Ribasphere may cause birth defects and/or death of the exposed fetus. Ribasphere 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 Ribasphere.
Ribasphere therapy should not be started unless a report of a negative pregnancy test has been obtained immediately prior to planned initiation of therapy. Extreme care must be taken to avo >BOXED WARNING, CONTRAINDICATIONS (4), USE IN SPECIFIC POPULATIONS (8.1), and PATIENT COUNSELING INFORMATION (17)].
Nucleos > In vitro data indicate Ribasphere reduces phosphorylation of lamivudine, stavudine, and z >
In Study NR15961 among the CHC/HIV coinfected cirrhotic patients receiving NRTIs, cases of hepatic decompensation (some fatal) were observed .
Patients receiving peginterferon alfa-2a/Ribasphere and NRTIs should be closely monitored for treatment-associated toxicities. Physicians should refer to prescribing information for the respective NRTIs for gu >WARNINGS AND PRECAUTIONS (5.3) and DOSAGE AND ADMINISTRATION (2.3) ].
Co-administration of Ribasphere and d >CONTRAINDICATIONS (4) ].
In Study NR15961, patients who were administered zidovudine in combination with peginterferon alfa-2a/Ribasphere 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.
Where can I find more information about Ribasphere?
- Recommendations on the HIV-related uses of Ribasphere, from the Gu >Centers for Disease Control and Prevention , the National Institutes of Health , and the HIV Medicine Association of the Infectious Diseases Society of America
- Recommendations on the HIV-related uses of Ribasphere, from the AASLD- >Liver Diseases and the Infectious Diseases Society of America
- Ribasphere-related research studies, from the A >ClinicalTrials.gov study summaries
The above Patient Version drug summary is based on the following FDA label(s): Capsule, liquid; Tablet (film coated).
Multiple dose Ribasphere pharmacokinetic data are available for HCV patients who received Ribasphere in combination with peginterferon alfa-2a. Following administration of 1200 mg/day with food for 12 weeks mean±SD (n=39; body weight greater than 75 kg) AUC 0-12hr was 25,361±7110 ng·hr/mL and C max was 2748±818 ng/mL. The average time to reach C max was 2 hours. Trough Ribasphere 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 greater than 75 kg).
The terminal half-life of Ribasphere following administration of a single oral dose of Ribasphere is about 120 to 170 hours. The total apparent clearance following administration of a single oral dose of Ribasphere is about 26 L/h. There is extensive accumulation of Ribasphere after multiple dosing (twice daily) such that the C max at steady state was four-fold higher than that of a single dose.
Effect of Food on Absorption of Ribasphere
Bioavailability of a single oral dose of Ribasphere was increased by co-administration with a high-fat meal. The absorption was slowed (T max was doubled) and the AUC 0-192h and C max increased by 42% and 66%, respectively, when Ribasphere was taken with a high-fat meal compared with fasting conditions .
Elimination and Metabolism
The contribution of renal and hepatic pathways to Ribasphere elimination after administration of Ribasphere is not known. In vitro studies indicate that Ribasphere is not a substrate of CYP450 enzymes.
A clinical trial evaluated 50 CHC subjects with either moderate (creatinine clearance 30 to 50 mL/min) or severe (creatinine clearance less than 30 mL/min) renal impairment or end stage renal disease (ESRD) requiring chronic hemodialysis (HD). The apparent clearance of Ribasphere was reduced in subjects with creatinine clearance less than or equal to 50 mL/min, including subjects with ESRD on HD, exhibiting approximately 30% of the value found in subjects with normal renal function. Pharmacokinetic modeling and simulation indicates that a dose of 200 mg daily in patients with severe renal impairment and a dose of 200 mg daily alternating with 400 mg the following day in patients with moderate renal impairment will provide plasma Ribasphere exposures similar to that observed in patients with normal renal function receiving the standard 1000/1200 mg Ribasphere daily dose. These doses have not been studied in patients.
In 18 subjects with ESRD receiving chronic HD, Ribasphere was administered at a dose of 200 mg daily. Ribasphere plasma exposures in these subjects were approximately 20% lower compared to subjects with normal renal function receiving the standard 1000/1200 mg Ribasphere daily dose .
Plasma Ribasphere is removed by hemodialysis with an extraction ratio of approximately 50%; however, due to the large volume of distribution of Ribasphere, plasma exposure is not expected to change with hemodialysis.
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Ribasphere did not cause an increase in any tumor type when administered for 6 months in the transgenic p53 deficient mouse model at doses up to 300 mg/kg (estimated human equivalent of 25 mg/kg based on body surface area adjustment for a 60 kg adult; approximately 1.9 times the maximum recommended human daily dose). Ribasphere was noncarcinogenic when administered for 2 years to rats at doses up to 40 mg/kg (estimated human equivalent of 5.71 mg/kg based on body surface area adjustment for a 60 kg adult).
Ribasphere demonstrated increased inc >In Vitro Cell Transformation Assay. Mutagenic activity was observed in the mouse lymphoma assay, and at doses of 20 to 200 mg/kg (estimated human equivalent of 1.67 to 16.7 mg/kg, based on body surface area adjustment for a 60 kg adult; 0.1 to 1 times the maximum recommended human 24-hour dose of Ribasphere) in a mouse micronucleus assay. A dominant lethal assay in rats was negative, indicating that if mutations occurred in rats they were not transmitted through male gametes.
Impairment of Fertility
In studies in mice to evaluate the time course and reversibility of Ribasphere-induced testicular degeneration at doses of 15 to 150 mg/kg/day (estimated human equivalent of 1.25 to 12.5 mg/kg/day, based on body surface area adjustment for a 60-kg adult; 0.1-0.8 times the maximum human 24-hour dose of Ribasphere) administered for 3 or 6 months, abnormalities in sperm occurred. Upon cessation of treatment, recovery from Ribasphere-induced testicular toxicity was mostly apparent within 1 or 2 spermatogenesis cycles.