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 Indications, Dosage, Storage, Stability - Ribavirin
Rebetol Indications, Dosage, Storage, Stability - Ribavirin
INDICATIONS
AND USES
REBETOL (ribavirin, USP) Capsules is indicated in combination with INTRON
A (interferon alfa-2b, recombinant) Injection for the treatment of chronic
hepatitis C in patients with compensated liver disease previously untreated
with alpha interferon or who have relapsed following alpha interferon
therapy.
Description of Clinical Studies
Previously Untreated Patients Adults with compensated
chronic hepatitis C and detectable HCV RNA (assessed by a central laboratory
using a research-based RT-PCR assay) who were previously untreated with
alpha interferon therapy were enrolled into two multicenter, double-blind
trials (US and International) and randomized to receive REBETOL Capsules
1200 mg/day (1000 mg/day for patients weighing ≤75 kg) plus INTRON
A Injection 3 MIU TIW or INTRON A Injection plus placebo for 24 or 48
weeks followed by 24 weeks of off-therapy follow-up. The International
study did not contain a 24-week INTRON A plus placebo treatment arm. The
US study enrolled 912 patients who, at baseline, were 67% male, 89% caucasian
with a mean Knodell HAI score (I + II + III) of 7.5, and 72% genotype
1. The International study, conducted in Europe, Israel, Canada, and Australia,
enrolled 799 patients (65% male, 95% caucasian, mean Knodell score 6.8,
and 58% genotype 1). Study results are summarized in TABLE 2.
TABLE 2. Virologic and Histologic Responses:
Previously Untreated Patients *
|
|
US Study |
International Study |
|
|
24 weeks of treatment |
48 weeks of treatment |
24 weeks of
treatment |
48 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=265) |
INTRON A
plus
REBETOL
(N=268) |
INTRON A
plus
Placebo
(N=266) |
|
Virologic Response
|
|
-Responder 1
|
65 (29) |
13 (6) |
85 (37) |
27 (12) |
86 (32) |
113 (42) |
46 (17) |
|
-Nonresponder
|
147 (64) |
194 (84) |
110 (48) |
168 (75) |
158 (60) |
120 (45) |
196 (74) |
|
-Missing data
|
16 (7) |
24 (10) |
33 (14) |
30 (13) |
21 (8) |
35 (13) |
24 (9) |
|
Histologic Response
|
|
-Improvement 2
|
102 (45) |
77 (33) |
96 (42) |
65 (29) |
103 (39) |
102 (38) |
69 (26) |
|
-No improvement
|
77 (34) |
99 (43) |
61 (27) |
93 (41) |
85 (32) |
58 (22) |
111 (41) |
|
-Missing data
|
49 (21) |
55 (24) |
71 (31) |
67 (30) |
77 (29) |
108 (40) |
86 (32) |
|
*Number (%) of patients
|
|
1 Defined as HCV RNA below limit of detection
using a research-based RT-PCR assay at end of treatment and during
follow-up period.
|
|
2 Defined as posttreatment (end of follow-up)
minus pretreatment liver biopsy Knodell HAI score (I+II+III) improvement
of ≥2 points.
|
Of patients who had not achieved HCV RNA below the limit of detection
of the research-based assay by week 24 of REBETOL/INTRON A treatment,
less than 5% responded to an additional 24 weeks of combination treatment.
Among patients with HCV genotype 1 treated with REBETOL/INTRON A therapy
who achieved HCV RNA below the detection limit of the research-based assay
by 24 weeks, those randomized to 48 weeks of treatment had higher virologic
responses compared to those in the 24-week treatment group. There was
no observed increase in response rates for patients with HCV nongenotype
1 randomized to REBETOL/INTRON A therapy for 48 weeks compared to 24 weeks.
Relapse Patients Patients with compensated chronic
hepatitis C and detectable HCV RNA (assessed by a central laboratory using
a research-based RT-PCR assay) who had relapsed following one or two courses
of interferon therapy (defined as abnormal serum ALT levels) were enrolled
into two multicenter, double-blind trials (US and International) and randomized
to receive REBETOL 1200 mg/day (1000 mg/day for patients weighing ≤75
kg) plus INTRON A 3 MIU TIW or INTRON A plus placebo for 24 weeks followed
by 24 weeks of off-therapy follow-up. The US study enrolled 153 patients
who, at baseline, were 67% male, 92% caucasian with a mean Knodell HAI
score (I + II + III) of 6.8, and 58% genotype 1. The International study,
conducted in Europe, Israel, Canada, and Australia, enrolled 192 patients
(64% male, 95% caucasian, mean Knodell score 6.6, and 56% genotype 1).
Study results are summarized in TABLE 3 .
TABLE 3. Virologic and Histologic Responses:
Relapse Patients *
|
|
US Study |
International Study |
|
|
INTRON A
plus
REBETOL
(N=77) |
INTRON A
plus
Placebo
(N=76) |
INTRON A
plus
REBETOL
(N=96) |
INTRON A
plus
Placebo
(N=96) |
|
Virologic Response
|
|
-Responder 1
|
33 (43) |
3 (4) |
46 (48) |
5 (5) |
|
-Nonresponder
|
36 (47) |
66 (87) |
45 (47) |
91 (95) |
|
-Missing data
|
8 (10) |
7 (9) |
5 (5) |
0 (0) |
|
Histologic Response
|
|
-Improvement 2
|
38 (49) |
27 (36) |
49 (51) |
30 (31) |
|
-No improvement
|
23 (30) |
37 (49) |
29 (30) |
44 (46) |
|
-Missing data
|
16 (21) |
12 (16) |
18 (19) |
22 (23) |
|
*Number (%) of patients
|
|
1 Defined as HCV RNA below limit of detection
using a research-based RT-PCR assay at end of treatment and during
follow-up period.
|
|
2 Defined as posttreatment (end of follow-up)
minus pretreatment liver biopsy Knodell HAI score (I+II+III) improvement
of ≥2 points.
|
Virologic and histologic responses were similar among male and female
patients in both the previously untreated and relapse studies.
DOSAGE AND ADMINISTRATION
INTRON A Injection should be administered subcutaneously and REBETOL
Capsules should be administered orally (see TABLE 6 ).
The recommended dose of REBETOL Capsules depends on the patient's body
weight. The recommended doses of REBETOL and INTRON A are given in TABLE
6 .
The recommended duration of treatment for patients previously untreated
with interferon is 24 to 48 weeks. The duration of treatment should be
individualized to the patient depending on baseline disease characteristics,
response to therapy, and tolerability of the regimen (see Description
of Clinical Studies and ADVERSE REACTIONS
). After 24 weeks of treatment virologic response should be assessed.
Treatment discontinuation should be considered in any patient who has
not achieved an HCV RNA below the limit of detection of the assay by 24
weeks. There are no safety and efficacy data on treatment for longer than
48 weeks in the previously untreated patient population.
In patients who relapse following interferon therapy, the recommended
duration of treatment is 24 weeks. There are no safety and efficacy data
on treatment for longer than 24 weeks in the relapse patient populations.
TABLE 6. Recommended Dosing
|
Body weight
|
REBETOL Capsules
|
INTRON A Injection
|
|
≤75 kg
|
2 × 200-mg capsules AM,
3 × 200-mg capsules PM daily p.o.
|
3 million IU 3 times weekly s.c.
|
|
>75 kg
|
3 × 200-mg capsules AM,
3 × 200-mg capsules PM daily p.o.
|
3 million IU 3 times weekly s.c.
|
REBETOL may be administered without regard to food, but should be administered
in a consistent manner. (See CLINICAL
PHARMACOLOGY .)
Dose Modifications (TABLE 7)
In clinical trials, approximately 26% of patients required modification
of their dose of REBETOL Capsules, INTRON A Injection, or both agents.
If severe adverse reactions or laboratory abnormalities develop during
combination REBETOL/INTRONA therapy, the dose should be modified, or discontinued
if appropriate, until the adverse reactions abate. If intolerance persists
after dose adjustment, REBETOL/INTRON A therapy should be discontinued.
REBETOL/INTRON A therapy should be administered with caution to patients
with pre-existing cardiac disease. Patients should be assessed before
commencement of therapy and should be appropriately monitored during therapy.
If there is any deterioration of cardiovascular status, therapy should
be stopped. (See WARNINGS.)
For patients with a history of stable cardiovascular disease, a permanent
dose reduction is required if the hemoglobin decreases by ≥2 g/dL
during any 4-week period. In addition, for these cardiac history patients,
if the hemoglobin remains <12 g/dL after 4 weeks on a reduced dose,
the patient should discontinue combination REBETOL/INTRON A therapy.
It is recommended that a patient whose hemoglobin level falls below 10
g/dL have his/her REBETOL dose reduced to 600 mg daily (1 × 200-mg capsule
AM, 2 × 200-mg capsules PM). A patient whose hemoglobin level falls below
8.5 g/dL should be permanently discontinued from REBETOL/INTRON A therapy
(See WARNINGS .)
It is recommended that a patient who experiences moderate depression
(persistent low mood, loss of interest, poor self image, and/or hopelessness)
have his/her INTRON A dose temporarily reduced and/or be considered for
medical therapy. A patient experiencing severe depression or suicidal
ideation/attempt should be discontinued from REBETOL/INTRON A therapy
and followed closely with appropriate medical management. (See WARNINGS
.)
TABLE 7. Guidelines for Dose Modifications
|
|
Dose Reduction *
REBETOL - 600 mg daily
INTRON A - 1.5 million IU TIW |
Permanent Discontinuation
of Treatment
REBETOL and INTRON A |
|
Hemoglobin
|
<10 g/dL (REBETOL)
Cardiac History Patients Only.
≥2 g/dL decrease during any
4-week period during treatment
(REBETOL/INTRON A) |
<8.5 g/dL
Cardiac History Patients Only.
<12 g/dL after 4 weeks of
dose reduction |
|
White blood count
|
<1.5 × 10 9 /L (INTRON A) |
<1.0 × 10 9 /L |
|
Neutrophil count
|
<0.75 × 10 9 /L (INTRON A) |
<0.5 × 10 9 /L |
|
Platelet count
|
<50 × 10 9 /L (INTRON A) |
<25 × 10 9 /L |
|
*Study medication to be dose reduced is shown in
parenthesis.
|
Administration of INTRON A Injection
At the discretion of the physician, the patient may self-administer the
INTRON A. (See illustrated MEDICATION GUIDE for instructions.)
The INTRON A Injection is supplied as a clear and colorless solution.
The appropriate INTRON A dose should be withdrawn from the vial or set
on the multidose pen and injected subcutaneously. After administration
of INTRON A Injection, it is essential to follow the procedure for proper
disposal of syringes and needles. (See MEDICATION GUIDE for detailed
instructions.)
TABLE 7. Guidelines for Dose Modifications
|
|
Dose Reduction *
REBETOL - 600 mg daily
INTRON A - 1.5 million IU TIW |
Permanent Discontinuation
of Treatment
REBETOL and INTRON A |
|
Hemoglobin
|
<10 g/dL (REBETOL)
Cardiac History Patients Only.
≥2 g/dL decrease during any
4-week period during treatment
(REBETOL/INTRON A) |
<8.5 g/dL
Cardiac History Patients Only.
<12 g/dL after 4 weeks of
dose reduction |
|
White blood count
|
<1.5 × 10 9 /L (INTRON A) |
<1.0 × 10 9 /L |
|
Neutrophil count
|
<0.75 × 10 9 /L (INTRON A) |
<0.5 × 10 9 /L |
|
Platelet count
|
<50 × 10 9 /L (INTRON A) |
<25 × 10 9 /L |
|
*Study medication to be dose reduced is shown in
parenthesis.
|
Parenteral drug products should be inspected visually for particulate
matter and discoloration prior to administration, whenever solution and
container permit. INTRON A Injection may be administered using either
sterilized glass or plastic disposable syringes.
Stability INTRON A Injection provided in vials is
stable at 35°C (95°F) for up to 7 days and at 30°C (86°F) for up to 14
days. INTRON A Injection provided in a multidose pen is stable at 30°C
(86°F) for up to 2 days. The solution is clear and colorless.
HOW SUPPLIED
REBETOL 200-mg Capsules are white, opaque capsules with REBETOL, 200
mg, and the Schering Corporation logo imprinted on the capsule shell;
the capsules are packaged in a bottle.
INTRON A Injection is a clear, colorless solution packaged in single-dose
and multidose vials, and a multidose pen.
INTRON A Injection and REBETOL Capsules are available in the following
combination package presentations:
|
|
Each REBETRON Combination Package Consists
of:
|
|
|
For Patients
≤75 kg
|
A box containing 6 vials of INTRON A Injection
(3 million IU in 0.5 mL per vial), 6 syringes,
alcohol swabs, and one bottle containg 70
REBETOL Capsules.
|
(NDC 0085-1241-02)
|
|
One 18 million IU multidose vial of INTRON
A
Injection (22.8 million IU per 3.8 mL; 3 million
IU/0.5 mL), 6 syringes, alcohol swabs, and
one bottle containing 70 REBETOL Capsules.
|
(NDC 0085-1236-02)
|
|
One 18 million IU INTRON A Injection multidose
pen (22.5 million IU per 1.5 mL; 3 million IU/0.2
mL), 6 disposable needles, alcohol swabs, and
one bottle containing 70 REBETOL Capsules.
|
(NDC 0085-1258-02)
|
|
For Patients
>75 kg
|
A box containing 6 vials of INTRON A Injection
(3 million IU in 0.5 mL per vial), 6 syringes,
alcohol swabs, and one bottle containing 84
REBETOL Capsules.
|
(NDC 0085-1241-01)
|
|
One 18 million IU multidose vial of INTRON
A
Injection (22.8 million IU per 3.8 mL; 3 million
IU/0.5 mL), 6 syringes, alcohol swabs, and
one bottle containing 84 REBETOL Capsules.
|
(NDC 0085-1236-01)
|
|
One 18 million IU INTRON A Injection multidose
pen (22.5 million IU per 1.5 mL; 3 million IU/0.2
mL), 6 disposable needles, alcohol swabs, and
one bottle containing 84 REBETOL Capsules.
|
(NDC 0085-1258-01)
|
|
For REBETOL
Dose Reduction
|
A box containing 6 vials of INTRON A Injection
(3 million IU in 0.5 mL per vial), 6 syringes,
alcohol swabs, and one bottle containing 42
REBETOL Capsules.
|
(NDC 0085-1241-03)
|
|
One 18 million IU multidose of INTRON A
Injection (22.8 million IU per 3.8 mL; 3 million
IU/0.5 mL), 6 syringes, alcohol swabs, and
one bottle containing 42 REBETOL Capsules.
|
(NDC 0085-1236-03)
|
|
One 18 million IU INTRON A Injection multidose
pen (22.5 million IU per 1.5 mL; 3 million IU/0.2
mL), 6 disposable needles, alcohol swabs, and
one bottle containing 42 REBETOL Capsules.
|
(NDC 0085-1258-03)
|
STORAGE CONDITIONS
Store the REBETOL Capsules plus INTRON A Injection combination package
refrigerated between 2° and 8°C (36° and 46°F).
When separated, the individual bottle of REBETOL Capsules should be
stored refrigerated between 2° and 8°C (36° and 46°F) or at 25° (77°F);
excursions are permitted between 15° and 30°C (59° and 86°F).
When separated, the individuals vials of INTRON A Injection and the
INTRON A multidose pen should be stored refrigerated between 2° and 8°C
(36° and 46°F).
Schering Corporation
Kenilworth, NJ 07033 USA
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