Ribavirin capsules are a nucleoside analogue indicated in combination with interferon alfa-2b (pegylated and nonpegylated) for the treatment of Chronic Hepatitis C (CHC) in patients 3 years of age or older with compensated liver disease. ( 1.1 ) Patients with the following characteristics are less likely to benefit from re-treatment after failing a course of therapy: previous nonresponse, previous pegylated interferon treatment, significant bridging fibrosis or cirrhosis, and genotype 1 infection.
1.1Chronic Hepatitis C (CHC)
Ribavirin capsules in combination with interferon alfa-2b (pegylated and nonpegylated) are 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 ribavirin capsules combination therapy with PegIntron ® or INTRON A ® : Combination therapy with ribavirin capsules/PegIntron is preferred over ribavirin capsules/INTRON A as this combination provides substantially better response rates [see Clinical Studies (14) ].
Patients with the following characteristics are less likely to benefit from re-treatment 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 duration lasting longer than one year.
Contre-indications
Ribavirin capsules combination therapy is contraindicated in: pregnancy. Ribavirin capsules may cause fetal harm when administered to a pregnant woman. Ribavirin capsules are contraindicated in women who are pregnant or planning to become pregnant. If a patient becomes pregnant while taking ribavirin capsules, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.1) , and Use in Specific Populations (8.1, 8.3) ]. men whose female partners are pregnant [see Use in Specific Populations (8.3) ] patients with known hypersensitivity reactions such as Stevens-Johnson syndrome, toxic, epidermal necrolysis, and erythema multiforme to ribavirin or any component of the product patients with autoimmune hepatitis patients with hemoglobinopathies (e.g., thalassemia major, sickle-cell anemia) patients with creatinine clearance less than 50 mL/min [see Clinical Pharmacology (12.3) ] when coadministered with didanosine because exposure to the active metabolite of didanosine (dideoxyadenosine 5’-triphosphate) is increased.
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Fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis, has been reported in patients receiving didanosine in combination with ribavirin [see Drug Interactions (7.1) ]. Pregnancy and men whose female partners are pregnant ( 4 , 5.1 , 8.1 , 8.3 ) Known hypersensitivity reactions such as Stevens-Johnson syndrome, toxic, epidermal necrolysis, and erythema multiforme to ribavirin or any component of the product ( 4 ) Autoimmune hepatitis ( 4 ) Hemoglobinopathies ( 4 ) Creatinine clearance less than 50 mL/min ( 4 , 12.3 ) Coadministration with didanosine ( 4 , 7.1 )
Mises en garde et précautions d’emploi
Embryo-Fetal Toxicity: May cause fetal harm. Patients should have a negative pregnancy test prior to therapy and use effective contraception and undergo periodic pregnancy tests. ( 5.1 , 8.1 , 8.3 ) 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. ( 5.2 ) Pancreatitis.
( 5.3 ) Pulmonary infiltrates or pulmonary function impairment. ( 5.4 ) New or worsening ophthalmologic disorders. ( 5.5 ) Severe decreases in neutrophil and platelet counts, and hematologic, endocrine (e.g., TSH), and hepatic abnormalities. ( 5.6 ) Dental/periodontal disorders reported with combination therapy. ( 5.7 ) Concomitant administration of azathioprine. ( 5.8 ) Weight loss and growth inhibition reported during combination therapy in pediatric patients.
Long-term growth inhibition (height) reported in some patients. ( 5.9 ) Monotherapy with ribavirin is not permitted. ( 5.10 )
5.1Embryo-Fetal Toxicity
Ribavirin capsules may cause birth defects, miscarriage or stillbirth. Ribavirin therapy should not be started until a report of a negative pregnancy test has been obtained immediately prior to planned initiation of therapy. Female patients should use effective contraception and have periodic monitoring with pregnancy tests during treatment and during the 9-month period after treatment has been stopped. Male patients and their female partners should use effective contraception 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. Ribavirin has demonstrated significant teratogenic and embryocidal effects in all animal species tested. These effects occurred at doses as low as one twentieth of the recommended human dose of ribavirin. [see Boxed Warning , Contraindications (4) , and Use in Specific Populations (8.1 , 8.3) ].
5.2Anemia
Hemolytic anemia was observed in approximately 10% of ribavirin/INTRON A-treated subjects in clinical trials. The anemia associated with ribavirin occurs within 1 to 2 weeks of initiation of therapy. Because the initial drop in hemoglobin may be significant, obtain hemoglobin or hematocrit levels before the start of treatment 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 (2.5 , 2.6) ].
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 (2.5 , 2.6) ].
Because cardiac disease may be worsened by drug-induced anemia, patients with a history of significant or unstable cardiac disease should not use ribavirin.
5.3Pancreatitis
Suspend ribavirin and INTRON A or PegIntron combination therapy in patients with signs and symptoms of pancreatitis and discontinue in patients with confirmed pancreatitis.
5.4Pulmonary Disorders
Pulmonary symptoms, including dyspnea, pulmonary infiltrates, pneumonitis, pulmonary hypertension, and pneumonia, have been reported during ribavirin with alpha interferon combination therapy; 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, closely monitor the patient, and if appropriate, discontinue combination therapy.
5.5Ophthalmologic Disorders
Ribavirin is used in combination therapy with INTRON A or PegIntron. Refer to labeling for PegIntron for additional information.
5.6Laboratory Tests PegIntron
in combination with ribavirin may cause severe decreases in neutrophil and platelet counts, and hematologic, endocrine (e.g., TSH), and hepatic abnormalities. Obtain hematology and blood chemistry testing in patients on PegIntron/ribavirin combination therapy before the start of treatment and then periodically thereafter. In the adult clinical trial, complete blood counts (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) ].
5.7Dental 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 pegylated or nonpegylated interferon alfa-2b. Advise patients to brush their teeth thoroughly twice daily and have regular dental examinations.
If vomiting occurs, advise patients to rinse out their mouth thoroughly afterwards.
5.8Concomitant 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.
Discontinue PegIntron, ribavirin, and azathioprine for pancytopenia, and do not reintroduce pegylated interferon/ribavirin with concomitant azathioprine [see Drug Interactions (7.4) ].
5.9 Impact on Growth in Pediatric Patients Data on the effects of PegIntron and ribavirin on growth come from an open-label study in subjects 3 through 17 years of age, in which weight and height changes were compared to U.S. normative population data. In general, the weight and height gain of pediatric subjects treated with PegIntron and ribavirin lagged behind that predicted by normative population data for the entire length of treatment.
Severely inhibited growth velocity (less than 3 rd percentile) was observed in 70% of the subjects while on treatment. Following treatment, rebound growth and weight gain occurred in most subjects. Long-term follow-up data in pediatric subjects, however, indicates that PegIntron in combination therapy with ribavirin may induce a growth inhibition that results in reduced adult height in some patients [see Adverse Reactions (6.1) ].
Similarly, an impact on growth was seen in subjects after treatment with ribavirin and INTRON A combination therapy for one year. In a long-term follow-up trial of a limited number of these subjects, combination therapy resulted in reduced final adult height in some subjects [see Adverse Reactions (6.1) ] .
5.10Not Recommended for Monotherapy and Risks Associated with Combination Therapy Based
on results of clinical trials, ribavirin monotherapy is not effective for the treatment of chronic hepatitis C virus infection; therefore, ribavirin capsules must not be used alone. The safety and efficacy of ribavirin capsules have only been established when used together with INTRON A or PegIntron (not other interferons) as combination therapy. The safety and efficacy of ribaviri
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Interactions
Nucleoside analogues: Closely monitor for toxicities. Discontinue nucleoside reverse transcriptase inhibitors or reduce dose or discontinue interferon, ribavirin or both with worsening toxicities. ( 7.2 )
7.1Didanosine Exposure
to didanosine or its active metabolite (dideoxyadenosine 5’-triphosphate) is increased when didanosine is coadministered with ribavirin, which could cause or worsen clinical toxicities; therefore, coadministration of ribavirin capsules and didanosine is contraindicated [see Contraindications (4) ] . Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in clinical trials.
7.2Nucleoside Analogues
Hepatic decompensation (some fatal) has occurred in cirrhotic HIV/HCV co-infected patients receiving combination antiretroviral therapy for HIV and interferon alpha and ribavirin. Patients receiving interferon with ribavirin and nucleoside reverse transcriptase inhibitors (NRTIs) should be closely monitored for treatment-associated toxicities, especially hepatic decompensation and anemia. Discontinuation of NRTIs should be considered as medically appropriate (see labeling for individual NRTI product).
Dose reduction or discontinuation of interferon, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Ribavirin may antagonize the cell culture antiviral activity of stavudine and zidovudine against HIV. Ribavirin has been shown in cell culture to inhibit phosphorylation of lamivudine, stavudine, and zidovudine, which could lead to decreased antiretroviral activity.
However, in a study with another pegylated interferon in combination with ribavirin, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV/HCV virologic suppress) interaction was observed when ribavirin and lamivudine (n=18), stavudine (n=10), or zidovudine (n=6) were coadministered as part of a multidrug regimen in HIV/HCV co-infected subjects.
Concomitant use of ribavirin with any of these drugs should be done with caution.
7.3 Drugs Metabolized by Cytochrome P-450 Results of in vitro studies using both human and rat liver microsome preparations indicated little or no cytochrome P-450 enzyme-mediated metabolism of ribavirin, with minimal potential for P-450 enzyme-based drug interactions. No pharmacokinetic interactions were noted between INTRON A and ribavirin capsules in a multiple-dose pharmacokinetic study.
7.4Azathioprine
The use of ribavirin for the treatment of chronic hepatitis C in patients receiving azathioprine has been reported to induce severe pancytopenia and may increase the risk of azathioprine-related myelotoxicity. Inosine monophosphate dehydrogenase (IMDH) is required for one of the metabolic pathways of azathioprine. Ribavirin is known to inhibit IMDH, thereby leading to accumulation of an azathioprine metabolite, 6-methylthioinosine monophosphate (6-MTITP), which is associated with myelotoxicity (neutropenia, thrombocytopenia, and anemia).
Patients receiving azathioprine with ribavirin should have complete blood counts, including platelet counts, monitored weekly for the first month, twice monthly for the second and third months of treatment, then monthly or more frequently if dosage or other therapy changes are necessary [see Warnings and Precautions (5.8) ].
Grossesse et allaitement
8.1Pregnancy Risk Summary
Ribavirin is contraindicated for use in pregnant women and in men whose female partners are pregnant [see Contraindications (4) ] . Based on animal data, ribavirin use in pregnancy may be associated with birth defects. Data from the Ribavirin Pregnancy Registry are insufficient to identify a drug-associated risk of birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data) . Ribavirin is known to accumulate in intracellular components from where it is cleared very slowly.
In animal studies, ribavirin exposure was shown to have teratogenic and/or embryocidal effects (see Data) . All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage is 2 to 4% and 15 to 20%, respectively.
Data Human Data Available data from the Ribavirin Pregnancy Registry on 88 live births from pregnancies in women directly exposed and 98 live births from pregnancies in women indirectly exposed (by a male partner) to ribavirin during pregnancy or during the 6 months prior to pregnancy show a higher rate of birth defects (9.09% and 6.12%, respectively) compared to a background birth defect rate of 2.72% in the Metropolitan Atlanta Congenital Defects Program (MACDP) birth defects surveillance system.
No pattern of birth defects can be identified from these reports. The miscarriage rate was approximately 21%. The current sample size is insufficient for reaching definitive conclusions based on statistical analysis. Trends suggesting a common etiology or relationship with ribavirin exposure were not observed. Methodologic limitations of the Ribavirin Pregnancy Registry include the use of MACDP as the external comparator group.
Limitations of using an external comparator include differences in methodology and populations, as well as confounding due to the underlying disease and comorbidities. Animal Data Embryotoxicity/teratogenicity studies with ribavirin were conducted in rats (oral doses of 0.3, 1 and 10 mg/kg on Gestation Days 6 to 15) and rabbits (oral dose of 0.1, 0.3 and 1 mg/kg on Gestation Days 6 to 18). Ribavirin demonstrated significant embryocidal and teratogenic effects at doses well below the recommended human dose in all animal species in which adequate studies have been conducted.
Malformations of the skull, palate, eye, jaw, limbs, skeleton, and gastrointestinal tract were noted. The incidence and severity of teratogenic effects increased with escalation of the drug dose. Survival of fetuses and offspring was reduced [see Contraindications (4) and Warnings and Precautions (5.1) ].
Effets indésirables
The following serious adverse drug reactions are discussed in other sections of the labeling: Embryo-Fetal Toxicity [see Warnings and Precautions (5.1) ] Anemia [see Warnings and Precautions (5.2) ] Pancreatitis [see Warnings and Precautions (5.3) ] Pulmonary Disorders [see Warnings and Precautions (5.4) ] Ophthalmic Disorders [see Warnings and Precautions (5.5) ] Dental and Periodontal Disorders [see Warnings and Precautions (5.7) ] Impact on Growth in Pediatric Patients [see Warnings and Precautions (5.9) ] Hemolytic anemia occurred in more than 10% of adult patients receiving ribavirin/PegIntron or INTRON A combination therapy.
( 6.1 ) Most common adverse reactions (40% or greater) in adult patients receiving ribavirin/PegIntron or INTRON A combination therapy are injection site reaction, fatigue/asthenia, headache, rigors, fevers, nausea, myalgia and anxiety/emotional lability/irritability. ( 6.1 ) Most common adverse reactions (greater than 25%) in pediatric patients receiving ribavirin/PegIntron therapy are: pyrexia, headache, neutropenia, fatigue, anorexia, injection site erythema, and vomiting.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Clinical trials with ribavirin in combination with PegIntron or INTRON A have been conducted in over 7,800 subjects from 3 to 76 years of age. The primary toxicity of ribavirin is hemolytic anemia.
Reductions in hemoglobin levels occurred within the first 1 to 2 weeks of oral therapy. Cardiac and pulmonary reactions associated with anemia occurred in approximately 10% of patients [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 PegIntron or INTRON A in combination with ribavirin were injection site inflammation/reaction, fatigue/asthenia, headache, rigors, fevers, nausea, myalgia and anxiety/emotional lability/irritability.
The most common adverse reactions in pediatric subjects, ages 3 and older, receiving ribavirin in combination with PegIntron or INTRON A were pyrexia, headache, neutropenia, fatigue, anorexia, injection site erythema, and vomiting. The Adverse Reactions section references the following clinical trials: Ribavirin/PegIntron Combination therapy trials: Clinical Study 1 – evaluated PegIntron monotherapy (not further described in this label; see labeling for PegIntron for information about this trial).
Study 2 – evaluated ribavirin 800 mg/day flat dose in combination with 1.5 mcg/kg/week PegIntron or with INTRON A. Study 3 – evaluated PegIntron/weight-based ribavirin in combination with PegIntron/flat dose ribavirin regimen. Study 4 – compared two PegIntron (1.5 mcg/kg/week and 1 mcg/kg/week) doses in combination with ribavirin and a third treatment group receiving Pegasys ® (180 mcg/week)/Copegus ® (1000 to 1200 mg/day).
Study 5 – evaluated PegIntron (1.5 mcg/kg/week) in combination with weight-based ribavirin in prior treatment failure subjects. PegIntron/Ribavirin Combination Therapy in Pediatric Patients Ribavirin/INTRON A Combination Therapy trials for adults and pediatrics Serious adverse reactions have occurred in approximately 12% of subjects in clinical trials with PegIntron with or without ribavirin [see Boxed Warning , Warnings and Precautions (5) ].
The most common serious events occurring in subjects treated with PegIntron and ribavirin were depression and suicidal ideation [see Warnings and Precautions (5.10) ], each occurring at a frequency of less than 1%. Suicidal ideation or attempts occurred more frequently among pediatric patients, primarily adolescents, compared to adult patients (2.4% versus 1%) during treatment and off-therapy follow-up [ see Warnings and Precautions (5.10) ].
The most common fatal reaction occurring in subjects treated with PegIntron and ribavirin was cardiac arrest, suicidal ideation, and suicide attempt [see Warnings and Precautions (5.10)] , all occurring in less than 1% of subjects. Adverse Reaction - Ribavirin/PegIntron Combination Therapy Adult Subjects Adverse reactions that occurred in the clinical trial at greater than 5% incidence are provided by treatment group from the ribavirin/PegIntron Combination Therapy (Study 2) in Table 5.
Table 5: Adverse Reactions Occurring in Greater Than 5% of Adult Subjects * A subject may have reported more than one adverse reaction within a body system/organ class category. Adverse Reactions Percentage of Subjects Reporting Adverse Reactions* Adverse Reactions Percentage of Subjects Reporting Adverse Reactions* PegIntron 1.5 mcg/kg/ Ribavirin (N=511) INTRON A/ Ribavirin (N=505) PegIntron 1.5 mcg/kg/ Ribavirin (N=511) INTRON A/ Ribavirin (N=505) Application Site Musculoskeletal Injection Site Inflammation Injection Site Reaction 25 58 18 36 Myalgia 56 50 Arthralgia 34 28 Autonomic Nervous System Musculoskeletal Pain 21 19 Dry Mouth 12 8 Psychiatric Increased Sweating 11 7 Insomnia 40 41 Flushing 4 3 Depression 31 34 Body as a Whole Anxiety/Emotional Lability/Irritability 47 47 Fatigue/Asthenia 66 63 Concentration Impaired 17 21 Headache 62 58 Agitation 8 5 Rigors 48 41 Nervousness 6 6 Fever 46 33 Reproductive, Female Weight Loss 29 20 Menstrual Disorder 7 6 Right Upper Quadrant Pain 12 6 Resistance Mechanism Chest Pain 8 7 Viral Infection 12 12 Malaise 4 6 Fungal Infection 6 1 Central/Peripheral Nervous System Respiratory System Dizziness 21 17 Dyspnea 26 24 Endocrine Coughing 23 16 Hypothyroidism 5 4 Pharyngitis 12 13 Gastrointestinal Rhinitis 8 6 Nausea 43 33 Sinusitis 6 5 Anorexia 32 27 Skin and Appendages Diarrhea 22 17 Alopecia 36 32 Vomiting 14 12 Pruritus 29 28 Abdominal Pain 13 13 Rash 24 23 Dyspepsia 9 8 Skin Dry 24 23 Constipation 5 5 Special Senses, Other Hematologic Disorders Taste Perversion 9 4 Neutropenia 26 14 Vision Disorders Anemia 12 17 Vision Blurred 5 6 Leukopenia 6 5 Conjunctivitis 4 5 Thrombocytopenia 5 2 Liver and Biliary System Hepatomegaly 4 4 Table 6 summarizes the treatment-related adverse reactions in Study 4 that occurred at a greater than or equal to 10% incidence.
In Study 2, the incidence of serious adverse reactions was 17% in the PegIntron/ribavirin groups compared to 14% in the INTRON A/ribavirin group. In Study 3, there was a similar incidence of serious adverse reactions reported for the weight-based ribavirin group (12%) and for the flat-dose ribavirin regimen. In many but not all cases, adverse reactions resolved after dose reduction or discontinuation of therapy. Some subjects experienced ongoing or new serious adverse reactions during the 6-m
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