A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Rebetron Patient, Information, Instructions - Ribavirin
Rebetron Patient, Information, Instructions - Ribavirin
PATIENT INFORMATION
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).
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