A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Rebetron Side Effects, and Drug Interactions - Ribavirin
Rebetron Side Effects, and Drug Interactions - Ribavirin
SIDE EFFECTS
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 approxi-mately
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. The following adverse event
has also been reported during the marketing surveillance of REBETOL/INTRON A
therapy: hypertriglyceridemia.
Selected treatment-emergent adverse events that occurred in
the US studies with >5% incidence are provided in TABLE 4 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, nervous-ness, and pruritus.
|
TABLE 4. 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
|
|
mylagia
|
61
|
57
|
64
|
63
|
61
|
58
|
|
arthralgia
|
30
|
27
|
33
|
36
|
29
|
29
|
|
musculoskeletal pain
|
20
|
26
|
28
|
32
|
22
|
28
|
|
Psychiatic Disorders
|
|
insomnia
|
39
|
27
|
39
|
30
|
26
|
25
|
|
irritablility
|
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 5).
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 x 109/L and in the International
study was 1.5 x 109/L. In relapse patients the mean maximum decrease
in neutrophil count in the US study was 1.3 x 109/L and in the International
study was 1.6 x 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 5. 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 plus REBETOL (N=228)
|
INTRON plus Placebo (N=225)
|
INTRON 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 (x109/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(x109/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(x109/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 INTERACTIONS
Nucleoside Analogues. Administration of nucleoside analogues
has resulted in lactic acidosis. Coadministration of ribavirin and nucleoside
analogues should be undertaken with caution and only if the potential benefit
outweighs the potential risks.
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