Ribavirin (ribavirin 200 mg) Dailymed

Recent Major Changes Section

Boxed Warning	10/2010
Indications and Usage (1)	10/2010
Dosage and Administration (2.2, 2.3, 2.4, 2.5)	10/2010
Contraindications (4)	12/2010
Warnings and Precautions (5.1, 5.2, 5.3, 5.5, 5.6, 5.7, 5.8, 5.9)	10/2010
Warnings and Precautions, Hepatic Failure (5.3)	12/2010

Warning: Risk Of Serious Disorders And Ribavirin-associated Effects

• • Ribavirin monotherapy is not effective for the treatment of chronic hepatitis C virus infection and should not be used alone for this indication.
• • The primary clinical toxicity of ribavirin is hemolytic anemia. The anemia associated with ribavirin therapy may result in worsening of cardiac disease and lead to fatal and nonfatal myocardial infarctions. Patients with a history of significant or unstable cardiac disease should not be treated with ribavirin [see Warnings and Precautions (5.2), Adverse Reactions (6.1), and Dosage and Administration (2.3)].
• • 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. Therefore, ribavirin, including ribavirin tablets, 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 post treatment follow-up period [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.1)].

WARNING: RISK OF SERIOUS DISORDERS AND RIBAVIRIN-ASSOCIATED EFFECTS

See full prescribing information for complete boxed warning.

• • Ribavirin monotherapy, including ribavirin tablets, is not effective for the treatment of chronic hepatitis C virus infection (Boxed Warning).
• • The hemolytic anemia associated with ribavirin therapy may result in worsening of cardiac disease and lead to fatal and nonfatal myocardial infarctions. Patients with a history of significant or unstable cardiac disease should not be treated with ribavirin (2.3, 5.2, 6.1).
• • Significant teratogenic and embryocidal effects have been demonstrated in all animal species exposed to ribavirin. Therefore, ribavirin is contraindicated in women who are pregnant and in the male partners of women who are pregnant. Extreme care must be taken to avoid pregnancy during therapy and for 6 months after completion of treatment in both female patients and in female partners of male patients who are taking ribavirin therapy (4, 5.1, 8.1).

• •CHC: Ribavirin tablets are administered according to body weight and genotype (2.1)
• •CHC with HIV coinfection: 800 mg by mouth daily for a total of 48 weeks, regardless of genotype (2.2)
• •Dose reduction or discontinuation is recommended in patients experiencing certain adverse reactions or renal impairment (2.4, 2.5)

2.1 Chronic Hepatitis C Monoinfection

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 ).

Ribavirin tablets should be taken with food.

Table 1. Peginterferon alfa-2a and Ribavirin Tablet Dosing Recommendations

Hepatitis C Virus (HCV) Genotype	Peginterferon alfa-2a Dose See peginterferon alfa-2a Package Insert for further details on peginterferon alfa-2a dosing and administration.	Ribavirin Tablet Dose	Duration
Genotypes 1, 4	180 mcg	< 75 kg = 1000 mg	48 weeks
		≥ 75 kg = 1200 mg	48 weeks
Genotypes 2, 3	180 mcg	800 mg	24 weeks

Genotypes 2 and 3 showed no increased response to treatment beyond 24 weeks (see Table 6 ).Data on genotypes 5 and 6 are insufficient for dosing recommendations.

2.2 Chronic Hepatitis C With HIV Coinfection

The recommended dose for treatment of chronic hepatitis C in patients coinfected with HIV is peginterferon alfa-2a 180 mcg subcutaneous once weekly and ribavirin tablets, 800 mg by mouth daily for a total duration of 48 weeks, regardless of HCV genotype.

Ribavirin tablets should be taken with food.

2.3 Dose Modifications

If severe adverse reactions or laboratory abnormalities develop during combination ribavirin tablet/peginterferon alfa-2a therapy, the dose should be modified or discontinued, if appropriate, until the adverse reactions abate or decrease in severity. If intolerance persists after dose adjustment, ribavirin tablet/peginterferon alfa-2a therapy should be discontinued. Table 2 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 preexisting 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 ) ].

Table 2. Ribavirin Tablet Dosage Modification Guidelines

Laboratory Values	Reduce Only Ribavirin Tablet Dose to 600 mg/day One 200 mg tablet in the morning and two 200 mg tablets in the evening. if:	Discontinue Ribavirin Tablets if:
Hemoglobin in patients with no cardiac disease	< 10 g/dL	< 8.5 g/dL
Hemoglobin in patients with history of stable cardiac disease	≥ 2 g/dL decrease in hemoglobin during any 4 week period treatment	< 12 g/dL despite 4 weeks at reduced dose

Once ribavirin tablets have been withheld due to either a laboratory abnormality or clinical manifestation, 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).

See peginterferon alfa-2a full prescribing information for recommendations on peginterferon alfa-2a dose modification.

2.4 Discontinuation of Dosing

Discontinuation of peginterferon alfa-2a/ribavirin tablet therapy should be considered if the patient has failed to demonstrate at least a 2 log₁₀ reduction from baseline in HCV RNA by 12 weeks of therapy, or undetectable HCV RNA levels after 24 weeks of therapy.

Peginterferon alfa-2a/ribavirin tablet therapy should be discontinued in patients who develop hepatic decompensation during treatment [see Warnings and Precautions ( 5.3 ) ].

2.5 Renal Impairment

Ribavirin tablets should not be used in patients with creatinine clearance < 50 mL/min [see Use in Specific Populations ( 8.7 ) ].

3 Dosage Forms And Strengths

Ribavirin tablets are available as a light-pink to pink, round standard normal convex, coated tablets for oral administration. Each tablet contains 200 mg of ribavirin.

• •Ribavirin tablets 200 mg (3)

4 Contraindications

Ribavirin tablets are contraindicated in:

• • 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 ) ].

Ribavirin tablets and peginterferon alfa-2a combination therapy is contraindicated in patients with:

• • Autoimmune hepatitis.
• • Hepatic decompensation (Child-Pugh score greater than 6; class B and C) in cirrhotic CHC monoinfected patients before treatment [see Warnings and Precautions ( 5.3 ) ].
• • Hepatic decompensation (Child-Pugh score greater than or equal to 6) in cirrhotic CHC patients coinfected with HIV before treatment [see Warnings and Precautions ( 5.3 ) ].

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

Ribavirin tablets in combination with peginterferon alfa-2a are contraindicated in patients with:

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

5 Warnings And Precautions

Significant adverse reactions associated with ribavirin/peginterferon alfa-2a combination therapy include severe depression and suicidal ideation, hemolytic anemia, suppression of bone marrow function, autoimmune and infectious disorders, ophthalmologic disorders, cerebrovascular disorders, pulmonary dysfunction, colitis, pancreatitis, and diabetes.

The peginterferon alfa-2a Package Insert should be reviewed in its entirety for additional safety information prior to initiation of combination treatment.

• •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)

Peginterferon alfa-2a/Ribavirin: Patients exhibiting the following conditions should be closely monitored and may require dose reduction or discontinuation of therapy:

• •Hemolytic anemia may occur with a significant initial drop in hemoglobin. This may result in worsening cardiac disease leading to fatal or nonfatal myocardial infarctions (5.2, 6.1)
• •Risk of hepatic failure and death: Monitor hepatic function during treatment and discontinue treatment for hepatic decompensation (5.3)
• •Severe hypersensitivity reactions including urticaria, angioedema, bronchoconstriction, and anaphylaxis, and serious skin reactions such as Stevens-Johnson syndrome (5.4)
• •Pulmonary disorders, including pulmonary function impairment and pneumonitis, including fatal cases of pneumonia (5.6)
• •Severe depression and suicidal ideation, autoimmune and infectious disorders, suppression of bone marrow function, pancreatitis, and diabetes (5)
• •Bone marrow suppression with azathioprine coadministration (5.7)

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 [see Boxed Warning , Contraindications ( 4 ), Use in Specific Populations ( 8.1 ), and Patient Counseling Information ( 17 ) ].

5.2 Anemia

The primary toxicity of ribavirin is hemolytic anemia, which was observed in approximately 13% of all ribavirin/peginterferon alfa-2a-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 preexisting 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 ) ].

5.3 Hepatic Failure

Chronic hepatitis C (CHC) patients with cirrhosis may be at risk of hepatic decompensation and death when treated with alpha interferons, including peginterferon alfa-2a. Cirrhotic CHC patients coinfected with HIV receiving highly active antiretroviral therapy (HAART) and interferon alfa-2a with or without 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 ribavirin/peginterferon alfa-2a 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 peginterferon alfa-2a 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 peginterferon alfa-2a with and without ribavirin. Patients developing signs or symptoms of severe skin reactions must discontinue therapy [see Adverse Reactions ( 6.2 ) ].

5.5 Renal Impairment

Ribavirin should not be used in patients with creatinine clearance < 50 mL/min [see Use in Specific Populations ( 8.7 ) ].

5.6 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/peginterferon alfa-2a treatment should be discontinued.

5.7 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. Peginterferon alfa-2a, ribavirin, and azathioprine should be discontinued for pancytopenia, and pegylated interferon/ribavirin should not be re-introduced with concomitant azathioprine [see Drug Interactions ( 7.3 ) ].

5.8 Pancreatitis

Ribavirin and peginterferon alfa-2a therapy should be suspended in patients with signs and symptoms of pancreatitis, and discontinued in patients with confirmed pancreatitis.

5.9 Laboratory Tests

Before beginning peginterferon alfa-2a/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 preexisting cardiac abnormalities should have electrocardiograms administered before treatment with peginterferon alfa-2a/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 the 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. 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 peginterferon alfa-2a may be considered as a guideline to acceptable baseline values for initiation of treatment:

• • Platelet count ≥ 90,000 cells/mm³ (as low as 75,000 cells/mm³ in HCV patients with cirrhosis or 70,000 cells/mm³ in patients with CHC and HIV)
• • Absolute neutrophil count (ANC) ≥ 1500 cells/mm³
• • TSH and T₄ within normal limits or adequately controlled thyroid function
• • CD4+ cell count ≥ 200 cells/μL or CD4+ cell count ≥ 100 cells/μL but < 200 cells/μL and HIV-1 RNA < 5000 copies/mL in patients coinfected with HIV
• • Hemoglobin ≥ 12 g/dL for women and ≥ 13 g/dL for men in CHC monoinfected patients
• • Hemoglobin ≥ 11 g/dL for women and ≥ 12 g/dL for men in patients with CHC and HIV

6 Adverse Reactions

Peginterferon alfa-2a in combination with ribavirin causes a broad variety of serious adverse reactions [see Boxed Warning and Warnings and Precautions (5)]. The most common serious or life-threatening adverse reactions induced or aggravated by ribavirin/peginterferon alfa-2a include depression, suicide, relapse of drug abuse/overdose, and bacterial infections each occurring at a frequency of < 1%. Hepatic decompensation occurred in 2% (10/574) CHC/HIV patients [see Warnings and Precautions (5.3)].


The most common adverse reactions (frequency > 40%) in adults receiving combination therapy are fatigue/asthenia, pyrexia, myalgia, and headache (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact TEVA USA, PHARMACOVIGILANCE at 1-888-838-2872, X6351 or drug.safety@tevausa.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

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 peginterferon alfa-2a 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 < 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 3 shows rates of adverse events occurring in ≥ 5% 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 peginterferon alfa-2a 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 peginterferon alfa-2a and/or ribavirin therapy. The most common reason for dose modification of peginterferon alfa-2a in CHC and CHC/HIV patients was for laboratory abnormalities; neutropenia (20% and 27%, respectively) and thrombocytopenia (4% and 6%, respectively). The most common reason for dose modification of ribavirin in CHC and CHC/HIV patients was anemia (22% and 16%, respectively).

Peginterferon alfa-2a dose was reduced in 12% of patients receiving 1000 mg to 1200 mg 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 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 modification 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.

Table 3. Adverse Reactions Occurring in ≥ 5% of Patients in Chronic Hepatitis C Clinical Trials (Study NV15801)

Body System	CHC Combination Therapy Study NV15801
	Peginterferon alfa-2a 180 mcg + 1000 mg or 1200 mg Ribavirin Tablets 48 weeks	Interferon alfa-2b + 1000 mg or 1200 mg Ribavirin Capsules 48 weeks
	N = 451	N = 443
	%	%
Application Site Disorders
Injection site reaction	23	16
Endocrine Disorders
Hypothyroidism	4	5
Flu-like Symptoms and Signs
Fatigue/Asthenia	65	68
Pyrexia	41	55
Rigors	25	37
Pain	10	9
Gastrointestinal
Nausea/Vomiting	25	29
Diarrhea	11	10
Abdominal pain	8	9
Dry mouth	4	7
Dyspepsia	6	5
Hematologic Severe hematologic abnormalities (lymphocyte < 0.5 x 109/L; hemoglobin < 10 g/dL;neutrophil < 0.75 x 109/L; platelet < 50 x 109/L).
Lymphopenia	14	12
Anemia	11	11
Neutropenia	27	8
Thrombocytopenia	5	< 1
Metabolic and Nutritional
Anorexia	24	26
Weight decrease	10	10
Musculoskeletal, Connective Tissue and Bone
Myalgia	40	49
Arthralgia	22	23
Back pain	5	5
Neurological
Headache	43	49
Dizziness (excluding vertigo)	14	14
Memory impairment	6	5
Psychiatric
Irritability/Anxiety/Nervousness	33	38
Insomnia	30	37
Depression	20	28
Concentration impairment	10	13
Mood alteration	5	6
Resistance Mechanism Disorders
Overall	12	10
Respiratory, Thoracic and Mediastinal
Dyspnea	13	14
Cough	10	7
Dyspnea exertional	4	7
Skin and Subcutaneous Tissue
Alopecia	28	33
Pruritus	19	18
Dermatitis	16	13
Dry skin	10	13
Rash	8	5
Sweating increased	6	5
Eczema	5	4
Visual Disorders
Vision blurred	5	2

Common Adverse Reactions in CHC With HIV Coinfection

The adverse event profile of coinfected patients treated with peginterferon alfa-2a/ribavirin in Study NR15961 was generally similar to that shown for monoinfected patients in Study NV15801 (Table 3). Events occurring more frequently in coinfected patients were neutropenia (40%), anemia (14%), thrombocytopenia (8%), weight decrease (16%), and mood alteration (9%).

Laboratory Test Abnormalities

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 (2.3)].

Table 4. Selected Laboratory Abnormalities During Treatment With Ribavirin in Combination With Either Peginterferon alfa-2a or Interferon alfa-2b

Laboratory Parameter	Peginterferon alfa-2a + Ribavirin 1000/1200 mg 48 wks	Interferon alfa-2b + Ribavirin 1000/1200 mg 48 wks
	(N = 887)	(N = 443)
Neutrophils (x 109/L)
1.0 to 1.49	34%	38%
0.5 to 0.99	49%	21%
< 0.5	5%	1%
Platelets (x 109/L)
50 to 74.9	11%	4%
20 to 49.9	5%	< 1%
< 20	0	0
Hemoglobin (g/dL)
8.5 to 9.9	11%	11%
< 8.5	2%	< 1%

6.2 Postmarketing Experience

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

Blood and Lymphatic System disorders

Pure red cell aplasia

Ear and Labyrinth disorders

Hearing impairment, hearing loss

Eye disorders

Serous retinal detachment

Immune disorders

Liver and renal graft rejection

Metabolism and Nutrition disorders

Dehydration

Skin and Subcutaneous Tissue disorders

Stevens-Johnson syndrome (SJS)

Toxic epidermal necrolysis (TEN)