Ribavirin

Description

11 DESCRIPTION Ribavirin, is a nucleoside analogue with antiviral activity. The chemical name of ribavirin is 1-β-D-­ribofuranosyl-1 H -1,2,4-triazole-3-carboxamide and has the following structural formula: The molecular formula of ribavirin is C 8 H 12 N 4 O 5 and the molecular weight is 244.2. Ribavirin USP is a white crystalline powder. It is freely soluble in water and slightly soluble in anhydrous alcohol. Ribavirin USP is available as a light pink colored, capsule shaped, film-coated tablet for oral administration. Each tablet contains 200 mg of ribavirin USP and the following inactive ingredients: microcrystalline cellulose, pregelatinised starch (maize), sodium starch glycolate, povidone (Kollidon 30), colloidal silicon dioxide, magnesium stearate, ethyl cellulose, triacetin, hypromellose, iron oxide red, titanium dioxide, and yellow iron oxide. Chemical Structure

What Is Ribavirin Used For?

1 INDICATIONS AND USAGE Ribavirin tablets in combination with PEGASYS ® (peginterferon alfa-2a) are indicated for the treatment of patients 5 years of age and older with chronic hepatitis C (CHC) virus infection who have compensated liver disease and have not been previously treated with interferon alpha. The following points should be considered when initiating ribavirin tablets combination therapy with PEGASYS ® : This indication is based on clinical trials of combination therapy in patients with CHC and compensated liver disease, some of whom had histological evidence of cirrhosis (Child-Pugh class A), and in adult patients with clinically stable HIV disease and CD4 count greater than 100 cells/mm 3 . This indication is based on achieving undetectable HCV RNA after treatment for 24 or 48 weeks, based on HCV genotype, and maintaining a Sustained Virologic Response (SVR) 24 weeks after the last dose. Safety and efficacy data are not available for treatment longer than 48 weeks. The safety and efficacy of ribavirin tablets and PEGASYS ® therapy have not been established in liver or other organ transplant recipients, patients with decompensated liver disease, or previous non-responders to interferon therapy. The safety and efficacy of ribavirin tablets 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. Ribavirin tablets are a nucleoside analogue indicated for the treatment of chronic hepatitis C (CHC) virus infection in combination with PEGASYS ® in patients 5 years of age and older with compensated liver disease not previously treated with interferon alpha, and in adult CHC patients coinfected with HIV (1)

Dosage and Administration

2 DOSAGE AND ADMINISTRATION Ribavirin tablets should be taken with food. Ribavirin tablets should be given in combination with PEGASYS ® ; it is important to note that ribavirin tablets should never be given as monotherapy. See PEGASYS ® Package Insert for all instructions regarding PEGASYS ® dosing and administration. CHC: Ribavirin tablets are administered according to body weight and genotype (2.1) CHC with HIV coinfection: 800 mg by mouth daily for a total of 48 weeks, regardless of genotype (2.2) Dose reduction or discontinuation is recommended in patients experiencing certain adverse reactions or renal impairment (2.3 , 2.4) 2.1 Chronic Hepatitis C Monoinfection Adult Patients The recommended dose of ribavirin tablets is provided in Table 1 . The recommended duration of treatment for patients previously untreated with ribavirin and interferon is 24 to 48 weeks. The daily dose of ribavirin tablets is 800 mg to 1200 mg administered orally in two divided doses. The dose should be individualized to the patient depending on baseline disease characteristics (e.g., genotype), response to therapy, and tolerability of the regimen (see Table 1 ). Table 1 PEGASYS ® and Ribavirin Tablets Dosing Recommendations Genotypes 2 and 3 showed no increased response to treatment beyond 24 weeks (see Table 10 ). Data on genotypes 5 and 6 are insufficient for dosing recommendations. * See PEGASYS ® Package Insert for further details on PEGASYS ® dosing and administration, including dose modification in patients with renal impairment. Hepatitis C Virus (HCV) Genotype PEGASYS ® Dose* (once weekly) Ribavirin Tablets Dose (daily) Duration Genotypes 1, 4 180 mcg <75 kg = 1000 mg ≥75 kg = 1200 mg 48 weeks 48 weeks Genotypes 2, 3 180 mcg 800 mg 24 weeks Pediatric Patients PEGASYS ® is administered as 180 mcg/1.73m 2 x BSA once weekly subcutaneously, to a maximum dose of 180 mcg, and should be given in combination with ribavirin. The recommended treatment duration for patients with genotype 2 or 3 is 24 weeks and for other genotypes is 48 weeks. Ribavirin tablets should be given in combination with PEGASYS ® . Ribavirin tablets are available only as a 200 mg tablet and therefore the healthcare provider should determine if this sized tablet can be swallowed by the pediatric patient. The recommended doses for ribavirin tablets are provided in Table 2 . Patients who initiate treatment prior to their 18 th birthday should maintain pediatric dosing through the completion of therapy. Table 2 Ribavirin Tablets Dosing Recommendations for Pediatric Patients *approximately 15 mg/kg/day Body Weight in kilograms (kg) Ribavirin Tablets Daily Dose* Ribavirin Tablets Number of Tablets 23 to 33 400 mg/day 1 x 200 mg tablet A.M. 1 x 200 mg tablet P.M. 34 to 46 600 mg/day 1 x 200 mg tablet A.M. 2 x 200 mg tablets P.M. 47 to 59 800 mg/day 2 x 200 mg tablets A.M. 2 x 200 mg tablets P.M. 60 to 74 1000 mg/day 2 x 200 mg tablets A.M. 3 x 200 mg tablets P.M. ≥75 1200 mg/day 3 x 200 mg tablets...

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS PEGASYS ® in combination with ribavirin causes a broad variety of serious adverse reactions [see Boxed Warning and Warnings and Precautions (5) ] . The most common serious or life-threatening adverse reactions induced or aggravated by ribavirin/PEGASYS ® include depression, suicide, relapse of drug abuse/overdose, and bacterial infections each occurring at a frequency of less than 1%. Hepatic decompensation occurred in 2% (10/574) CHC/HIV patients [see Warnings and Precautions (5.3) ] . The most common adverse reactions (frequency greater than 40%) in adults receiving combination therapy are fatigue/asthenia, pyrexia, myalgia, and headache. (6.1) The most common adverse reactions in pediatric subjects were similar to those seen in adults. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Adult Patients In the pivotal registration trials NV15801 and NV15942, 886 patients received ribavirin for 48 weeks at doses of 1000/1200 mg based on body weight. In these trials, one or more serious adverse reactions occurred in 10% of CHC monoinfected subjects and in 19% of CHC/HIV subjects receiving PEGASYS ® alone or in combination with ribavirin. 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 serious adverse reactions occurred at a frequency of less than 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. The percentage of patients in clinical trials who experienced one or more adverse events was 98%. 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. Table 5 shows rates of adverse events occurring in greater than or equal to 5% of subjects receiving pegylated interferon and ribavirin combination therapy in the CHC Clinical Trial, NV15801. Ten percent of CHC monoinfected patients receiving 48 weeks of therapy with PEGASYS ® in combination with ribavirin 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 PEGASYS ® and/or ribavirin therapy. The most common reason for dose modification of PEGASYS ® 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 in CHC and CHC/HIV patients was anemia (22% and 16%, respectively). PEGASYS ® dose was reduced in 12% of patients receiving 1000 mg to 1200 mg ribavirin for 48 weeks and in 7%...

Drug Interactions

7 DRUG INTERACTIONS Results from a pharmacokinetic sub-study demonstrated no pharmacokinetic interaction between PEGASYS ® (peginterferon alfa-2a) and ribavirin. Nucleoside analogues: Closely monitor for toxicities. Discontinue nucleoside reverse transcriptase inhibitors or reduce dose or discontinue interferon, ribavirin or both with worsening toxicities (7.1) Azathioprine: Concomitant use of azathioprine with ribavirin has been reported to induce severe pancytopenia and may increase the risk of azathioprine-related myelotoxicity (7.3) 7.1 Nucleoside Reverse Transcriptase Inhibitors (NRTIs) 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 coadministered as part of a multi-drug regimen to HCV/HIV coinfected patients. In Study NR15961 among the CHC/HIV coinfected cirrhotic patients receiving NRTIs, cases of hepatic decompensation (some fatal) were observed [see Warnings and Precautions (5.3) ] . Patients receiving PEGASYS ® /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 PEGASYS ® , ribavirin or both should also be considered if worsening toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than or equal to 6) [see Warnings and Precautions (5.3) and Dosage and Administration (2.3) ] . Didanosine Coadministration of ribavirin and didanosine is contraindicated. Didanosine or its active metabolite (dideoxyadenosine 5’-triphosphate) concentrations are increased when didanosine is coadministered with ribavirin, which could cause or worsen clinical toxicities. Reports of fatal hepatic failure as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in clinical trials [see Contraindications (4) ] . Zidovudine In Study NR15961, patients who were administered zidovudine in combination with PEGASYS ® /ribavirin developed severe neutropenia (ANC less than 500) and severe anemia (hemoglobin less than 8 g/dL) more frequently than similar patients not receiving zidovudine (neutropenia 15% vs. 9%) (anemia 5% vs. 1%). Discontinuation of zidovudine should be considered as medically appropriate. 7.2 Drugs Metabolized by Cytochrome P450 In vitro studies indicate that ribavirin does not inhibit CYP 2C9, CYP 2C19, CYP 2D6 or CYP 3A4. 7.3 Azathioprine The use of ribavirin to treat chronic hepatitis C in patients receiving azathioprine has been reported to induce severe pancytopenia and may increase the risk of azathioprine-related...

Contraindications

4 CONTRAINDICATIONS Ribavirin tablets are contraindicated in: Women who are pregnant. Ribavirin tablets may cause fetal harm when administered to a pregnant woman. Ribavirin tablets are contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.1) , Use in Specific Populations (8.1) , and Patient Counseling Information (17) ] . Men whose female partners are pregnant. Patients with hemoglobinopathies (e.g., thalassemia major or sickle-cell anemia). In combination with didanosine. Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in clinical trials [see Drug Interactions (7.1) ] . Ribavirin tablets and PEGASYS ® combination therapy are contraindicated in patients with: Autoimmune hepatitis. Hepatic decompensation (Child-Pugh score greater than 6; class B and C) in cirrhotic CHC monoinfected patients before treatment [see Warnings and Precautions (5.3) ] . Hepatic decompensation (Child-Pugh score greater than or equal to 6) in cirrhotic CHC patients coinfected with HIV before treatment [see Warnings and Precautions (5.3) ] . Pregnant women and men whose female partners are pregnant (4 , 5.1 , 8.1 ) Hemoglobinopathies (4) Coadministration with didanosine (4 , 7.1) Ribavirin tablets in combination with PEGASYS ® are contraindicated in patients with: Autoimmune hepatitis (4) Hepatic decompensation in cirrhotic patients (4 , 5.3)

Pregnancy and Breastfeeding

8.1 Pregnancy Pregnancy: Category X [see Contraindications (4) ] . 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 [see Contraindications (4) and Warnings and Precautions (5.1) ] . 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 daily human 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 daily human dose of ribavirin). Treatment and Post-Treatment: 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. 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 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 unless the patient and his/her partner are using effective contraception (two reliable forms) during therapy and for 6 months post therapy [see Contraindications (4) ] .

8.3 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 ribavirin, based on the importance of the therapy to the mother.

Overdosage

10 OVERDOSAGE No cases of overdose with ribavirin have been reported in clinical trials. Hypocalcemia and hypomagnesemia have been observed in persons administered greater than the recommended dosage of ribavirin. In most of these cases, ribavirin was administered intravenously at dosages up to and in some cases exceeding four times the recommended maximum oral daily dose.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING Ribavirin Tablets USP, 200 mg are light pink colored, capsule shaped, film-coated tablets debossed with ‘F’ on one side and ‘10’ on the other side. Bottles of 168 NDC 65862-207-68 Bottles of 500 NDC 65862-207-05 Storage and Handling Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Keep bottle tightly closed.