Ribavirin (ribavirin 200 mg) Dailymed

Significant adverse reactions associated with ribavirin tablets/ 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 tablets: 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 tablets 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 tablets 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 tablets 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 tablets/ PEGASYS^®-treated subjects in clinical trials. Anemia associated with ribavirin tablets 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 tablets. Patients should be assessed for underlying cardiac disease before initiation of ribavirin therapy. Patients with pre-existing cardiac disease should have electrocardiograms administered before treatment, and should be appropriately monitored during therapy. If there is any deterioration of cardiovascular status, therapy should be suspended or discontinued [see Dosage and Administration (2.3)]. Because cardiac disease may be worsened by drug-induced anemia, patients with a history of significant or unstable cardiac disease should not use ribavirin tablets [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 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 tablets 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 tablets should be discontinued immediately and appropriate medical therapy instituted. Serious skin reactions including vesiculobullous eruptions, reactions in the spectrum of Stevens-Johnson Syndrome (erythema multiforme major) with varying degrees of skin and mucosal involvement and exfoliative dermatitis (erythroderma) have been reported in patients receiving PEGASYS^® with and without ribavirin. Patients developing signs or symptoms of severe skin reactions must discontinue therapy [see Adverse Reactions (6.2)].

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

5.7 Pancreatitis

Ribavirin tablets 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 tablets 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 tablets.

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 tablets 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/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) greater than or equal to 1500 cells/mm³
• •TSH and T₄ within normal limits or adequately controlled thyroid function
• •CD4+ cell count greater than or equal to 200 cells/mm³ or CD4+ cell count greater than or equal to 100 cells/mm³ but less than 200 cells/mm³ and HIV-1 RNA less than 5000 copies/mL 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

6 Adverse Reactions

PEGASYS^® in combination with ribavirin tablets 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 tablets/ PEGASYS^® include depression, suicide, relapse of drug abuse/overdose, and bacterial infections each occurring at a frequency of less than 1%. Hepatic decompensation occurred in 2% (10/574) CHC/HIV patients [see Warnings and Precautions (5.3)].


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

The most common adverse reactions in pediatric subjects were similar to those seen in adults. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 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.

Adult Patients

In the pivotal registration trials NV15801 and NV15942, 886 patients received ribavirin tablets for 48 weeks at doses of 1000/1200 mg based on body weight. In these trials, one or more serious adverse reactions occurred in 10% of CHC monoinfected subjects and in 19% of CHC/HIV subjects receiving PEGASYS^® alone or in combination with ribavirin tablets. The most common serious adverse event (3% in CHC and 5% in CHC/HIV) was bacterial infection (e.g., sepsis, osteomyelitis, endocarditis, pyelonephritis, pneumonia).

Other serious adverse reactions occurred at a frequency of less than 1% and included: suicide, suicidal ideation, psychosis, aggression, anxiety, drug abuse and drug overdose, angina, hepatic dysfunction, fatty liver, cholangitis, arrhythmia, diabetes mellitus, autoimmune phenomena (e.g., hyperthyroidism, hypothyroidism, sarcoidosis, systemic lupus erythematosus, rheumatoid arthritis), peripheral neuropathy, aplastic anemia, peptic ulcer, gastrointestinal bleeding, pancreatitis, colitis, corneal ulcer, pulmonary embolism, coma, myositis, cerebral hemorrhage, thrombotic thrombocytopenic purpura, psychotic disorder, and hallucination.

The percentage of patients in clinical trials who experienced one or more adverse events was 98%. The most commonly reported adverse reactions were psychiatric reactions, including depression, insomnia, irritability, anxiety, and flu-like symptoms such as fatigue, pyrexia, myalgia, headache and rigors. Other common reactions were anorexia, nausea and vomiting, diarrhea, arthralgias, injection site reactions, alopecia, and pruritus. Table 5 shows rates of adverse events occurring in greater than or equal to 5% of subjects receiving pegylated interferon and ribavirin combination therapy in the CHC Clinical Trial, NV15801.

Ten percent of CHC monoinfected patients receiving 48 weeks of therapy with PEGASYS^® in combination with ribavirin tablets discontinued therapy; 16% of CHC/HIV coinfected patients discontinued therapy. The most common reasons for discontinuation of therapy were psychiatric, flu-like syndrome (e.g., lethargy, fatigue, headache), dermatologic and gastrointestinal disorders and laboratory abnormalities (thrombocytopenia, neutropenia, and anemia).

Overall 39% of patients with CHC or CHC/HIV required modification of PEGASYS^® and/or ribavirin tablets therapy. The most common reason for dose modification of PEGASYS^® in CHC and CHC/HIV patients was for laboratory abnormalities; neutropenia (20% and 27%, respectively) and thrombocytopenia (4% and 6%, respectively). The most common reason for dose modification of ribavirin tablets in CHC and CHC/HIV patients was anemia (22% and 16%, respectively).

PEGASYS^® dose was reduced in 12% of patients receiving 1000 mg to 1200 mg ribavirin tablets for 48 weeks and in 7% of patients receiving 800 mg ribavirin tablets for 24 weeks. Ribavirin tablets dose was reduced in 21% of patients receiving 1000 mg to 1200 mg ribavirin tablets for 48 weeks and in 12% of patients receiving 800 mg ribavirin tablets for 24 weeks.

Chronic hepatitis C monoinfected patients treated for 24 weeks with PEGASYS^® and 800 mg ribavirin tablets were observed to have lower incidence of serious adverse events (3% vs. 10%), hemoglobin less than 10 g/dL (3% vs. 15%), dose modification of PEGASYS^® (30% vs. 36%) and ribavirin tablets (19% vs. 38%), and of withdrawal from treatment (5% vs. 15%) compared to patients treated for 48 weeks with PEGASYS^® and 1000 mg or 1200 mg ribavirin tablets. On the other hand, the overall incidence of adverse events appeared to be similar in the two treatment groups.

Table 5. Adverse Reactions Occurring in greater than or equal to 5% of Patients in Chronic Hepatitis C Clinical Trials (Study NV15801)

	CHC Combination Therapy Study NV15801
	PEGASYS® 180 mcg + 1000 mg or 1200 mg Ribavirin Tablets 48 weeks	Interferonalfa-2b + 1000 mg or 1200 mg Rebetol® 48 weeks
	N=451	N=443
Body System	%	%
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 less than 500 cells/mm3; hemoglobin less than 10 g/dL; neutrophil less than 750 cells/mm3; platelet less than 50,000 cells/mm3).
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

Pediatric Patients

In a clinical trial with 114 pediatric subjects (5 to 17 years of age) treated with PEGASYS^® alone or in combination with ribavirin, dose modifications were required in approximately one-third of subjects, most commonly for neutropenia and anemia. In general, the safety profile observed in pediatric subjects was similar to that seen in adults. In the pediatric study, the most common adverse events in subjects treated with combination therapy PEGASYS^® and ribavirin for up to 48 weeks were influenza-like illness (91%), upper respiratory tract infection (60%), headache (64%), gastrointestinal disorder (56%), skin disorder (47%), and injection-site reaction (45%). Seven subjects receiving combination PEGASYS^® and ribavirin treatment for 48 weeks discontinued therapy for safety reasons (depression, psychiatric evaluation abnormal, transient blindness, retinal exudates, hyperglycemia, type 1 diabetes mellitus, and anemia). Severe adverse events were reported in 2 subjects in the PEGASYS^® plus ribavirin combination therapy group (hyperglycemia and cholecystectomy).

Table 6 Percentage of Pediatric Subjects with Adverse ReactionsDisplayed adverse drug reactions include all grades of reported adverse clinical events considered possibly, probably, or definitely related to study drug. During First 24 Weeks of Treatment by Treatment Group and for 24 Weeks Post-treatment (in at Least 10% of Subjects)

	Study NV17424
System Organ Class	PEGASYS® 180 mcg/1.73 m2 xBSA +Ribavirin15 mg/kg(N=55)	PEGASYS® 180 mcg/1.73 m2 xBSA +Placebo Subjects in the PEGASYS® plus placebo arm who did not achieve undetectable viral load at week 24 switched to combination treatment thereafter. Therefore, only the first 24 weeks are presented for the comparison of combination therapy with monotherapy. (N=59)
	%	%
General disorders andadministration siteconditions
Influenza like illness	91	81
Injection site reaction	44	42
Fatigue	25	20
Irritability	24	14
Gastrointestinaldisorders
Gastrointestinal disorder	49	44
Nervous systemdisorders
Headache	51	39
Skin and subcutaneoustissue disorders
Rash	15	10
Pruritus	11	12
Musculoskeletal,connective tissueand bone disorders
Musculoskeletal pain	35	29
Psychiatric disorders
Insomnia	9	12
Metabolism andnutrition disorders
Decreased appetite	11	14

In pediatric subjects randomized to combination therapy, the incidence of most adverse reactions was similar for the entire treatment period (up to 48 weeks plus 24 weeks follow-up) in comparison to the first 24 weeks, and increased only slightly for headache, gastrointestinal disorder, irritability and rash. The majority of adverse reactions occurred in the first 24 weeks of treatment.

Growth Inhibition in Pediatric Subjects [see Warnings and Precautions (5.8)].

Pediatric subjects treated with PEGASYS^® plus ribavirin combination therapy showed a delay in weight and height increases with up to 48 weeks of therapy compared with baseline. Both weight for age and height for age z-scores as well as the percentiles of the normative population for subject weight and height decreased during treatment. At the end of 2 years follow-up after treatment, most subjects had returned to baseline normative curve percentiles for weight (64th mean percentile at baseline, 60th mean percentile at 2 years post-treatment) and height (54th mean percentile at baseline, 56th mean percentile at 2 years post-treatment). At the end of treatment, 43% (23 of 53) of subjects experienced a weight percentile decrease of more than 15 percentiles, and 25% (13 of 53) experienced a height percentile decrease of more than 15 percentiles on the normative growth curves. At 2 years post-treatment, 16% (6 of 38) of subjects were more than 15 percentiles below their baseline weight curve and 11% (4 of 38) were more than 15 percentiles below their baseline height curve.

Thirty-eight of the 114 subjects enrolled in the long-term follow-up study, extending up to 6 years post‑ treatment. For most subjects, post-treatment recovery in growth at 2 years post-treatment was maintained to 6 years post-treatment.

Common Adverse Reactions in CHC with HIV Coinfection (Adults)

The adverse event profile of coinfected patients treated with PEGASYS^®/ribavirin tablets in Study NR15961 was generally similar to that shown for monoinfected patients in Study NV15801 (Table 5). Events occurring more frequently in coinfected patients were neutropenia (40%), anemia (14%), thrombocytopenia (8%), weight decrease (16%), and mood alteration (9%).

Laboratory Test Abnormalities

Adult Patients

Anemia due to hemolysis is the most significant toxicity of ribavirin therapy. Anemia (hemoglobin less than 10 g/dL) was observed in 13% of all ribavirin tablets and PEGASYS^® combination-treated patients in clinical trials. The maximum drop in hemoglobin occurred during the first 8 weeks of initiation of ribavirin therapy [see Dosage and Administration (2.3)].

Table 7. Selected Laboratory Abnormalities During Treatment with Ribavirin Tablets in Combination with Either PEGASYS^® or Interferon alfa-2b

	PEGASYS® + Ribavirin 1000/1200 mg 48 wks	Interferonalfa-2b + Ribavirin 1000/1200 mg 48 wks
Laboratory Parameter	(N=887)	(N=443)
Neutrophils (cells/mm3)
1,000 <1,500	34%	38%
500 <1,000	49%	21%
<500	5%	1%
Platelets (cells/mm3)
50,000 – <75,000	11%	4%
20,000 – <50,000	5%	<1%
<20,000	0	0
Hemoglobin (g/dL)
8.5 – 9.9	11%	11%
<8.5	2%	<1%

Pediatric Patients

Decreases in hemoglobin, neutrophils and platelets may require dose reduction or permanent discontinuation from treatment [see Dosage and Administration (2.4)]. Most laboratory abnormalities noted during the clinical trial returned to baseline levels shortly after discontinuation of treatment.

Table 8. Selected Hematologic Abnormalities During First 24 Weeks of Treatment by Treatment Group in Previously Untreated Pediatric Subjects

	PEGASYS® +180 mcg/1.73 m2 xBSA + Ribavirin 15 mg/kg (N=55)	PEGASYS® +180 mcg/1.73 m2 xBSA +Placebo Subjects in the PEGASYS® plus placebo arm who did not achieve undetectable viral load at week 24 switched to combination treatment thereafter. Therefore, only the first 24 weeks are presented for the comparison of combination therapy with monotherapy. (N=59)
Laboratory Parameter
Neutrophils (cells/mm3)
1,000 - <1,500	31%	39%
750 - <1,000	27%	17%
500 - <750	25%	15%
<500	7%	5%
Platelets (cells/mm3)
75,000 - <100,000	4%	2%
50,000 - <75,000	0%	2%
<50,000	0%	0%
Hemoglobin (g/dL)
8.5 - <10	7%	3%
<8.5	0%	0%

In patients randomized to combination therapy, the incidence of abnormalities during the entire treatment phase (up to 48 weeks plus 24 weeks follow-up) in comparison to the first 24 weeks increased slightly for neutrophils between 500 and 1,000 cells/mm³ and hemoglobin values between 8.5 and 10 g/dL. The majority of hematologic abnormalities occurred in the first 24 weeks of treatment.

6.2 Postmarketing Experience

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