Included as part of the PRECAUTIONS section.
Significant adverse reactions associated with
COPEGUS/PEGASYS 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 PEGASYS Package Insert should be reviewed in its
entirety for additional safety information prior to initiation of combination
COPEGUS 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.
COPEGUS 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 COPEGUS 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 COPEGUS/PEGASYS-treated subjects
in clinical trials. Anemia associated with COPEGUS 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 COPEGUS. 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 COPEGUS [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 PEGASYS. 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 PEGASYS/COPEGUS 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
PEGASYS and COPEGUS 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 PEGASYS with
and without ribavirin. Patients developing signs or symptoms of severe skin
reactions must discontinue therapy [see ADVERSE REACTIONS].
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 COPEGUS/PEGASYS
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. PEGASYS, COPEGUS, and azathioprine
should be discontinued for pancytopenia, and pegylated interferon/ribavirin
should not be re-introduced with concomitant azathioprine [see DRUG
COPEGUS and PEGASYS 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
PEGASYS 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 PEGASYS/COPEGUS 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 PEGASYS/COPEGUS.
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
COPEGUS and PEGASYS 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 HIV
- 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. COPEGUS 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 COPEGUS therapy and for 6 months post therapy. Patients
should use two reliable methods of birth control while taking COPEGUS therapy
and for 6 months post therapy. COPEGUS 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 COPEGUS 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
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 COPEGUS 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 COPEGUS with food.
Patients should be questioned about prior history of drug
abuse before initiating COPEGUS/PEGASYS, as relapse of drug addiction and drug
overdoses have been reported in patients treated with interferons.
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 COPEGUS. 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
Patients should be informed that the effect of
PEGASYS/COPEGUS 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 COPEGUS. 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 effects.
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
ribavirin-induced 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
COPEGUS unless the patient and his/her partner are using effective
contraception (two reliable forms). Based on a multiple dose half-life (t½) 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 PEGASYS in combination with COPEGUS. 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
Category X [see CONTRAINDICATIONS].
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
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.
COPEGUS 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 COPEGUS 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 COPEGUS, based on
the importance of the therapy to the mother.
Pharmacokinetic evaluations in pediatric patients have
not been performed.
Safety and effectiveness of COPEGUS have not been
established in patients below the age of 5 years.
Clinical studies of COPEGUS and PEGASYS 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 COPEGUS should be reduced in patients with creatinine clearance
less than or equal to 50 mL/min; and the dose of PEGASYS 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 COPEGUS by estimating the patient's creatinine clearance.
A clinical trial evaluated treatment with COPEGUS and
PEGASYS 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, COPEGUS 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 COPEGUS (due to COPEGUS-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 COPEGUS 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 COPEGUS daily dose.
Subjects with moderate (n=17) or severe (n=14) renal
impairment did not tolerate 600 mg or 400 mg daily doses of COPEGUS, respectively,
due to COPEGUS-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 COPEGUS. 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 COPEGUS. 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 COPEGUS; and patients with creatinine
clearance less than 30 mL/min should receive a reduced dose of PEGASYS. The
clinical and hematologic status of patients with creatinine clearance less than
or equal to 50 mL/min receiving COPEGUS 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 PEGASYS Package
The effect of hepatic impairment on the pharmacokinetics
of ribavirin following administration of COPEGUS has not been evaluated. The clinical
trials of COPEGUS were restricted to patients with Child-Pugh class A disease.
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 Transplant Recipients
The safety and efficacy of PEGASYS and COPEGUS 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 PEGASYS, alone or in combination with COPEGUS [see ADVERSE