psychiatric adverse reactions occurred in 58% of subjects in the PegIntron 1.5 mcg/REBETOL arm, 55% of subjects in the PegIntron 1 mcg/REBETOL arm, and 57% of subjects in the Pegasys 180 mcg/Copegus arm.
PegIntron 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) tended to decrease as treatment continued. In Studies 1 and 2, application site inflammation and reaction (e.g., bruise, itchiness, and irritation) occurred at approximately twice the incidence with PegIntron 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/PegIntron as re-treatment after failing a previous interferon combination regimen reported adverse reactions similar to those previously associated with this regimen during clinical trials of treatment-naive subjects.

## Pediatric Subjects
In general, the adverse-reaction profile in the pediatric population was similar to that observed in adults. In the pediatric trial, 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 trial 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, three with clinical hypothyroidism and two with asymptomatic TSH elevations. Weight and height gain of pediatric subjects treated with PegIntron plus REBETOL lagged behind that predicted by normative population data for the entire length of treatment. Severely inhibited growth velocity (less than 3rd percentile) was observed in 70% of the subjects while on treatment.
Dose modifications of PegIntron 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 a greater than or equal to 10% incidence in the pediatric trial subjects are provided in Table 7.
Ninety-four of 107 subjects enrolled in a 5 year long-term follow-up trial. The long-term effects on growth were less in those subjects treated for 24 weeks than those treated for 48 weeks. Twenty-four percent of subjects (11/46) treated for 24 weeks and 40% of subjects (19/48) treated for 48 weeks had a >15 percentile height-for-age decrease from pre-treatment to the end of 5 year long-term follow-up compared to pre-treatment baseline percentiles. Eleven percent of subjects (5/46) treated for 24 weeks and 13% of subjects (6/48) treated for 48 weeks were observed to have a decrease from pre-treatment baseline of >30 height-for-age percentiles to the end of the 5 year long-term follow-up. While observed across all age groups, the highest risk for reduced height at the end of long-term follow-up appeared to correlate with initiation of combination therapy during the years of expected peak growth velocity. 

## Laboratory Values

### Adult and Pediatric Subjects
The adverse reaction profile in Study 3, which compared PegIntron/weight-based REBETOL combination to a PegIntron/flat dose REBETOL 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 treatment are described below. Decreases in hemoglobin, leukocytes, neutrophils, and platelets may require dose reduction or permanent discontinuation from therapy . Changes in selected laboratory values during therapy are described in Table 8. Most of the changes in laboratory values in the PegIntron/REBETOL trial with pediatrics were mild or moderate.
Hemoglobin. Hemoglobin levels decreased to less than 11 g/dL in about 30% of subjects in Study 2. In Study 3, 47% of subjects receiving WBD REBETOL and 33% on flat-dose REBETOL had decreases in hemoglobin levels less than 11 g/dl. Reductions in hemoglobin to less than 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 PegIntron/REBETOL and INTRON A/REBETOL groups. In Study 4, subjects receiving PegIntron (1.5 mcg/kg)/REBETOL had decreases in hemoglobin levels to between 8.5 to less than 10 g/dL (28%) and to less than 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 became 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 PegIntron monotherapy trial, hemoglobin decreases were generally mild and dose modifications were rarely necessary .
Neutrophils. Decreases in neutrophil counts were observed in a majority of adult subjects treated with combination therapy with REBETOL in Study 2 (85%) and INTRON A/REBETOL (60%). Severe potentially life-threatening neutropenia (less than 0.5  109/L) occurred in 2% of subjects treated with INTRON A/REBETOL and in approximately 4% of subjects treated with PegIntron/REBETOL in Study 2. Eighteen percent of subjects receiving PegIntron/REBETOL in Study 2 required modification of interferon dosage. Few subjects (less than 1%) required permanent discontinuation of treatment. Neutrophil counts generally returned to pre-treatment levels 4 weeks after cessation of therapy .
Platelets. Platelet counts decreased to less than 100,000/mm3 in approximately 20% of subjects treated with PegIntron alone or with REBETOL and in 6% of adult subjects treated with INTRON A/REBETOL. Severe decreases in platelet counts (less than 50,000/mm3) occur in less than 4% of adult subjects. Patients may require discontinuation or dose modification as a result of platelet decreases . In Study 2, 1% or 3% of subjects required dose modification of INTRON A or PegIntron, respectively. Platelet counts generally returned to pretreatment levels 4 weeks after the cessation of therapy.
Thyroid Function. Development of TSH abnormalities, with or without clinical manifestations, is associated with interferon therapies. In Study 2, clinically apparent thyroid disorders occurred among subjects treated with either INTRON A or PegIntron (with or without REBETOL) 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 Trials Experience  REBETOL/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 trials with greater than or equal to 5% incidence are provided by treatment group (see Table 9). In general, the selected treatment-related adverse reactions were reported with lower incidence in the international trials as compared to the US trials, 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 greater than or equal to 5% incidence among all pediatric subjects who received the recommended dose of REBETOL/INTRON A combination therapy are provided in Table 9.
During a 48-week course of therapy there was a decrease in the rate of linear growth (mean percentile assignment decrease of 7%) and a decrease in the rate of weight gain (mean percentile assignment decrease of 9%). A general reversal of these trends was noted during the 24-week post-treatment period. Long-term data in a limited number of patients, however, suggests that combination therapy may induce a growth inhibition that results in reduced final adult height in some patients .

### Laboratory Values
Changes in selected hematologic values (hemoglobin, white blood cells, neutrophils, and platelets) during therapy are described below (see Table 10).
Hemoglobin. Hemoglobin decreases among subjects receiving REBETOL 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 trial and 2.9 g/dL in the international trial. In relapse subjects, the mean maximum decrease from baseline was 2.8 g/dL in the US trial and 2.6 g/dL in the international trial. 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 occurred most frequently in subjects with a previous diagnosis of Gilbert's syndrome. This has not been associated with hepatic dysfunction or clinical morbidity.

## Postmarketing Experiences
The following adverse reactions have been identified and reported during post approval use of REBETOL in combination with INTRON A or PegIntron. 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