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 Indications, Dosage, Storage, Stability - Ribavirin
Rebetron Indications, Dosage, Storage, Stability - Ribavirin
INDICATIONS
AND USAGE
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 inter-feron 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
|
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
|
|
-Responder1
|
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
|
|
-Improvement2
|
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 ³
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 labora-tory 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
|
|
|
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
|
|
—Responder1
|
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
|
|
—Improvement2
|
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 population.
|
TABLE 6. Recommended Dosing
|
|
Body weight
|
REBETOL Capsules
|
INTRON A Injection
|
|
£ 75 kg
|
2 x 200-mg capsules AM,
3 x 200-mg capsules PM daily p.o.
|
3 million IU 3 times weekly s.c.
|
|
³ 75 kg
|
3 x 200-mg capsules AM,
3 x 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/INTRON A 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 preexisting 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 ³
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 x 200-mg
capsule AM, 2 x 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 REBETOL 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 x 109/L (INTRON A)
|
<1.0 x 109/L
|
|
Neutrophil count
|
<0.75 x 109/L (INTRON A)
|
<0.5 x 109/L
|
|
Platelet count
|
<50 x 109/L (INTRON A)
|
<25 x 109/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. The INTRON A Injection
supplied with the B-D Safety LokTM syringes contain a plastic sleeve
to be pulled over the needle after use. The syringe locks with an audible click
when the green stripe on the safety sleeve covers the red stripe on the needle.
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.)
|
Vial/Pen Label Strength
|
Fill Volume
|
Concentration
|
|
3 million IU vial
|
0.5 mL
|
3 million IU/0.5 mL
|
|
18 million IU multidose vial†
|
3.8 mL
|
3 million IU/0.5 mL
|
|
18 million IU multidose pen††
|
1.5 mL
|
3 million IU/0.2 mL
|
†This is a multidose vial which contains a total
of 22.8 million IU of interferon alfa-2b, recombinant per 3.8 mL in order to
provide the delivery of six 0.5-mL doses, each containing 3 million IU of interferon
alfa-2b, recombinant (for a label strength of 18 million IU).
††This is a multidose pen which contains a total
of 22.5 million IU of interferon alfa-2b, recombinant per 1.5 mL in order to
provide the delivery of six 0.2-mL doses, each containing 3 million IU of interferon
alfa-2b, recombinant (for a label strength of 18 million IU).
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 £ kg
|
A box containing 6 vials of INTRON A Injection (3 million
IU in 0.5 mL per vial), 6 B-D Safety LokTM syringes with a
safety sleeve, alcohol swabs, and one bottle containing 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 B-D Safety LokTM
syringes with a safety sleeve, 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 >kg
|
A box containing 6 vials of INTRON A Injection (3 million
IU in 0.5 mL per vial), 6 B-D Safety LokTM syringes with a
safety sleeve, 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 B-D Safety LokTM
syringes with a safety sleeve, 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 B-D Safety LokTM syringes with a
safety sleeve, alcohol swabs, and one bottle containing 42 REBETOL Capsules.
|
(NDC 0085-1241-03)
|
|
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 B-D Safety LokTM
syringes with a safety sleeve, 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°C (77°F);
excursions are permitted between 15° and 30°C (59° and 86°F).
When separated, the individual 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,U.S.
Patents 4,530,901 & 4,211,771 25272900T,Copyright © 1998, Schering
Corporation. All rights reserved. Rev. 6/01, Copyright
© 2001, Schering Corporation, Kenilworth, NJ 07033. All rights reserved.
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