**F-21617679**

**PRODUCT**

**INFORMATION**

### REBETRON™

**Combination Therapy**

***containing***

**REBETOL^®^ (ribavirin, USP) Capsules**

***and***

**INTRON^®^ A (interferon alfa-2b, recombinant) Injection**

CONTRAINDICATIONS AND WARNINGS

Combination REBETOL/INTRON A therapy is contraindicated in women who are
pregnant and in the male partners of women who are pregnant. Extreme
care must be taken to avoid pregnancy during therapy and for 6 months
after completion of treatment in female patients, and in female partners
of male patients who are taking combination REBETOL/INTRON A therapy.
Women of childbearing potential and men must use two reliable forms of
effective contraception during treatment and during the 6-month
posttreatment follow-up period. Significant teratogenic and/or
embryocidal effects have been demonstrated for ribavirin in all animal
species studied. See CONTRAINDICATIONS and WARNINGS.

REBETOL monotherapy is not effective for the treatment of chronic
hepatitis C and should not be used for this indication. See WARNINGS.

### DESCRIPTION

***REBETOL^®^***

REBETOL is Schering Corporation's brand name for ribavirin, a nucleoside
analog with antiviral activity. The chemical name of ribavirin is
1-ß-D-ribofuranosyl-1*H*-1,2,4-triazole-3-carboxamide and has the
following structural formula:

![](media/image1.wmf)

Ribavirin is a white, crystalline powder. It is freely soluble in water
and slightly soluble in anhydrous alcohol. The empirical formula is
C~8~H~12~N~4~O~5~ and the molecular weight is 244.21.

REBETOL Capsules consist of a white powder in a white, opaque, gelatin
capsule. Each capsule contains 200 mg ribavirin and the inactive
ingredients microcrystalline cellulose, lactose monohydrate,
croscarmellose sodium, and magnesium stearate. The capsule shell
consists of gelatin, sodium lauryl sulfate, silicon dioxide, and
titanium dioxide. The capsule is printed with edible blue pharmaceutical
ink which is made of shellac, anhydrous ethyl alcohol, isopropyl
alcohol, n-butyl alcohol, propylene glycol, ammonium hydroxide, and FD&C
Blue #2 aluminum lake.

***Intron^®^ A***

INTRON A is Schering Corporation's brand name for interferon alfa-2b,
recombinant, a purified, sterile, recombinant interferon product.

Interferon alfa-2b, recombinant has been classified as an alpha
interferon and is a water-soluble protein composed of 165 amino acids
with a molecular weight of 19,271 daltons produced by recombinant DNA
techniques. It is obtained from the bacterial fermentation of a strain
of *Escherichia coli* bearing a genetically engineered plasmid
containing an interferon alfa-2b gene from human leukocytes. The
fermentation is carried out in a defined nutrient medium containing the
antibiotic tetracycline hydrochloride at a concentration of 5 to 10
mg/L; the presence of this antibiotic is not detectable in the final
product.

INTRON A Injection is a clear, colorless solution. The 3 million IU vial
of INTRON A Injection contains 3 million IU of interferon alfa-2b,
recombinant per 0.5 mL. The 18 million IU multidose vial of INTRON A
Injection contains a total of 22.8 million IU of interferon alfa-2b,
recombinant per 3.8 mL (3 million IU/0.5 mL) in order to provide the
delivery of six 0.5 mL doses, each containing 3 million IU of INTRON  A
(for a label strength of 18 million IU). The 18 million IU INTRON A
Injection multidose pen contains a total of 22.5 million IU of
interferon alfa-2b, recombinant per 1.5 mL (3 million IU/0.2 mL) in
order to provide the delivery of six 0.2-mL doses, each containing 3
million IU of Intron A (for a label strength of 18 million IU). Each mL
also contains 7.5 mg sodium chloride, 1.8 mg sodium phosphate dibasic,
1.3 mg sodium phosphate monobasic, 0.1 mg edetate disodium, 0.1 mg
polysorbate 80, and 1.5 mg m-cresol as a preservative.

Based on the specific activity of approximately 2.6 x 10^8^ IU/mg
protein as measured by HPLC assay, the corresponding quantities of
interferon alfa-2b, recombinant in the vials and pen described above are
approximately 0.012 mg, 0.088 mg, and 0.087 mg protein, respectively.

**Mechanism of Action**

*Ribavirin/Interferon alfa-2b, recombinant* The mechanism of inhibition
of hepatitis C virus (HCV) RNA by combination therapy with REBETOL and
INTRON A has not been established.

### CLINICAL PHARMACOLOGY

**Pharmacokinetics**

*Interferon alfa-2b, recombinant* Single- and multiple-dose
pharmacokinetic properties of INTRON A (interferon alfa-2b, recombinant)
are summarized in **Table 1**. Following a single 3 million IU (MIU)
subcutaneous dose in 12 patients with chronic hepatitis C, mean (% CV\*)
serum concentrations peaked at 7 (44%) hours. Following 4 weeks of
subcutaneous dosing with 3 MIU three times a week (TIW), interferon
serum concentrations were undetectable predose. However, a twofold
increase in bioavailability was noted upon multiple dosing of
interferon; the reason for this is unknown. Mean half-life values
following single- and multiple-dose administrations were 6.8 (24%) hours
and 6.5 (29%) hours, respectively.

*Ribavirin* Single- and multiple-dose pharmacokinetic properties in
adults with chronic hepatitis C are summarized in **Table 1**. Ribavirin
was rapidly and extensively absorbed following oral administration.
However, due to first-pass metabolism, the absolute bioavailability
averaged 64% (44%). There was a linear relationship between dose and
AUC~tf~ (AUC from time zero to last measurable concentration) following
single doses of 200-1200 mg ribavirin. The relationship between dose and
C~max~ was curvilinear, tending to asymptote above single doses of
400-600 mg.

Upon multiple oral dosing, based on AUC12~hr~, a sixfold accumulation of
ribavirin was observed in plasma. Following oral dosing with 600 mg BID,
steady-state was reached by approximately 4 weeks, with mean
steady-state plasma concentrations of 2200 (37%) ng/mL. Upon
discontinuation of dosing, the mean half-life was 298 (30%) hours, which
probably reflects slow elimination from nonplasma compartments.

*Effect of Food on Absorption of Ribavirin* Both AUC~tf~ and C~max~
increased by 70% when Rebetol Capsules were administered with a high-fat
meal (841 kcal, 53.8 g fat, 31.6 g protein, and 57.4 g carbohydrate) in
a single-dose pharmacokinetic study. There are insufficient data to
address the clinical relevance of these results. Clinical efficacy
studies were conducted without instructions with respect to food
consumption. (See **DOSAGE AND ADMINISTRATION**.)

*Effect of Antacid on Absorption of Ribavirin* Coadministration with an
antacid containing magnesium, aluminum, and simethicone (Mylanta^^)
resulted in a 14% decrease in mean ribavirin AUC~tf~. The clinical
relevance of results from this single-dose study is unknown.

+---------------------+-----------+------------+-----------+----------+
| **Table 1. Mean (%  |           |            |           |          |
| CV) Pharmacokinetic |           |            |           |          |
| Parameters for      |           |            |           |          |
| Intron A and        |           |            |           |          |
| Rebetol when        |           |            |           |          |
| administered        |           |            |           |          |
| individually to     |           |            |           |          |
| Adults with Chronic |           |            |           |          |
| Hepatitis C**       |           |            |           |          |
+---------------------+-----------+------------+-----------+----------+
| Parameter           | Intron A  |            | Rebetol   |          |
|                     | (N=12)    |            | (N=12)    |          |
+---------------------+-----------+------------+-----------+----------+
|                     | Single    | Multiple   | Single    | Multiple |
|                     | Dose      | Dose       | Dose      | Dose     |
|                     |           |            |           |          |
|                     | 3 MIU     | 3 MIU tiw  | 600 mg    | 600 mg   |
|                     |           |            |           | bid      |
+---------------------+-----------+------------+-----------+----------+
| T ~max~ (hr)        | 7 (44)    | 5 (37)     | 1.7 (46)  | 3 (60)   |
|                     |           |            | \*\*\*    |          |
+---------------------+-----------+------------+-----------+----------+
| C~max~ \*           | 13.9 (32) | 29.7 (33)  | 782 (37)  | 3680     |
|                     |           |            |           | (85)     |
| AUC~tf~ \*\*        | 142 (43)  | 333 (39)   | 13400     |          |
|                     |           |            | (48)      | 228000   |
|                     |           |            |           | (25)     |
+---------------------+-----------+------------+-----------+----------+
| T~1/2~ (hr)         | 6.8 (24)  | 6.5 (29)   | 43.6 (47) | 298 (30) |
+---------------------+-----------+------------+-----------+----------+
| Apparent Volume of  |           |            | 2825      |          |
| Distribution (L)    |           |            | (9)^†^    |          |
+---------------------+-----------+------------+-----------+----------+
| Apparent Clearance  | 14.3 (17) |            | 38.2 (40) |          |
| (L/hr)              |           |            |           |          |
+---------------------+-----------+------------+-----------+----------+
| Absolute            |           |            | 64%       |          |
| Bioavailability     |           |            | (44)^††^  |          |
+---------------------+-----------+------------+-----------+----------+

\* IU/mL for Intron A and ng/mL for Rebetol

\*\* IU.hr/mL for Intron A and ng.hr/mL for Rebetol

^†^ data obtained from a single-dose pharmacokinetic study using ^14^C
labeled ribavirin; N = 5

^††^ N = 6

\*\*\* n = 11

Ribavirin transport into nonplasma compartments has been most
extensively studied in red blood cells, and has been identified to be
primarily via an e~s~-type equilibrative nucleoside transporter. This
type of transporter is present on virtually all cell types and may
account for the extensive volume of distribution. Ribavirin does not
bind to plasma proteins.

Ribavirin has two pathways of metabolism: (i) a reversible
phosphorylation pathway in nucleated cells; and (ii) a degradative
pathway involving deribosylation and amide hydrolysis to yield a
triazole carboxylic acid metabolite. Ribavirin and its triazole
carboxamide and triazole carboxylic acid metabolites are excreted
renally. After oral administration of 600 mg of ^14^C-ribavirin,
approximately 61% and 12% of the radioactivity was eliminated in the
urine and feces, respectively, in 336 hours. Unchanged ribavirin
accounted for 17% of the administered dose.

Results of *in vitro* studies using both human and rat liver microsome
preparations indicated little or no cytochrome P450 enzyme-mediated
metabolism of ribavirin, with minimal potential for P450 enzyme-based
drug interactions.

No pharmacokinetic interactions were noted between INTRON A Injection
and REBETOL Capsules in a multiple-dose pharmacokinetic study.

***Special Populations***

*Renal Dysfunction* The pharmacokinetics of ribavirin were assessed
after administration of a single oral dose (400 mg) of ribavirin to
subjects with varying degrees of renal dysfunction. The mean AUC~tf~
value was threefold greater in subjects with creatinine clearance values
between 10 to 30 mL/min when compared to control subjects (creatinine
clearance \>90 mL/min). This appears to be due to reduction of apparent
clearance in these patients. Ribavirin was not removed by hemodialysis.
Rebetol is not recommended for patients with severe renal impairment
(see **Warnings**).

*Hepatic Dysfunction* The effect of hepatic dysfunction was assessed
after a single oral dose of ribavirin (600 mg). The mean AUC~tf~ values
were not significantly different in subjects with mild, moderate, or
severe hepatic dysfunction (Child-Pugh Classification A, B, or C), when
compared to control subjects. However, the mean C~max~ values increased
with severity of hepatic dysfunction and was twofold greater in subjects
with severe hepatic dysfunction when compared to control subjects.

*Pediatric Patients* Pharmacokinetic evaluations for pediatric subjects
have not been performed.

*Elderly Patients* Pharmacokinetic evaluations for elderly subjects have
not been performed.

*Gender* There were no clinically significant pharmacokinetic
differences noted in a single-dose study of eighteen male and eighteen
female subjects.

\* ***In this section of the label, numbers in parenthesis indicate %
coefficient of variation.***

### 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 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     |      |        |       | I      |        |       |
|         | Study  |      |        |       | nterna |        |       |
|         |        |      |        |       | tional |        |       |
|         |        |      |        |       | Study  |        |       |
+---------+--------+------+--------+-------+--------+--------+-------+
|         | 24     |      | 48     |       | 24     | 48     |       |
|         | weeks  |      | weeks  |       | weeks  | weeks  |       |
|         | of     |      | of     |       | of     | of     |       |
|         | tre    |      | tre    |       | tre    | tre    |       |
|         | atment |      | atment |       | atment | atment |       |
+---------+--------+------+--------+-------+--------+--------+-------+
|         | **     | **IN | **     | **I   | **     | **     | **I   |
|         | INTRON | TRON | INTRON | NTRON | INTRON | INTRON | NTRON |
|         | A plus | A    | A plus | A     | A plus | A plus | A     |
|         | REB    | pl   | REB    | p     | REB    | REB    | p     |
|         | ETOL** | us** | ETOL** | lus** | ETOL** | ETOL** | lus** |
|         |        |      |        |       |        |        |       |
|         | **(N=  | **P  | **(N=  | *     | **(N=  | **(N=  | *     |
|         | 228)** | lace | 228)** | *Plac | 265)** | 268)** | *Plac |
|         |        | bo** |        | ebo** |        |        | ebo** |
|         |        |      |        |       |        |        |       |
|         |        | **(  |        | *     |        |        | *     |
|         |        | N=23 |        | *(N=2 |        |        | *(N=2 |
|         |        | 1)** |        | 25)** |        |        | 66)** |
+---------+--------+------+--------+-------+--------+--------+-------+
| **Vi    | 65(29) | 1    | 85(37) | 2     | 86(32) | 1      | 4     |
| rologic |        | 3(6) |        | 7(12) |        | 13(42) | 6(17) |
| Res     | 1      |      | 1      |       | 1      |        |       |
| ponse** | 47(64) | 194  | 10(48) | 16    | 58(60) | 1      | 19    |
|         |        | (84) |        | 8(75) |        | 20(45) | 6(74) |
| -Respo  | 16(7)  |      | 33(14) |       | 21(8)  |        |       |
| nder^1^ |        | 24   |        | 3     |        | 35(13) | 24(9) |
|         |        | (10) |        | 0(13) |        |        |       |
| -Nonre  |        |      |        |       |        |        |       |
| sponder |        |      |        |       |        |        |       |
|         |        |      |        |       |        |        |       |
| -       |        |      |        |       |        |        |       |
| Missing |        |      |        |       |        |        |       |
| Data    |        |      |        |       |        |        |       |
+---------+--------+------+--------+-------+--------+--------+-------+
| **His   | 1      | 77   | 96(42) | 6     | 1      | 1      | 6     |
| tologic | 02(45) | (33) |        | 5(29) | 03(39) | 02(38) | 9(26) |
| Res     |        |      | 61(27) |       |        |        |       |
| ponse** | 77(34) | 99   |        | 9     | 85(32) | 58(22) | 11    |
|         |        | (43) | 71(31) | 3(41) |        |        | 1(41) |
| -       | 49(21) |      |        |       | 77(29) | 1      |       |
| Improve |        | 55   |        | 6     |        | 08(40) | 8     |
| ment^2^ |        | (24) |        | 7(30) |        |        | 6(32) |
|         |        |      |        |       |        |        |       |
| -No     |        |      |        |       |        |        |       |
| impr    |        |      |        |       |        |        |       |
| ovement |        |      |        |       |        |        |       |
|         |        |      |        |       |        |        |       |
| -       |        |      |        |       |        |        |       |
| Missing |        |      |        |       |        |        |       |
| Data    |        |      |        |       |        |        |       |
+---------+--------+------+--------+-------+--------+--------+-------+

\* 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 [\>]{.underline}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 |          | Inter    |          |
|                       |          |          | national |          |
|                       |          |          | Study    |          |
+-----------------------+----------+----------+----------+----------+
|                       | **INTRON | **INTRON | **INTRON | **INTRON |
|                       | A plus   | A plus** | A plus   | A plus** |
|                       | R        |          | R        |          |
|                       | EBETOL** | **P      | EBETOL** | **P      |
|                       |          | lacebo** |          | lacebo** |
|                       | **N=77** |          | **N=96** |          |
|                       |          | **N=76** |          | **N=96** |
+-----------------------+----------+----------+----------+----------+
| **Virologic           | 33(43)   | 3(4)     | 46(48)   | 5(5)     |
| Response**            |          |          |          |          |
|                       | 36(47)   | 66(87)   | 45(47)   | 91(95)   |
| -Responder^1^         |          |          |          |          |
|                       | 8(10)    | 7(9)     | 5(5)     | 0(0)     |
| -Nonresponder         |          |          |          |          |
|                       |          |          |          |          |
| -Missing Data         |          |          |          |          |
+-----------------------+----------+----------+----------+----------+
| **Histologic          | 38(49)   | 27(36)   | 49(51)   | 30(31)   |
| Response**            |          |          |          |          |
|                       | 23(30)   | 37(49)   | 29(30)   | 44(46)   |
| -Improvement^2^       |          |          |          |          |
|                       | 16(21)   | 12(16)   | 18(19)   | 22(23)   |
| -No improvement       |          |          |          |          |
|                       |          |          |          |          |
| -Missing Data         |          |          |          |          |
+-----------------------+----------+----------+----------+----------+

\* 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 [\>]{.underline}2
points.

Virologic and histologic responses were similar among male and female
patients in both the previously untreated and relapse studies.

### CONTRAINDICATIONS

Combination REBETOL/INTRON A therapy must not be used by women who are
pregnant or by men whose female partners are pregnant. Extreme care must
be taken to avoid pregnancy in female patients and in female partners of
male patients taking combination REBETOL/INTRON A therapy. Combination
REBETOL/INTRON A therapy should not be initiated until a report of a
negative pregnancy test has been obtained immediately prior to
initiation of therapy. Women of childbearing potential and men must use
two forms of effective contraception during treatment and during the 6
months after treatment has been concluded. Significant teratogenic
and/or embryocidal effects have been demonstrated for ribavirin in all
animal species in which adequate studies have been conducted. These
effects occurred at doses as low as one twentieth of the recommended
human dose of REBETOL Capsules. If pregnancy occurs in a patient or
partner of a patient during treatment or during the 6 months after
treatment stops, physicians are encouraged to report such cases by
calling (800) 727-7064. **See boxed CONTRAINDICATIONS AND WARNINGS. See
WARNINGS.**

REBETOL Capsules in combination with INTRON A Injection is
contraindicated in patients with a history of hypersensitivity to
ribavirin and/or alpha interferon or any component of the capsule and/or
injection.

Patients with autoimmune hepatitis must not be treated with combination
REBETOL/INTRON A therapy.

### WARNINGS

**Pregnancy**

**Category X, may cause birth defects. See boxed CONTRAINDICATIONS AND
WARNINGS. See CONTRAINDICATIONS.**

**Anemia**

**HEMOLYTIC Anemia (hemoglobin \<10 g/dl) was observed in APPROXIMATELY
10% of REBETOL/INTRON A-treated patients in clinical trials (see adverse
reactions laboratory values - *hemoglobin*). anemia occurred within 1 -
2 weeks of initiation of ribavirin therapy. because of this initial
acute drop in hemoglobin, it is advised that complete blood counts (cbc)
should be obtained pretreatment and at week 2 and week 4 of therapy or
more frequently if clinically indicated. Patients should then be
followed as clinically appropriate.**

The anemia associated with REBETOL/INTRON A therapy may result in
deterioration of cardiac function and/or exacerbation of the symptoms of
coronary disease. Patients should be assessed before initiation of
therapy and should be appropriately monitored during therapy. If there
is any deterioration of cardiovascular status, therapy should be
suspended or discontinued. (See **DOSAGE AND ADMINISTRATION.**) Because
cardiac disease may be worsened by drug induced anemia, patients with a
history of significant or unstable cardiac disease should not use
combination REBETOL/INTRON A therapy. (See **ADVERSE REACTIONS.**)

Similarly, patients with hemoglobinopathies (eg, thalassemia,
sickle-cell anemia) should not be treated with combination
REBETOL/INTRON A therapy.

**Psychiatric**

**Severe psychiatric adverse events, including depression, psychoses,
aggressive behavior, hallucinations, violent behavior (suicidal
ideation, suicidal attempts, suicides) and rare instances of homicidal
ideation have occurred during combination Rebetol/Intron A therapy, both
in patients with and without a previous psychiatric disorder.
Rebetol/Intron A therapy should be used with extreme caution in patients
with a history of pre-existing psychiatric disorders, and all patients
should be carefully monitored for evidence of depression and other
psychiatric symptoms. Suspension of Rebetol/Intron A therapy should be
considered if psychiatric intervention and/or dose reduction is
unsuccessful in controlling psychiatric symptoms. In severe cases,
therapy should be stopped immediately and psychiatric intervention
sought.** (See **ADVERSE REACTIONS**.)

**Pulmonary**

Pulmonary symptoms, including dyspnea, pulmonary infiltrates,
pneumonitis and pneumonia, including fatality, have been reported during
therapy with REBETOL/INTRON A. If there is evidence of pulmonary
infiltrates or pulmonary function impairment, the patient should be
closely monitored, and, if appropriate, combination REBETOL/INTRON A
treatment should be discontinued.

**Other**

-   REBETOL Capsule monotherapy is not effective for the treatment of
    chronic hepatitis C and should not be used for this indication.

-   Fatal and nonfatal pancreatitis has been observed in patients
    treated with REBETOL/INTRON A therapy. REBETOL/INTRON A therapy
    should be suspended in patients with signs and symptoms of
    pancreatitis and discontinued in patients with confirmed
    pancreatitis.

-   Combination REBETOL/INTRON A therapy should be used with caution in
    patients with creatinine clearance \<50 mL/min.

-   Diabetes mellitus and hyperglycemia have been observed in patients
    treated with INTRON A.

-   Ophthalmologic disorders have been reported with treatment with
    alpha interferons (including INTRON A therapy). Investigators using
    alpha interferons have reported the occurrence of retinal
    hemorrhages, cotton wool spots, and retinal artery or vein
    obstruction in rare instances. Any patient complaining of loss of
    visual acuity or visual field should have an eye examination.
    Because these ocular events may occur in conjunction with other
    disease states, a visual exam prior to initiation of combination
    REBETOL/INTRON A therapy is recommended in patients with diabetes
    mellitus or hypertension.

•Acute serious hypersensitivity reactions (eg, urticaria, angioedema,
bronchoconstriction, anaphylaxis) have been observed in INTRON A-treated
patients; if such an acute reaction develops, combination REBETOL/INTRON
A therapy should be discontinued immediately and appropriate medical
therapy instituted. •Combination REBETOL/INTRON A therapy should be
discontinued for patients developing thyroid abnormalities during
treatment whose thyroid function cannot be controlled by medication.

### PRECAUTIONS

Exacerbation of autoimmune disease has been reported in patients
receiving alpha interferon therapy (including INTRON A therapy).
REBETOL/INTRON A therapy should be used with caution in patients with
other autoimmune disorders.

There have been reports of interferon, including INTRON A (interferon
alfa-2b, recombinant) exacerbating pre-existing psoriasis; therefore,
combination REBETOL/INTRON A therapy should be used in these patients
only if the potential benefit justifies the potential risk.

The safety and efficacy of REBETOL/INTRON A therapy has not been
established in liver or other organ transplant patients, decompensated
hepatitis C patients, patients who are nonresponders to interferon
therapy, or patients coinfected with HBV or HIV.

The safety and efficacy of REBETOL Capsule monotherapy for the treatment
of HIV infection, adenovirus, early RSV infection, parainfluenza, or
influenza have not been established and REBETOL Capsules should not be
used for these indications.

There is no information regarding the use of REBETOL Capsules with other
interferons.

**Information for Patients** Combination REBETOL/INTRON A therapy must
not be used by women who are pregnant or by men whose female partners
are pregnant. Extreme care must be taken to avoid pregnancy in female
patients and in female partners of male patients taking combination
REBETOL/INTRON A therapy. Combination REBETOL/INTRON A therapy should
not be initiated until a report of a negative pregnancy test has been
obtained immediately prior to initiation of therapy. Patients must
perform a pregnancy test monthly during therapy and for 6 months
posttherapy. Women of childbearing potential must be counseled about use
of effective contraception (two reliable forms) prior to initiating
therapy. Patients (male and female) must be advised of the
teratogenic/embryocidal risks and must be instructed to practice
effective contraception during combination REBETOL/INTRON A therapy and
for 6 months posttherapy. Patients (male and female) should be advised
to notify the physician immediately in the event of a pregnancy. (See
**CONTRAINDICATIONS.**)

If pregnancy does occur during treatment or during 6 months posttherapy,
the patient must be advised of the significant teratogenic risk of
REBETOL therapy to the fetus. Patients, or partners of patients, should
immediately report any pregnancy that occurs during treatment or within
6 months after treatment cessation to their physician. Physicians are
encouraged to report such cases by calling (800) 727-7064.

Patients receiving combination REBETOL/INTRON A treatment should be
directed in its appropriate use, informed of the benefits and risks
associated with treatment, and referred to the patient **MEDICATION
GUIDE**. There are no data evaluating whether REBETOL/INTRON A therapy
will prevent transmission of infection to others. Also, it is not known
if treatment with REBETOL/INTRON A therapy will cure hepatitis C or
prevent cirrhosis, liver failure, or liver cancer that may be the result
of infection with the hepatitis C virus.

If home use is prescribed, a puncture-resistant container for the
disposal of used syringes and needles should be supplied to the patient.
Patients should be thoroughly instructed in the importance of proper
disposal and cautioned against any reuse of needles and syringes. The
full container should be disposed of according to the directions
provided by the physician (see **MEDICATION GUIDE**).

The most common adverse experiences occurring with combination
REBETOL/INTRON A therapy are \"flu-like\" symptoms, such as headache,
fatigue, myalgia, and fever (see **ADVERSE REACTIONS**) and appear to
decrease in severity as treatment continues. Some of these \"flu-like\"
symptoms may be minimized by bedtime administration of INTRON A therapy.
Antipyretics should be considered to prevent or partially alleviate the
fever and headache. Another common adverse experience associated with
INTRON A therapy is thinning of the hair.

Patients should be advised that laboratory evaluations are required
prior to starting therapy and periodically thereafter (see **Laboratory
Tests**). It is advised that patients be well hydrated, especially
during the initial stages of treatment.

.

**Laboratory Tests** The following laboratory tests are recommended for
all patients on combination REBETOL/INTRON A therapy, prior to beginning
treatment and then periodically thereafter.

> •Standard hematologic tests - including hemoglobin (pretreatment, week
> 2 and week 4 of therapy, and as clinically appropriate \[see
> **WARNINGS**\]), complete and differential white blood cell counts,
> and platelet count.
>
> •Blood chemistries - liver function tests and TSH.

•Pregnancy - including monthly monitoring for women of childbearing
potential.

**Carcinogenesis and Mutagenesis** Carcinogenicity studies with
interferon alfa-2b, recombinant have not been performed because
neutralizing activity appears in the serum after multiple dosing in all
of the animal species tested.

Adequate studies to assess the carcinogenic potential of ribavirin in
animals have not been conducted. However, ribavirin is a nucleoside
analog that has produced positive findings in multiple *in vitro* and
animal *in vivo* genotoxicity assays, and should be considered a
potential carcinogen. Further studies to assess the carcinogenic
potential of ribavirin in animals are ongoing.

Mutagenicity studies have demonstrated that interferon alfa-2b,
recombinant is not mutagenic. Ribavirin demonstrated increased
incidences of mutation and cell transformation in multiple genotoxicity
assays. Ribavirin was active in the Balb/3T3 *In Vitro* Cell
Transformation Assay. Mutagenic activity was observed in the mouse
lymphoma assay, and at doses of 20-200 mg/kg (estimated human equivalent
of 1.67 - 16.7 mg/kg, based on body surface area adjustment for a 60 kg
adult; 0.1 - 1 X the maximum recommended human 24-hour dose of
ribavirin) in a mouse micronucleus assay. A dominant lethal assay in
rats was negative, indicating that if mutations occurred in rats they
were not transmitted through male gametes.

**Impairment of Fertility** No reproductive toxicology studies have been
performed using interferon alfa-2b, recombinant in combination with
ribavirin. However, evidence provided below for interferon alfa-2b,
recombinant and ribavirin when administered alone indicate that both
agents have adverse effects on reproduction. It should be assumed that
the effects produced by either agent alone will also be caused by the
combination of the two agents. Interferons may impair human fertility.
In studies of interferon alfa-2b recombinant administration in nonhuman
primates, menstrual cycle abnormalities have been observed. Decreases in
serum estradiol and progesterone concentrations have been reported in
women treated with human leukocyte interferon. In addition, ribavirin
demonstrated significant embryocidal and/or teratogenic effects at doses
well below the recommended human dose in all animal species in which
adequate studies have been conducted.

Fertile women and partners of fertile women should not receive
combination REBETOL/INTRON A therapy unless the patient and his/her
partner are using effective contraception (two reliable forms). Based on
a multiple dose half-life (t~1/2~ ) of ribavirin of 12 days, effective
contraception must be utilized for 6 months posttherapy (eg, 15
half-lives of clearance for ribavirin).

Combination REBETOL/INTRON A therapy should be used with caution in
fertile men. In studies in mice to evaluate the time course and
reversibility of ribavirin-induced testicular degeneration at doses of
15 to 150 mg/kg/day (estimated human equivalent of 1.25 - 12.5
mg/kg/day, based on body surface area adjustment for a 60 kg adult;
0.1 - 0.8 X the maximum human 24-hour dose of ribavirin) administered
for 3 or 6 months, abnormalities in sperm occurred. Upon cessation of
treatment, essentially total recovery from ribavirin-induced testicular
toxicity was apparent within 1 or 2 spermatogenesis cycles.

**Animal Toxicology** Long-term studies in the mouse and rat (18 - 24
months; doses of 20 - 75 and 10 - 40 mg/kg/day, respectively \[estimated
human equivalent doses of 1.67 - 6.25 and 1.43 - 5.71 mg/kg/day,
respectively, based on body surface area adjustment for a 60 kg adult;
approximately 0.1 - 0.4 X the maximum human 24-hour dose of ribavirin\])
have demonstrated a relationship between chronic ribavirin exposure and
increased incidences of vascular lesions (microscopic hemorrhages) in
mice. In rats, retinal degeneration occurred in controls, but the
incidence was increased in ribavirin-treated rats.

**Pregnancy Category X (**see **CONTRAINDICATIONS)** Interferon alfa-2b,
recombinant has been shown to have abortifacient effects in *Macaca
mulatta* (rhesus monkeys) at 15 and 30 million IU/kg (estimated human
equivalent of 5 and 10 million IU/kg, based on body surface area
adjustment for a 60 kg adult). There are no adequate and well-controlled
studies in pregnant women.

Ribavirin produced significant embryocidal and/or teratogenic effects in
all animal species in which adequate studies have been conducted.
Malformations of the skull, palate, eye, jaw, limbs, skeleton, and
gastrointestinal tract were noted. The incidence and severity of
teratogenic effects increased with escalation of the drug dose. Survival
of fetuses and offspring was reduced. In conventional
embryotoxicity/teratogenicity studies in rats and rabbits, observed no
effect dose levels were well below those for proposed clinical use (0.3
mg/kg/day for both the rat and rabbit; approximately 0.06 X the
recommended human 24-hour dose of ribavirin). No maternal toxicity or
effects on offspring were observed in a peri/postnatal toxicity study in
rats dosed orally at up to 1 mg/kg/day (estimated human equivalent dose
of 0.17 mg/kg based on body surface area adjustment for a 60 kg adult;
approximately 0.01 X the maximum recommended human 24-hour dose of
ribavirin).

*Treatment and Posttreatment: Potential Risk to the Fetus* Ribavirin is
known to accumulate in intracellular components from where it is cleared
very slowly. It is not known whether ribavirin contained in sperm will
exert a potential teratogenic effect upon fertilization of the ova. In a
study in rats, it was concluded that dominant lethality was not induced
by ribavirin at doses up to 200 mg/kg for 5 days (estimated human
equivalent doses of 7.14 - 28.6 mg/kg, based on body surface area
adjustment for a 60 kg adult; up to 1.7 X the maximum recommended human
dose of ribavirin). However, because of the potential human teratogenic
effects of ribavirin, male patients should be advised to take every
precaution to avoid risk of pregnancy for their female partners.

Women of childbearing potential should not receive combination
REBETOL/INTRON A therapy unless they are using effective contraception
(two reliable forms) during the therapy period. In addition, effective
contraception should be utilized for 6 months posttherapy based on a
multiple dose half-life (t~1/2~ ) of ribavirin of 12 days.

Male patients and their female partners must practice effective
contraception (two reliable forms) during treatment with combination
REBETOL/INTRON A therapy and for the 6-month posttherapy period (eg, 15
half-lives for ribavirin clearance from the body).

If pregnancy occurs in a patient or partner of a patient during
treatment or during the 6 months after treatment cessation, physicians
are encouraged to report such cases by calling (800) 727-7064.

**Nursing Mothers** It is not known whether REBETOL and INTRON A are
excreted in human milk. However, studies in mice have shown that mouse
interferons are excreted into the milk. Because of the potential for
serious adverse reactions from the drugs in nursing infants, a decision
should be made whether to discontinue nursing or to discontinue
combination REBETOL/INTRON A therapy, taking into account the importance
of the therapy to the mother.

**Pediatric Use** Use of REBETOL/INTRON A combination therapy in
pediatric patients from 3 to 16 years of age is supported by
pharmacokinetic studies and evidence from ongoing open label studies in
this pediatric age group. Safety and efficacy results in a small subset
of patients who received a full 48 week course of therapy and completed
24 weeks of post-treatment follow-up are similar to the profile achieved
for adults given the recommended doses.

### 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,
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 style="width:100%;">
<colgroup>
<col style="width: 28%" />
<col style="width: 0%" />
<col style="width: 0%" />
<col style="width: 12%" />
<col style="width: 0%" />
<col style="width: 11%" />
<col style="width: 0%" />
<col style="width: 0%" />
<col style="width: 10%" />
<col style="width: 0%" />
<col style="width: 11%" />
<col style="width: 0%" />
<col style="width: 0%" />
<col style="width: 12%" />
<col style="width: 0%" />
<col style="width: 11%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="16"><strong>Table 4. Selected Treatment-Emergent Adverse
Events: Previously Untreated and Relapse Patients</strong></td>
</tr>
<tr class="even">
<td colspan="16">Percentage of Patients</td>
</tr>
<tr class="odd">
<td colspan="11">US Previously Untreated Study</td>
<td colspan="5">US Relapse Study</td>
</tr>
<tr class="even">
<td></td>
<td colspan="5">24 weeks of treatment</td>
<td colspan="5">48 weeks of treatment</td>
<td colspan="5">24 weeks of treatment</td>
</tr>
<tr class="odd">
<td colspan="2"><strong>Patients Reporting Adverse
Events</strong><sup>*</sup></td>
<td colspan="2"><p><strong>INTRON A</strong></p>
<p><strong>plus</strong></p>
<p><strong>REBETOL</strong></p>
<p><strong>(N=228)</strong></p></td>
<td colspan="3"><blockquote>
<p><strong>INTRON A plus</strong></p>
<p><strong>Placebo</strong></p>
<p><strong>(N=231)</strong></p>
</blockquote></td>
<td colspan="2"><p>INTRON A plus REBETOL</p>
<p><strong>(N=228)</strong></p></td>
<td colspan="3"><p><strong>INTRON A plus</strong></p>
<p><strong>Placebo</strong></p>
<p><strong>(N=225)</strong></p></td>
<td colspan="3"><p><strong>INTRON A</strong></p>
<p><strong>plus</strong></p>
<p><strong>REBETOL</strong></p>
<p><strong>(N=77)</strong></p></td>
<td><p><strong>INTRON A</strong></p>
<p><strong>plus</strong></p>
<p><strong>Placebo</strong></p>
<p><strong>(N=76)</strong></p></td>
</tr>
<tr class="even">
<td colspan="3"><strong>Application Site Disorders</strong></td>
<td colspan="2"></td>
<td colspan="3"></td>
<td colspan="2"></td>
<td colspan="3"></td>
<td></td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td colspan="3">injection site inflammation</td>
<td colspan="2">13</td>
<td colspan="3">10</td>
<td colspan="2">12</td>
<td colspan="3">14</td>
<td>6</td>
<td colspan="2">8</td>
</tr>
<tr class="even">
<td colspan="3">injection site reaction</td>
<td colspan="2">7</td>
<td colspan="3">9</td>
<td colspan="2">8</td>
<td colspan="3">9</td>
<td>5</td>
<td colspan="2">3</td>
</tr>
<tr class="odd">
<td colspan="3"><strong>Body as a Whole - General
Disorders</strong></td>
<td colspan="2"></td>
<td colspan="3"></td>
<td colspan="2"></td>
<td colspan="3"></td>
<td></td>
<td colspan="2"></td>
</tr>
<tr class="even">
<td colspan="3">headache</td>
<td colspan="2">63</td>
<td colspan="3">63</td>
<td colspan="2">66</td>
<td colspan="3">67</td>
<td>66</td>
<td colspan="2">68</td>
</tr>
<tr class="odd">
<td colspan="3">fatigue</td>
<td colspan="2">68</td>
<td colspan="3">62</td>
<td colspan="2">70</td>
<td colspan="3">72</td>
<td>60</td>
<td colspan="2">53</td>
</tr>
<tr class="even">
<td colspan="3">rigors</td>
<td colspan="2">40</td>
<td colspan="3">32</td>
<td colspan="2">42</td>
<td colspan="3">39</td>
<td>43</td>
<td colspan="2">37</td>
</tr>
<tr class="odd">
<td colspan="3">fever</td>
<td colspan="2">37</td>
<td colspan="3">35</td>
<td colspan="2">41</td>
<td colspan="3">40</td>
<td>32</td>
<td colspan="2">36</td>
</tr>
<tr class="even">
<td colspan="3">influenza-like symptoms</td>
<td colspan="2">14</td>
<td colspan="3">18</td>
<td colspan="2">18</td>
<td colspan="3">20</td>
<td>13</td>
<td colspan="2">13</td>
</tr>
<tr class="odd">
<td colspan="3">asthenia</td>
<td colspan="2">9</td>
<td colspan="3">4</td>
<td colspan="2">9</td>
<td colspan="3">9</td>
<td>10</td>
<td colspan="2">4</td>
</tr>
<tr class="even">
<td colspan="3">chest pain</td>
<td colspan="2">5</td>
<td colspan="3">4</td>
<td colspan="2">9</td>
<td colspan="3">8</td>
<td>6</td>
<td colspan="2">7</td>
</tr>
<tr class="odd">
<td colspan="3"><p><strong>Central &amp; Peripheral Nervous</strong></p>
<p><strong>System Disorders</strong></p></td>
<td colspan="2"></td>
<td colspan="3"></td>
<td colspan="2"></td>
<td colspan="3"></td>
<td></td>
<td colspan="2"></td>
</tr>
<tr class="even">
<td colspan="3">dizziness</td>
<td colspan="2">17</td>
<td colspan="3">15</td>
<td colspan="2">23</td>
<td colspan="3">19</td>
<td>26</td>
<td colspan="2">21</td>
</tr>
<tr class="odd">
<td colspan="3"><strong>Gastrointestinal System Disorders</strong></td>
<td colspan="2"></td>
<td colspan="3"></td>
<td colspan="2"></td>
<td colspan="3"></td>
<td></td>
<td colspan="2"></td>
</tr>
<tr class="even">
<td colspan="3">nausea</td>
<td colspan="2">38</td>
<td colspan="3">35</td>
<td colspan="2">46</td>
<td colspan="3">33</td>
<td>47</td>
<td colspan="2">33</td>
</tr>
<tr class="odd">
<td colspan="3">anorexia</td>
<td colspan="2">27</td>
<td colspan="3">16</td>
<td colspan="2">25</td>
<td colspan="3">19</td>
<td>21</td>
<td colspan="2">14</td>
</tr>
<tr class="even">
<td colspan="3">dyspepsia</td>
<td colspan="2">14</td>
<td colspan="3">6</td>
<td colspan="2">16</td>
<td colspan="3">9</td>
<td>16</td>
<td colspan="2">9</td>
</tr>
<tr class="odd">
<td colspan="3">vomiting</td>
<td colspan="2">11</td>
<td colspan="3">10</td>
<td colspan="2">9</td>
<td colspan="3">13</td>
<td>12</td>
<td colspan="2">8</td>
</tr>
<tr class="even">
<td colspan="3"><strong>Musculoskeletal System Disorders</strong></td>
<td colspan="2"></td>
<td colspan="3"></td>
<td colspan="2"></td>
<td colspan="3"></td>
<td></td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td colspan="3">myalgia</td>
<td colspan="2">61</td>
<td colspan="3">57</td>
<td colspan="2">64</td>
<td colspan="3">63</td>
<td>61</td>
<td colspan="2">58</td>
</tr>
<tr class="even">
<td colspan="3">arthralgia</td>
<td colspan="2">30</td>
<td colspan="3">27</td>
<td colspan="2">33</td>
<td colspan="3">36</td>
<td>29</td>
<td colspan="2">29</td>
</tr>
<tr class="odd">
<td colspan="3">musculoskeletal pain</td>
<td colspan="2">20</td>
<td colspan="3">26</td>
<td colspan="2">28</td>
<td colspan="3">32</td>
<td>22</td>
<td colspan="2">28</td>
</tr>
<tr class="even">
<td colspan="3"><strong>Psychiatric Disorders</strong></td>
<td colspan="2"></td>
<td colspan="3"></td>
<td colspan="2"></td>
<td colspan="3"></td>
<td></td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td colspan="3">insomnia</td>
<td colspan="2">39</td>
<td colspan="3">27</td>
<td colspan="2">39</td>
<td colspan="3">30</td>
<td>26</td>
<td colspan="2">25</td>
</tr>
<tr class="even">
<td colspan="3">irritability</td>
<td colspan="2">23</td>
<td colspan="3">19</td>
<td colspan="2">32</td>
<td colspan="3">27</td>
<td>25</td>
<td colspan="2">20</td>
</tr>
<tr class="odd">
<td colspan="3">depression</td>
<td colspan="2">32</td>
<td colspan="3">25</td>
<td colspan="2">36</td>
<td colspan="3">37</td>
<td>23</td>
<td colspan="2">14</td>
</tr>
<tr class="even">
<td colspan="3">emotional lability</td>
<td colspan="2">7</td>
<td colspan="3">6</td>
<td colspan="2">11</td>
<td colspan="3">8</td>
<td>12</td>
<td colspan="2">8</td>
</tr>
<tr class="odd">
<td colspan="3">concentration impaired</td>
<td colspan="2">11</td>
<td colspan="3">14</td>
<td colspan="2">14</td>
<td colspan="3">14</td>
<td>10</td>
<td colspan="2">12</td>
</tr>
<tr class="even">
<td colspan="3">nervousness</td>
<td colspan="2">4</td>
<td colspan="3">2</td>
<td colspan="2">4</td>
<td colspan="3">4</td>
<td>5</td>
<td colspan="2">4</td>
</tr>
<tr class="odd">
<td colspan="3"><strong>Respiratory System Disorders</strong></td>
<td colspan="2"></td>
<td colspan="3"></td>
<td colspan="2"></td>
<td colspan="3"></td>
<td></td>
<td colspan="2"></td>
</tr>
<tr class="even">
<td colspan="3">dyspnea</td>
<td colspan="2">19</td>
<td colspan="3">9</td>
<td colspan="2">18</td>
<td colspan="3">10</td>
<td>17</td>
<td colspan="2">12</td>
</tr>
<tr class="odd">
<td colspan="3">sinusitis</td>
<td colspan="2">9</td>
<td colspan="3">7</td>
<td colspan="2">10</td>
<td colspan="3">14</td>
<td>12</td>
<td colspan="2">7</td>
</tr>
<tr class="even">
<td colspan="3"><strong>Skin and Appendages Disorders</strong></td>
<td colspan="2"></td>
<td colspan="3"></td>
<td colspan="2"></td>
<td colspan="3"></td>
<td></td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td colspan="3">alopecia</td>
<td colspan="2">28</td>
<td colspan="3">27</td>
<td colspan="2">32</td>
<td colspan="3">28</td>
<td>27</td>
<td colspan="2">26</td>
</tr>
<tr class="even">
<td colspan="3">rash</td>
<td colspan="2">20</td>
<td colspan="3">9</td>
<td colspan="2">28</td>
<td colspan="3">8</td>
<td>21</td>
<td colspan="2">5</td>
</tr>
<tr class="odd">
<td colspan="3">pruritus</td>
<td colspan="2">21</td>
<td colspan="3">9</td>
<td colspan="2">19</td>
<td colspan="3">8</td>
<td>13</td>
<td colspan="2">4</td>
</tr>
<tr class="even">
<td colspan="3"><strong>Special Senses, Other Disorders</strong></td>
<td colspan="2"></td>
<td colspan="3"></td>
<td colspan="2"></td>
<td colspan="3"></td>
<td></td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td colspan="3">taste perversion</td>
<td colspan="2">7</td>
<td colspan="3">4</td>
<td colspan="2">8</td>
<td colspan="3">4</td>
<td>6</td>
<td colspan="2">5</td>
</tr>
</tbody>
</table>

\* 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 - 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 10^9^ /L and in
the International study was 1.5 x 10^9^ /L. In relapse patients the mean
maximum decrease in neutrophil count in the US study was 1.3 x 10^9^ /L
and in the International study was 1.6 x 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 treatment) 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>
<colgroup>
<col style="width: 5%" />
<col style="width: 12%" />
<col style="width: 5%" />
<col style="width: 10%" />
<col style="width: 6%" />
<col style="width: 5%" />
<col style="width: 13%" />
<col style="width: 10%" />
<col style="width: 5%" />
<col style="width: 12%" />
<col style="width: 9%" />
<col style="width: 5%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="11"><strong>TABLE 5. Selected Hematologic Values During
Treatment with REBETOL plus INTRON A: Previously Untreated and Relapse
Patients</strong></td>
<td></td>
</tr>
<tr class="even">
<td colspan="11">Percentage of Patients</td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2"></td>
<td colspan="6">US Previously Untreated Study</td>
<td colspan="3">US Relapse Study</td>
<td></td>
</tr>
<tr class="even">
<td colspan="2"></td>
<td colspan="3">24 weeks of treatment</td>
<td colspan="3">48 weeks of treatment</td>
<td colspan="3">24 weeks of treatment</td>
<td></td>
</tr>
<tr class="odd">
<td></td>
<td colspan="2"></td>
<td><p><strong>INTRON A plus REBETOL</strong></p>
<p><strong>(N=228)</strong></p></td>
<td colspan="2"><p><strong>INTRON A plus</strong></p>
<p><strong>Placebo</strong></p>
<p><strong>(N=231)</strong></p></td>
<td><p><strong>INTRON A</strong></p>
<p><strong>plus</strong></p>
<p><strong>REBETOL</strong></p>
<p><strong>(N=228)</strong></p></td>
<td colspan="2"><p><strong>INTRON A</strong></p>
<p><strong>plus</strong></p>
<p><strong>Placebo</strong></p>
<p><strong>(N=225)</strong></p></td>
<td><p><strong>INTRON A</strong></p>
<p><strong>plus</strong></p>
<p><strong>REBETOL</strong></p>
<p><strong>(N=77)</strong></p></td>
<td colspan="2"><p><strong>INTRON A</strong></p>
<p><strong>plus</strong></p>
<p><strong>Placebo</strong></p>
<p><strong>(N=76)</strong></p></td>
</tr>
<tr class="even">
<td></td>
<td colspan="2">Hemoglobin (g/dL)</td>
<td></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td></td>
<td colspan="2">9.5-10.9</td>
<td>24</td>
<td colspan="2">1</td>
<td>32</td>
<td colspan="2">1</td>
<td>21</td>
<td colspan="2">3</td>
</tr>
<tr class="even">
<td></td>
<td colspan="2">8.0-9.4</td>
<td>5</td>
<td colspan="2">0</td>
<td>4</td>
<td colspan="2">0</td>
<td>4</td>
<td colspan="2">0</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="2">6.5-7.9</td>
<td>0</td>
<td colspan="2">0</td>
<td>0</td>
<td colspan="2">0.4</td>
<td>0</td>
<td colspan="2">0</td>
</tr>
<tr class="even">
<td></td>
<td colspan="2">&lt;6.5</td>
<td>0</td>
<td colspan="2">0</td>
<td>0</td>
<td colspan="2">0</td>
<td>0</td>
<td colspan="2">0</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
</tr>
<tr class="even">
<td></td>
<td colspan="2">Leukocytes (x10<sup>9</sup>/L)</td>
<td></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td></td>
<td colspan="2">2.0-2.9</td>
<td>40</td>
<td colspan="2">20</td>
<td>38</td>
<td colspan="2">23</td>
<td>45</td>
<td colspan="2">26</td>
</tr>
<tr class="even">
<td></td>
<td colspan="2">1.5-1.9</td>
<td>4</td>
<td colspan="2">1</td>
<td>9</td>
<td colspan="2">2</td>
<td>5</td>
<td colspan="2">3</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="2">1.0-1.4</td>
<td>0.9</td>
<td colspan="2">0</td>
<td>2</td>
<td colspan="2">0</td>
<td>0</td>
<td colspan="2">0</td>
</tr>
<tr class="even">
<td></td>
<td colspan="2">&lt;1.0</td>
<td>0</td>
<td colspan="2">0</td>
<td>0</td>
<td colspan="2">0</td>
<td>0</td>
<td colspan="2">0</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
</tr>
<tr class="even">
<td></td>
<td colspan="2">Neutrophils (x10<sup>9</sup>/L)</td>
<td></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td></td>
<td colspan="2">1.0-1.49</td>
<td>30</td>
<td colspan="2">32</td>
<td>31</td>
<td colspan="2">44</td>
<td>42</td>
<td colspan="2">34</td>
</tr>
<tr class="even">
<td></td>
<td colspan="2">0.75-0.99</td>
<td>14</td>
<td colspan="2">15</td>
<td>14</td>
<td colspan="2">11</td>
<td>16</td>
<td colspan="2">18</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="2">0.5-0.74</td>
<td>9</td>
<td colspan="2">9</td>
<td>14</td>
<td colspan="2">7</td>
<td>8</td>
<td colspan="2">4</td>
</tr>
<tr class="even">
<td></td>
<td colspan="2">&lt;0.5</td>
<td>11</td>
<td colspan="2">8</td>
<td>11</td>
<td colspan="2">5</td>
<td>5</td>
<td colspan="2">8</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
</tr>
<tr class="even">
<td></td>
<td colspan="2">Platelets (x10<sup>9</sup>/L)</td>
<td></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td></td>
<td colspan="2">70-99</td>
<td>9</td>
<td colspan="2">11</td>
<td>11</td>
<td colspan="2">14</td>
<td>6</td>
<td colspan="2">12</td>
</tr>
<tr class="even">
<td></td>
<td colspan="2">50-69</td>
<td>2</td>
<td colspan="2">3</td>
<td>2</td>
<td colspan="2">3</td>
<td>0</td>
<td colspan="2">5</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="2">30-49</td>
<td>0</td>
<td colspan="2">0.4</td>
<td>0</td>
<td colspan="2">0.4</td>
<td>0</td>
<td colspan="2">0</td>
</tr>
<tr class="even">
<td></td>
<td colspan="2">&lt;30</td>
<td>0.9</td>
<td colspan="2">0</td>
<td>1</td>
<td colspan="2">0.9</td>
<td>0</td>
<td colspan="2">0</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
</tr>
<tr class="even">
<td></td>
<td colspan="2">Total Bilirubin (mg/dL)</td>
<td></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td></td>
<td colspan="2">1.5 -3.0</td>
<td>27</td>
<td colspan="2">13</td>
<td>32</td>
<td colspan="2">13</td>
<td>21</td>
<td colspan="2">7</td>
</tr>
<tr class="even">
<td></td>
<td colspan="2">3.1-6.0</td>
<td>0.9</td>
<td colspan="2">0.4</td>
<td>2</td>
<td colspan="2">0</td>
<td>3</td>
<td colspan="2">0</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="2">6.1-12.0</td>
<td>0</td>
<td colspan="2">0</td>
<td>0.4</td>
<td colspan="2">0</td>
<td>0</td>
<td colspan="2">0</td>
</tr>
<tr class="even">
<td></td>
<td colspan="2">&gt;12.0</td>
<td>0</td>
<td colspan="2">0</td>
<td>0</td>
<td colspan="2">0</td>
<td>0</td>
<td colspan="2">0</td>
</tr>
</tbody>
</table>

### OVERDOSAGE

In combination REBETOL/INTRON A clinical trials, the maximum overdose
reported was a dose of 39 million units of INTRON A (13 subcutaneous
injections of 3 million IU each) taken with 10 g of REBETOL (fifty
200-mg capsules) in an investigator-initiated trial. The patient was
observed for 2 days in the emergency room during which time no adverse
event from the overdose was noted.

### 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. |                         |                               |
| R          |                         |                               |
| ecommended |                         |                               |
| Dosing**   |                         |                               |
+------------+-------------------------+-------------------------------+
| Body       | REBETOL Capsules        | INTRON A Injection            |
| weight     |                         |                               |
+------------+-------------------------+-------------------------------+
| ≤ 75 kg    | 2 x 200 mg capsules     | 3 million IU 3 times weekly   |
|            | [AM]{.smallcaps},       | s.c.                          |
|            |                         |                               |
|            | 3 x 200 mg capsules PM  |                               |
|            |                         |                               |
|            | daily p.o.              |                               |
+------------+-------------------------+-------------------------------+
| \> 75 kg   | 3 x 200 mg capsules AM, | 3 million IU 3 times weekly   |
|            |                         | s.c.                          |
|            | 3 x 200 mg capsules PM  |                               |
|            |                         |                               |
|            | daily p.o.              |                               |
+------------+-------------------------+-------------------------------+

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 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 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 f |                       |                       |
| or Dose Modifications |                       |                       |
+-----------------------+-----------------------+-----------------------+
|                       | Dose Reduction^\*^    | Permanent             |
|                       |                       | Discontinuation of    |
|                       | REBETOL - 600 mg      | Treatment             |
|                       | daily                 |                       |
|                       |                       | REBETOL and INTRON A  |
|                       | INTRON A - 1.5        |                       |
|                       | million IU TIW        |                       |
+-----------------------+-----------------------+-----------------------+
| Hemoglobin            | \<10 g/dL (REBETOL)   | \<8.5 g/dL            |
|                       |                       |                       |
|                       | **Cardiac History     | **Cardiac History     |
|                       | Patients only.**      | Patients only.**      |
|                       |                       |                       |
|                       | **≥2 g/dL decrease    | **\<12 g/dL after 4   |
|                       | during any 4-**       | weeks of dose         |
|                       |                       | reduction**           |
|                       | **week period during  |                       |
|                       | treatment**           |                       |
|                       |                       |                       |
|                       | **(REBETOL/INTRON     |                       |
|                       | A)**                  |                       |
+-----------------------+-----------------------+-----------------------+
| White blood count     | \<1.5 x 10^9^/L       | \<1.0 x 10^9^/L       |
|                       | (INTRON A)            |                       |
+-----------------------+-----------------------+-----------------------+
| Neutrophil count      | \<0.75 x 10^9^/L      | \<0.5 x 10^9^/L       |
|                       | (INTRON A)            |                       |
+-----------------------+-----------------------+-----------------------+
| Platelet count        | \<50 x 10^9^/L        | \<25 x 10^9^/L        |
|                       | (INTRON A)            |                       |
+-----------------------+-----------------------+-----------------------+
| ^\*^Study medication  |                       |                       |
| to be dose reduced is |                       |                       |
| shown in parenthesis  |                       |                       |
+-----------------------+-----------------------+-----------------------+

*[Administration of INTRON A Injection]{.underline}*

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.)

  ----------------------- ----------------------- -----------------------
  Vial/Pen Label Strength Fill Volume             Concentration

  3 million IU vial       0.5 mL                  3 million IU/0.5 mL

  18 million IU multidose 3.8 mL                  3 million IU/0.5 mL
  vial†                                           

  18 million IU multidose 1.5 mL                  3 million IU/0.2 mL
  pen††                                           
  ----------------------- ----------------------- -----------------------

^†^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    A box containing 6 vials of Intron A (NDC 0085-1241-02)
  ≤75 kg          Injection (3 million IU in 0.5 mL    
                  per vial), 6 syringes, alcohol swabs 
                  and one bottle containing 70 Rebetol 
                  Capsules .                           

                  one 18 million IU multidose vial of  (NDC 0085-1236-02)
                  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.        

                  One 18 million IU INTRON A Injection (NDC 0085-1258-02)
                  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.                            

  For Patients    A box containing 6 vials of Intron A (NDC 0085-1241-01)
  \>75 kg         Injection (3 million IU in 0.5 mL    
                  per vial), 6 syringes, alcohol swabs 
                  and one bottle containing 84 Rebetol 
                  Capsules.                            

                  one 18 million IU multidose vial of  (NDC 0085-1236-01)
                  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.                            

                  One 18 million IU INTRON A Injection (NDC 0085-1258-01)
                  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.                            

  For REBETOL     A box containing 6 vials of Intron A (NDC 0085-1241-03)
  Dose Reduction  Injection (3 million IU in 0.5 mL    
                  per vial), 6 syringes, alcohol       
                  swabs, and one bottle containing 42  
                  Rebetol Capsules.                    

                  one 18 million IU multidose vial of  (NDC 0085-1236-03)
                  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.                            

                  One 18 million IU INTRON A Injection (NDC 0085-1258-03)
                  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.                            
  --------------- ------------------------------------ ------------------

### STORAGE CONDITIONS

**Store the REBETOL Capsules plus INTRON A Injection combination package
refrigerated between 2°C 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).**

![](media/image2.png){width="0.31180555555555556in"
height="0.27291666666666664in"} Schering Corporation

Kenilworth, NJ 07033 USA

U.S. Patents 4,530,901 & 4,211,771

Copyright © 1998, Schering Corporation. All rights reserved.

B-21617679 Rev. 5/00