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 anti-hepatitis B virus (HBV) therapy, including telbivudine.1 (See Exacerbations 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 antiretroviral agents.1 (See Lactic Acidosis and Severe Hepatomegaly with Steatosis under Cautions.)

Introduction

Antiviral; synthetic thymidine nucleoside analog.1 2

Uses for Telbivudine

Chronic Hepatitis B Virus (HBV) Infection

Management of chronic HBV infection in adults and adolescents ≥16 years of age with evidence of active HBV replication and either persistent elevations in serum aminotransaminases (ALT or AST) or histologic evidence of active disease.1 2 Relationship between treatment response and long-term outcomes of the disease (e.g., hepatocellular carcinoma, decompensated cirrhosis) not known.1

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Has been effective for HBeAg-positive or -negative chronic HBV infection with compensated liver disease in patients who were nucleoside-naive (had not previously received treatment with nucleoside antivirals).1 2 3

Not systematically evaluated to date in patients with lamivudine- or adefovir-resistant HBV.1 (See HBV Resistance under Cautions.)

Safety and efficacy not established for treatment of chronic HBV infection in liver transplant patients.1 (See Liver Transplant Recipients under Cautions.)

No data to date regarding treatment of HBV infection in patients coinfected with HIV, hepatitis C virus (HCV), or hepatitis D virus (HDV).1

Treatment of chronic HBV infection is complex and rapidly evolving and should be directed by clinicians familiar with the disease; consult a specialist to obtain the most up-to-date information.4

Telbivudine Dosage and Administration

Administration

Oral Administration

Administer orally without regard to meals.1

Dosage

Optimal duration of treatment for chronic HBV infection unknown.1

Pediatric Patients

Chronic Hepatitis B Virus (HBV) Infection
Oral

Adolescents ≥16 years of age: 600 mg once daily.1

Adults

Chronic Hepatitis B Virus (HBV) Infection
Oral

600 mg once daily.1

Special Populations

Hepatic Impairment

Dosage adjustment not required.1

Renal Impairment

Increase dosing interval in those with Clcr <50 mL/minute, including those undergoing hemodialysis.1

Dosage for Treatment of Chronic HBV Infection in Patients with Renal Impairment

Clcr(mL/min)

Dosage

≥50

600 mg once daily1 9

30–49

600 mg once every 48 hours1

<30 (not requiring dialysis)

600 mg once every 72 hours1

Hemodialysis patients

600 mg once every 96 hours; give dose after hemodialysis1

Cautions for Telbivudine

Contraindications

  • Known hypersensitivity to telbivudine or any ingredient in the formulation.1

Warnings/Precautions

Warnings

Exacerbations of Hepatitis

Clinical and laboratory evidence of severe acute exacerbations of hepatitis may occur following discontinuance of HBV therapy, including telbivudine.1 Data insufficient to date regarding incidence of exacerbation of hepatitis following discontinuance of 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 clinically and with laboratory studies at repeated intervals for at least several months after telbivudine discontinuance.1 If appropriate, resumption of anti-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

Musculoskeletal Effects

Myopathy (persistent unexplained muscle pain, tenderness, or weakness in conjunction with increased serum CK concentrations) reported.1 Risk factors for myopathy not identified.1 Uncomplicated myalgia also reported.1

Consider myopathy in patients presenting with musculoskeletal symptoms suggestive of this adverse event.1 Temporarily interrupt therapy if myopathy suspected; discontinue if myopathy diagnosed.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 hydroxymethylglutaryl-CoA [HMG-CoA] reductase inhibitors [statins], zidovudine).1 If such concomitant therapy is considered, weigh potential benefits and risks.1 Carefully monitor patient, especially during dosage titration.1

General Precautions

HBV Resistance

Telbivudine-resistant HBV detected in patients receiving the drug; diminished treatment response reported.1 2 After 2 years of therapy, viral rebound due to telbivudine resistance was reported in 21.6% of HBeAg-positive patients and 8.6% of HBeAg-negative patients.2

Not systematically evaluated in patients with lamivudine-resistant HBV.1 Lamivudine-resistant HBV with substitutions at rtM204I or rtL180M/rtM204V have high level of cross-resistance to telbivudine.1 Strains with substitutions at rtM204V (a mutation associated with lamivudine resistance) have reduced susceptibility to telbivudine (1.2-fold reduction).1

Not systematically evaluated in patients with adefovir-resistant HBV.1 Telbivudine has in vitro activity against adefovir-resistant strains with substitutions at rtN236T but not against adefovir-resistant strains with substitutions at rtA181V.1

Liver Transplant Recipients

Safety and efficacy in liver transplant recipients not evaluated.1 If telbivudine 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 Drugs Affecting or Eliminated by Renal Excretion under Interactions.)

Specific Populations

Pregnancy

Category B.1 Pregnancy registry at 800-258-4263.1

Data not available regarding the effect of telbivudine therapy during pregnancy on transmission of HBV to the infant; use appropriate interventions to prevent neonatal acquisition of HBV infection (hepatitis B immune globulin [HBIG] and HBV vaccine).1 4 8

Lactation

Not known whether distributed into human milk.1 Do not breast-feed infants while receiving telbivudine.1

Pediatric Use

Safety and efficacy not established in children <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 adjustment recommended in patients with Clcr <50 mL/minute, including those undergoing hemodialysis.1 (See Dosage in Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Upper respiratory tract infection, GI symptoms (abdominal pain, nausea, vomiting, diarrhea or loose stools, dyspepsia), fatigue, malaise, nasopharyngitis, headache, influenza or influenza-like symptoms, elevated CK concentrations, cough, pyrexia, arthralgia, rash, back pain, dizziness, myalgia, insomnia.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

Drugs Affecting or 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 If telbivudine is used with an immunosuppressive agent that alters renal function, monitor renal function before and during telbivudine therapy.1

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

Pharmacokinetic interaction unlikely1 5

In vitro evidence of additive antiviral effects against HBV1

Cyclosporine

Pharmacokinetic interaction unlikely1

Monitor renal function1

Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs)

Lamivudine: Pharmacokinetic interaction unlikely1 5

Abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zidovudine: No in vitro evidence of reduced antiretroviral activity1

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

Peginterferon alfa-2a

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

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 is 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 is 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

Tablets

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

Actions and Spectrum

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

  • Active metabolite, telbivudine triphosphate, inhibits activities of HBV DNA polymerase (reverse transcriptase).1

  • Not active against HIV-1 (EC50 >100 mcM).1

  • HBV strains with reduced susceptibility to telbivudine have emerged during therapy with the drug.1 2 3

  • Cross-resistance may occur among some nucleoside analogs active against HBV.1 Lamivudine-resistant HBV with reduced susceptibility to telbivudine have been observed in vitro.1 Some adefovir-resistant HBV are resistant to telbivudine; other strains remain susceptible to telbivudine.1 2

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 10

  • 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

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

  • Importance of HBV therapy compliance.1 10 Telbivudine is not a cure for HBV infection; it is not known whether the drug will prevent long-term sequelae (cirrhosis, liver cancer).1

  • Patients should be advised of available measures to prevent spread of HBV infection to close contacts.1 10 HBV transmission via sexual contact, sharing needles, or blood contamination is not prevented by telbivudine therapy.1 10

  • 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.

Telbivudine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

600 mg

Tyzeka (with povidone)

Idenix

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 10/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Tyzeka 600MG Tablets (NOVARTIS): 30/$816.03 or 90/$2,208.88

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions October 3, 2014. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Idenix Pharmaceuticals. Tyzeka (telbivudine) tablet prescribing information. Cambridge, MA; 2006 Oct.

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]

4. Lok ASF, McMahon BJ. Chronic hepatitis B. AASLD practice guidelines. Hepatology. 2007; 45:507-39. [PubMed 17256718]

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]

8. American Academy of Pediatrics. 2006 Red book: Report of the Committee on Infectious Diseases. 27th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2006.

9. Idenix Pharmaceuticals. Cambridge, MA, Personal communication.

10. Idenix Pharmaceuticals. Patient information: Tyzeka. Cambridge, MA; 2006 Oct.

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