Prescription Drugs

CLINICAL PHARMACOLOGY Pharmacokinetics Interferon alfa-2b, recombinant Single and multiple dose pharmacokinetic properties of INTRON A (interferon alfa-2b, recombinant) are summarized in Table 1 . Following a single 3 million IU (MIU) subcutaneous dose in 12 patients with chronic hepatitis C, mean (% CV*) serum concentrations peaked at 7 (44%) hours. Following 4 weeks of subcutaneous dosing with 3 MIU three times a week (TIW), interferon serum concentrations were undetectable predose. However, a twofold increase in bioavailability was noted upon multiple dosing of interferon; the reason for this is unknown. Mean half-life values following single- and multiple- dose administrations were 6.8 (24%) hours and 6.5 (29%) hours, respectively. Ribavirin Single- and multiple- dose pharmacokinetic properties in adults with chronic hepatitis C are summarized in Table 1 . Ribavirin was rapidly and extensively absorbed following oral administration. However, due to first-pass metabolism, the absolute bioavailability averaged 64% (44%). There was a linear relationship between dose and AUCtf (AUC from time zero to last measurable concentration) following single doses of 200-1200 mg ribavirin. The relationship between dose and Cmax was curvilinear, tending to asymptote above single doses of 400-600 mg. Upon multiple oral dosing, based on AUC12 hr , a sixfold accumulation of ribavirin was observed in plasma. Following oral dosing with 600 mg BID, steady-state was reached by approximately 4 weeks, with mean steady-state plasma concentrations of 2200 (37%) ng/mL. Upon discontinuation of dosing, the mean half-life was 298 (30%) hours, which probably reflects slow elimination from nonplasma compartments. Effect of Food on Absorption of Ribavirin Both AUC tf and Cmax increased by 70% when Rebetol Capsules were administered with a high-fat meal (841 kcal, 53.8 g fat, 31.6 g protein, and 57.4 g carbohydrate) in a single-dose pharmacokinetic study. There are insufficient data to address the clinical relevance of these results. Clinical efficacy studies were conducted without instructions with respect to food consumption. (See DOSAGE AND ADMINISTRATION .) Effect of Antacid on Absorption of Ribavirin Coadministration with an antacid containing magnesium, aluminum, and simethicone (Mylanta®) resulted in a 14% decrease in mean ribavirin AUCtf. The clinical relevance of results from this single-dose study is unknown. Table 1. Mean (% CV) Pharmacokinetic Parameters for Intron A and Rebetol when administered individually to Adults with Chronic Hepatitis C Parameter Intron A (N=12) Rebetol (N=12) Single Dose 3 MIU Multiple Dose 3 MIU tiw Single Dose 600 mg Multiple Dose 600 mg bid Tmax(hr) 7 (44) 5 (37) 1.7 (46) *** 3 (60) Cmax* 13.9 (32) 29.7 (33) 782 (37) 3680 (85) AUCtf ** 142 (43) 333 (39) 13400 (48) 228000 (25) T1/2 (hr) 6.8 (24) 6.5 (29) 43.6 (47) 298 (30) Apparent Volume of Distribution (L) 2825 (9)  Apparent Clearance (L/hr) 14.3 (17) 38.2 (40) Absolute Bioavailability 64% (44)    * IU/mL for Intron A and ng/mL for Rebetol ** IU. hr/mL for Intron A and ng. hr/mL for Rebetol   data obtained from a single-dose pharmacokinetic study using 14C labeled ribavirin; N = 5    N = 6 *** n = 11 Ribavirin transport into nonplasma compartments has been most extensively studied in red blood cells, and has been identified to be primarily via an es-type equilibrative nucleoside transporter. This type of transporter is present on virtually all cell types and may account for the extensive volume of distribution. Ribavirin does not bind to plasma proteins. Ribavirin has two pathways of metabolism: (i) a reversible phosphorylation pathway in nucleated cells; and (ii) a degradative pathway involving deribosylation and amide hydrolysis to yield a triazole carboxylic acid metabolite. Ribavirin and its triazole carboxamide and triazole carboxylic acid metabolites are excreted renally. After oral administration of 600 mg of 14 C-ribavirin, approximately 61% and 12% of the radioactivity was eliminated in the urine and feces, respectively, in 336 hours. Unchanged ribavirin accounted for 17% of the administered dose. Results of in vitro studies using both human and rat liver microsome preparations indicated little or no cytochrome P450 enzyme mediated metabolism of ribavirin, with minimal potential for P450 enzyme-based drug interactions. No pharmacokinetic interactions were noted between INTRON A Injection and REBETOL Capsules in a multiple-dose pharmacokinetic study. Special Populations Renal Dysfunction The pharmacokinetics of ribavirin were assessed after administration of a single oral dose (400 mg) of ribavirin to subjects with varying degrees of renal dysfunction. The mean AUCtf value was threefold greater in subjects with creatinine clearance values between 10 to 30 mL/min when compared to control subjects (creatinine clearance >90 mL/min). This appears to be due to reduction of apparent clearance in these patients. Ribavirin was not removed by hemodialysis. Rebetol is not recommended for patients with severe renal impairment (see WARNINGS ). Hepatic Dysfunction The effect of hepatic dysfunction was assessed after a single oral dose of ribavirin (600 mg). The mean AUC tf values were not significantly different in subjects with mild, moderate, or severe hepatic dysfunction (Child- Pugh Classification A, B, or C), when compared to control subjects. However, the mean C max values increased with severity of hepatic dysfunction and was twofold greater in subjects with severe hepatic dysfunction when compared to control subjects. Pediatric Patients Pharmacokinetic evaluations for pediatric subjects have not been performed. Elderly Patients Pharmacokinetic evaluations for elderly subjects have not been performed. Gender There were no clinically significant pharmacokinetic differences noted in a single-dose study of eighteen male and eighteen female subjects. * In this section of the label, numbers in parenthesis indicate % coefficient of variation.

INDICATIONS REBETOL (ribavirin, USP) Capsules is indicated in combination with INTRON A (interferon alfa-2b, recombinant) Injection for the treatment of chronic hepatitis C in patients with compensated liver disease previously untreated with alpha interferon or who have relapsed following alpha interferon therapy. Description of Clinical Studies Previously Untreated Patients Adults with compensated chronic hepatitis C and detectable HCV RNA (assessed by a central laboratory using a research based RT-PCR assay) who were previously untreated with alpha interferon therapy were enrolled into two multicenter, double-blind trials (US and International) and randomized to receive REBETOL Capsules 1200 mg/day (1000 mg/day for patients weighing £75kg) plus INTRON A Injection 3 MIU TIW or INTRON A Injection plus placebo for 24 or 48 weeks followed by 24 weeks of off-therapy follow-up. The International study did not contain a 24 week INTRON A plus placebo treatment arm. The US study enrolled 912 patients who, at baseline, were 67% male, 89% caucasian with a mean Knodell HAI score (I+II+III) of 7.5, and 72% genotype 1. The International study, conducted in Europe, Israel, Canada, and Australia, enrolled 799 patients (65% male, 95% caucasian, mean Knodell score 6.8, and 58% genotype 1). Study results are summarized in Table 2 . Table 2. Virologic and Histologic Responses: Previously Untreated Patients* US Study International Study 24 weeks of treatment 48 weeks of treatment 24 weeks of treatment 48 weeks of treatment INTRON A plus REBETOL (N=228) INTRON A plus Placebo (N=231) INTRON A plus REBETOL (N=228) INTRON A plus Placebo (N=225) INTRON A plus REBETOL (N=265) INTRON A plus REBETOL (N=268) INTRON A plus Placebo (N=266) Virologic Response -Responder 1 -Nonresponder -Missing Data 65(29) 147(64) 16(7) 13(6) 194(84) 24(10) 85(37) 110(48) 33(14) 27(12) 168(75) 30(13) 86(32) 158(60) 21(8) 113(42) 120(45) 35(13) 46(17) 196(74) 24(9) Histologic Response -Improvement2 -No improvement -Missing Data 102(45) 77(34) 49(21) 77(33) 99(43) 55(24) 96(42) 61(27) 71(31) 65(29) 93(41) 67(30) 103(39) 85(32) 77(29) 102(38) 58(22) 108(40) 69(26) 111(41) 86(32) * Number (%) of Patients 1. Defined as HCV RNA below limit of detection using a research based RT-PCR assay at end of treatment and during follow-up period. 2. Defined as posttreatment (end of follow-up) minus pretreatment liver biopsy Knodell HAI score (I+II+III) improvement of ³2 points. Of patients who had not achieved HCV RNA below the limit of detection of the research based assay by week 24 of REBETOL/INTRON A treatment, less than 5% responded to an additional 24 weeks of combination treatment. Among patients with HCV Genotype 1 treated with REBETOL/INTRON A therapy who achieved HCV RNA below the detection limit of the research based assay by 24 weeks, those randomized to 48 weeks of treatment had higher virologic responses compared to those in the 24 week treatment group. There was no observed increase in response rates for patients with HCV non-genotype 1 randomized to REBETOL/INTRON A therapy for 48 weeks compared to 24 weeks. Relapse Patients Patients with compensated chronic hepatitis C and detectable HCV RNA (assessed by a central laboratory using a research based RT-PCR assay) who had relapsed following one or two courses of interferon therapy (defined as abnormal serum ALT levels) were enrolled into two multicenter, double-blind trials (US and International) and randomized to receive REBETOL 1200 mg/day (1000 mg/day for patients weighing £75 kg) plus INTRON A 3 MIU TIW or INTRON A plus placebo for 24 weeks followed by 24 weeks of off-therapy follow-up. The US study enrolled 153 patients who, at baseline, were 67% male, 92% caucasian with a mean Knodell HAI score (I+II+III) of 6.8, and 58% genotype 1. The International study, conducted in Europe, Israel, Canada, and Australia, enrolled 192 patients (64% male, 95% caucasian, mean Knodell score 6.6, and 56% genotype 1). Study results are summarized in table 3 . Table 3. Virologic and Histologic Responses: Relapse Patients* US Study International Study INTRON A plus REBETOL N=77 INTRON A plus Placebo N=76 INTRON A plus REBETOL N=96 INTRON A plus Placebo N=96 Virologic Response -Responder1 -Nonresponder -Missing Data 33(43) 36(47) 8(0) 3(4) 66(87) 7(9) 46(48) 45(47) 5(5) 5(5) 91(95) 0(0) Histologic Response -Improvement2 -No improvement -Missing Data 38(49) 23(30) 16(21) 27(36) 37(49) 12(16) 49(51) 29(30) 18(19) 30(31) 44(46) 22(23) * Number (%) of Patients. 1. Defined as HCV RNA below limit of detection using a research based RT-PCR assay at end of treatment and during follow-up period. 2. Defined as post treatment (end of follow-up) minus pretreatment liver biopsy Knodell HAI score (I+II+III) improvement of ³2 points. Virologic and histologic responses were similar among male and female patients in both the previously untreated and relapse studies. DOSAGE AND ADMINISTRATION INTRON A Injection should be administered subcutaneously and Rebetol Capsules should be administered orally (see Table 6). The recommended dose of REBETOL Capsules depends on the patients body weight. The recommended doses of Rebetol and INTRON A are given in Table 6. The recommended duration of treatment for patients previously untreated with interferon is 24 to 48 weeks. The duration of treatment should be individualized to the patient depending on baseline disease characteristics, response to therapy, and tolerability of the regimen (see INDICATIONSDescription of Clinical Studies and ADVERSE REACTIONS). After 24 weeks of treatment virologic response should be assessed. Treatment discontinuation should be considered in any patient who has not achieved an HCV-RNA below the limit of detection of the assay by 24 weeks. There are no safety and efficacy data on treatment for longer than 48 weeks in the previously untreated patient population. In patients who relapse following interferon therapy, the recommended duration of treatment is 24 weeks. There are no safety and efficacy data on treatment for longer than 24 weeks in the relapse patient population. Table 6. Recommended Dosing Body weight REBETOL Capsules INTRON A Injection £ 75 kg 2 x 200 mg capsules Am, 3 x 200 mg capsules PM daily p.o. 3 million IU 3 times weekly s. c. > 75 kg 3 x 200 mg capsules AM, 3 x 200 mg capsules PM, daily p.o. 3 million IU 3 times weekly s. c. REBETOL may be administered without regard to food, but should be administered in a consistent manner. (See CLINICAL PHARMACOLOGY.) Dose Modifications ( TABLE 7 ) In clinical trials, approximately 26% of patients required modification of their dose of REBETOL Capsules, INTRON A Injection, or both agents. If severe adverse reactions or laboratory abnormalities develop during combination REBETOL/INTRON A therapy the dose should be modified, or discontinued if appropriate, until the adverse reactions abate. If intolerance persists after dose adjustment, REBETOL/INTRON A therapy should be discontinued. REBETOL/INTRON A therapy 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. ) For patients with a history of stable cardiovascular disease, a permanent dose reduction is required if the hemoglobin decreases by ³2 g/dL during any 4-week period. In addition, for these cardiac history patients, if the hemoglobin remains <12 g/dL after 4 weeks on a reduced dose, the patient should discontinue combination REBETOL/INTRON A therapy. It is recommended that a patient whose hemoglobin level falls below 10 g/dL have his/her REBETOL dose reduced to 600 mg daily (1 x 200 mg capsule AM , 2 x 200 mg capsules PM ). A patient whose hemoglobin level falls below 8.5 g/dL should be permanently discontinued from REBETOL/INTRON A therapy. (See WARNINGS.) It is recommended that a patient who experiences moderate depression (persistent low mood, loss of interest, p.o. self image, and/or hopelessness) have his/her INTRON A dose temporarily reduced and/or be considered for medical therapy. A patient experiencing severe depression or suicidal ideation/attempt should be discontinued from REBETOL/INTRON A therapy and followed closely with appropriate medical management. (See WARNINGS.) TABLE 7. Guidelines for Dose Modifications Dose Reduction * REBETOL - 600 mg daily INTRON A - 1.5 million IU TIW Permanent Discontinuation of Treatment REBETOL and INTRON A Hemoglobin

PATIENT INFORMATION Combination REBETOL/ INTRON A therapy must not be used by women who are pregnant or by men whose female partners are pregnant. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients taking combination REBETOL/ INTRON A therapy. Combination REBETOL/ INTRON A therapy should not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Patients must perform a pregnancy test monthly during therapy and for 6 months posttherapy. Women of childbearing potential must be counseled about use of effective contraception (two reliable forms) prior to initiating therapy. Patients (male and female) must be advised of the teratogenic/ embryocidal risks and must be instructed to practice effective contraception during combination REBETOL/ INTRON A therapy and for 6 months posttherapy. Patients (male and female) should be advised to notify the physician immediately in the event of a pregnancy. (See CONTRAINDICATIONS.) If pregnancy does occur during treatment or during 6 months posttherapy, the patient must be advised of the significant teratogenic risk of REBETOL therapy to the fetus. Patients, or partners of patients, should immediately report any pregnancy that occurs during treatment or within 6 months after treatment cessation to their physician. Physicians are encouraged to report such cases by calling (800) 727- 7064. Patients receiving combination REBETOL/ INTRON A treatment should be directed in its appropriate use, informed of the benefits and risks associated with treatment, and referred to the patient MEDICATION GUIDE . There are no data evaluating whether REBETOL/ INTRON A therapy will prevent transmission of infection to others. Also, it is not known if treatment with REBETOL/ INTRON A therapy will cure hepatitis C or prevent cirrhosis, liver failure, or liver cancer that may be the result of infection with the hepatitis C virus. If home use is prescribed, a puncture-resistant container for the disposal of used syringes and needles should be supplied to the patient. Patients should be thoroughly instructed in the importance of proper disposal and cautioned against any reuse of needles and syringes. The full container should be disposed of according to the directions provided by the physician (see MEDICATION GUIDE ). The most common adverse experiences occurring with combination REBETOL/ INTRON A therapy are "flu-like" symptoms, such as headache, fatigue, myalgia, and fever (see ADVERSE REACTIONS ) and appear to decrease in severity as treatment continues. Some of these "flu-like" symptoms may be minimized by bedtime administration of INTRON A therapy. Antipyretics should be considered to prevent or partially alleviate the fever and headache. Another common adverse experience associated with INTRON A therapy is thinning of the hair. Patients should be advised that laboratory evaluations are required prior to starting therapy and periodically thereafter (see PRECAUTIONS: Laboratory Tests). It is advised that patients be well hydrated, especially during the initial stages of treatment.

SIDE EFFECTS Clinical trials with REBETOL in combination with PegIntron or INTRON A have been conducted in over 7800 subjects from 3 to 76 years of age. The primary toxicity of ribavirin is hemolytic anemia. Reductions in hemoglobin levels occurred within the first 1 to 2 weeks of oral therapy. Cardiac and pulmonary reactions associated with anemia occurred in approximately 10% of patients [see WARNINGS AND PRECAUTIONS]. Greater than 96% of all subjects in clinical trials experienced one or more adverse reactions. The most commonly reported adverse reactions in adult subjects receiving PegIntron or INTRON A in combination with REBETOL were injection site inflammation/reaction, fatigue/asthenia, headache, rigors, fevers, nausea, myalgia and anxiety/emotional lability/irritability. The most common adverse reactions in pediatric subjects, ages 3 and older, receiving REBETOL in combination with PegIntron or INTRON A were pyrexia, headache, neutropenia, fatigue, anorexia, injection site erythema, and vomiting. The Adverse Reactions section references the following clinical trials: REBETOL/PegIntron Combination therapy trials: Clinical Study 1 – evaluated PegIntron monotherapy (not further described in this label; see labeling for PegIntron for information about this trial). Study 2 – evaluated REBETOL 800 mg/day flat dose in combination with 1.5 mcg/kg/week PegIntron or with INTRON A. Study 3 – evaluated PegIntron/weight-based REBETOL in combination with PegIntron/flat dose REBETOL regimen. Study 4 – compared two PegIntron (1.5 mcg/kg/week and 1 mcg/kg/week) doses in combination with REBETOL and a third treatment group receiving Pegasys® (180 mcg/week)/Copegus® (1000-1200 mg/day). Study 5 – evaluated PegIntron (1.5 mcg/kg/week) in combination with weight-based REBETOL in prior treatment failure subjects. PegIntron/REBETOL Combination Therapy in Pediatric Patients REBETOL/INTRON A Combination Therapy trials for adults and pediatrics Serious adverse reactions have occurred in approximately 12% of subjects in clinical trials with PegIntron with or without REBETOL [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. The most common serious events occurring in subjects treated with PegIntron and REBETOL were depression and suicidal ideation [see WARNINGS AND PRECAUTIONS], each occurring at a frequency of less than 1%. Suicidal ideation or attempts occurred more frequently among pediatric patients, primarily adolescents, compared to adult patients (2.4% versus 1%) during treatment and off-therapy follow-up [see WARNINGS AND PRECAUTIONS]. The most common fatal reaction occurring in subjects treated with PegIntron and REBETOL was cardiac arrest, suicide ideation, and suicide attempt [see WARNINGS AND PRECAUTIONS], all occurring in less than 1% of subjects. Because clinical trials are conducted under widely varying conditions, adverse reactions 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. Clinical Trials Experience – REBETOL/PegIntron Combination Therapy Adult Subjects Adverse reactions that occurred in the clinical trial at greater than 5% incidence are provided by treatment group from the REBETOL/PegIntron Combination Therapy (Study 2) in Table 5. Table 5: Adverse Reactions Occurring in Greater Than 5% of Adult Subjects Adverse Reactions Percentage of Subjects Reporting Adverse Reactions* Adverse Reactions Percentage of Subjects Reporting Adverse Reactions* PegIntron 1.5 mcg/kg/ REBETOL (N=511) INTRON A/ REBETOL (N=505) PegIntron 1.5 mcg/kg/ REBETOL (N=511) INTRON A/ REBETOL (N=505) Application Site Musculoskeletal Injection Site Inflammation 25 18 Myalgia 56 50 Injection Site Reaction 58 36 Arthralgia 34 28 Autonomic Nervous System Musculoskeletal Pain 21 19 Dry Mouth 12 8 Psychiatric Increased Sweating 11 7 Insomnia 40 41 Flushing 4 3 Depression 31 34 Body as a Whole Anxiety/Emotional Lability/Irritability 47 47 Fatigue/Asthenia 66 63 Concentration Impaired 17 21 Headache 62 58 Agitation 8 5 Rigors 48 41 Nervousness 6 6 Fever 46 33 Reproductive, Female Weight Loss 29 20 Menstrual Disorder 7 6 Right Upper Quadrant Pain 12 6 Resistance Mechanism Chest Pain 8 7 Viral Infection 12 12 Malaise 4 6 Fungal Infection 6 1 Central/Peripheral Nervous System Respiratory System Dizziness 21 17 Dyspnea 26 24 Endocrine Coughing 23 16 Hypothyroidism 5 4 Pharyngitis 12 13 Gastrointestinal Rhinitis 8 6 Nausea 43 33 Sinusitis 6 5 Anorexia 32 27 Skin and Appendages Diarrhea 22 17 Alopecia 36 32 Vomiting 14 12 Pruritus 29 28 Abdominal Pain 13 13 Rash 24 23 Dyspepsia 9 8 Skin Dry 24 23 Constipation 5 5 Special Senses, Other Hematologic Disorders Taste Perversion 9 4 Neutropenia 26 14 Vision Disorders Anemia 12 17 Vision Blurred 5 6 Leukopenia 6 5 Conjunctivitis 4 5 Thrombocytopenia 5 2 Liver and Biliary System Hepatomegaly 4 4 * A subject may have reported more than one adverse reaction within a body system/organ class category. Table 6 summarizes the treatment-related adverse reactions in Study 4 that occurred at a greater than or equal to 10% incidence. Table 6: Treatment-Related Adverse Reactions (Greater Than or Equal to 10% Incidence) By Descending Frequency Adverse Reactions Study 4 Percentage of Subjects Reporting Treatment-Related Adverse Reactions PegIntron 1.5 mcg/kgwith REBETOL (N=1019) PegIntron 1 mcg/kgwith REBETOL (N=1016) Pegasys 180 mcg withCopegus (N=1035) Fatigue 67 68 64 Headache 50 47 41 Nausea 40 35 34 Chills 39 36 23 Insomnia 38 37 41 Anemia 35 30 34 Pyrexia 35 32 21 Injection Site Reactions 34 35 23 Anorexia 29 25 21 Rash 29 25 34 Myalgia 27 26 22 Neutropenia 26 19 31 Irritability 25 25 25 Depression 25 19 20 Alopecia 23 20 17 Dyspnea 21 20 22 Arthralgia 21 22 22 Pruritus 18 15 19 Influenza-like Illness 16 15 15 Dizziness 16 14 13 Diarrhea 15 16 14 Cough 15 16 17 Weight Decreased 13 10 10 Vomiting 12 10 9 Unspecified Pain 12 13 9 Dry Skin 11 11 12 Anxiety 11 11 10 Abdominal Pain 10 10 10 Leukopenia 9 7 10 The incidence of serious adverse reactions was comparable in all trials. In Study 3, there was a similar incidence of serious adverse reactions reported for the weight-based REBETOL group (12%) and for the flat-dose REBETOL regimen. In Study 2, the incidence of serious adverse reactions was 17% in the PegIntron/REBETOL groups compared to 14% in the INTRON A/REBETOL group. In many but not all cases, adverse reactions resolved after dose reduction or discontinuation of therapy. Some subjects experienced ongoing or new serious adverse reactions during the 6-month follow-up period. In Study 2, many subjects continued to experience adverse reactions several months after discontinuation of therapy. By the end of the 6-month follow-up period, the incidence of ongoing adverse reactions by body class in the PegIntron 1.5/REBETOL group was 33% (psychiatric), 20% (musculoskeletal), and 10% (for endocrine and for GI). In approximately 10 to 15% of subjects, weight loss, fatigue, and headache had not resolved. There have been 31 subject deaths that occurred during treatment or during follow-up in these clinical trials. In Study 1, there was 1 suicide in a subject receiving PegIntron monotherapy and 2 deaths among subjects receiving INTRON A monotherapy (1 murder/suicide and 1 sudden death). In Study 2, there was 1 suicide in a subject receiving PegIntron/REBETOL combination therapy; and 1 subject death in the INTRON A/REBETOL group (motor vehicle accident). In Study 3, there were 14 deaths, 2 of which were probable suicides and 1 was an unexplained death in a person with a relevant medical history of depression. In Study 4, there were 12 deaths, 6 of which occurred in subjects who received PegIntron/REBETOL combination therapy, 5 in the PegIntron 1.5 mcg/REBETOL arm (N=1019) and 1 in the PegIntron 1 mcg/REBETOL arm (N=1016), and 6 of which occurred in subjects receiving Pegasys/Copegus (N=1035); there were 3 suicides that occurred during the off treatment follow-up period in subjects who received PegIntron (1.5 mcg/kg)/REBETOL combination therapy. In Studies 1 and 2, 10 to 14% of subjects receiving PegIntron, alone or in combination with REBETOL, discontinued therapy compared with 6% treated with INTRON A alone and 13% treated with INTRON A in combination with REBETOL. Similarly in Study 3, 15% of subjects receiving PegIntron in combination with weight-based REBETOL and 14% of subjects receiving PegIntron and flat dose REBETOL discontinued therapy due to an adverse reaction. The most common reasons for discontinuation of therapy were related to known interferon effects of psychiatric, systemic (e.g., fatigue, headache), or gastrointestinal adverse reactions. In Study 4, 13% of subjects in the PegIntron 1.5 mcg/REBETOL arm, 10% in the PegIntron 1 mcg/REBETOL arm and 13% in the Pegasys 180 mcg/Copegus arm discontinued due to adverse events. In Study 2, dose reductions due to adverse reactions occurred in 42% of subjects receiving PegIntron (1.5 mcg/kg)/REBETOL and in 34% of those receiving INTRON A/REBETOL. The majority of subjects (57%) weighing 60 kg or less receiving PegIntron (1.5 mcg/kg)/REBETOL required dose reduction. Reduction of interferon was dose-related (PegIntron 1.5 mcg/kg greater than PegIntron 0.5 mcg/kg or INTRON A), 40%, 27%, 28%, respectively. Dose reduction for REBETOL was similar across all three groups, 33 to 35%. The most common reasons for dose modifications were neutropenia (18%), or anemia (9%) (see Laboratory Values). Other common reasons included depression, fatigue, nausea, and thrombocytopenia. In Study 3, dose modifications due to adverse reactions occurred more frequently with weight-based dosing (WBD) compared to flat dosing (29% and 23%, respectively). In Study 4, 16% of subjects had a dose reduction of PegIntron to 1 mcg/kg in combination with REBETOL, with an additional 4% requiring the second dose reduction of PegIntron to 0.5 mcg/kg due to adverse events compared to 15% of subjects in the Pegasys/Copegus arm, who required a dose reduction to 135 mcg/week with Pegasys, with an additional 7% in the Pegasys/Copegus arm requiring second dose reduction to 90 mcg/week with Pegasys. In the PegIntron/REBETOL combination trials the most common adverse reactions were psychiatric, which occurred among 77% of subjects in Study 2 and 68% to 69% of subjects in Study 3. These psychiatric adverse reactions included most commonly depression, irritability, and insomnia, each reported by approximately 30% to 40% of subjects in all treatment groups. Suicidal behavior (ideation, attempts, and suicides) occurred in 2% of all subjects during treatment or during follow-up after treatment cessation [see WARNINGS AND PRECAUTIONS]. In Study 4, psychiatric adverse reactions occurred in 58% of subjects in the PegIntron 1.5 mcg/REBETOL arm, 55% of subjects in the PegIntron 1 mcg/REBETOL arm, and 57% of subjects in the Pegasys 180 mcg/Copegus arm. PegIntron induced fatigue or headache in approximately two-thirds of subjects, with fever or rigors in approximately half of the subjects. The severity of some of these systemic symptoms (e.g., fever and headache) tended to decrease as treatment continued. In Studies 1 and 2, application site inflammation and reaction (e.g., bruise, itchiness, and irritation) occurred at approximately twice the incidence with PegIntron therapies (in up to 75% of subjects) compared with INTRON A. However, injection site pain was infrequent (2 to 3%) in all groups. In Study 3, there was a 23% to 24% incidence overall for injection site reactions or inflammation. Subjects receiving REBETOL/PegIntron as re-treatment after failing a previous interferon combination regimen reported adverse reactions similar to those previously associated with this regimen during clinical trials of treatment-naïve subjects. Pediatric Subjects In general, the adverse-reaction profile in the pediatric population was similar to that observed in adults. In the pediatric trial, the most prevalent adverse reactions in all subjects were pyrexia (80%), headache (62%), neutropenia (33%), fatigue (30%), anorexia (29%), injection-site erythema (29%) and vomiting (27%). The majority of adverse reactions reported in the trial were mild or moderate in severity. Severe adverse reactions were reported in 7% (8/107) of all subjects and included injection site pain (1%), pain in extremity (1%), headache (1%), neutropenia (1%), and pyrexia (4%). Important adverse reactions that occurred in this subject population were nervousness (7%; 7/107), aggression (3%; 3/107), anger (2%; 2/107), and depression (1%; 1/107). Five subjects received levothyroxine treatment, three with clinical hypothyroidism and two with asymptomatic TSH elevations. Weight and height gain of pediatric subjects treated with PegIntron plus REBETOL lagged behind that predicted by normative population data for the entire length of treatment. Severely inhibited growth velocity (less than 3rd percentile) was observed in 70% of the subjects while on treatment. Dose modifications of PegIntron and/or ribavirin were required in 25% of subjects due to treatment-related adverse reactions, most commonly for anemia, neutropenia and weight loss. Two subjects (2%; 2/107) discontinued therapy as the result of an adverse reaction. Adverse reactions that occurred with a greater than or equal to 10% incidence in the pediatric trial subjects are provided in Table 7. Table 7: Percentage of Pediatric Subjects with Treatment-Related Adverse Reactions (in At Least 10% of All Subjects) System Organ Class Preferred Term All Subjects (N=107) Blood and Lymphatic System Disorders Neutropenia 33% Anemia 11% Leukopenia 10% Gastrointestinal Disorders Abdominal Pain 21% Abdominal Pain Upper 12% Vomiting 27% Nausea 18% General Disorders and Administration Site Conditions Pyrexia 80% Fatigue 30% Injection-site Erythema 29% Chills 21% Asthenia 15% Irritability 14% Investigations Weight Loss 19% Metabolism and Nutrition Disorders Anorexia 29% Decreased Appetite 22% Musculoskeletal and Connective Tissue Disorders Arthralgia 17% Myalgia 17% Nervous System Disorders Headache 62% Dizziness 14% Skin and Subcutaneous Tissue Disorders Alopecia 17% Ninety-four of 107 subjects enrolled in a 5 year long-term follow-up trial. The long-term effects on growth were less in those subjects treated for 24 weeks than those treated for 48 weeks. Twenty-four percent of subjects (11/46) treated for 24 weeks and 40% of subjects (19/48) treated for 48 weeks had a > 15 percentile height-for-age decrease from pre-treatment to the end of 5 year long-term follow-up compared to pre-treatment baseline percentiles. Eleven percent of subjects (5/46) treated for 24 weeks and 13% of subjects (6/48) treated for 48 weeks were observed to have a decrease from pre-treatment baseline of > 30 height-for-age percentiles to the end of the 5 year long-term follow-up. While observed across all age groups, the highest risk for reduced height at the end of long-term follow-up appeared to correlate with initiation of combination therapy during the years of expected peak growth velocity. [See WARNINGS AND PRECAUTIONS] Laboratory Values Adult and Pediatric Subjects The adverse reaction profile in Study 3, which compared PegIntron/weight-based REBETOL combination to a PegIntron/flat dose REBETOL regimen, revealed an increased rate of anemia with weight-based dosing (29% vs. 19% for weight-based vs. flat dose regimens, respectively). However, the majority of cases of anemia were mild and responded to dose reductions. Changes in selected laboratory values during treatment in combination with REBETOL treatment are described below. Decreases in hemoglobin, leukocytes, neutrophils, and platelets may require dose reduction or permanent discontinuation from therapy [see DOSAGE AND ADMINISTRATION ]. Changes in selected laboratory values during therapy are described in Table 8. Most of the changes in laboratory values in the PegIntron/REBETOL trial with pediatrics were mild or moderate. Table 8: Selected Laboratory Abnormalities During Treatment with REBETOL and PegIntron or REBETOL and INTRON A in Previously Untreated Subjects Laboratory Parameters* Percentage of Subjects Adults (Study 2) Pediatrics PegIntron/ REBETOL (N=511) INTRON A/ REBETOL (N=505) PegIntron/ REBETOL (N=107)* Hemoglobin (g/dL) 9.5 to < 11.0 26 27 30 8.0 to < 9.5 3 3 2 6.5-7.9 0.2 0.2 - Leukocytes (x 109/L) 2.0-2.9 46 41 39 1.5 to < 2.0 24 8 3 1.0-1.4 5 1 - Neutrophils (x 109/L) 1.0-1.5 33 37 35 0.75 to < 1.0 25 13 26 0.5 to < 0.75 18 7 13 < 0.5 4 2 3 Platelets (x 109/L) 70-100 15 5 1 50 to < 70 3 0.8 - 30-49 0.2 0.2 - 25 to < 50 - - 1 Total Bilirubin (mg/dL) (μmole/L) 1.5-3.0 10 13 - 1.26-2.59 x ULN† - - 7 3.1-6.0 0.6 0.2 - 2.6-5 x ULN† - - - 6.1-12.0 0 0.2 - ALT (U/L) 2 x Baseline 0.6 0.2 1 2.1-5 x Baseline 3 1 5 5.1-10 x Baseline 0 0 3 * The table summarizes the worst category observed within the period per subject per laboratory test. Only subjects with at least one treatment value for a given laboratory test are included. † ULN=Upper limit of normal. Hemoglobin Hemoglobin levels decreased to less than 11 g/dL in about 30% of subjects in Study 2. In Study 3, 47% of subjects receiving WBD REBETOL and 33% on flat-dose REBETOL had decreases in hemoglobin levels less than 11 g/dl. Reductions in hemoglobin to less than 9 g/dL occurred more frequently in subjects receiving WBD compared to flat dosing (4% and 2%, respectively). In Study 2, dose modification was required in 9% and 13% of subjects in the PegIntron/REBETOL and INTRON A/REBETOL groups. In Study 4, subjects receiving PegIntron (1.5 mcg/kg)/REBETOL had decreases in hemoglobin levels to between 8.5 to less than 10 g/dL (28%) and to less than 8.5 g/dL (3%), whereas in patients receiving Pegasys 180 mcg/Copegus these decreases occurred in 26% and 4% of subjects respectively. Hemoglobin levels became stable by treatment Weeks 4-6 on average. The typical pattern observed was a decrease in hemoglobin levels by treatment Week 4 followed by stabilization and a plateau, which was maintained to the end of treatment. In the PegIntron monotherapy trial, hemoglobin decreases were generally mild and dose modifications were rarely necessary [see DOSAGE AND ADMINISTRATION]. Neutrophils Decreases in neutrophil counts were observed in a majority of adult subjects treated with combination therapy with REBETOL in Study 2 (85%) and INTRON A/REBETOL (60%). Severe potentially life-threatening neutropenia (less than 0.5 x 109/L) occurred in 2% of subjects treated with INTRON A/REBETOL and in approximately 4% of subjects treated with PegIntron/REBETOL in Study 2. Eighteen percent of subjects receiving PegIntron/REBETOL in Study 2 required modification of interferon dosage. Few subjects (less than 1%) required permanent discontinuation of treatment. Neutrophil counts generally returned to pre-treatment levels 4 weeks after cessation of therapy [see DOSAGE AND ADMINISTRATION]. Platelets Platelet counts decreased to less than 100,000/mm³ in approximately 20% of subjects treated with PegIntron alone or with REBETOL and in 6% of adult subjects treated with INTRON A/REBETOL. Severe decreases in platelet counts (less than 50,000/mm³) occur in less than 4% of adult subjects. Patients may require discontinuation or dose modification as a result of platelet decreases [see DOSAGE AND ADMINISTRATION]. In Study 2, 1% or 3% of subjects required dose modification of INTRON A or PegIntron, respectively. Platelet counts generally returned to pretreatment levels 4 weeks after the cessation of therapy. Thyroid Function Development of TSH abnormalities, with or without clinical manifestations, is associated with interferon therapies. In Study 2, clinically apparent thyroid disorders occurred among subjects treated with either INTRON A or PegIntron (with or without REBETOL) at a similar incidence (5% for hypothyroidism and 3% for hyperthyroidism). Subjects developed new onset TSH abnormalities while on treatment and during the follow-up period. At the end of the follow-up period 7% of subjects still had abnormal TSH values. Bilirubin And Uric Acid In Study 2, 10 to 14% of subjects developed hyperbilirubinemia and 33 to 38% developed hyperuricemia in association with hemolysis. Six subjects developed mild to moderate gout. Clinical Trials Experience – REBETOL/INTRON A Combination Therapy Adult Subjects In clinical trials, 19% and 6% of previously untreated and relapse subjects, respectively, discontinued therapy due to adverse reactions in the combination arms compared to 13% and 3% in the interferon arms. Selected treatment-related adverse reactions that occurred in the US trials with greater than or equal to 5% incidence are provided by treatment group (see Table 9). In general, the selected treatment-related adverse reactions were reported with lower incidence in the international trials as compared to the US trials, with the exception of asthenia, influenza-like symptoms, nervousness, and pruritus. Pediatric Subjects In clinical trials of 118 pediatric subjects 3 to 16 years of age, 6% discontinued therapy due to adverse reactions. Dose modifications were required in 30% of subjects, most commonly for anemia and neutropenia. In general, the adverse-reaction profile in the pediatric population was similar to that observed in adults. Injection site disorders, fever, anorexia, vomiting, and emotional lability occurred more frequently in pediatric subjects compared to adult subjects. Conversely, pediatric subjects experienced less fatigue, dyspepsia, arthralgia, insomnia, irritability, impaired concentration, dyspnea, and pruritus compared to adult subjects. Selected treatment-related adverse reactions that occurred with greater than or equal to 5% incidence among all pediatric subjects who received the recommended dose of REBETOL/INTRON A combination therapy are provided in Table 9. Table 9: Selected Treatment-Related Adverse Reactions: Previously Untreated and Relapse Adult Subjects and Previously Untreated Pediatric Subjects Percentage of Subjects US Previously Untreated Study US Relapse Study Pediatric Subjects 24 weeks of treatment 48 weeks of treatment 24 weeks of treatment 48 weeks of treatment INTRON A/ REBETOL (N=228) INTRON A/ Placebo (N=231) INTRON A/ REBETOL (N=228) INTRON A/ Placebo (N=225) INTRON A/ REBETOL (N=77) INTRON A/ Placebo (N=76) INTRON A/ REBETOL (N=118) Application Site Disorders Injection Site Inflammation 13 10 12 14 6 8 14 Injection Site Reaction 7 9 8 9 5 3 19 Body as a Whole -General Disorders Headache 63 63 66 67 66 68 69 Fatigue 68 62 70 72 60 53 58 Rigors 40 32 42 39 43 37 25 Fever 37 35 41 40 32 36 61 Influenza-like Symptoms 14 18 18 20 13 13 31 Asthenia 9 4 9 9 10 4 5 Chest Pain 5 4 9 8 6 7 5 Central & Peripheral Nervous System Disorders Dizziness 17 15 23 19 26 21 20 Gastrointestinal System Disorders Nausea 38 35 46 33 47 33 33 Anorexia 27 16 25 19 21 14 51 Dyspepsia 14 6 16 9 16 9 < 1 Vomiting 11 10 9 13 12 8 42 Musculoskeletal System Disorders Myalgia 61 57 64 63 61 58 32 Arthralgia 30 27 33 36 29 29 15 Musculoskeletal Pain 20 26 28 32 22 28 21 Psychiatric Disorders Insomnia 39 27 39 30 26 25 14 Irritability 23 19 32 27 25 20 10 Depression 32 25 36 37 23 14 13 Emotional Lability 7 6 11 8 12 8 16 Concentration Impaired 11 14 14 14 10 12 5 Nervousness 4 2 4 4 5 4 3 Respiratory System Disorders Dyspnea 19 9 18 10 17 12 5 Sinusitis 9 7 10 14 12 7 < 1 Skin and Appendages Disorders Alopecia 28 27 32 28 27 26 23 Rash 20 9 28 8 21 5 17 Pruritus 21 9 19 8 13 4 12 Special Senses, Other Disorders Taste Perversion 7 4 8 4 6 5 < 1 * Subjects reporting one or more adverse reactions. A subject may have reported more than one adverse reaction within a body system/organ class category. During a 48-week course of therapy there was a decrease in the rate of linear growth (mean percentile assignment decrease of 7%) and a decrease in the rate of weight gain (mean percentile assignment decrease of 9%). A general reversal of these trends was noted during the 24-week post-treatment period. Long-term data in a limited number of patients, however, suggests that combination therapy may induce a growth inhibition that results in reduced final adult height in some patients [see WARNINGS AND PRECAUTIONS]. Laboratory Values Changes in selected hematologic values (hemoglobin, white blood cells, neutrophils, and platelets) during therapy are described below (see Table 10). Hemoglobin Hemoglobin decreases among subjects receiving REBETOL therapy began at Week 1, with stabilization by Week 4. In previously untreated subjects treated for 48 weeks, the mean maximum decrease from baseline was 3.1 g/dL in the US trial and 2.9 g/dL in the international trial. In relapse subjects, the mean maximum decrease from baseline was 2.8 g/dL in the US trial and 2.6 g/dL in the international trial. Hemoglobin values returned to pretreatment levels within 4 to 8 weeks of cessation of therapy in most subjects. Bilirubin and Uric Acid Increases in both bilirubin and uric acid, associated with hemolysis, were noted in clinical trials. Most were moderate biochemical changes and were reversed within 4 weeks after treatment discontinuation. This observation occurred most frequently in subjects with a previous diagnosis of Gilbert’s syndrome. This has not been associated with hepatic dysfunction or clinical morbidity. Table 10: Selected Laboratory Abnormalities During Treatment With REBETOL and INTRON A: Previously Untreated and Relapse Adult Subjects and Previously Untreated Pediatric Subjects Percentage of Subjects US Previously Untreated Study US Relapse Study Pediatric Subjects 24 weeks of treatment 48 weeks of treatment 24 weeks of treatment 48 weeks of treatment INTRON A/ REBETOL (N=228) INTRON A/ Placebo (N=231) INTRON A/ REBETOL (N=228) INTRON A/ Placebo (N=225) INTRON A/ REBETOL (N=77) INTRON A/ Placebo (N=76) INTRON A/ REBETOL (N=118) Hemoglobin (g/dL) 9.5 to 10.9 24 1 32 1 21 3 24 8.0 to 9.4 5 0 4 0 4 0 3 6.5 to 7.9 0 0 0 0.4 0 0 0 < 6.5 0 0 0 0 0 0 0 Leukocytes (x 109/L) 2.0 to 2.9 40 20 38 23 45 26 35 1.5 to 1.9 4 1 9 2 5 3 8 1.0 to 1.4 0.9 0 2 0 0 0 0 < 1.0 0 0 0 0 0 0 0 Neutrophils (x 109/L) 1.0 to 1.49 30 32 31 44 42 34 37 0.75 to 0.99 14 15 14 11 16 18 15 0.5 to 0.74 9 9 14 7 8 4 16 < 0.5 11 8 11 5 5 8 3 Platelets (x 109/L) 70 to 99 9 11 11 14 6 12 0.8 50 to 69 2 3 2 3 0 5 2 30 to 49 0 0.4 0 0.4 0 0 0 < 30 0.9 0 1 0.9 0 0 0 Total Bilirubin (mg/dL) 1.5 to 3.0 27 13 32 13 21 7 2 3.1 to 6.0 0.9 0.4 2 0 3 0 0 6.1 to 12.0 0 0 0.4 0 0 0 0 > 12.0 0 0 0 0 0 0 0 Postmarketing Experiences The following adverse reactions have been identified and reported during post approval use of REBETOL in combination with INTRON A or PegIntron. 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, aplastic anemia Ear and Labyrinth disorders Hearing disorder, vertigo Respiratory, Thoracic and Mediastinal disorders Pulmonary hypertension Eye disorders Serous retinal detachment Endocrine disorders Diabetes DRUG INTERACTIONS Didanosine Exposure to didanosine or its active metabolite (dideoxyadenosine 5'-triphosphate) is increased when didanosine is coadministered with ribavirin, which could cause or worsen clinical toxicities; therefore, coadministration of REBETOL capsules or oral solution and didanosine is contraindicated. Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in clinical trials. Nucleoside Analogues Hepatic decompensation (some fatal) has occurred in cirrhotic HIV/HCV co-infected patients receiving combination antiretroviral therapy for HIV and interferon alpha and ribavirin. Adding treatment with alpha interferons alone or in combination with ribavirin may increase the risk in this patient population. Patients receiving interferon with ribavirin and nucleoside reverse transcriptase inhibitors (NRTIs) should be closely monitored for treatment-associated toxicities, especially hepatic decompensation and anemia. Discontinuation of NRTIs should be considered as medically appropriate (see labeling for individual NRTI product). Dose reduction or discontinuation of interferon, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Ribavirin may antagonize the cell culture antiviral activity of stavudine and zidovudine against HIV. Ribavirin has been shown in cell culture to inhibit phosphorylation of lamivudine, stavudine, and zidovudine, which could lead to decreased antiretroviral activity. However, in a study with another pegylated interferon in combination with ribavirin, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV/HCV virologic suppress) interaction was observed when ribavirin and lamivudine (n=18), stavudine (n=10), or zidovudine (n=6) were coadministered as part of a multidrug regimen in HIV/HCV co-infected subjects. Therefore, concomitant use of ribavirin with either of these drugs should be used with caution. Drugs Metabolized by Cytochrome P-450 Results of in vitro studies using both human and rat liver microsome preparations indicated little or no cytochrome P-450 enzyme-mediated metabolism of ribavirin, with minimal potential for P-450 enzyme-based drug interactions. No pharmacokinetic interactions were noted between INTRON A and REBETOL capsules in a multiple-dose pharmacokinetic study. Azathioprine The use of ribavirin for the treatment of 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. 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 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].

WARNINGS Pregnancy Category X, may cause birth defects. See CONTRAINDICATIONS boxed CONTRAINDICATIONS AND WARNINGS Anemia HEMOLYTIC Anemia (hemoglobin