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Rebetol Intron A (Ribavirin / Interferon Alfa-2B) - Side Effects and Adverse Reactions

 
 



ADVERSE REACTIONS

The safety of combination REBETOL/INTRON A therapy was evaluated in controlled trials of 1010 HCV-infected adults who were previously untreated with interferon therapy and were subsequently treated for 24 or 48 weeks with combination REBETOL/INTRON A therapy and in 173 HCV-infected patients who had relapsed after interferon therapy and were subsequently treated for 24 weeks with combination REBETOL/INTRON A therapy. (See Description of Clinical Studies.) Overall, 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.

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

The most common psychiatric events occurring in US studies of previously untreated and relapse patients treated with REBETOL/INTRON A therapy, respectively, were insomnia (39%, 26%), depression (34%, 23%), and irritability (27%, 25%). Suicidal behavior (ideation, attempts, and suicides) occurred in 1% of patients. (See WARNINGS.) In addition, hearing disorders (tinnitus and hearing loss) and vertigo have occurred in patients treated with combination REBETOL/INTRON A therapy.

Selected treatment-emergent adverse events that occurred in the US studies with >/=5% incidence are provided in TABLE 5 by treatment group. In general, the selected treatment-emergent adverse events 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.

TABLE 5. Selected Treatment-Emergent Adverse Events: Previously Untreated and Relapse Patients
     Percentage of Patients
US Previously Untreated Study US Relapse Study
24 weeks of treatment 48 weeks of treatment 24 weeks of treatment
Patients Reporting Adverse Events * INTRON A
plus REBETOL (N=228)
INTRON A
plus
Placebo (N=231)
INTRON A
plus REBETOL (N=228)
INTRON A
plus
Placebo (N=225)
INTRON A
plus REBETOL (N=77)
INTRON A
plus
Placebo (N=76)
Application Site Disorders
  injection site inflammation 13 10 12 14   6   8
  injection site reaction   7   9   8   9   5   3
Body as a Whole - General Disorders
  headache 63 63 66 67 66 68
  fatigue 68 62 70 72 60 53
  rigors 40 32 42 39 43 37
  fever 37 35 41 40 32 36
  influenza-like symptoms 14 18 18 20 13 13
  asthenia   9   4   9   9 10   4
  chest pain   5   4   9   8   6   7
Central & Peripheral Nervous System Disorders
  dizziness 17 15 23 19 26 21
Gastrointestinal System Disorders
  nausea 38 35 46 33 47 33
  anorexia 27 16 25 19 21 14
  dyspepsia 14   6 16   9 16   9
  vomiting 11 10   9 13 12   8
Musculoskeletal System Disorders
  myalgia 61 57 64 63 61 58
  arthralgia 30 27 33 36 29 29
  musculoskeletal pain 20 26 28 32 22 28
Psychiatric Disorders
  insomnia 39 27 39 30 26 25
  irritability 23 19 32 27 25 20
  depression 32 25 36 37 23 14
  emotional lability   7   6 11   8 12   8
  concentration impaired 11 14 14 14 10 12
  nervousness   4   2   4   4   5   4
Respiratory System Disorders
  dyspnea 19   9 18 10 17 12
  sinusitis   9   7 10 14 12   7
Skin and Appendages Disorders
  alopecia 28 27 32 28 27 26
  rash 20   9 28   8 21   5
  pruritus 21   9 19   8 13   4
Special Senses, Other Disorders
  taste perversion   7   4   8   4   6   5
*Patients reporting one or more adverse events. A patient may have reported more than one adverse event within a body system/organ class category.

LABORATORY VALUES

Changes in selected hematologic values (hemoglobin, white blood cells, neutrophils, and platelets) during combination REBETOL/INTRON A treatment are described below (see TABLE 6).

Hemoglobin    Hemoglobin decreases among patients on combination 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 to 8 weeks of cessation of therapy in most patients.

Neutrophils    There were decreases in neutrophil counts in both the combination REBETOL/INTRON A and INTRON A plus placebo dose groups. In previously untreated patients treated for 48 weeks, the mean maximum decrease in neutrophil count in the US study was 1.3 × 109/L and in the International study was 1.5 × 109/L. In relapse patients the mean maximum decrease in neutrophil count in the US study was 1.3 × 109/L and in the International study was 1.6 × 109/L. Neutrophil counts returned to pretreatment levels within 4 weeks of cessation of therapy in most patients.

Platelets    In both previously untreated and relapse patients mean platelet counts generally remained in the normal range in all treatment groups; however, mean platelet counts were 10% to 15% lower in the INTRON A plus placebo group than the REBETOL/INTRON A group. Mean platelet counts returned to baseline levels within 4 weeks after treatment discontinuation.

Thyroid Function    Of patients who entered the previously untreated (24 and 48 week treatments) and relapse (24 week treatment) studies without thyroid abnormalities, approximately 3% to 6% and 1% to 2%, respectively, developed thyroid abnormalities requiring clinical intervention.

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 6. Selected Hematologic Values During Treatment with REBETOL
plus INTRON A: Previously Untreated and Relapse Patients
     Percentage of Patients
US Previously Untreated Study US Relapse Study
24 weeks of treatment 48 weeks of treatment 24 weeks of treatment
INTRON A
plus REBETOL (N=228)
INTRON A
plus
Placebo (N=231)
INTRON A
plus REBETOL (N=228)
INTRON A
plus
Placebo (N=225)
INTRON A
plus REBETOL (N=77)
INTRON A
plus
Placebo (N=76)
Hemoglobin
(g/dL)
  9.5-10.9 24   1 32   1 21   3
  8.0-9.4   5   0   4   0   4   0
  6.5-7.9   0   0   0 0.4   0   0
 <6.5   0   0   0   0   0   0
Leukocytes
(× 109/L)
  2.0-2.9 40 20 38 23 45 26
  1.5-1.9   4   1   9   2   5   3
  1.0-1.4 0.9   0   2   0   0   0
 <1.0   0   0   0   0   0   0
Neutrophils
(× 109/L)
  1.0-1.49 30 32 31 44 42 34
  0.75-0.99 14 15 14 11 16 18
  0.5-0.74   9   9 14   7   8   4
 <0.5 11   8 11   5   5   8
Platelets
(× 109/L)
  70-99   9 11 11 14   6 12
  50-69   2   3   2   3   0   5
  30-49   0 0.4   0 0.4   0   0
 <30 0.9   0   1 0.9   0   0
Total Bilirubin
(mg/dL)
  1.5-3.0 27 13 32 13 21 7
  3.1-6.0 0.9 0.4   2   0   3   0
  6.1-12.0   0   0 0.4   0   0   0
 >12.0   0   0   0   0   0   0

Drug label data at the top of this Page last updated: 2006-09-05

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