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ribavirin tablet, film coated
Ribavirin is a nucleoside analogue with antiviral activity. The chemical name of ribavirin is 1-ß-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide and has the following structural formula:
The empirical formula of ribavirin is C8H12N4O5 and the molecular weight is 244.2. Ribavirin is a white to off-white powder. It is freely soluble in water and slightly soluble in anhydrous alcohol.
Ribavirin tablets are available as round, film-coated white, tablets. Each tablet, for oral administration, contains 200 mg ribavirin. In addition, each tablet contains the following inactive ingredients: croscarmellose sodium, hypromellose, magnesium stearate, mannitol, povidone and sodium starch glycolate. The coating of the tablets contain Opadry White (made by using hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol and polysorbate 80).
Multiple dose ribavirin pharmacokinetic data are available for HCV patients who received ribavirin in combination with peginterferon alfa-2a. Following administration of 1200 mg/day with food for 12 weeks mean±SD (n=39; body weight >75 kg) AUC0-12hr was 25,361±7110 ng•hr/mL and Cmax was 2748±818 ng/mL. The average time to reach Cmax was 2 hours. Trough ribavirin plasma concentrations following 12 weeks of dosing with food were 1662±545 ng/mL in HCV infected patients who received 800 mg/day (n=89), and 2112±810 ng/mL in patients who received 1200 mg/day (n=75; body weight >75 kg).
The terminal half-life of ribavirin following administration of a single oral dose of ribavirin tablets is about 120 to 170 hours. The total apparent clearance following administration of a single oral dose of ribavirin tablets is about 26 L/h. There is extensive accumulation of ribavirin after multiple dosing (twice daily) such that the Cmax at steady state was four-fold higher than that of a single dose.
Effect of Food on Absorption of Ribavirin
Bioavailability of a single oral dose of ribavirin was increased by co-administration with a high-fat meal. The absorption was slowed (Tmax was doubled) and the AUC0-192h and Cmax increased by 42% and 66%, respectively, when ribavirin tablets were taken with a high-fat meal compared with fasting conditions (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
A pharmacokinetic study in 42 subjects demonstrated there is no clinically significant difference in ribavirin pharmacokinetics among Black (n=14), Hispanic (n=13) and Caucasian (n=15) subjects.
The pharmacokinetics of ribavirin following administration of ribavirin tablets have not been studied in patients with renal impairment and there are limited data from clinical trials on administration of ribavirin tablets in patients with creatinine clearance <50 mL/min. Therefore, patients with creatinine clearance <50 mL/min should not be treated with ribavirin tablets (see WARNINGS and DOSAGE AND ADMINISTRATION).
The effect of hepatic impairment on the pharmacokinetics of ribavirin following administration of ribavirin tablets has not been evaluated. The clinical trials of ribavirin tablets were restricted to patients with Child-Pugh class A disease.
In vitro studies indicate that ribavirin does not inhibit CYP450 enzymes.
In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n=18), stavudine (n=10), or zidovudine (n=6) were co-administered as part of a multi-drug regimen to HCV/HIV coinfected patients (see PRECAUTIONS: Drug Interactions).
In vitro, didanosine or its active metabolite (dideoxyadenosine 5’-triphosphate) is increased when didanosine is co-administered with ribavirin, which could cause or worsen clinical toxicities (see PRECAUTIONS: Drug Interactions).
Drugs Metabolized by Cytochrome P450
There was no effect on the pharmacokinetics of representative drugs metabolized by CYP 2C9, CYP 2C19, CYP 2D6 or CYP 3A4. Treatment with peginterferon alfa-2a once weekly for 4 weeks in healthy subjects was associated with an inhibition of P450 1A2 and a 25% increase in theophylline AUC (see PRECAUTIONS: Drug Interactions).
The safety and effectiveness of peginterferon alfa-2a in combination with ribavirin tablets for the treatment of hepatitis C virus infection were assessed in two randomized controlled clinical trials. All patients were adults, had compensated liver disease, detectable hepatitis C virus, liver biopsy diagnosis of chronic hepatitis, and were previously untreated with interferon. Approximately 20% of patients in both studies had compensated cirrhosis (Child-Pugh class A). Patients coinfected with HIV were excluded from these studies.
In study NV15801 (described as Study 4 in the Peginterferon alfa-2a Package Insert), patients were randomized to receive either peginterferon alfa-2a 180 mcg sc once weekly (qw) with an oral placebo, peginterferon alfa-2a 180 mcg qw with ribavirin tablets 1000 mg po (body weight <75 kg) or 1200 mg po (body weight ≥75 kg) or interferon alfa-2b 3 MIU sc tiw plus ribavirin 1000 mg or 1200 mg po. All patients received 48 weeks of therapy followed by 24 weeks of treatment-free follow-up. Ribavirin tablets or placebo treatment assignment was blinded. Sustained virological response was defined as undetectable (<50 IU/mL) HCV RNA on or after study week 68. Peginterferon alfa-2a in combination with ribavirin tablets resulted in a higher SVR compared to peginterferon alfa-2a alone or interferon alfa-2b and ribavirin (Table 1). In all treatment arms, patients with viral genotype 1, regardless of viral load, had a lower response rate to peginterferon alfa-2a in combination with ribavirin tablets compared to patients with other viral genotypes.
In study NV15942 (described as Study 5 in the Peginterferon alfa-2a Package Insert), all patients received peginterferon alfa-2a 180 mcg sc qw and were randomized to treatment for either 24 or 48 weeks and to a ribavirin tablets dose of either 800 mg or 1000 mg/1200 mg (for body weight <75 kg/≥75 kg).Assignment to the four treatment arms was stratified by viral genotype and baseline HCV viral titer. Patients with genotype 1 and high viral titer (defined as >2 x 106 HCV RNA copies/mL serum) were preferentially assigned to treatment for 48 weeks.
HCV 1 and 4
Irrespective of baseline viral titer, treatment for 48 weeks with peginterferon alfa-2a and 1000 mg or 1200 mg of ribavirin tablets resulted in higher SVR (defined as undetectable HCV RNA at the end of the 24-week treatment-free follow-up period) compared to shorter treatment (24 weeks) and/or 800 mg ribavirin tablets.
HCV 2 and 3
Irrespective of baseline viral titer, treatment for 24 weeks with peginterferon alfa-2a and 800 mg of ribavirin tablets resulted in a similar SVR compared to longer treatment (48 weeks) and/or 1000 mg or 1200 mg of ribavirin tablets (see Table 2).
The numbers of patients with genotype 5 and 6 were too few to allow for meaningful assessment.
Other Treatment Response Predictors
Treatment response rates are lower in patients with poor prognostic factors receiving pegylated interferon alpha therapy. In studies NV15801 and NV15942, treatment response rates were lower in patients older than 40 years (50% vs. 66%), in patients with cirrhosis (47% vs. 59%), in patients weighing over 85 kg (49% vs. 60%),and in patients with genotype 1 with high vs. low viral load (43% vs. 56%). African-American patients had lower response rates compared to Caucasians.
Paired liver biopsies were performed on approximately 20% of patients in studies NV15801 and NV15942. Modest reductions in inflammation compared to baseline were seen in all treatment groups.
In studies NV15801 and NV15942, lack of early virologic response by 12 weeks (defined as HCV RNA undetectable or >2log10 lower than baseline) was grounds for discontinuation of treatment. Of patients who lacked an early viral response by 12 weeks and completed a recommended course of therapy despite a protocol-defined option to discontinue therapy, 5/39 (13%) achieved an SVR. Of patients who lacked an early viral response by 24 weeks, 19 completed a full course of therapy and none achieved an SVR.
CHC and Coinfection with HIV (CHC/HIV): Study NR15961
In Study NR15961 (described as Study 6 in the Peginterferon alfa-2a Package Insert), patients with CHC/HIV were randomized to receive either peginterferon alfa-2a 180 mcg sc once weekly (qw) plus an oral placebo, peginterferon alfa-2a 180 mcg qw plus ribavirin tablets 800 mg po daily or interferon alfa-2a, 3 MIU sc tiw plus ribavirin tablets 800 mg po daily. All patients received 48 weeks of therapy and sustained virologic response (SVR) was assessed at 24 weeks of treatment-free follow-up. ribavirin tablets or placebo treatment assignment was blinded in the peginterferon alfa-2a treatment arms. All patients were adults, had compensated liver disease, detectable hepatitis C virus, liver biopsy diagnosis of chronic hepatitis C, and were previously untreated with interferon. Patients also had CD4+ cell count ≥200 cells/µL or CD4+ cell count ≥100 cells/µL but <200 cells/µL and HIV-1 RNA <5000 copies/mL, and stable status of HIV. Approximately 15% of patients in the study had cirrhosis. Results are shown in Table 3.
Treatment response rates are lower in CHC/HIV patients with poor prognostic factors (including HCV genotype 1, HCV RNA >800,000 IU/mL, and cirrhosis) receiving pegylated interferon alpha therapy. Geographic region is not a prognostic factor for response. However, poor prognostic factors occur more frequently in the US population than in the non-US population.
Of the patients who did not demonstrate either undetectable HCV RNA or at least a 2log10 reduction from baseline in HCV RNA titer by 12 weeks of peginterferon alfa-2a and ribavirin tablets combination therapy, 2% (2/85) achieved an SVR.
In CHC patients with HIV coinfection who received 48 weeks of peginterferon alfa-2a alone or in combination with ribavirin tablets treatment, mean and median HIV RNA titers did not increase above baseline during treatment or 24 weeks posttreatment.
INDICATIONS AND USAGE
Ribavirin tablets in combination with peginterferon alfa-2a is indicated for the treatment of adults with chronic hepatitis C virus infection who have compensated liver disease and have not been previously treated with interferon alpha. Patients in whom efficacy was demonstrated included patients with compensated liver disease and histological evidence of cirrhosis (Child-Pugh class A) and patients with HIV disease that is clinically stable (e.g., antiretroviral therapy not required or receiving stable antiretroviral therapy).
Ribavirin tablets are contraindicated in:
Ribavirin tablets and peginterferon alfa-2a combination therapy is contraindicated in patients with:
Ribavirin tablets must not be used alone because ribavirin monotherapy is not effective for the treatment of chronic hepatitis C virus infection. The safety and efficacy of ribavirin tablets have only been established when used together with peginterferon alfa-2a (pegylated interferon alfa-2a, recombinant).
Ribavirin tablets and peginterferon alfa-2a should be discontinued in patients who develop evidence of hepatic decompensation during treatment.
There are significant adverse events caused by ribavirin tablets/peginterferon alfa-2a therapy, including severe depression and suicidal ideation, hemolytic anemia, suppression of bone marrow function, autoimmune and infectious disorders, pulmonary dysfunction, pancreatitis, and diabetes. The Peginterferon alfa-2a Package Insert and MEDICATION GUIDE should be reviewed in their entirety prior to initiation of combination treatment for additional safety information.
Treatment with ribavirin tablets and peginterferon alfa-2a should be administered under the guidance of a qualified physician and may lead to moderate to severe adverse experiences requiring dose reduction, temporary dose cessation or discontinuation of therapy.
Ribavirin may cause birth defects and/or death of the exposed fetus. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin has demonstrated significant teratogenic and/or embryocidal effects in all animal species in which adequate studies have been conducted. These effects occurred at doses as low as one twentieth of the recommended human dose of ribavirin. 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. 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 CONTRAINDICATIONS and PRECAUTIONS: Information for Patients and Pregnancy:Category X).
The primary toxicity of ribavirin is hemolytic anemia (hemoglobin <10 g/dL), which was observed in approximately 13% of all ribavirin tablets and peginterferon alfa-2a treated patients in clinical trials (see PRECAUTIONS: Laboratory Tests). The 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.
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: Ribavirin Tablets Dosage Modification Guidelines ). Because cardiac disease may be worsened by drug induced anemia, patients with a history of significant or unstable cardiac disease should not use ribavirin tablets (see ADVERSE REACTIONS).
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 (described as Study 6 in the Peginterferon alfa-2a Package Insert), 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, and peginterferon alfa-2a treatment should be immediately discontinued if decompensation (Child-Pugh score ≥6) is observed (see CONTRAINDICATIONS).
Severe acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, and anaphylaxis) have been rarely observed during alpha interferon and ribavirin therapy. If such reaction occurs, therapy with peginterferon alpha-2a and ribavirin tablets should be discontinued and appropriate medical therapy immediately 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 rarely reported in patients receiving peginterferon alpha-2a with and without ribavirin. Patients developing signs or symptoms of severe skin reactions must discontinue therapy. (see ADVERSE REACTIONS: Postmarketing Experience).
Pulmonary symptoms, including dyspnea, pulmonary infiltrates, pneumonitis and occasional cases of fatal pneumonia, have been reported during therapy with ribavirin and interferon. In addition, sarcoidosis or the exacerbation of sarcoidosis has been reported. If there is evidence of pulmonary infiltrates or pulmonary function impairment, the patient should be closely monitored and, if appropriate, combination ribavirin tablets/peginterferon alfa-2a treatment should be discontinued.
Ribavirin tablets and peginterferon alfa-2a therapy should be suspended in patients with signs and symptoms of pancreatitis, and discontinued in patients with confirmed pancreatitis.
Ribavirin tablets should not be used in patients with creatinine clearance <50 mL/min (see CLINICAL PHARMACOLOGY: Special Populations).
Ribavirin tablets must be discontinued immediately and appropriate medical therapy instituted if an acute hypersensitivity reaction (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) develops. Transient rashes do not necessitate interruption of treatment.
The safety and efficacy of ribavirin tablets and peginterferon alfa-2a therapy for the treatment of adenovirus, RSV, parainfluenza or influenza infections have not been established. Ribavirin tablets 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.
The safety and efficacy of ribavirin tablets and peginterferon alfa-2a therapy have not been established in liver or other organ transplant patients, patients with decompensated liver disease due to hepatitis C virus infection, patients who are non-responders to interferon therapy or patients coinfected with HBV or HIV and a CD4+ cell count <100 cells/µL.
Information for Patients
Patients must be informed that ribavirin may cause birth defects and/or death of the exposed fetus. Ribavirin tablets therapy must not be used by women who are pregnant or by men whose female partners are pregnant. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients taking ribavirin tablets therapy and for 6 months posttherapy. Ribavirin tablets therapy should not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Patients must perform a pregnancy test monthly during therapy and for 6 months posttherapy.
Female patients of childbearing potential and male patients with female partners of childbearing potential must be advised of the teratogenic/embryocidal risks and must be instructed to practice effective contraception during ribavirin tablets therapy and for 6 months posttherapy. Patients should be advised to notify the healthcare provider immediately in the event of a pregnancy (see CONTRAINDICATIONS and WARNINGS).
The most common adverse event associated with ribavirin is anemia, which may be severe (see ADVERSE REACTIONS). Patients should be advised that laboratory evaluations are required prior to starting ribavirin tablets therapy and periodically thereafter (see Laboratory Tests). It is advised that patients be well hydrated, especially during the initial stages of treatment.
Patients who develop dizziness, confusion, somnolence, and fatigue should be cautioned to avoid driving or operating machinery.
Patients should be informed regarding the potential benefits and risks attendant to the use of ribavirin tablets. Instructions on appropriate use should be given, including review of the contents of the enclosed MEDICATION GUIDE, which is not a disclosure of all or possible adverse effects.
Patients should be advised to take ribavirin tablets with food.
Before beginning ribavirin tablets therapy, standard hematological and biochemical laboratory tests must be conducted for all patients. Pregnancy screening for women of childbearing potential must be done.
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. Monthly pregnancy testing should be done during combination therapy and for 6 months after discontinuing therapy.
The entrance criteria used for the clinical studies of ribavirin tablets and peginterferon alfa-2a combination therapy may be considered as a guideline to acceptable baseline values for initiation of treatment:
The maximum drop in hemoglobin usually occurred during the first 8 weeks of initiation of ribavirin tablets therapy. Because of this initial acute drop in hemoglobin, it is advised that a complete blood count should be obtained pretreatment and at week 2 and week 4 of therapy or more frequently if clinically indicated. Additional testing should be performed periodically during therapy. Patients should then be followed as clinically appropriate.
Results from a pharmacokinetic sub-study demonstrated no pharmacokinetic interaction between peginterferon alfa-2a and ribavirin.
In Study NR15961 among the CHC/HIV coinfected cirrhotic patients receiving NRTIs cases of hepatic decompensation (some fatal) were observed (see WARNINGS: Hepatic Failure).
Patients receiving peginterferon alfa-2a/ribavirin tablets and NRTIs should be closely monitored for treatment associated toxicities. Physicians should refer to prescribing information for the respective NRTIs for guidance regarding toxicity management. In addition, dose reduction or discontinuation of peginterferon alfa-2a , ribavirin tablets or both should also be considered if worsening toxicities are observed (see WARNINGS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION: Dose Modifications).
Co-administration of ribavirin tablets and didanosine is not recommended. Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in clinical trials (see CLINICAL PHARMACOLOGY: Drug Interactions).
In Study NR15961, patients who were administered zidovudine in combination with peginterferon alfa-2a/ribavirin tablets developed severe neutropenia (ANC <500) and severe anemia (hemoglobin <8 g/dL) more frequently than similar patients not receiving zidovudine (neutropenia 15% vs. 9%) (anemia 5% vs. 1%).
Lamivudine, Stavudine, and Zidovudine
In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogs such as lamivudine, stavudine, and zidovudine. No evidence of a pharmacokinetic or pharmacodynamic interaction was seen when ribavirin was co-administered with lamivudine, stavudine, and/or zidovudine in HIV/HCV coinfected patients (see CLINICAL PHARMACOLOGY: Drug Interactions).
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a p53 (+/-) mouse carcinogenicity study and a rat 2-year carcinogenicity study at doses up to the maximum tolerated doses of 100 mg/kg/day and 60 mg/kg/day, respectively, ribavirin was not oncogenic. On a body surface area basis, these doses are approximately 0.5 and 0.6 times the maximum recommended human 24-hour dose of ribavirin.
Ribavirin demonstrated mutagenic activity in the in vitro mouse lymphoma assay. No clastogenic activity was observed in an in vivo mouse micronucleus assay at doses up to 2000 mg/kg. However, results from studies published in the literature show clastogenic activity in the in vivo mouse micronucleus assay at oral doses up to 2000 mg/kg. A dominant lethal assay in rats was negative, indicating that if mutations occurred in rats they were not transmitted through male gametes. However, potential carcinogenic risk to humans cannot be excluded.
Impairment of Fertility
In a fertility study in rats, ribavirin showed a marginal reduction in sperm counts at the dose of 100 mg/kg/day with no effect on fertility. Upon cessation of treatment, total recovery occurred after 1 spermatogenesis cycle. Abnormalities in sperm were observed in studies in mice designed to evaluate the time course and reversibility of ribavirin-induced testicular degeneration at doses of 15 to 150 mg/kg/day (approximately 0.1 to 0.8 times the maximum recommended human 24-hour dose of ribavirin) administered for 3 to 6 months. Upon cessation of treatment, essentially total recovery from ribavirin-induced testicular toxicity was apparent within 1 or 2 spermatogenic cycles.
Female patients of childbearing potential and male patients with female partners of childbearing potential should not receive ribavirin tablets unless the patient and his/her partner are using effective contraception (two reliable forms). Based on a multiple dose half-life (t1/2) of ribavirin of 12 days, effective contraception must be utilized for 6 months posttherapy (ie, 15 half-lives of clearance for ribavirin).
No reproductive toxicology studies have been performed using peginterferon alfa-2a in combination with ribavirin tablets. However, peginterferon alfa-2a and ribavirin when administered separately, each has adverse effects on reproduction. It should be assumed that the effects produced by either agent alone would also be caused by the combination of the two agents.
Pregnancy Category X
Ribavirin produced significant embryocidal and/or teratogenic effects 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.
In conventional embryotoxicity/teratogenicity studies in rats and rabbits, observed no-effect dose levels were well below those for proposed clinical use (0.3 mg/kg/day for both the rat and rabbit; approximately 0.06 times the recommended human 24-hour dose of ribavirin). No maternal toxicity or effects on offspring were observed in a peri/postnatal toxicity study in rats dosed orally at up to 1 mg/kg/day (approximately 0.01 times the maximum recommended human 24-hour dose of ribavirin).
Treatment and Posttreatment
Potential Risk to the Fetus
Ribavirin is known to accumulate in intracellular components from where it is cleared very slowly. It is not known whether ribavirin is contained in sperm, and if so, will exert a potential teratogenic effect upon fertilization of the ova. In a study in rats, it was concluded that dominant lethality was not induced by ribavirin at doses up to 200 mg/kg for 5 days (up to 1.7 times the maximum recommended human dose of ribavirin). However, because of the potential human teratogenic effects of ribavirin, male patients should be advised to take every precaution to avoid risk of pregnancy for their female partners.
Ribavirin tablets should not be used by pregnant women or by men whose female partners are pregnant. Female patients of childbearing potential and male patients with female partners of childbearing potential should not receive ribavirin tablets unless the patient and his/her partner are using effective contraception (two reliable forms) during therapy and for 6 months posttherapy.
Ribavirin Pregnancy Registry
A Ribavirin Pregnancy Registry has been established to monitor maternal-fetal outcomes of pregnancies of female patients and female partners of male patients exposed to ribavirin during treatment and for 6 months following cessation of treatment. Healthcare providers and patients are encouraged to report such cases by calling 1-800-593-2214.
Long-term study in the mouse and rat (18 to 24 months; dose 20 to 75 and 10 to 40 mg/kg/day, respectively, approximately 0.1 to 0.4 times the maximum human daily dose of ribavirin) have demonstrated a relationship between chronic ribavirin exposure and an increased incidence of vascular lesions (microscopic hemorrhages) in mice. In rats, retinal degeneration occurred in controls, but the incidence was increased in ribavirin-treated rats.
It is not known whether ribavirin is excreted in human milk. Because many drugs are excreted in human milk and to avoid any potential for serious adverse reactions in nursing infants from ribavirin, a decision should be made either to discontinue nursing or therapy with ribavirin tablets, based on the importance of the therapy to the mother.
Safety and effectiveness of ribavirin tablets have not been established in patients below the age of 18.
Clinical studies of ribavirin tablets and peginterferon alfa-2a did not include sufficient numbers of subjects aged 65 or over to determine whether they respond differently from younger subjects. Specific pharmacokinetic evaluations for ribavirin in the elderly have not been performed. The risk of toxic reactions to this drug may be greater in patients with impaired renal function. Ribavirin tablets should not be administered to patients with creatinine clearance <50 mL/min. (see CLINICAL PHARMACOLOGY: Special Populations).
The most common life-threatening or fatal events induced or aggravated by peginterferon alfa-2a and ribavirin tablets were depression, suicide, relapse of drug abuse/overdose, and bacterial infections, each occurring at a frequency of <1%. Hepatic decompensation occurred in 2% (10/574) of CHC/HIV patients (see WARNINGS: Hepatic Failure).
In all studies, one or more serious adverse reactions occurred in 10% of CHC monoinfected patients and in 19% of CHC/HIV patients receiving peginterferon alfa-2a 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 SAEs occurred at a frequency of <1% and included: suicide, suicidal ideation, psychosis, aggression, anxiety, drug abuse and drug overdose, angina, hepatic dysfunction, fatty liver, cholangitis, arrhythmia, diabetes mellitus, autoimmune phenomena (e.g., hyperthyroidism, hypothyroidism, sarcoidosis, systemic lupus erythematosus, rheumatoid arthritis), peripheral neuropathy, aplastic anemia, peptic ulcer, gastrointestinal bleeding, pancreatitis, colitis, corneal ulcer, pulmonary embolism, coma, myositis, cerebral hemorrhage, thrombotic thrombocytopenic purpura, psychotic disorder, and hallucination.
Nearly all patients in clinical trials experienced one or more adverse events. The most commonly reported adverse reactions were psychiatric reactions, including depression, insomnia, irritability, anxiety, and flu-like symptoms such as fatigue, pyrexia, myalgia, headache and rigors. Other common reactions were anorexia, nausea and vomiting, diarrhea, arthralgias, injection site reactions, alopecia, and pruritus.
Ten percent of CHC monoinfected patients receiving 48 weeks of therapy with peginterferon alfa-2a in combination with ribavirin 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 peginterferon alfa-2a and/or ribavirin tablets 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 tablets 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 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 peginterferon alfa-2a and 800 mg ribavirin tablets were observed to have lower incidence of serious adverse events (3% vs. 10%), hemoglobin <10g/dL (3% vs. 15%), dose modification of peginterferon alfa-2a (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 peginterferon alfa-2a 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.
Because clinical trials are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug. Also, the adverse event rates listed here may not predict the rates observed in a broader patient population in clinical practice.
Common Adverse Reactions in CHC With HIV Coinfection
The adverse event profile of coinfected patients treated with peginterferon alfa-2a and ribavirin tablets in Study NR15961 was generally similar to that shown for monoinfected patients in Study NV15801 (Table 4). Events occurring more frequently in coinfected patients were neutropenia (40%), anemia (14%), thrombocytopenia (8%), weight decrease (16%), and mood alteration (9%).
Laboratory Test Values
Anemia due to hemolysis is the most significant toxicity of ribavirin therapy. Anemia (hemoglobin <10 g/dL) was observed in 13% of all ribavirin tablets and peginterferon alfa-2a combination-treated patients in clinical trials. The maximum drop in hemoglobin occurred during the first 8 weeks of initiation of ribavirin therapy (see DOSAGE AND ADMINISTRATION: Dose Modifications).
The following adverse reactions have been identified and reported during post-approval use of peginterferon alfa-2a therapy: dehydration, hearing impairment, hearing loss, and serious skin reactions (see WARNINGS: Hypersensitivity).
No cases of overdose with ribavirin tablets have been reported in clinical trials. Hypocalcemia and hypomagnesemia have been observed in persons administered greater than the recommended dosage of ribavirin. In most of these cases, ribavirin was administered intravenously at dosages up to and in some cases exceeding four times the recommended maximum oral daily dose.
DOSAGE AND ADMINISTRATION
The recommended dose of ribavirin tablets is provided in Table 5. 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 5).
In the pivotal clinical trials, patients were instructed to take ribavirin tablets with food; therefore, patients are advised to take ribavirin tablets with food.
Genotypes non-1 showed no increased response to treatment beyond 24 weeks (see Table 2). Data on genotypes 5 and 6 are insufficient for dosing recommendations.
CHC with HIV Coinfection
The recommended dose for hepatitis C in HCV/HIV coinfected patients is peginterferon alfa-2a 180 mcg sc once weekly and ribavirin tablets 800 mg po daily for a total of 48 weeks, regardless of genotype.
If severe adverse reactions or laboratory abnormalities develop during combination ribavirin tablets/peginterferon alfa-2a therapy, the dose should be modified or discontinued, if appropriate, until the adverse reactions abate. If intolerance persists after dose adjustment, ribavirin tablets/peginterferon alfa-2a therapy should be discontinued.
Ribavirin tablets should be administered with caution to patients with pre-existing cardiac disease (see Table 6). 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).
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 depending upon the physician’s judgment. However, it is not recommended that ribavirin tablets be increased to its original assigned dose (1000 mg to 1200 mg).
Ribavirin tablets, 200 mg, are available for oral administration. Each tablet is round, debossed SZ over 395 on one side and plain on the reverse side, film-coated white, and is supplied as follows:
NDC 0781-5177-42 in bottles of 42 tablets
NDC 0781-5177-16 in bottles of 56 tablets
NDC 0781-5177-67 in bottles of 70 tablets
NDC 0781-5177-04 in bottles of 84 tablets
NDC 0781-5177-01 in bottles of 100 tablets
NDC 0781-5177-28 in bottles of 168 tablets
NDC 0781-5177-10 in bottles of 1000 tablets
Dispense in a tight container as defined in the USP. Store at 20°-25°C (68°-77°F). Keep bottle tightly closed.
Read this Medication Guide carefully before you start taking ribavirin tablets and read the Medication Guide each time you get more ribavirin tablets. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.
What is the most important information I should know about ribavirin tablets?
What is ribavirin?
Ribavirin is an antiviral medicine. It is used in combination with a medicine called peginterferon alfa-2a to treat some adults with chronic hepatitis C whose liver still works normally, and who have not been treated before with a medicine called an interferon alpha. It is not known how ribavirin tablets and peginterferon alfa-2a work together to fight hepatitis C virus infections.
It is not known if treatment with ribavirin and peginterferon alfa-2a combination therapy can cure hepatitis C or if it can prevent liver damage (cirrhosis), liver failure or liver cancer that is caused by hepatitis C virus infections. It is not known if treatment with ribavirin and peginterferon alfa-2a combination therapy will prevent an infected person from spreading the hepatitis C virus to another person.
Treatment with ribavirin tablets has not been studied in children under 18 years of age.
Who should not take ribavirin tablets?
Do not use ribavirin tablets if:
Tell your healthcare provider before starting treatment with ribavirin tablets in combination with peginterferon alfa-2a (see also the peginterferon alfa-2a Medication Guide) if you have any of the following medical conditions:
Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins or herbal supplements. Some medicines can cause serious side effects if taken while you also take ribavirin tablets. Some medicines may affect how ribavirin tablets work or ribavirin tablets may affect how your other medicines work. Be especially sure to tell your healthcare provider if you take any medicines to treat HIV.
For more information see the Peginterferon alfa-2a Medication Guide.
How should I take ribavirin tablets?
It is also important not to use other ribavirin medicines without talking to your healthcare provider. Please see the Peginterferon alfa-2a Medication Guide for the proper use of peginterferon alfa-2a injection.
What should I avoid while taking ribavirin tablets?
Avoid the following during ribavirin tablets treatment:
What are the possible side effects of ribavirin tablets?
The most serious possible side effects of ribavirin tablets are:
Call your healthcare provider right away if you have any of the following symptoms. They may be signs of a serious side effect of ribavirin tablets and peginterferon alfa-2a treatment.
The most common side effects of ribavirin tablets are likely to be the same as for other ribavirin products. These are:
These are not all the possible side effects of ribavirin tablets treatment. For more information, ask your doctor or pharmacist and see the Peginterferon alfa-2a Medication Guide.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
What should I know about hepatitis C infection?
Hepatitis C infection is a disease caused by a virus that infects the liver. Hepatitis C is more serious for some people than others. Most people who get hepatitis C carry the virus in their blood for the rest of their lives. Most of these people will have some liver damage, but many do not feel sick from the disease. In some people, the liver becomes badly damaged and scarred. This is called cirrhosis. Cirrhosis can cause the liver to stop working. Some people may get liver cancer or liver failure from the hepatitis C virus.
Hepatitis C virus is spread from one person to another by contact with an infected person’s blood. You should talk to your healthcare provider about ways to prevent you from infecting others.
How should I store ribavirin tablets?
Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). Please refer to the Peginterferon alfa-2a Medication Guide for storage information about peginterferon alfa-2a injection.
General information about the safe and effective use of ribavirin tablets
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ribavirin tablets for a condition for which it was not prescribed. Do not give ribavirin tablets to other people, even if they have the same symptoms that you have.
This Medication Guide summarizes the most important information about ribavirin tablets. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about ribavirin tablets that is written for healthcare professionals.
What are the ingredients in ribavirin tablets?
Active Ingredient: ribavirin
Inactive Ingredients: croscarmellose sodium, hypromellose, magnesium stearate, mannitol, povidone and sodium starch glycolate. The coating of the tablets contain Opadry White (made by using hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol and polysorbate 80).
This Medication Guide has been approved by the US Food and Drug Administration.
Princeton, NJ 08540
Revised: 09/2009 Sandoz Inc
Reproduced with permission of U.S. National Library of Medicine
Copyright © 2017
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