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Telbivudine

Class: Nucleosides and Nucleotides
VA Class: AM800
Chemical Name: 1-[(2S,4R,5S)-4-hydroxy-5-hydroxymethyltetrahydrofuran-2-yl]-5-methyl-1 H-pyrimidine-2,4-dione
Molecular Formula: C10H14N2O5
CAS Number: 3424-98-4
Brands: Tyzeka

Warning(s)

  • Severe acute exacerbations of hepatitis reported in patients who have discontinued HBV therapy, including telbivudine.1 (See Exacerbation of Hepatitis under Cautions.) Closely monitor hepatic function in patients who discontinue anti-HBV therapy; if appropriate, resumption of therapy may be warranted.1

  • Lactic acidosis and severe hepatomegaly with steatosis (including some fatalities) reported in patients receiving nucleoside analogs alone or in conjunction with antiretrovirals.1 (See Lactic Acidosis and Severe Hepatomegaly with Steatosis under Cautions.)

Introduction

Antiviral; thymidine nucleoside analog.1 2

Uses for Telbivudine

Chronic HBV Infection

Treatment of chronic HBV infection in adults and adolescents ≥16 years of age with evidence of active HBV replication and either persistent elevations in serum aminotransferases (ALT or AST) or histologic evidence of active disease.1 2 10 11 12

For treatment of hepatitis B e antigen (HBeAg)-positive patients, initiate telbivudine only in those with baseline serum HBV DNA levels <9 log10 copies/mL and ALT concentrations ≥2 times ULN.1

For treatment of HBeAg-negative patients, initiate telbivudine only in those with baseline serum HBV DNA levels <7 log10 copies/mL.1

Safety and efficacy for treatment of patients with established nucleoside analog reverse transcriptase inhibitor-resistant HBV infection not studied in well-controlled trials;1 cross-resistance between telbivudine and lamivudine expected.1

Safety and efficacy not established for treatment of chronic HBV infection in patients coinfected with HIV.1 (See HBV-infected Individuals Coinfected with HIV under Cautions.)

Safety and efficacy not established for treatment of chronic HBV infection in patients with decompensated liver disease, liver transplant recipients, patients coinfected with HCV or hepatitis D virus (HDV), or black or Hispanic patients.1 (See Liver Transplant Recipients and see Specific Populations under Cautions.)

Treatment of chronic HBV infection is complex and evolving; consult specialized references and experts.97 98 Information from the American Association for the Study of Liver Diseases (AASLD) regarding management of HBV infection, including recommendations for initial treatment, is available at .97

Telbivudine Dosage and Administration

General

  • Determine serum levels of HBV DNA and ALT prior to and during telbivudine therapy;1 higher rates of HBV resistance may occur if long-term telbivudine treatment is used in patients with incomplete viral suppression.1

  • HBeAg-positive patients: Initiate telbivudine only if baseline serum HBV DNA levels are <9 log10 copies/mL and ALT concentrations are ≥2 times ULN.1

  • HBeAg-negative patients: Initiate telbivudine only if baseline serum HBV DNA levels are <7 log10 copies/mL.1

  • After telbivudine initiated, assess serum HBV DNA levels at 24 weeks to assure complete viral suppression (i.e., serum HBV DNA levels <300 copies/mL).1 Initiate alternative treatment in patients with detectable HBV DNA after 24 weeks of treatment;1 use further resistance testing to guide optimal therapy.1

  • If serum HBV DNA levels undetectable at 24 weeks, monitor serum HBV DNA levels every 6 months to assure continued response.1 If patient tests positive for HBV DNA at any time after initial response, initiate alternative treatment and use resistance testing to guide optimal therapy.1

Administration

Oral Administration

Administer orally without regard to meals.1

Administer oral solution using oral dosing cup according to manufacturer’s instructions.1 If oral solution used, advise patients on low-sodium diet that each 600-mg dose (30 mL of oral solution containing 20 mg/mL) contains approximately 47 mg of sodium.1

Dosage

Pediatric Patients

Chronic HBV Infection
Oral

Adolescents ≥16 years of age: 600 mg (one 600-mg tablet) once daily.1

Alternatively, those who have difficulty swallowing may receive the oral solution in a dosage of 600 mg (30 mL of oral solution containing 20 mg/mL) once daily.1

Optimal duration of treatment unknown.1 Use response to guide continued therapy.1 (See General under Dosage and Administration.)

Adults

Chronic HBV Infection
Oral

600 mg (one 600-mg tablet) once daily.1

Alternatively, those who have difficulty swallowing may receive the oral solution in a dosage of 600 mg (30 mL or oral solution containing 20 mg/mL) once daily.1

Optimal duration of treatment unknown.1 Use response to guide continued therapy.1 (See General under Dosage and Administration.)

Special Populations

Hepatic Impairment

Dosage adjustments not needed.1

Renal Impairment

Baseline Clcr <50 mL/minute: Adjust dosage.1 If using tablets, adjust dosing interval;1 if using oral solution, adjust dose.1 (See Table 1.)

When a dose is indicated on a hemodialysis day, give dose after hemodialysis session.

Table 1: Dosage of Telbivudine for Patients with Renal Impairment1

Clcr (mL/minute)

Dosage of Telbivudine Oral Solution Containing 20 mg/mL

Dosage of Telbivudine Tablets

30–49

400 mg (20 mL) once daily

600 mg once every 48 hours

<30 (not requiring dialysis)

200 mg (10 mL) once daily

600 mg once every 72 hours

End-stage renal disease receiving hemodialysis

120 mg (6 mL) once daily

600 mg once every 96 hours

Geriatric Patients

Adjust dosage based on renal impairment;1 monitor renal function.1

Cautions for Telbivudine

Contraindications

  • Concomitant use with peginterferon alfa-2a.1 (See Peripheral Neuropathy under Cautions.)

Warnings/Precautions

Warnings

Exacerbation of Hepatitis

Severe acute exacerbations of hepatitis reported following discontinuance of HBV therapy, including telbivudine.1

Exacerbations of hepatitis or ALT flare (e.g., ALT elevations >10 times ULN and >2 times baseline) reported during telbivudine treatment in 3% of patients.1

Closely monitor hepatic function with both clinical and laboratory follow-up for at least several months after telbivudine discontinued.1 If appropriate, resumption of HBV therapy may be warranted.1

Lactic Acidosis and Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including some fatalities, reported in patients receiving nucleoside analogs alone or in conjunction with antiretrovirals.1 Most reported cases involved women;1 obesity and long-term therapy with nucleoside reverse transcriptase inhibitors (NRTIs) also may be risk factors.1

Use nucleoside analogs with particular caution in patients with known risk factors for liver disease; however, lactic acidosis and severe hepatomegaly with steatosis reported in patients with no known risk factors.1

Discontinue telbivudine in any patient with clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked aminotransferase elevations).1

Other Warnings/Precautions

Musculoskeletal Effects

Myopathy (persistent unexplained muscle pain, tenderness, or weakness in conjunction with increased serum CK concentrations) reported.1 Myopathy/myositis has occurred several weeks to months after initiation of telbivudine, but no pattern with regard to degree or timing of CK elevations observed and predisposing factors not identified.1

Uncomplicated myalgia also reported in clinical studies;1 rhabdomyolysis reported during postmarketing experience.1

Consider possibility of myopathy in patients presenting with diffuse myalgias, muscle tenderness, or muscle weakness.1 Temporarily interrupt therapy if myopathy suspected;1 discontinue if myopathy confirmed.1

Not known if risk of myopathy is increased by concomitant administration of other drugs associated with myopathy (e.g., corticosteroids, chloroquine, hydroxychloroquine, cyclosporine, niacin, fibric acid derivatives [e.g., gemfibrozil], macrolide antibiotics [i.e., erythromycin], penicillamine, certain azole antifungals [i.e., itraconazole, ketoconazole], certain HMG-CoA reductase inhibitors [statins], zidovudine).1 If concomitant treatment with any drug associated with myopathy is initiated, closely monitor for signs or symptoms of unexplained muscle pain, tenderness, or weakness.1

Peripheral Neuropathy

Peripheral neuropathy reported with telbivudine alone or in conjunction with peginterferon alfa-2a.1 Safety and efficacy of telbivudine in conjunction with pegylated or other interferons for treatment of chronic HBV not demonstrated.1

Advise patients to report any numbness, tingling, and/or burning sensations in the arms and/or legs, with or without gait disturbance.1

Interrupt telbivudine therapy if peripheral neuropathy suspected;1 discontinue if peripheral neuropathy confirmed.1

HBV-infected Individuals Coinfected with HIV

Safety and efficacy not evaluated in HBV-infected patients coinfected with HIV.1

Some experts state do not use telbivudine for treatment of HBV infection in HIV-infected patients.200

Liver Transplant Recipients

Safety and efficacy not evaluated in liver transplant recipients.1

If considered necessary in liver transplant recipients who have received or are receiving an immunosuppressive agent that may affect renal function (e.g., cyclosporine, tacrolimus), monitor renal function prior to and during telbivudine treatment.1 (See Specific Drugs under Interactions.)

Specific Populations

Pregnancy

Category B.1

Pregnancy registry at 800-258-4263.1

No adequate, well-controlled trials in pregnant women.1 Use during pregnancy only if potential benefits outweigh potential risks.1

Not teratogenic in preclinical studies.1 Crosses placenta in rats and rabbits;1 no harm to fetuses observed at dosages up to 1 g/kg daily (exposures in rats or rabbits was 6- or 37-fold higher, respectively, than humans exposures at usual recommended dosage).1

Data not available regarding effect of telbivudine therapy during pregnancy on transmission of HBV to the infant.1 Routine screening for HBV infection recommended for all pregnant women.105 For prevention of perinatal transmission of HBV, US Public Health Service Advisory Committee on Immunization Practices (ACIP), AAP, and others state that infants born to hepatitis B surface antigen (HBsAg)-positive women should receive first dose of hepatitis B vaccine and a dose of hepatitis B immune globulin (HBIG) within 12 hours of birth.9 105

Lactation

Distributed into milk in rats;1 not known whether distributed into human milk.1

Manufacturer states do not breast-feed infants while receiving telbivudine.1

Pediatric Use

Safety and efficacy not established in pediatric patients <16 years of age.1

Geriatric Use

Experience in those ≥65 years of age insufficient to determine whether they respond differently than younger adults.1

Use with caution due to the greater frequency of decreased renal function and of concomitant disease and drug therapy in the elderly.1 Monitor renal function and adjust dosage accordingly.1 (See Renal Impairment under Dosage and Administration.)

Renal Impairment

Dosage adjustments recommended in patients with Clcr <50 mL/minute, including those undergoing hemodialysis.1 (See Renal Impairment under Dosage and Administration.)

Black or Hispanic Patients

Manufacturer states safety and efficacy not established in black or Hispanic patients;1 not known whether safety and efficacy data from clinical trials can be extrapolated to such patients.1

No substantial race-related differences in telbivudine pharmacokinetics.1

Common Adverse Effects

GI symptoms (abdominal pain, nausea, diarrhea, dyspepsia, abdominal distension), fatigue, headache, elevated CK concentrations, pharyngolaryngeal pain, cough, pyrexia, arthralgia, rash, back pain, dizziness, increased ALT concentrations, myalgia, insomnia, pruritus, HBV exacerbation.1

Interactions for Telbivudine

Telbivudine is not a substrate for CYP isoenzymes.1 It does not inhibit CYP isoenzymes 1A2, 2C9, 2C19, 2D26, 2E1, or 3A4.1

Pharmacokinetic interactions with drugs metabolized by CYP isoenzymes unlikely.1

Nephrotoxic Drugs or Drugs Eliminated by Renal Excretion

Interaction with other drugs eliminated by renal excretion unlikely.1

Concomitant use with drugs that affect renal function may alter plasma concentrations of telbivudine.1 Monitor closely if used with immunosuppressive agent that alters renal function.1 (See Specific Drugs under Interactions.)

Drugs Associated with Myopathy

Not known if risk of myopathy is increased by concomitant use of other drugs associated with myopathy.1 (See Musculoskeletal Effects under Cautions.)

Specific Drugs

Drug

Interaction

Comments

Adefovir

No pharmacokinetic interactions1 5

In vitro evidence of additive antiviral effects against HBV1

HIV nucleoside and nucleotide antiretroviral agents (HIV NRTIs)

Lamivudine, tenofovir disoproxil fumarate (tenofovir DF): No pharmacokinetic interactions1 5

Abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zidovudine: No in vitro evidence of antagonistic antiretroviral effects against HIV1

Didanosine, stavudine, tenofovir: No in vitro evidence of antagonistic antiviral effects against HBV1 36

Immunosuppressive agents (cyclosporine, tacrolimus)

Cyclosporine: Pharmacokinetic interaction unlikely1

Monitor renal function prior to and during telbivudine treatment in patients receiving immunosuppressive agents that may affect renal function1

Peginterferon alfa-2a

No change in pharmacokinetics of telbivudine;1 effect on pharmacokinetics of peginterferon alfa-2a unclear due to high interindividual variability in disposition of peginterferon alfa-2a1

Increased risk of peripheral neuropathy1

Concomitant use contraindicated1

Telbivudine Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations attained within 1–4 hours after a dose.1 Steady-state concentrations achieved after 5–7 days of once-daily administration with approximately 1.5-fold accumulation.1

Food

Food (high-fat, high-calorie meal) does not appear to affect absorption.1 6

Distribution

Extent

Widely distributed into tissues.1

Not known whether telbivudine distributed into human milk.1

Plasma Protein Binding

3.3%.1

Elimination

Metabolism

Undergoes phosphorylation by cellular enzymes to form active metabolite, telbivudine triphosphate.1

Telbivudine not metabolized by CYP isoenzymes.1

Elimination Route

Eliminated primarily as unchanged drug in urine.1

Hemodialysis removes approximately 23% of a dose.1

Half-life

Terminal elimination half-life: 40–49 hours.1

Special Populations

Impaired hepatic function: Pharmacokinetics not affected.1 7

Impaired renal function: Decreased clearance.1

Stability

Storage

Oral

Solution

In original container at 25°C (may be exposed to 15–30°C).1 Do not freeze.1 After opening, discard within 2 months.1

Tablets

In original container at 25°C (may be exposed to 15–30°C).1

Actions and Spectrum

  • Thymidine nucleoside analog antiviral agent that is active in vitro and vivo against HBV.1 2

  • Undergoes phosphorylation by cellular enzymes to form the active metabolite, telbivudine triphosphate.1 Inhibits activities of HBV DNA polymerase (reverse transcriptase).1

  • HBV with reduced susceptibility to telbivudine have emerged during therapy with the drug.1 2 3 The rtM204I/V substitution is associated with virologic failure and virologic rebound.1

  • Cross-resistance can occur among the nucleoside and nucleotide antivirals used for treatment of HBV.1 36 Lamivudine-resistant HBV with reduced susceptibility to telbivudine reported.1 Some adefovir-resistant HBV have reduced susceptibility to telbivudine;1 other strains remain susceptible to telbivudine.1

Advice to Patients

  • Importance of providing a copy of the manufacturer’s patient information.1

  • Importance of taking telbivudine exactly as prescribed and not discontinuing or interrupting therapy unless instructed by a clinician; importance of regular medical follow-up.1

  • Advise patients that deterioration of liver disease has occurred when telbivudine therapy is discontinued and that any change in treatment should be discussed with the clinician.1

  • Advise patients telbivudine is not a cure for HBV infection and long-term treatment benefits unknown.1 Relationship between treatment response and long-term outcomes of HBV infection (e.g., hepatocellular carcinoma, decompensated cirrhosis) unknown.1

  • Patients should be advised of available measures to prevent spread of HBV infection to close contacts.1 HBV transmission via sexual contact, sharing needles, or blood contamination is not prevented by telbivudine therapy.1

  • Importance of immediately reporting any unexplained muscle weakness, tenderness, or pain.1

  • Importance of immediately reporting any numbness, tingling, and/or burning sensations in the arms and/or legs, with or without difficulty walking.1

  • Advise patients on a low-sodium diet that telbivudine oral solution contains approximately 47 mg of sodium per 600-mg dose (30 mL of oral solution).1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, and any concomitant illnesses (e.g., renal disease).1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Telbivudine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Solution

20 mg/mL

Tyzeka

Novartis

Oral

Tablets, film-coated

600 mg

Tyzeka

Novartis

AHFS DI Essentials. © Copyright 2017, Selected Revisions October 23, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Novartis Pharmaceuticals. Tyzeka (telbivudine) tablet and oral solution prescribing information. East Hanover, NJ; 2013 Jan.

2. Anon. Telbivudine (Tyzeka) for chronic hepatitis B. Med Lett Drugs Ther. 2007; 49:11-12.

3. Lai CL, Leung N, Teo EK et al. A 1-year trial of telbivudine, lamivudine, and the combination in patients with hepatitis B e antigen-positive chronic hepatitis B. Gastroenterology. 2005; 129:528-36. [PubMed 16083710]

5. Zhou XJ, Fielman BA, Lloyd DM et al. Pharmacokinetics of telbivudine in healthy subjects and absence of drug interactions with lamivudine or adefovir dipivoxil. Antimicrob Agents Chemother. 2006; 50:2309-15. [PubMed 16801406]

6. Zhou XJ, Lloyd DM, Chao GC, Brown NA. Absence of food effect on the pharmacokinetics of telbivudine following oral administration in healthy subjects. J Clin Pharmacol. 2006; 46:275-81. [PubMed 16490803]

7. Zhou XJ, Marbury TC, Alcorn HW et al. Pharmacokinetics of telbivudine in subjects with various degrees of hepatic impairment. Antimicrob Agents Chemother. 2006; 50:1721-6. [PubMed 16641441]

9. Centers for Disease Control and Prevention. Recommended immunization schedule for children and adolescents aged 18 years or younger—United States, 2017. Updates may be available at CDC website.

10. Liaw YF, Gane E, Leung N et al. 2-Year GLOBE trial results: telbivudine Is superior to lamivudine in patients with chronic hepatitis B. Gastroenterology. 2009; 136:486-95. [PubMed 19027013]

11. Wang Y, Thongsawat S, Gane EJ et al. Efficacy and safety of continuous 4-year telbivudine treatment in patients with chronic hepatitis B. J Viral Hepat. 2013; 20:e37-46. [PubMed 23490388]

12. Lai CL, Gane E, Liaw YF et al. Telbivudine versus lamivudine in patients with chronic hepatitis B. N Engl J Med. 2007; 357:2576-88. [PubMed 18094378]

36. Gilead Sciences. Vemlidy (tenofovir alafenamide fumarate) tablets prescribing information. Foster City, CA; 2017 Apr.

97. Terrault NA, Bzowej NH, Chang KM et al. AASLD guidelines for treatment of chronic hepatitis B. Hepatology. 2016; 63:261-83. [PubMed 26566064]

98. World Health Organization. Guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection. March 2015. Geneva: World Health Organization; 2015.

105. American Academy of Pediatrics. Red Book: 2015 Report of the Committee on Infectious Diseases. 30th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2015.

200. Panel on Antiretroviral Guidelines for Adults and Adolescents, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (July 14, 2016). Updates may be available at HHS AIDS Information (AIDSinfo) website.

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