PDR MEMBER LOGIN:
  • PDR Search

    Required field
  • Advertisement
  • CLASSES

    Nucleoside and Nucleotide Analog Antivirals for Hepatitis B

    BOXED WARNING

    Hepatitis B exacerbation

    If telbivudine is discontinued, closely monitor hepatic function for at least several months. Severe, acute hepatitis B exacerbation has been reported in patients who have discontinued anti-hepatitis B therapy such as telbivudine; resumption of therapy may be warranted.

    DEA CLASS

    Rx

    DESCRIPTION

    Thymidine nucleoside analog
    Used for chronic hepatitis B infection
    Activity against lamivudine- or adefovir-resistant strains is not known

    COMMON BRAND NAMES

    Tyzeka

    DOSAGE & INDICATIONS

    For the treatment of chronic hepatitis B infection in patients with evidence of viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.
    NOTE: The indication is based on virologic, serologic, biochemical, and histologic responses after one year of treatment in nucleoside-treatment-naive patients with HBeAg-positive and HBeAg-negative chronic hepatitis B with compensated liver disease.
    NOTE: Resistance may develop with prolonged treatment in patients with incomplete viral suppression; therefore, only initiate telbivudine therapy if pre-treatment HBV DNA and ALT measurements are known and meet recommended starting levels. For HBeAg-positive patients, HBV DNA should be < 9 log10 copies/ml and ALT should be >= 2x upper limits of normal prior to treatment with telbivudine. For HBeAg-negative patients, HBV DNA should be < 7 log10 copies/ml prior to treatment.
    Oral dosage
    Adults and Adolescents >= 16 years

    600 mg PO once daily with or without food. Monitor HBV DNA concentrations after the initial 24 weeks of treatment to assess viral suppression. If viral suppression is incomplete, indicated by a HBV DNA concentration of >= 300 copies/ml, an alternate therapy should be started. To assure continued response, HBV DNA should continued to be monitored every 6 months. Patients with a positive HBV DNA test at any time after the initial response should be changed to an alternate therapy. The optimal duration of therapy has not been established.

    MAXIMUM DOSAGE

    Adults

    600 mg PO once daily.

    Geriatric

    600 mg PO once daily.

    Adolescents

    >= 16 years: 600 mg PO once daily.
    < 16 years: Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    CrCl >= 50 ml/minute: No dosage adjustment is necessary.
    CrCl 30—49 ml/minute: 600 mg tablet PO once every 48 hours or 400 mg of oral solution PO daily.
    CrCl < 30 ml/minute (not requiring dialysis): 600 mg tablet PO once every 72 hours or 200 mg of oral solution PO daily.
     
    Intermittent hemodialysis
    600 mg tablet PO once every 96 hours or 120 mg of oral solution PO daily. When administered on dialysis days, administer telbivudine after hemodialysis.
     
    Continuous ambulatory peritoneal dialysis (CAPD)
    600 mg tablet PO once every 96 hours or 120 mg of oral solution PO daily.

    ADMINISTRATION

    Oral Administration

    May be taken with or without food.

    STORAGE

    Tyzeka:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    The combination of telbivudine and pegylated interferon alfa-2a is contraindicated because of an increased risk of peripheral neuropathy (see Drug Interactions).

    Dialysis, geriatric, renal disease, renal failure, renal impairment

    Patients with renal disease or renal impairment may need a reduced telbivudine dose. Dosage reduction is needed for patients with a creatinine clearance less than 50 mL/minute, including patients with renal failure on dialysis (e.g., hemodialysis or continuous ambulatory peritoneal dialysis). Use telbivudine cautiously in geriatric patients taking into consideration the greater frequency of decreased renal function in this population; monitor renal function, and adjust the telbivudine dosage, as needed.

    Hepatotoxicity or lactic acidosis, myopathy, pancreatitis, rhabdomyolysis

    Hepatotoxicity or lactic acidosis, including fatal cases, have been reported with the use of nucleoside analogs. Cases of telbivudine-induced lactic acidosis are often associated with other serious conditions or muscle-related events (e.g., rhabdomyolysis, myopathy, myosis). Some cases were also associated with pancreatitis, hepatic failure, hepatic steatosis, and renal failure. Treatment with telbivudine should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

    Hepatitis B exacerbation

    If telbivudine is discontinued, closely monitor hepatic function for at least several months. Severe, acute hepatitis B exacerbation has been reported in patients who have discontinued anti-hepatitis B therapy such as telbivudine; resumption of therapy may be warranted.

    Pregnancy

    Telbivudine is a FDA pregnancy category B drug, but there are no adequate and well-controlled studies in pregnant women. NRTIs are known to induce mitochondrial dysfunction. An association of mitochondrial dysfunction in infants and in-utero antiretroviral exposure has been suggested, but not established. While the development of severe or fatal mitochondrial disease in exposed infants appears to be extremely rare, more intensive monitoring of hematologic and electrolyte parameters during the first few weeks of life is advised. Nucleoside analogs have been associated with the development of lactic acidosis, especially during pregnancy. It is unclear if pregnancy augments the incidence of lactic acidosis/hepatic steatosis in patients receiving nucleoside analogs. However, because pregnancy itself can mimic some of the early symptoms of the lactic acid/hepatic steatosis syndrome or be associated with other significant disorders of liver metabolism, clinicians need to be alert for early diagnosis of this syndrome. Pregnant women receiving nucleoside analogs should have LFTs and serum electrolytes assessed more frequently during the last trimester of pregnancy and any new symptoms should be evaluated thoroughly. Only use telbivudine in a pregnant woman if the potential benefits outweigh the potential risks. The ability of telbivudine to help prevent HBV transmission from mother to child is unknown. During labor, use appropriate interventions to prevent neonatal acquisition of HBV infection. Enroll pregnant women exposed to telbivudine in the AntiRetroviral Pregnancy Registry by calling 1—800—258—4263.

    Breast-feeding

    It is not known whether telbivudine is excreted in human breast milk as studies in nursing mothers have not been conducted. Antiviral medications whose passage into human breast milk have been evaluated include tenofovir and lamivudine. According to the manufacturer, mothers should be instructed not to breast-feed if receiving telbivudine; however, a consensus among health care providers has not been established. In a survey of 226 physicians, 30.5% would recommend breast-feeding for HBV-infected mothers on antiviral therapy, 44% would not recommend breast-feeding during antiviral therapy, and 25.2% stated they were unsure. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Children, infants, neonates

    Safety and effectiveness of telbivudine have not been established in neonates, infants, children and adolescents < 16 years of age.

    Hepatitis B and HIV coinfection, human immunodeficiency virus (HIV) infection, human immunodeficiency virus (HIV) infection resistance

    Telbivudine may have some activity against the human immunodeficiency virus; patients being treated with telbivudine who have unrecognized or untreated human immunodeficiency virus (HIV) infection are at risk of developing human immunodeficiency virus (HIV) infection resistance. Prior to initiating therapy, HIV antibody testing should be offered to all patients. Telbivudine is not FDA approved for use in patients coinfected with human immunodeficiency virus (HIV) infection, hepatitis C virus, or hepatitis D virus. HIV treatment guidelines recommend against use of telbivudine in patients with hepatitis B and HIV coinfection. Data regarding use of telbivudine in these patients are limited; and compared with other treatment regimens, telbivudine is associated with higher incidence of toxicities and increased rates of HBV treatment failure. Instead, guidelines recommend these patients receive a fully suppressive antiretroviral (ARV) regimen that contains a dual NRTI backbone of emtricitabine; tenofovir alafenamide or tenofovir disoproxil fumarate with either emtricitabine or lamivudine. If tenofovir cannot be used, entecavir should be given in combination with a fully suppressive ARV regimen (note: entecavir should not be considered part of the ARV regimen). Most coinfected patients should continue treatment indefinitely with the goal of maximal HIV suppression and prevention of HBV relapse. If treatment must be discontinued, monitor transaminase concentrations every 6 weeks for the first 3 months, and every 3 to 6 months thereafter. For patients who refuse a fully suppressive ARV regimen, but still requires treatment for HBV, consider 48 weeks of peginterferon alfa; do not administer HIV-active medications in the absence of a fully suppressive ARV regimen. Instruct patients to avoid consuming alcohol, and offer vaccinations against hepatitis A and hepatitis B as appropriate.

    Liver transplant

    Use telbivudine cautiously in patients with a liver transplant. The safety and efficacy of telbivudine in liver transplant recipients are unknown. Of note, telbivudine pharmacokinetic parameter values are not significantly altered in patients with hepatic impairment. If telbivudine is used concurrently with an immunosuppressant that may affect renal function such as cyclosporine or tacrolimus, monitor the patient's renal function both before and during telbivudine treatment.]

    Antimicrobial resistance

    Some strains of HBV are resistant to telbivudine, and antimicrobial resistance can develop with telbivudine therapy (see Adverse Reactions). In cell culture, telbivudine had >= 1000-fold reduced susceptibility 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. The A181V substitution conferred 3 to 5-fold reduced susceptibility to telbivudine in cell culture. Also, the A181S and A181T substitutions conferred 2.7- and 3.5-fold reductions in susceptibility to telbivudine, respectively. The A181T substitution is associated with decreased clinical response in patients with HBV treated with adefovir and entecavir. HBV encoding the adefovir resistance-associated substitution N236T remained susceptible to telbivudine. Patients with higher baseline viral load had higher rates of genotypic resistance to telbivudine. For example, among HBeAg-positive subjects with baseline viral DNA concentrations >= 9 log10 copies/ml, 32% developed genotypic resistance to telbivudine by week 104 as compared with 15% of the patients with viral DNA concentrations < 9 log10 copies/ml. Among HBeAg-negative patients with baseline viral DNA concentrations >= 7 log10 copies/ml, 17% developed genotypic resistance to telbivudine as compared with 5% of the patients with viral DNA concentrations < 7 log10 copies/ml. Only initiate telbivudine therapy if pre-treatment HBV DNA and ALT measurements are known and meet recommended starting levels. For HBeAg-positive patients, HBV DNA should be < 9 log10 copies/ml and ALT should be >= 2x upper limits of normal prior to treatment with telbivudine. For HBeAg-negative patients, HBV DNA should be < 7 log10 copies/ml prior to telbivudine receipt.

    Black patients, Hispanic patients

    Safety and efficacy of telbivudine have not been established in Black patients or Hispanic patients. According to the manufacturer, it is not known if data from studied populations can be extrapolated to Black or Hispanic patients.

    ADVERSE REACTIONS

    Severe

    rhabdomyolysis / Delayed / Incidence not known
    hepatotoxicity / Delayed / Incidence not known
    lactic acidosis / Delayed / Incidence not known
    hepatitis B exacerbation / Delayed / Incidence not known

    Moderate

    antimicrobial resistance / Delayed / 7.0-22.0
    elevated hepatic enzymes / Delayed / 3.0-7.0
    neutropenia / Delayed / 2.0-2.0
    myopathy / Delayed / 0-1.0
    peripheral neuropathy / Delayed / 0-1.0
    hyperamylasemia / Delayed / 0-1.0
    hyperbilirubinemia / Delayed / 0-1.0
    thrombocytopenia / Delayed / 0-1.0
    flank pain / Delayed / Incidence not known
    chest pain (unspecified) / Early / Incidence not known
    steatosis / Delayed / Incidence not known
    hepatomegaly / Delayed / Incidence not known

    Mild

    fatigue / Early / 13.0-13.0
    headache / Early / 10.0-10.0
    diarrhea / Early / 6.0-6.0
    abdominal pain / Early / 3.0-6.0
    cough / Delayed / 6.0-6.0
    nausea / Early / 5.0-5.0
    arthralgia / Delayed / 4.0-4.0
    back pain / Delayed / 4.0-4.0
    dizziness / Early / 4.0-4.0
    fever / Early / 4.0-4.0
    rash / Early / 4.0-4.0
    myalgia / Early / 3.0-3.0
    dyspepsia / Early / 3.0-3.0
    insomnia / Early / 3.0-3.0
    pruritus / Rapid / 2.0-2.0
    weakness / Early / Incidence not known
    musculoskeletal pain / Early / Incidence not known
    muscle cramps / Delayed / Incidence not known
    paresthesias / Delayed / Incidence not known
    hypoesthesia / Delayed / Incidence not known
    vomiting / Early / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Moderate) The risk of myopathy may be increased if zidovudine is coadministered with telbivudine. Monitor patients for any signs or symptoms of unexplained muscle pain, tenderness, or weakness, particularly during periods of upward dosage titration.
    Acyclovir: (Moderate) Drugs that alter renal function such as acyclovir may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Adefovir: (Major) Patients who are concurrently taking adefovir with telbivudine are at risk of developing lactic acidosis and severe hepatomegaly with steatosis. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with antiretrovirals. A majority of these cases have been in women; obesity and prolonged nucleoside exposure may also be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for hepatic disease; however, cases have also been reported in patients with no known risk factors. Suspend adefovir in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
    Amikacin: (Moderate) Drugs that alter renal function such as aminoglycosides may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Amphotericin B cholesteryl sulfate complex (ABCD): (Moderate) Drugs that alter renal function such as amphotericin B may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Amphotericin B lipid complex (ABLC): (Moderate) Drugs that alter renal function such as amphotericin B may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Amphotericin B liposomal (LAmB): (Moderate) Drugs that alter renal function such as amphotericin B may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Amphotericin B: (Moderate) Drugs that alter renal function such as amphotericin B may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Angiotensin-converting enzyme inhibitors: (Moderate) Drugs that alter renal function such as angiotensin-converting enzyme inhibitors may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Celecoxib: (Moderate) Drugs that alter renal function such as NSAIDs may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Chloroquine: (Moderate) The risk of myopathy may be increased if chloroquine is coadministered with telbivudine. Monitor patients for any signs or symptoms of unexplained muscle pain, tenderness, or weakness, particularly during periods of upward dosage titration.
    Cidofovir: (Moderate) Drugs that alter renal function such as cidofovir may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Cisplatin: (Moderate) Drugs that alter renal function such as cisplatin may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Corticosteroids: (Moderate) The risk of myopathy may be increased if corticosteroids are coadministered with telbivudine. Monitor patients for any signs or symptoms of unexplained muscle pain, tenderness, or weakness, particularly during periods of upward dosage titration.
    Cyclosporine: (Moderate) Monitor renal function before and during telbivudine treatment, and also monitor for myopathy, especially when prescribed with other drugs that may affect renal function or cause myopathy. Cyclosporine may alter renal function and it may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Additionally, it is not known if the risk of myopathy during treatment with telbivudine is increased with concurrent administration of other drugs associated with myopathy such as cyclosporine. 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.
    Diclofenac: (Moderate) Drugs that alter renal function such as NSAIDs may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Diclofenac; Misoprostol: (Moderate) Drugs that alter renal function such as NSAIDs may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Diflunisal: (Moderate) Drugs that alter renal function such as NSAIDs may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Diphenhydramine; Ibuprofen: (Moderate) Drugs that alter renal function such as NSAIDs may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Diphenhydramine; Naproxen: (Moderate) Drugs that alter renal function such as NSAIDs may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Echinacea: (Moderate) Use Echinacea sp. with caution in patients taking medications for human immunodeficiency virus (HIV) infection. Some experts have suggested that Echinacea's effects on the immune system might cause problems for patients with HIV infection, particularly with long-term use. There may be less risk with short-term use (less than 2 weeks). A few pharmacokinetic studies have shown reductions in blood levels of some antiretroviral medications when Echinacea was given, presumably due to CYP induction. However, more study is needed for various HIV treatment regimens. Of the agents studied, the interactions do not appear to be significant or to require dose adjustments at the time of use. Although no dose adjustments are required, monitoring drug concentrations may give reassurance during co-administration. Monitor viral load and other parameters carefully during therapy.
    Erythromycin: (Moderate) The risk of myopathy may be increased if erythromycin is coadministered with telbivudine. Monitor patients for any signs or symptoms of unexplained muscle pain, tenderness, or weakness, particularly during periods of upward dosage titration.
    Erythromycin; Sulfisoxazole: (Moderate) The risk of myopathy may be increased if erythromycin is coadministered with telbivudine. Monitor patients for any signs or symptoms of unexplained muscle pain, tenderness, or weakness, particularly during periods of upward dosage titration.
    Esomeprazole; Naproxen: (Moderate) Drugs that alter renal function such as NSAIDs may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Etodolac: (Moderate) Drugs that alter renal function such as NSAIDs may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Famotidine; Ibuprofen: (Moderate) Drugs that alter renal function such as NSAIDs may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Fenoprofen: (Moderate) Drugs that alter renal function such as NSAIDs may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Fibric acid derivatives: (Moderate) The risk of myopathy may be increased if a fibric acid derivative is coadministered with telbivudine. Monitor patients for any signs or symptoms of unexplained muscle pain, tenderness, or weakness, particularly during periods of upward dosage titration.
    Fluconazole: (Moderate) The risk of myopathy may be increased if fluconazole is coadministered with telbivudine. Monitor patients for any signs or symptoms of unexplained muscle pain, tenderness, or weakness, particularly during periods of upward dosage titration.
    Flurbiprofen: (Moderate) Drugs that alter renal function such as NSAIDs may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Food: (Moderate) The pharmacokinetic parameters of anti-retroviral medications (anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs), anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs), anti-retroviral nucleotide reverse transcriptase inhibitors, and anti-retroviral protease inhibitors) metabolized through the CYP isoenzyme system are slightly altered by smoked and oral marijuana. Despite this interaction, marijuana is not expected to adversely affect anti-retroviral efficacy. However, the incidence of marijuana associated adverse effects may change following coadministration with anti-retroviral drugs. Many anti-retrovirals are inhibitors of CYP3A4, an isoenzyme partially responsible for the metabolism of marijuana's most psychoactive compound, delta-9-tetrahydrocannabinol (Delta-9-THC). When given concurrently with anti-retrovirals, the amount of Delta-9-THC converted to the active metabolite 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) may be reduced. These changes in Delta-9-THC and 11-OH-THC plasma concentrations may result in an altered marijuana adverse event profile.
    Foscarnet: (Moderate) Drugs that alter renal function such as foscarnet may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Ganciclovir: (Moderate) Drugs that alter renal function such as ganciclovir may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    HMG-CoA reductase inhibitors: (Moderate) The risk of myopathy may be increased if an HMG-CoA reductase inhibitor is coadministered with telbivudine. Monitor patients for any signs or symptoms of unexplained muscle pain, tenderness, or weakness, particularly during periods of upward dosage titration.
    Hydrocodone; Ibuprofen: (Moderate) Drugs that alter renal function such as NSAIDs may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Hydroxychloroquine: (Moderate) The risk of myopathy may be increased if hydroxychloroquine is coadministered with telbivudine. Monitor patients for any signs or symptoms of unexplained muscle pain, tenderness, or weakness, particularly during periods of upward dosage titration.
    Ibuprofen: (Moderate) Drugs that alter renal function such as NSAIDs may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Ibuprofen; Oxycodone: (Moderate) Drugs that alter renal function such as NSAIDs may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Ibuprofen; Pseudoephedrine: (Moderate) Drugs that alter renal function such as NSAIDs may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Indomethacin: (Moderate) Drugs that alter renal function such as NSAIDs may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Interferon Alfa-2a: (Major) An increased risk and severity of peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons. Patients should be advised to report any numbness, tingling, and/or burning sensations in the arms and/or legs, with or without gait disturbance. Interrupt telbivudine if peripheral neuropathy is suspected, and discontinue the drug if peripheral neuropathy is confirmed. Since both interferons and telbivudine may cause hepatotoxicity, hepatic function should also be closely monitored.
    Interferon Alfa-2b: (Major) An increased risk and severity of peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons. Patients should be advised to report any numbness, tingling, and/or burning sensations in the arms and/or legs, with or without gait disturbance. Interrupt telbivudine if peripheral neuropathy is suspected, and discontinue the drug if peripheral neuropathy is confirmed. Since both interferons and telbivudine may cause hepatotoxicity, hepatic function should also be closely monitored.
    Interferon Alfa-2b; Ribavirin: (Major) An increased risk and severity of peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons. Patients should be advised to report any numbness, tingling, and/or burning sensations in the arms and/or legs, with or without gait disturbance. Interrupt telbivudine if peripheral neuropathy is suspected, and discontinue the drug if peripheral neuropathy is confirmed. Since both interferons and telbivudine may cause hepatotoxicity, hepatic function should also be closely monitored. (Major) The concomitant use of ribavirin and telbivudine should be done with caution. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons, with or without ribavirin, appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. While ribavirin inhibits the phosphorylation reactions required to activate lamivudine, stavudine, d4T, and zidovudine, no evidence of a pharmacokinetic or pharmacodynamic interaction was seen.
    Interferon Alfacon-1: (Major) An increased risk and severity of peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons. Patients should be advised to report any numbness, tingling, and/or burning sensations in the arms and/or legs, with or without gait disturbance. Interrupt telbivudine if peripheral neuropathy is suspected, and discontinue the drug if peripheral neuropathy is confirmed. Since both interferons and telbivudine may cause hepatotoxicity, hepatic function should also be closely monitored.
    Interferon Alfa-n3: (Major) An increased risk and severity of peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons. Patients should be advised to report any numbness, tingling, and/or burning sensations in the arms and/or legs, with or without gait disturbance. Interrupt telbivudine if peripheral neuropathy is suspected, and discontinue the drug if peripheral neuropathy is confirmed. Since both interferons and telbivudine may cause hepatotoxicity, hepatic function should also be closely monitored.
    Interferon Beta-1a: (Major) An increased risk and severity of peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons. Patients should be advised to report any numbness, tingling, and/or burning sensations in the arms and/or legs, with or without gait disturbance. Interrupt telbivudine if peripheral neuropathy is suspected, and discontinue the drug if peripheral neuropathy is confirmed. Since both interferons and telbivudine may cause hepatotoxicity, hepatic function should also be closely monitored.
    Interferon Beta-1b: (Major) An increased risk and severity of peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons. Patients should be advised to report any numbness, tingling, and/or burning sensations in the arms and/or legs, with or without gait disturbance. Interrupt telbivudine if peripheral neuropathy is suspected, and discontinue the drug if peripheral neuropathy is confirmed. Since both interferons and telbivudine may cause hepatotoxicity, hepatic function should also be closely monitored.
    Interferon Gamma-1b: (Major) An increased risk and severity of peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons. Patients should be advised to report any numbness, tingling, and/or burning sensations in the arms and/or legs, with or without gait disturbance. Interrupt telbivudine if peripheral neuropathy is suspected, and discontinue the drug if peripheral neuropathy is confirmed. Since both interferons and telbivudine may cause hepatotoxicity, hepatic function should also be closely monitored.
    Interferons: (Major) An increased risk and severity of peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons. Patients should be advised to report any numbness, tingling, and/or burning sensations in the arms and/or legs, with or without gait disturbance. Interrupt telbivudine if peripheral neuropathy is suspected, and discontinue the drug if peripheral neuropathy is confirmed. Since both interferons and telbivudine may cause hepatotoxicity, hepatic function should also be closely monitored.
    Itraconazole: (Moderate) The risk of myopathy may be increased if itraconazole is coadministered with telbivudine. Monitor patients for any signs or symptoms of unexplained muscle pain, tenderness, or weakness, particularly during periods of upward dosage titration.
    Ketoconazole: (Moderate) The risk of myopathy may be increased if ketoconazole is coadministered with telbivudine. Monitor patients for any signs or symptoms of unexplained muscle pain, tenderness, or weakness, particularly during periods of upward dosage titration.
    Ketoprofen: (Moderate) Drugs that alter renal function such as NSAIDs may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Ketorolac: (Moderate) Drugs that alter renal function such as NSAIDs may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Lamivudine, 3TC; Zidovudine, ZDV: (Moderate) The risk of myopathy may be increased if zidovudine is coadministered with telbivudine. Monitor patients for any signs or symptoms of unexplained muscle pain, tenderness, or weakness, particularly during periods of upward dosage titration.
    Lansoprazole; Naproxen: (Moderate) Drugs that alter renal function such as NSAIDs may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Lovastatin; Niacin: (Moderate) The risk of myopathy may be increased if niacin is coadministered with telbivudine. Physicians considering concomitant treatment 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.
    Meclofenamate Sodium: (Moderate) Drugs that alter renal function such as NSAIDs may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Mefenamic Acid: (Moderate) Drugs that alter renal function such as NSAIDs may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Meloxicam: (Moderate) Drugs that alter renal function such as NSAIDs may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Nabumetone: (Moderate) Drugs that alter renal function such as NSAIDs may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Naproxen: (Moderate) Drugs that alter renal function such as NSAIDs may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Naproxen; Pseudoephedrine: (Moderate) Drugs that alter renal function such as NSAIDs may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Naproxen; Sumatriptan: (Moderate) Drugs that alter renal function such as NSAIDs may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Niacin, Niacinamide: (Moderate) The risk of myopathy may be increased if niacin is coadministered with telbivudine. Physicians considering concomitant treatment 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.
    Niacin; Simvastatin: (Moderate) The risk of myopathy may be increased if niacin is coadministered with telbivudine. Physicians considering concomitant treatment 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.
    Non-Ionic Contrast Media: (Moderate) Drugs that alter renal function, such as radiopaque contrast agents, may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Nonsteroidal antiinflammatory drugs: (Moderate) Drugs that alter renal function such as NSAIDs may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Orlistat: (Major) According to the manufacturer of orlistat, HIV RNA levels should be frequently monitored in patients receiving orlistat while being treated for HIV infection with anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs). Loss of virological control has been reported in HIV-infected patients taking orlistat with atazanavir, ritonavir, tenofovir disoproxil fumarate, emtricitabine, lopinavir; ritonavir, and emtricitabine; efavirenz; tenofovir disoproxil fumarate. The exact mechanism for this interaction is not known, but may involve inhibition of systemic absorption of the anti-retroviral agent. If an increased HIV viral load is confirmed, orlistat should be discontinued.
    Oxaprozin: (Moderate) Drugs that alter renal function such as NSAIDs may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Pamidronate: (Moderate) Drugs that alter renal function such as pamidronate may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Peginterferon Alfa-2a: (Major) An increased risk and severity of peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons. Patients should be advised to report any numbness, tingling, and/or burning sensations in the arms and/or legs, with or without gait disturbance. Interrupt telbivudine if peripheral neuropathy is suspected, and discontinue the drug if peripheral neuropathy is confirmed. Since both interferons and telbivudine may cause hepatotoxicity, hepatic function should also be closely monitored.
    Peginterferon Alfa-2b: (Major) An increased risk and severity of peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons. Patients should be advised to report any numbness, tingling, and/or burning sensations in the arms and/or legs, with or without gait disturbance. Interrupt telbivudine if peripheral neuropathy is suspected, and discontinue the drug if peripheral neuropathy is confirmed. Since both interferons and telbivudine may cause hepatotoxicity, hepatic function should also be closely monitored.
    Peginterferon beta-1a: (Major) An increased risk and severity of peripheral neuropathy has been reported with telbivudine alone or in combination with pegylated interferon alfa-2a and other interferons. Patients should be advised to report any numbness, tingling, and/or burning sensations in the arms and/or legs, with or without gait disturbance. Interrupt telbivudine if peripheral neuropathy is suspected, and discontinue the drug if peripheral neuropathy is confirmed. Since both interferons and telbivudine may cause hepatotoxicity, hepatic function should also be closely monitored.
    Penicillamine: (Moderate) The risk of myopathy may be increased if penicillamine is coadministered with telbivudine. Monitor patients for any signs or symptoms of unexplained muscle pain, tenderness, or weakness, particularly during periods of upward dosage titration.
    Piroxicam: (Moderate) Drugs that alter renal function such as NSAIDs may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Ribavirin: (Major) The concomitant use of ribavirin and telbivudine should be done with caution. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons, with or without ribavirin, appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, NRTIs have been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Didanosine and stavudine are most frequently involved in liver-related mitochondrial toxicity. Additionally, the long-term use of didanosine is an independent factor for developing advanced liver fibrosis in HIV-positive patients in whom other causes of liver damage were excluded. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. While ribavirin inhibits the phosphorylation reactions required to activate lamivudine, stavudine, d4T, and zidovudine, no evidence of a pharmacokinetic or pharmacodynamic interaction was seen.
    Rofecoxib: (Moderate) Drugs that alter renal function such as NSAIDs may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Sulindac: (Moderate) Drugs that alter renal function such as NSAIDs may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Tacrolimus: (Moderate) Drugs that alter renal function such as tacrolimus may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Tolmetin: (Moderate) Drugs that alter renal function such as NSAIDs may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Valacyclovir: (Moderate) Drugs that alter renal function such as valacyclovir may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Valdecoxib: (Moderate) Drugs that alter renal function such as NSAIDs may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Valganciclovir: (Moderate) Drugs that alter renal function such as valganciclovir may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Vancomycin: (Moderate) Drugs that alter renal function such as vancomycin may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.
    Voriconazole: (Moderate) The risk of myopathy may be increased if voriconazole is coadministered with telbivudine. Monitor patients for any signs or symptoms of unexplained muscle pain, tenderness, or weakness, particularly during periods of upward dosage titration.
    Zidovudine, ZDV: (Moderate) The risk of myopathy may be increased if zidovudine is coadministered with telbivudine. Monitor patients for any signs or symptoms of unexplained muscle pain, tenderness, or weakness, particularly during periods of upward dosage titration.
    Zoledronic Acid: (Moderate) Drugs that alter renal function such as zoledronic acid may alter telbivudine plasma concentrations because telbivudine is eliminated primarily by renal excretion. Monitor renal function before and during telbivudine treatment.

    PREGNANCY AND LACTATION

    Pregnancy

    Telbivudine is a FDA pregnancy category B drug, but there are no adequate and well-controlled studies in pregnant women. NRTIs are known to induce mitochondrial dysfunction. An association of mitochondrial dysfunction in infants and in-utero antiretroviral exposure has been suggested, but not established. While the development of severe or fatal mitochondrial disease in exposed infants appears to be extremely rare, more intensive monitoring of hematologic and electrolyte parameters during the first few weeks of life is advised. Nucleoside analogs have been associated with the development of lactic acidosis, especially during pregnancy. It is unclear if pregnancy augments the incidence of lactic acidosis/hepatic steatosis in patients receiving nucleoside analogs. However, because pregnancy itself can mimic some of the early symptoms of the lactic acid/hepatic steatosis syndrome or be associated with other significant disorders of liver metabolism, clinicians need to be alert for early diagnosis of this syndrome. Pregnant women receiving nucleoside analogs should have LFTs and serum electrolytes assessed more frequently during the last trimester of pregnancy and any new symptoms should be evaluated thoroughly. Only use telbivudine in a pregnant woman if the potential benefits outweigh the potential risks. The ability of telbivudine to help prevent HBV transmission from mother to child is unknown. During labor, use appropriate interventions to prevent neonatal acquisition of HBV infection. Enroll pregnant women exposed to telbivudine in the AntiRetroviral Pregnancy Registry by calling 1—800—258—4263.

    It is not known whether telbivudine is excreted in human breast milk as studies in nursing mothers have not been conducted. Antiviral medications whose passage into human breast milk have been evaluated include tenofovir and lamivudine. According to the manufacturer, mothers should be instructed not to breast-feed if receiving telbivudine; however, a consensus among health care providers has not been established. In a survey of 226 physicians, 30.5% would recommend breast-feeding for HBV-infected mothers on antiviral therapy, 44% would not recommend breast-feeding during antiviral therapy, and 25.2% stated they were unsure. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Telbivudine works by inhibiting HBV DNA polymerase. Telbivudine is phosphorylated by cellular kinases to the active triphosphate form, telbivudine 5'-triphosphate, which inhibits HBV DNA polymerase by competing with the natural substrate, thymidine 5'-triphosphate. Incorporation of telbivudine 5'-triphosphate into viral DNA causes DNA chain termination, which results in inhibition of HBV replication.
     
    In vitro, the concentration of telbivudine that effectively inhibited 50% of viral DNA synthesis (EC50) in a human hepatoma cell line was approximately 0.2 micromolar. Telbivudine is an inhibitor of both HBV first strand (EC50 value = 1.3 +/- 1.6 micromolar) and second strand synthesis (EC50 value = 0.2 +/- 0.2 micromolar), although unlike other nucleoside analogs including lamivudine, telbivudine preferentially inhibits HBV second strand synthesis. This difference in mechanism may lead to an increased potency of telbivudine. Telbivudine 5'-triphosphate at concentrations up to 100 micromolar did not inhibit human cellular DNA polymerases alpha, beta, or gamma. No appreciable mitochondrial toxicity was observed in HepG2 cells treated with telbivudine at concentrations up to 10 micromolar.
     
    Genotypic analysis of paired baseline and treatment failure isolates from 181 subjects in the GLOBE study found the rtM204I/V substitution to be associated with virologic failure and virologic rebound. The rtM204I/V substitution was detected in 78% (142/181) of the isolates, and was frequently found with rtL80I/V and rtL180M substitutions. After continuing telbivudine monotherapy for 2 years, 83% of patients who lost viral suppression had detectable rtM204I/V substitution. Additionally, cross-resistance has been observed among HBV nucleoside analogues. In cell-based assays, lamivudine-resistant HBV strains containing either the rtM204I mutation or the rtL180M/rtM204V double mutation had at least 1000-fold reduced susceptibility to telbivudine. Telbivudine retained wild-type phenotypic activity (1.2-fold reduction) against the lamivudine resistance-associated substitution rtM204V alone. The efficacy of telbivudine against HBV harboring the rtM204V mutation has not been established in clinical trials. HBV encoding the adefovir resistance-associated substitution rtA181V showed 3- to 5- fold reduced susceptibility to telbivudine in cell culture. A 2.7- and 3.5-fold reduction in telbivudine susceptibility was also associated with rtA181S and rtA181T substitutions, respectively. HBV encoding the adefovir resistance-associated substitution rtN236T remained susceptible to telbivudine.

    PHARMACOKINETICS

    Telbivudine is administered orally. At steady state, which is achieved within 5—7 days, peak serum concentrations are achieved 1—4 hours after a dose.  In vitro binding to human plasma proteins is 3.3%, but telbivudine is widely distributed into tissues. It is eliminated primarily by urinary excretion of unchanged drug, and no metabolites have been detected. The renal clearance approaches normal glomerular filtration rate, which suggests 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. The terminal elimination half-life is 40—49 hours.
     
    Affected cytochrome P450 isoenzymes and drug transporters:  none
    Telbivudine is neither a substrate nor an inhibitor of the cytochrome P450 enzyme system.

    Oral Route

    Telbivudine absorption and exposure are not affected when administered with food.