Pegintron / Rebetol Combo Pack

Ribavirin:

• Warning: risk of serious disorders and ribavirin-associated effects
• Recent major changes
• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Pegintron / Rebetol Combo Pack (Ribavirin) reviews

WARNING: RISK OF SERIOUS DISORDERS AND RIBAVIRIN-ASSOCIATED EFFECTS

WARNING: RISK OF SERIOUS DISORDERS AND RIBAVIRINASSOCIATED EFFECTS

See full prescribing information for complete boxed warning.

• Pegintron / Rebetol Combo Pack (Ribavirin) monotherapy, including Pegintron / Rebetol Combo Pack (Ribavirin), is not effective for the treatment of chronic hepatitis C virus infection (Boxed Warning).
• The hemolytic anemia associated with Pegintron / Rebetol Combo Pack (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 Pegintron / Rebetol Combo Pack (Ribavirin) (2.3, 5.2, 6.1).
• Significant teratogenic and embryocidal effects have been demonstrated in all animal species exposed to Pegintron / Rebetol Combo Pack (Ribavirin). Therefore, Pegintron / Rebetol Combo Pack (Ribavirin) 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 Pegintron / Rebetol Combo Pack (Ribavirin) therapy (4, 5.1, 8.1).

Pegintron / Rebetol Combo Pack (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 Pegintron / Rebetol Combo Pack (Ribavirin) is hemolytic anemia. The anemia associated with Pegintron / Rebetol Combo Pack (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 Pegintron / Rebetol Combo Pack (Ribavirin).

Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to Pegintron / Rebetol Combo Pack (Ribavirin). In addition, Pegintron / Rebetol Combo Pack (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, Pegintron / Rebetol Combo Pack (Ribavirin), including Pegintron / Rebetol Combo Pack (Ribavirin), 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 Pegintron / Rebetol Combo Pack (Ribavirin) therapy. At least two reliable forms of effective contraception must be utilized during treatment and during the 6month post treatment follow-up period.

RECENT MAJOR CHANGES

Warnings and Precautions (5.8) 08/2015

1 INDICATIONS AND USAGE

Pegintron / Rebetol Combo Pack (Ribavirin) is a nucleoside analogue indicated for the treatment of chronic hepatitis C (CHC) virus infection in combination with peginterferon alfa-2a 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)

Pegintron / Rebetol Combo Pack (Ribavirin) tablets in combination with peginterferon alfa-2a are 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 Pegintron / Rebetol Combo Pack (Ribavirin) tablets combination therapy with peginterferon alfa-2a:

• 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.
• 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.
• Safety and efficacy data are not available for treatment longer than 48 weeks.
• The safety and efficacy of Pegintron / Rebetol Combo Pack (Ribavirin) tablets and peginterferon alfa-2a therapy have not been established in liver or other organ transplant recipients, patients with decompensated liver disease, or previous non-responders to interferon therapy.
• The safety and efficacy of Pegintron / Rebetol Combo Pack (Ribavirin) tablets therapy for the treatment of adenovirus, RSV, parainfluenza or influenza infections have not been established. Pegintron / Rebetol Combo Pack (Ribavirin) tablets should not be used for these indications. Pegintron / Rebetol Combo Pack (Ribavirin) for inhalation has a separate package insert, which should be consulted if Pegintron / Rebetol Combo Pack (Ribavirin) inhalation therapy is being considered.

2 DOSAGE AND ADMINISTRATION

• CHC: Pegintron / Rebetol Combo Pack is administered according to body weight and 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)

Pegintron / Rebetol Combo Pack (Ribavirin) should be taken with food. Pegintron / Rebetol Combo Pack (Ribavirin) should be given in combination with peginterferon alfa-2a; it is important to note that Pegintron / Rebetol Combo Pack (Ribavirin) should never be given as monotherapy. See peginterferon alfa-2a Package Insert for all instructions regarding peginterferon alfa-2a dosing and administration.

2.1 Chronic Hepatitis C Monoinfection

Adult Patients

The recommended dose of Pegintron / Rebetol Combo Pack (Ribavirin) tablets is provided in Table 1. The recommended duration of treatment for patients previously untreated with Pegintron / Rebetol Combo Pack (Ribavirin) and interferon is 24 to 48 weeks.

The daily dose of Pegintron / Rebetol Combo Pack (Ribavirin) 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).

Hepatitis C Virus ( HCV ) Genotype	Peginterferon Alfa - 2a Dose * ( once weekly )	Ribavirin Dose ( daily )	Duration
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 Peginterferon alfa-2a Package Insert for further details on peginterferon alfa-2a dosing and administration, including dose modification in patients with renal impairment.
Genotypes 1, 4	180 mcg	< 75 kg = 1000 mg ≥ 75 kg = 1200 mg	48 weeks 48 weeks
Genotypes 2, 3	180 mcg	800 mg	24 weeks

Pediatric Patients

Peginterferon alfa-2a 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 Pegintron / Rebetol Combo Pack (Ribavirin). The recommended treatment duration for patients with genotype 2 or 3 is 24 weeks and for other genotypes is 48 weeks.

Pegintron / Rebetol Combo Pack (Ribavirin) should be given in combination with peginterferon alfa-2a. Pegintron / Rebetol Combo Pack (Ribavirin) 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 Pegintron / Rebetol Combo Pack (Ribavirin) are provided in Table 2. Patients who initiate treatment prior to their 18th birthday should maintain pediatric dosing through the completion of therapy

*approximately 15 mg/kg/day
Body Weight in kilograms ( kg )	Ribavirin Daily Dose *	Ribavirin Number of Tablets
23 to 33	400 mg/day	1 x 200 mg tablet A.M. 1 x 200 mg tablet P.M.
34 to 46	600 mg/day	1 x 200 mg tablet A.M. 2 x 200 mg tablets P.M.
47 to 59	800 mg/day	2 x 200 mg tablets A.M. 2 x 200 mg tablets P.M.
60 to 74	1000 mg/day	2 x 200 mg tablets A.M. 3 x 200 mg tablets P.M.
≥ 75	1200 mg/day	3 x 200 mg tablets A.M. 3 x 200 mg tablets P.M.

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 peginterferon alfa-2a 180 mcg subcutaneous once weekly and Pegintron / Rebetol Combo Pack 800 mg by mouth daily for a total duration of 48 weeks, regardless of HCV genotype.

2.3 Dose Modifications

Adult and Pediatric Patients

If severe adverse reactions or laboratory abnormalities develop during combination ribavirin/peginterferon alfa-2a 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, ribavirin/peginterferon alfa-2a therapy should be discontinued. Table 3 provides guidelines for dose modifications and discontinuation based on the patient's hemoglobin concentration and cardiac status.

Pegintron / Rebetol Combo Pack (Ribavirin) 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)].

Body weight in kilograms ( kg )	Laboratory Values
	Hemoglobin <10 g/dL in patients with no cardiac disease, or Decrease in hemoglobin of ≥2 g/dL during any 4 week period in patients with history of stable cardiac disease	Hemoglobin <8.5 g/dL in patients with no cardiac disease, or Hemoglobin <12 g/dL despite 4 weeks at reduced dose in patients with history of stable cardiac disease
Adult Patients older than 18 years of age
Any weight	1 x 200 mg tablet A.M. 2 x 200 mg tablets P.M.	Discontinue Ribavirin
Pediatric Patients 5 to 18 years of age
23 to 33 kg	1 x 200 mg tablet A.M.
34 to 46 kg	1 x 200 mg tablet A.M. 1 x 200 mg tablet P.M.
47 to 59 kg	1 x 200 mg tablet A.M. 1 x 200 mg tablet P.M.	Discontinue Ribavirin
60 to 74 kg	1 x 200 mg tablet A.M. 2 x 200 mg tablets P.M.
≥ 75kg	1 x 200 mg tablet A.M. 2 x 200 mg tablets P.M.

The guidelines for Pegintron / Rebetol Combo Pack (Ribavirin) dose modifications outlined in this table also apply to laboratory abnormalities or adverse reactions other than decreases in hemoglobin values.

Adult Patients

Once Pegintron / Rebetol Combo Pack (Ribavirin) has been withheld due to either a laboratory abnormality or clinical adverse reaction, an attempt may be made to restart Pegintron / Rebetol Combo Pack (Ribavirin) at 600 mg daily and further increase the dose to 800 mg daily. However, it is not recommended that Pegintron / Rebetol Combo Pack (Ribavirin) 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 Pegintron / Rebetol Combo Pack (Ribavirin) dose to the original dose may be attempted depending upon the physician's judgment. If Pegintron / Rebetol Combo Pack (Ribavirin) has been withheld due to a laboratory abnormality or clinical adverse reaction, an attempt may be made to restart Pegintron / Rebetol Combo Pack (Ribavirin) at one-half the full dose.

2.4 Renal Impairment

The total daily dose of Pegintron / Rebetol Combo Pack should be reduced for patients with creatinine clearance less than or equal to 50 mL/min; and the weekly dose of peginterferon alfa-2a 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 Peginterferon Alfa-2a PACKAGE INSERT].

Creatinine Clearance	Peginterferon Alfa - 2a Dose ( once weekly )	Ribavirin Dose ( daily )
30 to 50 mL/min	180 mcg	Alternating doses, 200 mg and 400 mg every other day
Less than 30 mL/min	135 mcg	200 mg daily
Hemodialysis	135 mcg	200 mg daily

The dose of Pegintron / Rebetol Combo Pack (Ribavirin) should not be further modified in patients with renal impairment. If severe adverse reactions or laboratory abnormalities develop, Pegintron / Rebetol Combo Pack (Ribavirin) should be discontinued, if appropriate, until the adverse reactions abate or decrease in severity. If intolerance persists after restarting Pegintron / Rebetol Combo Pack (Ribavirin), Pegintron / Rebetol Combo Pack (Ribavirin) /peginterferon alfa-2a therapy should be discontinued.

No data are available for pediatric subjects with renal impairment.

2.5 Discontinuation of Dosing

Discontinuation of peginterferon alfa-2a /ribavirin 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.

Peginterferon alfa-2a/ribavirin therapy should be discontinued in patients who develop hepatic decompensation during treatment [see WARNINGS AND PRECAUTIONS (5.3)].

3 DOSAGE FORMS AND STRENGTHS

• Pegintron / Rebetol Combo Pack (Ribavirin) tablets 200 mg or 400 mg or 500 mg or 600 mg (3)

Pegintron / Rebetol Combo Pack (Ribavirin) tablets for oral administration are available as:

200 mg - light pink to pink, round, biconvex, beveled, film-coated tablets;

400 mg - light pink to pink, capsule shaped, biconvex, film-coated tablets;

500 mg - light pink to pink, modified capsule shaped, biconvex, film-coated tablets;

600 mg - light pink to pink, modified capsule shaped, biconvex, film-coated tablets

4 CONTRAINDICATIONS

• Pregnant women and men whose female partners are pregnant (4, 5.1, 8.1)
• Hemoglobinopathies (4)
• Coadministration with didanosine (4, 7.1)

Pegintron / Rebetol Combo Pack (Ribavirin) in combination with peginterferon alfa-2a is contraindicated in patients with:

• Autoimmune hepatitis (4)
• Hepatic decompensation in cirrhotic patients (4, 5.3)

Pegintron / Rebetol Combo Pack (Ribavirin) is contraindicated in:

• Women who are pregnant. Pegintron / Rebetol Combo Pack (Ribavirin) may cause fetal harm when administered to a pregnant woman. Pegintron / Rebetol Combo Pack (Ribavirin) 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)].
• Men whose female partners are pregnant.
• 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, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in clinical trials.

Pegintron / Rebetol Combo Pack (Ribavirin) and peginterferon alfa-2a combination therapy is contraindicated in patients with:

• Autoimmune hepatitis.
• 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)].
• Hepatic decompensation (Child-Pugh score greater than or equal to 6) in cirrhotic CHC patients coinfected with HIV before treatment.

5 WARNINGS AND PRECAUTIONS

• Birth defects and fetal death with Pegintron / Rebetol Combo Pack : Do not use in pregnancy and 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)

Peginterferon alfa-2a/Ribavirin: 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 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)

Significant adverse reactions associated with ribavirin/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.

5.1 Pregnancy

Pegintron / Rebetol Combo Pack (Ribavirin) may cause birth defects and/or death of the exposed fetus. Pegintron / Rebetol Combo Pack (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 Pegintron / Rebetol Combo Pack (Ribavirin).

Pegintron / Rebetol Combo Pack (Ribavirin) 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 Pegintron / Rebetol Combo Pack (Ribavirin) 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 Pegintron / Rebetol Combo Pack is hemolytic anemia, which was observed in approximately 13% of all ribavirin/peginterferon alfa-2a- treated subjects in clinical trials. Anemia associated with Pegintron / Rebetol Combo Pack (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 (2.3)].

Fatal and nonfatal myocardial infarctions have been reported in patients with anemia caused by Pegintron / Rebetol Combo Pack (Ribavirin). Patients should be assessed for underlying cardiac disease before initiation of Pegintron / Rebetol Combo Pack (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 Pegintron / Rebetol Combo Pack (Ribavirin) [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 peginterferon alfa-2a. Cirrhotic CHC patients coinfected with HIV receiving highly active antiretroviral therapy (HAART) and interferon alfa-2a with or without Pegintron / Rebetol Combo Pack (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 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/ Pegintron / Rebetol Combo Pack (Ribavirin) should be discontinued immediately in patients with hepatic decompensation [see CONTRAINDICATIONS (4)]

5.4 Hypersensitivity

Severe acute hypersensitivity reactions have been observed during alpha interferon and Pegintron / Rebetol Combo Pack (Ribavirin) therapy. If such a reaction occurs, therapy with peginterferon alfa-2a and Pegintron / Rebetol Combo Pack (Ribavirin) 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 Pegintron / Rebetol Combo Pack (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 Pegintron / Rebetol Combo Pack (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 ribavirin/peginterferon alfa-2a treatment should be discontinued.

5.6 Bone Marrow Suppression

Pancytopenia 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, Pegintron / Rebetol Combo Pack (Ribavirin), 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

Pegintron / Rebetol Combo Pack (Ribavirin) and peginterferon alfa-2a 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 peginterferon alfa-2a plus Pegintron / Rebetol Combo Pack, 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 .

5.9 Laboratory Tests

Before beginning ribavirin/peginterferon alfa-2a 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 ribavirin/peginterferon alfa-2a.

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 Pegintron / Rebetol Combo Pack (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 1500 cells/mm3
• TSH and T4 within normal limits or adequately controlled thyroid function
• CD4+ cell count greater than or equal to 200 cells/mm3or 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

6 ADVERSE REACTIONS

The most common adverse reactions 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 Zydus Pharmaceuticals USA Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

Peginterferon alfa-2a in combination with Pegintron / Rebetol Combo Pack (Ribavirin) 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 ribavirin/peginterferon alfa-2a 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 Pegintron / Rebetol Combo Pack (Ribavirin) 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 peginterferon alfa-2a alone or in combination with Pegintron / Rebetol Combo Pack (Ribavirin). 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. Table 5 shows rates of adverse events occurring in greater than or equal to 5% of subjects receiving pegylated interferon and Pegintron / Rebetol Combo Pack (Ribavirin) combination therapy in the CHC Clinical Trial, NV15801.

Ten percent of CHC monoinfected patients receiving 48 weeks of therapy with peginterferon alfa-2a in combination with Pegintron / Rebetol Combo Pack (Ribavirin) 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 peginterferon alfa-2a and/or Pegintron / Rebetol Combo Pack (Ribavirin) therapy. The most common reason for dose modification of peginterferon alfa-2a 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 Pegintron / Rebetol Combo Pack (Ribavirin) in CHC and CHC/HIV patients was anemia (22% and 16%, respectively).

Peginterferon alfa-2a dose was reduced in 12% of patients receiving 1000 mg to 1200 mg Pegintron / Rebetol Combo Pack (Ribavirin) for 48 weeks and in 7% of patients receiving 800 mg Pegintron / Rebetol Combo Pack (Ribavirin) for 24 weeks. Pegintron / Rebetol Combo Pack (Ribavirin) dose was reduced in 21% of patients receiving 1000 mg to 1200 mg Pegintron / Rebetol Combo Pack (Ribavirin) for 48 weeks and in 12% of patients receiving 800 mg Pegintron / Rebetol Combo Pack (Ribavirin) for 24 weeks.

Chronic hepatitis C monoinfected patients treated for 24 weeks with peginterferon alfa-2a and 800 mg Pegintron / Rebetol Combo Pack (Ribavirin) were observed to have lower incidence of serious adverse events (3% vs. 10%), hemoglobin less than 10g/dL (3% vs. 15%), dose modification of peginterferon alfa-2a (30% vs. 36%) and Pegintron / Rebetol Combo Pack (Ribavirin) (19% vs. 38%), and of withdrawal from treatment (5% vs. 15%) compared to patients treated for 48 weeks with peginterferon alfa-2a and 1000 mg or 1200 mg Pegintron / Rebetol Combo Pack (Ribavirin). On the other hand, the overall incidence of adverse events appeared to be similar in the two treatment groups.

	CHC Combination Therapy Study NV15801
*Severe hematologic abnormalities (lymphocyte less than 500 cells/mm3; hemoglobin less than 10 g/dL; neutrophil less than 750 cells/mm3; platelet less than 50,000 cells/mm3).
Body System	Peginterferon Alfa - 2a 180 mcg + 1000 mg or 1200 mg Ribavirin Tablets 48 weeks	Interferon alfa - 2b + 1000 mg or 1200 mg Ribavirin Capsules 48 weeks
	N = 451	N = 443
	%	%
Application Site Disorders
Injection site reaction	23	16
Endocrine Disorders
Hypothyroidism	4	5
Flu - like Symptoms and Signs
Fatigue/Asthenia	65	68
Pyrexia	41	55
Rigors	25	37
Pain	10	9
Gastrointestinal
Nausea/Vomiting	25	29
Diarrhea	11	10
Abdominal pain	8	9
Dry mouth	4	7
Dyspepsia	6	5
Hematologic *
Lymphopenia	14	12
Anemia	11	11
Neutropenia	27	8
Thrombocytopenia	5	< 1
Metabolic and Nutritional
Anorexia	24	26
Weight decrease	10	10
Musculoskeletal , Connective Tissue and Bone
Myalgia	40	49
Arthralgia	22	23
Back pain	5	5
Neurological
Headache	43	49
Dizziness (excluding vertigo)	14	14
Memory impairment	6	5
Psychiatric
Irritability/Anxiety/Nervousness	33	38
Insomnia	30	37
Depression	20	28
Concentration impairment	10	13
Mood alteration	5	6
Resistance Mechanism Disorders
Overall	12	10
Respiratory , Thoracic and Mediastinal
Dyspnea	13	14
Cough	10	7
Dyspnea exertional	4	7
Skin and Subcutaneous Tissue
Alopecia	28	33
Pruritus	19	18
Dermatitis	16	13
Dry skin	10	13
Rash	8	5
Sweating increased	6	5
Eczema	5	4
Visual Disorders
Vision blurred	5	2

Pediatric Patients

In a clinical trial with 114 pediatric subjects (5 to 17 years of age) treated with peginterferon alfa-2a alone or in combination with Pegintron / Rebetol Combo Pack (Ribavirin), dose modifications were required in approximately one-third of subjects, most commonly for neutropenia and anemia. In general, the safety profile observed in pediatric subjects was similar to that seen in adults. In the pediatric study, the most common adverse events in subjects treated with combination therapy peginterferon alfa-2a and Pegintron / Rebetol Combo Pack (Ribavirin) for up to 48 weeks were influenza-like illness (91%), upper respiratory tract infection (60%), headache (64%), gastrointestinal disorder (56%), skin disorder (47%), and injection-site reaction (45%). Seven subjects receiving combination peginterferon alfa-2a and Pegintron / Rebetol Combo Pack (Ribavirin) treatment for 48 weeks discontinued therapy for safety reasons (depression, psychiatric evaluation abnormal, transient blindness, retinal exudates, hyperglycemia, type 1 diabetes mellitus, and anemia). Severe adverse events were reported in 2 subjects in the peginterferon alfa-2a plus Pegintron / Rebetol Combo Pack (Ribavirin) combination therapy group (hyperglycemia and cholecystectomy).

* Displayed adverse drug reactions include all grades of reported adverse clinical events considered possibly, probably, or definitely related to study drug.
**Subjects in the peginterferon alfa-2a plus placebo arm who did not achieve undetectable viral load at week 24 switched to combination treatment thereafter. Therefore, only the first 24 weeks are presented for the comparison of combination therapy with monotherapy.
	Study NV17424
System Organ Class	Peginterferon Alfa - 2a 180 mcg / 1 . 73 m ² x BSA + Pegintron / Rebetol Combo Pack (Ribavirin) 15 mg / kg ( N = 55 )	Peginterferon Alfa - 2a 180 mcg / 1 . 73 m ² x BSA + Placebo ** ( N = 59 )
	%	%
General disorders and administration site conditions
Influenza like illness	91	81
Injection site reaction	44	42
Fatigue	25	20
Irritability	24	14
Gastrointestinal disorders
Gastrointestinal disorder	49	44
Nervous system disorders
Headache	51	39
Skin and subcutaneous tissue disorders
Rash	15	10
Pruritus	11	12
Musculoskeletal , connective tissue and bone disorders
Musculoskeletal pain	35	29
Psychiatric disorders
Insomnia	9	12
Metabolism and nutrition disorders
Decreased appetite	11	14

In pediatric subjects randomized to combination therapy, the incidence of most adverse reactions was similar for the entire treatment period (up to 48 weeks plus 24 weeks follow-up) in comparison to the first 24 weeks, and increased only slightly for headache, gastrointestinal disorder, irritability and rash. The majority of adverse reactions occurred in the first 24 weeks of treatment.

Growth Inhibition in Pediatric Subjects .

Pediatric subjects treated with PEGASYS plus Pegintron / Rebetol Combo Pack (Ribavirin) combination therapy showed a delay in weight and height increases with up to 48 weeks of therapy compared with baseline. Both weight for age and height for age z-scores as well as the percentiles of the normative population for subject weight and height decreased during treatment. At the end of 2 years follow-up after treatment, most subjects had returned to baseline normative curve percentiles for weight (64th mean percentile at baseline, 60th mean percentile at 2 years post-treatment) and height (54th mean percentile at baseline, 56th mean percentile at 2 years post-treatment). At the end of treatment, 43% (23 of 53) of subjects experienced a weight percentile decrease of more than 15 percentiles, and 25% (13 of 53) experienced a height percentile decrease of more than 15 percentiles on the normative growth curves. At 2 years post-treatment, 16% (6 of 38) of subjects were more than 15 percentiles below their baseline weight curve and 11% (4 of 38) were more than 15 percentiles below their baseline height curve.

Thirty-eight of the 114 subjects enrolled in the long-term follow-up study, extending up to 6 years posttreatment. For most subjects, post-treatment recovery in growth at 2 years post-treatment was maintained to 6 years post-treatment.

Common Adverse Reactions in CHC with HIV Coinfection (Adults)

The adverse event profile of coinfected patients treated with peginterferon alfa-2a/ribavirin in Study NR15961 was generally similar to that shown for monoinfected patients in Study NV15801 (Table 5). Events occurring more frequently in coinfected patients were neutropenia (40%), anemia (14%), thrombocytopenia (8%), weight decrease (16%), and mood alteration (9%).

Laboratory Test Abnormalities

Adult Patients

Anemia due to hemolysis is the most significant toxicity of Pegintron / Rebetol Combo Pack (Ribavirin) therapy. Anemia (hemoglobin less than 10 g/dL) was observed in 13% of all Pegintron / Rebetol Combo Pack (Ribavirin) and peginterferon alfa-2a combination-treated patients in clinical trials. The maximum drop in hemoglobin occurred during the first 8 weeks of initiation of Pegintron / Rebetol Combo Pack (Ribavirin) therapy [see DOSAGE AND ADMINISTRATION (2.3)].

Laboratory Parameter	Peginterferon Alfa - 2a + Ribavirin 1000 / 1200 mg 48 wks	Interferon alfa - 2b + Ribavirin 1000 / 1200 mg 48 wks
	( N = 887 )	( N = 443 )
Neutrophils ( cells / mm3 )
1,000 <1,500	34%	38%
500 <1,000	49%	21%
<500	5%	1%
Platelets ( cells / mm3 )
50,000 - <75,000	11%	4%
20,000 - <50,000	5%	< 1%
<20,000	0	0
Hemoglobin ( g / dL )
8.5 - 9.9	11%	11%
<8.5	2%	< 1%

Pediatric Patients

Decreases in hemoglobin, neutrophils and platelets may require dose reduction or permanent discontinuation from treatment [see DOSAGE AND ADMINISTRATION (2.4)]. Most laboratory abnormalities noted during the clinical trial returned to baseline levels shortly after discontinuation of treatment.

* Subjects in the peginterferon alfa-2a plus placebo arm who did not achieve undetectable viral load at week 24 switched to combination treatment thereafter. Therefore, only the first 24 weeks are presented for the comparison of combination therapy with monotherapy.
Laboratory Parameter	Peginterferon Alfa - 2a 180 mcg / 1 . 73 m ² x BSA + Ribavirin 15 mg / kg ( N = 55 )	Peginterferon Alfa - 2a 180 mcg / 1 . 73 m ² x BSA + Placebo * ( N = 59 )
Neutrophils ( cells / mm3 )
1,000 to < 1,500	31%	39%
750 to < 1,000	27%	17%
500 to < 750	25%	15%
< 500	7%	5%
Platelets ( cells / mm3 )
75,000 to < 100,000	4%	2%
50,000 to < 75,000	0%	2%
< 50,000	0%	0%
Hemoglobin ( g / dL )
8.5 to < 10	7%	3%
< 8.5	0%	0%

In patients randomized to combination therapy, the incidence of abnormalities during the entire treatment phase (up to 48 weeks plus 24 weeks follow-up) in comparison to the first 24 weeks increased slightly for neutrophils between 500 and 1,000 cells/mm and hemoglobin values between 8.5 and 10 g/dL. The majority of hematologic abnormalities occurred in the first 24 weeks of treatment.

6.2 Postmarketing Experience

The following adverse reactions have been identified and reported during post-approval use of peginterferon alfa-2a/ribavirin combination therapy. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System disorders

Pure red cell aplasia

Ear and Labyrinth disorders

Hearing impairment, hearing loss

Eye disorders

Serous retinal detachment

Immune disorders

Liver and renal graft rejection

Metabolism and Nutrition disorders

Dehydration

Skin and Subcutaneous Tissue disorders

Stevens-Johnson Syndrome (SJS)

Toxic epidermal necrolysis (TEN)

7 DRUG INTERACTIONS

• Nucleoside analogues: Closely monitor for toxicities. Discontinue nucleoside reverse transcriptase inhibitors or reduce dose or discontinue interferon, Pegintron / Rebetol Combo Pack or both with worsening toxicities (7.1)
• Azathioprine: Concomitant use of azathioprine with Pegintron / Rebetol Combo Pack (Ribavirin) has been reported to induce severe pancytopenia and may increase the risk of azathioprine-related myelotoxicity (7.3)

Results from a pharmacokinetic sub-study demonstrated no pharmacokinetic interaction between peginterferon alfa-2a and Pegintron / Rebetol Combo Pack (Ribavirin).

7.1 Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

In vitro data indicate Pegintron / Rebetol Combo Pack (Ribavirin) reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV/HCV virologic suppression) interaction was observed when Pegintron / Rebetol Combo Pack (Ribavirin) and lamivudine (n=18), stavudine (n=10), or zidovudine (n=6) were co-administered as part of a multi-drug regimen to HCV/HIV coinfected patients.

In Study NR15961 among the CHC/HIV coinfected cirrhotic patients receiving NRTIs, cases of hepatic decompensation (some fatal) were observed [see WARNINGS AND PRECAUTIONS (5.3)].

Patients receiving peginterferon alfa-2a/ribavirin and NRTIs should be closely monitored for treatment-associated toxicities. Physicians should refer to prescribing information for the respective NRTIs for guidance regarding toxicity management. In addition, dose reduction or discontinuation of peginterferon alfa-2a, Pegintron / Rebetol Combo Pack (Ribavirin) or both should also be considered if worsening toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than or equal to 6) [see WARNINGS AND PRECAUTIONS (5.3) and DOSAGE AND ADMINISTRATION (2.3)].

Didanosine

Co-administration of Pegintron / Rebetol Combo Pack (Ribavirin) and didanosine is contraindicated. Didanosine or its active metabolite (dideoxyadenosine 5'-triphosphate) concentrations are increased when didanosine is co-administered with Pegintron / Rebetol Combo Pack (Ribavirin), which could cause or worsen clinical toxicities. Reports of fatal hepatic failure as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in clinical trials [see CONTRAINDICATIONS (4)].

Zidovudine

In Study NR15961, patients who were administered zidovudine in combination with peginterferon alfa-2a/ribavirin developed severe neutropenia (ANC less than 500) and severe anemia (hemoglobin less than 8 g/dL) more frequently than similar patients not receiving zidovudine (neutropenia 15% vs. 9%) (anemia 5% vs. 1%). Discontinuation of zidovudine should be considered as medically appropriate.

7.2 Drugs Metabolized by Cytochrome P450

In vitro studies indicate that Pegintron / Rebetol Combo Pack does not inhibit CYP 2C9, CYP 2C19, CYP 2D6 or CYP 3A4.

7.3 Azathioprine

The use of Pegintron / Rebetol Combo Pack (Ribavirin) to treat chronic hepatitis C in patients receiving azathioprine has been reported to induce severe pancytopenia and may increase the risk of azathioprine-related myelotoxicity. Inosine monophosphate dehydrogenase (IMDH) is required for one of the metabolic pathways of azathioprine. Pegintron / Rebetol Combo Pack (Ribavirin) is known to inhibit IMDH, thereby leading to accumulation of an azathioprine metabolite, 6-methylthioinosine monophosphate (6-MTITP), which is associated with myelotoxicity (neutropenia, thrombocytopenia, and anemia). Patients receiving azathioprine with Pegintron / Rebetol Combo Pack (Ribavirin) should have complete blood counts, including platelet counts, monitored weekly for the first month, twice monthly for the second and third months of treatment, then monthly or more frequently if dosage or other therapy changes are necessary [see WARNINGS AND PRECAUTIONS (5.6)].

8 USE IN SPECIFIC POPULATIONS

• Pegintron / Rebetol Combo Pack Pregnancy Registry (8.1)
• 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)

8.1 Pregnancy

Teratogenic Effects

Pregnancy: Category X.

Pegintron / Rebetol Combo Pack (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 (4) and WARNINGS AND PRECAUTIONS (5.1)].

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 Pegintron / Rebetol Combo Pack (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 Pegintron / Rebetol Combo Pack (Ribavirin)).

Treatment and Post-treatment: Potential Risk to the Fetus

Pegintron / Rebetol Combo Pack (Ribavirin) is known to accumulate in intracellular components from where it is cleared very slowly. It is not known whether Pegintron / Rebetol Combo Pack (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 Pegintron / Rebetol Combo Pack (Ribavirin), male patients should be advised to take every precaution to avoid risk of pregnancy for their female partners.

Pegintron / Rebetol Combo Pack (Ribavirin) 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 Pegintron / Rebetol Combo Pack (Ribavirin) unless the patient and his/her partner are using effective contraception (two reliable forms) during therapy and for 6 months post therapy [see CONTRAINDICATIONS (4)].

Pegintron / Rebetol Combo Pack (Ribavirin) Pregnancy Registry

A Pegintron / Rebetol Combo Pack (Ribavirin) Pregnancy Registry has been established to monitor maternal-fetal outcomes of pregnancies of female patients and female partners of male patients exposed to Pegintron / Rebetol Combo Pack (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.

8.3 Nursing Mothers

It is not known whether Pegintron / Rebetol Combo Pack 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 Pegintron / Rebetol Combo Pack (Ribavirin), a decision should be made either to discontinue nursing or therapy with Pegintron / Rebetol Combo Pack (Ribavirin), based on the importance of the therapy to the mother.

8.4 Pediatric Use

Pharmacokinetic evaluations in pediatric patients have not been performed.

Safety and effectiveness of Pegintron / Rebetol Combo Pack (Ribavirin) have not been established in patients below the age of 5 years.

8.5 Geriatric Use

Clinical studies of Pegintron / Rebetol Combo Pack 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 Pegintron / Rebetol Combo Pack (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 Pegintron / Rebetol Combo Pack (Ribavirin) 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 (2.4); USE IN SPECIFIC POPULATIONS (8.7)].

8.6 Race

A pharmacokinetic study in 42 subjects demonstrated there is no clinically significant difference in Pegintron / Rebetol Combo Pack (Ribavirin) pharmacokinetics among Black (n=14), Hispanic (n=13) and Caucasian (n=15) subjects.

8.7 Renal Impairment

Renal function should be evaluated in all patients prior to initiation of Pegintron / Rebetol Combo Pack by estimating the patient's creatinine clearance.

A clinical trial evaluated treatment with Pegintron / Rebetol Combo Pack (Ribavirin) and peginterferon alfa-2a in 50 CHC subjects with moderate (creatinine clearance 30 to 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, Pegintron / Rebetol Combo Pack (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 Pegintron / Rebetol Combo Pack (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 Pegintron / Rebetol Combo Pack (Ribavirin) for 48 weeks. Pegintron / Rebetol Combo Pack (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 Pegintron / Rebetol Combo Pack (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 Pegintron / Rebetol Combo Pack (Ribavirin), respectively, due to ribavirin-related adverse reactions, mainly anemia, and exhibited 20% to 30% higher Pegintron / Rebetol Combo Pack (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 Pegintron / Rebetol Combo Pack (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 Pegintron / Rebetol Combo Pack (Ribavirin) exposure similar to patients with normal renal function receiving the approved regimen of Pegintron / Rebetol Combo Pack (Ribavirin). These doses have not been studied in patients [see DOSAGE AND ADMINISTRATION (2.4), and CLINICAL PHARMACOLOGY (12.3)].

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 Pegintron / Rebetol Combo Pack (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 Pegintron / Rebetol Combo Pack (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 (2.4), CLINICAL PHARMACOLOGY (12.3), and PEGINTERFERON ALFA-2A PACKAGE INSERT].

8.8 Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of Pegintron / Rebetol Combo Pack (Ribavirin) following administration of Pegintron / Rebetol Combo Pack (Ribavirin) has not been evaluated. The clinical trials of Pegintron / Rebetol Combo Pack (Ribavirin) were restricted to patients with Child-Pugh class A disease.

8.9 Gender

No clinically significant differences in the pharmacokinetics of Pegintron / Rebetol Combo Pack were observed between male and female subjects.

Pegintron / Rebetol Combo Pack (Ribavirin) pharmacokinetics, when corrected for weight, are similar in male and female patients.

8.10 Organ Transplant Recipients

The safety and efficacy of peginterferon alfa-2a and Pegintron / Rebetol Combo Pack (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 Pegintron / Rebetol Combo Pack (Ribavirin) [see ADVERSE REACTIONS (6.2)].

10 OVERDOSAGE

No cases of overdose with Pegintron / Rebetol Combo Pack (Ribavirin) have been reported in clinical trials. Hypocalcemia and hypomagnesemia have been observed in persons administered greater than the recommended dosage of Pegintron / Rebetol Combo Pack (Ribavirin). In most of these cases, Pegintron / Rebetol Combo Pack (Ribavirin) was administered intravenously at dosages up to and in some cases exceeding four times the recommended maximum oral daily dose.

11 DESCRIPTION

Pegintron / Rebetol Combo Pack (Ribavirin) is a nucleoside analogue with antiviral activity. The chemical name of Pegintron / Rebetol Combo Pack (Ribavirin) is 1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide and has the following structural formula:

The molecular formula of Pegintron / Rebetol Combo Pack (Ribavirin) is C₈H₁₂N₄O₅ and the molecular weight is 244.2.

Pegintron / Rebetol Combo Pack (Ribavirin), USP is white, crystalline powder. It is freely soluble in water and slightly soluble in dehydrated alcohol.

Each film-coated Pegintron / Rebetol Combo Pack (Ribavirin) tablet intended for oral administration contains 200 mg or 400 mg or 500 mg or 600 mg of Pegintron / Rebetol Combo Pack (Ribavirin). In addition, each tablet contains the following inactive ingredients: crospovidone, hypromellose, iron oxide red, iron oxide yellow, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, silicon dioxide, talc and titanium dioxide.

Organic test number pending in the USP.

structured formula for Pegintron / Rebetol Combo Pack (Ribavirin)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Pegintron / Rebetol Combo Pack is an antiviral drug [see MICROBIOLOGY (12.4)].

12.3 Pharmacokinetics

Multiple dose Pegintron / Rebetol Combo Pack (Ribavirin) pharmacokinetic data are available for HCV patients who received Pegintron / Rebetol Combo Pack (Ribavirin) in combination with peginterferon alfa-2a. Following administration of 1200 mg/day with food for 12 weeks mean±SD (n=39; body weight greater than 75 kg) AUC_0-12hr was 25,361±7110 ng·hr/mL and C_max was 2748±818 ng/mL. The average time to reach C_max was 2 hours. Trough Pegintron / Rebetol Combo Pack (Ribavirin) plasma concentrations following 12 weeks of dosing with food were 1662±545 ng/mL in HCV infected patients who received 800 mg/day (n=89), and 2112±810 ng/mL in patients who received 1200 mg/day (n=75; body weight greater than 75 kg).

The terminal half-life of Pegintron / Rebetol Combo Pack (Ribavirin) following administration of a single oral dose of Pegintron / Rebetol Combo Pack (Ribavirin) is about 120 to 170 hours. The total apparent clearance following administration of a single oral dose of Pegintron / Rebetol Combo Pack (Ribavirin) is about 26 L/h. There is extensive accumulation of Pegintron / Rebetol Combo Pack (Ribavirin) after multiple dosing (twice daily) such that the C_max at steady state was four-fold higher than that of a single dose.

Effect of Food on Absorption of Pegintron / Rebetol Combo Pack (Ribavirin)

Bioavailability of a single oral dose of Pegintron / Rebetol Combo Pack (Ribavirin) was increased by co-administration with a high-fat meal. The absorption was slowed (T_max was doubled) and the AUC_0-192h and C_max increased by 42% and 66%, respectively, when Pegintron / Rebetol Combo Pack (Ribavirin) was taken with a high-fat meal compared with fasting conditions [see DOSAGE AND ADMINISTRATION (2) and PATIENT COUNSELING INFORMATION (17)].

Elimination and Metabolism

The contribution of renal and hepatic pathways to Pegintron / Rebetol Combo Pack (Ribavirin) elimination after administration of Pegintron / Rebetol Combo Pack (Ribavirin) is not known. In vitro studies indicate that Pegintron / Rebetol Combo Pack (Ribavirin) is not a substrate of CYP450 enzymes.

Renal Impairment

A clinical trial evaluated 50 CHC subjects with either moderate (creatinine clearance 30 to 50 mL/min) or severe (creatinine clearance less than 30 mL/min) renal impairment or end stage renal disease (ESRD) requiring chronic hemodialysis (HD). The apparent clearance of Pegintron / Rebetol Combo Pack (Ribavirin) was reduced in subjects with creatinine clearance less than or equal to 50 mL/min, including subjects with ESRD on HD, exhibiting approximately 30% of the value found in subjects with normal renal function. Pharmacokinetic modeling and simulation indicates 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 Pegintron / Rebetol Combo Pack (Ribavirin) exposures similar to that observed in patients with normal renal function receiving the standard 1000/1200 mg Pegintron / Rebetol Combo Pack (Ribavirin) daily dose. These doses have not been studied in patients.

In 18 subjects with ESRD receiving chronic HD, Pegintron / Rebetol Combo Pack (Ribavirin) was administered at a dose of 200 mg daily. Pegintron / Rebetol Combo Pack (Ribavirin) plasma exposures in these subjects were approximately 20% lower compared to subjects with normal renal function receiving the standard 1000/1200 mg Pegintron / Rebetol Combo Pack (Ribavirin) daily dose [see DOSAGE AND ADMINISTRATION (2.4), USE IN SPECIFIC POPULATIONS (8.7)].

Plasma Pegintron / Rebetol Combo Pack (Ribavirin) is removed by hemodialysis with an extraction ratio of approximately 50%; however, due to the large volume of distribution of Pegintron / Rebetol Combo Pack (Ribavirin), plasma exposure is not expected to change with hemodialysis.

12.4 Microbiology

Mechanism of Action

The mechanism by which Pegintron / Rebetol Combo Pack (Ribavirin) contributes to its antiviral efficacy in the clinic is not fully understood. Pegintron / Rebetol Combo Pack (Ribavirin) has direct antiviral activity in tissue culture against many RNA viruses. Pegintron / Rebetol Combo Pack (Ribavirin) increases the mutation frequency in the genomes of several RNA viruses and Pegintron / Rebetol Combo Pack (Ribavirin) triphosphate inhibits HCV polymerase in a biochemical reaction.

Antiviral Activity in Cell Culture

In the stable HCV cell culture model system (HCV replicon), Pegintron / Rebetol Combo Pack (Ribavirin) inhibited autonomous HCV RNA replication with a 50% effective concentration (EC₅₀) value of 11 to 21 mcM. In the same model, PEG-IFN α-2a also inhibited HCV RNA replication, with an EC₅₀ value of 0.1 to 3 ng/mL. The combination of PEG-IFN α-2a and Pegintron / Rebetol Combo Pack (Ribavirin) was more effective at inhibiting HCV RNA replication than either agent alone.

Resistance

Different HCV genotypes display considerable clinical variability in their response to PEG-IFN-α and Pegintron / Rebetol Combo Pack (Ribavirin) therapy. Viral genetic determinants associated with the variable response have not been definitively identified.

Cross-resistance

Cross-resistance between IFN α and Pegintron / Rebetol Combo Pack (Ribavirin) has not been observed.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In a p53 mouse carcinogenicity study up to the maximum tolerated dose of 100 mg/kg/day, Pegintron / Rebetol Combo Pack (Ribavirin) was not oncogenic. Pegintron / Rebetol Combo Pack (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 Pegintron / Rebetol Combo Pack (Ribavirin), respectively.

Mutagenesis

Pegintron / Rebetol Combo Pack (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, Pegintron / Rebetol Combo Pack (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 Pegintron / Rebetol Combo Pack (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 cycles.

Female patients of childbearing potential and male patients with female partners of childbearing potential should not receive Pegintron / Rebetol Combo Pack (Ribavirin) unless the patient and his/her partner are using effective contraception (two reliable forms). Based on a multiple dose half-life (t_1/2) of Pegintron / Rebetol Combo Pack (Ribavirin) of 12 days, effective contraception must be utilized for 6 months post therapy (i.e., 15 half-lives of clearance for Pegintron / Rebetol Combo Pack (Ribavirin)).

No reproductive toxicology studies have been performed using peginterferon alfa-2a in combination with Pegintron / Rebetol Combo Pack (Ribavirin). However, peginterferon alfa-2a and Pegintron / Rebetol Combo Pack (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.

13.2 ANIMAL PHARMACOLOGY AND OR TOXICOLOGY

In a study in rats, it was concluded that dominant lethality was not induced by Pegintron / Rebetol Combo Pack (Ribavirin) at doses up to 200 mg/kg for 5 days (up to 1.7 times the maximum recommended human dose of Pegintron / Rebetol Combo Pack (Ribavirin)).

Long-term studies in the mouse and rat (18 to 24 months; dose 20 to 75, and 10 to 40 mg/kg/day, respectively, approximately 0.1 to 0.4 times the maximum daily human dose of Pegintron / Rebetol Combo Pack (Ribavirin)) have demonstrated a relationship between chronic Pegintron / Rebetol Combo Pack (Ribavirin) exposure and an increased incidence of vascular lesions (microscopic hemorrhages) in mice. In rats, retinal degeneration occurred in controls, but the incidence was increased in ribavirin-treated rats.

14 CLINICAL STUDIES

14.1 Chronic Hepatitis C Patients

Adult Patients

The safety and effectiveness of peginterferon alfa-2a in combination with Pegintron / Rebetol Combo Pack for the treatment of hepatitis C virus infection were assessed in two randomized controlled clinical trials. All patients were adults, had compensated liver disease, detectable hepatitis C virus, liver biopsy diagnosis of chronic hepatitis, and were previously untreated with interferon. Approximately 20% of patients in both studies had compensated cirrhosis (Child-Pugh class A). Patients coinfected with HIV were excluded from these studies.

In Study NV15801, patients were randomized to receive either peginterferon alfa-2a 180 mcg subcutaneous once weekly with an oral placebo, peginterferon alfa-2a 180 mcg once weekly with Pegintron / Rebetol Combo Pack (Ribavirin) 1000 mg by mouth (body weight less than 75 kg) or 1200 mg by mouth (body weight greater than or equal to 75 kg) or interferon alfa-2b 3 MIU subcutaneous three times a week plus Pegintron / Rebetol Combo Pack (Ribavirin) 1000 mg or 1200 mg by mouth. All patients received 48 weeks of therapy followed by 24 weeks of treatment-free follow-up. Pegintron / Rebetol Combo Pack (Ribavirin) or placebo treatment assignment was blinded. Sustained virological response was defined as undetectable (less than 50 IU/mL) HCV RNA on or after study week 68. Peginterferon alfa-2a in combination with Pegintron / Rebetol Combo Pack (Ribavirin) resulted in a higher SVR compared to peginterferon alfa-2a alone or interferon alfa-2b and Pegintron / Rebetol Combo Pack (Ribavirin) (Table 9). In all treatment arms, patients with viral genotype 1, regardless of viral load, had a lower response rate to peginterferon alfa-2a in combination with Pegintron / Rebetol Combo Pack (Ribavirin) compared to patients with other viral genotypes.

	Interferon alfa - 2b + Ribavirin 1000 mg or 1200 mg	Peginterferon Alfa - 2a + Placebo	Peginterferon Alfa - 2a + Ribavirin 1000 mg or 1200 mg
All patients	197/444 (44%)	65/224 (29%)	241/453 (53%)
Genotype 1	103/285 (36%)	29/145 (20%)	132/298 (44%)
Genotypes 2 to 6	94/159 (59%)	36/79 (46%)	109/155 (70%)

Difference in overall treatment response (Peginterferon alfa-2a/ribavirin – Interferon alfa-2b/ribavirin) was 9% (95% CI 2.3, 15.3).

In Study NV15942, all patients received peginterferon alfa-2a 180 mcg subcutaneous once weekly and were randomized to treatment for either 24 or 48 weeks and to a Pegintron / Rebetol Combo Pack (Ribavirin) dose of either 800 mg or 1000 mg/1200 mg (for body weight less than 75 kg/ greater than or equal to 75 kg). Assignment to the four treatment arms was stratified by viral genotype and baseline HCV viral titer. Patients with genotype 1 and high viral titer (defined as greater than 2 x 10⁶HCV RNA copies/mL serum) were preferentially assigned to treatment for 48 weeks.

Sustained Virologic Response (SVR) and HCV Genotype

HCV 1 and 4–Irrespective of baseline viral titer, treatment for 48 weeks with peginterferon alfa-2a and 1000 mg or 1200 mg of Pegintron / Rebetol Combo Pack (Ribavirin) resulted in higher SVR (defined as undetectable HCV RNA at the end of the 24 week treatment-free follow-up period) compared to shorter treatment (24 weeks) and/or 800 mg Pegintron / Rebetol Combo Pack (Ribavirin).

HCV 2 and 3– Irrespective of baseline viral titer, treatment for 24 weeks with peginterferon alfa-2a and 800 mg of Pegintron / Rebetol Combo Pack (Ribavirin) resulted in a similar SVR compared to longer treatment (48 weeks) and/or 1000 mg or 1200 mg of Pegintron / Rebetol Combo Pack (Ribavirin) (see Table 10).

The numbers of patients with genotype 5 and 6 were too few to allow for meaningful assessment.

	24 Weeks Treatment		48 Weeks Treatment
*1000 mg for body weight less than 75 kg; 1200 mg for body weight greater than or equal to 75 kg.
	Peginterferon Alfa - 2a + Ribavirin 800 mg ( N = 207 )	Peginterferon Alfa - 2a + Ribavirin 1000 mg or 1200 mg * ( N = 280 )	Peginterferon Alfa - 2a + Ribavirin 800 mg ( N = 361 )	Peginterferon Alfa - 2a + Ribavirin 1000 mg or 1200 mg * ( N = 436 )
Genotype 1	29/101 (29%)	48/118 (41%)	99/250 (40%)	138/271 (51%)
Genotypes 2, 3	79/96 (82%)	116/144 (81%)	75/99 (76%)	117/153 (76%)
Genotype 4	0/5 (0%)	7/12 (58%)	5/8 (63%)	9/11 (82%)

Pediatric Patients

Previously untreated pediatric subjects 5 through 17 years of age (55% less than 12 years old) with chronic hepatitis C, compensated liver disease and detectable HCV RNA were treated with Pegintron / Rebetol Combo Pack (Ribavirin) approximately 15 mg/kg/day plus peginterferon alfa-2a 180 mcg/1.73 m2 x body surface area once weekly for 48 weeks. All subjects were followed for 24 weeks post-treatment. Sustained virological response (SVR) was defined as undetectable (less than 50 IU/mL) HCV RNA on or after study week 68. A total of 114 subjects were randomized to receive either combination treatment of Pegintron / Rebetol Combo Pack (Ribavirin) plus peginterferon alfa-2a or peginterferon alfa-2a monotherapy; subjects failing peginterferon alfa-2a monotherapy at 24 weeks or later could receive open-label Pegintron / Rebetol Combo Pack (Ribavirin) plus peginterferon alfa-2a. The initial randomized arms were balanced for demographic factors; 55 subjects received initial combination treatment of Pegintron / Rebetol Combo Pack (Ribavirin) plus peginterferon alfa-2a and 59 received peginterferon alfa-2a plus placebo; in the overall intent-to-treat population, 45% were female, 80% were Caucasian, and 81% were infected with HCV genotype 1. The SVR results are summarized in Table 11.

*Results indicate undetectable HCV RNA defined as HCV RNA less than 50 IU/mL at 24 weeks post-treatment using the AMPLICOR HCV test v2
**Scheduled treatment duration was 48 weeks regardless of the genotype
***Includes HCV genotypes 2,3 and others
	Peginterferon alfa - 2a 180 mcg / 1 . 73 m ² x BSA + Ribavirin 15 mg / kg * ( N = 55 )	Peginterferon alfa - 2a 180 mcg / 1 . 73 m ² x BSA + Placebo * ( N = 59 )
All HCV genotypes **	29 (53%)	12 (20%)
HCV genotype 1	21/45 (47%)	8/47 (17%)
HCV non - genotype 1 ***	8/10 (80%)	4/12 (33%)

14.2 Other Treatment Response Predictors

Treatment response rates are lower in patients with poor prognostic factors receiving pegylated interferon alpha therapy. In studies NV15801 and NV15942, treatment response rates were lower in patients older than 40 years (50% vs. 66%), in patients with cirrhosis (47% vs. 59%), in patients weighing over 85 kg (49% vs. 60%), and in patients with genotype 1 with high vs. low viral load (43% vs. 56%). African-American patients had lower response rates compared to Caucasians.

In studies NV15801 and NV15942, lack of early virologic response by 12 weeks (defined as HCV RNA undetectable or greater than 2 log₁₀ lower than baseline) was grounds for discontinuation of treatment. Of patients who lacked an early viral response by 12 weeks and completed a recommended course of therapy despite a protocol-defined option to discontinue therapy, 5/39 (13%) achieved an SVR. Of patients who lacked an early viral response by 24 weeks, 19 completed a full course of therapy and none achieved an SVR.

14.3 Chronic Hepatitis C/HIV Coinfected Patients

In Study NR15961, patients with CHC/HIV were randomized to receive either peginterferon alfa-2a 180 mcg subcutaneous once weekly plus an oral placebo, peginterferon alfa-2a 180 mcg once weekly plus Pegintron / Rebetol Combo Pack (Ribavirin) 800 mg by mouth daily or interferon alfa-2a, 3 MIU subcutaneous three times a week plus Pegintron / Rebetol Combo Pack (Ribavirin) 800 mg by mouth daily. All patients received 48 weeks of therapy and sustained virologic response (SVR) was assessed at 24 weeks of treatment-free follow-up. Pegintron / Rebetol Combo Pack (Ribavirin) or placebo treatment assignment was blinded in the peginterferon alfa-2a treatment arms. All patients were adults, had compensated liver disease, detectable hepatitis C virus, liver biopsy diagnosis of chronic hepatitis C, and were previously untreated with interferon. Patients also had 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 5000 copies/mL, and stable status of HIV. Approximately 15% of patients in the study had cirrhosis. Results are shown in Table 12.

	Interferon Alfa - 2a + Ribavirin 800 mg ( N = 289 )	Peginterferon Alfa - 2a + Placebo ( N = 289 )	Peginterferon Alfa - 2a + Ribavirin 800 mg ( N = 290 )
All patients	33 (11%)	58 (20%)	116 (40%)
Genotype 1	12/171 (7%)	24/175 (14%)	51/176 (29%)
Genotypes 2, 3	18/89 (20%)	32/90 (36%)	59/95 (62%)

Treatment response rates were lower in CHC/HIV patients with poor prognostic factors (including HCV genotype 1, HCV RNA greater than 800,000 IU/mL, and cirrhosis) receiving pegylated interferon alpha therapy.

Of the patients who did not demonstrate either undetectable HCV RNA or at least a 2 log₁₀ reduction from baseline in HCV RNA titer by 12 weeks of peginterferon alfa-2a and Pegintron / Rebetol Combo Pack (Ribavirin) combination therapy, 2% (2/85) achieved an SVR.

In CHC patients with HIV coinfection who received 48 weeks of peginterferon alfa-2a alone or in combination with Pegintron / Rebetol Combo Pack (Ribavirin) treatment, mean and median HIV RNA titers did not increase above baseline during treatment or 24 weeks post-treatment.

16 HOW SUPPLIED/STORAGE AND HANDLING

Pegintron / Rebetol Combo Pack (Ribavirin) Tablets, 200 mg are light pink to pink, round, biconvex, beveled, film-coated tablets debossed with the logo of 'ZC19' on one side, other side plain and supplied as follows:

NDC 68382-046-03 in bottle of 168 tablets

NDC 68382-046-28 in bottle of 180 tablets

NDC 68382-046-10 in bottle of 1000 tablets

NDC 68382-046-77 in unit-dose blister cartons of 100 (10 x 10) unit-dose tablets

Pegintron / Rebetol Combo Pack (Ribavirin) Tablets, 400 mg are light pink to pink, capsule shaped, biconvex, film-coated tablets debossed with 'ZD' and '07' on one side and plain on other side and supplied as follows:

NDC 68382-127-17 in bottle of 28 tablets

NDC 68382-127-07 in bottle of 56 tablets

NDC 68382-127-14 in bottle of 60 tablets

Pegintron / Rebetol Combo Pack (Ribavirin) Tablets, 500 mg are light pink to pink, modified capsule shaped, biconvex, film-coated tablets debossed with 'ZC56' on one side and plain on the other side and supplied as follows:

NDC 68382-128-17 in bottle of 28 tablets

NDC 68382-128-07 in bottle of 56 tablets

NDC 68382-128-14 in bottle of 60 tablets

Pegintron / Rebetol Combo Pack (Ribavirin) Tablets, 600 mg are light pink to pink, modified capsule shaped, biconvex, film-coated tablets debossed with 'ZD' and '08' on one side and plain on other side and supplied as follows:

NDC 68382-129-17 in bottle of 28 tablets

NDC 68382-129-07 in bottle of 56 tablets

NDC 68382-129-14 in bottle of 60 tablets

Storage and Handling

Store at 20° to 25°C (68° to 77°F).

Keep bottle tightly closed.

17 PATIENT COUNSELING INFORMATION

• See FDA-approved patient labeling (Medication Guide)

Pregnancy

Patients must be informed that Pegintron / Rebetol Combo Pack (Ribavirin) may cause birth defects and/or death of the exposed fetus. Pegintron / Rebetol Combo Pack (Ribavirin) 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 Pegintron / Rebetol Combo Pack (Ribavirin) therapy and for 6 months post therapy. Patients should use two reliable methods of birth control while taking Pegintron / Rebetol Combo Pack (Ribavirin) therapy and for 6 months post therapy. Pegintron / Rebetol Combo Pack (Ribavirin) 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 Pegintron / Rebetol Combo Pack (Ribavirin) 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 (4) and WARNINGS AND PRECAUTIONS (5.1)].

Anemia

The most common adverse event associated with Pegintron / Rebetol Combo Pack (Ribavirin) is anemia, which may be severe [see BOXED WARNING, WARNINGS AND PRECAUTIONS (5.2) and ADVERSE REACTIONS (6.1)]. Patients should be advised that laboratory evaluations are required prior to starting Pegintron / Rebetol Combo Pack (Ribavirin) therapy and periodically thereafter [see WARNINGS AND PRECAUTIONS (5.9)]. 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 Pegintron / Rebetol Combo Pack (Ribavirin) with food.

Patients should be questioned about prior history of drug abuse before initiating ribavirin/peginterferon alfa-2a, 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 Pegintron / Rebetol Combo Pack (Ribavirin). 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/ribavirin 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 Pegintron / Rebetol Combo Pack (Ribavirin). 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.

Manufactured by:

Cadila Healthcare Ltd.

Ahmedabad, India

Distributed by:

Zydus Pharmaceuticals USA Inc.

Pennington, NJ 08534

Rev.: 10/15

MEDICATION GUIDE

Pegintron / Rebetol Combo Pack (Ribavirin)

(rye-ba-VYE-rin)

Tablets

Read this Medication Guide carefully before you start taking Pegintron / Rebetol Combo Pack (Ribavirin) and read the Medication Guide each time you get more Pegintron / Rebetol Combo Pack (Ribavirin). There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.

Also read the Medication Guide for peginterferon alfa-2a.

What is the most important information I should know about Pegintron / Rebetol Combo Pack (Ribavirin)?

• You should not take Pegintron / Rebetol Combo Pack (Ribavirin) alone to treat chronic hepatitis C infection. Pegintron / Rebetol Combo Pack (Ribavirin) should be used with peginterferon alfa-2a to treat chronic hepatitis C infection.
• Pegintron / Rebetol Combo Pack (Ribavirin) may cause you to have a blood problem (hemolytic anemia) that can worsen any heart problems you have, and cause you to have a heart attack or die. Tell your healthcare provider if you have ever had any heart problems. Pegintron / Rebetol Combo Pack (Ribavirin) may not be right for you. If you have chest pain while you take Pegintron / Rebetol Combo Pack (Ribavirin), get emergency medical attention right away.
• Pegintron / Rebetol Combo Pack (Ribavirin) may cause birth defects or death of your unborn baby. If you are pregnant or your sexual partner is pregnant, do not take Pegintron / Rebetol Combo Pack (Ribavirin). You or your sexual partner should not become pregnant while you take Pegintron / Rebetol Combo Pack (Ribavirin) and for 6 months after treatment is over. You must use two forms of birth control when you take Pegintron / Rebetol Combo Pack (Ribavirin) and for the 6 months after treatment.

• Females must have a pregnancy test before starting Pegintron / Rebetol Combo Pack (Ribavirin), every month while treated with Pegintron / Rebetol Combo Pack (Ribavirin), and every month for the 6 months after treatment with Pegintron / Rebetol Combo Pack (Ribavirin).
• If you or your female sexual partner becomes pregnant while taking Pegintron / Rebetol Combo Pack (Ribavirin) or within 6 months after you stop taking Pegintron / Rebetol Combo Pack (Ribavirin), tell your healthcare provider right away. You or your healthcare provider should contact the Pegintron / Rebetol Combo Pack (Ribavirin) Pregnancy Registry by calling 1-800-593-2214. The Pegintron / Rebetol Combo Pack (Ribavirin) Pregnancy Registry collects information about what happens to mothers and their babies if the mother takes Pegintron / Rebetol Combo Pack (Ribavirin) while she is pregnant.

What is R ibavirin?

Pegintron / Rebetol Combo Pack (Ribavirin) is a prescription medicine used with another medicine called peginterferon alfa-2a to treat chronic (lasting a long time) hepatitis C infection in people 5 years and older whose liver still works normally, and who have not been treated before with a medicine called an interferon alpha. It is not known if Pegintron / Rebetol Combo Pack (Ribavirin) is safe and will work in children under 5 years of age.

Who should not take Pegintron / Rebetol Combo Pack (Ribavirin)?

See "What is the most important information I should know about Pegintron / Rebetol Combo Pack (Ribavirin)?"

Do not take Pegintron / Rebetol Combo Pack (Ribavirin) if you:

• have certain types of hepatitis caused by your immune system attacking your liver (autoimmune hepatitis)
• have certain blood disorders, such as thalassemia major or sickle-cell anemia (hemoglobinopathies)
• take didanosine (Videx or Videx EC)

Talk to your healthcare provider before starting treatment with Pegintron / Rebetol Combo Pack (Ribavirin) if you have any of these medical conditions.

What should I tell my healthcare provider before taking Pegintron / Rebetol Combo Pack (Ribavirin)?

Before you take Pegintron / Rebetol Combo Pack (Ribavirin), tell your healthcare provider if you have or have had:

• treatment for hepatitis C that did not work for you
• serious allergic reactions to Pegintron / Rebetol Combo Pack (Ribavirin) or to any of the ingredients in Pegintron / Rebetol Combo Pack (Ribavirin). See the end of this Medication Guide for a list of ingredients.
• breathing problems. Pegintron / Rebetol Combo Pack (Ribavirin) may cause or worsen your breathing problems you already have.
• vision problems. Pegintron / Rebetol Combo Pack (Ribavirin) may cause eye problems or worsen eye problems you already have. You should have an eye exam before you start treatment with Pegintron / Rebetol Combo Pack (Ribavirin).
• certain blood disorders such as anemia
• high blood pressure, heart problems or have had a heart attack. Your healthcare provider should test your blood and heart before you start treatment with Pegintron / Rebetol Combo Pack (Ribavirin).
• thyroid problems
• diabetes. Pegintron / Rebetol Combo Pack (Ribavirin) and peginterferon alfa-2a combination therapy may make your diabetes worse or harder to treat.
• liver problems other than hepatitis C virus infection
• human immunodeficiency virus (HIV) or other immunity problems
• mental health problems, including depression or thoughts of suicide
• kidney problems
• an organ transplant
• drug addiction or abuse
• infection with hepatitis B virus
• any other medical condition
• are breastfeeding. It is not known if Pegintron / Rebetol Combo Pack (Ribavirin) passes into your breastmilk. You and your healthcare provider should decide if you will take Pegintron / Rebetol Combo Pack (Ribavirin) or breastfeed.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Some medicines can cause serious side effects if taken while you also take Pegintron / Rebetol Combo Pack (Ribavirin). Some medicines may affect how Pegintron / Rebetol Combo Pack (Ribavirin) works or Pegintron / Rebetol Combo Pack (Ribavirin) may affect how your other medicines work.

Especially tell your healthcare provider if you take any medicines to treat HIV, including didanosine (Videx or Videx EC), or if you take azathioprine (Imuran or Azasan).

Know the medicines you take. Keep a list of them to show your healthcare provider or pharmacist when you get a new medicine.

How should I take Pegintron / Rebetol Combo Pack (Ribavirin)?

• Take Pegintron / Rebetol Combo Pack (Ribavirin) exactly as your healthcare provider tells you. Your healthcare provider will tell you how much Pegintron / Rebetol Combo Pack (Ribavirin) to take and when to take it. For children 5 years of age and older your healthcare provider will prescribe the dose of Pegintron / Rebetol Combo Pack (Ribavirin) based on weight.
• Take Pegintron / Rebetol Combo Pack (Ribavirin) with food.
• If you miss a dose of Pegintron / Rebetol Combo Pack (Ribavirin), take the missed dose as soon as possible during the same day. Do not double the next dose. If you have questions about what to do, call your healthcare provider.
• If you take too much Pegintron / Rebetol Combo Pack (Ribavirin), call your healthcare provider or local Poison Control Center right away, or go the nearest hospital emergency room right away.
• Your healthcare provider should do blood tests before you start treatment with Pegintron / Rebetol Combo Pack (Ribavirin), at weeks 2 and 4 of treatment, and then as needed to see how well you are tolerating treatment and to check for side effects. Your healthcare provider may change your dose of Pegintron / Rebetol Combo Pack (Ribavirin) based on blood test results or side effects you may have.
• If you have heart problems, your healthcare provider should check your heart by doing an electrocardiogram before you start treatment with Pegintron / Rebetol Combo Pack (Ribavirin), and if needed during treatment.

What should I avoid while taking Pegintron / Rebetol Combo Pack (Ribavirin)?

• Pegintron / Rebetol Combo Pack (Ribavirin) can make you feel tired, dizzy, or confused. You should not drive or operate machinery if you have any of these symptoms.
• Do not drink alcohol, including beer, wine, and liquor. This may make your liver disease worse.

What are the possible side effects of Pegintron / Rebetol Combo Pack (Ribavirin)?

Pegintron / Rebetol Combo Pack (Ribavirin) may cause serious side effects including:

See "What is the most important information I should know about Pegintron / Rebetol Combo Pack (Ribavirin)?"

• Swelling and irritation of your pancreas (pancreatitis). You may have stomach pain, nausea, vomiting or diarrhea.
• Severe allergic reactions. Symptoms may include hives, wheezing, trouble breathing, chest pain, swelling of your mouth, tongue, or lips, or severe rash.
• Serious breathing problems. Difficulty breathing may be a sign of a serious lung infection (pneumonia) that can lead to death.
• Serious eye problems that may lead to vision loss or blindness.
• Liver problems. Some people may get worsening of liver function. Tell your healthcare provider right away if you have any of these symptoms: stomach bloating, confusion, brown urine, and yellow eyes.
• Severe depression
• Suicidal thoughts and attempts
• Effect on growth in children. Children can experience a delay in weight gain and height increase while being treated with peginterferon alfa-2a and Pegintron / Rebetol Combo Pack (Ribavirin). Catch-up in growth happens after treatment stops, but some children may not reach the height that they were expected to have before treatment. Talk to your healthcare provider if you are concerned about your child's growth during treatment with peginterferon alfa-2a and Pegintron / Rebetol Combo Pack (Ribavirin).

Call your healthcare provider or get medical help right away if you have any of the symptoms listed above. These may be signs of a serious side effect of Pegintron / Rebetol Combo Pack (Ribavirin) treatment.

Common side effects of Pegintron / Rebetol Combo Pack (Ribavirin) taken with peginterferon alfa-2a include:

• flu-like symptoms-feeling tired, headache, shaking along with high temperature (fever), and muscle or joint aches
• mood changes, feeling irritable, anxiety, and difficulty sleeping
• loss of appetite, nausea, vomiting, and diarrhea
• hair loss
• itching

Tell your healthcare provider about any side effect that bothers you or that does not go away.

These are not all the possible side effects of Pegintron / Rebetol Combo Pack (Ribavirin) treatment. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Please address medical inquiries to, (MedicalAffairsPegintron / Rebetol Combo Pack (Ribavirin)zydususa.com) Tel.: 1-877-993-8779.

How should I store Pegintron / Rebetol Combo Pack (Ribavirin)?

• Store Pegintron / Rebetol Combo Pack (Ribavirin) tablets between 20° to 25°C (68° to 77°F).59°F.
• Keep the bottle tightly closed.

Keep Pegintron / Rebetol Combo Pack (Ribavirin) and all medicines out of the reach of children.

General information about the safe and effective use of Pegintron / Rebetol Combo Pack (Ribavirin)

It is not known if treatment with Pegintron / Rebetol Combo Pack (Ribavirin) in combination with peginterferon alfa-2a will prevent an infected person from spreading the hepatitis C virus to another person while on treatment.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Pegintron / Rebetol Combo Pack (Ribavirin) for a condition for which it was not prescribed. Do not give Pegintron / Rebetol Combo Pack (Ribavirin) to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about Pegintron / Rebetol Combo Pack (Ribavirin). If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Pegintron / Rebetol Combo Pack (Ribavirin) that is written for healthcare professionals.

What are the ingredients in Pegintron / Rebetol Combo Pack (Ribavirin) Tablets?

Active Ingredient: Pegintron / Rebetol Combo Pack (Ribavirin), USP

Inactive Ingredients: crospovidone, hypromellose, iron oxide red, iron oxide yellow, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, silicon dioxide, talc and titanium dioxide.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

This product's label may have been updated. For current full prescribing information, please visit www.zydususa.com.

Manufactured by:

Cadila Healthcare Ltd.

Ahmedabad, India

Distributed by:

Zydus Pharmaceuticals USA Inc.

Pennington, NJ 08534

Rev.: 02/15

NDC 68382-046-03 in bottle of 168 tablets

Pegintron / Rebetol Combo Pack (Ribavirin) Tablets, 200 mg

R_x only

168 tablets

ZYDUS

NDC 68382-127-07 in bottle of 56 tablets

Pegintron / Rebetol Combo Pack (Ribavirin) Tablets, 400 mg

R_x only

56 tablets

ZYDUS

NDC 68382-128-07 in bottle of 56 tablets

Pegintron / Rebetol Combo Pack (Ribavirin) Tablets, 500 mg

R_x only

56 tablets

ZYDUS

NDC 68382-129-07 in bottle of 56 tablets

Pegintron / Rebetol Combo Pack (Ribavirin) Tablets, 600 mg

R_x only

56 tablets

ZYDUS

Pegintron / Rebetol Combo Pack (Ribavirin) tablets, 200 mg Pegintron / Rebetol Combo Pack (Ribavirin) tablet,400 mg Pegintron / Rebetol Combo Pack (Ribavirin) Tablet 500 mg Pegintron / Rebetol Combo Pack (Ribavirin) tablet 600 mg