Ribavirin capsules in combination with interferon alfa-2b (pegylated and nonpegylated) are indicated for the treatment of Chronic Hepatitis C (CHC) in patients 3 years of age and older with compensated liver disease [see Warnings and Precautions (5.9, 5.10), and Use in Specific Populations (8.4)].

The following points should be considered when initiating ribavirin capsules combination therapy with PegIntron® or INTRON A®:

Do not open, crush or break ribavirin capsules. Ribavirin capsules should be taken with food [see Clinical Pharmacology (12.3)].

Adult Patients

The recommended dose of ribavirin capsules when used in combination with PegIntron is 800 mg to 1,400 mg based on patient body weight in two divided doses (see Table 1). Refer to PegIntron labeling for PegIntron dosing information.

Duration of Treatment – Interferon Alpha-naïve Patients The treatment duration for patients with genotype 1 is 48 weeks. Discontinuation of therapy should be considered in patients who do not achieve at least a 2 log10 drop or loss of hepatitis C virus (HCV)-RNA at 12 weeks, or if HCV-RNA remains detectable after 24 weeks of therapy. Patients with genotype 2 and 3 should be treated for 24 weeks. Duration of Treatment – Re-treatment with PegIntron/Ribavirin capsules of Prior Treatment Failures The treatment duration for patients who previously failed therapy is 48 weeks, regardless of HCV genotype. Re-treated patients who fail to achieve undetectable HCV-RNA at Week 12 of therapy, or whose HCV-RNA remains detectable after 24 weeks of therapy, are highly unlikely to achieve SVR and discontinuation of therapy should be considered [see Clinical Studies (14.1)].

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 1: Recommended Adult Dosing for Ribavirin capsules in Combination with PegIntron </span> </caption> <colgroup> <col width="26.12%"/> <col width="26.12%"/> <col width="47.74%"/> </colgroup> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule Toprule"><span class="Bold">Body Weight (kg)</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"><span class="Bold">Ribavirin capsules Daily Dose</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"><span class="Bold">Ribavirin Number of Capsules</span> <br/> </th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" valign="middle">Less than 66<br/> </td><td align="center" class="Rrule" valign="middle">800 mg/day<br/> </td><td align="center" class="Rrule" valign="middle">2 x 200 mg capsules AM<br/>2 x 200 mg capsules PM<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle">66 to 80<br/> </td><td align="center" class="Rrule" valign="middle">1,000 mg/day<br/> </td><td align="center" class="Rrule" valign="middle">2 x 200 mg capsules AM<br/>3 x 200 mg capsules PM<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle">81 to 105<br/> </td><td align="center" class="Rrule" valign="middle">1,200 mg/day<br/> </td><td align="center" class="Rrule" valign="middle">3 x 200 mg capsules AM<br/>3 x 200 mg capsules PM<br/> </td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule" valign="middle">Greater than 105<br/> </td><td align="center" class="Rrule" valign="middle">1,400 mg/day<br/> </td><td align="center" class="Rrule" valign="middle">3 x 200 mg capsules AM<br/>4 x 200 mg capsules PM<br/> </td> </tr> </tbody> </table></div>

Pediatric Patients Dosing of ribavirin in pediatric patients is determined by body weight. The recommended dose of ribavirin when used in combination with PegIntron in pediatric patients ages 3 to 17 years is 15 mg/kg/day in two divided doses (see Table 2). Refer to PegIntron labeling for PegIntron dosing information. The treatment duration for patients with genotype 1 is 48 weeks. Patients with genotype 2 and 3 should be treated for 24 weeks.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="99%"> <caption> <span>Table 2: Recommended Pediatric Ribavirin Dosing in Combination with PegIntron </span> </caption> <colgroup> <col width="26.32%"/> <col width="25.32%"/> <col width="48.36%"/> </colgroup> <tfoot> <tr class="First Last"> <td align="justify" colspan="3">* Ribavirin Oral Solution may be used in any patient regardless of body weight.<br/> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" valign="middle"><span class="Bold">Body Weight (kg)</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Ribavirin Daily Dose</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Ribavirin Number of Capsules</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle">Less than 47<br/> </td><td align="center" class="Rrule" valign="middle">15 mg/kg/day<br/> </td><td align="center" class="Rrule" valign="middle">Use Ribavirin Oral Solution*<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle">47 to 59<br/> </td><td align="center" class="Rrule" valign="middle">800 mg/day<br/> </td><td align="center" class="Rrule" valign="middle">2 x 200 mg capsules AM<br/>2 x 200 mg capsules PM<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle">60 to 73<br/> </td><td align="center" class="Rrule" valign="middle">1,000 mg/day<br/> </td><td align="center" class="Rrule" valign="middle">2 x 200 mg capsules AM<br/>3 x 200 mg capsules PM<br/> </td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule" valign="middle">Greater than 73<br/> </td><td align="center" class="Rrule" valign="middle">1,200 mg/day<br/> </td><td align="center" class="Rrule" valign="middle">3 x 200 mg capsules AM<br/>3 x 200 mg capsules PM<br/> </td> </tr> </tbody> </table></div>

Adults

Duration of Treatment – Interferon Alpha-naïve Patients The recommended dose of ribavirin capsules when used in combination with INTRON A depends on the patient’s body weight (see Table 3). Refer to Intron A labeling for interferon dosing information. 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 Indications and Usage (1.1),  Adverse Reactions (6.1), and Clinical Studies (14)]. 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 for treatment duration lasting longer than 48 weeks in the previously untreated patient population.

Duration of Treatment – Re-treatment with INTRON A/Ribavirin capsules in Relapse Patients In patients who relapse following nonpegylated interferon monotherapy, the recommended duration of treatment is 24 weeks.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="298.2525"> <caption> <span>Table 3: Recommended Ribavirin capsules Dosing in Combination with INTRON A </span> </caption> <colgroup> <col width="28.4280936454849%"/> <col width="71.5719063545151%"/> </colgroup> <thead> <tr class="First Last"> <th align="justify" class="Lrule Rrule Toprule" colspan="1">Body Weight<br/> </th><th align="justify" class="Lrule Rrule Toprule" colspan="1">Ribavirin Capsules<br/> </th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" valign="middle"> <br/>At least<br/> 75 kg</td><td align="justify" class="Rrule" valign="middle"> 2 x 200 mg capsules AM <br/>  3 x 200 mg capsules PM daily orally <br/> </td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule" valign="middle"> <br/>Greater than<br/> 75 kg</td><td align="justify" class="Rrule" valign="middle"> 3 x 200 mg capsules AM <br/>  3 x 200 mg capsules PM daily orally <br/> </td> </tr> </tbody> </table></div>

Pediatrics The recommended dose of ribavirin when used in combination with INTRON A is 15 mg/kg per day orally in two divided doses (see Table 2). Refer to Intron A labeling for interferon dosing information.

The recommended duration of treatment is 48 weeks for pediatric patients with genotype 1. 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 this time. The recommended duration of treatment for pediatric patients with genotype 2 and 3 is 24 weeks.

The following laboratory tests are recommended in all patients treated with ribavirin capsules prior to initiation of treatment and periodically thereafter.

If severe adverse reactions or laboratory abnormalities develop during ribavirin capsules combination therapy, modify or discontinue the dose until the adverse reaction abates or decreases in severity (see Table 4) [see Warnings and Precautions (5)]. If intolerance persists after dose adjustment, combination therapy should be discontinued. Refer to PegIntron labeling for additional information regarding dose reduction of PegIntron.

Dose reduction in pediatric patients is accomplished by modifying the recommended ribavirin capsules dose from the original starting dose of 15 mg/kg daily in a two-step process to 12 mg/kg/day, then to 8 mg/kg/day, if needed (see Table 4).

Ribavirin capsules are contraindicated in patients with creatinine clearance less than 50 mL/min [see Contraindications (4)]. Patients with impaired renal function and those over the age of 50 should be carefully monitored with respect to development of anemia [see Warnings and Precautions (5.2), Use in Specific Populations (8.5), and Clinical Pharmacology (12.3)].

Ribavirin capsules should be administered with caution to patients with pre-existing cardiac disease. Assess cardiovascular status before initiation of treatment and during therapy. If there is any deterioration of cardiovascular status, discontinue combination therapy [see Warnings and Precautions (5.2)].

In patients with a history of stable cardiovascular disease, a permanent dose reduction is required if the hemoglobin decreases by 2 g/dL or more during any 4-week period. If the hemoglobin level remains below 12 g/dL after 4 weeks on a reduced dose, discontinue combination therapy.

Modify or discontinue ribavirin capsules dosing in any patient whose hemoglobin level falls below 10 g/dL (see Table 4) [see Warnings and Precautions (5.2)].

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 4: Guidelines for Dose Modification and Discontinuation of Ribavirin capsules in combination with PegIntron or INTRON A Based on Laboratory Parameters in Adults and Pediatrics </span> </caption> <colgroup> <col width="15.8%"/> <col width="24.42%"/> <col width="34.18%"/> <col width="25.58%"/> </colgroup> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule Toprule"><span class="Bold">Laboratory Parameters</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"><span class="Bold">Reduce Ribavirin capsules  Daily Dose (see note 1) if:</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"><span class="Bold">Reduce PegIntron or</span> <br/> <span class="Bold">INTRON A Dose </span> <br/> <span class="Bold">(see note 2) if:</span> <br/> </th><th align="center" class="Lrule Rrule Toprule"><span class="Bold">Discontinue Therapy if:</span> <br/> </th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="justify" colspan="4">Note 1: <span class="Italics">Adult patients: </span>1<span class="Sup">st</span> dose reduction of ribavirin is by 200 mg/day (except in patients receiving the 1,400 mg, dose reduction should be by 400 mg/day). If needed, 2<span class="Sup">nd</span> dose reduction of ribavirin is by an additional 200 mg/day. Patients whose dose of ribavirin is reduced to 600 mg daily receive one 200 mg capsule in the morning and two 200 mg capsules in the evening.<br/> <span class="Italics">            Pediatric patients:</span> 1<span class="Sup">st</span> dose reduction of ribavirin is to 12 mg/kg/day, 2<span class="Sup">nd</span> dose reduction of ribavirin is to 8 mg/kg/day.<br/>Note 2: <span class="Italics">Adult patients treated with </span><span class="Italics">ribavirin capsules</span><span class="Italics"> and PegIntron: </span>1<span class="Sup">st </span>dose reduction of PegIntron is to 1 mcg/kg/week. If needed, 2<span class="Sup">nd </span>dose reduction of PegIntron is to 0.5 mcg/kg/week.<br/>            <span class="Italics">Pediatric patients treated with </span><span class="Italics">ribavirin capsules</span><span class="Italics"> and PegIntron: </span>1<span class="Sup">st </span>dose reduction of PegIntron is to 40 mcg/m<span class="Sup">2</span>/week, 2<span class="Sup">nd </span>dose reduction of PegIntron is to 20 mcg/m<span class="Sup">2</span>/week.<span class="Bold"></span> <br/> <span class="Italics">For patients on </span><span class="Italics">ribavirin capsules</span><span class="Italics">/INTRON A combination therapy</span>: reduce INTRON A dose by 50%.<br/> <span class="Sup">*</span> Pediatric patients who have pre-existing cardiac conditions and experience a hemoglobin decrease greater than or equal to 2 g/dL during any 4-week period during treatment should have weekly evaluations and hematology testing.<br/> <span class="Sup">†</span> These guidelines are for patients with stable cardiac disease. Patients with a history of significant or unstable cardiac disease should not be treated with PegIntron/ribavirin capsules combination therapy <span class="Italics">[see <span class="Italics"><a href="#Section_5.2">Warnings and Precautions (5.2)</a></span>]</span>.<br/> <br/> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td class="Lrule Rrule" valign="middle">WBC<br/> </td><td align="center" class="Rrule" valign="middle">N/A<br/> </td><td align="center" class="Rrule" valign="middle">1.0 to &lt;1.5 x 10<span class="Sup">9</span>/L<br/> </td><td align="center" class="Rrule" valign="middle">&lt;1.0 x 10<span class="Sup">9</span>/L<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Neutrophils<br/> </td><td align="center" class="Rrule" valign="middle">N/A<br/> </td><td align="center" class="Rrule" valign="middle">0.5 to &lt;0.75 x 10<span class="Sup">9</span>/L<br/> </td><td align="center" class="Rrule" valign="middle">&lt;0.5 x 10<span class="Sup">9</span>/L<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" rowspan="2" valign="middle">Platelets<br/> </td><td align="center" class="Rrule" valign="middle">N/A<br/> </td><td align="center" class="Rrule" valign="middle">25 to &lt; 50 x 10<span class="Sup">9</span>/L (adults)<br/> </td><td align="center" class="Rrule" valign="middle">&lt;25 x 10<span class="Sup">9</span>/L (adults)<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle">N/A<br/> </td><td align="center" class="Rrule" valign="middle">50 to &lt;70 x 10<span class="Sup">9</span>/L (pediatrics)<br/> </td><td align="center" class="Rrule" valign="middle">&lt;50 x 10<span class="Sup">9</span>/L (pediatrics)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Creatinine<br/> </td><td align="center" class="Rrule" valign="middle">N/A<br/> </td><td align="center" class="Rrule" valign="middle">N/A<br/> </td><td align="center" class="Rrule" valign="middle">&gt;2 mg/dL (pediatrics)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Hemoglobin in patients without history of cardiac disease<br/> </td><td align="center" class="Rrule" valign="middle">8.5 to &lt;10 g/dL<br/> </td><td align="center" class="Rrule" valign="middle">N/A<br/> </td><td align="center" class="Rrule" valign="middle">&lt;8.5 g/dL<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" colspan="2" valign="middle"><span class="Bold">Reduce Ribavirin capsules Dose by 200 mg/day and PegIntron or INTRON A Dose by Half if:</span> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="middle">Hemoglobin in patients with history of stable cardiac disease<span class="Sup">*†</span> <br/> </td><td align="center" class="Rrule" colspan="2" valign="middle">≥2 g/dL decrease in hemoglobin during any four-week period during treatment<br/> </td><td align="center" class="Rrule" valign="middle">&lt;8.5 g/dL or &lt;12 g/dL after four weeks of dose reduction<br/> </td> </tr> </tbody> </table></div>

Refer to labeling for INTRON A or PegIntron for additional information about how to reduce an INTRON A or PegIntron dose.

Adults In HCV genotype 1, interferon-alfa-naïve patients receiving PegIntron in combination with ribavirin, discontinue therapy if there is not at least a 2 log10 drop or loss of HCV-RNA at 12 weeks of therapy, or if HCV-RNA levels remain detectable after 24 weeks of therapy. Regardless of genotype, previously treated patients who have detectable HCV-RNA at Week 12 or 24 are highly unlikely to achieve SVR and discontinuation of therapy should be considered.

Pediatrics (3 to 17 years of age) In patients receiving PegIntron/ribavirin capsules combination (excluding HCV Genotype 2 and 3), discontinue therapy at 12 weeks if HCV-RNA has dropped less than 2 log10 compared to pretreatment level, or at 24 weeks if HCV-RNA is still detectable.

Ribavirin Capsules USP, 200 mg are white/white, size ‘1’ hard gelatin capsule filled with white to off-white granular powder and imprinted with ‘E’ on white cap and ‘81’ on white body with black ink.  

{ "type": "p", "children": [], "text": "\nRibavirin Capsules USP, 200 mg are white/white, size ‘1’ hard gelatin capsule filled with white to off-white granular powder and imprinted with ‘E’ on white cap and ‘81’ on white body with black ink.   " }

Ribavirin capsules combination therapy is contraindicated in:

{ "type": "p", "children": [], "text": "Ribavirin capsules combination therapy is contraindicated in:" }

{ "type": "ul", "children": [ "pregnancy. Ribavirin capsules may cause fetal harm when administered to a pregnant woman. Ribavirin capsules are contraindicated in women who are pregnant or planning to become pregnant. If a patient becomes pregnant while taking ribavirin capsules, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.3)]. \n", "men whose female partners are pregnant [see Use in Specific Populations (8.3)]\n", "patients with known hypersensitivity reactions such as Stevens-Johnson syndrome, toxic, epidermal necrolysis, and erythema multiforme to ribavirin or any component of the product", "patients with autoimmune hepatitis ", "patients with hemoglobinopathies (e.g., thalassemia major, sickle-cell anemia) ", "patients with creatinine clearance less than 50 mL/min [see Clinical Pharmacology (12.3)] \n", "when coadministered with didanosine because exposure to the active metabolite of didanosine (dideoxyadenosine 5’-triphosphate) is increased. Fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis, has been reported in patients receiving didanosine in combination with ribavirin [see Drug Interactions (7.1)].    \n" ], "text": "" }

Ribavirin capsules may cause birth defects, miscarriage or stillbirth. Ribavirin therapy should not be started until a report of a negative pregnancy test has been obtained immediately prior to planned initiation of therapy. Female patients should use effective contraception and have periodic monitoring with pregnancy tests during treatment and during the 9-month period after treatment has been stopped. Male patients and their female partners should use effective contraception during treatment and during the 6-month period after treatment has been stopped. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin has demonstrated significant teratogenic and embryocidal effects in all animal species tested. These effects occurred at doses as low as one twentieth of the recommended human dose of ribavirin. [see Boxed Warning, Contraindications (4), and Use in Specific Populations (8.1, 8.3)].

Hemolytic anemia was observed in approximately 10% of ribavirin/INTRON A-treated subjects in clinical trials. The anemia associated with ribavirin occurs within 1 to 2 weeks of initiation of therapy. Because the initial drop in hemoglobin may be significant, obtain hemoglobin or hematocrit levels before the start of treatment and at Week 2 and Week 4 of therapy, or more frequently if clinically indicated. Patients should then be followed as clinically appropriate [see Dosage and Administration (2.5, 2.6)].

Fatal and nonfatal myocardial infarctions have been reported in patients with anemia caused by ribavirin. Patients should be assessed for underlying cardiac disease before initiation of ribavirin therapy. Patients with pre-existing cardiac disease should have electrocardiograms administered before treatment and should be appropriately monitored during therapy. If there is any deterioration of cardiovascular status, therapy should be suspended or discontinued [see Dosage and Administration (2.5, 2.6)]. Because cardiac disease may be worsened by drug-induced anemia, patients with a history of significant or unstable cardiac disease should not use ribavirin.

Suspend ribavirin and INTRON A or PegIntron combination therapy in patients with signs and symptoms of pancreatitis and discontinue in patients with confirmed pancreatitis.

Pulmonary symptoms, including dyspnea, pulmonary infiltrates, pneumonitis, pulmonary hypertension, and pneumonia, have been reported during ribavirin with alpha interferon combination therapy; 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, closely monitor the patient, and if appropriate, discontinue combination therapy.

Ribavirin is used in combination therapy with INTRON A or PegIntron. Refer to labeling for PegIntron for additional information.

PegIntron in combination with ribavirin may cause severe decreases in neutrophil and platelet counts, and hematologic, endocrine (e.g., TSH), and hepatic abnormalities.

Obtain hematology and blood chemistry testing in patients on PegIntron/ribavirin combination therapy before the start of treatment and then periodically thereafter. In the adult clinical trial, complete blood counts (including hemoglobin, neutrophil, and platelet counts) and chemistries (including AST, ALT, bilirubin, and uric acid) were measured during the treatment period at Weeks 2, 4, 8, 12, and then at 6-week intervals, or more frequently if abnormalities developed. In pediatric subjects, the same laboratory parameters were evaluated with additional assessment of hemoglobin at treatment Week 6. TSH levels were measured every 12 weeks during the treatment period. HCV-RNA should be measured periodically during treatment [see Dosage and Administration (2)].

Dental and periodontal disorders have been reported in patients receiving ribavirin and interferon or peginterferon combination therapy. In addition, dry mouth could have a damaging effect on teeth and mucous membranes of the mouth during long-term treatment with the combination of ribavirin and pegylated or nonpegylated interferon alfa-2b. Advise patients to brush their teeth thoroughly twice daily and have regular dental examinations. If vomiting occurs, advise patients to rinse out their mouth thoroughly afterwards.

Pancytopenia (marked decreases in red blood cells, neutrophils, and platelets) and bone marrow suppression have been reported in the literature to occur within 3 to 7 weeks after the concomitant administration of pegylated interferon/ribavirin and azathioprine. In this limited number of patients (n=8), myelotoxicity was reversible within 4 to 6 weeks upon withdrawal of both HCV antiviral therapy and concomitant azathioprine and did not recur upon reintroduction of either treatment alone. Discontinue PegIntron, ribavirin, and azathioprine for pancytopenia, and do not reintroduce pegylated interferon/ribavirin with concomitant azathioprine [see Drug Interactions (7.4)].

Data on the effects of PegIntron and ribavirin on growth come from an open-label study in subjects 3 through 17 years of age, in which weight and height changes were compared to U.S. normative population data. In general, the weight and height gain of pediatric subjects treated with PegIntron and ribavirin 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. Following treatment, rebound growth and weight gain occurred in most subjects. Long-term follow-up data in pediatric subjects, however, indicates that PegIntron in combination therapy with ribavirin may induce a growth inhibition that results in reduced adult height in some patients [see Adverse Reactions (6.1)].

Similarly, an impact on growth was seen in subjects after treatment with ribavirin and INTRON A combination therapy for one year. In a long-term follow-up trial of a limited number of these subjects, combination therapy resulted in reduced final adult height in some subjects [see Adverse Reactions (6.1)].

Based on results of clinical trials, ribavirin monotherapy is not effective for the treatment of chronic hepatitis C virus infection; therefore, ribavirin capsules must not be used alone. The safety and efficacy of ribavirin capsules have only been established when used together with INTRON A or PegIntron (not other interferons) as combination therapy.

The safety and efficacy of ribavirin with INTRON A or PegIntron combination therapy for the treatment of HIV infection, adenovirus, RSV, parainfluenza, or influenza infections have not been established. Ribavirin capsules should not be used for these indications.

There are significant adverse reactions caused by ribavirin/INTRON A or PegIntron combination therapy, including severe depression and suicidal or homicidal ideation, hemolytic anemia, suppression of bone marrow function, autoimmune and infectious disorders, pulmonary dysfunction, pancreatitis, and diabetes. 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. Labeling for INTRON A and PegIntron should be reviewed in their entirety for additional safety information prior to initiation of combination treatment.

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.

Clinical trials with ribavirin in combination with PegIntron or INTRON A have been conducted in over 7,800 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 (5.2)].

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 ribavirin 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 ribavirin 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:

Serious adverse reactions have occurred in approximately 12% of subjects in clinical trials with PegIntron with or without ribavirin [see Boxed Warning, Warnings and Precautions (5)]. The most common serious events occurring in subjects treated with PegIntron and ribavirin were depression and suicidal ideation [see Warnings and Precautions (5.10)], 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 (5.10)]. The most common fatal reaction occurring in subjects treated with PegIntron and ribavirin was cardiac arrest, suicidal ideation, and suicide attempt [see Warnings and Precautions (5.10)], all occurring in less than 1% of subjects.

Adverse Reaction - Ribavirin/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 ribavirin/PegIntron Combination Therapy (Study 2) in Table 5.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 5: Adverse Reactions Occurring in Greater Than 5% of Adult Subjects</span> </caption> <colgroup> <col width="29.96%"/> <col width="11.8%"/> <col width="11.8%"/> <col width="23.58%"/> <col width="11.44%"/> <col width="11.42%"/> </colgroup> <tfoot> <tr class="First Last"> <td colspan="6"><span class="Sup">* </span>A subject may have reported more than one adverse reaction within a body system/organ class category.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" rowspan="2" valign="top"><span class="Bold"> Adverse</span><span class="Bold"> Reactions</span> <br/> </td><td align="center" class="Rrule" colspan="2" valign="top"><span class="Bold"><span class="Italics"> Percentage</span></span><span class="Bold"><span class="Italics"> of Subjects Reporting Adverse Reactions*</span></span> <br/> </td><td align="center" class="Rrule" rowspan="2" valign="top"><span class="Bold"> Adverse</span><span class="Bold"> Reactions</span> <br/> </td><td align="center" class="Rrule" colspan="2" valign="top"><span class="Bold"><span class="Italics"> Percentage</span></span><span class="Bold"><span class="Italics"> of Subjects Reporting Adverse Reactions*</span></span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"><span class="Bold"> PegIntron</span> <br/> <span class="Bold"> 1.5</span><span class="Bold"></span><span class="Bold"> mcg/kg/</span><span class="Bold"></span><span class="Bold">Ribavirin</span> (N=511)<br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold"> INTRON</span><span class="Bold"></span><span class="Bold"> A/</span><span class="Bold"></span><span class="Bold">Ribavirin</span> (N=505)<br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold"> PegIntron</span> <br/> <span class="Bold"> 1.5</span><span class="Bold"></span><span class="Bold"> mcg/kg/</span><span class="Bold"></span><span class="Bold">Ribavirin</span><span class="Bold"></span> <br/> <span class="Bold">  </span> (N=511)<br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold"> INTRON</span><span class="Bold"></span><span class="Bold"> A/</span><span class="Bold"></span><span class="Bold">Ribavirin</span><span class="Bold"></span> <br/> (N=505)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold"> Application</span><span class="Bold"></span><span class="Bold"> Site</span> <br/> </td><td class="Rrule" colspan="2" valign="middle"> <br/> </td><td class="Rrule" valign="middle"><span class="Bold"> Musculoskeletal</span> <br/> </td><td class="Rrule" colspan="2" valign="top"> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" rowspan="2" valign="middle">     Injection Site Inflammation<br/> <br/>     Injection Site Reaction<br/> </td><td align="center" class="Rrule" rowspan="2" valign="middle"> 25<br/> <br/> 58<br/> </td><td align="center" class="Rrule" rowspan="2" valign="middle"> 18<br/> <br/> 36<br/> </td><td class="Rrule" valign="middle">     Myalgia<br/> </td><td align="center" class="Rrule" valign="middle"> 56<br/> </td><td align="center" class="Rrule" valign="middle"> 50<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Arthralgia<br/> </td><td align="center" class="Rrule" valign="middle"> 34<br/> </td><td align="center" class="Rrule" valign="middle"> 28<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold"> Autonomic</span><span class="Bold"> Nervous System</span> <br/> </td><td class="Rrule" colspan="2" valign="middle"> <br/> </td><td class="Rrule" valign="middle">     Musculoskeletal Pain<br/> </td><td align="center" class="Rrule" valign="middle"> 21<br/> </td><td align="center" class="Rrule" valign="middle"> 19<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Dry Mouth<br/> </td><td align="center" class="Rrule" valign="middle"> 12<br/> </td><td align="center" class="Rrule" valign="middle">8<br/> </td><td class="Rrule" valign="middle"><span class="Bold"> Psychiatric</span> <br/> </td><td align="center" class="Rrule" colspan="2" valign="middle"> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Increased Sweating<br/> </td><td align="center" class="Rrule" valign="middle"> 11<br/> </td><td align="center" class="Rrule" valign="middle">7<br/> </td><td class="Rrule" valign="middle">     Insomnia<br/> </td><td align="center" class="Rrule" valign="middle"> 40<br/> </td><td align="center" class="Rrule" valign="middle"> 41<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Flushing<br/> </td><td align="center" class="Rrule" valign="middle">4<br/> </td><td align="center" class="Rrule" valign="middle">3<br/> </td><td class="Rrule" valign="middle">     Depression<br/> </td><td align="center" class="Rrule" valign="middle"> 31<br/> </td><td align="center" class="Rrule" valign="middle"> 34<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold">Body as a Whole</span> <br/> </td><td class="Rrule" colspan="2" valign="top"> <br/> </td><td class="Rrule" valign="middle">     Anxiety/Emotional<br/>     Lability/Irritability<br/> </td><td align="center" class="Rrule" valign="middle"> 47<br/> </td><td align="center" class="Rrule" valign="middle"> 47<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Fatigue/Asthenia<br/> </td><td align="center" class="Rrule" valign="middle"> 66<br/> </td><td align="center" class="Rrule" valign="middle"> 63<br/> </td><td class="Rrule" valign="middle">     Concentration Impaired<br/> </td><td align="center" class="Rrule" valign="middle"> 17<br/> </td><td align="center" class="Rrule" valign="middle"> 21<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Headache<br/> </td><td align="center" class="Rrule" valign="middle"> 62<br/> </td><td align="center" class="Rrule" valign="middle"> 58<br/> </td><td class="Rrule" valign="middle">     Agitation<br/> </td><td align="center" class="Rrule" valign="middle">8<br/> </td><td align="center" class="Rrule" valign="middle">5<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Rigors<br/> </td><td align="center" class="Rrule" valign="middle"> 48<br/> </td><td align="center" class="Rrule" valign="middle"> 41<br/> </td><td class="Rrule" valign="middle">     Nervousness<br/> </td><td align="center" class="Rrule" valign="middle">6<br/> </td><td align="center" class="Rrule" valign="middle">6<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Fever<br/> </td><td align="center" class="Rrule" valign="middle"> 46<br/> </td><td align="center" class="Rrule" valign="middle"> 33<br/> </td><td class="Rrule" valign="middle"><span class="Bold"> Reproductive, Female</span> <br/> </td><td align="center" class="Rrule" colspan="2" valign="middle"> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Weight Loss<br/> </td><td align="center" class="Rrule" valign="middle"> 29<br/> </td><td align="center" class="Rrule" valign="middle"> 20<br/> </td><td class="Rrule" valign="middle">     Menstrual Disorder<br/> </td><td align="center" class="Rrule" valign="middle">7<br/> </td><td align="center" class="Rrule" valign="middle">6<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Right Upper Quadrant Pain<br/> </td><td align="center" class="Rrule" valign="middle"> 12<br/> </td><td align="center" class="Rrule" valign="middle">6<br/> </td><td class="Rrule" valign="middle"><span class="Bold"> Resistance</span><span class="Bold"> Mechanism</span> <br/> </td><td class="Rrule" colspan="2" valign="middle"> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Chest Pain<br/> </td><td align="center" class="Rrule" valign="middle">8<br/> </td><td align="center" class="Rrule" valign="middle">7<br/> </td><td class="Rrule" valign="middle">     Viral Infection<br/> </td><td align="center" class="Rrule" valign="middle"> 12<br/> </td><td align="center" class="Rrule" valign="middle"> 12<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Malaise<br/> </td><td align="center" class="Rrule" valign="middle">4<br/> </td><td align="center" class="Rrule" valign="middle">6<br/> </td><td class="Rrule" valign="middle">     Fungal Infection<br/> </td><td align="center" class="Rrule" valign="middle">6<br/> </td><td align="center" class="Rrule" valign="middle">1<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="middle"><span class="Bold"> Central/Peripheral</span><span class="Bold"></span><span class="Bold"> Nervous</span><span class="Bold"> System</span> <br/> </td><td class="Rrule" valign="middle"><span class="Bold"> Respiratory</span><span class="Bold"></span><span class="Bold"> System</span> <br/> </td><td align="center" class="Rrule" colspan="2" valign="middle"> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Dizziness<br/> </td><td align="center" class="Rrule" valign="middle"> 21<br/> </td><td align="center" class="Rrule" valign="middle"> 17<br/> </td><td class="Rrule" valign="middle">     Dyspnea<br/> </td><td align="center" class="Rrule" valign="middle"> 26<br/> </td><td align="center" class="Rrule" valign="middle"> 24<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold"> Endocrine</span> <br/> </td><td align="center" class="Rrule" colspan="2" valign="middle"> <br/> </td><td class="Rrule" valign="middle">     Coughing<br/> </td><td align="center" class="Rrule" valign="middle"> 23<br/> </td><td align="center" class="Rrule" valign="middle"> 16<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Hypothyroidism<br/> </td><td align="center" class="Rrule" valign="middle">5<br/> </td><td align="center" class="Rrule" valign="middle">4<br/> </td><td class="Rrule" valign="middle">     Pharyngitis<br/> </td><td align="center" class="Rrule" valign="middle"> 12<br/> </td><td align="center" class="Rrule" valign="middle"> 13<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold"> Gastrointestinal</span> <br/> </td><td align="center" class="Rrule" colspan="2" valign="middle"> <br/> </td><td class="Rrule" valign="middle">     Rhinitis<br/> </td><td align="center" class="Rrule" valign="middle">8<br/> </td><td align="center" class="Rrule" valign="middle">6<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Nausea<br/> </td><td align="center" class="Rrule" valign="middle"> 43<br/> </td><td align="center" class="Rrule" valign="middle"> 33<br/> </td><td class="Rrule" valign="middle">     Sinusitis<br/> </td><td align="center" class="Rrule" valign="middle">6<br/> </td><td align="center" class="Rrule" valign="middle">5<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Anorexia<br/> </td><td align="center" class="Rrule" valign="middle"> 32<br/> </td><td align="center" class="Rrule" valign="middle"> 27<br/> </td><td class="Rrule" valign="middle"><span class="Bold"> Skin</span><span class="Bold"></span><span class="Bold"> and</span><span class="Bold"></span><span class="Bold"> Appendages</span> <br/> </td><td align="center" class="Rrule" colspan="2" valign="middle"> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Diarrhea<br/> </td><td align="center" class="Rrule" valign="middle"> 22<br/> </td><td align="center" class="Rrule" valign="middle"> 17<br/> </td><td class="Rrule" valign="middle">     Alopecia<br/> </td><td align="center" class="Rrule" valign="middle"> 36<br/> </td><td align="center" class="Rrule" valign="middle"> 32<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Vomiting<br/> </td><td align="center" class="Rrule" valign="middle"> 14<br/> </td><td align="center" class="Rrule" valign="middle"> 12<br/> </td><td class="Rrule" valign="middle">     Pruritus<br/> </td><td align="center" class="Rrule" valign="middle"> 29<br/> </td><td align="center" class="Rrule" valign="middle"> 28<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Abdominal Pain<br/> </td><td align="center" class="Rrule" valign="middle"> 13<br/> </td><td align="center" class="Rrule" valign="middle"> 13<br/> </td><td class="Rrule" valign="middle">     Rash<br/> </td><td align="center" class="Rrule" valign="middle"> 24<br/> </td><td align="center" class="Rrule" valign="middle"> 23<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Dyspepsia<br/> </td><td align="center" class="Rrule" valign="middle">9<br/> </td><td align="center" class="Rrule" valign="middle">8<br/> </td><td class="Rrule" valign="middle">    Skin Dry<br/> </td><td align="center" class="Rrule" valign="middle"> 24<br/> </td><td align="center" class="Rrule" valign="middle"> 23<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Constipation<br/> </td><td align="center" class="Rrule" valign="middle">5<br/> </td><td align="center" class="Rrule" valign="middle">5<br/> </td><td class="Rrule" valign="middle"><span class="Bold"> Special Senses, Other</span> <br/> </td><td class="Rrule" colspan="2" valign="middle"> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold"> Hematologic</span><span class="Bold"> Disorders</span> <br/> </td><td align="center" class="Rrule" colspan="2" valign="middle"> <br/> </td><td class="Rrule" valign="middle">    Taste Perversion<br/> </td><td align="center" class="Rrule" valign="middle">9<br/> </td><td align="center" class="Rrule" valign="middle">4<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Neutropenia<br/> </td><td align="center" class="Rrule" valign="middle"> 26<br/> </td><td align="center" class="Rrule" valign="middle"> 14<br/> </td><td class="Rrule" valign="middle"><span class="Bold"> Vision</span><span class="Bold"></span><span class="Bold"> Disorders</span> <br/> </td><td align="center" class="Rrule" colspan="2" valign="middle"> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Anemia<br/> </td><td align="center" class="Rrule" valign="middle"> 12<br/> </td><td align="center" class="Rrule" valign="middle"> 17<br/> </td><td class="Rrule" valign="middle">     Vision Blurred<br/> </td><td align="center" class="Rrule" valign="middle">5<br/> </td><td align="center" class="Rrule" valign="middle">6<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Leukopenia<br/> </td><td align="center" class="Rrule" valign="middle">6<br/> </td><td align="center" class="Rrule" valign="middle">5<br/> </td><td class="Rrule" valign="middle">     Conjunctivitis<br/> </td><td align="center" class="Rrule" valign="middle">4<br/> </td><td align="center" class="Rrule" valign="middle">5<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Thrombocytopenia<br/> </td><td align="center" class="Rrule" valign="middle">5<br/> </td><td align="center" class="Rrule" valign="middle">2<br/> </td><td class="Rrule" colspan="3" rowspan="3" valign="middle"> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold"> Liver</span><span class="Bold"></span><span class="Bold"> and</span><span class="Bold"></span><span class="Bold"> Biliary</span><span class="Bold"></span><span class="Bold"> System</span> <br/> </td><td align="center" class="Rrule" colspan="2" valign="middle"> <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="middle">     Hepatomegaly<br/> </td><td align="center" class="Rrule" valign="middle">4<br/> </td><td align="center" class="Rrule" valign="middle">4<br/> </td> </tr> </tbody> </table></div>

Table 6 summarizes the treatment-related adverse reactions in Study 4 that occurred at a greater than or equal to 10% incidence.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 6: Treatment-Related Adverse Reactions (Greater Than or Equal to 10% Incidence) By Descending Frequency</span> </caption> <colgroup> <col width="26.78%"/> <col width="24.4%"/> <col width="22.18%"/> <col width="26.66%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" valign="top"> <br/> </td><td align="center" class="Rrule" colspan="3" valign="middle"><span class="Bold">Study 4</span> <br/> <span class="Bold"><span class="Italics"> Percentage</span></span><span class="Bold"><span class="Italics"> of Subjects Reporting Treatment-Related Adverse Reactions</span></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold"> Adverse</span><span class="Bold"> Reactions</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold"> PegIntron</span><span class="Bold"></span><span class="Bold"> 1.5</span><span class="Bold"></span><span class="Bold"> mcg/kg</span><span class="Bold"></span><span class="Bold"> with</span><span class="Bold"></span><span class="Bold">  Ribavirin </span> <br/> <span class="Bold"> (N=1019)</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold"> PegIntron 1</span><span class="Bold"> mcg/kg with  Ribavirin (N=1016)</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold"> Pegasys</span><span class="Bold"> 180 mcg with Copegus</span> <br/> <span class="Bold"> (N=1035)</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Fatigue<br/> </td><td align="center" class="Rrule" valign="middle"> 67<br/> </td><td align="center" class="Rrule" valign="middle"> 68<br/> </td><td align="center" class="Rrule" valign="middle"> 64<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Headache<br/> </td><td align="center" class="Rrule" valign="middle"> 50<br/> </td><td align="center" class="Rrule" valign="middle"> 47<br/> </td><td align="center" class="Rrule" valign="middle"> 41<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Nausea<br/> </td><td align="center" class="Rrule" valign="middle"> 40<br/> </td><td align="center" class="Rrule" valign="middle"> 35<br/> </td><td align="center" class="Rrule" valign="middle"> 34<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Chills<br/> </td><td align="center" class="Rrule" valign="middle"> 39<br/> </td><td align="center" class="Rrule" valign="middle"> 36<br/> </td><td align="center" class="Rrule" valign="middle"> 23<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Insomnia<br/> </td><td align="center" class="Rrule" valign="middle"> 38<br/> </td><td align="center" class="Rrule" valign="middle"> 37<br/> </td><td align="center" class="Rrule" valign="middle"> 41<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Anemia<br/> </td><td align="center" class="Rrule" valign="middle"> 35<br/> </td><td align="center" class="Rrule" valign="middle"> 30<br/> </td><td align="center" class="Rrule" valign="middle"> 34<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Pyrexia<br/> </td><td align="center" class="Rrule" valign="middle"> 35<br/> </td><td align="center" class="Rrule" valign="middle"> 32<br/> </td><td align="center" class="Rrule" valign="middle"> 21<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Injection Site Reactions<br/> </td><td align="center" class="Rrule" valign="middle"> 34<br/> </td><td align="center" class="Rrule" valign="middle"> 35<br/> </td><td align="center" class="Rrule" valign="middle"> 23<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Anorexia<br/> </td><td align="center" class="Rrule" valign="middle"> 29<br/> </td><td align="center" class="Rrule" valign="middle"> 25<br/> </td><td align="center" class="Rrule" valign="middle"> 21<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Rash<br/> </td><td align="center" class="Rrule" valign="middle"> 29<br/> </td><td align="center" class="Rrule" valign="middle"> 25<br/> </td><td align="center" class="Rrule" valign="middle"> 34<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Myalgia<br/> </td><td align="center" class="Rrule" valign="middle"> 27<br/> </td><td align="center" class="Rrule" valign="middle"> 26<br/> </td><td align="center" class="Rrule" valign="middle"> 22<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Neutropenia<br/> </td><td align="center" class="Rrule" valign="middle"> 26<br/> </td><td align="center" class="Rrule" valign="middle"> 19<br/> </td><td align="center" class="Rrule" valign="middle"> 31<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Irritability<br/> </td><td align="center" class="Rrule" valign="middle"> 25<br/> </td><td align="center" class="Rrule" valign="middle"> 25<br/> </td><td align="center" class="Rrule" valign="middle"> 25<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Depression<br/> </td><td align="center" class="Rrule" valign="middle"> 25<br/> </td><td align="center" class="Rrule" valign="middle"> 19<br/> </td><td align="center" class="Rrule" valign="middle"> 20<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Alopecia<br/> </td><td align="center" class="Rrule" valign="middle"> 23<br/> </td><td align="center" class="Rrule" valign="middle"> 20<br/> </td><td align="center" class="Rrule" valign="middle"> 17<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Dyspnea<br/> </td><td align="center" class="Rrule" valign="middle"> 21<br/> </td><td align="center" class="Rrule" valign="middle"> 20<br/> </td><td align="center" class="Rrule" valign="middle"> 22<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Arthralgia<br/> </td><td align="center" class="Rrule" valign="middle"> 21<br/> </td><td align="center" class="Rrule" valign="middle"> 22<br/> </td><td align="center" class="Rrule" valign="middle"> 22<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Pruritus<br/> </td><td align="center" class="Rrule" valign="middle"> 18<br/> </td><td align="center" class="Rrule" valign="middle"> 15<br/> </td><td align="center" class="Rrule" valign="middle"> 19<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Influenza-like Illness<br/> </td><td align="center" class="Rrule" valign="middle"> 16<br/> </td><td align="center" class="Rrule" valign="middle"> 15<br/> </td><td align="center" class="Rrule" valign="middle"> 15<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Dizziness<br/> </td><td align="center" class="Rrule" valign="middle"> 16<br/> </td><td align="center" class="Rrule" valign="middle"> 14<br/> </td><td align="center" class="Rrule" valign="middle"> 13<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Diarrhea<br/> </td><td align="center" class="Rrule" valign="middle"> 15<br/> </td><td align="center" class="Rrule" valign="middle"> 16<br/> </td><td align="center" class="Rrule" valign="middle"> 14<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Cough<br/> </td><td align="center" class="Rrule" valign="middle"> 15<br/> </td><td align="center" class="Rrule" valign="middle"> 16<br/> </td><td align="center" class="Rrule" valign="middle"> 17<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Weight Decreased<br/> </td><td align="center" class="Rrule" valign="middle"> 13<br/> </td><td align="center" class="Rrule" valign="middle"> 10<br/> </td><td align="center" class="Rrule" valign="middle"> 10<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Vomiting<br/> </td><td align="center" class="Rrule" valign="middle"> 12<br/> </td><td align="center" class="Rrule" valign="middle"> 10<br/> </td><td align="center" class="Rrule" valign="middle">9<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Unspecified Pain<br/> </td><td align="center" class="Rrule" valign="middle"> 12<br/> </td><td align="center" class="Rrule" valign="middle"> 13<br/> </td><td align="center" class="Rrule" valign="middle">9<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Dry Skin<br/> </td><td align="center" class="Rrule" valign="middle"> 11<br/> </td><td align="center" class="Rrule" valign="middle"> 11<br/> </td><td align="center" class="Rrule" valign="middle"> 12<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Anxiety<br/> </td><td align="center" class="Rrule" valign="middle"> 11<br/> </td><td align="center" class="Rrule" valign="middle"> 11<br/> </td><td align="center" class="Rrule" valign="middle"> 10<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Abdominal Pain<br/> </td><td align="center" class="Rrule" valign="middle"> 10<br/> </td><td align="center" class="Rrule" valign="middle"> 10<br/> </td><td align="center" class="Rrule" valign="middle"> 10<br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="middle">     Leukopenia<br/> </td><td align="center" class="Rrule" valign="middle">9<br/> </td><td align="center" class="Rrule" valign="middle">7<br/> </td><td align="center" class="Rrule" valign="middle"> 10<br/> </td> </tr> </tbody> </table></div>

The incidence of serious adverse reactions was comparable in all trials. In Study 2, the incidence of serious adverse reactions was 17% in the PegIntron/ribavirin groups compared to 14% in the INTRON A/ribavirin group. In Study 3, there was a similar incidence of serious adverse reactions reported for the weight-based ribavirin group (12%) and for the flat-dose ribavirin regimen.

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/ribavirin 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 28 subject deaths that occurred during treatment or follow-up in Studies 2, 3, and 4. In Study 2, there was 1 suicide in a subject receiving PegIntron/ribavirin combination therapy; and 1 subject death in the INTRON A/ribavirin 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/ribavirin combination therapy, 5 in the PegIntron 1.5 mcg/ribavirin arm (N=1019) and 1 in the PegIntron 1 mcg/ribavirin 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)/ribavirin combination therapy.

In Studies 1 and 2, 10 to 14% of subjects receiving PegIntron, alone or in combination with ribavirin, discontinued therapy compared with 6% treated with INTRON A alone and 13% treated with INTRON A in combination with ribavirin. In Study 3, 15% of subjects receiving PegIntron in combination with weight-based ribavirin and 14% of subjects receiving PegIntron with flat-dose ribavirin discontinued therapy due to an adverse reaction. The most common reasons for discontinuation 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/ribavirin arm, 10% in the PegIntron 1 mcg/ribavirin arm, and 13% in the Pegasys 180 mcg/Copegus arm discontinued due to adverse events.

In Study 2, dose reductions for ribavirin were similar across all three groups [see Clinical Studies (14.1)], 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 ribavirin dosing 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 ribavirin, 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 a second dose reduction to 90 mcg/week with Pegasys.

In the PegIntron/ribavirin 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 (5)]. In Study 4, psychiatric adverse reactions occurred in 58% of subjects in the PegIntron 1.5 mcg/ribavirin arm, 55% of subjects in the PegIntron 1 mcg/ribavirin arm, and 57% of subjects in the Pegasys 180 mcg/Copegus arm.

In Study 2, PegIntron/ribavirin combination therapy 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.

Subjects receiving ribavirin/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 were pyrexia (80%), headache (62%), neutropenia (33%), fatigue (30%), anorexia (29%), injection-site erythema (29%) and vomiting (27%). The majority of adverse reactions 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 ribavirin 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.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="83%"> <caption> <span>Table 7: Percentage of Pediatric Subjects with Treatment-Related Adverse Reactions (in At Least 10% of All Subjects)</span> </caption> <colgroup> <col width="49.28%"/> <col width="50.72%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" valign="middle"><span class="Bold"> System</span><span class="Bold"></span><span class="Bold"> Organ</span><span class="Bold"></span><span class="Bold"> Class<br/>     </span> Preferred Term<br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold"> All</span><span class="Bold"></span><span class="Bold"> Subjects</span> <br/> (N=107)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="2" valign="middle"><span class="Bold"> Blood</span><span class="Bold"></span><span class="Bold"> and</span><span class="Bold"></span><span class="Bold"> Lymphatic</span><span class="Bold"> System Disorders</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Neutropenia<br/> </td><td align="center" class="Rrule" valign="middle"> 33%<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Anemia<br/> </td><td align="center" class="Rrule" valign="middle"> 11%<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Leukopenia<br/> </td><td align="center" class="Rrule" valign="middle"> 10%<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="2" valign="middle"><span class="Bold"> Gastrointestinal Disorders</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Abdominal Pain<br/> </td><td align="center" class="Rrule" valign="middle"> 21%<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Abdominal Pain Upper<br/> </td><td align="center" class="Rrule" valign="middle"> 12%<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Vomiting<br/> </td><td align="center" class="Rrule" valign="middle"> 27%<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Nausea<br/> </td><td align="center" class="Rrule" valign="middle"> 18%<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="2" valign="middle"><span class="Bold"> General</span><span class="Bold"></span><span class="Bold"> Disorders</span><span class="Bold"> and Administration Site Conditions</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Pyrexia<br/> </td><td align="center" class="Rrule" valign="middle"> 80%<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Fatigue<br/> </td><td align="center" class="Rrule" valign="middle"> 30%<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Injection-site Erythema<br/> </td><td align="center" class="Rrule" valign="middle"> 29%<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Chills<br/> </td><td align="center" class="Rrule" valign="middle"> 21%<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Asthenia<br/> </td><td align="center" class="Rrule" valign="middle"> 15%<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Irritability<br/> </td><td align="center" class="Rrule" valign="middle"> 14%<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="2" valign="middle"><span class="Bold"> Investigations</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Weight Loss<br/> </td><td align="center" class="Rrule" valign="middle"> 19%<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="2" valign="middle"><span class="Bold"> Metabolism and</span><span class="Bold"></span><span class="Bold"> Nutrition</span><span class="Bold"></span><span class="Bold"> Disorders</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Anorexia<br/> </td><td align="center" class="Rrule" valign="middle"> 29%<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Decreased Appetite<br/> </td><td align="center" class="Rrule" valign="middle"> 22%<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="2" valign="middle"><span class="Bold"> Musculoskeletal</span><span class="Bold"></span><span class="Bold"> and</span><span class="Bold"></span><span class="Bold"> Connective</span><span class="Bold"> Tissue Disorders</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Arthralgia<br/> </td><td align="center" class="Rrule" valign="middle"> 17%<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Myalgia<br/> </td><td align="center" class="Rrule" valign="middle"> 17%<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="2" valign="middle"><span class="Bold"> Nervous</span><span class="Bold"> System Disorders</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Headache<br/> </td><td align="center" class="Rrule" valign="middle"> 62%<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">     Dizziness<br/> </td><td align="center" class="Rrule" valign="middle"> 14%<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="2" valign="middle"><span class="Bold"> Skin</span><span class="Bold"></span><span class="Bold"> and</span><span class="Bold"></span><span class="Bold"> Subcutaneous</span><span class="Bold"></span><span class="Bold"> Tissue</span><span class="Bold"></span><span class="Bold"> Disorders</span> <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="middle">     Alopecia<br/> </td><td align="center" class="Rrule" valign="middle"> 17%<br/> </td> </tr> </tbody> </table></div>

Ninety-four of 107 subjects enrolled in a 5-year follow-up trial. The long-term effects on growth were less in subjects treated for 24 weeks than in 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 baseline to the end of 5-year follow-up. Eleven percent of subjects (5/46) treated for 24 weeks and 13% of subjects (6/48) treated for 48 weeks had a >30 percentile height-for-age decrease from pre-treatment baseline to the end of the 5-year follow-up. While observed across all age groups, the highest risk for reduced height at the end of long-term follow-up appeared to be initiation of combination therapy during the years of expected peak growth velocity [see Warnings and Precautions (5.9)].

Laboratory Values

Adult and Pediatric Subjects

The adverse reaction profile in Study 3, which compared PegIntron/weight-based ribavirin combination to a PegIntron/flat dose ribavirin 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 ribavirin treatment are described below. Decreases in hemoglobin, leukocytes, neutrophils, and platelets may require dose reduction or permanent discontinuation from therapy [see Dosage and Administration (2.5)]. Changes in selected laboratory values during therapy are described in Table 8. Most of the changes in laboratory values in the PegIntron/ribavirin trial with pediatrics were mild or moderate.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 8: Selected Laboratory Abnormalities During Treatment with Ribavirin and PegIntron or Ribavirin and INTRON A in Previously Untreated Subjects</span> </caption> <colgroup> <col width="27.76%"/> <col width="23.12%"/> <col width="23.12%"/> <col width="26%"/> </colgroup> <tfoot> <tr class="First Last"> <td colspan="4">* 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.<br/> <span class="Sup">†</span> ULN=Upper limit of normal.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" rowspan="3" valign="middle"><span class="Bold"> Laboratory</span><span class="Bold"></span><span class="Bold"> Parameters<span class="Sup">*</span></span> <br/> </td><td align="center" class="Rrule" colspan="3" valign="middle"><span class="Bold"> Percentage</span><span class="Bold"> of Subjects</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" colspan="2" valign="middle"><span class="Bold"> Adults</span><span class="Bold"> (Study 2)</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold"> Pediatrics</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle"><span class="Bold"> PegIntron/</span> <br/> <span class="Bold">Ribavirin </span><span class="Bold"></span> <br/> (N=511)<br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold"> INTRON</span><span class="Bold"></span><span class="Bold"> A/<br/> </span><span class="Bold">Ribavirin</span><span class="Bold"></span> <br/> (N=505)<br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold"> PegIntron/</span><span class="Bold"></span><span class="Bold">Ribavirin</span> (N=107)<span class="Sup">*</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="4" valign="middle"><span class="Bold">Hemoglobin </span><span class="Bold">(g/dL)</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    9.5 to &lt;11.0<br/> </td><td align="center" class="Rrule" valign="middle">26<br/> </td><td align="center" class="Rrule" valign="middle">27<br/> </td><td align="center" class="Rrule" valign="middle">30<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    8.0 to &lt;9.5<br/> </td><td align="center" class="Rrule" valign="middle">3<br/> </td><td align="center" class="Rrule" valign="middle">3<br/> </td><td align="center" class="Rrule" valign="middle">2<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    6.5 to 7.9<br/> </td><td align="center" class="Rrule" valign="middle">0.2<br/> </td><td align="center" class="Rrule" valign="middle">0.2<br/> </td><td align="center" class="Rrule" valign="middle">-<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="4" valign="middle"><span class="Bold">Leukocytes </span><span class="Bold">(x 10<span class="Sup">9</span>/L)</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    2.0 to 2.9<br/> </td><td align="center" class="Rrule" valign="middle">46<br/> </td><td align="center" class="Rrule" valign="middle">41<br/> </td><td align="center" class="Rrule" valign="middle">39<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    1.5 to &lt;2.0<br/> </td><td align="center" class="Rrule" valign="middle">24<br/> </td><td align="center" class="Rrule" valign="middle">8<br/> </td><td align="center" class="Rrule" valign="middle">3<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    1.0 to 1.4<br/> </td><td align="center" class="Rrule" valign="middle">5<br/> </td><td align="center" class="Rrule" valign="middle">1<br/> </td><td align="center" class="Rrule" valign="middle">-<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="4" valign="middle"><span class="Bold">Neutrophils </span><span class="Bold">(x 10<span class="Sup">9</span>/L)</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    1.0 to 1.5<br/> </td><td align="center" class="Rrule" valign="middle">33<br/> </td><td align="center" class="Rrule" valign="middle">37<br/> </td><td align="center" class="Rrule" valign="middle">35<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    0.75 to &lt;1.0<br/> </td><td align="center" class="Rrule" valign="middle">25<br/> </td><td align="center" class="Rrule" valign="middle">13<br/> </td><td align="center" class="Rrule" valign="middle">26<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    0.5 to &lt;0.75<br/> </td><td align="center" class="Rrule" valign="middle">18<br/> </td><td align="center" class="Rrule" valign="middle">7<br/> </td><td align="center" class="Rrule" valign="middle">13<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    &lt;0.5<br/> </td><td align="center" class="Rrule" valign="middle">4<br/> </td><td align="center" class="Rrule" valign="middle">2<br/> </td><td align="center" class="Rrule" valign="middle">3<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="4" valign="middle"><span class="Bold">Platelets </span><span class="Bold">(x 10<span class="Sup">9</span>/L)</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    70 to 100<br/> </td><td align="center" class="Rrule" valign="middle">15<br/> </td><td align="center" class="Rrule" valign="middle">5<br/> </td><td align="center" class="Rrule" valign="middle">1<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    50 to &lt;70<br/> </td><td align="center" class="Rrule" valign="middle">3<br/> </td><td align="center" class="Rrule" valign="middle">0.8<br/> </td><td align="center" class="Rrule" valign="middle">-<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    30 to 49<br/> </td><td align="center" class="Rrule" valign="middle">0.2<br/> </td><td align="center" class="Rrule" valign="middle">0.2<br/> </td><td align="center" class="Rrule" valign="middle">-<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    25 to &lt;50<br/> </td><td align="center" class="Rrule" valign="middle">-<br/> </td><td align="center" class="Rrule" valign="middle">-<br/> </td><td align="center" class="Rrule" valign="middle">1<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="middle"><span class="Bold">Total </span><span class="Bold">Bilirubin                                                             (mg/dL)</span> <br/> </td><td class="Rrule" valign="middle"><span class="Bold">(µmole/L)</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    1.5 to 3.0<br/> </td><td align="center" class="Rrule" valign="middle">10<br/> </td><td align="center" class="Rrule" valign="middle">13<br/> </td><td align="center" class="Rrule" valign="middle">-<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    1.26 to 2.59 x ULN<span class="Sup">†</span> <br/> </td><td align="center" class="Rrule" valign="middle">-<br/> </td><td align="center" class="Rrule" valign="middle">-<br/> </td><td align="center" class="Rrule" valign="middle">7<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    3.1 to 6.0<br/> </td><td align="center" class="Rrule" valign="middle">0.6<br/> </td><td align="center" class="Rrule" valign="middle">0.2<br/> </td><td align="center" class="Rrule" valign="middle">-<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    2.6 to 5 x ULN<span class="Sup">†</span> <br/> </td><td align="center" class="Rrule" valign="middle">-<br/> </td><td align="center" class="Rrule" valign="middle">-<br/> </td><td align="center" class="Rrule" valign="middle">-<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    6.1 to 12.0<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">0.2<br/> </td><td align="center" class="Rrule" valign="middle">-<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="4" valign="middle"><span class="Bold">ALT </span><span class="Bold">(U/L)</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    2 x Baseline<br/> </td><td align="center" class="Rrule" valign="middle">0.6<br/> </td><td align="center" class="Rrule" valign="middle">0.2<br/> </td><td align="center" class="Rrule" valign="middle">1<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    2.1 to 5 x Baseline<br/> </td><td align="center" class="Rrule" valign="middle">3<br/> </td><td align="center" class="Rrule" valign="middle">1<br/> </td><td align="center" class="Rrule" valign="middle">5<br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="middle">    5.1 to 10 x Baseline<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">3<br/> </td> </tr> </tbody> </table></div>

Hemoglobin. In Study 2, hemoglobin levels decreased to less than 11 g/dL in about 30% of subjects. In Study 3, 47% of subjects receiving weight-based dosing of ribavirin and 33% on flat-dose ribavirin had decreases in hemoglobin levels to less than 11 g/dL. Reductions in hemoglobin to less than 9 g/dL occurred more frequently in subjects receiving weight-based dosing compared to flat dosing (4% and 2%, respectively). In Study 2, dose modification was required in 9% and 13% of subjects in the PegIntron/ribavirin and INTRON A/ribavirin groups. In Study 4, subjects receiving PegIntron (1.5 mcg/kg)/ribavirin 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. On average, hemoglobin levels became stable by treatment Weeks 4 to 6. 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 [see Dosage and Administration (2.5)].

Neutrophils. In Study 2, decreases in neutrophil counts were observed in a majority of adult subjects treated with PegIntron/ribavirin (85%) and INTRON A/ribavirin (60%). Severe, potentially life-threatening neutropenia (less than 0.5 x 109/L) occurred in approximately 4% of subjects treated with PegIntron/ribavirin and 2% of subjects treated with INTRON A/ribavirin. Eighteen percent of subjects receiving PegIntron/ribavirin 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 (2.5)].

Platelets. In Study 2, platelet counts decreased to less than 100,000/mm3 in approximately 20% of subjects treated with PegIntron alone or with ribavirin and in 6% of adult subjects treated with INTRON A/ribavirin. Severe decreases in platelet counts (less than 50,000/mm3) occur in less than 4% of adult subjects. 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 [see Dosage and Administration (2.5)].

Thyroid Function. In Study 2, clinically apparent thyroid disorders occurred among subjects treated with either INTRON A or PegIntron (with or without ribavirin) 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.

Adverse Reactions with Ribavirin/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-only arms. Selected treatment-related adverse reactions that occurred in the U.S.  trials with incidence 5% or greater 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 U.S. trials, except for 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 incidence 5% or greater among all pediatric subjects who received the recommended dose of ribavirin/INTRON A combination therapy are provided in Table 9.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 9: Selected Treatment-Related Adverse Reactions: Previously Untreated and Relapse Adult Subjects and Previously Untreated Pediatric Subjects</span> </caption> <colgroup> <col width="16.5487977369165%"/> <col width="11.7397454031117%"/> <col width="11.7397454031117%"/> <col width="0.424328147100424%"/> <col width="11.1739745403112%"/> <col width="11.7397454031117%"/> <col width="12.3055162659123%"/> <col width="12.3055162659123%"/> <col width="12.022630834512%"/> </colgroup> <tfoot> <tr class="First Last"> <td colspan="9">* Subjects reporting one or more adverse reactions. A subject may have reported more than one adverse reaction within a body system/organ class category.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" rowspan="4" valign="middle"><span class="Bold">Subjects</span> <br/> <span class="Bold">Reporting</span> <br/> <span class="Bold">Adverse</span> <br/> <span class="Bold">Reactions*</span> <br/> </td><td align="center" class="Rrule" colspan="8" valign="middle"><span class="Bold">Percentage of Subjects</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" colspan="5" valign="middle"><span class="Bold">U.S. Previously Untreated Study</span> <br/> </td><td align="center" class="Rrule" colspan="2" valign="middle"><span class="Bold">U.S. Relapse Study</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Pediatric Subjects</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" colspan="3" valign="middle"><span class="Bold">24 weeks of treatment</span> <br/> </td><td align="center" class="Rrule" colspan="2" valign="middle"><span class="Bold">48 weeks of treatment</span> <br/> </td><td align="center" class="Rrule" colspan="2" valign="middle"><span class="Bold">24 weeks of treatment</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">48 weeks of</span> <br/> <span class="Bold">treatment</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"><span class="Bold">INTRON A/</span> <br/> <span class="Bold">Ribavirin<br/> </span>(N=228)<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">INTRON A/</span> <br/> <span class="Bold"> Placebo </span> <br/> <span class="Bold"> </span>(N=231)<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" colspan="2" valign="top"><span class="Bold">INTRON A/<br/>Ribavirin<br/> </span>(N=228)<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">INTRON A/<br/> Placebo </span> <br/>(N=225)<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">INTRON A/<br/>Ribavirin</span> <br/> (N=77)<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">INTRON A/<br/> Placebo</span> <br/> <span class="Bold"> </span>(N=76)<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">INTRON A/<br/> </span><span class="Bold">Ribavirin<br/> </span>(N=118)<span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="9" valign="middle"><span class="Bold">Application Site Disorders </span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    Injection Site<br/>     Inflammation <br/> </td><td align="center" class="Rrule" valign="middle">13<br/> </td><td align="center" class="Rrule" valign="middle">10<br/> </td><td align="center" class="Rrule" colspan="2" valign="middle">12<br/> </td><td align="center" class="Rrule" valign="middle">14<br/> </td><td align="center" class="Rrule" valign="middle">6<br/> </td><td align="center" class="Rrule" valign="middle">8<br/> </td><td align="center" class="Rrule" valign="middle">14<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    Injection Site Reaction <br/> </td><td align="center" class="Rrule" valign="middle">7<br/> </td><td align="center" class="Rrule" valign="middle">9<br/> </td><td align="center" class="Rrule" colspan="2" valign="middle">8<br/> </td><td align="center" class="Rrule" valign="middle">9<br/> </td><td align="center" class="Rrule" valign="middle">5<br/> </td><td align="center" class="Rrule" valign="middle">3<br/> </td><td align="center" class="Rrule" valign="middle">19<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="9" valign="middle"><span class="Bold">Body as a Whole - General Disorders</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    Headache <br/> </td><td align="center" class="Rrule" valign="middle">63<br/> </td><td align="center" class="Rrule" valign="middle">63<br/> </td><td align="center" class="Rrule" colspan="2" valign="middle">66<br/> </td><td align="center" class="Rrule" valign="middle">67<br/> </td><td align="center" class="Rrule" valign="middle">66<br/> </td><td align="center" class="Rrule" valign="middle">68<br/> </td><td align="center" class="Rrule" valign="middle">69<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    Fatigue <br/> </td><td align="center" class="Rrule" valign="middle">68<br/> </td><td align="center" class="Rrule" valign="middle">62<br/> </td><td align="center" class="Rrule" colspan="2" valign="middle">70<br/> </td><td align="center" class="Rrule" valign="middle">72<br/> </td><td align="center" class="Rrule" valign="middle">60<br/> </td><td align="center" class="Rrule" valign="middle">53<br/> </td><td align="center" class="Rrule" valign="middle">58<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    Rigors <br/> </td><td align="center" class="Rrule" valign="middle">40<br/> </td><td align="center" class="Rrule" valign="middle">32<br/> </td><td align="center" class="Rrule" colspan="2" valign="middle">42<br/> </td><td align="center" class="Rrule" valign="middle">39<br/> </td><td align="center" class="Rrule" valign="middle">43<br/> </td><td align="center" class="Rrule" valign="middle">37<br/> </td><td align="center" class="Rrule" valign="middle">25<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    Fever <br/> </td><td align="center" class="Rrule" valign="middle">37<br/> </td><td align="center" class="Rrule" valign="middle">35<br/> </td><td align="center" class="Rrule" colspan="2" valign="middle">41<br/> </td><td align="center" class="Rrule" valign="middle">40<br/> </td><td align="center" class="Rrule" valign="middle">32<br/> </td><td align="center" class="Rrule" valign="middle">36<br/> </td><td align="center" class="Rrule" valign="middle">61<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    Influenza-like Symptoms <br/> </td><td align="center" class="Rrule" valign="middle">14<br/> </td><td align="center" class="Rrule" valign="middle">18<br/> </td><td align="center" class="Rrule" colspan="2" valign="middle">18<br/> </td><td align="center" class="Rrule" valign="middle">20<br/> </td><td align="center" class="Rrule" valign="middle">13<br/> </td><td align="center" class="Rrule" valign="middle">13<br/> </td><td align="center" class="Rrule" valign="middle">31<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    Asthenia <br/> </td><td align="center" class="Rrule" valign="middle">9<br/> </td><td align="center" class="Rrule" valign="middle">4<br/> </td><td align="center" class="Rrule" colspan="2" valign="middle">9<br/> </td><td align="center" class="Rrule" valign="middle">9<br/> </td><td align="center" class="Rrule" valign="middle">10<br/> </td><td align="center" class="Rrule" valign="middle">4<br/> </td><td align="center" class="Rrule" valign="middle">5<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    Chest Pain <br/> </td><td align="center" class="Rrule" valign="middle">5<br/> </td><td align="center" class="Rrule" valign="middle">4<br/> </td><td align="center" class="Rrule" colspan="2" valign="middle">9<br/> </td><td align="center" class="Rrule" valign="middle">8<br/> </td><td align="center" class="Rrule" valign="middle">6<br/> </td><td align="center" class="Rrule" valign="middle">7<br/> </td><td align="center" class="Rrule" valign="middle">5<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="9" valign="middle"><span class="Bold">Central &amp; Peripheral Nervous System Disorders</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    Dizziness <br/> </td><td align="center" class="Rrule" valign="middle">17<br/> </td><td align="center" class="Rrule" valign="middle">15<br/> </td><td align="center" class="Rrule" colspan="2" valign="middle">23<br/> </td><td align="center" class="Rrule" valign="middle">19<br/> </td><td align="center" class="Rrule" valign="middle">26<br/> </td><td align="center" class="Rrule" valign="middle">21<br/> </td><td align="center" class="Rrule" valign="middle">20<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="9" valign="middle"><span class="Bold">Gastrointestinal System Disorders</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    Nausea<br/> </td><td align="center" class="Rrule" valign="middle">38<br/> </td><td align="center" class="Rrule" valign="middle">35<br/> </td><td align="center" class="Rrule" colspan="2" valign="middle">46<br/> </td><td align="center" class="Rrule" valign="middle">33<br/> </td><td align="center" class="Rrule" valign="middle">47<br/> </td><td align="center" class="Rrule" valign="middle">33<br/> </td><td align="center" class="Rrule" valign="middle">33<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    Anorexia<br/> </td><td align="center" class="Rrule" valign="middle">27<br/> </td><td align="center" class="Rrule" valign="middle">16<br/> </td><td align="center" class="Rrule" colspan="2" valign="middle">25<br/> </td><td align="center" class="Rrule" valign="middle">19<br/> </td><td align="center" class="Rrule" valign="middle">21<br/> </td><td align="center" class="Rrule" valign="middle">14<br/> </td><td align="center" class="Rrule" valign="middle">51<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    Dyspepsia<br/> </td><td align="center" class="Rrule" valign="middle">14<br/> </td><td align="center" class="Rrule" valign="middle">6<br/> </td><td align="center" class="Rrule" colspan="2" valign="middle">16<br/> </td><td align="center" class="Rrule" valign="middle">9<br/> </td><td align="center" class="Rrule" valign="middle">16<br/> </td><td align="center" class="Rrule" valign="middle">9<br/> </td><td align="center" class="Rrule" valign="middle">&lt;1<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    Vomiting<br/> </td><td align="center" class="Rrule" valign="middle">11<br/> </td><td align="center" class="Rrule" valign="middle">10<br/> </td><td align="center" class="Rrule" colspan="2" valign="middle">9<br/> </td><td align="center" class="Rrule" valign="middle">13<br/> </td><td align="center" class="Rrule" valign="middle">12<br/> </td><td align="center" class="Rrule" valign="middle">8<br/> </td><td align="center" class="Rrule" valign="middle">42<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="9" valign="middle"><span class="Bold">Musculoskeletal System Disorders</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    Myalgia<br/> </td><td align="center" class="Rrule" valign="middle">61<br/> </td><td align="center" class="Rrule" valign="middle">57<br/> </td><td align="center" class="Rrule" colspan="2" valign="middle">64<br/> </td><td align="center" class="Rrule" valign="middle">63<br/> </td><td align="center" class="Rrule" valign="middle">61<br/> </td><td align="center" class="Rrule" valign="middle">58<br/> </td><td align="center" class="Rrule" valign="middle">32<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    Arthralgia<br/> </td><td align="center" class="Rrule" valign="middle">30<br/> </td><td align="center" class="Rrule" valign="middle">27<br/> </td><td align="center" class="Rrule" colspan="2" valign="middle">33<br/> </td><td align="center" class="Rrule" valign="middle">36<br/> </td><td align="center" class="Rrule" valign="middle">29<br/> </td><td align="center" class="Rrule" valign="middle">29<br/> </td><td align="center" class="Rrule" valign="middle">15<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    Musculoskeletal Pain<br/> </td><td align="center" class="Rrule" valign="middle">20<br/> </td><td align="center" class="Rrule" valign="middle">26<br/> </td><td align="center" class="Rrule" colspan="2" valign="middle">28<br/> </td><td align="center" class="Rrule" valign="middle">32<br/> </td><td align="center" class="Rrule" valign="middle">22<br/> </td><td align="center" class="Rrule" valign="middle">28<br/> </td><td align="center" class="Rrule" valign="middle">21<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="9" valign="middle"><span class="Bold">Psychiatric Disorders </span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    Insomnia <br/> </td><td align="center" class="Rrule" valign="middle">39<br/> </td><td align="center" class="Rrule" valign="middle">27<br/> </td><td align="center" class="Rrule" colspan="2" valign="middle">39<br/> </td><td align="center" class="Rrule" valign="middle">30<br/> </td><td align="center" class="Rrule" valign="middle">26<br/> </td><td align="center" class="Rrule" valign="middle">25<br/> </td><td align="center" class="Rrule" valign="middle">14<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    Irritability <br/> </td><td align="center" class="Rrule" valign="middle">23<br/> </td><td align="center" class="Rrule" valign="middle">19<br/> </td><td align="center" class="Rrule" colspan="2" valign="middle">32<br/> </td><td align="center" class="Rrule" valign="middle">27<br/> </td><td align="center" class="Rrule" valign="middle">25<br/> </td><td align="center" class="Rrule" valign="middle">20<br/> </td><td align="center" class="Rrule" valign="middle">10<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    Depression <br/> </td><td align="center" class="Rrule" valign="middle">32<br/> </td><td align="center" class="Rrule" valign="middle">25<br/> </td><td align="center" class="Rrule" colspan="2" valign="middle">36<br/> </td><td align="center" class="Rrule" valign="middle">37<br/> </td><td align="center" class="Rrule" valign="middle">23<br/> </td><td align="center" class="Rrule" valign="middle">14<br/> </td><td align="center" class="Rrule" valign="middle">13<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    Emotional    Lability <br/> </td><td align="center" class="Rrule" valign="middle">7<br/> </td><td align="center" class="Rrule" valign="middle">6<br/> </td><td align="center" class="Rrule" colspan="2" valign="middle">11<br/> </td><td align="center" class="Rrule" valign="middle">8<br/> </td><td align="center" class="Rrule" valign="middle">12<br/> </td><td align="center" class="Rrule" valign="middle">8<br/> </td><td align="center" class="Rrule" valign="middle">16<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    Concentration   <br/>Impaired <br/> </td><td align="center" class="Rrule" valign="middle">11<br/> </td><td align="center" class="Rrule" valign="middle">14<br/> </td><td align="center" class="Rrule" colspan="2" valign="middle">14<br/> </td><td align="center" class="Rrule" valign="middle">14<br/> </td><td align="center" class="Rrule" valign="middle">10<br/> </td><td align="center" class="Rrule" valign="middle">12<br/> </td><td align="center" class="Rrule" valign="middle">5<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    Nervousness <br/> </td><td align="center" class="Rrule" valign="middle">4<br/> </td><td align="center" class="Rrule" valign="middle">2<br/> </td><td align="center" class="Rrule" colspan="2" valign="middle">4<br/> </td><td align="center" class="Rrule" valign="middle">4<br/> </td><td align="center" class="Rrule" valign="middle">5<br/> </td><td align="center" class="Rrule" valign="middle">4<br/> </td><td align="center" class="Rrule" valign="middle">3<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="9" valign="middle"><span class="Bold">Respiratory System Disorders </span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    Dyspnea<br/> </td><td align="center" class="Rrule" valign="middle">19<br/> </td><td align="center" class="Rrule" valign="middle">9<br/> </td><td align="center" class="Rrule" colspan="2" valign="middle">18<br/> </td><td align="center" class="Rrule" valign="middle">10<br/> </td><td align="center" class="Rrule" valign="middle">17<br/> </td><td align="center" class="Rrule" valign="middle">12<br/> </td><td align="center" class="Rrule" valign="middle">5<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    Sinusitis<br/> </td><td align="center" class="Rrule" valign="middle">9<br/> </td><td align="center" class="Rrule" valign="middle">7<br/> </td><td align="center" class="Rrule" colspan="2" valign="middle">10<br/> </td><td align="center" class="Rrule" valign="middle">14<br/> </td><td align="center" class="Rrule" valign="middle">12<br/> </td><td align="center" class="Rrule" valign="middle">7<br/> </td><td align="center" class="Rrule" valign="middle">&lt;1<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="9" valign="middle"><span class="Bold">Skin and Appendages Disorders </span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    Alopecia <br/> </td><td align="center" class="Rrule" valign="middle">28<br/> </td><td align="center" class="Rrule" valign="middle">27<br/> </td><td align="center" class="Rrule" colspan="2" valign="middle">32<br/> </td><td align="center" class="Rrule" valign="middle">28<br/> </td><td align="center" class="Rrule" valign="middle">27<br/> </td><td align="center" class="Rrule" valign="middle">26<br/> </td><td align="center" class="Rrule" valign="middle">23<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    Rash <br/> </td><td align="center" class="Rrule" valign="middle">20<br/> </td><td align="center" class="Rrule" valign="middle">9<br/> </td><td align="center" class="Rrule" colspan="2" valign="middle">28<br/> </td><td align="center" class="Rrule" valign="middle">8<br/> </td><td align="center" class="Rrule" valign="middle">21<br/> </td><td align="center" class="Rrule" valign="middle">5<br/> </td><td align="center" class="Rrule" valign="middle">17<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    Pruritus <br/> </td><td align="center" class="Rrule" valign="middle">21<br/> </td><td align="center" class="Rrule" valign="middle">9<br/> </td><td align="center" class="Rrule" colspan="2" valign="middle">19<br/> </td><td align="center" class="Rrule" valign="middle">8<br/> </td><td align="center" class="Rrule" valign="middle">13<br/> </td><td align="center" class="Rrule" valign="middle">4<br/> </td><td align="center" class="Rrule" valign="middle">12<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="9" valign="middle"><span class="Bold">Special Senses, Other Disorders </span> <br/> </td> </tr> <tr class="Botrule Last"> <td class="Lrule Rrule" valign="middle">    Taste Perversion <br/> </td><td align="center" class="Rrule" valign="middle">7<br/> </td><td align="center" class="Rrule" valign="middle">4<br/> </td><td align="center" class="Rrule" colspan="2" valign="middle">8<br/> </td><td align="center" class="Rrule" valign="middle">4<br/> </td><td align="center" class="Rrule" valign="middle">6<br/> </td><td align="center" class="Rrule" valign="middle">5<br/> </td><td align="center" class="Rrule" valign="middle">&lt;1<br/> </td> </tr> </tbody> </table></div>

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 (5.9)].

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 ribavirin 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 U.S. 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 U.S. 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 changes were moderate and 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.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 10: Selected Laboratory Abnormalities During Treatment with Ribavirin and INTRON A: Previously Untreated and Relapse Adult Subjects and Previously Untreated Pediatric Subjects </span> </caption> <colgroup> <col width="14.92%"/> <col width="12.98%"/> <col width="11.66%"/> <col width="11.26%"/> <col width="11.86%"/> <col width="12.32%"/> <col width="10.94%"/> <col width="14.06%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" rowspan="4" valign="top"> <br/> </td><td align="center" class="Rrule" colspan="7" valign="middle"><span class="Bold">Percentage of Subjects</span><span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" colspan="4" valign="middle"><span class="Bold">U.S. Previously Untreated Study</span> <br/> </td><td align="center" class="Rrule" colspan="2" valign="middle"><span class="Bold">U.S. Relapse Study</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Pediatric Subjects</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" colspan="2" valign="middle"><span class="Bold">24 weeks of treatment</span> <br/> </td><td align="center" class="Rrule" colspan="2" valign="middle"><span class="Bold">48 weeks of treatment</span> <br/> </td><td align="center" class="Rrule" colspan="2" valign="middle"><span class="Bold">24 weeks of treatment</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">48 weeks of treatment</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle"><span class="Bold">INTRON A/</span> <br/> <span class="Bold"> Ribavirin</span> <br/> (N=228)<br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">INTRON A</span><span class="Bold">/</span><span class="Bold"></span><span class="Bold"></span> <br/> <span class="Bold">Placebo</span> <br/>(N=231)<br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">INTRON A/ </span> <br/> <span class="Bold">Ribavirin<br/> </span>(N=228)<br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">INTRON A/ </span> <br/> <span class="Bold">Placebo</span> <br/>(N=225)<br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">INTRON A/ </span> <br/> <span class="Bold">Ribavirin<br/> </span>(N=77)<br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">INTRON A</span><span class="Bold">/</span><span class="Bold"></span><span class="Bold"></span> <br/> <span class="Bold">Placebo</span> <br/>(N=76)<br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">INTRON A/</span> <br/> <span class="Bold">Ribavirin</span> <br/>(N=118)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="8" valign="middle"><span class="Bold">Hemoglobin (g/dL)</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    9.5 to 10.9 <br/> </td><td align="center" class="Rrule" valign="middle">24<br/> </td><td align="center" class="Rrule" valign="middle">1<br/> </td><td align="center" class="Rrule" valign="middle">32<br/> </td><td align="center" class="Rrule" valign="middle">1<br/> </td><td align="center" class="Rrule" valign="middle">21<br/> </td><td align="center" class="Rrule" valign="middle">3<br/> </td><td align="center" class="Rrule" valign="middle">24<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    8.0 to 9.4 <br/> </td><td align="center" class="Rrule" valign="middle">5<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">4<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">4<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">3<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    6.5 to 7.9 <br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">0.4<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    &lt;6.5 <br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="8" valign="middle"><span class="Bold">Leukocytes  (x 10<span class="Sup">9</span>/L)</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    2.0 to 2.9 <br/> </td><td align="center" class="Rrule" valign="middle">40<br/> </td><td align="center" class="Rrule" valign="middle">20<br/> </td><td align="center" class="Rrule" valign="middle">38<br/> </td><td align="center" class="Rrule" valign="middle">23<br/> </td><td align="center" class="Rrule" valign="middle">45<br/> </td><td align="center" class="Rrule" valign="middle">26<br/> </td><td align="center" class="Rrule" valign="middle">35<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    1.5 to 1.9 <br/> </td><td align="center" class="Rrule" valign="middle">4<br/> </td><td align="center" class="Rrule" valign="middle">1<br/> </td><td align="center" class="Rrule" valign="middle">9<br/> </td><td align="center" class="Rrule" valign="middle">2<br/> </td><td align="center" class="Rrule" valign="middle">5<br/> </td><td align="center" class="Rrule" valign="middle">3<br/> </td><td align="center" class="Rrule" valign="middle">8<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    1.0 to 1.4 <br/> </td><td align="center" class="Rrule" valign="middle">0.9<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">2<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    &lt;1.0<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="8" valign="middle"><span class="Bold">Neutrophils (x 10<span class="Sup">9</span>/L)</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    1.0 to 1.49 <br/> </td><td align="center" class="Rrule" valign="middle">30<br/> </td><td align="center" class="Rrule" valign="middle">32<br/> </td><td align="center" class="Rrule" valign="middle">31<br/> </td><td align="center" class="Rrule" valign="middle">44<br/> </td><td align="center" class="Rrule" valign="middle">42<br/> </td><td align="center" class="Rrule" valign="middle">34<br/> </td><td align="center" class="Rrule" valign="middle">37<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    0.75 to 0.99 <br/> </td><td align="center" class="Rrule" valign="middle">14<br/> </td><td align="center" class="Rrule" valign="middle">15<br/> </td><td align="center" class="Rrule" valign="middle">14<br/> </td><td align="center" class="Rrule" valign="middle">11<br/> </td><td align="center" class="Rrule" valign="middle">16<br/> </td><td align="center" class="Rrule" valign="middle">18<br/> </td><td align="center" class="Rrule" valign="middle">15<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    0.5 to 0.74 <br/> </td><td align="center" class="Rrule" valign="middle">9<br/> </td><td align="center" class="Rrule" valign="middle">9<br/> </td><td align="center" class="Rrule" valign="middle">14<br/> </td><td align="center" class="Rrule" valign="middle">7<br/> </td><td align="center" class="Rrule" valign="middle">8<br/> </td><td align="center" class="Rrule" valign="middle">4<br/> </td><td align="center" class="Rrule" valign="middle">16<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    &lt;0.5 <br/> </td><td align="center" class="Rrule" valign="middle">11<br/> </td><td align="center" class="Rrule" valign="middle">8<br/> </td><td align="center" class="Rrule" valign="middle">11<br/> </td><td align="center" class="Rrule" valign="middle">5<br/> </td><td align="center" class="Rrule" valign="middle">5<br/> </td><td align="center" class="Rrule" valign="middle">8<br/> </td><td align="center" class="Rrule" valign="middle">3<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="8" valign="middle"><span class="Bold">Platelets (x 10<span class="Sup">9</span>/L) </span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    70 to 99 <br/> </td><td align="center" class="Rrule" valign="middle">9<br/> </td><td align="center" class="Rrule" valign="middle">11<br/> </td><td align="center" class="Rrule" valign="middle">11<br/> </td><td align="center" class="Rrule" valign="middle">14<br/> </td><td align="center" class="Rrule" valign="middle">6<br/> </td><td align="center" class="Rrule" valign="middle">12<br/> </td><td align="center" class="Rrule" valign="middle">0.8<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    50 to 69 <br/> </td><td align="center" class="Rrule" valign="middle">2<br/> </td><td align="center" class="Rrule" valign="middle">3<br/> </td><td align="center" class="Rrule" valign="middle">2<br/> </td><td align="center" class="Rrule" valign="middle">3<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">5<br/> </td><td align="center" class="Rrule" valign="middle">2<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    30 to 49 <br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">0.4<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">0.4<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    &lt;30 <br/> </td><td align="center" class="Rrule" valign="middle">0.9<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">1<br/> </td><td align="center" class="Rrule" valign="middle">0.9<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="8" valign="middle"><span class="Bold">Total Bilirubin (mg/dL)</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    1.5 to 3.0<br/> </td><td align="center" class="Rrule" valign="middle">27<br/> </td><td align="center" class="Rrule" valign="middle">13<br/> </td><td align="center" class="Rrule" valign="middle">32<br/> </td><td align="center" class="Rrule" valign="middle">13<br/> </td><td align="center" class="Rrule" valign="middle">21<br/> </td><td align="center" class="Rrule" valign="middle">7<br/> </td><td align="center" class="Rrule" valign="middle">2<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    3.1 to 6.0<br/> </td><td align="center" class="Rrule" valign="middle">0.9<br/> </td><td align="center" class="Rrule" valign="middle">0.4<br/> </td><td align="center" class="Rrule" valign="middle">2<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">3<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    6.1 to 12.0 <br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">0.4<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="middle">      &gt;12.0 <br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td> </tr> </tbody> </table></div>

The following adverse reactions have been identified and reported during post approval use of ribavirin 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

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 ribavirin capsules and didanosine is contraindicated [see Contraindications (4)]. Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in clinical trials.

Hepatic decompensation (some fatal) has occurred in cirrhotic HIV/HCV co-infected patients receiving combination antiretroviral therapy for HIV and interferon alpha and ribavirin. 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. Concomitant use of ribavirin with any of these drugs should be done with caution.

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 ribavirin capsules in a multiple-dose pharmacokinetic study.

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 (5.8)].

Risk Summary

Ribavirin is contraindicated for use in pregnant women and in men whose female partners are pregnant [see Contraindications (4)]. Based on animal data, ribavirin use in pregnancy may be associated with birth defects. Data from the Ribavirin Pregnancy Registry are insufficient to identify a drug-associated risk of birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). Ribavirin is known to accumulate in intracellular components from where it is cleared very slowly. In animal studies, ribavirin exposure was shown to have teratogenic and/or embryocidal effects (see Data).

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage is 2 to 4% and 15 to 20%, respectively.

Data

Human Data

Available data from the Ribavirin Pregnancy Registry on 88 live births from pregnancies in women directly exposed and 98 live births from pregnancies in women indirectly exposed (by a male partner) to ribavirin during pregnancy or during the 6 months prior to pregnancy show a higher rate of birth defects (9.09% and 6.12%, respectively) compared to a background birth defect rate of 2.72% in the Metropolitan Atlanta Congenital Defects Program (MACDP) birth defects surveillance system. No pattern of birth defects can be identified from these reports. The miscarriage rate was approximately 21%. The current sample size is insufficient for reaching definitive conclusions based on statistical analysis. Trends suggesting a common etiology or relationship with ribavirin exposure were not observed. Methodologic limitations of the Ribavirin Pregnancy Registry include the use of MACDP as the external comparator group. Limitations of using an external comparator include differences in methodology and populations, as well as confounding due to the underlying disease and comorbidities.

Animal Data

Embryotoxicity/teratogenicity studies with ribavirin were conducted in rats (oral doses of 0.3, 1 and 10 mg/kg on Gestation Days 6 to 15) and rabbits (oral dose of 0.1, 0.3 and 1 mg/kg on Gestation Days 6 to 18). Ribavirin demonstrated significant embryocidal and teratogenic effects at doses well below the recommended human dose 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)].

Risk Summary

There are no data on the presence of ribavirin in human milk or the effects on the breastfed infant or milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ribavirin and any potential adverse effects on the breastfed infant from ribavirin or from the underlying maternal condition.

Ribavirin may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing

Ribavirin therapy should not be started until a report of a negative pregnancy test has been obtained immediately prior to planned initiation of treatment. Patients should have periodic pregnancy tests during treatment and during the 9-month period after treatment has been stopped [see Warnings and Precautions (5.1)].

Contraception

Female patients of reproductive potential should use effective contraception during treatment and for 9 months post-therapy.

Male patients and their female partners should use effective contraception during treatment with ribavirin and for the 6-month post-therapy period [see Warnings and Precautions (5.1)].

Infertility

Based on animal data, ribavirin may impair male fertility. In animal studies, these effects were mostly reversible within a few months after drug cessation [see Nonclinical Toxicology (13.1)].    

Safety and effectiveness of ribavirin in combination with PegIntron has not been established in pediatric patients below the age of 3 years. For treatment with ribavirin/INTRON A, evidence of disease progression, such as hepatic inflammation and fibrosis, as well as prognostic factors for response, HCV genotype and viral load should be considered when deciding to treat a pediatric patient. The benefits of treatment should be weighed against the observed safety findings.

Long-term follow-up data in pediatric subjects indicates that ribavirin in combination with PegIntron or with INTRON A may induce a growth inhibition that results in reduced height in some patients [see Warnings and Precautions (5.9) and Adverse Reactions (6.1)].

Suicidal ideation or attempts occurred more frequently among pediatric patients, primarily adolescents, compared to adult patients (2.4% vs. 1%) during treatment and off-therapy follow-up [see Warnings and Precautions (5.10)]. As in adult patients, pediatric patients experienced other psychiatric adverse reactions (e.g., depression, emotional lability, somnolence), anemia, and neutropenia [see Warnings and Precautions (5.2)]. Juvenile Animal Toxicity Data In a study in which rat pups were dosed postnatally with ribavirin at doses of 10, 25, and 50 mg/kg/day, drug-related deaths occurred at 50 mg/kg (at rat pup plasma concentrations below human plasma concentrations at the human therapeutic dose) between study Days 13 and 48. Rat pups dosed from postnatal Days 7 through 63 demonstrated a minor, dose-related decrease in overall growth at all doses, which was subsequently manifested as slight decreases in body weight, crown-rump length, and bone length. These effects showed evidence of reversibility, and no histopathological effects on bone were observed. No ribavirin effects were observed regarding neurobehavioral or reproductive development.

Clinical trials of ribavirin combination therapy did not include sufficient numbers of subjects aged 65 and over to determine if they respond differently from younger subjects.

Ribavirin is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients often have decreased renal function, care should be taken in dose selection. Renal function should be monitored and dosage adjustments made accordingly. Ribavirin should not be used in patients with creatinine clearance less than 50 mL/min [see Contraindications (4)].

In general, ribavirin capsules should be administered to elderly patients cautiously, starting at the lower end of the dosing range, reflecting the greater frequency of decreased hepatic and cardiac function, and of concomitant disease or other drug therapy. In clinical trials, elderly subjects had a higher frequency of anemia (67%) than younger patients (28%) [see Warnings and Precautions (5.2)].  

The safety and efficacy of INTRON A and PegIntron alone or in combination with ribavirin for the treatment of hepatitis C in liver or other organ transplant recipients have not been established. In a small (n=16) single-center, uncontrolled case experience, renal failure in renal allograft recipients receiving interferon alpha and ribavirin combination therapy was more frequent than expected from the center’s previous experience with renal allograft recipients not receiving combination therapy. The relationship of the renal failure to renal allograft rejection is not clear.

The safety and efficacy of PegIntron/ribavirin and INTRON A/ribavirin for the treatment of patients with HCV co-infected with HIV or HBV have not been established.

There is limited experience with overdosage. Acute ingestion of up to 20 g of ribavirin capsules, INTRON A ingestion of up to 120 million units, and subcutaneous doses of INTRON A up to 10 times the recommended doses have been reported. Primary effects that have been observed are increased incidence and severity of the adverse reactions related to the therapeutic use of INTRON A and ribavirin. However, hepatic enzyme abnormalities, renal failure, hemorrhage, and myocardial infarction have been reported with administration of single subcutaneous doses of INTRON A that exceed dosing recommendations.

{ "type": "p", "children": [], "text": "There is limited experience with overdosage. Acute ingestion of up to 20 g of ribavirin capsules, INTRON A ingestion of up to 120 million units, and subcutaneous doses of INTRON A up to 10 times the recommended doses have been reported. Primary effects that have been observed are increased incidence and severity of the adverse reactions related to the therapeutic use of INTRON A and ribavirin. However, hepatic enzyme abnormalities, renal failure, hemorrhage, and myocardial infarction have been reported with administration of single subcutaneous doses of INTRON A that exceed dosing recommendations." }

There is no specific antidote for INTRON A or ribavirin overdose, and hemodialysis and peritoneal dialysis are not effective for treatment of overdose of these agents.  

{ "type": "p", "children": [], "text": "There is no specific antidote for INTRON A or ribavirin overdose, and hemodialysis and peritoneal dialysis are not effective for treatment of overdose of these agents.   " }

Ribavirin, is a synthetic nucleoside analogue (purine analogue). The chemical name of ribavirin is 1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide and has the following structural formula (see Figure 1). Figure 1: Structural Formula Ribavirin USP is a white, crystalline powder. It is freely soluble in water and slightly soluble in anhydrous alcohol. The molecular formula is C8H12N4O5 and the molecular weight is 244.21.

{ "type": "p", "children": [], "text": "Ribavirin, is a synthetic nucleoside analogue (purine analogue). The chemical name of ribavirin is 1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide and has the following structural formula (see Figure 1).\n\n\n Figure 1: Structural Formula\n\nRibavirin USP is a white, crystalline powder. It is freely soluble in water and slightly soluble in anhydrous alcohol. The molecular formula is C8H12N4O5 and the molecular weight is 244.21. " }

Ribavirin capsules USP consist of a white to off-white granular powder in a white, opaque, gelatin capsule. Each capsule contains 200 mg ribavirin and the inactive ingredients microcrystalline cellulose, lactose monohydrate, povidone-K 30, and magnesium stearate. The capsule shell consists of titanium dioxide, sodium lauryl sulfate, and gelatin. The capsule is printed with edible ink containing black iron oxide.

{ "type": "p", "children": [], "text": "Ribavirin capsules USP consist of a white to off-white granular powder in a white, opaque, gelatin capsule. Each capsule contains 200 mg ribavirin and the inactive ingredients microcrystalline cellulose, lactose monohydrate, povidone-K 30, and magnesium stearate. The capsule shell consists of titanium dioxide, sodium lauryl sulfate, and gelatin. The capsule is printed with edible ink containing black iron oxide." }

Meets USP dissolution test 2.

{ "type": "p", "children": [], "text": "Meets USP dissolution test 2." }

Ribavirin is an anti-HCV agent [see Microbiology (12.4)].  

Single- and multiple-dose pharmacokinetic properties in adults are summarized in Table 11. 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 to 1200 mg ribavirin. The relationship between dose and Cmax was curvilinear, tending to asymptote above single doses of 400 to 600 mg.

Upon multiple oral dosing, based on AUC12hr, a 6-fold accumulation of ribavirin was observed in plasma. Following oral dosing with 600 mg twice daily, steady-state was reached by approximately 4 weeks, with mean steady-state plasma concentrations of 2200 ng/mL (37%). Upon discontinuation of dosing, the mean half-life was 298 (30%) hours, which probably reflects slow elimination from nonplasma compartments.

Effect of Antacid on Absorption of Ribavirin: Coadministration of ribavirin capsules with an antacid containing magnesium, aluminum, and simethicone resulted in a 14% decrease in mean ribavirin AUCtf. The clinical relevance of results from this single-dose study is unknown.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 11: Mean (% CV) Pharmacokinetic Parameters for Ribavirin When Administered Individually to Adults</span> </caption> <colgroup> <col width="32.14%"/> <col width="21.96%"/> <col width="21.04%"/> <col width="24.86%"/> </colgroup> <tfoot> <tr class="First Last"> <td colspan="4"><span class="Sup">* </span>N=11.<br/> <span class="Sup">†  </span>Data obtained from a single-dose pharmacokinetic study using <span class="Sup">14</span>C labeled ribavirin; N=5. <br/> <span class="Sup">‡  </span>N=6.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" rowspan="2" valign="middle"><span class="Bold">Parameter</span> <br/> </td><td align="center" class="Rrule" colspan="3" valign="middle"><span class="Bold">Ribavirin</span><span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle"><span class="Bold">Single-Dose </span> <br/> <span class="Bold">600 mg </span> <br/> <span class="Bold">Oral Solution </span>(N=14)<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Single-Dose </span> <br/> <span class="Bold">600 mg Capsules</span> <br/>(N=12)<br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Multiple-Dose </span> <br/> <span class="Bold">600 mg</span> <br/> <span class="Bold">Capsules</span> <br/> <span class="Bold"> twice daily</span> <br/>(N=12)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">   T<span class="Sub">max</span> (hr) <br/> </td><td align="center" class="Rrule" valign="middle">1.00 (34)<br/> </td><td align="center" class="Rrule" valign="middle">1.7 (46)*<br/> </td><td align="center" class="Rrule" valign="middle">3 (60)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">   C<span class="Sub">max</span> (ng/mL) <br/> </td><td align="center" class="Rrule" valign="middle">872 (42)<br/> </td><td align="center" class="Rrule" valign="middle">782 (37)<br/> </td><td align="center" class="Rrule" valign="middle">3680 (85)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">   AUC<span class="Sub">tf</span> (ng·hr/mL)<br/> </td><td align="center" class="Rrule" valign="middle">14,098 (38)<br/> </td><td align="center" class="Rrule" valign="middle">13,400 (48)<br/> </td><td align="center" class="Rrule" valign="middle">228,000 (25)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">   T<span class="Sub">1/2</span> (hr) <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle">43.6 (47)<br/> </td><td align="center" class="Rrule" valign="middle">298 (30)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">   Apparent Volume of Distribution (L) <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle">2825 (9)<span class="Sup">†</span> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">   Apparent Clearance (L/hr) <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle">38.2 (40)<br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="middle">   Absolute Bioavailability <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle">64% (44)<span class="Sup">‡</span> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td> </tr> </tbody> </table></div>

Tissue Distribution:  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. Metabolism and Excretion:  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 14C-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. Special Populations: Renal Dysfunction The pharmacokinetics of ribavirin were assessed after administration of a single oral dose (400 mg) of ribavirin to non-HCV-infected 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 greater than 90 mL/min). In subjects with creatinine clearance values between 30 to 60 mL/min, AUCtf was twofold greater when compared to control subjects. The increased AUCtf appears to be due to reduction of renal and nonrenal clearance in these subjects. Phase 3 efficacy trials included subjects with creatinine clearance values greater than 50 mL/min. The multiple-dose pharmacokinetics of ribavirin cannot be accurately predicted in patients with renal dysfunction. Ribavirin is not effectively removed by hemodialysis. Patients with creatinine clearance less than 50 mL/min should not be treated with ribavirin [see Contraindications (4)]. Hepatic Dysfunction The effect of hepatic dysfunction was assessed after a single oral dose of ribavirin (600 mg). The mean AUCtf 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 Cmax values increased with severity of hepatic dysfunction and was twofold greater in subjects with severe hepatic dysfunction when compared to control subjects. Elderly Patients Pharmacokinetic evaluations in elderly subjects have not been performed. Gender There were no clinically significant pharmacokinetic differences noted in a single-dose trial of 18 male and 18 female subjects. Pediatric Patients Multiple-dose pharmacokinetic properties for ribavirin capsules and INTRON A in pediatric subjects with chronic hepatitis C between 5 and 16 years of age are summarized in Table 12. The pharmacokinetics of ribavirin and INTRON A (dose-normalized) are similar in adults and pediatric subjects. Complete pharmacokinetic characteristics of ribavirin oral solution have not been determined in pediatric subjects. Ribavirin Cmin values were similar following administration of ribavirin oral solution or ribavirin capsules during 48 weeks of therapy in pediatric subjects (3 to 16 years of age).

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 12: Mean (% CV) Multiple-dose Pharmacokinetic Parameters for INTRON A and Ribavirin Capsules When Administered to Pediatric Subjects with Chronic Hepatitis C</span> </caption> <colgroup> <col width="29.94%"/> <col width="35.04%"/> <col width="35.04%"/> </colgroup> <tfoot> <tr class="First Last"> <td colspan="3"><span class="Sup">* </span>AUC<span class="Sub">12</span> (ng·hr/mL) for ribavirin; AUC<span class="Sub">0</span><span class="Sub">-</span><span class="Sub">24</span> (IU·hr/mL) for INTRON A.<br/> <span class="Sup">† </span>ND=not done. </td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" valign="middle"><span class="Bold">Parameter</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Ribavirin</span> <br/> <span class="Bold"> 15 mg/kg/day </span> <br/> <span class="Bold">as 2 divided doses </span> <br/>(N=17)<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">INTRON A 3 MIU/m<span class="Sup">2</span></span> <br/> <span class="Bold">three times weekly </span> <br/>(N=54)<span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">   T<span class="Sub">max</span> (hr) <br/> </td><td align="center" class="Rrule" valign="middle">1.9 (83)<br/> </td><td align="center" class="Rrule" valign="middle">5.9 (36)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">   C<span class="Sub">max </span>(ng/mL) <br/> </td><td align="center" class="Rrule" valign="middle">3275 (25)<br/> </td><td align="center" class="Rrule" valign="middle">51 (48)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">   AUC* <br/> </td><td align="center" class="Rrule" valign="middle">29,774 (26)<br/> </td><td align="center" class="Rrule" valign="middle">622 (48)<br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="middle">   Apparent Clearance L/hr/kg <br/> </td><td align="center" class="Rrule" valign="middle">0.27 (27)<br/> </td><td align="center" class="Rrule" valign="middle">ND<span class="Sup">†</span> <br/> </td> </tr> </tbody> </table></div>

Note: numbers in parenthesis indicate % coefficient of variation.

A clinical trial in pediatric subjects with chronic hepatitis C between 3 and 17 years of age was conducted in which pharmacokinetics for PegIntron and ribavirin (capsules and oral solution) were evaluated. In pediatric subjects receiving body surface area-adjusted dosing of PegIntron at 60 mcg/m2/week, the log transformed ratio estimate of exposure during the dosing interval was predicted to be 58% [90% CI: 141%, 177%] higher than observed in adults receiving 1.5 mcg/kg/week. The pharmacokinetics of ribavirin (dose-normalized) in this trial were similar to those reported in a prior study of ribavirin in combination with INTRON A in pediatric subjects and in adults.

Effect of Food on Absorption of Ribavirin

Both AUCtf and Cmax increased by 70% when ribavirin 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 [see Dosage and Administration (2)].

Mechanism of Action

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

Antiviral Activity in Cell Culture

The antiviral activity of ribavirin in the HCV replicon is not well understood and has not been defined because of the cellular toxicity of ribavirin. Direct antiviral activity has been observed in cell culture of other RNA viruses. The anti-HCV activity of interferon was demonstrated in cell culture using self-replicating HCV RNA (HCV replicon cells) or HCV infection.

Resistance

HCV genotypes show wide variability in their response to pegylated recombinant human interferon/ribavirin therapy. Genetic changes associated with the variable response have not been identified.

Cross-resistance

There is no reported cross-resistance between pegylated/non-pegylated interferons and ribavirin.

Carcinogenesis

Ribavirin did not cause an increase in any tumor type when administered for 6 months in the transgenic p53 deficient mouse model at doses up to 300 mg/kg (estimated human equivalent of 25 mg/kg based on body surface area adjustment for a 60 kg adult; approximately 1.9 times the maximum recommended human daily dose). Ribavirin was noncarcinogenic when administered for 2 years to rats at doses up to 40 mg/kg (estimated human equivalent of 5.71 mg/kg based on body surface area adjustment for a 60 kg adult).

Mutagenesis

Ribavirin demonstrated increased incidences of mutation and cell transformation in multiple genotoxicity assays. Ribavirin was active in the Balb/3T3 In Vitro Cell Transformation Assay. Mutagenic activity was observed in the mouse lymphoma assay, and at doses of 20 to 200 mg/kg (estimated human equivalent of 1.67 to 16.7 mg/kg, based on body surface area adjustment for a 60 kg adult; 0.1 to 1 times the maximum recommended human 24-hour dose of ribavirin) in a mouse micronucleus assay. 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 studies in mice to evaluate the time course and reversibility of ribavirin-induced testicular degeneration at doses of 15 to 150 mg/kg/day (estimated human equivalent of 1.25 to 12.5 mg/kg/day, based on body surface area adjustment for a 60-kg adult; 0.1 to 0.8 times the maximum human 24-hour dose of ribavirin) administered for 3 or 6 months, abnormalities in sperm occurred. Upon cessation of treatment, recovery from ribavirin-induced testicular toxicity was mostly apparent within 1 or 2 spermatogenesis cycles.

Long-term studies in the mouse and rat [18 to 24 months; doses of 20 to 75 and 10 to 40 mg/kg/day, respectively (estimated human equivalent doses of 1.67 to 6.25 and 1.43 to 5.71 mg/kg/day, respectively, based on body surface area adjustment for a 60 kg adult; approximately 0.1 to 0.4 times the maximum human 24-hour dose of ribavirin)] have demonstrated a relationship between chronic ribavirin exposure and increased incidences of vascular lesions (microscopic hemorrhages) in mice. In rats, retinal degeneration occurred in controls, but the incidence was increased in ribavirin-treated rats.

Adult Subjects

Study 2 A randomized trial compared treatment with two PegIntron/ribavirin regimens [PegIntron 1.5 mcg/kg subcutaneously once weekly/ribavirin 800 mg orally daily (in divided doses); PegIntron 1.5 mcg/kg subcutaneously once weekly for 4 weeks then 0.5 mcg/kg subcutaneously once weekly for 44 weeks/ribavirin 1000 or 1200 mg orally daily (in divided doses)] with INTRON A [3 MIU subcutaneously three times weekly/ribavirin 1000 or 1200 mg orally daily (in divided doses)] in 1,530 adults with chronic hepatitis C. Interferon-naïve subjects were treated for 48 weeks and followed for 24 weeks post-treatment. Eligible subjects had compensated liver disease, detectable HCV-RNA, elevated ALT, and liver histopathology consistent with chronic hepatitis.

Response to treatment was defined as undetectable HCV-RNA at 24 weeks post-treatment (see Table 13). The response rate to the PegIntron 1.5 mcg/kg and ribavirin 800 mg dose was higher than the response rate to INTRON A/ribavirin (see Table 13). The response rate to PegIntron 1.5→0.5 mcg/kg/ribavirin was essentially the same as the response to INTRON A/ ribavirin (data not shown).

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 13: Rates of Response to Combination Treatment – Study 2</span> </caption> <colgroup> <col width="22.08%"/> <col width="38.96%"/> <col width="38.96%"/> </colgroup> <tfoot> <tr class="First Last"> <td colspan="3">* Serum HCV-RNA was measured with a research-based quantitative polymerase chain reaction assay by a central laboratory.<br/> <span class="Sup">†</span> Difference in overall treatment response (PegIntron/ribavirin vs. INTRON A/ribavirin) is 6% with 95% confidence interval of (0.18, 11.63) adjusted for viral genotype and presence of cirrhosis at baseline. Response to treatment was defined as undetectable HCV-RNA at 24 weeks post-treatment.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" valign="top"> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold"> PegIntron</span><span class="Bold"></span><span class="Bold"> 1.5 </span><span class="Bold"> mcg/kg</span><span class="Bold"></span><span class="Bold"> once</span><span class="Bold"></span><span class="Bold"> weekly</span><span class="Bold"></span><span class="Bold"> Ribavirin</span><span class="Bold"> 800 </span><span class="Bold">mg once daily</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold"> INTRON </span><span class="Bold">A 3 MIU three times weekly Ribavirin 1000/1200 mg once daily</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">    Overall response*,<span class="Sup">†</span> <br/> </td><td align="center" class="Rrule" valign="top"> <br/>52% (264/511)</td><td align="center" class="Rrule" valign="top">46% (231/505)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">   Genotype 1<br/> </td><td align="center" class="Rrule" valign="top"> <br/>41% (141/348)</td><td align="center" class="Rrule" valign="top">33% (112/343)<br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="top">   Genotype 2 to 6<br/> </td><td align="center" class="Rrule" valign="top"> <br/>75% (123/163)</td><td align="center" class="Rrule" valign="top">73% (119/162)<br/> </td> </tr> </tbody> </table></div>

Subjects with viral genotype 1, regardless of viral load, had a lower response rate to PegIntron (1.5 mcg/kg)/ribavirin (800 mg) compared to subjects with other viral genotypes. Subjects with both poor prognostic factors (genotype 1 and high viral load) had a response rate of 30% (78/256) compared to a response rate of 29% (71/247) with INTRON A/ ribavirin combination therapy.

Subjects with lower body weight tended to have higher adverse-reaction rates [see Adverse Reactions (6.1)] and higher response rates than subjects with higher body weights. Differences in response rates between treatment arms did not substantially vary with body weight.

Treatment response rates with PegIntron/ribavirin combination therapy were 49% in men and 56% in women. Response rates were lower in African American and Hispanic subjects and higher in Asians compared to Caucasians. Although African Americans had a higher proportion of poor prognostic factors compared to Caucasians, the number of non-Caucasians studied (11% of the total) was insufficient to allow meaningful conclusions about differences in response rates after adjusting for prognostic factors in this trial.

Liver biopsies were obtained before and after treatment in 68% of subjects. Compared to baseline, approximately two-thirds of subjects in all treatment groups were observed to have a modest reduction in inflammation.

Study 3 In a large United States community-based trial, 4,913 subjects with chronic hepatitis C were randomized to receive PegIntron 1.5 mcg/kg subcutaneously once weekly in combination with a ribavirin dose of 800 to 1400 mg (weight-based dosing [WBD]) or 800 mg (flat) orally daily (in divided doses) for 24 or 48 weeks based on genotype. Response to treatment was defined as undetectable HCV-RNA (based on an assay with a lower limit of detection of 125 IU/mL) at 24 weeks post-treatment.

Treatment with PegIntron 1.5 mcg/kg and ribavirin 800 to 1400 mg resulted in a higher sustained virologic response compared to PegIntron in combination with a flat 800 mg daily dose of ribavirin. Subjects weighing greater than 105 kg obtained the greatest benefit with WBD, although a modest benefit was also observed in subjects weighing greater than 85 to 105 kg (see Table 14). The benefit of WBD in subjects weighing greater than 85 kg was observed with HCV genotypes 1 to 3. Insufficient data were available to reach conclusions regarding other genotypes. Use of WBD resulted in an increased incidence of anemia [see Adverse Reactions (6.1)].

Table 14: SVR Rate by Treatment and Baseline Weight - Study 3

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <colgroup> <col width="21.18%"/> <col width="19.7%"/> <col width="19.7%"/> <col width="19.7%"/> <col width="19.72%"/> </colgroup> <tfoot> <tr class="First Last"> <td align="justify" colspan="5">* <span class="Italics">P</span>=0.01, primary efficacy comparison (based on data from subjects weighing 65 kg or higher at baseline and utilizing a logistic regression analysis that includes treatment [WBD or Flat], genotype and presence/absence of advanced fibrosis, in the model).<br/> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" rowspan="2" valign="top"><span class="Bold">Treatment</span><span class="Bold"> Group</span> <br/> </td><td align="center" class="Rrule" colspan="4" valign="top"><span class="Bold">Subject B</span><span class="Bold">aseline Weight</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle"><span class="Bold">&lt;65</span><span class="Bold"> kg</span> <br/> <span class="Bold">(&lt;143</span><span class="Bold"> lb)</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">65 to 85</span><span class="Bold"> kg</span> <br/> <span class="Bold">(143 to 188</span><span class="Bold"> lb)</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">&gt;85 to 105</span><span class="Bold"> kg</span> <br/> <span class="Bold">(&gt;188 to 231</span><span class="Bold"> lb)</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">&gt;105</span><span class="Bold"> kg</span> <br/> <span class="Bold">(&gt;231</span><span class="Bold"> lb)</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">   WBD*<br/> </td><td align="center" class="Rrule" valign="top"> <br/>50% (173/348)</td><td align="center" class="Rrule" valign="top"> <br/>45% (449/994)</td><td align="center" class="Rrule" valign="top"> <br/>42% (351/835)</td><td align="center" class="Rrule" valign="top"> <br/>47% (138/292)</td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="top">   Flat<br/> </td><td align="center" class="Rrule" valign="top"> <br/>51% (173/342)</td><td align="center" class="Rrule" valign="top"> <br/>44% (443/1011)</td><td align="center" class="Rrule" valign="top"> <br/>39% (318/819)</td><td align="center" class="Rrule" valign="top"> <br/>33% (91/272)</td> </tr> </tbody> </table></div>

A total of 1,552 subjects weighing greater than 65 kg in Study 3 had genotype 2 or 3 and were randomized to 24 or 48 weeks of therapy. No additional benefit was observed with the longer treatment duration.

Study 4 A large randomized trial compared the safety and efficacy of treatment for 48 weeks with two PegIntron/ribavirin regimens [PegIntron 1.5 mcg/kg and 1 mcg/kg subcutaneously once weekly both in combination with ribavirin 800 to 1400 mg PO daily (in two divided doses)] and Pegasys 180 mcg subcutaneously once weekly in combination with Copegus 1000 to 1200 mg PO daily (in two divided doses) in 3,070 treatment-naïve adults with chronic hepatitis C genotype 1. In this trial, lack of early virologic response (undetectable HCV-RNA or greater than or equal to 2 log10 reduction from baseline) by treatment Week 12 was the criterion for discontinuation of treatment. SVR was defined as undetectable HCV-RNA (Roche COBAS TaqMan assay, a lower limit of quantitation of 27 IU/mL) at 24 weeks post-treatment (see Table 15).

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 15: SVR Rate by Treatment – Study 4</span> </caption> <colgroup> <col width="36.28%"/> <col width="34.2%"/> <col width="29.52%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" colspan="3" valign="middle"><span class="Bold">% (number) of Subjects</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle"><span class="Bold">PegIntron</span> <br/> <span class="Bold">1.5 </span><span class="Bold">mcg/kg/</span><span class="Bold">Ribavirin</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">PegIntron</span> <br/> <span class="Bold">1 mcg/kg/</span><span class="Bold">Ribavirin</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Pegasys</span> <br/> <span class="Bold">180</span><span class="Bold"> mcg/Copegus</span> <br/> </td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule" valign="middle">40 (406/1019)<br/> </td><td align="center" class="Rrule" valign="middle">38 (386/1016)<br/> </td><td align="center" class="Rrule" valign="middle">41 (423/1035)<br/> </td> </tr> </tbody> </table></div>

Overall SVR rates were similar among the three treatment groups. Regardless of treatment group, SVR rates were lower in subjects with poor prognostic factors. Subjects with poor prognostic factors randomized to PegIntron (1.5 mcg/kg)/ribavirin or Pegasys/Copegus, however, achieved higher SVR rates compared to similar subjects randomized to PegIntron 1 mcg/kg/ribavirin. For the PegIntron 1.5 mcg/kg and ribavirin dose, SVR rates for subjects with and without the following prognostic factors were as follows: cirrhosis (10% vs. 42%), normal ALT levels (32% vs. 42%), baseline viral load greater than 600,000 IU/mL (35% vs. 61%), 40 years of age and older (38% vs. 50%), and African American race (23% vs. 44%). In subjects with undetectable HCV-RNA at treatment Week 12 who received PegIntron (1.5 mcg/kg)/ribavirin, the SVR rate was 81% (328/407).

Study 5 - Ribavirin/PegIntron Combination Therapy in Prior Treatment Failures In a noncomparative trial, 2,293 subjects with moderate to severe fibrosis who failed previous treatment with combination alpha interferon/ribavirin were re-treated with PegIntron, 1.5 mcg/kg subcutaneously, once weekly, in combination with weight adjusted ribavirin. Eligible subjects included prior nonresponders (subjects who were HCV-RNA positive at the end of a minimum 12 weeks of treatment) and prior relapsers (subjects who were HCV-RNA negative at the end of a minimum 12 weeks of treatment and subsequently relapsed after post-treatment follow-up). Subjects who were negative at Week 12 were treated for 48 weeks and followed for 24 weeks post-treatment. Response to treatment was defined as undetectable HCV-RNA at 24 weeks post-treatment (measured using a research-based test, limit of detection 125 IU/mL). The overall response rate was 22% (497/2293) (99% CI: 19.5, 23.9). Subjects with the following characteristics were less likely to benefit from re-treatment: previous nonresponse, previous pegylated interferon treatment, significant bridging fibrosis or cirrhosis, and genotype 1 infection. The re-treatment sustained virologic response rates by baseline characteristics are summarized in Table 16.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 16: SVR Rates by Baseline Characteristics of Prior Treatment Failures - Study 5</span> </caption> <colgroup> <col width="14.18%"/> <col width="20.5%"/> <col width="22.42%"/> <col width="18.48%"/> <col width="24.42%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" rowspan="3" valign="middle"><span class="Bold">HCV</span> <br/> <span class="Bold">Genotype/</span><span class="Bold"></span><span class="Bold">Metavir </span><span class="Bold">Fibrosis </span><span class="Bold">Score</span> <br/> </td><td align="center" class="Rrule" colspan="4" valign="middle"> <br/> <span class="Bold">Overall </span><span class="Bold">SVR by Previous Response and Treatment</span></td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" colspan="2" valign="middle"><span class="Bold">Nonresponder</span> <br/> </td><td align="center" class="Rrule" colspan="2" valign="middle"><span class="Bold">Relapser</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle"><span class="Bold">interferon </span><span class="Bold">alfa/ribavirin</span> <br/> <span class="Bold">% (number of subjects)</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">peginterferon </span><span class="Bold">(2a a</span><span class="Bold">nd 2b combined)/ribavirin</span> <br/> <span class="Bold">% (number of subjects)</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">interferon </span><span class="Bold">alfa/ribavirin</span> <br/> <span class="Bold">% (number of subjects)</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">peginterferon </span><span class="Bold">(2a a</span><span class="Bold">nd 2b combined)/ribavirin</span> <br/> <span class="Bold">% (number of subjects)</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Overall<br/> </td><td class="Rrule" valign="middle">18 (158/903)<br/> </td><td class="Rrule" valign="middle">6 (30/476)<br/> </td><td class="Rrule" valign="middle">43 (130/300)<br/> </td><td class="Rrule" valign="middle">35 (113/344)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">HCV 1<br/> </td><td class="Rrule" valign="middle">13 (98/761)<br/> </td><td class="Rrule" valign="middle">4 (19/431)<br/> </td><td class="Rrule" valign="middle">32 (67/208)<br/> </td><td class="Rrule" valign="middle">23 (56/243)<br/> </td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule" valign="middle">F2<br/> </td><td align="right" class="Rrule" valign="middle">18 (36/202)<br/> </td><td align="right" class="Rrule" valign="middle">6 (7/117)<br/> </td><td align="right" class="Rrule" valign="middle">42 (33/79)<br/> </td><td align="right" class="Rrule" valign="middle">32 (23/72)<br/> </td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule" valign="middle">F3<br/> </td><td align="right" class="Rrule" valign="middle">16 (38/233)<br/> </td><td align="right" class="Rrule" valign="middle">4 (4/112)<br/> </td><td align="right" class="Rrule" valign="middle">28 (16/58)<br/> </td><td align="right" class="Rrule" valign="middle">21 (14/67)<br/> </td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule" valign="middle">F4<br/> </td><td align="right" class="Rrule" valign="middle">7 (24/325)<br/> </td><td align="right" class="Rrule" valign="middle">4 (8/202)<br/> </td><td align="right" class="Rrule" valign="middle">26 (18/70)<br/> </td><td align="right" class="Rrule" valign="middle">18 (19/104)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">HCV 2/3<br/> </td><td class="Rrule" valign="middle">49 (53/109)<br/> </td><td class="Rrule" valign="middle">36 (10/28)<br/> </td><td class="Rrule" valign="middle">67 (54/81)<br/> </td><td class="Rrule" valign="middle">57 (52/92)<br/> </td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule" valign="middle">F2<br/> </td><td align="right" class="Rrule" valign="middle">68 (23/34)<br/> </td><td align="right" class="Rrule" valign="middle">56 (5/9)<br/> </td><td align="right" class="Rrule" valign="middle">76 (19/25)<br/> </td><td align="right" class="Rrule" valign="middle">61 (11/18)<br/> </td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule" valign="middle">F3<br/> </td><td align="right" class="Rrule" valign="middle">39 (11/28)<br/> </td><td align="right" class="Rrule" valign="middle">38 (3/8)<br/> </td><td align="right" class="Rrule" valign="middle">67 (18/27)<br/> </td><td align="right" class="Rrule" valign="middle">62 (18/29)<br/> </td> </tr> <tr class="Botrule"> <td align="right" class="Lrule Rrule" valign="middle">F4<br/> </td><td align="right" class="Rrule" valign="middle">40 (19/47)<br/> </td><td align="right" class="Rrule" valign="middle">18 (2/11)<br/> </td><td align="right" class="Rrule" valign="middle">59 (17/29)<br/> </td><td align="right" class="Rrule" valign="middle">51 (23/45)<br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="middle">HCV 4<br/> </td><td class="Rrule" valign="middle">17 (5/29)<br/> </td><td class="Rrule" valign="middle">7 (1/15)<br/> </td><td class="Rrule" valign="middle">88 (7/8)<br/> </td><td class="Rrule" valign="middle">50 (4/8)<br/> </td> </tr> </tbody> </table></div>

Achievement of an undetectable HCV-RNA at treatment Week 12 was a strong predictor of SVR. In this trial, 1,470 (64%) subjects did not achieve an undetectable HCV-RNA at treatment Week 12, and were offered enrollment into long-term treatment trials, due to an inadequate treatment response. Of the 823 (36%) subjects who were HCV-RNA undetectable at treatment Week 12, those infected with genotype 1 had an SVR of 48% (245/507), with a range of responses by fibrosis scores (F4-F2) of 39 to 55%. Subjects infected with genotype 2/3 who were HCV-RNA undetectable at treatment Week 12 had an overall SVR of 70% (196/281), with a range of responses by fibrosis scores (F4-F2) of 60 to 83%. For all genotypes, higher fibrosis scores were associated with a decreased likelihood of achieving SVR.

Pediatric Subjects

Previously untreated pediatric subjects 3 to 17 years of age with compensated chronic hepatitis C and detectable HCV-RNA were treated with ribavirin 15 mg/kg per day and PegIntron 60 mcg/m2 once weekly for 24 or 48 weeks based on HCV genotype and baseline viral load. All subjects were to be followed for 24 weeks post-treatment. A total of 107 subjects received treatment, of which 52% were female, 89% were Caucasian, and 67% were infected with HCV Genotype 1. Subjects infected with Genotypes 1, 4 or Genotype 3 with HCV-RNA greater than or equal to 600,000 IU/mL received 48 weeks of therapy while those infected with Genotype 2 or Genotype 3 with HCV-RNA less than 600,000 IU/mL received 24 weeks of therapy. The trial results are summarized in Table 17.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 17: Sustained Virologic Response Rates by Genotype and Assigned Treatment Duration – Pediatric Trial</span> </caption> <colgroup> <col width="20.38%"/> <col width="35.82%"/> <col width="43.8%"/> </colgroup> <tfoot> <tr class="First Last"> <td colspan="3"><span class="Sup">*</span> Response to treatment was defined as undetectable HCV-RNA at 24 weeks post-treatment.<br/> <span class="Sup">†</span> N=number of responders/number of subjects with given genotype and assigned treatment duration. <br/> <span class="Sup">‡</span> Subjects with genotype 3 low viral load (less than 600,000 IU/mL) were to receive 24 weeks of treatment while those with genotype 3 and high viral load were to receive 48 weeks of treatment.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" rowspan="3" valign="top"><span class="Bold"> <br/>                    Genotype</span></td><td align="center" class="Rrule" colspan="2" valign="middle"><span class="Bold">All </span><span class="Bold">Subjects</span><span class="Bold"></span> <br/> <span class="Bold">N=107</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle"><span class="Bold">24 </span><span class="Bold">Weeks</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">48 </span><span class="Bold">Weeks</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle"><span class="Bold">Virologic</span><span class="Bold"> Response </span> <br/> <span class="Bold">N<span class="Sup">*,†</span></span><span class="Bold"> </span><span class="Bold">(%)</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Virologic</span><span class="Bold"> Response </span> <br/> <span class="Bold">N<span class="Sup">*,†</span></span><span class="Bold"> </span><span class="Bold">(%)</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/>All  <br/> </td><td align="center" class="Rrule" valign="middle">26/27 (96.3)<br/> </td><td align="center" class="Rrule" valign="middle">44/80 (55.0)<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/>1</td><td align="center" class="Rrule" valign="middle">-<br/> </td><td align="center" class="Rrule" valign="middle">38/72 (52.8)<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/>2</td><td align="center" class="Rrule" valign="middle">14/15 (93.3)<br/> </td><td align="center" class="Rrule" valign="middle">-<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"> <br/>3<span class="Sup">‡</span></td><td align="center" class="Rrule" valign="middle">12/12 (100)<br/> </td><td align="center" class="Rrule" valign="middle">2/3 (66.7)<br/> </td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule" valign="top"> <br/>4</td><td align="center" class="Rrule" valign="middle">-<br/> </td><td align="center" class="Rrule" valign="middle">4/5 (80.0)<br/> </td> </tr> </tbody> </table></div>

Adult Subjects

Previously Untreated Subjects

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 (U.S. and international) and randomized to receive ribavirin capsules 1200 mg/day (1000 mg/day for subjects weighing less than or equal to 75 kg) and INTRON A 3 MIU three times weekly or INTRON A and placebo for 24 or 48 weeks followed by 24 weeks of off-therapy follow-up. The international trial did not contain a 24-week INTRON A and placebo treatment arm. The U.S. trial enrolled 912 subjects 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 trial, conducted in Europe, Israel, Canada, and Australia, enrolled 799 subjects (65% male, 95% Caucasian, mean Knodell score 6.8, and 58% genotype 1).

Trial results are summarized in Table 18.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 18: Virologic and Histologic Responses: Previously Untreated Subjects<span class="Sup">*</span></span> </caption> <colgroup> <col width="16.3%"/> <col width="11.94%"/> <col width="11.96%"/> <col width="11.94%"/> <col width="11.98%"/> <col width="12%"/> <col width="11.94%"/> <col width="11.96%"/> </colgroup> <tfoot> <tr class="First Last"> <td align="justify" colspan="8">* Number (%) of subjects. <br/> <span class="Sup">†</span><span class="Sup"></span>Defined as HCV-RNA below limit of detection using a research-based RT-PCR assay at end of treatment and during follow-up period. <br/> <span class="Sup">‡</span><span class="Sup"></span>Defined as post-treatment (end of follow-up) minus pretreatment liver biopsy Knodell HAI score (I+II+III) improvement of greater than or equal to 2 points.<br/> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" rowspan="3" valign="top"> <br/> </td><td align="center" class="Rrule" colspan="4" valign="middle"><span class="Bold">U.S. Trial</span> <br/> </td><td align="center" class="Rrule" colspan="3" valign="middle"><span class="Bold">International Trial</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" colspan="2" valign="middle"><span class="Bold">24 weeks of treatment</span> <br/> </td><td align="center" class="Rrule" colspan="2" valign="middle"><span class="Bold">48 weeks of treatment</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">24 weeks of treatment</span> <br/> </td><td align="center" class="Rrule" colspan="2" valign="middle"><span class="Bold">48 weeks of treatment</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle"><span class="Bold">INTRON A/Ribavirin<span class="Sup"></span></span>(N=228)<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">INTRON A/Placebo </span>(N=231)<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">INTRON A/Ribavirin </span>(N=228)<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">INTRON A/Placebo </span>(N=225)<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">INTRON A/Ribavirin </span>(N=265)<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">INTRON A/Ribavirin </span>(N=268)<span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">INTRON A/Placebo </span>(N=266)<span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="8" valign="middle"><span class="Bold">Virologic </span> <br/> <span class="Bold">Response</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    Responder<span class="Sup">†</span> <br/> </td><td align="center" class="Rrule" valign="middle">65 (29)<br/> </td><td align="center" class="Rrule" valign="middle">13 (6)<br/> </td><td align="center" class="Rrule" valign="middle">85 (37)<br/> </td><td align="center" class="Rrule" valign="middle">27 (12)<br/> </td><td align="center" class="Rrule" valign="middle">86 (32)<br/> </td><td align="center" class="Rrule" valign="middle">113 (42)<br/> </td><td align="center" class="Rrule" valign="middle">46 (17)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    Nonresponder <br/> </td><td align="center" class="Rrule" valign="middle">147 (64)<br/> </td><td align="center" class="Rrule" valign="middle">194 (84)<br/> </td><td align="center" class="Rrule" valign="middle">110 (48)<br/> </td><td align="center" class="Rrule" valign="middle">168 (75)<br/> </td><td align="center" class="Rrule" valign="middle">158 (60)<br/> </td><td align="center" class="Rrule" valign="middle">120 (45)<br/> </td><td align="center" class="Rrule" valign="middle">196 (74)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    Missing Data <br/> </td><td align="center" class="Rrule" valign="middle">16 (7)<br/> </td><td align="center" class="Rrule" valign="middle">24 (10)<br/> </td><td align="center" class="Rrule" valign="middle">33 (14)<br/> </td><td align="center" class="Rrule" valign="middle">30 (13)<br/> </td><td align="center" class="Rrule" valign="middle">21 (8)<br/> </td><td align="center" class="Rrule" valign="middle">35 (13)<br/> </td><td align="center" class="Rrule" valign="middle">24 (9)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="8" valign="middle"><span class="Bold">Histologic</span> <br/> <span class="Bold"> Response </span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    Improvement<span class="Sup">‡</span> <br/> </td><td align="center" class="Rrule" valign="middle">102 (45)<br/> </td><td align="center" class="Rrule" valign="middle">77 (33)<br/> </td><td align="center" class="Rrule" valign="middle">96 (42)<br/> </td><td align="center" class="Rrule" valign="middle">65 (29)<br/> </td><td align="center" class="Rrule" valign="middle">103 (39)<br/> </td><td align="center" class="Rrule" valign="middle">102 (38)<br/> </td><td align="center" class="Rrule" valign="middle">69 (26)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    No improvement <br/> </td><td align="center" class="Rrule" valign="middle">77 (34)<br/> </td><td align="center" class="Rrule" valign="middle">99 (43)<br/> </td><td align="center" class="Rrule" valign="middle">61 (27)<br/> </td><td align="center" class="Rrule" valign="middle">93 (41)<br/> </td><td align="center" class="Rrule" valign="middle">85 (32)<br/> </td><td align="center" class="Rrule" valign="middle">58 (22)<br/> </td><td align="center" class="Rrule" valign="middle">111 (41)<br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="middle">    Missing Data <br/> </td><td align="center" class="Rrule" valign="middle">49 (21)<br/> </td><td align="center" class="Rrule" valign="middle">55 (24)<br/> </td><td align="center" class="Rrule" valign="middle">71 (31)<br/> </td><td align="center" class="Rrule" valign="middle">67 (30)<br/> </td><td align="center" class="Rrule" valign="middle">77 (29)<br/> </td><td align="center" class="Rrule" valign="middle">108 (40)<br/> </td><td align="center" class="Rrule" valign="middle">86 (32)<br/> </td> </tr> </tbody> </table></div>

Of subjects who had not achieved HCV-RNA below the limit of detection of the research-based assay by Week 24 of ribavirin/INTRON A treatment, less than 5% responded to an additional 24 weeks of combination treatment.

Among subjects with HCV Genotype 1 treated with ribavirin/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 subjects with HCV non-genotype 1 randomized to ribavirin/INTRON A therapy for 48 weeks compared to 24 weeks.

Relapse Subjects

Subjects 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 (U.S. and international) and randomized to receive ribavirin 1200 mg/day (1000 mg/day for subjects weighing ≤75 kg) and INTRON A 3 MIU three times weekly or INTRON A and placebo for 24 weeks followed by 24 weeks of off-therapy follow-up. The U.S. trial enrolled 153 subjects 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 trial, conducted in Europe, Israel, Canada, and Australia, enrolled 192 subjects (64% male, 95% Caucasian, mean Knodell score 6.6, and 56% genotype 1). Trial results are summarized in Table 19.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 19: Virologic and Histologic Responses: Relapse Subjects* </span> </caption> <colgroup> <col width="23.62%"/> <col width="18.32%"/> <col width="19.34%"/> <col width="19.34%"/> <col width="19.34%"/> </colgroup> <tfoot> <tr class="First Last"> <td align="justify" colspan="5"><span class="Sup">*</span> Number (%) of subjects. <br/> <span class="Sup">† </span>Defined as HCV-RNA below limit of detection using a research-based RT-PCR assay at end of treatment and during follow-up period. <br/> <span class="Sup">‡</span><span class="Sup"></span>Defined as post-treatment (end of follow-up) minus pretreatment liver biopsy Knodell HAI score (I+II+III) improvement of greater than or equal to 2 points.<br/> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td align="justify" class="Lrule Rrule" rowspan="2" valign="top"></td><td align="center" class="Rrule" colspan="2" valign="middle"><span class="Bold">U.S. Trial</span> <br/> </td><td align="center" class="Rrule" colspan="2" valign="middle"><span class="Bold">International Trial</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle"><span class="Bold">INTRON A/<br/> </span><span class="Bold">Ribavirin </span><span class="Bold"></span> <br/>(N=77)<br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">INTRON A/<br/> Placebo</span> <br/>(N=76)<br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">INTRON A/<br/> </span><span class="Bold">Ribavirin</span><span class="Bold"></span> <br/>(N=96)<br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">INTRON A/<br/> Placebo</span> <br/>(N=96)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="5" valign="middle"><span class="Bold">Virologic Response</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    Responder<span class="Sup">†</span> <br/> </td><td align="center" class="Rrule" valign="middle">33 (43)<br/> </td><td align="center" class="Rrule" valign="middle">3 (4)<br/> </td><td align="center" class="Rrule" valign="middle">46 (48)<br/> </td><td align="center" class="Rrule" valign="middle">5 (5)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    Nonresponder <br/> </td><td align="center" class="Rrule" valign="middle">36 (47)<br/> </td><td align="center" class="Rrule" valign="middle">66 (87)<br/> </td><td align="center" class="Rrule" valign="middle">45 (47)<br/> </td><td align="center" class="Rrule" valign="middle">91 (95)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    Missing Data <br/> </td><td align="center" class="Rrule" valign="middle">8 (10)<br/> </td><td align="center" class="Rrule" valign="middle">7 (9)<br/> </td><td align="center" class="Rrule" valign="middle">5 (5)<br/> </td><td align="center" class="Rrule" valign="middle">0 (0)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="5" valign="middle"><span class="Bold">Histologic Response </span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    Improvement<span class="Sup">‡</span> <br/> </td><td align="center" class="Rrule" valign="middle">38 (49)<br/> </td><td align="center" class="Rrule" valign="middle">27 (36)<br/> </td><td align="center" class="Rrule" valign="middle">49 (51)<br/> </td><td align="center" class="Rrule" valign="middle">30 (31)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    No improvement <br/> </td><td align="center" class="Rrule" valign="middle">23 (30)<br/> </td><td align="center" class="Rrule" valign="middle">37 (49)<br/> </td><td align="center" class="Rrule" valign="middle">29 (30)<br/> </td><td align="center" class="Rrule" valign="middle">44 (46)<br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="middle">    Missing Data <br/> </td><td align="center" class="Rrule" valign="middle">16 (21)<br/> </td><td align="center" class="Rrule" valign="middle">12 (16)<br/> </td><td align="center" class="Rrule" valign="middle">18 (19)<br/> </td><td align="center" class="Rrule" valign="middle">22 (23)<br/> </td> </tr> </tbody> </table></div>

Virologic and histologic responses were similar among male and female subjects in both the previously untreated and relapse trials.

Pediatric Subjects

Pediatric subjects 3 to 16 years of age with compensated chronic hepatitis C and detectable HCV-RNA (assessed by a central laboratory using a research-based RT-PCR assay) were treated with ribavirin 15 mg/kg per day and INTRON A 3 MIU/m2 three times weekly for 48 weeks followed by 24 weeks of off-therapy follow-up. A total of 118 subjects received treatment, of which 57% were male, 80% Caucasian, and 78% genotype 1. Subjects less than 5 years of age received ribavirin oral solution and those 5 years of age or older received either ribavirin oral solution or capsules.

Trial results are summarized in Table 20.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 20: Virologic Response: Previously Untreated Pediatric Subjects* </span> </caption> <colgroup> <col width="50%"/> <col width="50%"/> </colgroup> <tfoot> <tr class="First Last"> <td colspan="2"><span class="Sup">*</span> Number (%) of subjects.<br/> <span class="Sup">†  </span>Defined as HCV-RNA below limit of detection using a research-based RT-PCR assay at end of treatment and during follow-up period.<br/> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" valign="top"> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">INTRON A 3 MIU/m<span class="Sup">2</span> three times weekly/</span><span class="Bold">Ribavirin </span><span class="Bold"> 15 mg/kg/day</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">   Overall Response<span class="Sup">†</span> (N=118) <br/> </td><td align="center" class="Rrule" valign="middle">54 (46)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">   Genotype 1 (N=92) <br/> </td><td align="center" class="Rrule" valign="middle">33 (36)<br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="middle">   Genotype non-1 (N=26) <br/> </td><td align="center" class="Rrule" valign="middle">21 (81)<br/> </td> </tr> </tbody> </table></div>

Subjects with viral genotype 1, regardless of viral load, had a lower response rate to INTRON A/ribavirin combination therapy compared to subjects with genotype non-1, 36% vs. 81%. Subjects with both poor prognostic factors (genotype 1 and high viral load) had a response rate of 26% (13/50).

Ribavirin Capsules USP, 200 mg are white/white, size ‘1’ hard gelatin capsule filled with white to off-white granular powder and imprinted with ‘E’ on white cap and ‘81’ on white body with black ink.

{ "type": "p", "children": [], "text": "\nRibavirin Capsules USP, 200 mg are white/white, size ‘1’ hard gelatin capsule filled with white to off-white granular powder and imprinted with ‘E’ on white cap and ‘81’ on white body with black ink." }

            Bottles of 42                            NDC 65862-290-42            Bottles of 56                            NDC 65862-290-56            Bottles of 70                            NDC 65862-290-70            Bottles of 84                            NDC 65862-290-84            Bottles of 180                          NDC 65862-290-18            Bottles of 500                          NDC 65862-290-05 

{ "type": "p", "children": [], "text": "            Bottles of 42                            NDC 65862-290-42            Bottles of 56                            NDC 65862-290-56            Bottles of 70                            NDC 65862-290-70            Bottles of 84                            NDC 65862-290-84            Bottles of 180                          NDC 65862-290-18            Bottles of 500                          NDC 65862-290-05 " }

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

{ "type": "p", "children": [], "text": "\nStore at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]." }

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

{ "type": "p", "children": [], "text": "Advise the patient to read the FDA-approved patient labeling (Medication Guide)." }

Anemia

{ "type": "p", "children": [], "text": "\nAnemia\n" }

The most common adverse experience occurring with ribavirin capsules is anemia, which may be severe [see Warnings and Precautions (5.2) and Adverse Reactions (6)]. Advise patients that laboratory evaluations are required prior to starting therapy and periodically thereafter [see Dosage and Administration (2.4)]. Advise patients to be well hydrated, especially during the initial stages of treatment.

{ "type": "p", "children": [], "text": "The most common adverse experience occurring with ribavirin capsules is anemia, which may be severe [see Warnings and Precautions (5.2) and Adverse Reactions (6)]. Advise patients that laboratory evaluations are required prior to starting therapy and periodically thereafter [see Dosage and Administration (2.4)]. Advise patients to be well hydrated, especially during the initial stages of treatment." }

Embryo-Fetal Toxicity

{ "type": "p", "children": [], "text": "\nEmbryo-Fetal Toxicity\n" }

Inform females of reproductive potential and pregnant women that ribavirin capsules may cause birth defects, miscarriage, and stillbirth. Advise females of reproductive potential that they must have a pregnancy test prior to initiating treatment and periodically during therapy. Advise female patients of reproductive potential to use effective contraception during treatment with ribavirin and for 9 months post therapy and male patients with female partners of reproductive potential to use effective contraception during treatment with ribavirin and for 6 months post therapy. Advise patients to notify the physician immediately in the event of a pregnancy [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.3)].

{ "type": "p", "children": [], "text": "Inform females of reproductive potential and pregnant women that ribavirin capsules may cause birth defects, miscarriage, and stillbirth. Advise females of reproductive potential that they must have a pregnancy test prior to initiating treatment and periodically during therapy. Advise female patients of reproductive potential to use effective contraception during treatment with ribavirin and for 9 months post therapy and male patients with female partners of reproductive potential to use effective contraception during treatment with ribavirin and for 6 months post therapy. Advise patients to notify the physician immediately in the event of a pregnancy [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.3)].\n" }

Missed Dose

{ "type": "p", "children": [], "text": "\nMissed Dose\n" }

Inform patients that in the event a dose is missed, the missed dose should be taken as soon as possible during the same day. Patients should not double the next dose. Advise patients to contact their healthcare provider if they have questions.  

{ "type": "p", "children": [], "text": "Inform patients that in the event a dose is missed, the missed dose should be taken as soon as possible during the same day. Patients should not double the next dose. Advise patients to contact their healthcare provider if they have questions.   " }

Dental and Periodontal Disorders

{ "type": "p", "children": [], "text": "\nDental and Periodontal Disorders\n" }

Advise patients to brush their teeth thoroughly twice daily and have regular dental examinations. If vomiting occurs, advise patients to rinse out their mouth thoroughly afterwards [see Warnings and Precautions (5.7)].

{ "type": "p", "children": [], "text": "Advise patients to brush their teeth thoroughly twice daily and have regular dental examinations. If vomiting occurs, advise patients to rinse out their mouth thoroughly afterwards [see Warnings and Precautions (5.7)]." }

The brands listed are trademarks of their respective owners and are not trademarks of Aurobindo Pharma Limited. Dispense with Medication Guide available at: www.aurobindousa.com/medication-guides Distributed by: Aurobindo Pharma USA, Inc. 279 Princeton-Hightstown Road East Windsor, NJ 08520 Manufactured by: Aurobindo Pharma Limited Hyderabad-500 032, India Revised: 07/2023 Dispense with Medication Guide available at: www.aurobindousa.com/medication-guides

{ "type": "p", "children": [], "text": "The brands listed are trademarks of their respective owners and are not trademarks of Aurobindo Pharma Limited.\n\n Dispense with Medication Guide available at: www.aurobindousa.com/medication-guides\n\n Distributed by:\nAurobindo Pharma USA, Inc.\n279 Princeton-Hightstown Road East Windsor, NJ 08520\n Manufactured by:\nAurobindo Pharma Limited\nHyderabad-500 032, India\n Revised: 07/2023\n\n Dispense with Medication Guide available at: www.aurobindousa.com/medication-guides\n" }

Ribavirin (rye” ba vye’ rin) Capsules

{ "type": "p", "children": [], "text": "\nRibavirin (rye” ba vye’ rin) Capsules\n" }

What is the most important information I should know about ribavirin capsules? 1. Ribavirin capsules may cause birth defects, miscarriage or death of your unborn baby. Do not take ribavirin capsules if you or your sexual partner is pregnant or plan to become pregnant.

{ "type": "p", "children": [], "text": "\nWhat is the most important information I should know about ribavirin capsules?\n\n 1. Ribavirin capsules may cause birth defects, miscarriage or death of your unborn baby. Do not take ribavirin capsules if you or your sexual partner is pregnant or plan to become pregnant.\n" }

In females: Do not become pregnant during treatment or within 9 months after you stop treatment with ribavirin capsules.

{ "type": "p", "children": [], "text": "\nIn females: Do not become pregnant during treatment or within 9 months after you stop treatment with ribavirin capsules. \n" }

{ "type": "ul", "children": [ "Females must have a pregnancy test before starting ribavirin capsules, during    treatment with ribavirin capsules, and for 9 months after you stop treatment with ribavirin capsules. ", "You must use effective birth control during treatment and for 9 months after you stop treatment with ribavirin capsules." ], "text": "" }

In males: Your sexual partner should not become pregnant during your treatment or within 6 months after you stop treatment with ribavirin capsules. You and your female sexual partner must use effective birth control during treatment and for 6 months after you stop treatment with ribavirin capsules.

{ "type": "p", "children": [], "text": "\nIn males: Your sexual partner should not become pregnant during your treatment or within 6 months after you stop treatment with ribavirin capsules. You and your female sexual partner must use effective birth control during treatment and for 6 months after you stop treatment with ribavirin capsules. " }

Tell your healthcare provider right away if:

{ "type": "p", "children": [], "text": "\nTell your healthcare provider right away if:\n" }

{ "type": "ul", "children": [ "You become pregnant during treatment or within 9 months after you stop taking ribavirin capsules. ", "Your female sexual partner becomes pregnant during your treatment or within 6 months after you stop treatment with ribavirin capsules. " ], "text": "" }

2. Ribavirin capsules may cause a significant drop in your red blood cell count and cause anemia in some cases. Anemia has been associated with worsening of heart problems, and in rare cases can cause a heart attack and death. Tell your healthcare provider if you have ever had any heart problems. Ribavirin capsules may not be right for you. Get medical help right away if you experience chest pain. 3. Do not take ribavirin capsules alone to treat chronic hepatitis C infection. Ribavirin capsules should be used in combination with either interferon alfa-2b or peginterferon alfa-2b to treat chronic hepatitis C infection. What are ribavirin capsules?

{ "type": "p", "children": [], "text": "2. Ribavirin capsules may cause a significant drop in your red blood cell count and cause anemia in some cases. Anemia has been associated with worsening of heart problems, and in rare cases can cause a heart attack and death. Tell your healthcare provider if you have ever had any heart problems. Ribavirin capsules may not be right for you. Get medical help right away if you experience chest pain.\n\n 3. Do not take ribavirin capsules alone to treat chronic hepatitis C infection. Ribavirin capsules should be used in combination with either interferon alfa-2b or peginterferon alfa-2b to treat chronic hepatitis C infection.\n\n What are ribavirin capsules?\n" }

Ribavirin capsules are a medicine used with either interferon alfa-2b or peginterferon alfa-2b to treat chronic (lasting a long time) hepatitis C infection in people 3 years and older with liver disease.

{ "type": "p", "children": [], "text": "Ribavirin capsules are a medicine used with either interferon alfa-2b or peginterferon alfa-2b to treat chronic (lasting a long time) hepatitis C infection in people 3 years and older with liver disease. " }

It is not known if ribavirin capsules use for longer than 1 year is safe and will work.

{ "type": "p", "children": [], "text": "It is not known if ribavirin capsules use for longer than 1 year is safe and will work. " }

It is not known if ribavirin capsules use in children younger than 3 years old is safe and will work.

{ "type": "p", "children": [], "text": "It is not known if ribavirin capsules use in children younger than 3 years old is safe and will work. " }

Who should not take ribavirin capsules?

{ "type": "p", "children": [], "text": "\nWho should not take ribavirin capsules? \n" }

See “What is the most important information I should know about ribavirin capsules?”

{ "type": "p", "children": [], "text": "\nSee “What is the most important information I should know about ribavirin capsules?”\n" }

Do not take ribavirin capsules if you have:

{ "type": "p", "children": [], "text": "\nDo not take ribavirin capsules if you have:\n" }

{ "type": "ul", "children": [ "ever had serious allergic reactions to the ingredients in ribavirin capsules. See the end of this Medication Guide for a complete list of ingredients. ", "certain types of hepatitis (autoimmune hepatitis). ", "certain blood disorders (hemoglobinopathies). ", "severe kidney disease. ", "taken or currently take didanosine. " ], "text": "" }

Talk to your healthcare provider before taking ribavirin capsules if you have any of these conditions.

{ "type": "p", "children": [], "text": "Talk to your healthcare provider before taking ribavirin capsules if you have any of these conditions." }

What should I tell my healthcare provider before taking ribavirin capsules?

{ "type": "p", "children": [], "text": "\nWhat should I tell my healthcare provider before taking ribavirin capsules?\n" }

Before you take ribavirin capsules, tell your healthcare provider if you have or ever had:

{ "type": "p", "children": [], "text": "\nBefore you take ribavirin capsules, tell your healthcare provider if you have or ever had:\n" }

{ "type": "ul", "children": [ "treatment for hepatitis C that did not work for you ", "breathing problems. Ribavirin capsules may cause or worsen breathing problems you already have. ", "vision problems. Ribavirin capsules may cause eye problems or worsen eye problems you already have. You should have an eye exam before you start treatment with ribavirin capsules. ", "certain blood disorders such as anemia (low red blood cell count) ", "high blood pressure, heart problems, or have had a heart attack. Your healthcare provider should check your blood and heart before you start treatment with ribavirin capsules. ", "thyroid problems", "liver problems other than hepatitis C infection", "human immunodeficiency virus (HIV) or any immunity problems", "mental health problems, including depression and thoughts of hurting yourself or others", "kidney problems", "an organ transplant ", "diabetes. Ribavirin capsules may make your diabetes worse or harder to treat.", "any other medical condition", "are breastfeeding. It is not known if ribavirin passes into your breast milk. You and your healthcare provider should decide if you will take ribavirin capsules or breastfeed.\n" ], "text": "" }

Tell your healthcare provider about all the medicines you take, including prescription medicines, vitamins, and herbal supplements. Ribavirin capsules may affect the way other medicines work.

{ "type": "p", "children": [], "text": "\nTell your healthcare provider about all the medicines you take, including prescription medicines, vitamins, and herbal supplements. Ribavirin capsules may affect the way other medicines work." }

Especially tell your healthcare provider if you take didanosine or a medicine that contains azathioprine.

{ "type": "p", "children": [], "text": "\nEspecially tell your healthcare provider if you take didanosine or a medicine that contains azathioprine.\n" }

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

{ "type": "p", "children": [], "text": "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 ribavirin capsules?

{ "type": "p", "children": [], "text": "\nHow should I take ribavirin capsules?\n" }

{ "type": "ul", "children": [ "Take ribavirin capsules exactly as your healthcare provider tells you. Your healthcare provider will tell you how much ribavirin capsules to take and when to take them. ", "Take ribavirin capsules with food. ", "Take ribavirin capsules whole. Do not open, break, or crush ribavirin capsules before swallowing. If you cannot swallow ribavirin capsules whole, tell your healthcare provider. ", "If you miss a dose of ribavirin capsules, 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 ribavirin capsules, call your healthcare provider or go to the nearest hospital emergency room right away." ], "text": "" }

What are the possible side effects of ribavirin capsules?

{ "type": "p", "children": [], "text": "\nWhat are the possible side effects of ribavirin capsules?\n" }

Ribavirin capsules may cause serious side effects, including:

{ "type": "p", "children": [], "text": "\nRibavirin capsules may cause serious side effects, including:\n" }

See “What is the most important information I should know about ribavirin capsules?”

{ "type": "p", "children": [], "text": "\nSee “What is the most important information I should know about ribavirin capsules?”\n" }

{ "type": "ul", "children": [ "\nSwelling and irritation of your pancreas (pancreatitis). Symptoms may include: stomach pain, nausea, vomiting, or diarrhea. ", "\nSerious breathing problems. Difficulty breathing may be a sign of a serious lung infection (pneumonia) that can lead to death. ", "\nSerious eye problems that may lead to vision loss or blindness. ", "\nDental problems. Brush your teeth well 2 times each day. Get regular dental exams. If you vomit at any time during treatment with ribavirin capsules, rinse out your mouth well. ", "\nSevere blood disorders. You may have an increased risk of developing severe blood disorders when ribavirin capsules is used in combination with pegylated alpha interferons and azathioprine. Your healthcare provider should do blood tests during your treatment with ribavirin capsules in combination with pegylated alpha interferon and azathioprine to check you for these problems. ", "\nGrowth problems in children. Weight loss and slowed growth are common in children during combination treatment with ribavirin capsules and peginterferon alfa-2b or interferon alfa-2b. Most children will go through a growth spurt and gain weight after treatment stops. 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 ribavirin capsules and peginterferon alfa-2b or with ribavirin capsules and interferon alfa-2b. ", "\nSevere depression. \n", "\nThoughts of hurting yourself or others, and suicide attempts. Adults and children who take ribavirin capsules, especially teenagers, are more likely to have suicidal thoughts or attempt to hurt themselves during treatment with ribavirin capsules. Call your healthcare provider right away or go to the nearest hospital emergency room if you have new or worse depression or thoughts about hurting yourself or others or dying. " ], "text": "" }

The most common side effects of ribavirin capsules in adults include:

{ "type": "p", "children": [], "text": "\nThe most common side effects of ribavirin capsules in adults include:\n" }

{ "type": "ul", "children": [ "flu-like symptoms - feeling tired or weak, headache, shaking chills along with high temperature (fever), nausea, and muscle aches ", "mood changes, feeling irritable " ], "text": "" }

The most common side effects of ribavirin capsules in children include:

{ "type": "p", "children": [], "text": "\nThe most common side effects of ribavirin capsules in children include:\n" }

{ "type": "ul", "children": [ "fever ", "headache ", "a decrease in blood cells that fight infection (neutropenia) ", "tiredness ", "decreased appetite ", "vomiting " ], "text": "" }

These are not all the possible side effects of ribavirin capsules. For more information ask your healthcare provider or pharmacist.

{ "type": "p", "children": [], "text": "These are not all the possible side effects of ribavirin capsules. 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.

{ "type": "p", "children": [], "text": "Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088." }

How should I store ribavirin capsules?

{ "type": "p", "children": [], "text": "\nHow should I store ribavirin capsules?\n" }

{ "type": "ul", "children": [ "Store ribavirin capsules at room temperature between 68°F to 77°F (20°C to 25°C)." ], "text": "" }

Keep ribavirin capsules and all medicines out of the reach of children.

{ "type": "p", "children": [], "text": "\nKeep ribavirin capsules and all medicines out of the reach of children.\n" }

General information about the safe and effective use of ribavirin capsules. It is not known if treatment with ribavirin capsules will cure hepatitis C virus infections or prevent cirrhosis, liver failure, or liver cancer that can be caused by hepatitis C virus infections. It is not known if taking ribavirin capsules will prevent you from infecting another person with the hepatitis C virus. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ribavirin capsules for a condition for which it was not prescribed. Do not give ribavirin capsules to other people, even if they have the same symptoms that you have. They may harm them. You can ask your pharmacist or healthcare provider for information about ribavirin capsules that is written for health professionals.

{ "type": "p", "children": [], "text": "\nGeneral information about the safe and effective use of ribavirin capsules.\n\n It is not known if treatment with ribavirin capsules will cure hepatitis C virus infections or prevent cirrhosis, liver failure, or liver cancer that can be caused by hepatitis C virus infections.\n It is not known if taking ribavirin capsules will prevent you from infecting another person with the hepatitis C virus.\n Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ribavirin capsules for a condition for which it was not prescribed. Do not give ribavirin capsules to other people, even if they have the same symptoms that you have. They may harm them.\n You can ask your pharmacist or healthcare provider for information about ribavirin capsules that is written for health professionals." }

What are the ingredients in ribavirin capsules?

{ "type": "p", "children": [], "text": "\nWhat are the ingredients in ribavirin capsules?\n" }

Active ingredient: ribavirin

{ "type": "p", "children": [], "text": "\nActive ingredient: ribavirin" }

Inactive ingredients: microcrystalline cellulose, lactose monohydrate, povidone-K 30, and magnesium stearate. The capsule shell consists of titanium dioxide, sodium lauryl sulfate, and gelatin. The capsule is printed with edible ink containing black iron oxide. For more information, call Aurobindo Pharma USA, Inc. at 1-866-850-2876. Distributed by: Aurobindo Pharma USA, Inc. 279 Princeton-Hightstown RoadEast Windsor, NJ 08520 Manufactured by: Aurobindo Pharma Limited Hyderabad-500 032, India This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 07/2023

{ "type": "p", "children": [], "text": "\nInactive ingredients: microcrystalline cellulose, lactose monohydrate, povidone-K 30, and magnesium stearate. The capsule shell consists of titanium dioxide, sodium lauryl sulfate, and gelatin. The capsule is printed with edible ink containing black iron oxide.\n For more information, call Aurobindo Pharma USA, Inc. at 1-866-850-2876.\n Distributed by:\nAurobindo Pharma USA, Inc.\n279 Princeton-Hightstown RoadEast Windsor, NJ 08520\n Manufactured by:\nAurobindo Pharma Limited\nHyderabad-500 032, India\n This Medication Guide has been approved by the U.S. Food and Drug Administration.\n Revised: 07/2023\n" }

NDC 65862-290-05 Rx only Ribavirin Capsules USP  200 mg PHARMACIST: Dispense the accompanying Medication Guide to each patient.  AUROBINDO     500 Capsules  

{ "type": "p", "children": [], "text": "\nNDC 65862-290-05\n\nRx only\n\nRibavirin Capsules USP \n200 mg\n\nPHARMACIST: Dispense the accompanying Medication Guide to each patient. \n\nAUROBINDO     500 Capsules\n\n \n" }

Ribavirin tablets in combination with PEGASYS® (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 ribavirin tablets combination therapy with PEGASYS®: 

{ "type": "p", "children": [], "text": "Ribavirin tablets in combination with PEGASYS® (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.\n The following points should be considered when initiating ribavirin tablets combination therapy with PEGASYS®: " }

{ "type": "ul", "children": [ "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 ribavirin tablets and PEGASYS® therapy have not been established in liver or other organ transplant recipients, patients with decompensated liver disease, or previous non-responders to interferon therapy. ", "The safety and efficacy of ribavirin tablets therapy for the treatment of adenovirus, RSV, parainfluenza or influenza infections have not been established. Ribavirin tablets should not be used for these indications. Ribavirin for inhalation has a separate package insert, which should be consulted if ribavirin inhalation therapy is being considered." ], "text": "" }

Adult Patients The recommended dose of ribavirin tablets is provided in Table 1. The recommended duration of treatment for patients previously untreated with ribavirin and interferon is 24 to 48 weeks. The daily dose of ribavirin tablets 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).  

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 1 PEGASYS<span class="Sup">® </span>and Ribavirin Tablets Dosing Recommendations </span> </caption> <colgroup> <col width="25%"/> <col width="25%"/> <col width="28.84%"/> <col width="21.16%"/> </colgroup> <tfoot> <tr class="First Last"> <td align="justify" colspan="4">Genotypes 2 and 3 showed no increased response to treatment beyond 24 weeks (see <span class="Bold">Table 10</span>).<br/>Data on genotypes 5 and 6 are insufficient for dosing recommendations.<br/>* See PEGASYS<span class="Sup">® </span>Package Insert for further details on PEGASYS<span class="Sup">® </span>dosing and administration, including dose modification in patients with renal impairment.<br/> </td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" valign="top"><span class="Bold">Hepatitis C Virus</span> <br/> <span class="Bold"> (HCV) Genotype</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">PEGASYS<span class="Sup">®</span> Dose*</span> <br/> <span class="Bold">(once weekly)</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">Ribavirin </span><span class="Bold">Tablets</span> <br/> <span class="Bold">Dose</span> <br/> <span class="Bold">(daily)</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">Duration</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top">  Genotypes 1, 4 <br/> </td><td align="center" class="Rrule" valign="top">180 mcg<br/> </td><td align="center" class="Rrule" valign="top">&lt;75 kg = 1000 mg<br/>≥75 kg = 1200 mg<br/> </td><td align="center" class="Rrule" valign="middle">48 weeks<br/>48 weeks<br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="middle">  Genotypes 2, 3 <br/> </td><td align="center" class="Rrule" valign="middle">180 mcg<br/> </td><td align="center" class="Rrule" valign="middle">800 mg<br/> </td><td align="center" class="Rrule" valign="middle">24 weeks<br/> </td> </tr> </tbody> </table></div>

Pediatric Patients PEGASYS® is administered as 180 mcg/1.73m2 x BSA once weekly subcutaneously, to a maximum dose of 180 mcg, and should be given in combination with ribavirin. The recommended treatment duration for patients with genotype 2 or 3 is 24 weeks and for other genotypes is 48 weeks. Ribavirin tablets should be given in combination with PEGASYS®. Ribavirin tablets are 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 ribavirin tablets are provided in Table 2. Patients who initiate treatment prior to their 18th birthday should maintain pediatric dosing through the completion of therapy.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 2 Ribavirin Tablets Dosing Recommendations for Pediatric Patients </span> </caption> <colgroup> <col width="22.18%"/> <col width="35.36%"/> <col width="42.46%"/> </colgroup> <tfoot> <tr class="First Last"> <td colspan="3">*approximately 15 mg/kg/day</td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" valign="middle"><span class="Bold">Body Weight in kilograms (kg)</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Ribavirin Tablets </span> <br/> <span class="Bold">Daily Dose*</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Ribavirin Tablets </span> <br/> <span class="Bold">Number of Tablets</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle">23 to 33<br/> </td><td align="center" class="Rrule" valign="middle">400 mg/day<br/> </td><td align="center" class="Rrule" valign="middle">1 x 200 mg tablet A.M.<br/>1 x 200 mg tablet P.M.<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle">34 to 46<br/> </td><td align="center" class="Rrule" valign="middle">600 mg/day<br/> </td><td align="center" class="Rrule" valign="middle">1 x 200 mg tablet A.M.<br/>2 x 200 mg tablets P.M.<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle">47 to 59<br/> </td><td align="center" class="Rrule" valign="middle">800 mg/day<br/> </td><td align="center" class="Rrule" valign="middle">2 x 200 mg tablets A.M.<br/>2 x 200 mg tablets P.M.<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle">60 to 74<br/> </td><td align="center" class="Rrule" valign="middle">1000 mg/day<br/> </td><td align="center" class="Rrule" valign="middle">2 x 200 mg tablets A.M.<br/>3 x 200 mg tablets P.M.<br/> </td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule" valign="middle">≥75<br/> </td><td align="center" class="Rrule" valign="middle">1200 mg/day<br/> </td><td align="center" class="Rrule" valign="middle">3 x 200 mg tablets A.M.<br/>3 x 200 mg tablets P.M.<br/> </td> </tr> </tbody> </table></div>

Adult Patients The recommended dose for treatment of chronic hepatitis C in patients coinfected with HIV is PEGASYS® 180 mcg subcutaneous once weekly and ribavirin tablets 800 mg by mouth daily for a total duration of 48 weeks, regardless of HCV genotype.

Adult and Pediatric Patients If severe adverse reactions or laboratory abnormalities develop during combination ribavirin tablets/PEGASYS® therapy, the dose should be modified or discontinued, if appropriate, until the adverse reactions abate or decrease in severity. If intolerance persists after dose adjustment, ribavirin tablets/PEGASYS® therapy should be discontinued. Table 3 provides guidelines for dose modifications and discontinuation based on the patient’s hemoglobin concentration and cardiac status. Ribavirin tablets 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)].

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="831.25"> <caption> <span>Table 3 Ribavirin Tablets Dose Modification Guidelines in Adults and Pediatrics </span> </caption> <colgroup> <col width="17.92%"/> <col width="41.76%"/> <col width="40.32%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" rowspan="2" valign="middle"><span class="Bold">Body weight in kilograms (kg) </span> <br/> </td><td align="center" class="Rrule" colspan="2" valign="middle"><span class="Bold">Laboratory Values</span> <br/> </td> </tr> <tr class="Botrule"> <td align="justify" class="Lrule Rrule" valign="top">Hemoglobin &lt;10 g/dL in patients with no cardiac disease, or<br/> <br/>Decrease in hemoglobin of ≥2 g/dL during any 4 week period in patients with history of stable cardiac disease <br/> </td><td align="justify" class="Rrule" valign="top">Hemoglobin &lt;8.5 g/dL in patients with no cardiac disease, or<br/> <br/>Hemoglobin &lt;12 g/dL despite 4 weeks at reduced dose in patients with history of stable cardiac disease <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="middle">Adult Patients older than 18 years of age <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle">Any weight<br/> </td><td align="center" class="Rrule" valign="middle">1 x 200 mg tablet A.M.<br/>2 x 200 mg tablets P.M.<br/> </td><td align="center" class="Rrule" valign="middle">Discontinue ribavirin tablets <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" colspan="3" valign="middle">Pediatric Patients 5 to 18 years of age <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle">23 to 33 kg<br/> </td><td align="center" class="Rrule" valign="middle">1 x 200 mg tablet A.M.<br/> </td><td align="center" class="Rrule" rowspan="5" valign="middle">Discontinue ribavirin tablets <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle">34 to 46 kg<br/> </td><td align="center" class="Rrule" valign="middle">1 x 200 mg tablet A.M.<br/>1 x 200 mg tablet P.M.<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle">47 to 59 kg<br/> </td><td align="center" class="Rrule" valign="middle">1 x 200 mg tablet A.M.<br/>1 x 200 mg tablet P.M.<br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle">60 to 74 kg<br/> </td><td align="center" class="Rrule" valign="middle">1 x 200 mg tablet A.M.<br/>2 x 200 mg tablets P.M.<br/> </td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule" valign="middle">≥75 kg<br/> </td><td align="center" class="Rrule" valign="middle">1 x 200 mg tablet A.M.<br/>2 x 200 mg tablets P.M.<br/> </td> </tr> </tbody> </table></div>

The guidelines for ribavirin tablets dose modifications outlined in this table also apply to laboratory abnormalities or adverse reactions other than decreases in hemoglobin values. Adult Patients Once ribavirin tablets have been withheld due to either a laboratory abnormality or clinical adverse reaction, an attempt may be made to restart ribavirin tablets at 600 mg daily and further increase the dose to 800 mg daily. However, it is not recommended that ribavirin tablets 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 ribavirin tablets dose to the original dose may be attempted depending upon the physician’s judgment. If ribavirin tablets have been withheld due to a laboratory abnormality or clinical adverse reaction, an attempt may be made to restart ribavirin tablets at one-half the full dose.

The total daily dose of ribavirin tablets should be reduced for patients with creatinine clearance less than or equal to 50 mL/min; and the weekly dose of PEGASYS® should be reduced for creatinine clearance less than 30 mL/min as follows in Table 4 [see Use in Specific Populations (8.7), Pharmacokinetics (12.3), and PEGASYS® Package Insert].

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="100%"> <caption> <span>Table 4 Dosage Modification for Renal Impairment </span> </caption> <colgroup> <col width="32.06%"/> <col width="32.02%"/> <col width="35.9%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td align="center" class="Lrule Rrule" valign="middle"><span class="Bold">Creatinine Clearance</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">PEGASYS<span class="Sup">®</span> Dose</span> <br/> <span class="Bold"> (once weekly)</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">Ribavirin Tablets Dose (daily)</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">30 to 50 mL/min<br/> </td><td align="center" class="Rrule" valign="middle">180 mcg<br/> </td><td align="center" class="Rrule" valign="middle">Alternating doses, 200 mg and<br/> 400 mg every other day<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">Less than 30 mL/min<br/> </td><td align="center" class="Rrule" valign="middle">135 mcg<br/> </td><td align="center" class="Rrule" valign="middle">200 mg daily<br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="middle">Hemodialysis<br/> </td><td align="center" class="Rrule" valign="middle">135 mcg<br/> </td><td align="center" class="Rrule" valign="middle">200 mg daily<br/> </td> </tr> </tbody> </table></div>

The dose of ribavirin tablets should not be further modified in patients with renal impairment. If severe adverse reactions or laboratory abnormalities develop, ribavirin tablets should be discontinued, if appropriate, until the adverse reactions abate or decrease in severity. If intolerance persists after restarting ribavirin tablets, ribavirin tablets/PEGASYS® therapy should be discontinued. No data are available for pediatric subjects with renal impairment.

Discontinuation of PEGASYS®/ribavirin tablets therapy should be considered if the patient has failed to demonstrate at least a 2 log10 reduction from baseline in HCV RNA by 12 weeks of therapy, or undetectable HCV RNA levels after 24 weeks of therapy. PEGASYS®/Ribavirin tablets therapy should be discontinued in patients who develop hepatic decompensation during treatment [see Warnings and Precautions (5.3)].

Ribavirin is available as a light pink colored, capsule shaped, film-coated tablet for oral administration. Each tablet contains 200 mg of ribavirin.

{ "type": "p", "children": [], "text": "Ribavirin is available as a light pink colored, capsule shaped, film-coated tablet for oral administration. Each tablet contains 200 mg of ribavirin." }

Ribavirin tablets are contraindicated in:

{ "type": "p", "children": [], "text": "Ribavirin tablets are contraindicated in:" }

{ "type": "ul", "children": [ "Women who are pregnant. Ribavirin tablets may cause fetal harm when administered to a pregnant woman. Ribavirin tablets are 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 [see Drug Interactions (7.1)]." ], "text": "" }

Ribavirin tablets and PEGASYS® combination therapy are contraindicated in patients with:

{ "type": "p", "children": [], "text": "Ribavirin tablets and PEGASYS® combination therapy are contraindicated in patients with:" }

{ "type": "ul", "children": [ "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 [see Warnings and Precautions (5.3)]." ], "text": "" }

Ribavirin may cause birth defects and/or death of the exposed fetus. Ribavirin has demonstrated significant teratogenic and/or embryocidal effects in all animal species in which adequate studies have been conducted. These effects occurred at doses as low as one twentieth of the recommended human dose of ribavirin. 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 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)].

The primary toxicity of ribavirin is hemolytic anemia, which was observed in approximately 13% of all ribavirin/PEGASYS®-treated subjects in clinical trials. Anemia associated with ribavirin occurs within 1 to 2 weeks of initiation of therapy. Because the initial drop in hemoglobin may be significant, it is advised that hemoglobin or hematocrit be obtained pretreatment and at week 2 and week 4 of therapy or more frequently if clinically indicated. Patients should then be followed as clinically appropriate. Caution should be exercised in initiating treatment in any patient with baseline risk of severe anemia (e.g., spherocytosis, history of gastrointestinal bleeding) [see Dosage and Administration (2.3)]. Fatal and nonfatal myocardial infarctions have been reported in patients with anemia caused by ribavirin. Patients should be assessed for underlying cardiac disease before initiation of ribavirin therapy. Patients with pre-existing cardiac disease should have electrocardiograms administered before treatment, and should be appropriately monitored during therapy. If there is any deterioration of cardiovascular status, therapy should be suspended or discontinued [see Dosage and Administration (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 ribavirin [see Boxed Warning and Dosage and Administration (2.3)].

Chronic hepatitis C (CHC) patients with cirrhosis may be at risk of hepatic decompensation and death when treated with alpha interferons, including PEGASYS®. Cirrhotic CHC patients coinfected with HIV receiving highly active antiretroviral therapy (HAART) and interferon alfa-2a with or without ribavirin appear to be at increased risk for the development of hepatic decompensation compared to patients not receiving HAART. In Study NR15961 [see Clinical Studies (14.3)], among 129 CHC/HIV cirrhotic patients receiving HAART, 14 (11%) of these patients across all treatment arms developed hepatic decompensation resulting in 6 deaths. All 14 patients were on NRTIs, including stavudine, didanosine, abacavir, zidovudine, and lamivudine. These small numbers of patients do not permit discrimination between specific NRTIs or the associated risk. During treatment, patients’ clinical status and hepatic function should be closely monitored for signs and symptoms of hepatic decompensation. Treatment with PEGASYS®/ribavirin should be discontinued immediately in patients with hepatic decompensation [see Contraindications (4)].

Severe acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, and anaphylaxis) have been observed during alpha interferon and ribavirin therapy. If such a reaction occurs, therapy with PEGASYS® and 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 PEGASYS® with and without ribavirin. Patients developing signs or symptoms of severe skin reactions must discontinue therapy [see Adverse Reactions (6.2)].

Dyspnea, pulmonary infiltrates, pneumonitis, pulmonary hypertension, and pneumonia have been reported during therapy with ribavirin and interferon. Occasional cases of fatal pneumonia have occurred. In addition, sarcoidosis or the exacerbation of sarcoidosis has been reported. If there is evidence of pulmonary infiltrates or pulmonary function impairment, patients should be closely monitored and, if appropriate, combination ribavirin/PEGASYS® treatment should be discontinued.

Pancytopenia (marked decreases in RBCs, neutrophils and platelets) and bone marrow suppression have been reported in the literature to occur within 3 to 7 weeks after the concomitant administration of pegylated interferon/ribavirin and azathioprine. In this limited number of patients (n=8), myelotoxicity was reversible within 4 to 6 weeks upon withdrawal of both HCV antiviral therapy and concomitant azathioprine and did not recur upon reintroduction of either treatment alone. PEGASYS®, 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)].

Ribavirin and PEGASYS® therapy should be suspended in patients with signs and symptoms of pancreatitis, and discontinued in patients with confirmed pancreatitis.

During combination therapy for up to 48 weeks with PEGASYS® plus ribavirin, growth inhibition was observed in pediatric subjects 5 to 17 years of age. Decreases in weight for age z-score and height for age z-score up to 48 weeks of therapy compared with baseline were observed. At 2 years post-treatment, 16% of pediatric subjects were more than 15 percentiles below their baseline weight curve and 11% were more than 15 percentiles below their baseline height curve. The available longer term data on subjects who were followed up to 6 years post-treatment are too limited to determine the risk of reduced adult height in some patients [see Clinical Studies Experience (6.1)].

Before beginning PEGASYS®/ribavirin combination therapy, standard hematological and biochemical laboratory tests are recommended for all patients. Pregnancy screening for women of childbearing potential must be performed. Patients who have pre-existing cardiac abnormalities should have electrocardiograms administered before treatment with PEGASYS®/ribavirin. After initiation of therapy, hematological tests should be performed at 2 weeks and 4 weeks and biochemical tests should be performed at 4 weeks. Additional testing should be performed periodically during therapy. In adult clinical studies, the CBC (including hemoglobin level and white blood cell and platelet counts) and chemistries (including liver function tests and uric acid) were measured at 1, 2, 4, 6, and 8 weeks, and then every 4 to 6 weeks or more frequently if abnormalities were found. In the pediatric clinical trial, hematological and chemistry assessments were at 1, 3, 5, and 8 weeks, then every 4 weeks. Thyroid stimulating hormone (TSH) was measured every 12 weeks. Monthly pregnancy testing should be performed during combination therapy and for 6 months after discontinuing therapy. The entrance criteria used for the clinical studies of ribavirin and PEGASYS® may be considered as a guideline to acceptable baseline values for initiation of treatment:  

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 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 PEGASYS® alone or in combination with 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 ribavirin combination therapy in the CHC Clinical Trial, NV15801. Ten percent of CHC monoinfected patients receiving 48 weeks of therapy with PEGASYS® in combination with 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 PEGASYS® and/or ribavirin therapy. The most common reason for dose modification of PEGASYS® in CHC and CHC/HIV patients was for laboratory abnormalities; neutropenia (20% and 27%, respectively) and thrombocytopenia (4% and 6%, respectively). The most common reason for dose modification of ribavirin in CHC and CHC/HIV patients was anemia (22% and 16%, respectively). PEGASYS® dose was reduced in 12% of patients receiving 1000 mg to 1200 mg ribavirin for 48 weeks and in 7% of patients receiving 800 mg ribavirin for 24 weeks. Ribavirin dose was reduced in 21% of patients receiving 1000 mg to 1200 mg ribavirin for 48 weeks and in 12% of patients receiving 800 mg ribavirin for 24 weeks. Chronic hepatitis C monoinfected patients treated for 24 weeks with PEGASYS® and 800 mg ribavirin were observed to have lower incidence of serious adverse events (3% vs. 10%), hemoglobin less than 10 g/dL (3% vs. 15%), dose modification of PEGASYS®(30% vs. 36%) and ribavirin (19% vs. 38%), and of withdrawal from treatment (5% vs. 15%) compared to patients treated for 48 weeks with PEGASYS® and 1000 mg or 1200 mg ribavirin. On the other hand, the overall incidence of adverse events appeared to be similar in the two treatment groups.  

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="624"> <caption> <span>Table 5    Adverse Reactions Occurring in Greater Than or Equal to 5% of Patients in Chronic Hepatitis C Clinical Trials (Study NV15801) </span> </caption> <colgroup> <col width="38.6538461538462%"/> <col width="30.5769230769231%"/> <col width="30.7692307692308%"/> </colgroup> <tfoot> <tr class="First Last"> <td colspan="3">* Severe hematologic abnormalities (lymphocyte less than 500 cells/mm<span class="Sup">3</span>; hemoglobin less than 10 g/dL; neutrophil less than 750 cells/mm<span class="Sup">3</span>; platelet less than 50,000 cells/mm<span class="Sup">3</span>). </td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" rowspan="4" valign="middle"><span class="Bold">Body System </span> <br/> </td><td align="center" class="Rrule" colspan="2" valign="middle"><span class="Bold">CHC Combination Therapy Study NV15801</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="top"><span class="Bold">PEGASYS<span class="Sup">®</span></span> <span class="Bold">180 mcg + 1000 mg or 1200 mg Ribavirin Tablets </span><span class="Bold">48 weeks</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">Interferon alfa-2b </span><span class="Bold">+ 1000 mg or </span> <br/> <span class="Bold">1200 mg REBETOL<span class="Sup">®</span> 48 weeks</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle"><span class="Bold">N=451</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">N=443</span> <br/> </td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" valign="middle"><span class="Bold">%</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">%</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold">Application Site Disorders</span> <br/>Injection site reaction <br/> </td><td align="center" class="Rrule" valign="bottom"> <br/>23<br/> </td><td align="center" class="Rrule" valign="bottom"> <br/>16<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold">Endocrine Disorders</span> <br/>Hypothyroidism <br/> </td><td align="center" class="Rrule" valign="bottom"> <br/>4<br/> </td><td align="center" class="Rrule" valign="bottom"> <br/>5<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="bottom"><span class="Bold">Flu-like Symptoms and Signs</span> <br/>Fatigue/Asthenia <br/>Pyrexia <br/>Rigors <br/>Pain <br/> </td><td align="center" class="Rrule" valign="bottom"> <br/>65<br/>41<br/>25<br/>10<br/> </td><td align="center" class="Rrule" valign="bottom"> <br/>68<br/>55<br/>37<br/>9<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="bottom"><span class="Bold">Gastrointestinal</span> <br/>Nausea/Vomiting<br/>Diarrhea<br/>Abdominal pain<br/>Dry mouth<br/>Dyspepsia<br/> </td><td align="center" class="Rrule" valign="bottom"> <br/>25<br/>11<br/>8<br/>4<br/>6<br/> </td><td align="center" class="Rrule" valign="bottom"> <br/>29<br/>10<br/>9<br/>7<br/>5<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="bottom"><span class="Bold">Hematologic*</span> <br/>Lymphopenia<br/>Anemia<br/>Neutropenia<br/>Thrombocytopenia <br/> </td><td align="center" class="Rrule" valign="bottom"> <br/>14<br/>11<br/>27<br/>5<br/> </td><td align="center" class="Rrule" valign="bottom"> <br/>12<br/>11<br/>8<br/>&lt;1<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold">Metabolic and Nutritional</span> <br/>Anorexia <br/>Weight decrease <br/> </td><td align="center" class="Rrule" valign="bottom"> <br/>24<br/>10<br/> </td><td align="center" class="Rrule" valign="bottom"> <br/>26<br/>10<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold">Musculoskeletal, Connective Tissue and Bone </span> <br/>Myalgia <br/>Arthralgia <span class="Bold"></span> <br/>Back pain <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top"> <br/> <br/>40<br/>22<br/>5<br/> </td><td align="center" class="Rrule" valign="top"> <br/> <br/>49<br/>23<br/>5<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold">Neurological </span> <br/>Headache <br/>Dizziness (excluding vertigo) <br/>Memory impairment <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top"> <br/>43<br/>14<br/>6<br/> </td><td align="center" class="Rrule" valign="top"> <br/>49<br/>14<br/>5<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold">Psychiatric  </span> <br/>Irritability/Anxiety/Nervousness  <br/>Insomnia <br/>Depression <br/>Concentration impairment <br/>Mood alteration <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top"> <br/>33<br/>30<br/>20<br/>10<br/>5<br/> </td><td align="center" class="Rrule" valign="top"> <br/>38<br/>37<br/>28<br/>13<br/>6<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold">Resistance Mechanism Disorders</span> <br/>Overall <br/> </td><td align="center" class="Rrule" valign="bottom"> <br/>12<br/> </td><td align="center" class="Rrule" valign="bottom"> <br/>10<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold">Respiratory, Thoracic and Mediastinal </span> <br/>Dyspnea <br/>Cough <br/>Dyspnea exertional <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top"> <br/> <br/>13<br/>10<br/>4<br/> </td><td align="center" class="Rrule" valign="top"> <br/> <br/>14<br/>7<br/>7<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold">Skin and Subcutaneous Tissue  </span> <br/>Alopecia <br/>Pruritus <br/>Dermatitis <br/>Dry skin <br/>Rash <br/>Sweating increased <br/>Eczema  <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top"> <br/>28<br/>19<br/>16<br/>10<br/>8<br/>6<br/>5<br/> </td><td align="center" class="Rrule" valign="top"> <br/>33<br/>18<br/>13<br/>13<br/>5<br/>5<br/>4<br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="middle"><span class="Bold">Visual Disorders </span> <br/>Vision blurred <span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top"> <br/>5<br/> </td><td align="center" class="Rrule" valign="top"> <br/>2<br/> </td> </tr> </tbody> </table></div>

Pediatric Patients

In a clinical trial with 114 pediatric subjects (5 to 17 years of age) treated with PEGASYS® alone or in combination with 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 PEGASYS® and 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 PEGASYS® and 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 PEGASYS® plus ribavirin combination therapy group (hyperglycemia and cholecystectomy). 

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="645"> <caption> <span>Table 6 Percentage of Pediatric Subjects with Adverse Reactions* During First 24 Weeks of Treatment by Treatment Group and for 24 Weeks Post-treatment (in at Least 10% of Subjects) </span> </caption> <colgroup> <col width="46.0051679586563%"/> <col width="28.8682170542636%"/> <col width="25.1266149870801%"/> </colgroup> <tfoot> <tr class="First Last"> <td colspan="3">* Displayed adverse drug reactions include all grades of reported adverse clinical events considered possibly, probably, or definitely related to study drug.<br/>** Subjects in the PEGASYS<span class="Sup">®</span> 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.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" valign="top"></td><td align="center" class="Rrule" colspan="2" valign="middle"><span class="Bold">Study NV17424</span><span class="Bold"></span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"><span class="Bold">System Organ Class</span><span class="Bold"></span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">PEGASYS<span class="Sup">®</span></span> <br/> <span class="Bold">180 mcg/1.73 m² x BSA + </span><span class="Bold">Ribavirin 15 mg/kg (N=55) </span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">PEGASYS<span class="Sup">®</span>  <br/> 180 mcg/1.73 m² x BSA + Placebo** (N=59) </span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"> <br/> <br/> </td><td align="center" class="Rrule" valign="middle">% <br/> </td><td align="center" class="Rrule" valign="middle">% <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold">General disorders and administration site conditions </span> <br/> </td><td class="Rrule" valign="middle"> <br/> </td><td class="Rrule" valign="middle"> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    Influenza like illness <br/> </td><td align="center" class="Rrule" valign="middle">91<br/> </td><td align="center" class="Rrule" valign="middle">81<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    Injection site reaction <br/> </td><td align="center" class="Rrule" valign="middle">44<br/> </td><td align="center" class="Rrule" valign="middle">42<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    Fatigue <br/> </td><td align="center" class="Rrule" valign="middle">25<br/> </td><td align="center" class="Rrule" valign="middle">20<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    Irritability <br/> </td><td align="center" class="Rrule" valign="middle">24<br/> </td><td align="center" class="Rrule" valign="middle">14<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold">Gastrointestinal disorders </span> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    Gastrointestinal disorder <br/> </td><td align="center" class="Rrule" valign="middle">49<br/> </td><td align="center" class="Rrule" valign="middle">44<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold">Nervous system disorders </span> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    Headache <br/> </td><td align="center" class="Rrule" valign="middle">51<br/> </td><td align="center" class="Rrule" valign="middle">39<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold">Skin and subcutaneous tissue disorders </span> <br/> </td><td class="Rrule" valign="top"> <br/> <br/> </td><td class="Rrule" valign="top"> <br/> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    Rash <br/> </td><td align="center" class="Rrule" valign="middle">15<br/> </td><td align="center" class="Rrule" valign="middle">10<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    Pruritus <br/> </td><td align="center" class="Rrule" valign="middle">11<br/> </td><td align="center" class="Rrule" valign="middle">12<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold">Musculoskeletal, connective tissue and bone disorders </span> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    Musculoskeletal pain <br/> </td><td align="center" class="Rrule" valign="middle">35<br/> </td><td align="center" class="Rrule" valign="middle">29<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold">Psychiatric disorders </span> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">    Insomnia <br/> </td><td align="center" class="Rrule" valign="middle">9<br/> </td><td align="center" class="Rrule" valign="middle">12<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold">Metabolism and nutrition disorders </span> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td><td align="center" class="Rrule" valign="middle"> <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="middle">    Decreased appetite <br/> </td><td align="center" class="Rrule" valign="top">11 <br/> </td><td align="center" class="Rrule" valign="top">14 <br/> </td> </tr> </tbody> </table></div>

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 [see Warnings and Precautions (5.8)]. Pediatric subjects treated with PEGASYS® plus 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, 60 th mean percentile at 2 years post-treatment) and height (54th mean percentile at baseline, 56 th 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 post-treatment. 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 PEGASYS®/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 ribavirin therapy. Anemia (hemoglobin less than 10 g/dL) was observed in 13% of all ribavirin and PEGASYS® combination-treated patients in clinical trials. The maximum drop in hemoglobin occurred during the first 8 weeks of initiation of ribavirin therapy [see Dosage and Administration (2.3)]. 

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="624"> <caption> <span>Table 7 Selected Laboratory Abnormalities During Treatment with Ribavirin in Combination With Either PEGASYS<span class="Sup">®</span> or Interferon alfa-2b </span> </caption> <colgroup> <col width="40.3952991452991%"/> <col width="29.8290598290598%"/> <col width="29.775641025641%"/> </colgroup> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" valign="top"><span class="Bold">Laboratory Parameter </span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">PEGASYS<span class="Sup">®</span></span><span class="Bold">+ Ribavirin 1000/1200 mg   48 wks</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">Interferon alfa-2b</span><span class="Bold"> + Ribavirin 1000/1200 mg</span> <br/> <span class="Bold">48 wks</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"> <br/> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">(N=887)</span> <br/> </td><td align="center" class="Rrule" valign="middle"><span class="Bold">(N=443)</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold">Neutrophils (cells/mm<span class="Sup">3</span>)</span> <br/> </td><td class="Rrule" valign="middle"></td><td class="Rrule" valign="middle"></td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">1,000 &lt;1,500 <br/> </td><td align="center" class="Rrule" valign="middle">34%<br/> </td><td align="center" class="Rrule" valign="middle">38%<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">500 &lt;1,000 <br/> </td><td align="center" class="Rrule" valign="middle">49%<br/> </td><td align="center" class="Rrule" valign="middle">21%<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">&lt;500 <br/> </td><td align="center" class="Rrule" valign="middle">5%<br/> </td><td align="center" class="Rrule" valign="middle">1%<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold">Platelets (cells/mm<span class="Sup">3</span>)</span> <br/> </td><td class="Rrule" valign="middle"></td><td class="Rrule" valign="middle"></td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">50,000 to &lt;75,000 <br/> </td><td align="center" class="Rrule" valign="middle">11%<br/> </td><td align="center" class="Rrule" valign="middle">4%<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">20,000 to &lt;50,000 <br/> </td><td align="center" class="Rrule" valign="middle">5%<br/> </td><td align="center" class="Rrule" valign="middle">&lt; 1%<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">&lt;20,000 <br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td><td align="center" class="Rrule" valign="middle">0<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold">Hemoglobin (g/dL) </span> <br/> </td><td class="Rrule" valign="middle"> <br/> <br/> </td><td class="Rrule" valign="middle"> <br/> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">8.5 to 9.9 <br/> </td><td align="center" class="Rrule" valign="middle">11%<br/> </td><td align="center" class="Rrule" valign="middle">11%<br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="middle">&lt;8.5 <br/> </td><td align="center" class="Rrule" valign="middle">2%<br/> </td><td align="center" class="Rrule" valign="middle">&lt; 1%<br/> </td> </tr> </tbody> </table></div>

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.  

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="630"> <caption> <span>Table 8   Selected Hematologic Abnormalities During First 24 Weeks of Treatment by Treatment Group in Previously Untreated Pediatric Subjects </span> </caption> <colgroup> <col width="40%"/> <col width="29.5238095238095%"/> <col width="30.4761904761905%"/> </colgroup> <tfoot> <tr class="First Last"> <td colspan="3"> * Subjects in the PEGASYS<span class="Sup">®</span> 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.</td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" valign="top"><span class="Bold">Laboratory Parameter</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">PEGASYS<span class="Sup">®</span></span> <br/> <span class="Bold">180 mcg/1.73 m² x BSA + Ribavirin</span> <br/> <span class="Bold">15 mg/kg<br/>  (N=55) </span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">PEGASYS<span class="Sup">®</span></span> <br/> <span class="Bold">180 mcg/1.73 m² x BSA + Placebo* <br/> (N=59) </span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"><span class="Bold">Neutrophils (cells/mm<span class="Sup">3</span>) </span> <br/> </td><td class="Rrule" valign="top"> <br/> <br/> </td><td class="Rrule" valign="top"> <br/> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">1,000 to &lt;1,500 <br/> </td><td align="center" class="Rrule" valign="middle">31% <br/> </td><td align="center" class="Rrule" valign="middle">39% <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">750 to &lt;1,000 <br/> </td><td align="center" class="Rrule" valign="middle">27% <br/> </td><td align="center" class="Rrule" valign="middle">17% <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">500 to &lt;750 <br/> </td><td align="center" class="Rrule" valign="middle">25% <br/> </td><td align="center" class="Rrule" valign="middle">15% <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">&lt;500 <br/> </td><td align="center" class="Rrule" valign="middle">7% <br/> </td><td align="center" class="Rrule" valign="middle">5% <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="top"><span class="Bold">Platelets (cells/mm<span class="Sup">3</span>) </span> <br/> </td><td class="Rrule" valign="top"> <br/> <br/> </td><td class="Rrule" valign="top"> <br/> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">75,000 to &lt;100,000 <br/> </td><td align="center" class="Rrule" valign="middle">4% <br/> </td><td align="center" class="Rrule" valign="middle">2% <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">50,000 to &lt;75,000 <br/> </td><td align="center" class="Rrule" valign="middle">0% <br/> </td><td align="center" class="Rrule" valign="middle">2% <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">&lt;50,000 <br/> </td><td align="center" class="Rrule" valign="middle">0% <br/> </td><td align="center" class="Rrule" valign="middle">0% <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle"><span class="Bold">Hemoglobin (g/dL) </span> <br/> </td><td class="Rrule" valign="top"> <br/> <br/> </td><td class="Rrule" valign="top"> <br/> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">8.5 to &lt;10 <br/> </td><td align="center" class="Rrule" valign="middle">7% <br/> </td><td align="center" class="Rrule" valign="middle">3% <br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="middle">&lt;8.5 <br/> </td><td align="center" class="Rrule" valign="middle">0% <br/> </td><td align="center" class="Rrule" valign="middle">0% <br/> </td> </tr> </tbody> </table></div>

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/mm³ and hemoglobin values between 8.5 and 10 g/dL. The majority of hematologic abnormalities occurred in the first 24 weeks of treatment.

The following adverse reactions have been identified and reported during post-approval use of PEGASYS®/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)

In vitro data indicate 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 ribavirin and lamivudine (n=18), stavudine (n=10), or zidovudine (n=6) were coadministered 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 PEGASYS®/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 PEGASYS®, 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  Coadministration of  ribavirin and didanosine is contraindicated. Didanosine or its active metabolite (dideoxyadenosine 5’-triphosphate) concentrations are increased when didanosine is coadministered with 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 PEGASYS®/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.

In vitro studies indicate that ribavirin does not inhibit CYP 2C9, CYP 2C19, CYP 2D6 or CYP 3A4.

The use of 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. 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 (5.6)].

Pregnancy: Category X [see Contraindications (4)].  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 ribavirin). No maternal toxicity or effects on offspring were observed in a peri/postnatal toxicity study in rats dosed orally at up to 1 mg/kg/day (approximately 0.01 times the maximum recommended daily human dose of ribavirin). Treatment and Post-Treatment: Potential Risk to the Fetus

Ribavirin is known to accumulate in intracellular components from where it is cleared very slowly. It is not known whether ribavirin is contained in sperm, and if so, will exert a potential teratogenic effect upon fertilization of the ova. However, because of the potential human teratogenic effects of ribavirin, male patients should be advised to take every precaution to avoid risk of pregnancy for their female partners. 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 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)].

It is not known whether ribavirin is excreted in human milk. Because many drugs are excreted in human milk and to avoid any potential for serious adverse reactions in nursing infants from ribavirin, a decision should be made either to discontinue nursing or therapy with ribavirin, based on the importance of the therapy to the mother.

Pharmacokinetic evaluations in pediatric patients have not been performed. Safety and effectiveness of ribavirin have not been established in patients below the age of 5 years.

Clinical studies of ribavirin and PEGASYS® did not include sufficient numbers of subjects aged 65 or over to determine whether they respond differently from younger subjects. Specific pharmacokinetic evaluations for ribavirin in the elderly have not been performed. The risk of toxic reactions to this drug may be greater in patients with impaired renal function. The dose of ribavirin should be reduced in patients with creatinine clearance less than or equal to 50 mL/min; and the dose of PEGASYS® should be reduced in patients with creatinine clearance less than 30 mL/min [see Dosage and Administration (2.4); Use in Specific Populations (8.7)].

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

Renal function should be evaluated in all patients prior to initiation of ribavirin by estimating the patient’s creatinine clearance. A clinical trial evaluated treatment with ribavirin and PEGASYS® 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, ribavirin was administered at a dose of 200 mg daily with no apparent difference in the adverse event profile in comparison to subjects with normal renal function. Dose reductions and temporary interruptions of ribavirin (due to ribavirin-related adverse reactions, mainly anemia) were observed in up to one-third ESRD/HD subjects during treatment; and only one-third of these subjects received ribavirin for 48 weeks. Ribavirin plasma exposures were approximately 20% lower in subjects with ESRD on HD compared to subjects with normal renal function receiving the standard 1000/1200 mg ribavirin daily dose. Subjects with moderate (n=17) or severe (n=14) renal impairment did not tolerate 600 mg or    400 mg daily doses of ribavirin, respectively, due to ribavirin-related adverse reactions, mainly anemia, and exhibited 20% to 30% higher ribavirin plasma exposures (despite frequent dose modifications) compared to subjects with normal renal function (creatinine clearance greater than 80 mL/min) receiving the standard dose of ribavirin. Discontinuation rates were higher in subjects with severe renal impairment compared to that observed in subjects with moderate renal impairment or normal renal function. Pharmacokinetic modeling and simulation indicate that a dose of 200 mg daily in patients with severe renal impairment and a dose of 200 mg daily alternating with 400 mg the following day in patients with moderate renal impairment will provide plasma ribavirin exposure similar to patients with normal renal function receiving the approved regimen of ribavirin. These doses have not been studied in patients [see Dosage and Administration (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 ribavirin; and patients with creatinine clearance less than 30 mL/min should receive a reduced dose of PEGASYS®. The clinical and hematologic status of patients with creatinine clearance less than or equal to 50 mL/min receiving 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 PEGASYS® Package Insert].

The effect of hepatic impairment on the pharmacokinetics of ribavirin following administration of ribavirin has not been evaluated. The clinical trials of ribavirin were restricted to patients with Child-Pugh class A disease.

No clinically significant differences in the pharmacokinetics of ribavirin were observed between male and female subjects. Ribavirin pharmacokinetics, when corrected for weight, are similar in male and female patients.

The safety and efficacy of PEGASYS® and ribavirin treatment have not been established in patients with liver and other transplantations. As with other alpha interferons, liver and renal graft rejections have been reported on PEGASYS®, alone or in combination with ribavirin [see Adverse Reactions (6.2)].

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

{ "type": "p", "children": [], "text": "No cases of overdose with ribavirin have been reported in clinical trials. Hypocalcemia and hypomagnesemia have been observed in persons administered greater than the recommended dosage of ribavirin. In most of these cases, ribavirin was administered intravenously at dosages up to and in some cases exceeding four times the recommended maximum oral daily dose." }

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

{ "type": "p", "children": [], "text": "Ribavirin, is a nucleoside analogue with antiviral activity. The chemical name of ribavirin is 1-β-D-­ribofuranosyl-1H-1,2,4-triazole-3-carboxamide and has the following structural formula:" }

The molecular formula of ribavirin is C8H12N4O5 and the molecular weight is 244.2. Ribavirin USP is a white crystalline powder. It is freely soluble in water and slightly soluble in anhydrous alcohol. Ribavirin USP is available as a light pink colored, capsule shaped, film-coated tablet for oral administration. Each tablet contains 200 mg of ribavirin USP and the following inactive ingredients: microcrystalline cellulose, pregelatinised starch (maize), sodium starch glycolate, povidone (Kollidon 30), colloidal silicon dioxide, magnesium stearate, ethyl cellulose, triacetin, hypromellose, iron oxide red, titanium dioxide, and yellow iron oxide.

{ "type": "p", "children": [], "text": "The molecular formula of ribavirin is C8H12N4O5 and the molecular weight is 244.2. Ribavirin USP is a white crystalline powder. It is freely soluble in water and slightly soluble in anhydrous alcohol.\n Ribavirin USP is available as a light pink colored, capsule shaped, film-coated tablet for oral administration. Each tablet contains 200 mg of ribavirin USP and the following inactive ingredients: microcrystalline cellulose, pregelatinised starch (maize), sodium starch glycolate, povidone (Kollidon 30), colloidal silicon dioxide, magnesium stearate, ethyl cellulose, triacetin, hypromellose, iron oxide red, titanium dioxide, and yellow iron oxide." }

Ribavirin is an antiviral drug [see Microbiology (12.4)].

Multiple dose ribavirin pharmacokinetic data are available for HCV patients who received 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) AUC0-12 hr was 25,361±7110 ng·hr/mL and Cmax was 2748±818 ng/mL. The average time to reach Cmax was 2 hours. Trough 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 ribavirin following administration of a single oral dose of ribavirin is about 120 to 170 hours. The total apparent clearance following administration of a single oral dose of ribavirin is about 26 L/h. There is extensive accumulation of ribavirin after multiple dosing (twice daily) such that the Cmax at steady state was four-fold higher than that of a single dose. Effect of Food on Absorption of Ribavirin Bioavailability of a single oral dose of ribavirin was increased by coadministration with a high-fat meal. The absorption was slowed (Tmax was doubled) and the AUC0-192 h and Cmax increased by 42% and 66%, respectively, when 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 ribavirin elimination after administration of ribavirin is not known. In vitro studies indicate that 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 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 ribavirin exposures similar to that observed in patients with normal renal function receiving the standard 1000/1200 mg ribavirin daily dose. These doses have not been studied in patients. In 18 subjects with ESRD receiving chronic HD, ribavirin was administered at a dose of 200 mg daily. Ribavirin plasma exposures in these subjects were approximately 20% lower compared to subjects with normal renal function receiving the standard 1000/1200 mg ribavirin daily dose [see Dosage and Administration (2.4), Use in Specific Populations (8.7)]. Plasma ribavirin is removed by hemodialysis with an extraction ratio of approximately 50%; however, due to the large volume of distribution of ribavirin, plasma exposure is not expected to change with hemodialysis.

Mechanism of Action The mechanism by which ribavirin contributes to its antiviral efficacy in the clinic is not fully understood. Ribavirin has direct antiviral activity in tissue culture against many RNA viruses. Ribavirin increases the mutation frequency in the genomes of several RNA viruses and ribavirin triphosphate inhibits HCV polymerase in a biochemical reaction. Antiviral Activity in Cell Culture   In the stable HCV cell culture model system (HCV replicon), 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 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 ribavirin therapy. Viral genetic determinants associated with the variable response have not been definitively identified. Cross-resistance  Cross-resistance between IFN α and ribavirin has not been observed.

Carcinogenesis  In a p53 (+/-) mouse carcinogenicity study up to the maximum tolerated dose of 100 mg/kg/day, ribavirin was not oncogenic. Ribavirin was also not oncogenic in a rat 2-year carcinogenicity study at doses up to the maximum tolerated dose of 60 mg/kg/day. On a body surface area basis, these doses are approximately 0.5 and 0.6 times the maximum recommended daily human dose of ribavirin, respectively.  Mutagenesis   Ribavirin demonstrated mutagenic activity in the in vitro mouse lymphoma assay. No clastogenic activity was observed in an in vivo mouse micronucleus assay at doses up to 2000 mg/kg. However, results from studies published in the literature show clastogenic activity in the in vivo mouse micronucleus assay at oral doses up to 2000 mg/kg. A dominant lethal assay in rats was negative, indicating that if mutations occurred in rats they were not transmitted through male gametes. Impairment of Fertility  In a fertility study in rats, ribavirin showed a marginal reduction in sperm counts at the dose of 100 mg/kg/day with no effect on fertility. Upon cessation of treatment, total recovery occurred after 1 spermatogenesis cycle. Abnormalities in sperm were observed in studies in mice designed to evaluate the time course and reversibility of ribavirin-induced testicular degeneration at doses of 15 to 150 mg/kg/day (approximately 0.1 to 0.8 times the maximum recommended daily human dose of ribavirin) administered for 3 to 6 months. Upon cessation of treatment, essentially total recovery from ribavirin-induced testicular toxicity was apparent within 1 or 2 spermatogenic cycles. Female patients of childbearing potential and male patients with female partners of childbearing potential should not receive ribavirin unless the patient and his/her partner are using effective contraception (two reliable forms). Based on a multiple dose half-life (t1/2) of ribavirin of 12 days, effective contraception must be utilized for 6 months post therapy (i.e., 15 half-lives of clearance for ribavirin). No reproductive toxicology studies have been performed using PEGASYS® in combination with ribavirin. However, peginterferon alfa-2a and ribavirin when administered separately, each has adverse effects on reproduction. It should be assumed that the effects produced by either agent alone would also be caused by the combination of the two agents.

In a study in rats, it was concluded that dominant lethality was not induced by ribavirin at doses up to 200 mg/kg for 5 days (up to 1.7 times the maximum recommended human dose of 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 ribavirin) have demonstrated a relationship between chronic 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.

Adult Patients The safety and effectiveness of PEGASYS® in combination with ribavirin 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 PEGASYS® 180 mcg subcutaneous once weekly with an oral placebo, PEGASYS® 180 mcg once weekly with 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 ribavirin 1000 mg or 1200 mg by mouth. All patients received 48 weeks of therapy followed by 24 weeks of treatment-free follow-up. 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. PEGASYS® in combination with ribavirin resulted in a higher SVR compared to PEGASYS® alone or interferon alfa-2b and ribavirin (Table 9). In all treatment arms, patients with viral genotype 1, regardless of viral load, had a lower response rate to PEGASYS® in combination with ribavirin compared to patients with other viral genotypes.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="624"> <caption> <span>Table 9 Sustained Virologic Response (SVR) to Combination Therapy (Study NV15801) </span> </caption> <colgroup> <col width="18.4294871794872%"/> <col width="27.8846153846154%"/> <col width="22.1153846153846%"/> <col width="31.5705128205128%"/> </colgroup> <thead> <tr class="First Last"> <th class="Lrule Rrule Toprule"></th><th align="center" class="Lrule Rrule Toprule">Interferon alfa-2b +<br/>Ribavirin 1000 mg or<br/>1200 mg</th><th align="center" class="Lrule Rrule Toprule">PEGASYS<span class="Sup">® </span>+<br/>Placebo</th><th align="center" class="Lrule Rrule Toprule">PEGASYS<span class="Sup">®</span> + Ribavirin<br/>1000 mg or 1200 mg</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td class="Lrule Rrule" valign="middle">   All patients <br/> </td><td align="center" class="Rrule" valign="middle">197/444 (44%)<br/> </td><td align="center" class="Rrule" valign="middle">65/224 (29%)<br/> </td><td align="center" class="Rrule" valign="middle">241/453 (53%)<br/> </td> </tr> <tr> <td class="Lrule Rrule" valign="middle">   Genotype 1 <br/> </td><td align="center" class="Rrule" valign="middle">103/285 (36%)<br/> </td><td align="center" class="Rrule" valign="middle">29/145 (20%)<br/> </td><td align="center" class="Rrule" valign="middle">132/298 (44%)<br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="middle">   Genotypes 2 to 6 <br/> </td><td align="center" class="Rrule" valign="middle">94/159 (59%)<br/> </td><td align="center" class="Rrule" valign="middle">36/79 (46%)<br/> </td><td align="center" class="Rrule" valign="middle">109/155 (70%)<br/> </td> </tr> </tbody> </table></div>

Difference in overall treatment response (PEGASYS®/ribavirin – Interferon alfa-2b/ribavirin) was 9% (95% CI 2.3, 15.3). In Study NV15942, all patients received PEGASYS® 180 mcg subcutaneous once weekly and were randomized to treatment for either 24 or 48 weeks and to a 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 106 HCV 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 PEGASYS® and 1000 mg or 1200 mg of 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 ribavirin. HCV 2 and 3 - Irrespective of baseline viral titer, treatment for 24 weeks with PEGASYS® and 800 mg of ribavirin resulted in a similar SVR compared to longer treatment (48 weeks) and/or 1000 mg or 1200 mg of ribavirin (see Table 10). The numbers of patients with genotype 5 and 6 were too few to allow for meaningful assessment.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="674"> <caption> <span>Table 10 Sustained Virologic Response as a Function of Genotype (Study NV15942) </span> </caption> <thead> <tr class="First"> <th class="Lrule Rrule Toprule" rowspan="2"></th><th align="center" class="Lrule Rrule Toprule" colspan="2">24 Weeks Treatment</th><th align="center" class="Lrule Rrule Toprule" colspan="2">48 Weeks Treatment</th> </tr> <tr class="Last"> <th align="center" class="Lrule Rrule Toprule">PEGASYS<span class="Sup">®</span> +<br/>Ribavirin 800 mg<br/>(N=207)</th><th align="center" class="Lrule Rrule Toprule">PEGASYS<span class="Sup">®</span> + <br/>Ribavirin 1000 mg<br/>or 1200 mg*<br/>(N=280)</th><th align="center" class="Lrule Rrule Toprule">PEGASYS<span class="Sup">®</span> +<br/>Ribavirin 800 mg<br/>(N=361)</th><th align="center" class="Lrule Rrule Toprule">PEGASYS<span class="Sup">®</span> +<br/>Ribavirin 1000 mg<br/>or 1200 mg*<br/>(N=436)</th> </tr> </thead> <tfoot> <tr class="First Last"> <td colspan="5">* 1000 mg for body weight less than 75 kg; 1200 mg for body weight greater than or equal to 75 kg. <br/> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td class="Lrule Rrule" valign="middle">   Genotype 1 <br/> </td><td align="center" class="Rrule" valign="middle">29/101 (29%)<br/> </td><td align="center" class="Rrule" valign="middle">48/118 (41%)<br/> </td><td align="center" class="Rrule" valign="middle">99/250 (40%)<br/> </td><td align="center" class="Rrule" valign="middle">138/271 (51%)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">   Genotypes 2, 3 <br/> </td><td align="center" class="Rrule" valign="middle">79/96 (82%)<br/> </td><td align="center" class="Rrule" valign="middle">116/144 (81%)<br/> </td><td align="center" class="Rrule" valign="middle">75/99 (76%)<br/> </td><td align="center" class="Rrule" valign="middle">117/153 (76%)<br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="middle">   Genotype 4 <br/> </td><td align="center" class="Rrule" valign="middle">0/5 (0%)<br/> </td><td align="center" class="Rrule" valign="middle">7/12 (58%)<br/> </td><td align="center" class="Rrule" valign="middle">5/8 (63%)<br/> </td><td align="center" class="Rrule" valign="middle">9/11 (82%)<br/> </td> </tr> </tbody> </table></div>

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 ribavirin approximately 15 mg/kg/day plus PEGASYS® 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 ribavirin plus PEGASYS® or PEGASYS®  monotherapy; subjects failing PEGASYS®  monotherapy at 24 weeks or later could receive open-label ribavirin plus PEGASYS®. The initial randomized arms were balanced for demographic factors; 55 subjects received initial combination treatment of ribavirin plus PEGASYS® and 59 received PEGASYS® 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. 

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="486"> <caption> <span>Table 11 Sustained Virologic Response (Study NV17424) </span> </caption> <colgroup> <col width="23.6625514403292%"/> <col width="35.8024691358025%"/> <col width="40.5349794238683%"/> </colgroup> <tfoot> <tr class="First Last"> <td align="justify" colspan="3">*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<br/>***Includes HCV genotypes 2, 3 and others</td> </tr> </tfoot> <tbody class="Headless"> <tr class="Botrule First"> <td class="Lrule Rrule" valign="top"> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">PEGASYS<span class="Sup">®</span></span> <br/> <span class="Bold">180 mcg/1.73 m<span class="Sup">2</span> x BSA + Ribavirin 15 mg/kg* (N=55)</span> <br/> </td><td align="center" class="Rrule" valign="top"><span class="Bold">PEGASYS<span class="Sup">®</span>  <br/> 180 mcg/1.73 m<span class="Sup">2</span> x BSA + Placebo*</span> <br/> <span class="Bold">(N=59)</span> <br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">   <span class="Bold">All HCV genotypes**</span> <br/> </td><td align="center" class="Rrule" valign="middle">29 (53%)<br/> </td><td align="center" class="Rrule" valign="middle">12 (20%)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">       <span class="Bold">HCV genotype 1</span> <br/> </td><td align="center" class="Rrule" valign="middle">21/45 (47%)<br/> </td><td align="center" class="Rrule" valign="middle">8/47 (17%)<br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="middle">       <span class="Bold">HCV non-genotype 1***</span> <br/> </td><td align="center" class="Rrule" valign="middle">8/10 (80%)<br/> </td><td align="center" class="Rrule" valign="middle">4/12 (33%)<br/> </td> </tr> </tbody> </table></div>

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.

In Study NR15961, patients with CHC/HIV were randomized to receive either PEGASYS® 180 mcg subcutaneous once weekly plus an oral placebo, PEGASYS® 180 mcg once weekly plus ribavirin 800 mg by mouth daily or interferon alfa-2a, 3 MIU subcutaneous three times a week plus 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. Ribavirin or placebo treatment assignment was blinded in the PEGASYS® 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.

<div class="scrollingtable"><table border="0" cellpadding="0" cellspacing="0" width="624"> <caption> <span>Table 12 Sustained Virologic Response in Patients with Chronic Hepatitis C Coinfected With HIV (Study NR15961) </span> </caption> <colgroup> <col width="16.5064102564103%"/> <col width="29.6474358974359%"/> <col width="25%"/> <col width="28.8461538461538%"/> </colgroup> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule Toprule"></th><th class="Lrule Rrule Toprule">Interferon alfa-2a +<br/>Ribavirin 800 mg<br/>(N=289)</th><th class="Lrule Rrule Toprule">PEGASYS<span class="Sup">®</span> <br/>+ Placebo<br/>(N=289)</th><th class="Lrule Rrule Toprule">PEGASYS<span class="Sup">®</span> + <br/>Ribavirin 800 mg<br/>(N=290)</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td class="Lrule Rrule" valign="middle">   All patients<br/> </td><td align="center" class="Rrule" valign="middle">33 (11%)<br/> </td><td align="center" class="Rrule" valign="middle">58 (20%)<br/> </td><td align="center" class="Rrule" valign="middle">116 (40%)<br/> </td> </tr> <tr class="Botrule"> <td class="Lrule Rrule" valign="middle">   Genotype 1<br/> </td><td align="center" class="Rrule" valign="middle">12/171 (7%)<br/> </td><td align="center" class="Rrule" valign="middle">24/175 (14%)<br/> </td><td align="center" class="Rrule" valign="middle">51/176 (29%)<br/> </td> </tr> <tr class="Last"> <td class="Lrule Rrule" valign="middle">   Genotypes 2, 3<br/> </td><td align="center" class="Rrule" valign="middle">18/89 (20%)<br/> </td><td align="center" class="Rrule" valign="middle">32/90 (36%)<br/> </td><td align="center" class="Rrule" valign="middle">59/95 (62%)<br/> </td> </tr> </tbody> </table></div>

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 PEGASYS® and ribavirin combination therapy, 2% (2/85) achieved an SVR. In CHC patients with HIV coinfection who received 48 weeks of PEGASYS® alone or in combination with ribavirin treatment, mean and median HIV RNA titers did not increase above baseline during treatment or 24 weeks post-treatment.

Ribavirin Tablets USP, 200 mg are light pink colored, capsule shaped, film-coated tablets debossed with ‘F’ on one side and ‘10’ on the other side.       Bottles of 168                            NDC 65862-207-68      Bottles of 500                            NDC 65862-207-05 Storage and Handling Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Keep bottle tightly closed.

{ "type": "p", "children": [], "text": "\nRibavirin Tablets USP, 200 mg are light pink colored, capsule shaped, film-coated tablets debossed with ‘F’ on one side and ‘10’ on the other side.\n      Bottles of 168                            NDC 65862-207-68      Bottles of 500                            NDC 65862-207-05\n\nStorage and Handling\n\n\n\nStore at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Keep bottle tightly closed." }

{ "type": "ul", "children": [ "See FDA-approved patient labeling (Medication Guide)\n" ], "text": "" }

Pregnancy   Patients must be informed that ribavirin may cause birth defects and/or death of the exposed fetus. 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 ribavirin therapy and for 6 months post therapy. Patients should use two reliable methods of birth control while taking ribavirin therapy and for 6 months post therapy. 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 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 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 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 ribavirin with food. Patients should be questioned about prior history of drug abuse before initiating ribavirin/PEGASYS®, as relapse of drug addiction and drug overdoses have been reported in patients treated with interferons. Patients should be advised not to drink alcohol, as alcohol may exacerbate chronic hepatitis C infection. Patients should be informed about what to do in the event they miss a dose of 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 PEGASYS®/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 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. Dispense with Medication Guide available at: www.aurobindousa.com/medication-guides Distributed by: Aurobindo Pharma USA, Inc. 279 Princeton-Hightstown Road East Windsor, NJ 08520

{ "type": "p", "children": [], "text": "\nPregnancy\n   Patients must be informed that ribavirin may cause birth defects and/or death of the exposed fetus. 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 ribavirin therapy and for 6 months post therapy. Patients should use two reliable methods of birth control while taking ribavirin therapy and for 6 months post therapy. 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.\n 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 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)].\n\n Anemia\n\n The most common adverse event associated with 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 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.\n Patients who develop dizziness, confusion, somnolence, and fatigue should be cautioned to avoid driving or operating machinery.\n Patients should be advised to take ribavirin with food.\n Patients should be questioned about prior history of drug abuse before initiating ribavirin/PEGASYS®, as relapse of drug addiction and drug overdoses have been reported in patients treated with interferons.\n Patients should be advised not to drink alcohol, as alcohol may exacerbate chronic hepatitis C infection.\nPatients should be informed about what to do in the event they miss a dose of 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.\n Patients should be informed that the effect of PEGASYS®/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.\nPatients should be informed regarding the potential benefits and risks attendant to the use of 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.\n\nDispense with Medication Guide available at: www.aurobindousa.com/medication-guides\n\n Distributed by:\nAurobindo Pharma USA, Inc.\n279 Princeton-Hightstown Road East Windsor, NJ 08520 " }

  Manufactured by: Aurobindo Pharma Limited Hyderabad–500 032, India Revised: 05/2023

{ "type": "p", "children": [], "text": "  Manufactured by:\nAurobindo Pharma Limited\nHyderabad–500 032, India\n Revised: 05/2023" }

Dispense with Medication Guide available at: www.aurobindousa.com/medication-guides

{ "type": "p", "children": [], "text": "\nDispense with Medication Guide available at: www.aurobindousa.com/medication-guides\n" }

Ribavirin Tablets, USP (rye" ba vye' rin) Read this Medication Guide carefully before you start taking ribavirin tablets and read the Medication Guide each time you get more ribavirin tablets. 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 PEGASYS® (peginterferon alfa-2a). What is the most important information I should know about ribavirin tablets?

{ "type": "p", "children": [], "text": "\nRibavirin Tablets, USP\n(rye\" ba vye' rin)\n\n Read this Medication Guide carefully before you start taking ribavirin tablets and read the Medication Guide each time you get more ribavirin tablets. 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.\n Also read the Medication Guide for PEGASYS® (peginterferon alfa-2a).\n\nWhat is the most important information I should know about ribavirin tablets?\n" }

1. You should not take ribavirin tablets alone to treat chronic hepatitis C infection. Ribavirin tablets should be used with PEGASYS® to treat chronic hepatitis C infection.

{ "type": "p", "children": [], "text": "\n1. You should not take ribavirin tablets alone to treat chronic hepatitis C infection. Ribavirin tablets should be used with PEGASYS® to treat chronic hepatitis C infection.\n" }

2. Ribavirin tablets 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. Ribavirin tablets may not be right for you. If you have chest pain while you take ribavirin tablets, get emergency medical attention right away.

{ "type": "p", "children": [], "text": "\n 2. Ribavirin tablets 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. Ribavirin tablets may not be right for you. If you have chest pain while you take ribavirin tablets, get emergency medical attention right away." }

3. Ribavirin tablets may cause birth defects or death of your unborn baby. If you are pregnant or your sexual partner is pregnant, do not take ribavirin tablets. You or your sexual partner should not become pregnant while you take ribavirin tablets and for 6 months after treatment is over. You must use two forms of birth control when you take ribavirin tablets and for the 6 months after treatment.

{ "type": "p", "children": [], "text": "\n3. Ribavirin tablets may cause birth defects or death of your unborn baby. If you are pregnant or your sexual partner is pregnant, do not take ribavirin tablets. You or your sexual partner should not become pregnant while you take ribavirin tablets and for 6 months after treatment is over. You must use two forms of birth control when you take ribavirin tablets and for the 6 months after treatment." }

{ "type": "ul", "children": [ "Females must have a pregnancy test before starting ribavirin tablets, every month while treated with ribavirin tablets, and every month for the 6 months after treatment with ribavirin tablets. ", "\nIf you or your female sexual partner becomes pregnant while taking ribavirin tablets or within 6 months after you stop taking ribavirin tablets, tell your healthcare provider right away. " ], "text": "" }

What are ribavirin tablets? Ribavirin tablets are a prescription medicine used with another medicine called PEGASYS® (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 ribavirin tablets are safe and will work in children under 5 years of age. Who should not take ribavirin tablets? See “What is the most important information I should know about ribavirin tablets?”

{ "type": "p", "children": [], "text": "\nWhat are ribavirin tablets?\n\n Ribavirin tablets are a prescription medicine used with another medicine called PEGASYS® (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 ribavirin tablets are safe and will work in children under 5 years of age.\n\n Who should not take ribavirin tablets?\n\n See “What is the most important information I should know about ribavirin tablets?”\n" }

Do not take ribavirin tablets if you:

{ "type": "p", "children": [], "text": "\nDo not take ribavirin tablets if you:\n" }

{ "type": "ul", "children": [ "\nhave certain types of hepatitis caused by your immune system attacking your liver (autoimmune hepatitis) ", "\nhave certain blood disorders, such as thalassemia major or sickle-cell anemia (hemoglobinopathies)\n", "\ntake didanosine (Videx or Videx EC)" ], "text": "" }

Talk to your healthcare provider before starting treatment with ribavirin tablets if you have any of these medical conditions.  What should I tell my healthcare provider before taking ribavirin tablets?  Before you take ribavirin tablets, tell your healthcare provider if you have or have had:

{ "type": "p", "children": [], "text": "Talk to your healthcare provider before starting treatment with ribavirin tablets if you have any of these medical conditions. \n\n What should I tell my healthcare provider before taking ribavirin tablets? \nBefore you take ribavirin tablets, tell your healthcare provider if you have or have had:\n" }

{ "type": "ul", "children": [ "\ntreatment for hepatitis C that did not work for you\n", "\nserious allergic reactions to ribavirin tablets or to any of the ingredients in ribavirin tablets. See the end of this Medication Guide for a list of ingredients. ", "\nbreathing problems. Ribavirin tablets may cause or worsen your breathing problems you already have. ", "\nvision problems. Ribavirin tablets may cause eye problems or worsen eye problems you already have. You should have an eye exam before you start treatment with ribavirin tablets. ", "\ncertain blood disorders such as anemia\n", "\nhigh blood pressure, heart problems or have had a heart attack. Your healthcare provider should test your blood and heart before you start treatment with ribavirin tablets. ", "\nthyroid problems\n", "\ndiabetes. Ribavirin tablets and PEGASYS® combination therapy may make your diabetes worse or harder to treat. ", "\nliver problems other than hepatitis C virus infection ", "\nhuman immunodeficiency virus (HIV) or other immunity problems\n", "\nmental health problems, including depression or thoughts of suicide ", "\nkidney problems\n", "\nan organ transplant\n", "\ndrug addiction or abuse\n", "\ninfection with hepatitis B virus\n", "\nany other medical condition\n", "\nare breast feeding. It is not known if ribavirin passes into your breast milk. You and your healthcare provider should decide if you will take ribavirin tablets or breastfeed." ], "text": "" }

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 ribavirin tablets. Some medicines may affect how ribavirin tablets work or ribavirin tablets 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 ribavirin tablets?  

{ "type": "p", "children": [], "text": "\nTell 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 ribavirin tablets. Some medicines may affect how ribavirin tablets work or ribavirin tablets may affect how your other medicines work.\nEspecially 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).\nKnow the medicines you take. Keep a list of them to show your healthcare provider or pharmacist when you get a new medicine.\n\nHow should I take ribavirin tablets?\n\n \n" }

{ "type": "ul", "children": [ "Take ribavirin tablets exactly as your healthcare provider tells you. Your healthcare provider will tell you how much ribavirin tablets to take and when to take them. For children 5 years of age and older your healthcare provider will prescribe the dose of ribavirin tablets based on weight.  ", "Take ribavirin tablets with food. ", "If you miss a dose of ribavirin tablets, 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 ribavirin tablets, 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 ribavirin tablets, 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 ribavirin tablets 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 ribavirin tablets, and if needed during treatment." ], "text": "" }

What should I avoid while taking ribavirin tablets?  

{ "type": "p", "children": [], "text": "\nWhat should I avoid while taking ribavirin tablets?\n\n \n" }

{ "type": "ul", "children": [ "\nRibavirin tablets can make you feel tired, dizzy, or confused. You should not drive or operate machinery if you have any of these symptoms.\n", "\nDo not drink alcohol, including beer, wine, and liquor. This may make your liver disease worse." ], "text": "" }

What are the possible side effects of ribavirin tablets? Ribavirin tablets may cause serious side effects including: See “What is the most important information I should know about ribavirin tablets?”

{ "type": "p", "children": [], "text": "\nWhat are the possible side effects of ribavirin tablets?\n\n\nRibavirin tablets may cause serious side effects including:\n\n\nSee “What is the most important information I should know about ribavirin tablets?” \n" }

{ "type": "ul", "children": [ "\nSwelling and irritation of your pancreas (pancreatitis). You may have stomach pain, nausea, vomiting or diarrhea. ", "\nSevere allergic reactions. Symptoms may include hives, wheezing, trouble breathing, chest pain, swelling of your mouth, tongue, or lips, or severe rash. ", "\nSerious breathing problems. Difficulty breathing may be a sign of a serious lung infection (pneumonia) that can lead to death. ", "\nSerious eye problems that may lead to vision loss or blindness. ", "\nLiver 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. ", "\nSevere depression\n", "\nSuicidal thoughts and attempts\n", "\nEffect on growth in children. Children can experience a delay in weight gain and height increase while being treated with PEGASYS® and ribavirin tablets. 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 PEGASYS® and ribavirin tablets." ], "text": "" }

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 ribavirin tablets treatment.

{ "type": "p", "children": [], "text": "\n\n 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 ribavirin tablets treatment.\n" }

Common side effects of ribavirin tablets taken with PEGASYS® include:

{ "type": "p", "children": [], "text": "\n\n Common side effects of ribavirin tablets taken with PEGASYS® include:\n" }

{ "type": "ul", "children": [ "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 " ], "text": "" }

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 ribavirin tablets 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. You may also report side effects to Aurobindo Pharma USA, Inc. at 1-866-850-2876.  How should I store ribavirin tablets?  

{ "type": "p", "children": [], "text": "Tell your healthcare provider about any side effect that bothers you or that does not go away.\nThese are not all the possible side effects of ribavirin tablets treatment. For more information, ask your healthcare provider or pharmacist.\nCall your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.\nYou may also report side effects to Aurobindo Pharma USA, Inc. at 1-866-850-2876. \n\nHow should I store ribavirin tablets?\n\n \n" }

{ "type": "ul", "children": [ "Store ribavirin tablets at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. ", "Keep the bottle tightly closed. " ], "text": "" }

Keep ribavirin tablets and all medicines out of the reach of children. General information about the safe and effective use of ribavirin tablets It is not known if treatment with ribavirin tablets in combination with PEGASYS® 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 ribavirin tablets for a condition for which it was not prescribed. Do not give ribavirin tablets to other people, even if they have the same symptoms that you have. They may harm them. This Medication Guide summarizes the most important information about ribavirin tablets. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about ribavirin tablets that is written for healthcare professionals. What are the ingredients in ribavirin tablets?  Active Ingredient: ribavirin Inactive Ingredients: microcrystalline cellulose, pregelatinised starch (maize), sodium starch glycolate, povidone (Kollidon 30), colloidal silicon dioxide, magnesium stearate, ethyl cellulose, triacetin, hypromellose, iron oxide red, titanium dioxide, and yellow iron oxide. This Medication Guide has been approved by the U.S. Food and Drug Administration. Trademarks are the property of their respective owners. Distributed by: Aurobindo Pharma USA, Inc. 279 Princeton-Hightstown Road East Windsor, NJ 08520

{ "type": "p", "children": [], "text": "\n Keep ribavirin tablets and all medicines out of the reach of children.\n\n\nGeneral information about the safe and effective use of ribavirin tablets\n\n It is not known if treatment with ribavirin tablets in combination with PEGASYS® will prevent an infected person from spreading the hepatitis C virus to another person while on treatment. \nMedicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ribavirin tablets for a condition for which it was not prescribed. Do not give ribavirin tablets to other people, even if they have the same symptoms that you have. They may harm them.\nThis Medication Guide summarizes the most important information about ribavirin tablets. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about ribavirin tablets that is written for healthcare professionals.\n\n What are the ingredients in ribavirin tablets? \nActive Ingredient: ribavirin \n Inactive Ingredients: microcrystalline cellulose, pregelatinised starch (maize), sodium starch glycolate, povidone (Kollidon 30), colloidal silicon dioxide, magnesium stearate, ethyl cellulose, triacetin, hypromellose, iron oxide red, titanium dioxide, and yellow iron oxide.\nThis Medication Guide has been approved by the U.S. Food and Drug Administration.\n Trademarks are the property of their respective owners.\n Distributed by:\nAurobindo Pharma USA, Inc.\n279 Princeton-Hightstown Road East Windsor, NJ 08520 " }

  Manufactured by: Aurobindo Pharma Limited Hyderabad–500 032, India Revised: 05/2023

{ "type": "p", "children": [], "text": "  Manufactured by:\nAurobindo Pharma Limited\nHyderabad–500 032, India\n Revised: 05/2023" }

NDC 65862-207-68 Rx only     Ribavirin Tablets, USP 200 mg PHARMACIST: DISPENSE THE MEDICATION GUIDE PROVIDED SEPARATELY TO EACH PATIENT.  AUROBINDO                                168 Tablets

{ "type": "p", "children": [], "text": "\nNDC 65862-207-68\n\nRx only    \n\nRibavirin Tablets, USP\n\n200 mg\n\nPHARMACIST: DISPENSE THE MEDICATION GUIDE PROVIDED SEPARATELY TO EACH PATIENT.\n AUROBINDO                                168 Tablets\n" }