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TYZEKA (Tablet, Film Coated)

Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/110

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TYZEKA (Tablet, Film Coated)
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Adults and Adolescents (���16 years of age): The recommended dose of telbivudine for the treatment of chronic hepatitis B is 600 mg once daily, taken orally, with or without food. The optimal treatment duration has not been established. Renally Impaired Subjects: Telbivudine may be used for the treatment of chronic hepatitis B in patients with impaired renal function. No adjustment to the recommended dose of telbivudine is necessary in patients whose creatinine clearance is���50 mL/min. Adjustment of dose interval is required in patients with creatinine clearance<50 mL/min including those with ESRD on hemodialysis (Table 6). For patients with ESRD, telbivudine should be administered after hemodialysis. No adjustment to the recommended dose of telbivudine is necessary in patients with hepatic impairment.
dailymed-instance:descripti...
TYZEKAis the trade name for telbivudine, a synthetic thymidine nucleoside analogue with activity against hepatitis B virus (HBV). The chemical name for telbivudine is 1-((2S,4R,5S)-4-hydroxy-5-hydroxymethyltetrahydrofuran-2-yl)-5-methyl-1H-pyrimidine-2,4-dione, or 1-(2-deoxy-��-L-ribofuranosyl)-5-methyluracil. Telbivudine is the unmodified��-L enantiomer of the naturally occurring nucleoside, thymidine. Its molecular formula is CHNO, which corresponds to a molecular weight of 242.23. Telbivudine has the following structural formula: Telbivudine is a white to slightly yellowish powder. Telbivudine is sparingly soluble in water (>20 mg/mL), and very slightly soluble in absolute ethanol (0.7 mg/mL) and n-octanol (0.1 mg/mL). TYZEKA(telbivudine) film-coated tablets are available for oral administration in 600 mg strength. TYZEKA 600 mg film-coated tablets contain the following inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate. The tablet coating contains titanium dioxide, polyethylene glycol, talc and hypromellose.
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Pharmacokinetics in Adults: The single- and multiple-dose pharmacokinetics of telbivudine were evaluated in healthy subjects and in patients with chronic hepatitis B. Telbivudine pharmacokinetics are similar between both populations.<br/>Absorption and Bioavailability: Following oral administration of telbivudine 600 mg once-daily in healthy subjects (n=12), steady state peak plasma concentration (C) was 3.69��1.25��g/mL (mean��SD) which occurred between 1 and 4 hours (median 2 hours), AUC was 26.1��7.2��g��h/mL (mean��SD), and trough plasma concentrations (C) were approximately 0.2-0.3��g/mL. Steady state was achieved after approximately 5 to 7 days of once-daily administration with ~1.5-fold accumulation, suggesting an effective half-life of ~15 hours.<br/>Effects of Food on Oral Absorption: Telbivudine absorption and exposure were unaffected when a single 600-mg dose was administered with a high-fat (~55 g), high-calorie (~950 kcal) meal. TYZEKA(telbivudine) may be taken with or without food.<br/>Distribution: In vitro binding of telbivudine to human plasma proteins is low (3.3%). After oral dosing, the estimated apparent volume of distribution is in excess of total body water, suggesting that telbivudine is widely distributed into tissues. Telbivudine was equally partitioned between plasma and blood cells.<br/>Metabolism and Elimination: No metabolites of telbivudine were detected following administration of [C]-telbivudine in humans. Telbivudine is not a substrate, or inhibitor of the cytochrome P450 (CYP450) enzyme system After reaching the peak concentration, plasma concentrations of telbivudine declined in a bi-exponential manner with a terminal elimination half-life (T) of 40 - 49 hours. Telbivudine is eliminated primarily by urinary excretion of unchanged drug. The renal clearance of telbivudine approaches normal glomerular filtration rate suggesting that passive diffusion is the main mechanism of excretion. Approximately 42% of the dose is recovered in the urine over 7 days following a single 600 mg oral dose of telbivudine. Because renal excretion is the predominant route of elimination, patients with moderate to severe renal dysfunction and those undergoing hemodialysis require a dose interval adjustment<br/>Cardiac Safety: In an in vitro hERG model, telbivudine was negative at concentrations up to 10,000��M. In a thorough QTc prolongation clinical study in healthy subjects, telbivudine had no effect on QT intervals or other electrocardiographic parameters after multiple daily doses up to 1800 mg.<br/>Special Populations: Gender: There are no significant gender-related differences in telbivudine pharmacokinetics. Race: There are no significant race-related differences in telbivudine pharmacokinetics. Pediatrics and Geriatrics: Pharmacokinetic studies have not been conducted in children or elderly subjects. Renal Impairment Single-dose pharmacokinetics of telbivudine have been evaluated in patients (without chronic hepatitis B) with various degrees of renal impairment (as assessed by creatinine clearance). Based on the results shown in Table 1, adjustment of the dose interval for TYZEKA is recommended in patients with creatinine clearance of<50 mL/min Renally Impaired Patients on Hemodialysis Hemodialysis (up to 4 hours) reduces systemic telbivudine exposure by approximately 23%. Following dose interval adjustment for creatinine clearance , no additional dose modification is necessary during routine hemodialysis. TYZEKA should be administered after hemodialysis. Hepatic Impairment The pharmacokinetics of telbivudine following a single 600-mg dose have been studied in patients (without chronic hepatitis B) with various degrees of hepatic impairment. There were no changes in telbivudine pharmacokinetics in hepatically impaired subjects compared to unimpaired subjects. Results of these studies indicate that no dosage adjustment is necessary for patients with hepatic impairment.<br/>Drug Interactions: Telbivudine is excreted mainly by passive diffusion so the potential for interactions between telbivudine and other drugs eliminated by renal excretion is low. However, because telbivudine is eliminated primarily by renal excretion, co-administration of telbivudine with drugs that alter renal function may alter plasma concentrations of telbivudine. Drug-drug interaction studies show that lamivudine, adefovir dipivoxil, cyclosporine and pegylated interferon-alfa 2a do not alter telbivudine pharmacokinetics. In addition, telbivudine does not alter the pharmacokinetics of lamivudine, adefovir dipivoxil, or cyclosporine. No definitive conclusion could be drawn regarding the effects of telbivudine on the pharmacokinetics of pegylated interferon-alfa 2a due to the high inter-individual variability of pegylated interferon-alfa 2a concentrations. At concentrations up to 12 times that in humans, telbivudine did not inhibit in vitro metabolism mediated by any of the following human hepatic microsomal cytochrome P450 (CYP) isoenzymes known to be involved in human medicinal product metabolism: 1A2, 2C9, 2C19, 2D26, 2E1, and 3A4. Based on the above results and the known elimination pathway of telbivudine, the potential for CYP450-mediated interactions involving telbivudine with other medicinal products is low.
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Telbivudine tablets are contraindicated in patients with previously demonstrated hypersensitivity to any component of the product.
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TYZEKA(telbivudine) 600-mg tablets are white to slightly yellowish film-coated, ovaloid-shaped tablets, imprinted with���LDT���on one side. Bottle of 30 tablets (NDC 24108-101-01) with child-resistant closure. Storage Store TYZEKAtablets in original container at 25��C (77��F), excursions permitted to 15-30��C (59-86��F) [See USP Controlled Room Temperature]. For all medical inquiries call: 1-877-8-TYZEKA (1-877-889-9352). Keep this and all drugs out of the reach of children. TYZEKAis a registered trademark of Idenix Pharmaceuticals, Inc. October 2006 Printed in U.S.A. Manufactured by: Novartis Pharma Stein AG Stein, Switzerland Distributed by: Idenix Pharmaceuticals, Incorporated Cambridge, MA 02139 Marketed by: Idenix Pharmaceuticals, Incorporated Cambridge, MA 02139 Novartis Pharmaceuticals Corporation East Hanover, NJ 07936
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WARNINGS: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination with antiretrovirals. Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy, including TYZEKA(telbivudine). Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate, resumption of anti-hepatitis B therapy may be warranted.
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General:<br/>Renal Function: Telbivudine is eliminated primarily by renal excretion, therefore dose interval adjustment is recommended in patients with creatinine clearance<50 mL/min, including patients on hemodialysis or continuous ambulatory peritoneal dialysis (CAPD). In addition, co-administration of TYZEKA(telbivudine) with drugs that affect renal function may alter plasma concentrations of telbivudine and/or the co-administered drug .<br/>Patients Resistant to Antiviral Drugs for Hepatitis B: There are no adequate and well controlled studies for telbivudine treatment of patients with established lamivudine-resistant hepatitis B virus infection. In cell culture, telbivudine is not active against HBV encoding amino acid substitutions M204I or M204V/L180M. Telbivudine retains wild-type phenotypic activity against the lamivudine resistance-associated substitution rtM204V alone; however, the efficacy of telbivudine against HBV harboring the rtM204V mutation has not been established in clinical trials. There are no adequate and well controlled studies for telbivudine treatment of patients with established adefovir-resistant hepatitis B virus infection. HBV encoding the adefovir resistance-associated substitution rtN236T remains susceptible to telbivudine, while HBV encoding an A181V amino acid substitution showed 3- to 5-fold reduced susceptibility to telbivudine in cell culture.<br/>Liver Transplant Recipients: The safety and efficacy of telbivudine in liver transplant recipients are unknown. The steady-state pharmacokinetics of telbivudine was not altered following multiple dose administration in combination with cyclosporine. If telbivudine treatment is determined to be necessary for a liver transplant recipient who has received or is receiving an immunosuppressant that may affect renal function, such as cyclosporine or tacrolimus, renal function should be monitored both before and during treatment with TYZEKA .<br/>Information for Patients: A patient package insert (PPI) for TYZEKA is available for patient information. Patients should remain under the care of a physician while taking TYZEKA. They should discuss any new symptoms or concurrent medications with their physician. Patients should be advised to report promptly unexplained muscle weakness, tenderness or pain. Patients should be advised that TYZEKA is not a cure for hepatitis B, that the long-term treatment benefits of telbivudine are unknown at this time and in particular, that the relationship of initial treatment response to outcomes such as hepatocellular carcinoma and decompensated cirrhosis is unknown. Patients should be informed that deterioration of liver disease may occur in some cases if treatment is discontinued, and that they should discuss any change in regimen with their physician. Patients should be advised that treatment with TYZEKA has not been shown to reduce the risk of transmission of HBV to others through sexual contact or blood contamination .<br/>Drug Interactions: Telbivudine is excreted mainly by passive diffusion so the potential for interactions between telbivudine and other drugs eliminated by renal excretion is low. However, because telbivudine is eliminated primarily by renal excretion, co-administration of telbivudine with drugs that alter renal function may alter plasma concentrations of telbivudine.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Telbivudine has shown no carcinogenic potential. Long term oral carcinogenicity studies with telbivudine were negative in mice and rats at exposures up to 14 times those observed in humans at the therapeutic dose of 600 mg/day. There was no evidence of genotoxicity based on in vitro or in vivo tests. Telbivudine was not mutagenic in the Ames bacterial reverse mutation assay using S. typhimurium and E. coli strains with or without metabolic activation. Telbivudine was not clastogenic in mammalian-cell gene mutation assays, including human lymphocyte cultures and an assay with Chinese hamster ovary cells with or without metabolic activation. Furthermore, telbivudine showed no effect in an in vivo micronucleus study in mice. In reproductive toxicology studies, no evidence of impaired fertility was seen in male or female rats at systemic exposures approximately 14 times that achieved in humans at the therapeutic dose.<br/>Pregnancy Category B: Telbivudine is not teratogenic and has shown no adverse effects in developing embryos and fetuses in preclinical studies. Studies in pregnant rats and rabbits showed that telbivudine crosses the placenta. Developmental toxicity studies revealed no evidence of harm to the fetus in rats and rabbits at doses up to 1000 mg/kg/day, providing exposure levels 6- and 37-times higher, respectively, than those observed with the 600 mg/day dose in humans. There are no adequate and well-controlled studies of telbivudine in pregnant women. Because animal reproductive toxicity studies are not always predictive of human response, telbivudine should be used during pregnancy only if potential benefits outweigh the risks. Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to telbivudine, healthcare providers are encouraged to register such patients in the AntiRetroviral Pregnancy Registry by calling 1-800-258-4263.<br/>Labor and Delivery: There are no studies in pregnant women and no data on the effect of telbivudine on transmission of HBV from mother to infant. Therefore, appropriate interventions should be used to prevent neonatal acquisition of HBV infection.<br/>Nursing Mothers: Telbivudine is excreted in the milk of rats. It is not known whether telbivudine is excreted in human milk. Mothers should be instructed not to breastfeed if they are receiving TYZEKA.<br/>Pediatric Use: Safety and effectiveness of telbivudine in pediatric patients have not been established.<br/>Geriatric Use: Clinical studies of telbivudine did not include sufficient numbers of patients���65 years of age to determine whether they respond differently from younger subjects. In general, caution should be exercised when prescribing TYZEKA to elderly patients, considering the greater frequency of decreased renal function due to concomitant disease or other drug therapy. Renal function should be monitored in elderly patients, and dosage adjustments should be made accordingly.<br/>Special Populations: Telbivudine has not been investigated in co-infected hepatitis B patients (e.g., patients co-infected with HIV, HCV or HDV).
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There is no information on intentional overdose of telbivudine, but one subject experienced an unintentional and asymptomatic overdose. Healthy subjects who received telbivudine doses up to 1800 mg/day for 4 days had no increase in or unexpected adverse events. A maximum tolerated dose for telbivudine has not been determined. In the event of an overdose, telbivudine should be discontinued, the patient must be monitored for evidence of toxicity, and appropriate general supportive treatment applied as necessary. In case of overdosage, hemodialysis may be considered. Within 2 hours, following a single 200-mg dose of telbivudine, a 4-hour hemodialysis session removed approximately 23% of the telbivudine dose.
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telbivudine
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TYZEKA (Tablet, Film Coated)
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Approximately 760 subjects have been treated with telbivudine in clinical studies at a dose of 600 mg once daily. Assessment of adverse reactions is primarily based on the pivotal 007 GLOBE study in which 1,367 patients with chronic hepatitis B received double-blind treatment with telbivudine 600 mg/day (n=680 patients) or lamivudine (n=687 patients) for up to 104 weeks. Medianduration of treatment in the 007 GLOBE study was 60 weeks for telbivudine- and lamivudine-treated patients. The safety profiles of telbivudine and lamivudine were generally comparable in this study.<br/>Clinical Adverse Events: In clinical studies telbivudine was generally well tolerated, with most adverse experiences classified as mild or moderate in severity and not attributed to telbivudine. In the 007 GLOBE study patient discontinuations for adverse events, clinical disease progression or lack of efficacy were 0.6% for telbivudine and 2.0% for lamivudine. Frequently occurring adverse events regardless of attributability to telbivudine were upper respiratory tract infection (14%), fatigue and malaise (12%), abdominal pain (12%), nasopharyngitis (11%), headache (11%), blood CPK increased (9%), cough (7%), nausea and vomiting (7%), influenza and influenza-like symptoms (7%), post-procedural pain (7%), diarrhea and loose stools (7%), pharyngolaryngeal pain (5%), pyrexia (4%), arthralgia (4%), rash (4%), back pain (4%), dizziness (4%), myalgia (3%), insomnia (3%), and dyspepsia (3%). Frequently occurring adverse events regardless of attributability to lamivudine were headache (14%), upper respiratory tract infection (13%), abdominal pain (13%), fatigue and malaise (11%), nasopharyngitis (10%), influenza and influenza-like symptoms (8%), blood CPK increased (7%), cough (6%), post-procedural pain (6%), nausea and vomiting (6%), dyspepsia (5%), diarrhea and loose stools (5%), dizziness (5%), pharyngolaryngeal pain (4%), rash (4%), hepatic/RUQ pain (4%), arthralgia (4%), back pain (4%), pyrexia (3%), rhinorrhea (3%), ALT increased (3%), and pruritus (3%). Selected, treatment-emergent, clinical adverse events of moderate to severe intensity, without consideration of study drug causality, during the pivotal 007 GLOBE study clinical trial are presented in Table 4. Frequencies of selected treatment-emergent laboratory abnormalities in the 007 GLOBE study are listed in Table 5. Creatine kinase (CK) elevations were more frequent among subjects on telbivudine treatment, as shown above in Table 5. CK elevations occurred in both treatment arms; however median CK levels were higher in telbivudine-treated patients by Week 52. Grade 1-4 CK elevations occurred in 72% of telbivudine-treated patients and 42% of lamivudine-treated patients, whereas Grade 3/4 CK elevations occurred in 9% of telbivudine-treated patients and 3% of lamivudine-treated patients. Most CK elevations were asymptomatic but the mean recovery time was longer for subjects on telbivudine than subjects on lamivudine. While there was not a uniform pattern with regard to the type of adverse event and timing with respectto the CK elevation, 8% of telbivudine-treated patients with Grade 1-4 CK elevations experienced a CK-related adverse event(within a 30-day window) compared to 6% of lamivudine-treated patients. In this subgroup of patients with CK-related adverse events, 9% of telbivudine-treated patients subsequently interrupted or discontinued study drug. These patients recovered after study drug discontinuation or interruption. Less than 1 % of telbivudine-subjects overall (n=3/680) were diagnosed with myopathy with muscular weakness; these patients also recovered after study drug discontinuation . As shown in Table 5, on-treatment ALT elevations were more frequent on lamivudine treatment. Additionally, the overall incidence of on-treatment ALT flares, using AASLD criteria (ALT>10 x ULN and>2.0 x baseline), was slightly higher in the lamivudine arm (5.1%) than the telbivudine arm (3.2%). The incidence of ALT flares was similar in the two treatment arms in the first six months. ALT flares occurred less frequently in both arms after Week 24, with a lower incidence in the telbivudine arm (0.4%) compared to the lamivudine arm (2.2%). For both lamivudine and telbivudine subjects, the occurrence of ALT flares was more common in HBeAg positive subjects than in HBeAg negative subjects. Periodic monitoring of hepatic function is recommended during treatment.<br/>Exacerbations of Hepatitis After Discontinuation of Treatment (See WARNINGS): There are insufficient data on post-treatment exacerbations of hepatitis after discontinuation of telbivudine treatment.
dailymed-instance:warning
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination with antiretrovirals. Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy, including TYZEKA(telbivudine). Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate, resumption of anti-hepatitis B therapy may be warranted.
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TYZEKA(telbivudine) is indicated for the treatment of chronic hepatitis B in adult patients with evidence of viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease. This indication is based on virologic, serologic, biochemical and histologic responses after one year of treatment in nucleoside-treatment-na��ve adult patients with HBeAg-positive and HBeAg-negative chronic hepatitis B with compensated liver disease (See Description of Clinical Studies).
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TYZEKA