Telbivudine (Tablets) Instructions for Use

Marketing Authorization Holder

Biocad, JSC (Russia)

Manufactured By

Pharmstandard-UfaVITA OJSC (Russia)

ATC Code

J05AF11 (Telbivudine)

Active Substance

Telbivudine (Rec.INN registered by WHO)

Dosage Form

Telbivudine

Film-coated tablets, 600 mg: 28 or 30 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets from white to slightly yellowish, capsule-shaped, biconvex; the cross-section of the tablet is white or almost white.

Excipients: microcrystalline cellulose – 161.5 mg, povidone – 15 mg, sodium carboxymethyl starch – 30 mg, magnesium stearate – 8.2 mg, colloidal silicon dioxide – 5.3 mg.
Shell composition film coating – 22 mg, which includes polyvinyl alcohol 31%, titanium dioxide 24%, talc 20%, hypromellose (6 mPa·s) 10%, soy lecithin 10%, hypromellose (15 mPa·s) 5%.

14 pcs. – blister packs (2) – cardboard boxes.
10 pcs. – blister packs (3) – cardboard boxes.

Clinical-Pharmacological Group

Antiviral drug active against hepatitis B virus

Pharmacotherapeutic Group

Antiviral agent

Pharmacological Action

An antiviral agent, a nucleoside reverse transcriptase inhibitor, a synthetic analogue of thymidine. It blocks the activity of the hepatitis B virus DNA polymerase enzyme. Telbivudine is effectively phosphorylated by cellular kinases to the active triphosphate form, which has an intracellular half-life of 14 hours. Telbivudine-5′-triphosphate competitively binds to and inhibits hepatitis B virus DNA polymerase (reverse transcriptase), disrupting the enzyme’s interaction with its endogenous substrate, thymidine-5′-triphosphate.

The incorporation of telbivudine-5′-triphosphate into the viral DNA structure causes chain termination and suppression of hepatitis B virus replication. Telbivudine more potently inhibits the synthesis of the second (50% effective concentration [EC50]=0.12-0.24 µmol) molecular strand of the hepatitis B virus than the first (EC50=0.4-1.3 µmol). Telbivudine-5′-phosphate at concentrations up to 100 µmol did not inhibit human cellular DNA polymerases (α, β, or γ). Telbivudine at concentrations up to 10 µmol did not have a significant toxic effect on mitochondrial structure, nor on DNA content and function, and did not increase lactate production in the human body.

Telbivudine has specific antiviral activity against the hepatitis B virus. It is not effective against other RNA and DNA viruses, including HIV.

When telbivudine was used for 104 weeks in HBeAg-positive patients, the development of a therapeutic response (HBV DNA <5 log₁₀ copies/mL, normalization of ALT activity, and disappearance of HBeAg) was noted in 63% of cases, the mean reduction in HBV DNA level was 5.74 log₁₀ copies/mL, normalization of ALT activity was observed in 70% of patients, and HBV DNA was undetectable (polymerase chain reaction) in 56% of patients.

In HBeAg-negative patients over 104 weeks of telbivudine therapy, the development of a therapeutic response (HBV DNA <5 log₁₀ copies/mL, normalization of ALT level) was observed in 78% of cases, the mean reduction in HBV DNA level was 5 log₁₀ copies/mL, normalization of ALT activity was observed in 78% of patients, and HBV DNA was undetectable (PCR reaction) in 82% of patients.

According to biopsy data at week 52 of treatment, a reduction in the severity of inflammation was detected in 71% of patients and improvement in pre-existing signs of fibrosis on the Ishak scale was observed in 42% of patients.

A reduction in HBV DNA levels below the sensitivity threshold (less than 300 copies/mL) with the use of telbivudine at a dose of 600 mg/day for 104 weeks was noted in 56.0% of HBeAg-positive and 82% of HBeAg-negative patients.

During this period, among HBeAg-positive patients, HBeAg loss and HBeAg seroconversion were observed in 35% and 30% of patients, respectively.

The use of telbivudine in HBeAg-positive patients with high ALT activity (more than 2 times the upper limit of normal), who were the most suitable patient group for interferon treatment, showed a significantly higher proportion of patients achieving seroconversion by week 104 (36%), which was maintained in most patients for 52 weeks after therapy discontinuation.

For patients in whom the serum hepatitis B virus DNA concentration decreases to an undetectable level by week 24 of treatment with the drug, the development of HBeAg seroconversion to anti-HBe, maintenance of undetectable hepatitis B virus DNA concentration, normal ALT level with minimal risk of resistance development over 1 year is more characteristic.

Telbivudine in in vitro studies at concentrations up to 10,000 µmol and in healthy volunteers at doses up to 1800 mg/day did not have a cardiotoxic effect and did not cause changes in the QT interval or any other ECG parameters.

Hepatitis B virus resistant to antiviral therapy

There is insufficient data on the use of telbivudine in patients infected with lamivudine-resistant hepatitis B virus. In vitro, Telbivudine is active against the M204V (single mutation) lamivudine-resistant hepatitis B virus strain, but does not show activity against lamivudine-resistant strains L180M/M204V (double mutation) and M204I (single mutation) of the hepatitis B virus.

There is insufficient data on the use of telbivudine in patients infected with adefovir-resistant hepatitis B virus. In vitro, Telbivudine shows activity against the N236T adefovir-resistant hepatitis B virus strain.

Clinical resistance to telbivudine, associated with YMDD mutation of the hepatitis B virus (M204V), was insignificant. During treatment with telbivudine, the formation of L180M/M204V strains, as well as previously unknown or specific Telbivudine-resistant mutant strains, was not detected.

Pharmacokinetics

After oral administration of the drug at a dose of 600 mg, the C_max of telbivudine in the plasma of healthy volunteers was 3.69±1.25 µg/mL and was reached in 1-4 hours (on average in 2 hours). AUC was 26.1±7.2 µg·h/mL. C_min was 0.2-0.3 µg/mL.

When used once daily, steady state is reached in 5-7 days with accumulation of approximately 1.5 times and an estimated T_1/2 of 15 hours. The absorption of telbivudine and systemic exposure were not changed with a single 600 mg dose taken with food.

The binding of telbivudine to human plasma proteins in vitro is low (about 3.3%). The apparent V_d of telbivudine exceeds the total body fluid, suggesting wide distribution of telbivudine in tissues. Telbivudine is distributed equally between plasma and intracellular fluid.

No metabolites of telbivudine were detected when ¹⁴C-telbivudine was used in humans.

Telbivudine is not a substrate, inhibitor, or inducer of the cytochrome P450 enzyme system.

After reaching C_max, the decrease in telbivudine plasma concentration occurs in a biexponential manner with a T_1/2 in the terminal phase of 40-49 hours.

Telbivudine is excreted primarily by the kidneys unchanged. The renal clearance of telbivudine corresponds to the normal glomerular filtration rate, suggesting its excretion mainly by passive diffusion. After a single oral dose of 600 mg of telbivudine, approximately 42% of the dose appears in the urine within 7 days.

In patients with moderate or severe renal impairment (CrCl ≤ 50 mL/min), increased bioavailability and decreased total clearance of telbivudine are observed. Hemodialysis (up to 4 hours) reduces the systemic exposure of telbivudine by approximately 23%.

Indications

Chronic hepatitis B in adult patients with confirmed viral replication and active inflammatory process in the liver.

ICD codes

Dosage Regimen

The standard oral dose is 600 mg once daily.

Take the tablet with or without food.

For patients with renal impairment, adjust the dosing interval based on creatinine clearance (CrCl).

Administer 600 mg every 48 hours for CrCl 30-49 mL/min.

Administer 600 mg every 72 hours for CrCl less than 30 mL/min (not on dialysis).

For patients with end-stage renal disease (CrCl less than 15 mL/min), administer 600 mg every 96 hours.

Patients undergoing hemodialysis must take the dose after the hemodialysis session.

Schedule the dose on hemodialysis days following the completion of the session.

No dose adjustment is required for patients with mild renal impairment (CrCl 50-80 mL/min).

No dose adjustment is necessary for patients with hepatic impairment.

Do not use in patients under 18 years of age.

Monitor renal function before and during treatment, especially in elderly patients.

Discontinuation of therapy may lead to severe exacerbation of hepatitis; monitor liver function closely for several months after stopping treatment.

Adverse Reactions

From the CNS and peripheral nervous system: frequent – mild dizziness (1.5%), headache; infrequent – peripheral neuropathy, dysgeusia, hypoesthesia, paresthesia, sciatica.

From the respiratory system: frequent – cough.

From the digestive system: frequent – increased blood amylase level, diarrhea, increased lipase level, nausea, abdominal pain.

From the hepatobiliary system: frequent – increased ALT level; sometimes – increased AST level.

From the skin and subcutaneous tissue: frequent – rash.

From the musculoskeletal system: frequent – increased blood CPK level; sometimes – myopathy, arthralgia, myalgia, limb pain, back pain, muscle spasms, neck pain, flank pain.

General disorders: frequent – mild fatigue; sometimes – moderate fatigue, discomfort.

In some patients who discontinued treatment with telbivudine, severe cases of hepatitis B exacerbation were noted. There are no data on the treatment of hepatitis B exacerbations after discontinuation of telbivudine therapy.

Contraindications

Use of telbivudine at a dose of 600 mg/day together with pegylated interferon alfa-2a (180 µg once weekly) and interferon alfa; children and adolescents under 18 years of age; hypersensitivity to telbivudine.

Use in Pregnancy and Lactation

There are no clinical data on the use of telbivudine in pregnant women. Telbivudine can be used during pregnancy if the expected benefit to the mother outweighs the potential risk to the fetus.

There are no data on the effect of telbivudine on the transmission of hepatitis B virus from mother to fetus. Measures should be taken to prevent neonatal infection with the hepatitis B virus.

It is not known whether Telbivudine is excreted in human breast milk. If it is necessary to use telbivudine during lactation, breastfeeding should be discontinued.

Special Precautions

The safety and efficacy of telbivudine in patients after liver transplantation have not been established. The pharmacokinetic parameters of telbivudine at steady state did not change against the background of multiple use in combination with cyclosporine. If it is necessary to carry out therapy with telbivudine in patients after liver transplantation who have received or are receiving therapy with immunosuppressants that affect renal function (e.g., cyclosporine or tacrolimus), renal function should be monitored during and after the use of telbivudine.

There is insufficient clinical experience with the use of telbivudine in patients aged 65 years and older. Given the higher frequency of decreased renal function due to comorbidities or concomitant use of other medications in this category of patients, Telbivudine should be used with caution.

No studies have been conducted on the use of telbivudine in patients with concomitant hepatitis B infections (HIV, hepatitis C and hepatitis D).

In patients who discontinued hepatitis B treatment with telbivudine, severe cases of hepatitis B exacerbation were noted. Careful clinical and laboratory monitoring of liver function is recommended for at least several months after discontinuation of hepatitis B treatment. If necessary, hepatitis B therapy should be resumed.

By week 52 of telbivudine treatment, an increase in CPK level (grade 3/4) was noted in 7.5% of patients receiving Telbivudine and in 3.1% of patients taking lamivudine. The mean CPK level was higher in patients taking Telbivudine. However, from week 53 of telbivudine treatment, no increase in CPK level was observed. In most cases, the increase in CPK level was asymptomatic. Usually, against the background of continuous telbivudine therapy, a decrease in CPK content was noted.

Within several weeks or months after starting treatment with telbivudine, cases of uncomplicated myopathy (persistent diffuse pain and tension in the muscles and/or muscle weakness of unclear etiology, regardless of the degree and time of CPK level increase) developed. Myopathy was also observed with the use of other synthetic thymidine nucleoside analogues.

Patients should immediately inform their doctor of any cases of persistent pain, tension in the muscles, or muscle weakness. If myopathy is confirmed, treatment should be discontinued.

Drug Interactions

Telbivudine is excreted mainly by the kidneys, therefore, when telbivudine is used with drugs that affect renal function, an increase in plasma concentrations of telbivudine and/or concomitantly used drugs is possible.

In a pilot clinical study investigating the combination of telbivudine 600 mg/day and peginterferon alfa-2a (180 µg once weekly subcutaneously), an increased risk of peripheral neuropathy was noted.

It is not known whether the risk of myopathy increases with the concomitant use of telbivudine with drugs that cause myopathy. When using telbivudine together with drugs that cause myopathy, the expected benefit of therapy and the potential risk of developing myopathy should be assessed, and patients should be monitored for the timely detection of pain, tension in the muscles, or muscle weakness of unclear etiology.

Cases of lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been observed with the use of nucleoside/nucleotide analogues alone or in combination with antiretroviral agents.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.