Included as part of the PRECAUTIONS section.
Significant adverse reactions associated with Moderiba
(ribavirin, USP)/peginterferon alfa-2a combination therapy include severe
depression and suicidal ideation, hemolytic anemia, suppression of bone marrow
function, autoimmune and infectious disorders, ophthalmologic disorders, cerebrovascular
disorders, pulmonary dysfunction, colitis, pancreatitis, and diabetes.
The Peginterferon alfa-2a Package Insert should be
reviewed in its entirety for additional safety information prior to initiation
of combination treatment.
Moderiba may cause birth defects and/or death of the
exposed fetus. Ribavirin has demonstrated significant teratogenic and/or
embryocidal effects 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 ribavirin.
Moderiba therapy should not be started unless a report
of a negative pregnancy test has been obtained immediately prior to planned
initiation of therapy. Extreme care must be taken to avoid pregnancy in
female patients and in female partners of male patients. Patients should be
instructed to use at least two forms of effective contraception during
treatment and for 6 months after treatment has been stopped. Pregnancy testing
should occur monthly during Moderiba therapy and for 6 months after therapy has
stopped [see BOXED WARNING, CONTRAINDICATIONS, Use In Specific
Populations, and PATIENT INFORMATION].
The primary toxicity of ribavirin is hemolytic anemia,
which was observed in approximately 13% of all ribavirin/peginterferon
alfa-2a-treated subjects in clinical trials. Anemia associated with ribavirin occurs
within 1 to 2 weeks of initiation of therapy. Because the initial drop in
hemoglobin may be significant, it is advised that hemoglobin or hematocrit 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.
Caution should be exercised in initiating treatment in any patient with
baseline risk of severe anemia (e.g., spherocytosis, history of
gastrointestinal bleeding) [see DOSAGE AND ADMINISTRATION].
Fatal and nonfatal myocardial infarctions have been
reported in patients with anemia caused by ribavirin. Patients should be
assessed for underlying cardiac disease before initiation of ribavirin therapy.
Patients with pre-existing cardiac disease should have
electrocardiograms administered before treatment, 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 Moderiba [see BOXED WARNING and DOSAGE AND ADMINISTRATION].
Chronic hepatitis C (CHC) patients with cirrhosis may be
at risk of hepatic decompensation and death when treated with alpha
interferons, including peginterferon alfa-2a. Cirrhotic CHC patients coinfected
with HIV receiving highly active antiretroviral therapy (HAART) and interferon
alfa-2a with or without ribavirin appear to be at increased risk for the
development of hepatic decompensation compared to patients not receiving HAART.
In Study NR15961 [see Clinical Studies], among 129 CHC/HIV cirrhotic
patients receiving HAART, 14 (11%) of these patients across all treatment arms
developed hepatic decompensation resulting in 6 deaths. All 14 patients were on
NRTIs, including stavudine, didanosine, abacavir, zidovudine, and lamivudine.
These small numbers of patients do not permit discrimination between specific
NRTIs or the associated risk. During treatment, patients' clinical status and
hepatic function should be closely monitored for signs and symptoms of hepatic
decompensation. Treatment with peginterferon alfa-2a/Moderiba should be
discontinued immediately in patients with hepatic decompensation [see CONTRAINDICATIONS].
Severe acute hypersensitivity reactions (e.g., urticaria,
angioedema, bronchoconstriction, and anaphylaxis) have been observed during
alpha interferon and ribavirin therapy. If such a reaction occurs, therapy with
peginterferon alfa-2a and Moderiba should be discontinued immediately and
appropriate medical therapy instituted. Serious skin reactions including
vesiculobullous eruptions, reactions in the spectrum of Stevens-Johnson
Syndrome (erythema multiforme major) with varying degrees of skin and mucosal
involvement and exfoliative dermatitis (erythroderma) have been reported in
patients receiving peginterferon alfa-2a with and without ribavirin. Patients
developing signs or symptoms of severe skin reactions must discontinue therapy [see
Dyspnea, pulmonary infiltrates, pneumonitis, pulmonary
hypertension, and pneumonia have been reported during therapy with ribavirin
and interferon. Occasional cases of fatal pneumonia have occurred. In addition,
sarcoidosis or the exacerbation of sarcoidosis has been reported. If there is
evidence of pulmonary infiltrates or pulmonary function impairment, patients
should be closely monitored and, if appropriate, combination
Moderiba/Peginterferon alfa-2a treatment should be discontinued.
Bone Marrow Suppression
Pancytopenia (marked decreases in RBCs, neutrophils and
platelets) and bone marrow suppression have been reported in the literature to
occur within 3 to 7 weeks after the concomitant administration of pegylated
interferon/ribavirin and azathioprine. In this limited number of patients
(n=8), myelotoxicity was reversible within 4 to 6 weeks upon withdrawal of both
HCV antiviral therapy and concomitant azathioprine and did not recur upon
reintroduction of either treatment alone. Peginterferon alfa-2a, Moderiba, and
azathioprine should be discontinued for pancytopenia, and pegylated
interferon/ribavirin should not be re-introduced with concomitant azathioprine [see
Moderiba and peginterferon alfa-2a therapy should be
suspended in patients with signs and symptoms of pancreatitis, and discontinued
in patients with confirmed pancreatitis.
Impact On Growth In Pediatric Patients
During combination therapy for up to 48 weeks with
peginterferon alfa-2a plus ribavirin, growth inhibition was observed in
pediatric subjects 5 to 17 years of age. Decreases in weight for age z-score and
height for age z-score up to 48 weeks of therapy compared with baseline were
observed. At 2 years post-treatment, 16% of pediatric subjects were more than
15 percentiles below their baseline weight curve and 11% were more than 15
percentiles below their baseline height curve.
The available longer term data on subjects who were
followed up to 6 years post-treatment are too limited to determine the risk of
reduced adult height in some patients [see Clinical Studies Experience].
Before beginning peginterferon alfa-2a/Moderiba
combination therapy, standard hematological and biochemical laboratory tests
are recommended for all patients. Pregnancy screening for women of childbearing
potential must be performed. Patients who have pre-existing cardiac
abnormalities should have electrocardiograms administered before treatment with
After initiation of therapy, hematological tests should
be performed at 2 weeks and 4 weeks and biochemical tests should be performed
at 4 weeks. Additional testing should be performed periodically during therapy.
In adult clinical studies, the CBC (including hemoglobin level and white blood
cell and platelet counts) and chemistries (including liver function tests and
uric acid) were measured at 1, 2, 4, 6, and 8 weeks, and then every 4 to 6
weeks or more frequently if abnormalities were found. In the pediatric clinical
trial, hematological and chemistry assessments were at 1, 3, 5, and 8 weeks,
then every 4 weeks. Thyroid stimulating hormone (TSH) was measured every 12
weeks. Monthly pregnancy testing should be performed during combination therapy
and for 6 months after discontinuing therapy.
The entrance criteria used for the clinical studies of
ribavirin and peginterferon alfa-2a may be considered as a guideline to
acceptable baseline values for initiation of treatment:
- Platelet count greater than or equal to 90,000 cells/mm³
(as low as 75,000 cells/mm³ in HCV patients with cirrhosis or 70,000 cells/mm³
in patients with CHC and HIV)
- Absolute neutrophil count (ANC) greater than or equal to
- TSH and T4 within normal limits or adequately controlled
- CD4+ cell count greater than or equal to 200 cells/mm³ or
CD4+ cell count greater than or equal to 100 cells/mm³ but less than 200
cells/mm³ and HIV-1 RNA less than 5,000 copies/mL in patients coinfected with
- Hemoglobin greater than or equal to 12 g/dL for women and
greater than or equal to 13 g/dL for men in CHC monoinfected patients
- Hemoglobin greater than or equal to 11 g/dL for women and
greater than or equal to 12 g/dL for men in patients with CHC and HIV
Patient Counseling Information
See FDA-approved patient labeling (Medication Guide)
Patients must be informed that ribavirin may cause birth
defects and/or death of the exposed fetus. Moderiba 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 Moderiba therapy and for 6 months post therapy.
Patients should use two reliable methods of birth control while taking Moderiba
therapy and for 6 months post therapy. Moderiba 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 post therapy.
Female patients of childbearing potential and male
patients with female partners of childbearing potential must be advised of the
teratogenic/embryocidal risks and must be instructed to practice effective
contraception during Moderiba therapy and for 6 months post therapy. Patients
should be advised to notify the healthcare provider immediately in the event of
a pregnancy [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].
The most common adverse event associated with ribavirin
is anemia, which may be severe [see BOXED WARNING, WARNINGS AND
PRECAUTIONS and ADVERSE REACTIONS]. Patients should be advised that laboratory
evaluations are required prior to starting Moderiba therapy and periodically
thereafter [see WARNINGS AND PRECAUTIONS]. It is advised that patients
be well hydrated, especially during the initial stages of treatment.
Patients who develop dizziness, confusion, somnolence,
and fatigue should be cautioned to avoid driving or operating machinery.
Patients should be advised to take Moderiba with food.
Patients should be questioned about prior history of drug
abuse before initiating Moderiba/peginterferon alfa-2a, as relapse of drug
addiction and drug overdoses have been reported in patients treated with
Patients should be advised not to drink alcohol, as
alcohol may exacerbate chronic hepatitis C infection. Patients should be
informed about what to do in the event they miss a dose of Moderiba. The missed
doses should be taken as soon as possible during the same day. Patients should
not double the next dose. Patients should be advised to call their healthcare
provider if they have questions.
Patients should be informed that the effect of
peginterferon alfa-2a/Moderiba treatment of hepatitis C infection on transmission
is not known, and that appropriate precautions to prevent transmission of hepatitis
C virus during treatment or in the event of treatment failure should be taken.
Patients should be informed regarding the potential
benefits and risks attendant to the use of Moderiba. Instructions on
appropriate use should be given, including review of the contents of the
enclosed MEDICATION GUIDE, which is not a disclosure of all or possible adverse
Carcinogenesis, Mutagenesis, Impairment Of Fertility
In a p53 (+/-) mouse carcinogenicity study up to the
maximum tolerated dose of 100 mg/kg/day, ribavirin was not oncogenic. Ribavirin
was also not oncogenic in a rat 2-year carcinogenicity study at doses up to the
maximum tolerated dose of 60 mg/kg/day. On a body surface area basis, these
doses are approximately 0.5 and 0.6 times the maximum recommended daily human
dose of ribavirin, respectively.
Ribavirin demonstrated mutagenic activity in the in vitro
mouse lymphoma assay. No clastogenic activity was observed in an in vivo mouse
micronucleus assay at doses up to 2000 mg/kg. However, results from studies
published in the literature show clastogenic activity in the in vivo mouse
micronucleus assay at oral doses up to 2000 mg/kg. 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
In a fertility study in rats, ribavirin showed a marginal
reduction in sperm counts at the dose of 100 mg/kg/day with no effect on
fertility. Upon cessation of treatment, total recovery occurred after 1 spermatogenesis
cycle. Abnormalities in sperm were observed in studies in mice designed to
evaluate the time course and reversibility of ribavirin-induced testicular
degeneration at doses of 15 to 150 mg/kg/day (approximately 0.1 to 0.8 times
the maximum recommended daily human dose of ribavirin) administered for 3 to 6
months. Upon cessation of treatment, essentially total recovery from
ribavirininduced testicular toxicity was apparent within 1 or 2 spermatogenic
Female patients of childbearing potential and male
patients with female partners of childbearing potential should not receive
Moderiba unless the patient and his/her partner are using effective contraception
(two reliable forms). Based on a multiple dose half-life (t ½) of ribavirin
of 12 days, effective contraception must be utilized for 6 months post therapy
(i.e., 15 half-lives of clearance for ribavirin).
No reproductive toxicology studies have been performed
using peginterferon alfa-2a in combination with ribavirin. However,
peginterferon alfa-2a and ribavirin when administered separately, each has adverse
effects on reproduction. It should be assumed that the effects produced by
either agent alone would also be caused by the combination of the two agents.
Use In Specific Populations
Pregnancy: Category X
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
[see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].
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 times the recommended daily human 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 (approximately 0.01 times the maximum
recommended daily human dose of ribavirin).
Treatment And Post-Treatment: 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 is contained in sperm, and if so, will exert a potential teratogenic
effect upon fertilization of the ova. 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.
Moderiba should not be used by pregnant women or by men
whose female partners are pregnant. Female patients of childbearing potential
and male patients with female partners of childbearing potential should not
receive Moderiba unless the patient and his/her partner are using effective
contraception (two reliable forms) during therapy and for 6 months post therapy
Ribavirin Pregnancy Registry
A Ribavirin Pregnancy Registry has been established to
monitor maternal-fetal outcomes of pregnancies of female patients and female
partners of male patients exposed to ribavirin during treatment and for 6 months
following cessation of treatment. Healthcare providers and patients are
encouraged to report such cases by calling 1-800-593-2214.
It is not known whether ribavirin is excreted in human
milk. Because many drugs are excreted in human milk and to avoid any potential
for serious adverse reactions in nursing infants from ribavirin, a decision should
be made either to discontinue nursing or therapy with Moderiba, based on the
importance of the therapy to the mother.
Pharmacokinetic evaluations in pediatric patients have
not been performed.
Safety and effectiveness of Moderiba tablets have not
been established in patients below the age of 5 years.
Clinical studies of ribavirin and peginterferon alfa-2a
did not include sufficient numbers of subjects aged 65 or over to determine
whether they respond differently from younger subjects. Specific pharmacokinetic
evaluations for ribavirin in the elderly have not been performed. The risk of
toxic reactions to this drug may be greater in patients with impaired renal
function. The dose of Moderiba should be reduced in patients with creatinine
clearance less than or equal to 50 mL/min; and the dose of peginterferon
alfa-2a should be reduced in patients with creatinine clearance less than 30
mL/min [see DOSAGE AND ADMINISTRATION; Use In Specific Populations].
A pharmacokinetic study in 42 subjects demonstrated there
is no clinically significant difference in ribavirin pharmacokinetics among
Black (n=14), Hispanic (n=13) and Caucasian (n=15) subjects.
Renal function should be evaluated in all patients prior
to initiation of Moderiba by estimating the patient's creatinine clearance.
A clinical trial evaluated treatment with ribavirin and
peginterferon alfa-2a in 50 CHC subjects with moderate (creatinine clearance 30
– 50 mL/min) or severe (creatinine clearance less than 30 mL/min) renal
impairment or end stage renal disease (ESRD) requiring chronic hemodialysis
(HD). In 18 subjects with ESRD receiving chronic HD, ribavirin was administered
at a dose of 200 mg daily with no apparent difference in the adverse event
profile in comparison to subjects with normal renal function. Dose reductions
and temporary interruptions of ribavirin (due to ribavirin-related adverse
reactions, mainly anemia) were observed in up to one-third ESRD/HD subjects
during treatment; and only one-third of these subjects received ribavirin for
48 weeks. Ribavirin plasma exposures were approximately 20% lower in subjects
with ESRD on HD compared to subjects with normal renal function receiving the standard
1000/1200 mg ribavirin daily dose.
Subjects with moderate (n=17) or severe (n=14) renal
impairment did not tolerate 600 mg or 400 mg daily doses of ribavirin,
respectively, due to ribavirin-related adverse reactions, mainly anemia, and exhibited
20% to 30% higher ribavirin plasma exposures (despite frequent dose
modifications) compared to subjects with normal renal function (creatinine
clearance greater than 80 mL/min) receiving the standard dose of ribavirin.
Discontinuation rates were higher in subjects with severe renal impairment
compared to that observed in subjects with moderate renal impairment or normal
renal function. Pharmacokinetic modeling and simulation indicate that a dose of
200 mg daily in patients with severe renal impairment and a dose of 200 mg
daily alternating with 400 mg the following day in patients with moderate renal
impairment will provide plasma ribavirin exposure similar to patients with normal
renal function receiving the approved regimen of ribavirin. These doses have
not been studied in patients [see DOSAGE AND ADMINISTRATION and CLINICAL
Based on the pharmacokinetic and safety results from this
trial, patients with creatinine clearance less than or equal to 50 mL/min
should receive a reduced dose of ribavirin; and patients with creatinine clearance
less than 30 mL/min should receive a reduced dose of peginterferon alfa-2a. The
clinical and hematologic status of patients with creatinine clearance less than
or equal to 50 mL/min receiving ribavirin should be carefully monitored.
Patients with clinically significant laboratory abnormalities or adverse
reactions which are persistently severe or worsening should have therapy
withdrawn [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY,
and Peginterferon alfa-2a Package Insert].
The effect of hepatic impairment on the pharmacokinetics
of ribavirin following administration of ribavirin has not been evaluated. The
clinical trials of ribavirin were restricted to patients with Child- Pugh class
No clinically significant differences in the
pharmacokinetics of ribavirin were observed between male and female subjects.
Ribavirin pharmacokinetics, when corrected for weight,
are similar in male and female patients.
Organ Trans Plant Recipients
The safety and efficacy of peginterferon alfa-2a and
ribavirin treatment have not been established in patients with liver and other
transplantations. As with other alpha interferons, liver and renal graft rejections
have been reported on peginterferon alfa-2a, alone or in combination with
ribavirin [see ADVERSE REACTIONS].