DESCRIPTION
REBETOL®
REBETOL is Schering Corporation's brand name for ribavirin, a nucleoside
analog with antiviral activity. The chemical name of ribavirin is
1-b-D-ribofuranosyl-1 H-1,2,4-triazole-3-carboxamide and has the
following structural formula:
Ribavirin is a white, crystalline powder. It is freely soluble in
water and slightly soluble in anhydrous alcohol. The empirical formula
is C8H12N4O5 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 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 colibearing 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 anti-biotic
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 metabo-lism, the absolute
bioavailability averaged 64% (44%). There was a linear relationship
between dose and AUCtf (AUC from time zero to last measurable
concentration) following single doses of 200-1200 mg ribavirin. The
relationship between dose and Cmax was curvilinear, tending to asymptote
above single doses of 400-600 mg.
Upon multiple oral dosing, based on AUC12hr, 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 concentra-tions 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 AUCtf and Cmax
increased by 70% when REBETOL Capsules were adminis-tered 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 AUCtf. The clinical
relevance of results from this single-dose study is unknown.
Ribavirin transport into nonplasma compartments has been most
extensively studied in red blood cells, and has been identified to be
primarily via an es-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 degrada-tive
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 AUCtf 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 AUCtf
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 Cmax 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 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 results
are summarized in TABLE 2.
| 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 |
|
| Histologic Response |
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 random-ized 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.
| 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 |
| Histologic Response |
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 hypersensi-tivity 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 TO 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 exacerba-tion 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 psy-chiatric intervention sought. (See
ADVERSE REACTIONS.)
Bone Marrow Toxicity
INTRON A therapy suppresses bone marrow function and may result in
severe cytopenias including very rare events of aplastic anemia. It is
advised that complete blood counts (CBC) be obtained pre-treatment and
monitored routinely during therapy (see PRECAUTIONS: Laboratory Tests).
INTRON A therapy should be discontinued in patients who develop severe
decreases in neutrophil (<0.5 x 10 9/L)
or platelet counts (<25 x 109/L) (see
DOSAGE AND ADMINISTRATION: Guidelines for Dose Modifications).
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 infec-tion,
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.
Drug Interactions Nucleoside Analogues.
Administration of nucleoside analogues has resulted in lactic acidosis.
Coadministration of ribavirin and nucleoside analogues should be
undertaken with caution and only if the potential benefit outweighs the
potential risks.
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 child-bearing 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
vitroand animal in vivogenotoxicity 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 VitroCell 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 (t1/2) 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 treat-ment,
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 recom-mended
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 (t1/2)
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 Safety and effectiveness in
pediatric patients below the age of 18 years have not been established.
Geriatric Use Clinical studies of REBETRON
Combination Therapy did not include sufficient numbers of subjects aged
65 and over to determine if they respond differently from younger
subjects. In clinical trials, elderly subjects had a higher frequency of
anemia (67%) than did younger patients (28%) (see WARNINGS).
In general, REBETOL (ribavirin) should be administered
to elderly patients cautiously, starting at the lower end of the dosing
range, reflecting the greater frequency of decreased renal, hepatic
and/or cardiac function, and of concomitant disease or other drug
therapy.
REBETOL (ribavirin) is known to be substantially
excreted by the kidney, and the risk of adverse reactions to ribavirin
may be greater in patients with impaired renal function. Because elderly
patients often have decreased renal function, care should be taken in
dose selection. Renal function should be monitored and dosage
adjustments of ribavirin should be made accord-ingly (see DOSAGE AND
ADMINISTRATION: Guidelines for Dose Modifications). REBETOL (ribavirin)
should be used in elderly patients with creatinine clearance <50 mL/min
only if the potential benefit outweighs the risk, and should not be
administered to patients with creatinine clearance <30 mL/min (see
WARNINGS).
REBETRON Combination Therapy should be used very
cautiously in elderly patients with a history of psychiatric disorders
(see WARNINGS).
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 approxi-mately 10% of patients treated with
REBETOL/INTRON A therapy. (See WARNINGS.)
The most common psychiatric events occurring in US
studies of previously untreated and relapse patients treated with
REBETOL/INTRON A therapy, respectively, were insomnia (39%, 26%),
depression (34%, 23%), and irritability (27%, 25%). Suicidal behavior
(ideation, attempts, and suicides) occurred in 1% of patients. (See
WARNINGS.) In addition, hearing disorders (tinnitus and hearing
loss) and vertigo have occurred in patients treated with combination
REBETOL/INTRON A therapy. The following adverse event has also been
reported during the marketing surveillance of REBETOL/INTRON A therapy:
hypertriglyceridemia.
Selected treatment-emergent adverse events that
occurred in the US studies with >5% incidence are provided in
TABLE 4 by treatment group. In general, the selected
treatment-emergent adverse events reported with lower incidence in the
international studies as compared to the US studies with the exception
of asthenia, influenza-like symptoms, nervous-ness, and pruritus.
| Application Site Disorders |
Body as a Whole —
General Disorders |
Central & Peripheral Nervous
System Disorders |
Gastrointestinal System
Disorders |
Musculoskeletal System
Disorders |
| Psychiatic Disorders |
| Respiratory System Disorders |
| Skin and Appendages Disorders |
| Special Senses, Other Disorders |
Laboratory Values
Changes in selected hematologic values (hemoglobin, white blood cells,
neutrophils, and platelets) during combination REBETOL/INTRON A
treatment are described below (see TABLE 5).
Hemoglobin Hemoglobin decreases among patients
on combination therapy began at Week 1, with stabilization by Week 4. In
previously untreated patients treated for 48 weeks, the mean maximum
decrease from baseline was 3.1 g/dL in the US study and 2.9 g/dL in the
International study. In relapse patients, the mean maximum decrease from
baseline was 2.8 g/dL in the US study and 2.6 g/dL in the International
study. Hemoglobin values returned to pretreatment levels within 4 to 8
weeks of cessation of therapy in most patients.
Neutrophils There were decreases in neutrophil
counts in both the combination REBETOL/INTRON A and INTRON A plus
placebo dose groups. In previously untreated patients treated for 48
weeks, the mean maximum decrease in neutrophil count in the US study was
1.3 x 109/L and in the International
study was 1.5 x 109/L. In relapse
patients the mean maximum decrease in neutrophil count in the US study
was 1.3 x 109/L and in the
International study was 1.6 x 109/L.
Neutrophil counts returned to pretreatment levels within 4 weeks of
cessation of therapy in most patients.
Platelets In both previously untreated and
relapse patients mean platelet counts generally remained in the normal
range in all treatment groups; however, mean platelet counts were 10% to
15% lower in the INTRON A plus placebo group than the REBETOL/INTRON A
group. Mean platelet counts returned to baseline levels within 4 weeks
after treatment discontinuation.
Thyroid Function Of patients who entered the
previously untreated (24 and 48 week treatments) and relapse (24 week
treatment) studies without thyroid abnormalities, approximately 3% to 6%
and 1% to 2%, respectively, developed thyroid abnormalities requiring
clinical intervention.
Bilirubin and Uric Acid Increases in both
bilirubin and uric acid, associated with hemolysis, were noted in
clinical trials. Most were moderate biochemical changes and were
reversed within 4 weeks after treatment discontinuation. This
observation occurs most frequently in patients with a previous diagnosis
of Gilbert's syndrome. This has not been associated with hepatic
dysfunction or clinical morbidity.
| INTRON A plus REBETOL (N=228) |
INTRON A plus Placebo (N=231) |
INTRON A plus REBETOL (N=228) |
INTRON A plus Placebo (N=225) |
INTRON A plus REBETOL (N=77) |
INTRON A plus Placebo (N=76) |
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.
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.)
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.)
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: |
|
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).
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