Ribasphere Tablets

RIBASPHERE (ribavirin, USP) is contraindicated in:

• Patients with known hypersensitivity to RIBASPHERE (ribavirin, USP) or to any component of the tablet.
• Women who are pregnant.
• Men whose female partners are pregnant.
• Patients with hemoglobinopathies (e.g., thalassemia major or sickle-cell anemia).

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

• Autoimmune hepatitis.
• Hepatic decompensation (Child-Pugh score greater than 6; class B and C) in cirrhotic CHC monoinfected patients before or during treatment.

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:

• Platelet count ≥90,000 cells/mm3 (as low as 75,000 cells/mm3 in patients with cirrhosis)
• Absolute neutrophil count (ANC) ≥1500 cells/mm3
• TSH and T4 within normal limits or adequately controlled thyroid function
• ECG (see WARNINGS)
• Hemoglobin ≥12 g/dL for women and ≥13 g/dL for men in CHC monoinfected patients

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.

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

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 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.

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

November 2007

Printed in USA

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