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
Rebetol Side Effects, and Drug Interactions - Ribavirin
Rebetol 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 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, the following spontaneous adverse events have been reported
during the marketing surveillance of REBETOL/INTRON A therapy: hearing
disorder and vertigo. Very rarely, combination REBETOL/INTRON A therapy
may be associated with aplastic anemia.
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, nervousness,
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
|
|
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 in 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 × 10 9
/L and in the International study was 1.5 × 10 9 /L.
In relapse patients the mean maximum decrease in neutrophil count in the
US study was 1.3 × 10 9 /L and in the International study was
1.6 × 10 9 /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 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 ( × 10 9 /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 |
|
Neutrophils ( × 10 9 /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 |
|
<5
|
11 |
8 |
11 |
5 |
5 |
8 |
|
Platelets ( × 10 9 /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
No Information Provided.
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