RIBAVIRIN — ribavirin tablet, film coated
State of Florida DOH Central Pharmacy
Ribavirin tablets monotherapy is not effective for the treatment of chronic hepatitis C virus infection and should not be used alone for this indication (see WARNINGS ).
The primary clinical toxicity of ribavirin is hemolytic anemia. The anemia associated with ribavirin therapy may result in worsening of cardiac disease that has led to fatal and nonfatal myocardial infarctions. Patients with a history of significant or unstable cardiac disease should not be treated with ribavirin (see WARNINGS, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION ).
Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. In addition, ribavirin has a multiple dose half-life of 12 days, and it may persist in non-plasma compartments for as long as 6 months. Ribavirin therapy is contraindicated in women who are pregnant and in the male partners of women who are pregnant. Extreme care must be taken to avoid pregnancy during therapy and for 6 months after completion of therapy in both female patients and in female partners of male patients who are taking ribavirin therapy. At least two reliable forms of effective contraception must be utilized during treatment and during the 6-month posttreatment follow-up period (see CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Information for Patients, and Pregnancy: Category X ).
Ribavirin tablet 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 molecular formula of ribavirin is C8 H12 N4 O5 and the molecular weight is 244.2. Ribavirin is a white crystalline powder. It is freely soluble in water and slightly soluble in anhydrous alcohol.
Each film-coated ribavirin tablet intended for oral administration contains 200 mg or 400 mg or 500 mg or 600 mg of ribavirin. In addition, each tablet contains the following inactive ingredients: crospovidone, hypromellose, iron oxide red, iron oxide yellow, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, silicon dioxide, talc and titanium dioxide.
Mechanism of Action
Ribavirin is a synthetic nucleoside analogue. The mechanism by which the combination of ribavirin and an interferon product exerts its effects against the hepatitis C virus has not been fully established.
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 tablet is about 120 to 170 hours. The total apparent clearance following administration of a single oral dose of ribavirin tablet 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 tablet was taken with a high-fat meal compared with fasting conditions (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Elimination and Metabolism
The contribution of renal and hepatic pathways to ribavirin elimination after administration of ribavirin tablet is not known. In vitro studies indicate that ribavirin is not a substrate of CYP450 enzymes.
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 tablet has not been evaluated. The clinical trials of ribavirin tablets were restricted to patients with Child-Pugh class A disease.
Pharmacokinetic evaluations in pediatric patients have not been performed.
Pharmacokinetic evaluations in elderly patients have not been performed.
Ribavirin pharmacokinetics, when corrected for weight, are similar in male and female patients.
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.
Interferon alfa-2b + Ribavirin 1000 mg or 1200 mg
Peginterferon alfa-2a + placebo
Peginterferon alfa-2a + Ribavirin Tablets 1000 mg or 1200 mg
Difference in overall treatment response (peginterferon alfa-2a/ribavirin tablets — Interferon alfa-2b/ribavirin) was 9% (95% CI 2.3, 15.3).
|197/444 (44%)||65/224 (29%)||241/453 (53%)|
|103/285 (36%)||29/145 (20%)||132/298 (44%)|
|94/159 (59%)||36/79 (46%)||109/155 (70%)|
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 tablet 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.
24 Weeks Treatment
48 Weeks Treatment
Peginterferon alfa-2a + Ribavirin Tablets 800 mg (N=207)
Peginterferon alfa-2a + Ribavirin Tablets 1000 mg or 1200 mg † (N=280)
Peginterferon alfa-2a + Ribavirin Tablets 800 mg (N=361)
Peginterferon alfa-2a + Ribavirin Tablets 1000 mg or 1200 mg †(N=436)
|Genotype 1||29/101 (29%)||48/118 (41%)||99/250 (40%)||138/271 (51%)|
|Genotypes 2, 3||79/96 (82%)||116/144(81%)||75/99(76%)||117/153 (76%)|
|Genotype 4||0/5 (0%)||7/12 (58%)||5/8 (63%)||9/11 (82%)|
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