Chronic Hepatitis C (CHC)
Ribasphere® (ribavirin capsules) in combination with interferon alfa-2b (pegylated and nonpegylated) is indicated for the treatment of Chronic Hepatitis C (CHC) in patients 3 years of age and older with compensated liver disease [see Warnings and Precautions (5.9, 5.10), and Use in Specific Populations (8.4)].
The following points should be considered when initiating Ribasphere combination therapy with peginterferon alfa-2b or interferon alpha-2b:
- These indications are based on achieving undetectable HCV-RNA after treatment for 24 or 48 weeks and maintaining a Sustained Virologic Response (SVR) 24 weeks after the last dose.
- Combination therapy with Ribasphere/peginterferon alfa-2b is preferred over Ribasphere/interferon alfa-2b as this combination provides substantially better response rates [see Clinical Studies (14)].
- Patients with the following characteristics are less likely to benefit from retreatment after failing a course of therapy: previous nonresponse, previous pegylated interferon treatment, significant bridging fibrosis or cirrhosis, and genotype 1 infection [see Clinical Studies (14)].
- No safety and efficacy data are available for treatment of longer than one year.
Ribasphere Dosage and Administration
Under no circumstances should Ribasphere capsules be opened, crushed, or broken. Ribasphere should be taken with food [see Clinical Pharmacology (12.3)]. Ribasphere should not be used in patients with creatinine clearance < 50 mL/min.
Ribasphere/Peginterferon alfa-2b Combination Therapy
Adult Patients
The recommended dose of peginterferon alfa-2b is 1.5 mcg/kg/week subcutaneously in combination with 800 to 1400 mg Ribasphere Capsules orally based on patient body weight (see Table 1). The volume of peginterferon alfa-2b to be injected depends on the strength of peginterferon alfa-2b and patient’s body weight (see Table 1).
Duration of Treatment – Interferon Alpha-naïve Patients
The treatment duration for patients with genotype 1 is 48 weeks. Discontinuation of therapy should be considered in patients who do not achieve at least a 2 log10 drop or loss of 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 – Retreatment with Peginterferon alfa-2b/ribavirin of Prior Treatment Failures
The treatment duration for patients who previously failed therapy is 48 weeks, regardless of HCV genotype. Re-treated patients who fail to achieve undetectable HCV-RNA at week 12 of therapy, or whose HCV-RNA remains detectable after 24 weeks of therapy, are highly unlikely to achieve SVR and discontinuation of therapy should be considered [see Clinical Studies (14.1)].
Table 1: Recommended Ribasphere/Peginterferon alfa-2b Combination Therapy Dosing (Adults)
|
| Body weight Kg (lbs) |
Peginterferon alfa-2b vial Strength to Use |
Amount of Peginterferon alfa-2b (mcg) to Administer |
Volume (mL) of Peginterferon alfa-2b to Administer |
Ribasphere Daily Dose |
Ribasphere
Number of Capsules |
<40
(<87) |
50 mcg per
0.5 mL |
50 |
0.5 |
800 mg/day |
2 x 200 mg capsules A.M.
2 x 200 mg capsules P.M. |
40-50
(87-111) |
80 mcg per
0.5 mL |
64 |
0.4 |
800 mg/day |
2 x 200 mg capsules A.M.
2 x 200 mg capsules P.M. |
51-60
(112-133) |
80 mcg per
0.5 mL |
80 |
0.5 |
800 mg/day |
2 x 200 mg capsules A.M.
2 x 200 mg capsules P.M. |
61-65
(133-144) |
120 mcg per
0.5 mL |
96 |
0.4 |
800 mg/day |
2 x 200 mg capsules A.M.
2 x 200 mg capsules P.M. |
66-75
(145-166) |
120 mcg per
0.5 mL |
96 |
0.4 |
1000 mg/day |
2 x 200 mg capsules A.M.
3 x 200 mg capsules P.M. |
76-80
(167-177) |
120 mcg per
0.5 mL |
120 |
0.5 |
1000 mg/day |
2 x 200 mg capsules A.M.
3 x 200 mg capsules P.M. |
81-85
(178-187) |
120 mcg per
0.5 mL |
120 |
0.5 |
1200 mg/day |
3 x 200 mg capsules A.M.
3 x 200 mg capsules P.M. |
86-105
(188-231) |
150 mcg per
0.5 mL |
150 |
0.5 |
1200 mg/day |
3 x 200 mg capsules A.M.
3 x 200 mg capsules P.M |
>105
(>231) |
|
† |
† |
1400 mg/day |
3 x 200 mg capsules A.M.
4 x 200 mg capsules P.M |
Pediatric Patients
Dosing for pediatric patients is determined by body surface area for peginterferon alfa-2b and by body weight for Ribasphere. The recommended dose of peginterferon alfa-2b is 60 mcg/m2/week subcutaneously in combination with 15 mg/kg/day of Ribasphere orally in two divided doses (see Table 2) for pediatric patients ages 3-17 years. Patients who reach their 18th birthday while receiving peginterferon alfa-2b/Ribasphere should remain on the pediatric dosing regimen. 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 Ribasphere Dosing in Combination Therapy (Pediatrics)
|
| Body weight kg (lbs) |
Ribasphere
Daily Dose |
Ribasphere Number of Capsules |
47–59
(103–131) |
800
mg/kg/day |
2 x 200 mg capsules A.M.
2 x 200 mg capsules P.M. |
60–73
(132–162) |
1000 mg/kg/day |
2 x 200 mg capsules A.M.
3 x 200 mg capsules P.M. |
>73
(>162) |
1200 mg/kg/day |
3 x 200 mg capsules A.M.
3 x 200 mg capsules P.M. |
Ribasphere/Interferon alfa-2b Combination Therapy
Adults
Duration of Treatment – Interferon Alpha-naïve Patients
The recommended dose of interferon alfa-2b is 3 million IU three times weekly subcutaneously. The recommended dose of Ribasphere Capsules depends on the patient’s body weight (refer to Table 3). The recommended duration of treatment for patients previously untreated with interferon is 24 to 48 weeks. The duration of treatment should be individualized to the patient depending on baseline disease characteristics, response to therapy, and tolerability of the regimen [see Indications and Usage (1.1), Adverse Reactions (6.1), and Clinical Studies (14)]. After 24 weeks of treatment, virologic response should be assessed. Treatment discontinuation should be considered in any patient who has not achieved an HCV-RNA below the limit of detection of the assay by 24 weeks. There are no safety and efficacy data on treatment for longer than 48 weeks in the previously untreated patient population.
Duration of Treatment – Retreatment with Interferon alfa-2b/Ribasphere in Relapse Patients
In patients who relapse following nonpegylated interferon monotherapy, the recommended duration of treatment is 24 weeks.
Table 3. Recommended Dosing
| Body Weight |
Ribasphere® (ribavirin capsules) |
| ≤75 kg |
2 times 200 mg capsules AM
3 times 200 mg capsules PM
daily orally |
| >75 kg |
3 times 200 mg capsules AM
3 times 200 mg capsules PM
daily orally |
Pediatrics
The recommended dose of Ribasphere is 15 mg/kg per day orally (divided dose AM and PM). Refer to Table 2 for Pediatric Dosing of Ribasphere in combination with interferon alfa-2b. Interferon alfa-2b for Injection by body weight of 25 kg to 61 kg is 3 million IU/m2 three times weekly subcutaneously. Refer to adult dosing table for > 61 kg body weight.
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 2/3 is 24 weeks.
Laboratory Tests
The following laboratory tests are recommended for all patients treated with Ribasphere, prior to beginning treatment and then periodically thereafter.
- Standard hematologic tests - including hemoglobin (pretreatment, Week 2 and Week 4 of therapy, and as clinically appropriate [see Warnings and Precautions (5.2, 5.7)], complete and differential white blood cell counts, and platelet count.
- Blood chemistries - liver function tests and TSH.
- Pregnancy - including monthly monitoring for women of childbearing potential.
- ECG [see Warnings and Precautions (5.2)].
Dose Modifications
If severe adverse reactions or laboratory abnormalities develop during combination Ribasphere/interferon alfa-2b therapy or Ribasphere/peginterferon alfa-2b therapy, modified, or discontinue the dose until the adverse reaction abates or decreases in severity [see Warnings and Precautions (5)]. If intolerance persists after dose adjustment, combination therapy should be discontinued. Dose reduction of peginterferon alfa-2b in adult patients on Ribasphere/peginterferon alfa-2b combination therapy is accomplished in a two-step process from the original starting dose of 1.5 mcg/kg/week, to 1 mcg/kg/week, then to 0.5 mcg/kg/week, if needed. Dose reduction of peginterferon alfa-2b in adults may be accomplished by utilizing a lower dose strength or administering a lesser volume as shown in Table 4.
In the adult combination therapy study 2 dose reductions occurred in 42% of subjects receiving peginterferon alfa-2b 1.5 mcg/kg plus Ribasphere 800 mg daily including 57% of those subjects weighing 60 kg or less. In Study 4, 16% of subjects had a dose reduction of peginterferon alfa-2b to 1 mcg/kg in combination with Ribasphere, with an additional 4% requiring the second dose reduction of peginterferon alfa-2b to 0.5 mcg/kg due to adverse events [see Adverse Reactions (6.1)].
Table 4. Two-Step Dose Reduction of Peginterferon alfa-2b in Combination Therapy in Adults
|
First Dose Reduction to Peginterferon alfa-2b
1 mcg/kg |
Second Dose Reduction to Peginterferon alfa-2b 0.5 mcg/kg |
| Body weight kg (lbs) |
Peginterferon alfa-2b Vial Strength to Use |
Amount of Peginterferon alfa-2b (mcg) to Administer |
Volume (mL) of Peginterferon alfa-2b to Administer |
Body weight kg (lbs) |
Peginterferon alfa-2b Vial Strength to Use |
Amount of Peginterferon alfa-2b (mcg) to Administer |
Volume (mL)* of Peginterferon alfa-2b to Administer |
<40
(<88) |
50 mcg per 0.5 mL |
35 |
0.35 |
<40
(<88) |
50 mcg per 0.5 mL |
20 |
0.2 |
40–50
(88–111) |
45 |
0.45 |
40–50
(88–111) |
25 |
0.25 |
|
|
51–60
(112–133) |
50 |
0.5 |
51–60
(112–133) |
50 mcg per 0.5 mL |
30 |
0.3 |
|
61–75
(134–166) |
80 mcg per 0.5 mL |
64 |
0.4 |
61–75
(134–166) |
35 |
0.35 |
|
76–85
(167–187) |
80 |
0.5 |
76–85
(167–187) |
45 |
0.45 |
|
|
86–104
(188–230) |
120 mcg per 0.5 mL |
96 |
0.4 |
86–104
(188–230) |
50 |
0.5 |
|
105–125
(231–275) |
108 |
0.45 |
105–125
(231–275) |
80 mcg per 0.5 mL |
64 |
0.4 |
|
>125
(>275) |
150 mcg per 0.5 mL |
135 |
0.45 |
>125
(>275) |
72 |
0.45 |
|
Dose reduction in pediatric patients is accomplished by modifying the recommended peginterferon alfa-2b dose in a two-step process from the original starting dose of 60 mcg/m2/week, to 40 mcg/m2/week, then to 20 mcg/m2/week, if needed (see Table 5). In the pediatric combination therapy trial, dose reductions occurred in 25% of subjects receiving peginterferon alfa-2b 60 mcg/m2 weekly plus Ribasphere 15 mg/kg daily. Dose reduction in pediatric patients is accomplished by modifying the recommended Ribasphere 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 5).
Ribasphere should not be used in patients with creatinine clearance < 50 mL/min. Subjects with impaired renal function and those over the age of 50 should be carefully monitored with respect to development of anemia [see Warnings and Precautions (5.2), Use in Specific Populations (8.5), and Clinical Pharmacology (12.3)].
Ribasphere should be administered with caution to patients with pre-existing cardiac disease. Patients should be assessed before commencement of therapy and should be appropriately monitored during therapy. If there is any deterioration of cardiovascular status, therapy should be stopped [see Warnings and Precautions (5.2)].
For patients with a history of stable cardiovascular disease, a permanent dose reduction is required if the hemoglobin decreases by ≥ 2 g/dL during any 4-week period. In addition, for these cardiac history patients, if the hemoglobin remains < 12 g/dL after 4 weeks on a reduced dose, the patient should discontinue combination therapy.
It is recommended that a patient whose hemoglobin level falls below 10 g/dL have his/her Ribasphere dose modified or discontinued per Table 5[see Warnings and Precautions (5.2)].
Table 5: Guidelines for Dose Modification and Discontinuation of Peginterferon alfa-2b, Interferon alfa-2b or Peginterferon alfa-2b/Ribasphere Capsules Based on Laboratory Parameters in Adults and Pediatrics
|
| Laboratory Values |
Adults |
Pediatrics |
Adults |
Pediatrics |
Peginterferon alfa-2b
/interferon
alfa-2b |
Peginterferon alfa-2b |
Interferon alfa-2b |
Ribavirin |
| Hgb < 10g/dL |
For patients with cardiac disease, reduce by 50% |
See footnote* |
See footnote* |
Adjust Dose |
1st reduction to 12 mg/kg/day
2nd reduction to 8 mg/kg/day |
WBC < 1.5 x 109/L
Neutrophils < 0.75 x 109/L
Platelets< 50 x 109/L (Adults)
< 70 x 109/L (Pediatrics) |
Adjust Dose |
1st reduction to 40 cg/m2/week
2nd reduction to 20 cg/m2/week |
Reduce by 50% |
No Dose Change |
No Dose Change |
Hgb < 8.5g/dL
WBC < 1 x 109/L
Neutrophils < 0.5 x 109/L
Creatinine > 2 mg/dL (Pediatrics)
Platelets < 25 x 109/L (Adults)
< 50 x 109/L (Pediatrics) |
Permanently Discontinue |
Permanently Discontinue |
Permanently Discontinue |
Permanently Discontinue |
Permanently Discontinue |
Refer to the Intron A Package Insert or PegIntron Powder for Injection Package Insert for additional information about how to reduce an interferon alfa-2b or peginterferon alfa-2b dose.
Discontinuation of Dosing
Adults
It is recommended that HCV genotype 1 interferon-alfa-naïve patients receiving peginterferon alfa-2b in combination with ribavirin, be discontinued from therapy if there is not at least a 2 log10 drop or loss of HCV-RNA at 12 weeks of therapy, or whose HCV-RNA levels remain detectable (>10-20 IU/mL) 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 (3-17 years of age)
It is recommended that patients receiving peginterferon alfa-2b/Ribasphere combination (excluding HCV Genotype 2 and 3) be discontinued from therapy at 12 weeks if their treatment Week 12 HCV-RNA dropped < 2 log10 compared to a pretreatment or at 24 weeks if they have detectable HCV-RNA (>10-20 IU/mL) at treatment Week 24.
Dosage Forms and Strengths
Ribasphere 200 mg Capsules
Contraindications
Ribasphere combination therapy is contraindicated in:
- women who are pregnant. Ribasphere may cause fetal harm when administered to a pregnant woman. Ribasphere is 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 a fetus [see Warnings and Precautions (5.1), Use in Specific Populations (8.1), and Patient Counseling Information (17.2)]
- men whose female partners are pregnant
- 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 < 50 mL/min. [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)]
- Coadministration of Ribasphere and didanosine is contraindicated as because exposure to the active metabolite of didanosine (dideoxyadenosine 5’-triphosphate) are increased. Fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in patients receiving both didanosine and ribavirin [see Drug Interactions (7.1)].
Warnings and Precautions
Pregnancy
Ribasphere (ribavirin capsules) may cause birth defects and death of the unborn child. Ribasphere therapy should not be started until a report of a negative pregnancy test has been obtained immediately prior to planned initiation of therapy. Patients should use at least two forms of contraception and have monthly pregnancy tests during treatment and during the 6-month period after treatment has been stopped. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribasphere has demonstrated significant teratogenic and 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 therapy should not be started until a report of a negative pregnancy test has been obtained immediately prior to planned initiation of therapy [see Boxed Warning, Contraindications (4), Use in Specific Populations (8.1), and Patient Counseling Information (17.2)].
Anemia
The primary toxicity of ribavirin is hemolytic anemia, which was observed in approximately 10% of Ribasphere/interferon alfa-2b-treated subjects in clinical trials. The anemia associated with Ribasphere capsules 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 [see Dosage and Administration (2.4, 2.5)].
Fatal and nonfatal myocardial infarctions have been reported in patients with anemia caused by ribavirin. Patients should be assessed for underlying cardiac disease before initiation of ribavirin therapy. Patients with pre-existing cardiac disease should have electrocardiograms administered before treatment, and should be appropriately monitored during therapy. If there is any deterioration of cardiovascular status, therapy should be suspended or discontinued [see Dosage and Administration (2.4, 2.5)]. Because cardiac disease may be worsened by drug induced anemia, patients with a history of significant or unstable cardiac disease should not use Ribasphere.
Pancreatitis
Ribasphere and interferon alfa-2b or peginterferon alfa-2b therapy should be suspended in patients with signs and symptoms of pancreatitis and discontinued in patients with confirmed pancreatitis.
Pulmonary Disorders
Pulmonary symptoms, including dyspnea, pulmonary infiltrates, pneumonitis, pulmonary hypertension, and pneumonia, have been reported during therapy with Ribasphere/interferon alfa-2b; 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, the patient should be closely monitored, and if appropriate, combination Ribasphere/interferon alfa-2b treatment should be discontinued.
Ophthalmologic Disorders
Ribavirin is used in combination therapy with alpha interferons. Decrease or loss of vision, retinopathy including macular edema, retinal artery or vein, thrombosis, retinal hemorrhages and cotton wool spots, optic neuritis, papilledema, and serous retinal detachment are induced or aggravated by treatment with alpha interferons. All patients should receive an eye examination at baseline. Patients with pre-existing ophthalmologic disorders (e.g., diabetic or hypertensive retinopathy) should receive periodic ophthalmologic exams during combination therapy with alpha interferon treatment. Any patient who develops ocular symptoms should receive a prompt and complete eye examination. Combination therapy with alpha interferons should be discontinued in patients who develop new or worsening ophthalmologic disorders.
Laboratory Tests
Peginterferon alfa-2b in combination with ribavirin may cause severe decreases in neutrophil and platelet counts, and hematologic, endocrine (e.g., TSH), and hepatic abnormalities.
Patients on peginterferon alfa-2b/Ribasphere combination therapy should have hematology and blood chemistry testing before the start of treatment and then periodically thereafter. In the adult clinical trial CBC (including hemoglobin, neutrophil, and platelet counts) and chemistries (including AST, ALT, bilirubin, and uric acid) were measured during the treatment period at weeks 2, 4, 8, 12, and then at 6-week intervals or more frequently if abnormalities developed. In pediatric subjects the same laboratory parameters were evaluated with additional assessment of hemoglobin at treatment week 6. TSH levels were measured every 12 weeks during the treatment period. HCV-RNA should be measured periodically during treatment [see Dosage and Administration (2)].
Dental and Periodontal Disorders
Dental and periodontal disorders have been reported in patients receiving ribavirin and interferon or peginterferon combination therapy. In addition, dry mouth could have a damaging effect on teeth and mucous membranes of the mouth during long-term treatment with the combination of ribavirin and interferon alfa-2b or pegylated interferon alfa-2b. Patients should brush their teeth thoroughly twice daily and have regular dental examinations. If vomiting occurs, they should be advised to rinse out their mouth thoroughly afterwards.
5.8 Concomitant Administration of Azathioprine
Pancytopenia (marked decreases in red blood cells, neutrophils and platelets) and bone marrow suppression have been reported in the literature to occur within 3 to 7 weeks after the concomitant administration of pegylated interferon/ribavirin and azathioprine. In this limited number of patients (n=8), myelotoxicity was reversible within 4 to 6 weeks upon withdrawal of both HCV antiviral therapy and concomitant azathioprine and did not recur upon reintroduction of either treatment alone. Peginterferon alfa-2b, Ribasphere and azathioprine should be discontinued for pancytopenia, and pegylated interferon/ribavirin should not be re-introduced with concomitant azathioprine [see Drug Interaction (7.4)].
Impact on Growth - Pediatric Use
Data on the effects of peginterferon alfa-2b plus ribavirin on growth come from an open-label study in subjects 3 through 17 years of age, and weight and height changes are compared to U.S. normative population data. In general, the weight and height gain of pediatric subjects treated with peginterferon alfa-2b plus ribavirin lags behind that predicted by normative population data for the entire length of treatment. After about 6 months posttreatment (Follow-Up Week 24), subjects had weight gain rebounds and regained their weight to 53rd percentile, above the average of the normative population and similar to that predicted by their average baseline weight (57th percentile). After about 6 months posttreatment, height gain stabilized and subjects treated with peginterferon alfa-2b plus ribavirin had an average height percentile of 44th percentile, which was less than the average of the normative population and less than their average baseline height (51st percentile). Severely inhibited growth velocity (< 3rd percentile) was observed in 70% of the subjects while on treatment. Of the subjects experiencing severely inhibited growth, 20% had continued inhibited growth velocity (< 3rd percentile) after 6 months of follow-up.
Among the boys studied, the age groups of 3-11 years old and 12-17 years old had similar height percentile decreases of approximately 5 percentiles after 6 months posttreatment; weight gain continued to be similar to their average baseline percentile. Girls who were 3-11 years old and treated for 48 weeks had the largest average drop in height and weight percentiles (13 percentiles and 7 percentiles, respectively), whereas girls 12-17 years old continued along their average baseline height and weight percentiles after 6 months posttreatment.
Usage Safeguards
Based on results of clinical trials, ribavirin monotherapy is not effective for the treatment of chronic hepatitis C virus infection; therefore, Ribasphere Capsules must not be used alone. The safety and efficacy of ribavirin capsules have only been established when used together with interferon alfa-2b or peginterferon alfa-2b (not other interferons) as a combination therapy.
The safety and efficacy of ribavirin/interferon alfa-2b and peginterferon alfa-2b therapy for the treatment of HIV infection, adenovirus, RSV, parainfluenza, or influenza infections have not been established. Ribasphere Capsules should not be used for these indications. Ribavirin for inhalation has a separate package insert, which should be consulted if ribavirin inhalation therapy is being considered.
There are significant adverse reactions caused by ribavirin/interferon alfa-2b or peginterferon alfa-2b therapy, including severe depression and suicidal ideation, hemolytic anemia, suppression of bone marrow function, autoimmune and infectious disorders, pulmonary dysfunction, pancreatitis, and diabetes. Suicidal ideation or attempts occurred more frequently among pediatric patients, primarily adolescents, compared to adult patients (2.4% versus 1%) during treatment and off-therapy follow-up. The interferon alfa-2b and peginterferon alfa-2b package inserts should be reviewed in their entirety for additional safety information prior to initiation of combination treatment.
Adverse Reactions
Clinical trials with ribavirin in combination with peginterferon alfa-2b or interferon alfa-2b have been conducted in over 7800 subjects from 3 to 76 years of age.
The primary toxicity of ribavirin is hemolytic anemia. Reductions in hemoglobin levels occurred within the first 1 to 2 weeks of oral therapy. Cardiac and pulmonary reactions associated with anemia occurred in approximately 10% of patients [see Warnings and Precautions (5.2)].
Greater than 96% of all subjects in clinical trials experienced one or more adverse reactions. The most commonly reported adverse reactions in adult subjects receiving peginterferon alfa-2b or interferon alfa-2b 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 peginterferon alfa-2b or interferon alfa-2b were pyrexia, headache, neutropenia, fatigue, anorexia, injection site erythema, and vomiting.
The Adverse Reactions section references the following clinical studies:
- Ribavirin/peginterferon alfa-2b Combination therapy studies:
- Clinical Study 1 - evaluated peginterferon alfa-2b monotherapy (not further described in this label; see Peginterferon alfa-2b Powder for Injection Package Insert for information about this study).
- Study 2 - evaluated ribavirin 800 mg/day flat dose in combination with 1.5 mcg/kg/week peginterferon alfa-2b or with interferon alfa-2b.
- Study 3 - evaluated peginterferon alfa-2b/weight-based ribavirin in combination with peginterferon alfa-2b/flat dose ribavirin regimen.
- Study 4- compared two peginterferon alfa-2b (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® (1000-1200 mg/day).
- Study 5 – evaluated peginterferon alfa-2b (1.5 mcg/kg/week) in combination with weight-based ribavirin in prior treatment failure subjects.
- Peginterferon alfa-2b/ribavirin Combination Therapy in Pediatric Patients
- Ribavirin/interferon alfa-2b Combination Therapy studies for adults and pediatrics
Serious adverse reactions have occurred in approximately 12% of subjects in clinical trials with peginterferon alfa-2b with or without ribavirin [see BOXED WARNING, Warnings and Precautions (5)]. The most common serious events occurring in subjects treated with peginterferon alfa-2b and ribavirin were depression and suicidal ideation [see Warnings and Precautions (5.2)], 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 peginterferon alfa-2b and ribavirin was cardiac arrest, suicide ideation, and suicide attempt [see Warnings and Precautions (5.10)], all occurring in less than 1% of subjects.
Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rated in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Clinical Studies Experience-Ribavirin/Peginterferon alfa-2b Combination Therapy
Adult Subjects
Adverse reactions that occurred in the clinical trial at > 5% incidence are provided by treatment group from the ribavirin/peginterferon alfa-2b Combination Therapy (Study 2) in Table 6.
