Exacerbations of Hepatitis After Discontinuation of Treatment

Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy. 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, initiation of anti-hepatitis B therapy may be warranted. (See ADVERSE REACTIONS, Exacerbations of Hepatitis After Discontinuation of Treatment.)

Skeletal Muscle

Cases of myopathy have been reported with telbivudine use several weeks to months after starting therapy. Myopathy has also been reported with some other drugs in this class.

Uncomplicated myalgia has been reported in telbivudine-treated patients (See ADVERSE REACTIONS). Myopathy, defined as persistent unexplained muscle aches and/or muscle weakness in conjunction with increases in creatine kinase (CK) values, should be considered in any patient with diffuse myalgias, muscle tenderness or muscle weakness. Among patients with telbivudine-associated myopathy, there has not been a uniform pattern with regard to the degree or timing of CK elevations. In addition, the predisposing factors for the development of myopathy among telbivudine recipients are unknown. Patients should be advised to report promptly unexplained muscle aches, pain, tenderness or weakness. Telbivudine therapy should be interrupted if myopathy is suspected, and discontinued if myopathy is diagnosed. It is not known if the risk of myopathy during treatment with drugs in this class is increased with concurrent administration of other drugs associated with myopathy, including corticosteroids, chloroquine, hydroxychloroquine, certain HMGCoA reductase inhibitors, fibric acid derivatives, penicillamine, zidovudine, cyclosporine, erythromycin, niacin, and/or azole antifungals. Physicians considering concomitant treatment with these or other agents associated with myopathy should weigh carefully the potential benefits and risks and should monitor patients for any signs or symptoms of unexplained muscle pain, tenderness, or weakness, particularly during periods of upward dosage titration.

General

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 (See DOSAGE AND ADMINISTRATION).

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.

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 (See CLINICAL PHARMACOLOGY, Special Populations and DOSAGE AND ADMINISTRATION).

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 (See PRECAUTIONS, Labor and Delivery).

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.

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.

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.

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.

Pediatric Use

Safety and effectiveness of telbivudine in pediatric patients have not been established.

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. (See PRECAUTIONS, Renal Function and DOSAGE AND ADMINISTRATION.)

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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