Rx Drugs Info

ribasphere (ribavirintablet, film coated 
[Three Rivers Pharmaceuticals, LLC ]

Rx only

RIBASPHERE (ribavirin, USP) 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).

DESCRIPTION

RIBASPHERE (ribavirin, USP), the Three Rivers Pharmaceuticals brand name for ribavirin, is a nucleoside analogue with antiviral activity. The chemical name of ribavirin is 1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide and has the following structural formula:

Image from Drug Label Content

The molecular 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.

RIBASPHERE (ribavirin, USP) is available as a blue-colored (shade depending on strength), capsule-shaped, film-coated tablet for oral administration. Each tablet contains 200 mg, 400 mg, or 600 mg of ribavirin and the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, povidone K27-33, magnesium stearate, and purified water. The coating of the 200-mg tablet contains partially hydrolyzed polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, talc, FD&C blue #2 [indigo carmine aluminum lake], and carnauba wax. The coating of the 400- and 600-mg tablet contains partially hydrolyzed polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, talc, FD&C blue #1 [brilliant blue FCF aluminum lake], and carnauba wax.

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.

CLINICAL PHARMACOLOGY

Pharmacokinetics

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 is about 120 to 170 hours. The total apparent clearance following administration of a single oral dose of ribavirin 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 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 is not known. In vitro studies indicate that ribavirin is not a substrate of CYP450 enzymes.

Special Populations

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 have not been studied in patients with renal impairment and there are limited data from clinical trials on administration of ribavirin in patients with creatinine clearance <50 mL/min. Therefore, patients with creatinine clearance <50 mL/min should not be treated with ribavirin (see WARNINGS and DOSAGE AND ADMINISTRATION).

Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of ribavirin following administration of ribavirin has not been evaluated. The clinical trials of ribavirin 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.

Drug Interactions

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.

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).

CLINICAL STUDIES

HCV Patients

The safety and effectiveness of peginterferon alfa-2a in combination with ribavirin 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 PEGASYS®¹ Package Insert), patients were randomized to receive either peginterferon alfa-2a 180 µg sc once weekly (qw) with an oral placebo, peginterferon alfa-2a 180 µg qw with ribavirin 1000 mg po (body weight <75 kg) or 1200 mg po (body weight ≥75 kg) or REBETRON² (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 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 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 alpha-2a in combination with ribavirin compared to patients with other viral genotypes.

Table 1  Sustained Virologic Response (SVR) to Combination Therapy (Study NV15801*)
Interferon alfa-2b +
Ribavirin 1000 mg or 1200 mg
Peginterferon alfa-2a+ placebo Peginterferon alfa-2a + Ribavirin 1000 mg or 1200 mg

Difference in overall treatment response (Peginterferon alfa-2a /ribavirin – Interferon alfa-2b/ribavirin) was 9% (95% CI 2.3, 15.3).

*Described as Study 4 in the PEGASYS Package Insert.

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%)

In Study NV15942 (described as Study 5 in the PEGASYS Package Insert), all patients received peginterferon alfa-2a 180 µg sc qw and were randomized to treatment for either 24 or 48 weeks and to a ribavirin 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 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 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.

HCV 2 and 3 – Irrespective of baseline viral titer, treatment for 24 weeks with peginterferon alfa-2a and 800 mg of ribavirin resulted in a similar SVR compared to longer treatment (48 weeks) and/or 1000 mg or 1200 mg of ribavirin (see Table 2).

The numbers of patients with genotype 5 and 6 were too few to allow for meaningful assessment.

Table 2  Sustained Virologic Response as a Function of Genotype (Study NV15942*)
24 Weeks Treatment 48 Weeks Treatment
Peginterferon
alfa-2a+ Ribavirin
800 mg
(N=207)
Peginterferon
alfa-2a+ Ribavirin
1000 mg or 1200 mg**
(N=280)
Peginterferon
alfa-2a+ Ribavirin
800 mg
(N=361)
Peginterferon
alfa-2a+ Ribavirin
1000 mg or 1200 mg**
(N=436)

* Described as Study 5 in the PEGASYS Package Insert.

**1000 mg for body weight <75 kg; 1200 mg for body weight ≥75 kg.

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%)

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.

INDICATIONS AND USAGE

RIBASPHERE (ribavirin, USP) 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).

CONTRAINDICATIONS

RIBASPHERE (ribavirin, USP) is contraindicated in:

RIBASPHERE (ribavirin, USP) and peginterferon alfa-2a combination therapy is contraindicated in patients with:

WARNINGS

RIBASPHERE (ribavirin, USP) 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 have only been established when used together with peginterferon alfa-2a, recombinant.

RIBASPHERE (ribavirin, USP) 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/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 PEGASYS package insert and MEDICATION GUIDE should be reviewed in their entirety prior to initiation of combination treatment for additional safety information.

General

Treatment with RIBASPHERE (ribavirin, USP) 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.

Pregnancy

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. RIBASPHERE (ribavirin, USP) 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 RIBASPHERE (ribavirin, USP) therapy and for 6 months after therapy has stopped (see CONTRAINDICATIONS and PRECAUTIONS: Information For Patients and Pregnancy: Category X).

Anemia

The primary toxicity of ribavirin is hemolytic anemia (hemoglobin <10 g/dL), which was observed in approximately 13% of all ribavirin and peginterferon alfa-2a treated patients in clinical trials (see PRECAUTIONS: Laboratory Tests). The anemia associated with ribavirin 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: RIBASPHERE (ribavirin, USP) 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 RIBASPHERE (ribavirin, USP) (see ADVERSE REACTIONS).

Hepatic Failure

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. 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).

Pulmonary

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 RIBASPHERE (ribavirin, USP)/peginterferon alfa-2a treatment should be discontinued.

Other

RIBASPHERE (ribavirin, USP) and peginterferon alfa-2a therapy should be suspended in patients with signs and symptoms of pancreatitis, and discontinued in patients with confirmed pancreatitis.

RIBASPHERE (ribavirin, USP) should not be used in patients with creatinine clearance <50 mL/min (see CLINICAL PHARMACOLOGY: Special Populations).

RIBASPHERE (ribavirin, USP) 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.

PRECAUTIONS

The safety and efficacy of RIBASPHERE (ribavirin, USP) and peginterferon alfa-2a therapy for the treatment of adenovirus, RSV, parainfluenza or influenza infections have not been established. RIBASPHERE (ribavirin, USP) 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 RIBASPHERE (ribavirin, USP) 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. RIBASPHERE (ribavirin, USP) 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 RIBASPHERE (ribavirin, USP) therapy and for 6 months posttherapy. RIBASPHERE (ribavirin, USP) 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 RIBASPHERE (ribavirin, USP) 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 RIBASPHERE (ribavirin, USP) 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 RIBASPHERE (ribavirin, USP). 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 RIBASPHERE (ribavirin, USP) with food.

Laboratory Tests

Before beginning RIBASPHERE (ribavirin, USP) 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 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 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.

Drug Interactions

Results from a pharmacokinetic sub-study demonstrated no pharmacokinetic interaction between peginterferon alfa-2a and ribavirin.

Nucleoside Analogues

NRTIs

Patients receiving peginterferon alfa-2a/ribavirin 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 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 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 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

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.

Mutagenesis

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 to150 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 RIBASPHERE (ribavirin, USP) 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 (i.e., 15 half-lives of clearance for ribavirin).

No reproductive toxicology studies have been performed using peginterferon alfa-2a in combination with RIBASPHERE (ribavirin, USP). 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

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.

RIBASPHERE (ribavirin, USP) 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 RIBASPHERE (ribavirin, USP) 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.

Nursing Mothers

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 RIBASPHERE (ribavirin, USP), based on the importance of the therapy to the mother.

Pediatric Use

Safety and effectiveness of RIBASPHERE (ribavirin, USP) have not been established in patients below the age of 18.

Geriatric Use

Clinical studies of ribavirin 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. RIBASPHERE (ribavirin, USP) should not be administered to patients with creatinine clearance <50 mL/min. (see CLINICAL PHARMACOLOGY: Special Populations).

Effect of Gender

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

ADVERSE REACTIONS

Peginterferon alfa-2a in combination with ribavirin 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 were depression, suicide, relapse of drug abuse/overdose, and bacterial infections, each occurring at a frequency of <1%.

In all studies, one or more serious adverse reactions occurred in 10% of CHC monoinfected patients receiving peginterferon alfa-2a alone or in combination with ribavirin. The most common serious adverse event (3% in CHC) 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, and thrombotic thrombocytopenic purpura.

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 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 required modification of peginterferon alfa-2a and/or ribavirin therapy. The most common reason for dose modification of peginterferon alfa-2a in CHC patients was for laboratory abnormalities; neutropenia (20%) and thrombocytopenia (4%). The most common reason for dose modification of ribavirin in CHC patients was anemia (22%).

Peginterferon alfa-2a dose was reduced in 12% of patients receiving 1000 mg to 1200 mg ribavirin for 48 weeks and in 7% of patients receiving 800 mg ribavirin for 24 weeks. Ribavirin dose was reduced in 21% of patients receiving 1000 mg to1200 mg ribavirin for 48 weeks and in 12% of patients receiving 800 mg ribavirin for 24 weeks.

Chronic hepatitis C monoinfected patients treated for 24 weeks with peginterferon alfa-2a and 800 mg ribavirin were observed to have lower incidence of serious adverse events (3% vs. 10%), hemoglobin <10 g/dL (3% vs. 15%), dose modifications of peginterferon alfa-2a (30% vs. 36%) and ribavirin (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. 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 3  Adverse Reactions Occurring in ≥ 5% of Patients in Chronic Hepatitis C Clinical Trials (Study NV15801*)
Body System CHC Combination Therapy
Study NV15801
Peginterferon alfa-2a 180 µg
+ 1000 mg or 1200 mg

Ribavirin
48 week
Interferon alfa-2b
+ 1000 mg or 1200 mg
Ribavirin
48 week

* Described as Study 4 in the PEGASYS Package Insert.

** Severe hematologic abnormalities (lymphocyte <0.5 x 109/L; hemoglobin <10 g/dL; neutrophil <0.75 x 109/L; platelet <50 x 109/L).

N=451 N=443
% %
Application Site Disorders
Injection site reaction

23

16
Endocrine Disorders
Hypothyroidism

4

5
Flu-like Symptoms and Signs
Fatigue/Asthenia
Pyrexia
Rigors
Pain

65
41
25
10

68
55
37
9
Gastrointestinal
Nausea/Vomiting
Diarrhea
Abdominal pain
Dry mouth
Dyspepsia

25
11
8
4
6

29
10
9
7
5
Hematologic**
Lymphopenia
Anemia
Neutropenia
Thrombocytopenia

14
11
27
5

12
11
8
<1
Metabolic and Nutritional
Anorexia
Weight decrease

24
10

26
10
Musculoskeletal, Connective Tissue and Bone
Myalgia
Arthralgia
Back pain

40
22
5

49
23
5
Neurological
Headache
Dizziness (excluding vertigo)
Memory impairment

43
14
6

49
14
5
Psychiatric
Irritability/Anxiety/Nervousness
Insomnia
Depression
Concentration impairment
Mood alteration

33
30
20
10
5

38
37
28
13
6
Resistance Mechanism Disorders
Overall

12

10
Respiratory, Thoracic and Mediastinal
Dyspnea
Cough
Dyspnea exertional

13
10
4

14
7
7
Skin and Subcutaneous Tissue
Alopecia
Pruritus
Dermatitis
Dry skin
Rash
Sweating increased
Eczema

28
19
16
10
8
6
5

33
18
13
13
5
5
4
Visual Disorders
Vision blurred

5

2

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 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).

OVERDOSAGE

No cases of overdose with ribavirin have been reported in clinical trials.

DOSAGE AND ADMINISTRATION

CHC Monoinfection

The recommended dose of RIBASPHERE (ribavirin, USP) tablets is provided in Table 4. The recommended duration of treatment for patients previously untreated with ribavirin and interferon is 24 to 48 weeks.

The daily dose of RIBASPHERE (ribavirin, USP) 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 4).

In the pivotal clinical trials, patients were instructed to take ribavirin with food; therefore, patients are advised to take RIBASPHERE (ribavirin, USP) with food.

Table 4   Peginterferon alfa-2a and RIBASPHERE (ribavirin, USP) Dosing Recommendations
Genotype Peginterferon alfa-2a Dose RIBASPHERE (ribavirin, USP) Dose Duration

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.

Genotypes 1, 4 180 µg <75 kg = 1000 mg
≥75 kg = 1200 mg
48 weeks
48 weeks
Genotypes 2, 3 180 µg 800 mg 24 weeks

Dose Modifications

If severe adverse reactions or laboratory abnormalities develop during combination RIBASPHERE (ribavirin, USP)/peginterferon alfa-2a therapy, the dose should be modified or discontinued, if appropriate, until the adverse reactions abate. If intolerance persists after dose adjustment, RIBASPHERE (ribavirin, USP)/ peginterferon alfa-2a therapy should be discontinued.

RIBASPHERE (ribavirin, USP) should be administered with caution to patients with pre-existing cardiac disease (see Table 5). 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).

Table 5   RIBASPHERE (ribavirin, USP) Dosage Modification Guidelines
Laboratory Values Reduce Only RIBASPHERE (ribavirin, USP) Dose to 600 mg/day* if: Discontinue RIBASPHERE (ribavirin, USP) if:
* One 200 mg tablet in the morning and either two 200 mg tablets or one 400 mg tablet in the evening.
Hemoglobin in patients with no cardiac disease <10 g/dL <8.5 g/dL
Hemoglobin in patients with history of stable cardiac disease ≥ 2 g/dL decrease in hemoglobin during any 4 week period treatment <12 g/dL despite 4 weeks at reduced dose

Once RIBASPHERE (ribavirin, USP) has been withheld due to either a laboratory abnormality or clinical manifestation, an attempt may be made to restart RIBASPHERE (ribavirin, USP) 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 RIBASPHERE (ribavirin, USP) be increased to its original assigned dose (1000 mg to 1200 mg).

Renal Impairment

RIBASPHERE (ribavirin, USP) should not be used in patients with creatinine clearance <50 mL/min (see WARNINGSand CLINICAL PHARMACOLOGY: Special Populations).

HOW SUPPLIED

RIBASPHERE (ribavirin, USP) is available as tablets for oral administration.

Each RIBASPHERE (ribavirin, USP) 200-mg tablet contains 200 mg of ribavirin and is a capsule-shaped, light blue colored, film-coated tablet, debossed with “200” on one side and the logo “3RP” on the other side.

Each RIBASPHERE (ribavirin, USP) 400-mg tablet contains 400 mg of ribavirin and is a capsule-shaped, medium blue colored, film-coated tablet, debossed with “400” on one side and the logo “3RP” on the other side.

Each RIBASPHERE (ribavirin, USP) 600-mg tablet contains 600 mg of ribavirin and is a capsule-shaped, dark blue colored, film-coated tablet, debossed with “600” on one side and the logo “3RP” on the other side.

They are packaged as follows:

200 mg          Bottles of 168 NDC 66435-102-16

200 mg          Bottles of 500 NDC 66435-102-95

400 mg          Bottles of 56 NDC 66435-103-56

400 mg          Bottles of 500 NDC 66435-103-95

600 mg          Bottles of 56 NDC 66435-104-56

600 mg          Bottles of 250 NDC 66435-104-92

Storage Conditions

Store the RIBASPHERE (ribavirin, USP) Tablets bottle at 25ºC (77ºF); excursions are permitted between 15ºC and 30ºC (59ºF and 86ºF) [see USP Controlled Room Temperature]. Keep bottle tightly closed.

¹ PEGASYS® is a registered trademark of Hoffmann–La Roche

² REBETRON is a trademark of Schering Corporation

Rx only

Manufactured by

DSM PHARMACEUTICALS, INC.

Greenville, NC 27834

for

THREE RIVERS PHARMACEUTICALS, LLC

Cranberry Township, PA 16066

XXXXXX

December 2005

Printed in USA

Copyright © 2005 by Three Rivers Pharmaceuticals, LLC. All rights reserved.

MEDICATION GUIDE

RIBASPHERE®(ribavirin, USP) TABLETS,

200 mg, 400 mg, and 600 mg

Rx Only

Read this Medication Guide carefully before you start taking RIBASPHERE (Rīb-a-sphere) and read the Medication Guide each time you get more RIBASPHERE. 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 RIBASPHERE?

1. RIBASPHERE, a form of ribavirin, may cause birth defects or death of an unborn child. Therefore, if you are pregnant or your partner is pregnant or plans to become pregnant, do not take RIBASPHERE. Female patients and female partners of male patients being treated with RIBASPHERE must not become pregnant during treatment and for 6 months after treatment has stopped.

During this time you must have pregnancy tests that show you are not pregnant. You must also use 2 effective forms of birth control during therapy and for 6 months after stopping therapy. Male patients should use a condom with spermicide as one of the two forms.

If pregnancy occurs, report the pregnancy to your healthcare provider right away. (See " What should I avoid while taking RIBASPHERE?".)

If you or a female sexual partner becomes pregnant, you should tell your healthcare provider. There is a Ribavirin Pregnancy Registry that collects information about pregnancy outcomes of female patients and female partners of male patients exposed to ribavirin. You or your healthcare provider are encouraged to contact the Registry at 1-800-593-2214.

2. RIBASPHERE can cause a dangerous drop in your red blood cell count. RIBASPHERE can cause anemia, which is a decrease in the number of red blood cells. This can be dangerous, especially if you have heart or breathing problems. This may cause a worsening of heart (cardiovascular) or circulatory problems. Some patients may get chest pain and rarely, a heart attack. Patients with a history of heart disease have the highest chance of this. Tell your healthcare provider, before taking RIBASPHERE if you have or have ever had any heart or breathing problems. Your healthcare provider should check your red blood cell count before you start treatment with RIBASPHERE and often during the first 4 weeks of treatment. Your red blood cell count may be done more often if you have any heart or breathing problems.

3. Do not take RIBASPHERE alone to treat hepatitis C virus infection. RIBASPHERE does not treat hepatitis C virus infections by itself. RIBASPHERE should be used in combination with PEGASYS®1 (peginterferon alfa-2a) to treat continuing (chronic) hepatitis C virus infections. You should read the Medication Guide for PEGASYS because it has additional important information about treatment that is not covered in this Medication Guide. Your healthcare provider or pharmacist should give you a copy of the PEGASYS Medication Guide.

What is RIBASPHERE?

RIBASPHERE is the antiviral medicine ribavirin. 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 RIBASPHERE and peginterferon alfa-2a work together to fight hepatitis C virus infections.

It is not known if treatment with RIBASPHERE 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 RIBASPHERE and peginterferon alfa-2a combination therapy will prevent an infected person from spreading the hepatitis C virus to another person.

Treatment with RIBASPHERE has not been studied in children under 18 years of age.

Who should not take RIBASPHERE?

Do not use RIBASPHERE if:

Tell your healthcare provider before starting treatment with RIBASPHERE in combination with peginterferon alfa-2a (see also the PEGASYS 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 RIBASPHERE. Some medicines may affect how RIBASPHERE works or RIBASPHERE 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 PEGASYS Medication Guide.

How should I take RIBASPHERE?

It is also important not to use other ribavirin medicines without talking to your healthcare provider. Please see the PEGASYS Medication Guide for the proper use of PEGASYS injection.

What should I avoid while taking RIBASPHERE?

Avoid the following during RIBASPHERE treatment:

Talk with your healthcare provider about birth control methods and how to avoid pregnancy. You must use extreme care to avoid pregnancy during and for 6 months after treatment in female and male patients.

What are the possible side effects of RIBASPHERE?

The most serious possible side effects of RIBASPHERE 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 RIBASPHERE and peginterferon alfa-2a treatment.

The most common side effects of RIBASPHERE are likely to be the same as for other ribavirin products. These are:

These are not all the possible side effects of RIBASPHERE treatment. For more information, ask your doctor or pharmacist and see the PEGASYS Medication Guide.

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 RIBASPHERE?

Store RIBASPHERE tablets at 25°C (77°F); excursions permitted to 15° and 30°C

(59° and 86°F). Keep bottle tightly closed.

Please refer to the PEGASYS Medication Guide for storage information about PEGASYS injection.

General information about the safe and effective use of RIBASPHERE

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use RIBASPHERE for a condition for which it was not prescribed. Do not give RIBASPHERE to other people, even if they have the same symptoms that you have.

This Medication Guide summarizes the most important information about RIBASPHERE. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about RIBASPHERE that is written for healthcare professionals.

What are the ingredients in RIBASPHERE?

Active Ingredient: ribavirin

Inactive Ingredients: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, NF, povidone K27-33, USP, magnesium stearate, NF, purified water, USP. The tablet is coated with partially hydrolyzed polyvinyl alcohol, polyethylene glycol 3350, talc, titanium dioxide, FD&C blue #2 [indigo carmine aluminum lake] (200 mg tablet only), FD&C blue #1 [brilliant blue FCF aluminum lake] (400 mg and 600 mg tablets only), and carnauba wax.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Rx Only

Manufactured by

DSM PHARMACEUTICALS, INC.

Greenville, NC 27834

for

THREE RIVERS PHARMACEUTICALS, LLC

Cranberry Township, PA 16066

XXXXXXXX

¹ PEGASYS® is a registered trademark of Hoffmann - LaRoche

December 2005

Printed in USA

Copyright © 2005 by Three Rivers Pharmaceuticals, LLC. All rights reserved.


RIBASPHERE (ribavirin)
PRODUCT INFO
Product Code 66435-102 Dosage Form TABLET, FILM COATED
Route Of Administration ORAL DEA Schedule
INGREDIENTS
Name (Active Moiety) Type Strength
ribavirin (ribavirin) Active 200 MILLIGRAM  In 1 TABLET
microcrystalline cellulose Inactive  
lactose monohydrate Inactive  
croscarmellose sodium Inactive  
povidone K27-33 Inactive  
magnesium stearate Inactive  
water Inactive  
IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance
Color blue (Light blue) Score 1
Shape OVAL (Capsule-shaped) Symbol true
Imprint Code 200;3RP Coating true
Size 12mm
PACKAGING
# NDC Package Description Multilevel Packaging
1 66435-102-16 168 TABLET In 1 BOTTLE None
2 66435-102-95 500 TABLET In 1 BOTTLE None

RIBASPHERE (ribavirin)
PRODUCT INFO
Product Code 66435-103 Dosage Form TABLET, FILM COATED
Route Of Administration ORAL DEA Schedule
INGREDIENTS
Name (Active Moiety) Type Strength
ribavirin (ribavirin) Active 400 MILLIGRAM  In 1 TABLET
microcrystalline cellulose Inactive  
lactose monohydrate Inactive  
croscarmellose sodium Inactive  
povidone K27-33 Inactive  
magnesium stearate Inactive  
water Inactive  
IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance
Color blue (Medium blue) Score 1
Shape OVAL (Capsule-shaped) Symbol true
Imprint Code 400;3RP Coating true
Size 18mm
PACKAGING
# NDC Package Description Multilevel Packaging
1 66435-103-56 56 TABLET In 1 BOTTLE None
2 66435-103-95 500 TABLET In 1 BOTTLE None

RIBASPHERE (ribavirin)
PRODUCT INFO
Product Code 66435-104 Dosage Form TABLET, FILM COATED
Route Of Administration ORAL DEA Schedule
INGREDIENTS
Name (Active Moiety) Type Strength
ribavirin (ribavirin) Active 600 MILLIGRAM  In 1 TABLET
microcrystalline cellulose Inactive  
lactose monohydrate Inactive  
croscarmellose sodium Inactive  
povidone K27-33 Inactive  
magnesium stearate Inactive  
water Inactive  
IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance
Color blue (Dark blue) Score 1
Shape OVAL (Capsule-shaped) Symbol true
Imprint Code 600;3RP Coating true
Size 19mm
PACKAGING
# NDC Package Description Multilevel Packaging
1 66435-104-56 56 TABLET In 1 BOTTLE None
2 66435-104-92 250 TABLET In 1 BOTTLE None

Revised: 10/2006Three Rivers Pharmaceuticals, LLC

Data are from FDA and U.S. National Library of Medicine.