RIBAVIRIN: 43,397 Adverse Event Reports & Safety Profile

DESCRIPTION VIRAZOLE ® (Ribavirin for Inhalation Solution, USP) is a brand name for ribavirin, a synthetic nucleoside with antiviral activity. VIRAZOLE for inhalation solution is a sterile, lyophilized powder to be reconstituted for aerosol administration.

Each

100 mL glass vial contains 6 grams of ribavirin, and when reconstituted to the recommended volume of 300 mL with Sterile Water for Injection, USP or Sterile Water for Inhalation (no preservatives added), will contain 20 mg of ribavirin per mL, pH approximately 5.5. Aerosolization is to be carried out in a Small Particle Aerosol Generator (SPAG ® -2) nebulizer only. Ribavirin is 1-beta-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide, with the following structural formula: Ribavirin is a stable, white crystalline compound with a maximum solubility in water of 142 mg/mL at 25°C and with only a slight solubility in ethanol. The empirical formula is C 8 H 12 N 4 O 5 and the molecular weight is 244.21. 541adf1b-figure-01

INDICATIONS AND USAGE Ribavirin for inhalation solution, USP is indicated for the treatment of hospitalized infants and young children with severe lower respiratory tract infections due to respiratory syncytial virus. Treatment early in the course of severe lower respiratory tract infection may be necessary to achieve efficacy. Only severe RSV lower respiratory tract infection should be treated with ribavirin for inhalation solution, USP. The vast majority of infants and children with RSV infection have disease that is mild, self-limited, and does not require hospitalization or antiviral treatment. Many children with mild lower respiratory tract involvement will require shorter hospitalization than would be required for a full course of ribavirin for inhalation solution, USP aerosol (3 to 7 days) and should not be treated with the drug. Thus the decision to treat with ribavirin for inhalation solution, USP should be based on the severity of the RSV infection. The presence of an underlying condition such as prematurity, immunosuppression or cardiopulmonary disease may increase the severity of clinical manifestations and complications of RSV infection. Use of aerosolized ribavirin for inhalation solution, USP in patients requiring mechanical ventilator assistance should be undertaken only by physicians and support staff familiar with this mode of administration and the specific ventilator being used (see WARNINGS , and DOSAGE AND ADMINISTRATION ). Diagnosis RSV infection should be documented by a rapid diagnostic method such as demonstration of viral antigen in respiratory tract secretions by immunofluorescence 3,4 or ELISA 5 before or during the first 24 hours of treatment. Treatment may be initiated while awaiting rapid diagnostic test results. However, treatment should not be continued without documentation of RSV infection. Non-culture antigen detection techniques may have false positive or false negative results. Assessment of the clinical situation, the time of year and other parameters may warrant reevaluation of the laboratory diagnosis. Description of Studies Non-Mechanically-Ventilated Infants: In two placebo controlled trials in infants hospitalized with RSV lower respiratory tract infection, aerosolized ribavirin for inhalation solution, USP treatment had a therapeutic effect, as judged by the reduction in severity of clinical manifestations of disease by treatment day 3. 3,4 Treatment was most effective when instituted within the first 3 days of clinical illness. Virus titers in respiratory secretions were also significantly reduced with ribavirin for inhalation solution, USP in one of these original studies. 4 Additional controlled studies conducted since these initial trials of aerosolized ribavirin for inhalation solution, USP in the treatment of RSV infection have supported these data. Mechanically-Ventilated Infants : A randomized, double-blind, placebo-controlled evaluation of aerosolized ribavirin for inhalation solution, USP at the recommended dose was conducted in 28 infants requiring mechanical ventilation for respiratory failure caused by documented RSV infection. 6 Mean age was 1.4 months (SD, 1.7 months). Seven patients had underlying diseases predisposing them to severe infection and 21 were previously normal. Aerosolized ribavirin for inhalation solution, USP treatment significantly decreased the duration of mechanical ventilation required (4.9 vs. 9.9 days, p=0.01) and duration of required supplemental oxygen (8.7 vs. 13.5 days, p=0.01). Intensive patient management and monitoring techniques were employed in this study. These included endotracheal tube suctioning every 1 to 2 hours; recording of proximal airway pressure, ventilatory rate, and F l O 2 every hour; and arterial blood gas monitoring every 2 to 6 hours. To reduce the risk of ribavirin for inhalation solution, USP precipitation and ventilator malfunction, heated wire tubing, two bacterial filters connected in series in the expiratory limb of the ventilator (with filter changes every 4 hours), and water column pressure release valves to monitor internal ventilator pressures were used in connecting ventilator circuits to the SPAG-2. Employing these techniques, no technical difficulties with ribavirin for inhalation solution, USP administration were encountered during the study. Adverse events consisted of bacterial pneumonia in one case, staphyloccus bacteremia in one case and two cases of post-extubation stridor. None were felt to be related to ribavirin for inhalation solution, USP administration.

AND ADMINISTRATION Ribavirin capsules are administered according to body weight. ( 2.1 , 2.2 , 2.3 ) Dose reduction or discontinuation is recommended in patients experiencing certain adverse reactions or renal dysfunction. ( 2.5 , 2.6 , 12.3 )

2.1 General Dosing Information Do not open, crush or break ribavirin capsules. Ribavirin capsules should be taken with food <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span>.

2.2 Ribavirin capsules/PegIntron Combination Therapy 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 log 10 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 <span class="opacity-50 text-xs">[see Clinical Studies (14.1) ]</span>.

Table

1: Recommended Adult Dosing for Ribavirin capsules in Combination with PegIntron Body Weight (kg) Ribavirin capsules Daily Dose Ribavirin Number of Capsules Less than 66 800 mg/day 2 x 200 mg capsules AM 2 x 200 mg capsules PM 66 to 80 1,000 mg/day 2 x 200 mg capsules AM 3 x 200 mg capsules PM 81 to 105 1,200 mg/day 3 x 200 mg capsules AM 3 x 200 mg capsules PM Greater than 105 1,400 mg/day 3 x 200 mg capsules AM 4 x 200 mg capsules PM 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.

Table

2: Recommended Pediatric Ribavirin Dosing in Combination with PegIntron * Ribavirin Oral Solution may be used in any patient regardless of body weight.

Body

Weight (kg)

Ribavirin Daily Dose Ribavirin

Number of Capsules Less than 47 15 mg/kg/day Use Ribavirin Oral Solution* 47 to 59 800 mg/day 2 x 200 mg capsules AM 2 x 200 mg capsules PM 60 to 73 1,000 mg/day 2 x 200 mg capsules AM 3 x 200 mg capsules PM Greater than 73 1,200 mg/day 3 x 200 mg capsules AM 3 x 200 mg capsules PM

2.3 Ribavirin capsules/INTRON A Combination Therapy 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 <span class="opacity-50 text-xs">[see Indications and Usage (1.1), Adverse Reactions (6.1) , and Clinical Studies (14) ]</span>.

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.

Table

3: Recommended Ribavirin capsules Dosing in Combination with INTRON A Body Weight Ribavirin Capsules At least 75 kg 2 x 200 mg capsules AM 3 x 200 mg capsules PM daily orally Greater than 75 kg 3 x 200 mg capsules AM 3 x 200 mg capsules PM daily orally 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.

2.4 Testing Prior to Initiation of Ribavirin capsules The following laboratory tests are recommended in all patients treated with ribavirin capsules prior to initiation of treatment and periodically thereafter. Standard hematologic tests - including hemoglobin (pretreatment, Week 2 and Week 4 of therapy, and as clinically appropriate <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2 , 5.6) ]</span>, complete and differential white blood cell counts, and platelet count. Blood chemistries - liver function tests and TSH. Pregnancy - in women of childbearing potential. ECG <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span>.

2.5 Dose Modifications 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) <span class="opacity-50 text-xs">[see Warnings and Precautions (5) ]</span>. 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 <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> . Patients with impaired renal function and those over the age of 50 should be carefully monitored with respect to development of anemia <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) , Use in Specific Populations (8.5) , and Clinical Pharmacology (12.3) ]</span> . 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span>. 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) <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</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 Laboratory Parameters Reduce Ribavirin capsules Daily Dose (see note 1) if: Reduce PegIntron or INTRON A Dose (see note 2) if: Discontinue Therapy if: Note 1: Adult patients: 1 st 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 nd 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. Pediatric patients: 1 st dose reduction of ribavirin is to 12 mg/kg/day, 2 nd dose reduction of ribavirin is to 8 mg/kg/day.

Note

2: Adult patients treated with ribavirin capsules and PegIntron: 1 st dose reduction of PegIntron is to 1 mcg/kg/week. If needed, 2 nd dose reduction of PegIntron is to 0.5 mcg/kg/week. Pediatric patients treated with ribavirin capsules and PegIntron: 1 st dose reduction of PegIntron is to 40 mcg/m 2 /week, 2 nd dose reduction of PegIntron is to 20 mcg/m 2 /week. For patients on ribavirin capsules /INTRON A combination therapy : reduce INTRON A dose by 50%. * 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. † 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 [see Warnings and Precautions (5.2) ] . WBC N/A 1.0 to <1.5 x 10 9 /L <1.0 x 10 9 /L Neutrophils N/A 0.5 to <0.75 x 10 9 /L <0.5 x 10 9 /L Platelets N/A 25 to < 50 x 10 9 /L (adults) <25 x 10 9 /L (adults) N/A 50 to <70 x 10 9 /L (pediatrics) <50 x 10 9 /L (pediatrics) Creatinine N/A N/A >2 mg/dL (pediatrics) Hemoglobin in patients without history of cardiac disease 8.5 to <10 g/dL N/A <8.5 g/dL Reduce Ribavirin capsules Dose by 200 mg/day and PegIntron or INTRON A Dose by Half if: Hemoglobin in patients with history of stable cardiac disease *† ≥2 g/dL decrease in hemoglobin during any four-week period during treatment <8.5 g/dL or <12 g/dL after four weeks of dose reduction Refer to labeling for INTRON A or PegIntron for additional information about how to reduce an INTRON A or PegIntron dose.

2.6 Discontinuation of Dosing 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 log 10 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 log 10 compared to pretreatment level, or at 24 weeks if HCV-RNA is still detectable.

Ribavirin capsules combination therapy is contraindicated in: 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) ]. men whose female partners are pregnant [see Use in Specific Populations (8.3) ] 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) ] 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) ]. Pregnancy and men whose female partners are pregnant ( 4 , 5.1 , 8.1 , 8.3 ) Known hypersensitivity reactions such as Stevens-Johnson syndrome, toxic, epidermal necrolysis, and erythema multiforme to ribavirin or any component of the product ( 4 ) Autoimmune hepatitis ( 4 ) Hemoglobinopathies ( 4 ) Creatinine clearance less than 50 mL/min ( 4 , 12.3 ) Coadministration with didanosine ( 4 , 7.1 )

REACTIONS The following serious adverse drug reactions are discussed in other sections of the labeling: Embryo-Fetal Toxicity [see Warnings and Precautions (5.1) ] Anemia [see Warnings and Precautions (5.2) ] Pancreatitis [see Warnings and Precautions (5.3) ]

Pulmonary

Disorders [see Warnings and Precautions (5.4) ]

Ophthalmic

Disorders [see Warnings and Precautions (5.5) ] Dental and Periodontal Disorders [see Warnings and Precautions (5.7) ] Impact on Growth in Pediatric Patients [see Warnings and Precautions (5.9) ] Hemolytic anemia occurred in more than 10% of adult patients receiving ribavirin/PegIntron or INTRON A combination therapy. ( 6.1 ) Most common adverse reactions (40% or greater) in adult patients receiving ribavirin/PegIntron or INTRON A combination therapy are injection site reaction, fatigue/asthenia, headache, rigors, fevers, nausea, myalgia and anxiety/emotional lability/irritability. ( 6.1 ) Most common adverse reactions (greater than 25%) in pediatric patients receiving ribavirin/PegIntron therapy are: pyrexia, headache, neutropenia, fatigue, anorexia, injection site erythema, and vomiting. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span>. 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: Ribavirin/PegIntron Combination therapy trials: Clinical Study 1 – evaluated PegIntron monotherapy (not further described in this label; see labeling for PegIntron for information about this trial).

Study

2 – evaluated ribavirin 800 mg/day flat dose in combination with 1.5 mcg/kg/week PegIntron or with INTRON A.

Study

3 – evaluated PegIntron/weight-based ribavirin in combination with PegIntron/flat dose ribavirin regimen.

Study

4 – compared two PegIntron (1.5 mcg/kg/week and 1 mcg/kg/week) doses in combination with ribavirin and a third treatment group receiving Pegasys ® (180 mcg/week)/Copegus ® (1000 to 1200 mg/day).

Study

5 – evaluated PegIntron (1.5 mcg/kg/week) in combination with weight-based ribavirin in prior treatment failure subjects. PegIntron/Ribavirin Combination Therapy in Pediatric Patients Ribavirin/INTRON A Combination Therapy trials for adults and pediatrics Serious adverse reactions have occurred in approximately 12% of subjects in clinical trials with PegIntron with or without 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.

Table

5: Adverse Reactions Occurring in Greater Than 5% of Adult Subjects * A subject may have reported more than one adverse reaction within a body system/organ class category.

Adverse Reactions

Percentage of Subjects Reporting Adverse Reactions* Adverse Reactions Percentage of Subjects Reporting Adverse Reactions* PegIntron 1.5 mcg/kg/ Ribavirin (N=511) INTRON A/ Ribavirin (N=505) PegIntron 1.5 mcg/kg/ Ribavirin (N=511) INTRON A/ Ribavirin (N=505)

Application Site Musculoskeletal Injection Site

Inflammation Injection Site Reaction 25 58 18 36 Myalgia 56 50 Arthralgia 34 28 Autonomic Nervous System Musculoskeletal Pain 21 19 Dry Mouth 12 8 Psychiatric Increased Sweating 11 7 Insomnia 40 41 Flushing 4 3 Depression 31 34 Body as a Whole Anxiety/Emotional Lability/Irritability 47 47 Fatigue/Asthenia 66 63 Concentration Impaired 17 21 Headache 62 58 Agitation 8 5 Rigors 48 41 Nervousness 6 6 Fever 46 33 Reproductive, Female Weight Loss 29 20 Menstrual Disorder 7 6 Right Upper Quadrant Pain 12 6 Resistance Mechanism Chest Pain 8 7 Viral Infection 12 12 Malaise 4 6 Fungal Infection 6 1 Central/Peripheral Nervous System Respiratory System Dizziness 21 17 Dyspnea 26 24 Endocrine Coughing 23 16 Hypothyroidism 5 4 Pharyngitis 12 13 Gastrointestinal Rhinitis 8 6 Nausea 43 33 Sinusitis 6 5 Anorexia 32 27 Skin and Appendages Diarrhea 22 17 Alopecia 36 32 Vomiting 14 12 Pruritus 29 28 Abdominal Pain 13 13 Rash 24 23 Dyspepsia 9 8 Skin Dry 24 23 Constipation 5 5 Special Senses, Other Hematologic Disorders Taste Perversion 9 4 Neutropenia 26 14 Vision Disorders Anemia 12 17 Vision Blurred 5 6 Leukopenia 6 5 Conjunctivitis 4 5 Thrombocytopenia 5 2 Liver and Biliary System Hepatomegaly 4 4 Table 6 summarizes the treatment-related adverse reactions in Study 4 that occurred at a greater than or equal to 10% incidence.

Table

6: Treatment-Related Adverse Reactions (Greater Than or Equal to 10% Incidence)

By Descending Frequency Study

4 Percentage of Subjects Reporting Treatment-Related Adverse Reactions Adverse Reactions PegIntron 1.5 mcg/kg with Ribavirin (N=1019) PegIntron 1 mcg/kg with Ribavirin (N=1016)

Pegasys

180 mcg with Copegus (N=1035)

Fatigue

67 68 64 Headache 50 47 41 Nausea 40 35 34 Chills 39 36 23 Insomnia 38 37 41 Anemia 35 30 34 Pyrexia 35 32 21 Injection Site Reactions 34 35 23 Anorexia 29 25 21 Rash 29 25 34 Myalgia 27 26 22 Neutropenia 26 19 31 Irritability 25 25 25 Depression 25 19 20 Alopecia 23 20 17 Dyspnea 21 20 22 Arthralgia 21 22 22 Pruritus 18 15 19 Influenza-like Illness 16 15 15 Dizziness 16 14 13 Diarrhea 15 16 14 Cough 15 16 17 Weight Decreased 13 10 10 Vomiting 12 10 9 Unspecified Pain 12 13 9 Dry Skin 11 11 12 Anxiety 11 11 10 Abdominal Pain 10 10 10 Leukopenia 9 7 10 The incidence of serious adverse reactions was comparable in all trials.

In Study

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.

Table

7: Percentage of Pediatric Subjects with Treatment-Related Adverse Reactions (in At Least 10% of All Subjects)

System Organ Class Preferred Term

All Subjects (N=107) Blood and Lymphatic System Disorders Neutropenia 33% Anemia 11% Leukopenia 10% Gastrointestinal Disorders Abdominal Pain 21% Abdominal Pain Upper 12% Vomiting 27% Nausea 18% General Disorders and Administration Site Conditions Pyrexia 80% Fatigue 30% Injection-site Erythema 29% Chills 21% Asthenia 15% Irritability 14% Investigations Weight Loss 19% Metabolism and Nutrition Disorders Anorexia 29% Decreased Appetite 22% Musculoskeletal and Connective Tissue Disorders Arthralgia 17% Myalgia 17% Nervous System Disorders Headache 62% Dizziness 14% Skin and Subcutaneous Tissue Disorders Alopecia 17% Ninety-four of 107 subjects enrolled in a 5-year 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.

Table

8: Selected Laboratory Abnormalities During Treatment with Ribavirin and PegIntron or Ribavirin and INTRON A in Previously Untreated Subjects * The table summarizes the worst category observed within the period per subject per laboratory test. Only subjects with at least one treatment value for a given laboratory test are included. † ULN=Upper limit of normal.

Laboratory

Parameters * Percentage of Subjects Adults (Study 2)

Pediatrics

PegIntron/ Ribavirin (N=511) INTRON A/ Ribavirin (N=505) PegIntron/ Ribavirin (N=107) * Hemoglobin (g/dL) 9.5 to <11.0 26 27 30 8.0 to <9.5 3 3 2 6.5 to 7.9 0.2 0.2 - Leukocytes (x 10 9 /L) 2.0 to 2.9 46 41 39 1.5 to <2.0 24 8 3 1.0 to 1.4 5 1 - Neutrophils (x 10 9 /L) 1.0 to 1.5 33 37 35 0.75 to <1.0 25 13 26 0.5 to <0.75 18 7 13 <0.5 4 2 3 Platelets (x 10 9 /L) 70 to 100 15 5 1 50 to <70 3 0.8 - 30 to 49 0.2 0.2 - 25 to <50 - - 1 Total Bilirubin (mg/dL) (µmole/L) 1.5 to 3.0 10 13 - 1.26 to 2.59 x ULN † - - 7 3.1 to 6.0 0.6 0.2 - 2.6 to 5 x ULN † - - - 6.1 to 12.0 0 0.2 - ALT (U/L) 2 x Baseline 0.6 0.2 1 2.1 to 5 x Baseline 3 1 5 5.1 to 10 x Baseline 0 0 3 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 10 9 /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/mm 3 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/mm 3 ) 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.

Table

9: Selected Treatment-Related Adverse Reactions: Previously Untreated and Relapse Adult Subjects and Previously Untreated Pediatric Subjects * Subjects reporting one or more adverse reactions. A subject may have reported more than one adverse reaction within a body system/organ class category.

Subjects Reporting Adverse

Reactions* Percentage of Subjects U.S.

Previously Untreated

Study U.S.

Relapse Study Pediatric Subjects

24 weeks of treatment 48 weeks of treatment 24 weeks of treatment 48 weeks of treatment INTRON A/ Ribavirin (N=228) INTRON A/ Placebo (N=231) INTRON A/ Ribavirin (N=228) INTRON A/ Placebo (N=225) INTRON A/ Ribavirin (N=77) INTRON A/ Placebo (N=76) INTRON A/ Ribavirin (N=118)

Application Site Disorders Injection Site

Inflammation 13 10 12 14 6 8 14 Injection Site Reaction 7 9 8 9 5 3 19 Body as a Whole - General Disorders Headache 63 63 66 67 66 68 69 Fatigue 68 62 70 72 60 53 58 Rigors 40 32 42 39 43 37 25 Fever 37 35 41 40 32 36 61 Influenza-like Symptoms 14 18 18 20 13 13 31 Asthenia 9 4 9 9 10 4 5 Chest Pain 5 4 9 8 6 7 5 Central & Peripheral Nervous System Disorders Dizziness 17 15 23 19 26 21 20 Gastrointestinal System Disorders Nausea 38 35 46 33 47 33 33 Anorexia 27 16 25 19 21 14 51 Dyspepsia 14 6 16 9 16 9 <1 Vomiting 11 10 9 13 12 8 42 Musculoskeletal System Disorders Myalgia 61 57 64 63 61 58 32 Arthralgia 30 27 33 36 29 29 15 Musculoskeletal Pain 20 26 28 32 22 28 21 Psychiatric Disorders Insomnia 39 27 39 30 26 25 14 Irritability 23 19 32 27 25 20 10 Depression 32 25 36 37 23 14 13 Emotional Lability 7 6 11 8 12 8 16 Concentration Impaired 11 14 14 14 10 12 5 Nervousness 4 2 4 4 5 4 3 Respiratory System Disorders Dyspnea 19 9 18 10 17 12 5 Sinusitis 9 7 10 14 12 7 <1 Skin and Appendages Disorders Alopecia 28 27 32 28 27 26 23 Rash 20 9 28 8 21 5 17 Pruritus 21 9 19 8 13 4 12 Special Senses, Other Disorders Taste Perversion 7 4 8 4 6 5 <1 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.

Table

10: Selected Laboratory Abnormalities During Treatment with Ribavirin and INTRON A: Previously Untreated and Relapse Adult Subjects and Previously Untreated Pediatric Subjects Percentage of Subjects U.S.

Previously Untreated

Study U.S.

Relapse Study Pediatric Subjects

24 weeks of treatment 48 weeks of treatment 24 weeks of treatment 48 weeks of treatment INTRON A/ Ribavirin (N=228) INTRON A / Placebo (N=231) INTRON A/ Ribavirin (N=228) INTRON A/ Placebo (N=225) INTRON A/ Ribavirin (N=77) INTRON A / Placebo (N=76) INTRON A/ Ribavirin (N=118) Hemoglobin (g/dL) 9.5 to 10.9 24 1 32 1 21 3 24 8.0 to 9.4 5 0 4 0 4 0 3 6.5 to 7.9 0 0 0 0.4 0 0 0 <6.5 0 0 0 0 0 0 0 Leukocytes (x 10 9 /L) 2.0 to 2.9 40 20 38 23 45 26 35 1.5 to 1.9 4 1 9 2 5 3 8 1.0 to 1.4 0.9 0 2 0 0 0 0 <1.0 0 0 0 0 0 0 0 Neutrophils (x 10 9 /L) 1.0 to 1.49 30 32 31 44 42 34 37 0.75 to 0.99 14 15 14 11 16 18 15 0.5 to 0.74 9 9 14 7 8 4 16 <0.5 11 8 11 5 5 8 3 Platelets (x 10 9 /L) 70 to 99 9 11 11 14 6 12 0.8 50 to 69 2 3 2 3 0 5 2 30 to 49 0 0.4 0 0.4 0 0 0 <30 0.9 0 1 0.9 0 0 0 Total Bilirubin (mg/dL) 1.5 to 3.0 27 13 32 13 21 7 2 3.1 to 6.0 0.9 0.4 2 0 3 0 0 6.1 to 12.0 0 0 0.4 0 0 0 0 >12.0 0 0 0 0 0 0 0

6.2 Postmarketing Experiences 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

AND PRECAUTIONS Significant adverse reactions associated with ribavirin/PEGASYS ® combination therapy include severe depression and suicidal ideation, hemolytic anemia, suppression of bone marrow function, autoimmune and infectious disorders, ophthalmologic disorders, cerebrovascular disorders, pulmonary dysfunction, colitis, pancreatitis, and diabetes. The PEGASYS ® Package Insert should be reviewed in its entirety for additional safety information prior to initiation of combination treatment. Birth defects and fetal death with ribavirin: Do not use in pregnancy and for 6 months after treatment. Patients must have a negative pregnancy test prior to therapy, use at least 2 forms of contraception and undergo monthly pregnancy tests (4 , 5.1 , 8.1) PEGASYS ® /Ribavirin: Patients exhibiting the following conditions should be closely monitored and may require dose reduction or discontinuation of therapy: Hemolytic anemia may occur with a significant initial drop in hemoglobin. This may result in worsening cardiac disease leading to fatal or nonfatal myocardial infarctions (5.2 , 6.1) Risk of hepatic failure and death: Monitor hepatic function during treatment and discontinue treatment for hepatic decompensation (5.3) Severe hypersensitivity reactions including urticaria, angioedema, bronchoconstriction, and anaphylaxis, and serious skin reactions such as Stevens-Johnson syndrome (5.4) Pulmonary disorders, including pulmonary function impairment and pneumonitis, including fatal cases of pneumonia (5.5) Severe depression and suicidal ideation, autoimmune and infectious disorders, suppression of bone marrow function, pancreatitis, and diabetes (5) Bone marrow suppression with azathioprine coadministration (5.6) Growth impairment with combination therapy in pediatric patients (5.8)

5.1 Pregnancy 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 <span class="opacity-50 text-xs">[see Boxed Warning , Contraindications (4) , Use in Specific Populations (8.1) , and Patient Counseling Information (17) ]</span>.

5.2 Anemia 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) <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> . 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> . Because cardiac disease may be worsened by drug-induced anemia, patients with a history of significant or unstable cardiac disease should not use ribavirin <span class="opacity-50 text-xs">[see Boxed Warning and Dosage and Administration (2.3) ]</span> .

5.3 Hepatic Failure Chronic hepatitis C (CHC) patients with cirrhosis may be at risk of hepatic decompensation and death when treated with alpha interferons, including PEGASYS ® . Cirrhotic CHC patients coinfected with HIV receiving highly active antiretroviral therapy (HAART) and interferon alfa-2a with or without ribavirin appear to be at increased risk for the development of hepatic decompensation compared to patients not receiving HAART.

In

Study NR15961 [see Clinical Studies (14.3) ], among 129 CHC/HIV cirrhotic patients receiving HAART, 14 (11%) of these patients across all treatment arms developed hepatic decompensation resulting in 6 deaths.

All

14 patients were on NRTIs, including stavudine, didanosine, abacavir, zidovudine, and lamivudine. These small 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) ].

5.4 Hypersensitivity Severe acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, and anaphylaxis) have been observed during alpha interferon and ribavirin therapy. If such a reaction occurs, therapy with PEGASYS ® and 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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span> .

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

5.6 Bone Marrow Suppression Pancytopenia (marked decreases in RBCs, neutrophils and platelets) and bone marrow suppression have been reported in the literature to occur within 3 to 7 weeks after the concomitant administration of pegylated interferon/ribavirin and azathioprine. In this limited number of patients (n=8), myelotoxicity was reversible within 4 to 6 weeks upon withdrawal of both HCV antiviral therapy and concomitant azathioprine and did not recur upon reintroduction of either treatment alone. PEGASYS ® , ribavirin, and azathioprine should be discontinued for pancytopenia, and pegylated interferon/ribavirin should not be re-introduced with concomitant azathioprine <span class="opacity-50 text-xs">[see Drug Interactions (7.3) ]</span> .

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

5.8 Impact on Growth in Pediatric Patients During combination therapy for up to 48 weeks with PEGASYS ® plus ribavirin, growth inhibition was observed in pediatric subjects 5 to 17 years of age. Decreases in weight for age z-score and height for age z-score up to 48 weeks of therapy compared with baseline were observed.

At

2 years post-treatment, 16% of pediatric subjects were more than 15 percentiles below their baseline weight curve and 11% were more than 15 percentiles below their baseline height curve. The available longer term data on subjects who were followed up to 6 years post-treatment are too limited to determine the risk of reduced adult height in some patients [see Clinical Studies Experience (6.1) ].

5.9 Laboratory Tests 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: Platelet count greater than or equal to 90,000 cells/mm 3 (as low as 75,000 cells/mm 3 in HCV patients with cirrhosis or 70,000 cells/mm 3 in patients with CHC and HIV) Absolute neutrophil count (ANC) greater than or equal to 1500 cells/mm 3 TSH and T 4 within normal limits or adequately controlled thyroid function CD4+ cell count greater than or equal to 200 cells/mm 3 or CD4+ cell count greater than or equal to 100 cells/mm 3 but less than 200 cells/mm 3 and HIV-1 RNA less than 5,000 copies/mL in patients coinfected with HIV Hemoglobin greater than or equal to 12 g/dL for women and greater than or equal to 13 g/dL for men in CHC monoinfected patients Hemoglobin greater than or equal to 11 g/dL for women and greater than or equal to 12 g/dL for men in patients with CHC and HIV

PRECAUTIONS General Patients with severe lower respiratory tract infection due to respiratory syncytial virus require optimum monitoring and attention to respiratory and fluid status (see SPAG-2 manual).

Drug Interactions

Clinical studies of interactions of ribavirin for inhalation solution, USP with other drugs commonly used to treat infants with RSV infections, such as digoxin, bronchodilators, other antiviral agents, antibiotics or anti-metabolites, have not been conducted. Interference by ribavirin for inhalation solution, USP with laboratory tests has not been evaluated. Carcinogenesis and Mutagenesis Ribavirin increased the incidence of cell transformations and mutations in mouse Balb/c 3T3 (fibroblasts) and L5178Y (lymphoma) cells at concentrations of 0.015 and 0.03-5.0 mg/mL, respectively (without metabolic activation). Modest increases in mutation rates (3-4x) were observed at concentrations between 3.75-10.0 mg/mL in L5178Y cells in vitro with the addition of a metabolic activation fraction. In the mouse micronucleus assay, ribavirin was clastogenic at intravenous doses of 20-200 mg/kg, (estimated human equivalent of 1.67-16.7 mg/kg, based on body surface area adjustment for a 60 kg adult). Ribavirin was not mutagenic in a dominant lethal assay in rats at intraperitoneal doses between 50-200 mg/kg when administered for 5 days (estimated human equivalent of 7.14-28.6 mg/kg, based on body surface area adjustment; see Pharmacokinetics ). In vivo carcinogenicity studies with ribavirin are incomplete. However, results of a chronic feeding study with ribavirin in rats, at doses of 16-100 mg/kg/day (estimated human equivalent of 2.3-14.3 mg/kg/day, based on body surface area adjustment for the adult), suggest that ribavirin may induce benign mammary, pancreatic, pituitary and adrenal tumors. Preliminary results of 2 oral gavage oncogenicity studies in the mouse and rat (18-24 months; doses of 20-75 and 10-40 mg/kg/day, respectively [estimated human equivalent of 1.67-6.25 and 1.43-5.71 mg/kg/day, respectively, based on body surface area adjustment for the adult]) are inconclusive as to the carcinogenic potential of ribavirin (see Pharmacokinetics ). However, these studies have demonstrated a relationship between chronic ribavirin exposure and increased incidences of vascular lesions (microscopic hemorrhages in mice) and retinal degeneration (in rats). Impairment of Fertility The fertility of ribavirin-treated animals (male or female) has not been fully investigated. However, in the mouse, administration of ribavirin at doses between 35-150 mg/kg/day (estimated human equivalent of 2.92-12.5 mg/kg/day, based on body surface area adjustment for the adult) resulted in significant seminiferous tubule atrophy, decreased sperm concentrations, and increased numbers of sperm with abnormal morphology. Partial recovery of sperm production was apparent 3-6 months following dose cessation. In several additional toxicology studies, ribavirin has been shown to cause testicular lesions (tubular atrophy) in adult rats at oral dose levels as low as 16 mg/kg/day (estimated human equivalent of 2.29 mg/kg/day, based on body surface area adjustment; see Pharmacokinetics ). Lower doses were not tested. The reproductive capacity of treated male animals has not been studied. Pregnancy: Category X Ribavirin has demonstrated significant teratogenic and/or embryocidal potential in all animal species in which adequate studies have been conducted. Teratogenic effects were evident after single oral doses of 2.5 mg/kg or greater in the hamster, and after daily oral doses of 0.3 and 1.0 mg/kg in the rabbit and rat, respectively (estimated human equivalent doses of 0.12 and 0.14 mg/kg, based on body surface area adjustment for the adult). 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. Ribavirin caused embryolethality in the rabbit at daily oral dose levels as low as 1 mg/kg. No teratogenic effects were evident in the rabbit and rat administered daily oral doses of 0.1 and 0.3 mg/kg, respectively with estimated human equivalent doses of 0.01 and 0.04 mg/kg, based on body surface area adjustment (see Pharmacokinetics ). These doses are considered to define the "No Observable Teratogenic Effects Level" (NOTEL) for ribavirin in the rabbit and rat. Following oral administration of ribavirin in the pregnant rat (1.0 mg/kg) and rabbit (0.3 mg/kg), mean plasma levels of drug ranged from 0.10-0.20 µM[0.024-0.049 µ/mL] at 1 hour after dosing, to undetectable levels at 24 hours.

At

1 hour following the administration of 0.3 or 0.1 mg/kg in the rat and rabbit (NOTEL), respectively, mean plasma levels of drug in both species were near or below the limit of detection (0.05 µM; see Pharmacokinetics ). Although clinical studies have not been performed, ribavirin for inhalation solution, USP may cause fetal harm in humans. As noted previously, ribavirin is concentrated in red blood cells and persists for the life of the cell. Thus the terminal half-life for the systemic elimination of ribavirin is essentially that of the half-life of circulating erythrocytes. The minimum interval following exposure to ribavirin for inhalation solution, USP before pregnancy may be safely initiated is unknown (see CONTRAINDICATIONS , WARNINGS , and Information for Health Care Personnel ).

Nursing Mothers

Ribavirin for inhalation solution, USP has been shown to be toxic to lactating animals and their offspring. It is not known if ribavirin for inhalation solution, USP is excreted in human milk. Information for Health Care Personnel Health care workers directly providing care to patients receiving aerosolized ribavirin for inhalation solution, USP should be aware that ribavirin has been shown to be teratogenic in all animal species in which adequate studies have been conducted (rodents and rabbits). Although no reports of teratogenesis in offspring of mothers who were exposed to aerosolized ribavirin for inhalation solution, USP during pregnancy have been confirmed, no controlled studies have been conducted in pregnant women. Studies of environmental exposure in treatment settings have shown that the drug can disperse into the immediate bedside area during routine patient care activities with highest ambient levels closest to the patient and extremely low levels outside of the immediate bedside area. Adverse reactions resulting from actual occupational exposure in adults are described below (see Adverse Events in Health Care Workers ). Some studies have documented ambient drug concentrations at the bedside that could potentially lead to systemic exposures above those considered safe for exposure during pregnancy (1/1000 of the NOTEL dose in the most sensitive animal species). 7,8,9 A 1992 study conducted by the National Institute of Occupational Safety and Health (NIOSH) demonstrated measurable urine levels of ribavirin in health care workers exposed to aerosol in the course of direct patient care. 7 Levels were lowest in workers caring for infants receiving aerosolized ribavirin for inhalation solution, USP with mechanical ventilation and highest in those caring for patients being administered the drug via an oxygen tent or hood. This study employed a more sensitive assay to evaluate ribavirin levels in urine than was available for several previous studies of environmental exposure that failed to detect measurable ribavirin levels in exposed workers. Creatinine adjusted urine levels in the NIOSH study ranged from less than 0.001 to 0.140 µM of ribavirin per gram of creatinine in exposed workers. However, the relationship between urinary ribavirin levels in exposed workers, plasma levels in animal studies, and the specific risk of teratogenesis in exposed pregnant women is unknown. It is good practice to avoid unnecessary occupational exposure to chemicals wherever possible. Hospitals are encouraged to conduct training programs to minimize potential occupational exposure to ribavirin for inhalation solution, USP. Health care workers who are pregnant should consider avoiding direct care of patients receiving aerosolized ribavirin for inhalation solution, USP. If close patient contact cannot be avoided, precautions to limit exposure should be taken. These include administration of ribavirin for inhalation solution, USP in negative pressure rooms; adequate room ventilation (at least six air exchanges per hour); the use of aerosol scavenging devices; turning off the SPAG-2 device for 5 to 10 minutes prior to prolonged patient contact; and wearing appropriately fitted respirator masks. Surgical masks do not provide adequate filtration of ribavirin for inhalation solution, USP particles. Further information is available from NIOSH's Hazard Evaluation and Technical Assistance Branch and additional recommendations have been published in an Aerosol Consensus Statement by the American Respiratory Care Foundation and the American Association for Respiratory Care. 10

INTERACTIONS Results from a pharmacokinetic sub-study demonstrated no pharmacokinetic interaction between PEGASYS ® (peginterferon alfa-2a) and ribavirin. Nucleoside analogues: Closely monitor for toxicities. Discontinue nucleoside reverse transcriptase inhibitors or reduce dose or discontinue interferon, ribavirin or both with worsening toxicities (7.1) Azathioprine: Concomitant use of azathioprine with ribavirin has been reported to induce severe pancytopenia and may increase the risk of azathioprine-related myelotoxicity (7.3)

7.1 Nucleoside Reverse Transcriptase Inhibitors (NRTIs) 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.

7.2 Drugs Metabolized by Cytochrome P450 In vitro studies indicate that ribavirin does not inhibit CYP 2C9, CYP 2C19, CYP 2D6 or CYP 3A4.

7.3 Azathioprine 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.6) ]</span> .