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RIBAVIRIN TABLETS | Ribavirin

05:44 EDT 27th August 2014 | BioPortfolio

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Rx only

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 CHNO 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.

IMAGE 24c3b88a-8839-40e5-83c0-07224e42c8f2-01.jpg

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) AUCwas 25,361±7110 ng.hr/mL and C was 2748±818 ng/mL. The average time to reach C 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 C 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 (Twas doubled) and the AUC and C 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.

Race

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.

Renal Dysfunction

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).

Hepatic Impairment

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.

Pediatric Patients

Pharmacokinetic evaluations in pediatric patients have not been performed.

Elderly Patients

Pharmacokinetic evaluations in elderly patients have not been performed.

Gender

Ribavirin pharmacokinetics, when corrected for weight, are similar in male and female patients.

In vitro studies indicate that ribavirin does not inhibit CYP450 enzymes.

Nucleoside Analogues

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 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 10 HCV RNA copies/mL serum) were preferentially assigned to treatment for 48 weeks.

HCV Genotypes

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.

Table 1 Sustained Virologic Response (SVR) to Combination Therapy (Study NV15801Described as study 4 in the peginterferon alfa-2a package insert.)

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).
All  patients
197/444 (44%)
65/224 (29%)
241/453 (53%)
Genotype  1
103/285 (36%)
29/145 (20%)
132/298 (44%)
Genotypes  2 - 6
94/159 (59%) 
36/79 (46%) 
109/155 (70%)
Table 2 Sustained Virologic Response as a Function of Genotype (Study NV15942Described as Study 5 in the peginterferon alfa-2a package insert.)

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 1000 mg for body weight <75 kg; 1200 mg for body weight ≥75 kg. 
( 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%) 

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 >2log 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.

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 2log 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.

Table 3 Sustained Virologic Response in Patients With Chronic Hepatitis C Coinfected With HIV (Study NR15961Peginterferon alfa-2a + Ribavirin vs. Peginterferon alfa-2a; Peginterferon alfa-2a + Ribavirin vs. Interferon alfa-2a + Ribavirin p-value <0.0001 (Cochran-Mantel-Haenszel).)

Interferon - a  +
Ribavirin  Tablets  800  mg
Peginterferon  alfa -
2a  +  Placebo
Peginterferon  alfa -
2a  +  Ribavirin  Tablets  800  mg

( N = 289 ) 
( N = 289 ) 
( N = 290 ) 
All patients 
33 (11%)
58 (20%)
116 (40%)
Genotype 1 
12/171 (7%) 
24/175 (14%) 
51/176 (29%) 
Genotypes 2, 3 
18/89 (20%) 
32/90 (36%) 
59/95 (62%) 

Ribavirin tablets in combination with peginterferon alfa-2a are 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 tablet is 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 six-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 alfa-2a and ribavirin 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 alfa-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.

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.

Nucleoside Analogues

NRTIs

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).

Didanosine

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).

Zidovudine

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).

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.

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 (t) of ribavirin of 12 days, effective contraception must be utilized for 6 months posttherapy (i.e., 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 (see CONTRAINDICATIONS)

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.

Animal Toxicology

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).

No clinically significant differences in the pharmacokinetics of ribavirin were observed between male and female subjects.

Peginterferon alfa-2a in combination with ribavirin tablets causes a broad variety of serious adverse reactions (see BOXED WARNING and WARNINGS).

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 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 tablet 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 <10 g/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.

Table 4 Adverse Reactions Occurring in ≥5% of Patients in Chronic Hepatitis C Clinical Trials (Study NV15801Described as study 4 in the peginterferon alfa-2a package insert.)
Body  System 
CHC  Combination  Therapy
Study  NV15801 

Peginterferon  alfa -
2a  180  mcg  +  1000  mg  or  1200  mg
Ribavirin  Tablets
48  week 
Interferon  alfa - 2b 

Manufacturer

American Health Packaging

Active Ingredients

Source

Drugs and Medications [55 Associated Drugs and Medications listed on BioPortfolio]

Ribavirin [Aurobindo Pharma Limited]

These highlights do not include all the information needed to use ribavirin safely and effectively. See full prescribing information for ribavirin tablets. Ribavirin Tablets Initial U.S. Approval: 200...

Ribavirin [Sandoz Inc]

These highlights do not include all the information needed to use Ribavirin safely and effectively. See full prescribing information for Ribavirin.Ribavirin Capsules Initial U.S. Approval: 1998

Ribavirin [American Health Packaging]

These highlights do not include all the information needed to use Ribavirin safely and effectively. See full prescribing information for Ribavirin.Ribavirin Capsules Initial U.S. Approval: 1998

Ribavirin [Sandoz Inc]

These highlights do not include all the information needed to use RIBAVIRIN TABLETS safely and effectively. See full prescribing information for RIBAVIRIN TABLETS. Ribavirin Tablets, oralInitial U.S. ...

Ribavirin [Cadila Healthcare Limited]

These highlights do not include all the information needed to use ribavirin safely and effectively. See full prescribing information for ribavirin. Initial U.S. Approval: 2002

Clinical Trials [504 Associated Clinical Trials listed on BioPortfolio]

Study Comparing Reduction and Viral Safety of IFN Alfa-2b XL + Ribavirin Versus PEG IFN Alfa-2b + Ribavirin in Patients With Chronic Hepatitis C Genotype 1

The purpose of this study is to confirm if IFN alfa-2b XL has a better antiviral activity and tolerability as compared with current marketed reference, while combined with ribavirin, in a ...

Ribavirin Pre-treatment Followed by Combined Standard Therapy in Hepatitis C Virus (HCV) Recipients

The results of antiviral therapy in patients with recurrent hepatitis C after liver transplantation are lower than standard. Ribavirin has immune-modulating effects and seems to be crucial...

A Phase I Study of Combination Therapy With Didanosine (ddI) and Ribavirin in HIV-Infected Children.

To compare the safety, toxicity, and tolerance of two doses of ribavirin in combination with didanosine (ddI) to HIV-infected children. To determine the toxicity of ddI/ribavirin and compa...

Phase I Pharmacokinetic and Tolerance Study of Ribavirin in Human Immunodeficiency Virus (HIV) - Infected Patients

To determine how fast ribavirin reaches the bloodstream, what concentration of ribavirin is reached in blood and how long it remains in the blood (pharmacokinetics) when given by different...

Safety and Efficacy of SCH 503034 in Previously Untreated Subjects With Chronic Hepatitis C Infected With Genotype 1 (Study P03523AM2)(COMPLETED)

This is a Phase 2, randomized, 7-arm , open-label safety and efficacy study comparing treatment with PegIntron (1.5 µg/kg QW) plus ribavirin (800-1400 mg/day) to treatment with SCH 503034...

PubMed Articles [79 Associated PubMed Articles listed on BioPortfolio]

Antiviral activity of Ribavirin nano-particles against measles virus.

Measles virus considers an important cause of child morbidity and mortality in some areas as Africa. Ribavirin's activity as a nucleoside analog can disclose the surprisingly broad spectrum action aga...

Ribavirin Dose Management in HCV Patients Receiving Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir with Ribavirin.

Some individuals with hepatitis C virus infection treated with direct-acting antivirals require ribavirin to maximize sustained virologic response rates. We describe the clinical management of ribavir...

Ribavirin has a Demonstrable Effect on Crimean-Congo Hemorrhagic Fever Viral Populations and Viral Load during Patient Treatment.

The use of ribavirin to treat infections of Crimean-Congo Hemorrhagic Fever virus (CCHFV) has been controversial based on uncertainties on its antiviral efficacy in clinical case studies. We studied t...

Ribavirin therapy of hepatitis E infection may cause hyporegenerative anemia in pediatric renal transplant patients.

HEV infection can lead to chronic hepatitis in immunosuppressed patients; extrahepatic manifestations are rarely seen. Here, we report a 13-year-old renal transplant patient with chronic hepatitis E a...

Hepatic Pharmacokinetics and Pharmacodynamics with Ombitasvir/Paritaprevir/Ritonavir Plus Dasabuvir Treatment and Variable Ribavirin Dosage.

It is unknown whether ribavirin (RBV) co-administration modifies the early rate of decline of hepatitis C virus (HCV) RNA in the liver versus plasma compartments, specifically.

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