FDA label 407bd650-df3e-468b-e054-00144ff88e88

BOXED WARNING RIBASPHERE (ribavirin, USP) monotherapy is not effective for the treatment of chronic hepatitis C virus infection and should not be used alone for this indication (seeWARNINGS). The primary clinical toxicity of ribavirin is hemolytic anemia. The anemia associated with ribavirin therapy may result in worsening of cardiac disease that has led to fatal and nonfatal myocardial infarctions. Patients with a history of significant or unstable cardiac disease should not be treated with ribavirin (seeWARNINGS,ADVERSE REACTIONS, andDOSAGE AND ADMINISTRATION). Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. In addition, ribavirin has a multiple dose half-life of 12 days, and it may persist in non-plasma compartments for as long as 6 months. Ribavirin therapy is contraindicated in women who are pregnant and in the male partners of women who are pregnant. Extreme care must be taken to avoid pregnancy during therapy and for 6 months after completion of therapy in both female patients and in female partners of male patients who are taking ribavirin therapy. At least two reliable forms of effective contraception must be utilized during treatment and during the 6-month posttreatment follow-up period (seeCONTRAINDICATIONS,WARNINGS, andPRECAUTIONS: Information for Patients, and Pregnancy: Category X).

WARNINGS RIBASPHERE(ribavirin, USP) must not be used alone because ribavirin monotherapy is not effective for the treatment of chronic hepatitis C virus infection. The safety and efficacy of ribavirin have only been established when used together with peginterferon alfa-2a, recombinant. RIBASPHERE (ribavirin, USP) and peginterferon alfa-2a should be discontinued in patients who develop evidence of hepatic decompensation during treatment. There are significant adverse events caused by ribavirin/peginterferon alfa-2a therapy, including severe depression and suicidal ideation, hemolytic anemia, suppression of bone marrow function, autoimmune and infectious disorders, pulmonary dysfunction, pancreatitis, and diabetes. The PEGASYS package insert and MEDICATION GUIDE should be reviewed in their entirety prior to initiation of combination treatment for additional safety information. General Treatment with RIBASPHERE (ribavirin, USP) and peginterferon alfa-2a should be administered under the guidance of a qualified physician and may lead to moderate to severe adverse experiences requiring dose reduction, temporary dose cessation or discontinuation of therapy. Pregnancy Ribavirin may cause birth defects and/or death of the exposed fetus. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. 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. RIBASPHERE (ribavirin, USP) THERAPY SHOULD NOT BE STARTED UNLESS A REPORT OF A NEGATIVE PREGNANCY TEST HAS BEEN OBTAINED IMMEDIATELY PRIOR TO PLANNED INITIATION OF THERAPY. 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 RIBASPHERE (ribavirin, USP) therapy and for 6 months after therapy has stopped (seeCONTRAINDICATIONSandPRECAUTIONS: Information for Patientsand Pregnancy: Category X). Anemia The primary toxicity of ribavirin is hemolytic anemia (hemoglobin <10 g/dL), which was observed in approximately 13% of all ribavirin and peginterferon alfa-2a treated patients in clinical trials (seePRECAUTIONS: Laboratory Tests). The 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. 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 (seeDOSAGE AND ADMINISTRATION: RIBASPHERE (ribavirin, USP) Dosage Modification Guidelines). Because cardiac disease may be worsened by drug induced anemia, patients with a history of significant or unstable cardiac disease should not use RIBASPHERE (ribavirin, USP) (seeADVERSE REACTIONS). Hepatic Failure Chronic hepatitis C (CHC) patients with cirrhosis may be at risk of hepatic decompensation and death when treated with alpha interferons, including peginterferon alfa-2a. During treatment, patients'clinical status and hepatic function should be closely monitored, and peginterferon alfa-2a treatment should be immediately discontinued if decompensation (Child-Pugh scoreis observed (see CONTRAINDICATIONS ). Hypersensitivity Severe acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, and anaphylaxis) have been rarely observed during alpha interferon and ribavirin therapy. If such reaction occurs, therapy with peginterferon alfa-2a and ribavirin should be discontinued and appropriate medical therapy immediately instituted. Serious skin reactions including vesilculobullous 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 rarely reported in the patients receiving peginterferon alfa-2a with and without ribavirin. Patients developing signs or symptoms of severe skin reactions must discontinue therapy. (see ADVERSE REACTIONS: Postmarketing Experience ). Pulmonary Pulmonary symptoms, including dyspnea, pulmonary infiltrates, pneumonitis and occasional cases of fatal pneumonia, have been reported during therapy with ribavirin and interferon. In addition, sarcoidosis or the exacerbation of sarcoidosis has been reported. If there is evidence of pulmonary infiltrates or pulmonary function impairment, the patient should be closely monitored and, if appropriate, combination RIBASPHERE (ribavirin, USP)/peginterferon alfa-2a treatment should be discontinued. Other RIBASPHERE (ribavirin, USP) and peginterferon alfa-2a therapy should be suspended in patients with signs and symptoms of pancreatitis, and discontinued in patients with confirmed pancreatitis. RIBASPHERE (ribavirin, USP) should not be used in patients with creatinine clearance <50 mL/min (see CLINICAL PHARMACOLOGY: Special Populations ). RIBASPHERE (ribavirin, USP) must be discontinued immediately and appropriate medical therapy instituted if an acute hypersensitivity reaction (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) develops. Transient rashes do not necessitate interruption of treatment.

ADVERSE REACTIONS Peginterferon alfa-2a in combination with ribavirin causes a broad variety of serious adverse reactions (see BOXED WARNING and WARNINGS ). The most common life-threatening or fatal events induced or aggravated by peginterferon alfa-2a and ribavirin were depression, suicide, relapse of drug abuse/overdose, and bacterial infections, each occurring at a frequency of <1%. In all studies, one or more serious adverse reactions occurred in 10% of CHC monoinfected patients receiving peginterferon alfa-2a alone or in combination with ribavirin. The most common serious adverse event (3% in CHC) was bacterial infection (e.g., sepsis, osteomyelitis, endocarditis, pyelonephritis, pneumonia). Other SAEs occurred at a frequency of <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. Nearly all patients in clinical trials experienced one or more adverse events. 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. Ten percent of CHC monoinfected patients receiving 48 weeks of therapy with peginterferon alfa-2a in combination with ribavirin 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 required modification of peginterferon alfa-2a and/or ribavirin therapy. The most common reason for dose modification of peginterferon alfa-2a in CHC patients was for laboratory abnormalities; neutropenia (20%) and thrombocytopenia (4%). The most common reason for dose modification of ribavirin in CHC patients was anemia (22%). Peginterferon alfa-2a 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 to1200 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 peginterferon alfa-2a and 800 mg ribavirin were observed to have lower incidence of serious adverse events (3% vs. 10%), hemoglobin <10 g/dL (3% vs. 15%), dose modifications of peginterferon alfa-2a (30% vs. 36%) and ribavirin (19% vs. 38%), and of withdrawal from treatment (5% vs. 15%) compared to patients treated for 48 weeks with peginterferon alfa-2a and 1000 mg or 1200 mg ribavirin. On the other hand, the overall incidence of adverse events appeared to be similar in the two treatment groups. Because clinical trials are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug. Also, the adverse event rates listed here may not predict the rates observed in a broader patient population in clinical practice. Table 3 Adverse Reactions Occurring inof Patients in Chronic Hepatitis C Clinical Trials (Study NV15801*) Body SystemCHC Combination Therapy Study NV15801Peginterferon alfa180+ 1000 mg or 1200 mg Ribavirin 48 weekInterferon alfa-2b + 1000 mg or 1200 mg Ribavirin 48 weekN=451N=443%%Application Site DisordersInjection site reaction2316Endocrine DisordersHypothyroidism45FluSymptoms and SignsFatigue/Asthenia6568Pyrexia4155Rigors2537Pain109GastrointestinalNausea/Vomiting2529Diarrhea1110Abdominal pain89Dry mouth47Dyspepsia65Hematologic**Lymphopenia1412Anemia1111Neutropenia278Thrombocytopenia5<1Metabolic and NutritionalAnorexia2426Weight decrease1010Musculoskeletal, Connective Tissue and BoneMyalgia4049Arthralgia2223Back pain55NeurologicalHeadache4349Dizziness (excluding vertigo)1414Memory impairment65PsychiatricIrritability/Anxiety/Nervousness3338Insomnia3037Depression2028Concentration impairment1013Mood alteration56Resistance Mechanism DisordersOverall1210Respiratory, Thoracic and MediastinalDyspnea1314Cough107Dyspnea exertional47Skin and Subcutaneous TissueAlopecia2833Pruritus1918Dermatitis1613Dry skin1013Rash85Sweating increased65Eczema54Visual DisordersVision blurred52 Laboratory Test Values Anemia due to hemolysis is the most significant toxicity of ribavirin therapy. Anemia (hemoglobin <10 g/dL) was observed in 13% of all ribavirin and peginterferon alfa-2a combination-treated patients in clinical trials. The maximum drop in hemoglobin occurred during the first 8 weeks of initiation of ribavirin therapy (see DOSAGE AND ADMINISTRATION: Dose Modifications ). Postmarketing Experience The following adverse reactions have been identified and reported during post-approval use of peginterferon alfa-2a therapy: hearing impairment, hearing loss, serious skin reactions, and dehydration (see WARNINGS: Hypersensitivity ).