HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`COPEGUS safely and effectively. See full prescribing information for
`COPEGUS.
`
`COPEGUS® (ribavirin) tablets, for oral use
`Initial U.S. Approval: 2002
`
`(cid:120)
`
`(cid:120)
`
`(cid:120)
`
`WARNING: RISK OF SERIOUS DISORDERS AND RIBAVIRIN-
`ASSOCIATED EFFECTS
`See full prescribing information for complete boxed warning.
`Ribavirin monotherapy, including COPEGUS, is not effective for
`the treatment of chronic hepatitis C virus infection (Boxed
`Warning).
`The hemolytic anemia associated with ribavirin therapy may result
`in worsening of cardiac disease and lead to fatal and nonfatal
`myocardial infarctions. Patients with a history of significant or
`unstable cardiac disease should not be treated with COPEGUS (2.3,
`5.2, 6.1).
`Significant teratogenic and embryocidal effects have been
`demonstrated in all animal species exposed to ribavirin. Therefore,
`COPEGUS is contraindicated in women who are pregnant and in
`the male partners of women who are pregnant. Extreme care must
`be taken to avoid pregnancy during therapy and for 6 months after
`completion of treatment in both female patients and in female
`partners of male patients who are taking COPEGUS therapy (4, 5.1,
`8.1).
`
`---------------------------RECENT MAJOR CHANGES ---------------------------
`Warnings and Precautions (5.8)
`08/2015
`
`--------------------------- INDICATIONS AND USAGE----------------------------
`COPEGUS is a nucleoside analogue indicated for the treatment of chronic
`hepatitis C (CHC) virus infection in combination with PEGASYS in patients
`5 years of age and older with compensated liver disease not previously treated
`with interferon alpha, and in adult CHC patients coinfected with HIV (1)
`
`-----------------------DOSAGE AND ADMINISTRATION -----------------------
`CHC: COPEGUS is administered according to body weight and
`(cid:120)
`genotype (2.1)
`CHC with HIV coinfection: 800 mg by mouth daily for a total of 48
`weeks, regardless of genotype (2.2)
`Dose reduction or discontinuation is recommended in patients
`experiencing certain adverse reactions or renal impairment (2.3, 2.4)
`
`(cid:120)
`
`(cid:120)
`
`--------------------- DOSAGE FORMS AND STRENGTHS----------------------
`COPEGUS tablets 200 mg (3)
`(cid:120)
`
`------------------------------ CONTRAINDICATIONS ------------------------------
`Pregnant women and men whose female partners are pregnant (4, 5.1,
`(cid:120)
`8.1)
`Hemoglobinopathies (4)
`Coadministration with didanosine (4, 7.1)
`
`(cid:120)
`(cid:120)
`
`COPEGUS in combination with PEGASYS is contraindicated in patients
`with:
`Autoimmune hepatitis (4)
`(cid:120)
`(cid:120)
`Hepatic decompensation in cirrhotic patients (4, 5.3)
`
`----------------------- WARNINGS AND PRECAUTIONS -----------------------
`Birth defects and fetal death with ribavirin: Do not use in pregnancy and
`(cid:120)
`for 6 months after treatment. Patients must have a negative pregnancy
`test prior to therapy, use at least 2 forms of contraception and undergo
`monthly pregnancy tests (4, 5.1, 8.1)
`
`(cid:120)
`
`(cid:120)
`
`PEGASYS/COPEGUS: Patients exhibiting the following conditions should be
`closely monitored and may require dose reduction or discontinuation of
`therapy:
`Hemolytic anemia may occur with a significant initial drop in
`(cid:120)
`hemoglobin. This may result in worsening cardiac disease leading to
`fatal or nonfatal myocardial infarctions (5.2, 6.1)
`Risk of hepatic failure and death: Monitor hepatic function during
`treatment and discontinue treatment for hepatic decompensation (5.3)
`Severe hypersensitivity reactions including urticaria, angioedema,
`bronchoconstriction, and anaphylaxis, and serious skin reactions such as
`Stevens-Johnson Syndrome (5.4)
`Pulmonary disorders, including pulmonary function impairment and
`pneumonitis, including fatal cases of pneumonia (5.5)
`Severe depression and suicidal ideation, autoimmune and infectious
`disorders, suppression of bone marrow function, pancreatitis, and
`diabetes (5)
`Bone marrow suppression with azathioprine coadministration (5.6)
`Growth impairment with combination therapy in pediatric patients (5.8)
`
`(cid:120)
`
`(cid:120)
`
`(cid:120)
`(cid:120)
`
`------------------------------ ADVERSE REACTIONS ------------------------------
`The most common adverse reactions (frequency greater than 40%) in adults
`receiving combination therapy are fatigue/asthenia, pyrexia, myalgia, and
`headache. (6.1)
`
`The most common adverse reactions in pediatric subjects were similar to
`those seen in adults. (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Genentech at
`1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`------------------------------ DRUG INTERACTIONS-------------------------------
`Nucleoside analogues: Closely monitor for toxicities. Discontinue
`(cid:120)
`nucleoside reverse transcriptase inhibitors or reduce dose or discontinue
`interferon, ribavirin or both with worsening toxicities (7.1)
`Azathioprine: Concomitant use of azathioprine with ribavirin has been
`reported to induce severe pancytopenia and may increase the risk of
`azathioprine-related myelotoxicity (7.3)
`
`(cid:120)
`
`----------------------- USE IN SPECIFIC POPULATIONS -----------------------
`Ribavirin Pregnancy Registry (8.1)
`(cid:120)
`(cid:120)
`Pediatrics: Safety and efficacy in pediatric patients less than 5 years old
`have not been established (8.4)
`Renal Impairment: Dose should be reduced in patients with creatinine
`clearance less than or equal to 50 mL/min (8.7)
`Organ Transplant: Safety and efficacy have not been studied (8.10)
`
`(cid:120)
`
`(cid:120)
`
`Revised: 08/2015
`____________________________________________________________________________________________________________________________________
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved Medication Guide.
`
`Reference ID: 3804614
`
`BMS 2014
`MYLAN v. BMS
`IPR2018-00892
`
`1
`
`

`

`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: RISK OF SERIOUS DISORDERS AND RIBAVIRIN-
`ASSOCIATED EFFECTS
`INDICATIONS AND USAGE
`1
`2 DOSAGE AND ADMINISTRATION
`2.1 Chronic Hepatitis C Monoinfection
`2.2 Chronic Hepatitis C with HIV Coinfection
`2.3 Dose Modifications
`2.4 Renal Impairment
`2.5 Discontinuation of Dosing
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Pregnancy
`5.2 Anemia
`5.3 Hepatic Failure
`5.4 Hypersensitivity
`5.5 Pulmonary Disorders
`5.6 Bone Marrow Suppression
`5.7 Pancreatitis
`5.8
`Impact on Growth in Pediatric Patients
`5.9 Laboratory Tests
`6 ADVERSE REACTIONS
`6.1 Clinical Studies Experience
`6.2 Postmarketing Experience
`7 DRUG INTERACTIONS
`7.1 Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
`7.2 Drugs Metabolized by Cytochrome P450
`7.3 Azathioprine
`____________________________________________________________________________________________________________________________________
`
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Race
`8.7 Renal Impairment
`8.8 Hepatic Impairment
`8.9 Gender
`8.10 Organ Transplant Recipients
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.3 Pharmacokinetics
`12.4 Microbiology
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.2 Animal Toxicology
`14 CLINICAL STUDIES
`14.1 Chronic Hepatitis C Patients
`14.2 Other Treatment Response Predictors
`14.3 Chronic Hepatitis C/HIV Coinfected Patients
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information are not
`listed
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`FULL PRESCRIBING INFORMATION
`WARNING: RISK OF SERIOUS DISORDERS AND RIBAVIRIN-ASSOCIATED EFFECTS
`COPEGUS (ribavirin) monotherapy is not effective for the treatment of chronic hepatitis C virus
`infection and should not be used alone for this indication.
`The primary clinical toxicity of ribavirin is hemolytic anemia. The anemia associated with ribavirin
`therapy may result in worsening of cardiac disease and lead to fatal and nonfatal myocardial infarctions.
`Patients with a history of significant or unstable cardiac disease should not be treated with COPEGUS
`[see Warnings and Precautions (5.2), Adverse Reactions (6.1), and Dosage and Administration (2.3)].
`Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed
`to ribavirin. In addition, ribavirin has a multiple dose half-life of 12 days, and it may persist in non-
`plasma compartments for as long as 6 months. Therefore, ribavirin, including COPEGUS,
`is
`contraindicated in women who are pregnant and in the male partners of women who are pregnant.
`Extreme care must be taken to avoid pregnancy during therapy and for 6 months after completion of
`therapy in both female patients and in female partners of male patients who are taking ribavirin therapy.
`At least two reliable forms of effective contraception must be utilized during treatment and during the
`6-month post treatment follow-up period [see Contraindications (4), Warnings and Precautions (5.1), and
`Use in Specific Populations (8.1)].
`1
`INDICATIONS AND USAGE
`COPEGUS in combination with PEGASYS (peginterferon alfa-2a) is indicated for the treatment of patients
`5 years of age and older with chronic hepatitis C (CHC) virus infection who have compensated liver disease and
`have not been previously treated with interferon alpha.
`The following points should be considered when initiating COPEGUS combination therapy with PEGASYS:
`(cid:120) This indication is based on clinical trials of combination therapy in patients with CHC and compensated
`liver disease, some of whom had histological evidence of cirrhosis (Child-Pugh class A), and in adult
`patients with clinically stable HIV disease and CD4 count greater than 100 cells/mm3.
`(cid:120) This indication is based on achieving undetectable HCV RNA after treatment for 24 or 48 weeks, based on
`HCV genotype, and maintaining a Sustained Virologic Response (SVR) 24 weeks after the last dose.
`(cid:120) Safety and efficacy data are not available for treatment longer than 48 weeks.
`(cid:120) The safety and efficacy of COPEGUS and PEGASYS therapy have not been established in liver or other
`organ transplant recipients, patients with decompensated liver disease, or previous non-responders to
`interferon therapy.
`(cid:120) The safety and efficacy of COPEGUS therapy for the treatment of adenovirus, RSV, parainfluenza or
`influenza infections have not been established. COPEGUS should not be used for these indications.
`Ribavirin for inhalation has a separate package insert, which should be consulted if ribavirin inhalation
`therapy is being considered.
`
`DOSAGE AND ADMINISTRATION
`2
`COPEGUS should be taken with food. COPEGUS should be given in combination with PEGASYS; it is
`important to note that COPEGUS should never be given as monotherapy. See PEGASYS Package Insert for all
`instructions regarding PEGASYS dosing and administration.
`2.1
`Chronic Hepatitis C Monoinfection
`Adult Patients
`The recommended dose of COPEGUS tablets is provided in Table 1. The recommended duration of treatment
`for patients previously untreated with ribavirin and interferon is 24 to 48 weeks.
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`

`The daily dose of COPEGUS is 800 mg to 1200 mg administered orally in two divided doses. The dose should
`be individualized to the patient depending on baseline disease characteristics (e.g., genotype), response to
`therapy, and tolerability of the regimen (see Table 1).
`Table 1
`PEGASYS and COPEGUS Dosing Recommendations
`PEGASYS Dose*
`COPEGUS Dose
`Duration
`Hepatitis C
`(once weekly)
`Virus (HCV)
`(daily)
`Genotype
`Genotypes 1, 4
`
`48 weeks
`<75 kg = 1000 mg
`(cid:116)75 kg = 1200 mg
`48 weeks
`24 weeks
`800 mg
`180 mcg
`Genotypes 2, 3
`Genotypes 2 and 3 showed no increased response to treatment beyond 24 weeks (see Table 10).
`Data on genotypes 5 and 6 are insufficient for dosing recommendations.
`*See PEGASYS Package Insert for further details on PEGASYS dosing and administration, including dose modification in patients
`with renal impairment.
`
`180 mcg
`
`Pediatric Patients
`PEGASYS is administered as 180 mcg/1.73m2 x BSA once weekly subcutaneously, to a maximum dose of
`180 mcg, and should be given in combination with ribavirin. The recommended treatment duration for patients
`with genotype 2 or 3 is 24 weeks and for other genotypes is 48 weeks.
`COPEGUS should be given in combination with PEGASYS. COPEGUS is available only as a 200 mg tablet
`and therefore the healthcare provider should determine if this sized tablet can be swallowed by the pediatric
`patient. The recommended doses for COPEGUS are provided in Table 2. Patients who initiate treatment prior
`to their 18th birthday should maintain pediatric dosing through the completion of therapy.
`Table 2
`COPEGUS Dosing Recommendations for Pediatric Patients
`Body Weight in kilograms
`COPEGUS Number of
`COPEGUS Daily Dose*
`(kg)
`Tablets
`1 x 200 mg tablet A.M.
`23 – 33
`1 x 200 mg tablet P.M.
`1 x 200 mg tablet A.M.
`2 x 200 mg tablets P.M.
`2 x 200 mg tablets A.M.
`2 x 200 mg tablets P.M.
`2 x 200 mg tablets A.M.
`3 x 200 mg tablets P.M.
`3 x 200 mg tablets A.M.
`3 x 200 mg tablets P.M.
`
`34 – 46
`
`47 – 59
`
`60 – 74
`
`(cid:149)(cid:26)(cid:24)
`*approximately 15 mg/kg/day
`
`400 mg/day
`
`600 mg/day
`
`800 mg/day
`
`1000 mg/day
`
`1200 mg/day
`
`2.2
`Chronic Hepatitis C with HIV Coinfection
`Adult Patients
`The recommended dose for treatment of chronic hepatitis C in patients coinfected with HIV is PEGASYS
`180 mcg subcutaneous once weekly and COPEGUS 800 mg by mouth daily for a total duration of 48 weeks,
`regardless of HCV genotype.
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`Decrease in hemoglobin of (cid:116)2 g/dL
`during any 4 week period in patients
`with history of stable cardiac disease
`Adult Patients older than 18 years of age
`1 x 200 mg tablet A.M.
`Any weight
`2 x 200 mg tablets P.M.
`Pediatric Patients 5 to 18 years of age
`23 – 33 kg
`1 x 200 mg tablet A.M.
`1 x 200 mg tablet A.M.
`34 – 46 kg
`1 x 200 mg tablet P.M.
`1 x 200 mg tablet A.M.
`1 x 200 mg tablet P.M.
`1 x 200 mg tablet A.M.
`2 x 200 mg tablets P.M.
`1 x 200 mg tablet A.M.
`2 x 200 mg tablets P.M.
`
`47 – 59 kg
`
`60 – 74 kg
`
`Hemoglobin <12 g/dL despite 4
`weeks at reduced dose in patients
`with history of stable cardiac disease
`
`Discontinue COPEGUS
`
`Discontinue COPEGUS
`
`Dose Modifications
`2.3
`Adult and Pediatric Patients
`If severe adverse reactions or laboratory abnormalities develop during combination COPEGUS/PEGASYS
`therapy, the dose should be modified or discontinued, if appropriate, until the adverse reactions abate or
`decrease in severity. If intolerance persists after dose adjustment, COPEGUS/PEGASYS therapy should be
`discontinued. Table 3 provides guidelines for dose modifications and discontinuation based on the patient’s
`hemoglobin concentration and cardiac status.
`COPEGUS 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 and Precautions (5.2)].
`Table 3
`COPEGUS Dose Modification Guidelines in Adults and Pediatrics
`Laboratory Values
`Hemoglobin <10 g/dL in patients with
`Hemoglobin <8.5 g/dL in patients
`no cardiac disease, or
`with no cardiac disease, or
`
`Body weight in
`kilograms (kg)
`
`(cid:149)(cid:26)(cid:24) kg
`
`The guidelines for COPEGUS dose modifications outlined in this table also apply to laboratory abnormalities or
`adverse reactions other than decreases in hemoglobin values.
`Adult Patients
`Once COPEGUS has been withheld due to either a laboratory abnormality or clinical adverse reaction, an
`attempt may be made to restart COPEGUS at 600 mg daily and further increase the dose to 800 mg daily.
`However, it is not recommended that COPEGUS be increased to the original assigned dose (1000 mg to
`1200 mg).
`Pediatric Patients
`Upon resolution of a laboratory abnormality or clinical adverse reaction, an increase in COPEGUS dose to the
`original dose may be attempted depending upon the physician’s judgment. If COPEGUS has been withheld due
`to a laboratory abnormality or clinical adverse reaction, an attempt may be made to restart COPEGUS at one-
`half the full dose.
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`Renal Impairment
`2.4
`The total daily dose of COPEGUS should be reduced for patients with creatinine clearance less than or equal
`to 50 mL/min; and the weekly dose of PEGASYS should be reduced for creatinine clearance less than
`30 mL/min as follows in Table 4 [see Use in Specific Populations (8.7), Pharmacokinetics (12.3), and
`PEGASYS Package Insert].
`Table 4
`Dosage Modification for Renal Impairment
`Creatinine
`PEGASYS Dose
`COPEGUS Dose
`Clearance
`(once weekly)
`(daily)
`30 to 50 mL/min
`180 mcg
`Alternating doses, 200 mg and
`400 mg every other day
`200 mg daily
`200 mg daily
`
`Less than 30 mL/min
`Hemodialysis
`
`135 mcg
`135 mcg
`
`The dose of COPEGUS should not be further modified in patients with renal impairment. If severe adverse
`reactions or laboratory abnormalities develop, COPEGUS should be discontinued, if appropriate, until the
`adverse reactions abate or decrease in severity. If intolerance persists after restarting COPEGUS,
`COPEGUS/PEGASYS therapy should be discontinued.
`No data are available for pediatric subjects with renal impairment.
`2.5
`Discontinuation of Dosing
`Discontinuation of PEGASYS/COPEGUS therapy should be considered if the patient has failed to demonstrate
`at least a 2 log10 reduction from baseline in HCV RNA by 12 weeks of therapy, or undetectable HCV RNA
`levels after 24 weeks of therapy.
`PEGASYS/COPEGUS therapy should be discontinued in patients who develop hepatic decompensation during
`treatment [see Warnings and Precautions (5.3)].
`3
`DOSAGE FORMS AND STRENGTHS
`COPEGUS (ribavirin) is available as a light pink to pink colored, flat, oval-shaped, film-coated tablet for oral
`administration. Each tablet contains 200 mg of ribavirin.
`4
`CONTRAINDICATIONS
`COPEGUS (ribavirin) is contraindicated in:
`(cid:120) Women who are pregnant. COPEGUS may cause fetal harm when administered to a pregnant woman.
`COPEGUS is contraindicated in women who are or may become pregnant. If this drug is used during
`pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the
`potential hazard to the fetus [see Warnings and Precautions (5.1), Use in Specific Populations (8.1), and
`Patient Counseling Information (17)].
`(cid:120) Men whose female partners are pregnant.
`(cid:120) Patients with hemoglobinopathies (e.g., thalassemia major or sickle-cell anemia).
`In combination with didanosine. Reports of fatal hepatic failure, as well as peripheral neuropathy,
`(cid:120)
`pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in clinical trials [see Drug
`Interactions (7.1)].
`COPEGUS and PEGASYS combination therapy is contraindicated in patients with:
`(cid:120) Autoimmune hepatitis.
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`

`(cid:120) Hepatic decompensation (Child-Pugh score greater than 6; class B and C) in cirrhotic CHC monoinfected
`patients before treatment [see Warnings and Precautions (5.3)].
`(cid:120) Hepatic decompensation (Child-Pugh score greater than or equal to 6) in cirrhotic CHC patients coinfected
`with HIV before treatment [see Warnings and Precautions (5.3)].
`
`WARNINGS AND PRECAUTIONS
`5
`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 treatment.
`5.1
`Pregnancy
`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 (4), Use in Specific Populations (8.1), and Patient Counseling Information (17)].
`5.2
`Anemia
`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 (2.3)].
`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 (2.3)]. 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 (2.3)].
`5.3
`Hepatic Failure
`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 (14.3)], 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
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`

`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 (4)].
`5.4
`Hypersensitivity
`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 (6.2)].
`5.5
`Pulmonary Disorders
`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.
`5.6
`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 Interactions (7.3)].
`5.7
`Pancreatitis
`COPEGUS and PEGASYS therapy should be suspended in patients with signs and symptoms of pancreatitis,
`and discontinued in patients with confirmed pancreatitis.
`5.8
`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 (6.1)].
`Laboratory Tests
`5.9
`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
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`

`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:
`(cid:120) 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)
`(cid:120) Absolute neutrophil count (ANC) greater than or equal to 1500 cells/mm3
`(cid:120) TSH and T4 within normal limits or adequately controlled thyroid function
`(cid:120) 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
`(cid:120) 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
`(cid:120) 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
`
`ADVERSE REACTIONS
`6
`PEGASYS in combination with COPEGUS causes a broad variety of serious adverse reactions [see Boxed
`Warning and Warnings and Precautions (5)]. The most common serious or life-threatening adverse reactions
`induced or aggravated by COPEGUS/PEGASYS include depression, suicide, relapse of drug abuse/overdose,
`and bacterial infections each occurring at a frequency of less than 1%. Hepatic decompensation occurred in 2%
`(10/574) CHC/HIV patients [see Warnings and Precautions (5.3)].
`6.1
`Clinical Studies Experience
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the
`clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not
`reflect the rates observed in clinical practice.
`Adult Patients
`In the pivotal registration trials NV15801 and NV15942, 886 patients received COPEGUS for 48 weeks at
`doses of 1000/1200 mg based on body weight. In these trials, one or more serious adverse reactions occurred in
`10% of CHC monoinfected subjects and in 19% of CHC/HIV subjects receiving PEGASYS alone or in
`combination with COPEGUS. The most common serious adverse event (3% in CHC and 5% in CHC/HIV) was
`bacterial infection (e.g., sepsis, osteomyelitis, endocarditis, pyelonephritis, pneumonia).
`Other serious adverse reactions occurred at a frequency of less than 1% and included: suicide, suicidal ideation,
`psychosis, aggression, anxiety, drug abuse and drug overdose, angina, hepatic dysfunction, fatty liver,
`cholangitis, arrhythmia, diabetes mellitus, autoimmune phenomena (e.g., hyperthyroidism, hypothyroidism,
`sarcoidosis, systemic lupus erythematosus, rheumatoid arthritis), peripheral neuropathy, aplastic anemia, peptic
`ulcer, gastrointestinal bleeding, pancreatitis, colitis, corneal ulcer, pulmonary embolism, coma, myositis,
`cerebral hemorrhage, thrombotic thrombocytopenic purpura, psychotic disorder, and hallucination.
`The percentage of patients in clinical trials who experienced one or more adverse events was 98%. The most
`commonly reported adverse reactions were psychiatric reactions, including depression, insomnia, irritability,
`anxiety, and flu-like symptoms such as fatigue, pyrexia, myalgia, headache and rigors. Other common reactions
`were anorexia, nausea and vomiting, diarrhea, arthralgias, injection site reactions, alopecia, and pruritus.
`
`Reference ID: 3804614
`
`9
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`

`

`Table 5 shows rates of adverse events occurring in greater than or equal to 5% of subjects receiving pegylated
`interferon and ribavirin combination therapy in the CHC Clinical Trial, NV15801.
`Ten percent of CHC monoinfected patients receiving 48 weeks of therapy with PEGASYS in combination with
`COPEGUS discontinued therapy; 16% of CHC/HIV coinfected patients discontinued therapy. The most
`common reasons for discontinuation of therapy were psychiatric, flu-like syndrome (e.g., lethargy, fatigue,
`headache), dermatologic and gastrointestinal disorders, and laboratory abnormalities (thrombocytopenia,
`neutropenia, and anemia).
`Overall 39% of patients with CHC or CHC/HIV required modification of PEGASYS and/or COPEGUS
`therapy. The most common reason for dose modification of PEGASYS in CHC and CHC/HIV patients was for
`laboratory abnormalities; neutropenia (20% and 27%, respectively) and thrombocytopenia (4% and 6%,
`respectively). The most common reason for dose modification of COPEGUS in CHC and CHC/HIV patients
`was anemia (22% and 16%, respectively).
`PEGASYS dose was reduced in 12% of patients receiving 1000 mg to 1200 mg COPEGUS for 48 weeks and in
`7% of patients receiving 800 mg COPEGUS for 24 weeks. COPEGUS dose was reduced in 21% of patients
`receiving 1000 mg to 1200 mg COPEGUS for 48 weeks and in 12% of patients receiving 800 mg COPEGUS
`for 24 weeks.
`Chronic hep