1. Name of the medicinal product

Telbivudine Tablet 600mg Taj Pharma

  1. Qualitative and quantitative composition

Telbivudine Tablet 600mg Taj Pharma
Each film-coated tablet contains:
Telbivudine 600mg
Excipients: Q.S.

For the full list of excipients, see section 6.1.

  1. Pharmaceutical form

Film-coated tablet

White to slightly yellowish, oval film-coated tablet,

  1. Clinical particulars
  • Therapeutic indications

Telbivudine Taj Pharma is indicated for the treatment of chronic hepatitis B in adult patients with compensated liver disease and evidence of viral replication, persistently elevated serum alanine aminotransferase (ALT) levels and histological evidence of active inflammation and/or fibrosis.

Initiation of Telbivudine Taj Pharma treatment should only be considered when the use of an alternative antiviral agent with a higher genetic barrier to resistance is not available or appropriate.

See section 5.1 for details of the study and specific patient characteristics on which this indication is based.

  • Posology and method of administration

Therapy must be initiated by a physician experienced in the management of chronic hepatitis B infection.

Posology

Adults

The recommended dose of Telbivudine Taj Pharma is 600mg (one tablet) once daily.

Telbivudine Taj Pharma oral solution may be considered for patients who have difficulties swallowing tablets.

Monitoring during treatment

On-treatment response at week 24 has been shown to be predictive of longer-term response (see Table 7 in section 5.1). HBV DNA levels should be monitored at 24 weeks of treatment to assure complete viral suppression (HBV DNA less than 300 copies/ml). For patients with detectable HBV DNA after 24 weeks of therapy, treatment modification should be considered.

HBV DNA should be monitored every 6 months to assure continued response. If patients test positive for HBV DNA at any time after their initial response, treatment modification should be considered. Optimal therapy should be guided by resistance testing.

Duration of therapy

The optimal treatment duration is unknown. Treatment discontinuation should be considered as follows:

  • In HBeAg-positive patients without cirrhosis, treatment should be administered for at least 6-12 months after HBeAg seroconversion (HBeAg loss and HBV DNA loss with anti-HBe detection) is confirmed or until HBsAg seroconversion or there is evidence of loss of efficacy. Serum ALT and HBV DNA levels should be followed regularly after treatment discontinuation to detect any late virological relapse.
  • In HBeAg-negative patients without cirrhosis, treatment should be administered at least until HBsAg seroconversion or until there is evidence of loss of efficacy. With prolonged treatment for more than 2 years, regular reassessment is recommended to confirm that continuation of the selected therapy remains appropriate for the patient.

Missed doses

If a dose is missed, the patient may take the missed dose only up to 4 hours prior to the next scheduled dose. The next dose should be taken at the usual time.

Elderly (age above 65 years)

No data are available to support a specific dose recommendation for patients over the age of 65 years (see section 4.4).

Renal impairment

No adjustment of the recommended dose of Telbivudine Taj Pharma is necessary in patients whose creatinine clearance is ≥ 50 ml/min. Adjustment of the dose is required in patients with creatinine clearance < 50 ml/min, including those with end-stage renal disease (ESRD) on haemodialysis. A reduction of the daily dose using Telbivudine Taj Pharma oral solution, as detailed in Table 1 below, is recommended. If use of the oral solution is not possible, Telbivudine Taj Pharma film-coated tablets could be used as an alternative and dosing should be adjusted by increasing the time interval between doses, as detailed in Table 1.

Table 1 Dosing regimen adjustment of Telbivudine Taj Pharma in patients with renal impairment

Creatinine clearance (ml/min)Telbivudine Taj Pharma 20mg/ml oral solution

Daily dose adjustment

Telbivudine Taj Pharma 600mg film-coated tablet

Alternative** dose adjustment with increased dose intervals

≥ 50600mg (30 ml) once daily600mg once daily
30-49400mg (20 ml) once daily600mg once every 48 hours
< 30 (not requiring dialysis)200mg (10 ml) once daily600mg once every 72 hours
ESRD*120mg (6 ml) once daily600mg once every 96 hours

* End stage renal disease

** In case use of the oral solution is not possible

The proposed dose modifications are based on extrapolation and may not be optimal. The safety and effectiveness of these dosing adjustment guidelines have not been clinically evaluated. Therefore, close clinical monitoring is recommended in these patients.

End-stage renal disease patients

For patients with ESRD, Telbivudine Taj Pharma should be administered after haemodialysis (see section 5.2).

Hepatic impairment

No adjustment to the recommended dose of Telbivudine Taj Pharma is necessary in patients with hepatic impairment (see section 5.2).

Paediatric population

The safety and efficacy of Telbivudine Taj Pharma in the paediatric population have not yet been established. No data are available.

Method of administration

Telbivudine Taj Pharma is to be taken orally, with or without food. The tablet should not be chewed, split or crushed.

  • Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Combination of Telbivudine Taj Pharma with pegylated or standard interferon alfa (see sections 4.4 and 4.5).

  • Special warnings and precautions for use

Severe acute exacerbations of chronic hepatitis B are relatively frequent, and are characterised by transient elevation of serum ALT. Following initiation of antiviral treatment, serum ALT may rise in some patients while serum levels of HBV DNA fall (see section 4.8). On average, 4-5 weeks elapsed prior to the occurrence of an exacerbation in patients treated with Telbivudine Taj Pharma. Overall, ALT flares occurred more frequently in HBeAg-positive patients than in HBeAg-negative patients. In patients with compensated liver disease, this elevation of serum ALT is generally not accompanied by elevated levels of serum bilirubin or by other signs of hepatic decompensation. The risk of hepatic decompensation – and of a subsequent exacerbation of hepatitis – may be elevated in patients with cirrhosis. Such patients should, therefore, be closely monitored.

Exacerbations of hepatitis have also been reported in patients who have terminated treatment of hepatitis B. Post-treatment ALT flares are normally associated with increases in serum HBV DNA levels, and the majority of such cases have proven to be self-limiting. Nonetheless, there have also been reports of severe – and sometimes fatal – post-treatment disease exacerbations. Therefore, hepatic function should be monitored at regular intervals with both clinical and laboratory follow-up for at least 6 months after discontinuation of hepatitis B therapy.

Lactic acidosis

Rare post-marketing cases of lactic acidosis have been reported with Telbivudine Taj Pharma. Cases were more often secondary to other serious conditions (e.g. rhabdomyolysis) and/or associated with muscle-related events (e.g. myopathy, myositis). When secondary to other conditions, some cases were also associated with pancreatitis, liver failure/hepatic steatosis and renal failure. In some cases, fatal outcomes were reported when lactic acidosis was secondary to rhabdomyolysis. Patients should be followed closely.

Treatment with Telbivudine Taj Pharma should be discontinued when metabolic/lactic acidosis of unknown aetiology occurs. Benign digestive symptoms, such as nausea, vomiting and abdominal pain, may be indicative of lactic acidosis development.

Muscular effects

Cases of myopathy and myalgia have been reported with Telbivudine Taj Pharma use several weeks to months after starting therapy (see section 4.8). Cases of rhabdomyolysis have been reported during post-marketing use of Telbivudine Taj Pharma (see section 4.8).

Myopathy, defined as persistent unexplained muscle aches and/or muscle weakness regardless of the degree of increases in creatine kinase (CK) levels, should be considered in any patient with diffuse unexplained myalgias, muscle tenderness, muscle weakness or myositis (defined as myopathy with histological evidence of muscle damage). Patients should be advised to report promptly any persistent unexplained muscle aches, pain, tenderness or weakness. If any of these symptoms are reported, a detailed muscle examination should be performed in order to evaluate muscle function. Telbivudine Taj Pharma therapy should be discontinued if myopathy is diagnosed.

It is not known whether the risk of myopathy during treatment with Telbivudine Taj Pharma is increased with concurrent administration of other medicinal products associated with myopathy (e.g. statins, fibrates, or ciclosporin). Physicians considering concomitant treatment with other agents associated with myopathy should weigh carefully the potential benefits and risks and should monitor patients for any signs or symptoms suggestive of myopathy.

Peripheral neuropathy

Peripheral neuropathy has been uncommonly reported in Telbivudine Taj Pharma-treated patients. If peripheral neuropathy is suspected, treatment with Telbivudine Taj Pharma should be reconsidered (see section 4.8).

An increased risk of developing peripheral neuropathy has been observed in one study when Telbivudine Taj Pharma and pegylated interferon alfa-2a were co-administered (see section 4.5). Such increased risk cannot be excluded for other interferon alfa (pegylated or standard). Moreover, the benefit of the combination of Telbivudine Taj Pharma with interferon alfa (pegylated or standard) is not currently established. Therefore, the combination of Telbivudine Taj Pharma with pegylated or standard interferon alfa is contraindicated (see section 4.3).

Renal function

Telbivudine Taj Pharma is eliminated primarily by renal excretion, therefore dose interval adjustment is recommended in patients with creatinine clearance < 50 ml/min, including patients on haemodialysis. The effectiveness of dosing interval adjustment has not been clinically evaluated. Therefore, virological response should be closely monitored in patients with increased dosage interval (see sections 4.2 and 5.2).

Patients with cirrhosis without decompensation

Due to the limited data available (about 3% of patients enrolled had cirrhosis), Telbivudine Taj Pharma should be used with particular caution in cirrhotic patients. These patients should be closely monitored for clinical, biochemical and virological parameters associated with hepatitis B during treatment and after treatment is discontinued.

Patients with cirrhosis with decompensation

There are no adequate efficacy and safety data in patients with decompensated cirrhosis.

Patients with previous exposure to nucleoside/nucleotide analogues

In vitro, Telbivudine Taj Pharma was not active against the HBV strains containing rtM204V/rtL180M or rtM204I mutations (see section 5.1). Telbivudine Taj Pharma monotherapy is not an option for patients with established lamivudine-resistant hepatitis B virus infection. Patients who failed to achieve virological response following treatment with lamivudine for more than 24 weeks are unlikely to benefit from Telbivudine Taj Pharma monotherapy. There is currently no clinical data to properly assess the benefit and risk of switching to Telbivudine Taj Pharma for lamivudine-treated patients who achieve complete viral suppression on lamivudine.

There are no data on Telbivudine Taj Pharma treatment in patients with established adefovir-resistant hepatitis B virus single mutations of rtN236T or A181V. Results from cell-based assays showed that the adefovir resistance-associated substitution A181V had 1.5- to approximately 4-fold reduced susceptibility to Telbivudine Taj Pharma.

Liver transplant recipients

The safety and efficacy of Telbivudine Taj Pharma in liver transplant recipients are unknown.

Elderly

Clinical studies of Telbivudine Taj Pharma did not include sufficient numbers of patients ≥ 65 years of age to determine whether they respond differently from younger subjects. In general, caution must be exercised when prescribing Telbivudine Taj Pharma to older patients in view of the greater frequency of decreased renal function due to concomitant disease or concomitant use of other medicinal products.

Other special populations

Telbivudine Taj Pharma has not been investigated in co-infected hepatitis B patients (e.g. patients co-infected with human immunodeficiency virus [HIV], hepatitis C virus [HCV] or hepatitis D virus [HDV]).

General

Patients should be advised that treatment with Telbivudine Taj Pharma has not been shown to reduce the risk of transmission of HBV to others through sexual contact or blood contamination.

Telbivudine Taj Pharma is not recommended to be used with lamivudine because in a phase II study, the treatment response observed with combination therapy of Telbivudine Taj Pharma and lamivudine was lower than with Telbivudine Taj Pharma alone.

There are currently no efficacy and safety data for other antiviral combinations with Telbivudine Taj Pharma.

  • Interaction with other medicinal products and other forms of interaction

Since Telbivudine Taj Pharma is eliminated primarily by renal excretion, co-administration of Telbivudine Taj Pharma with substances that affect renal function (such as aminoglycosides, loop diuretics, platinum compounds, vancomycin, amphotericin B) may affect plasma concentrations of Telbivudine Taj Pharma and/or the co-administered substance. The combination of Telbivudine Taj Pharma with these medicinal products should be used with caution. The steady-state pharmacokinetics of Telbivudine Taj Pharma were unaltered following multiple dose administration in combination with lamivudine, adefovir dipivoxil, tenofovir disoproxil fumarate, ciclosporin or pegylated interferon alfa-2a. In addition, Telbivudine Taj Pharma does not alter the pharmacokinetics of lamivudine, adefovir dipivoxil, tenofovir disoproxil fumarate or ciclosporin. No definitive conclusion could be drawn regarding the effects of Telbivudine Taj Pharma on the pharmacokinetics of pegylated interferon due to high interindividual variability of pegylated interferon alfa-2a concentrations. A clinical trial investigating the combination of Telbivudine Taj Pharma, 600mg daily, with pegylated interferon alfa-2a, 180 micrograms once weekly by subcutaneous administration, indicates that this combination is associated with an increased risk of developing peripheral neuropathy. The mechanism behind these events is not known (see section 4.4). The combination of Telbivudine Taj Pharma with any interferon alfa-containing product is contraindicated (see section 4.3).

Telbivudine Taj Pharma is not a substrate, inhibitor or inducer of the cytochrome P450 (CYP450) enzyme system (see section 5.2). Therefore, the potential for CYP450-mediated drug interactions involving Telbivudine Taj Pharma is low.

  • Fertility, pregnancy and lactation

Pregnancy

Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). Studies in pregnant rats and rabbits showed that Telbivudine Taj Pharma crosses the placenta. Studies in pregnant rabbits showed early delivery and/or abortion secondary to maternal toxicity.

Limited clinical data (less than 300 pregnancy outcomes) after exposure to Telbivudine Taj Pharma during the first trimester of pregnancy indicate no malformative toxicity and a large amount of data (more than 1000 pregnancy outcomes) after exposure during the second and third trimesters indicate no foetal/neonatal toxicity.

Telbivudine Taj Pharma should be used during pregnancy only if the benefit to the mother outweighs the potential risk to the foetus.

Literature shows that exposure to Telbivudine Taj Pharma in the second and/or third trimester of pregnancy has been shown to reduce the risk of HBV transmission from mother to infant if Telbivudine Taj Pharma is given in addition to Hepatitis B immune globulin and Hepatitis B vaccine.

Breast-feeding

Telbivudine Taj Pharma is excreted in the milk of rats. It is not known whether Telbivudine Taj Pharma is excreted in human milk. Women should not breastfeed if they are taking Telbivudine Taj Pharma.

Fertility

There are no clinical data on the effects of Telbivudine Taj Pharma on male or female fertility. In reproductive toxicology studies in adult animals, fertility was slightly reduced when both male and female rats received Telbivudine Taj Pharma. The adverse effects on fertility were greater in a separate study in juvenile animals when both sexes received Telbivudine Taj Pharma (see section 5.3).

  • Effects on ability to drive and use machines

Telbivudine Taj Pharma has minor influence on the ability to drive and use machines.

  • Undesirable effects

Summary of the safety profile

Assessment of adverse reactions is mainly based on two studies, NV-02B-007 (GLOBE) and NV-02B-015, in which 1,699 patients with chronic hepatitis B received double-blind treatment with Telbivudine Taj Pharma 600mg/day (n = 847) or lamivudine (n = 852) for 104 weeks.

In the 104-week clinical studies, reported adverse reactions were usually classified as mild or moderate in severity. The most common adverse reactions were grade 3 or 4 blood creatine kinase elevations (6.8%), fatigue (4.4%), headache (3.0%) and nausea (2.6%).

Tabulated list of adverse reactions

Table 2 lists the adverse reactions according to MedDRA system organ class and frequency using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 2 Adverse reactions

Metabolism and nutrition disorders
Rare*Lactic acidosis
Nervous system disorders
CommonDizziness, headache
UncommonPeripheral neuropathy, dysgeusia, hypoaesthesia, paresthesia, sciatica
Respiratory, thoracic and mediastinal disorders
CommonCough
Gastrointestinal disorders
CommonDiarrhoea, blood lipase increased, nausea, abdominal pain
Skin and subcutaneous tissue disorders
CommonRash
Musculoskeletal and connective tissue disorders
UncommonMyopathy/myositis, arthralgia, myalgia, pain in the extremities, back pain, muscle spasm, neck pain, flank pain
Rare*Rhabdomyolysis
General disorders and administration site conditions
CommonFatigue
UncommonMalaise
Investigations
CommonBlood creatine phosphokinase increased, blood alanine aminotransferase increased, blood amylase increased
UncommonAspartate aminotransferase increased

* This adverse reaction was identified through post-marketing surveillance but not observed in controlled clinical trials. The frequency category was estimated from a statistical calculation based on the total number of patients exposed to Telbivudine Taj Pharma in clinical trials (n = 8,914).

Description of selected adverse reactions

Creatine kinase elevation

In the pooled analysis from NV-02B-007 (GLOBE) and NV-02B-015, by 104 weeks of treatment grade 3 or4 CK elevations (> 7x ULN) occurred in 12.6% of Telbivudine Taj Pharma-treated patients (n = 847) and 4.0% of lamivudine-treated patients (n = 846). Most CK elevations were asymptomatic and CK values typically decreased by the next visit on continued treatment.

ALT flares

The incidence of on treatment alanine aminotransferase (ALT) flares in the two treatment arms according to AASLD (American Association for the Study of Liver Diseases) definition (ALT elevation > 2x baseline and > 10x ULN) are further described in Table 3 below.

Table 3 Summary of on-treatment ALT flares – Pooled NV-02B-007 (GLOBE) and NV-02B-015 studies

ALT flare:

ALT elevation > 2x baseline and > 10x ULN

Lamivudine

n/N (%)

Telbivudine Taj Pharma

n/N (%)

Overall67/852 (7.9)41/847 (4.8)
Baseline to week 2425/852 (2.9)25/847 (3.0)
Week 24 to end of study44/837 (5.3)17/834 (2.0)

Periodic monitoring of hepatic function is recommended during treatment (see section 4.4).

Exacerbations of hepatitis B after discontinuation of treatment

Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy including Telbivudine Taj Pharma (see section 4.4).

The incidence of post-treatment alanine aminotransferase (ALT) flares in the two treatment arms are further described in Table 4 below.

Table 4 Summary of post-treatment ALT flares – Pooled NV-02B-007 (GLOBE) and NV-02B-015 studies

LamivudineTelbivudine Taj Pharma
ALT flaren/N (%)n/N (%)
ALT elevation > 2x baseline and > 10x ULN10/180 (5.6)9/154 (5.8)

Results at 208 weeks

After 104 weeks of Telbivudine Taj Pharma therapy, 78% of patients (530/680) from study NV-02B-007 (GLOBE) and 82% (137/167) of patients from study NV-02B-015 enrolled into the extension study CLDT600A2303 (see section 5.1) to continue treatment for up to 208 weeks. The long-term safety population consisted of 655 patients including 518 from NV-02B-007 (GLOBE) and 137 from NV-02B-015. The overall safety profile from the pooled analysis up to 104 and 208 weeks was similar. Grade 3 or 4 CK elevations newly occurred in 15.9% of patients treated with Telbivudine Taj Pharma for 208 weeks. Most grade 3 or 4 CK elevations were asymptomatic and transient.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

  • Overdose

There is no information on intentional overdose of Telbivudine Taj Pharma, but one subject was given an unintentional overdose which was asymptomatic. Tested doses up to 1,800mg/day, three times greater than the recommended daily dose, have been well tolerated. A maximum tolerated dose of Telbivudine Taj Pharma has not been determined. In the event of an overdose, Telbivudine Taj Pharma should be discontinued and appropriate general supportive treatment applied as necessary.

  1. Pharmacological properties
  • Pharmacodynamic properties

Pharmacotherapeutic group: Antivirals for systemic use, nucleoside and nucleotide reverse transcriptase inhibitors,

Mechanism of action

Telbivudine Taj Pharma is a synthetic thymidine nucleoside analogue with activity against HBV DNA polymerase. It is efficiently phosphorylated by cellular kinases to the active triphosphate form, which has an intracellular half-life of 14 hours. Telbivudine Taj Pharma-5′-triphosphate inhibits HBV DNA polymerase (reverse transcriptase) by competing with the natural substrate, thymidine 5′-triphosphate. Incorporation of Telbivudine Taj Pharma-5′-triphosphate into viral DNA causes DNA chain termination, resulting in inhibition of HBV replication.

Pharmacodynamic effects

Telbivudine Taj Pharma is an inhibitor of both HBV first strand (EC50 = 0.4-1.3 μM) and second strand (EC50 = 0.12-0.24 μM) synthesis, and shows a distinct preference for inhibiting second strand production. By contrast, Telbivudine Taj Pharma-5′-triphosphate at concentrations up to 100 μM did not inhibit cellular DNA polymerases α, β, or γ. In assays relating to mitochondrial structure, function and DNA content, Telbivudine Taj Pharma lacked appreciable toxic effect at concentrations up to at 10 μM and did not increase lactic acid production in vitro.

The in vitro antiviral activity of Telbivudine Taj Pharma was assessed in the HBV-expressing human hepatoma cell line 2.2.15. The concentration of Telbivudine Taj Pharma that effectively inhibited 50% of viral synthesis (EC50) was approximately 0.2 μM. The antiviral activity of Telbivudine Taj Pharma is specific to the hepatitis B virus and related hepadnaviruses. Telbivudine Taj Pharma was not active against HIV in vitro. The absence of activity of Telbivudine Taj Pharma against HIV has not been evaluated in clinical trials. Transient reductions in HIV-1 RNA have been reported in a small number of patients after administration of Telbivudine Taj Pharma in the absence of antiretroviral therapy. The clinical significance of these reductions has not been determined.

Clinical experience

The safety and efficacy of long-term (104 weeks) Telbivudine Taj Pharma treatment were evaluated in two active-controlled clinical studies that included 1,699 patients with chronic hepatitis B (NV-02B-007 (GLOBE) and NV-02B-015).

Study NV-02B-007 (GLOBE)

The NV-02B-007 (GLOBE) study is a randomised, double-blind, multinational phase III study of Telbivudine Taj Pharma compared to lamivudine for a treatment period of 104 weeks in 1,367 nucleoside-naïve chronic hepatitis B HBeAg-positive and HBeAg-negative patients. The majority of the population enrolled was Asian. The most common HBV genotypes were B (26%) and C (51%). A small number (total of 98) of Caucasian patients were treated with Telbivudine Taj Pharma. The primary data analysis was conducted after all patients had reached week 52.

HBeAg-positive patients: The mean age of patients was 32 years, 74% were male, 82% were Asian, 12% were Caucasian, and 6% had previously received alfa-interferon therapy.

HBeAg-negative patients: The mean age of patients was 43 years, 79% were male, 65% were Asian, 23% were Caucasian, and 11% had previously received alfa-interferon therapy.

Clinical results at week 52

Clinical and virological efficacy endpoints were evaluated separately in the HBeAg-positive and HBeAg-negative patient populations. The primary endpoint of therapeutic response was a composite serological endpoint requiring suppression of HBV DNA to < 5 log10 copies/ml in conjunction with either loss of serum HBeAg or ALT normalised. Secondary endpoints included histological response, ALT normalisation, and various measures of antiviral efficacy.

Regardless of baseline characteristics, the majority of patients taking Telbivudine Taj Pharma showed histological, virological, biochemical, and serological responses to treatment. Baseline ALT levels > 2x ULN and baseline HBV DNA < 9 log10 copies/ml were associated with higher rates of HBeAg seroconversion in HBeAg-positive patients. Patients who achieve HBV DNA levels < 3 log10 copies/ml by week 24 had optimal responses to treatment; conversely patients with HBV DNA levels > 4 log10 copies/ml at 24 weeks had less favourable outcomes at week 52.

In HBeAg-positive patients, Telbivudine Taj Pharma was superior to lamivudine in therapeutic response (75.3% vs 67.0% responders; p = 0.0047). In HBeAg-negative patients, Telbivudine Taj Pharma was non-inferior to lamivudine (75.2% and 77.2% responders; p = 0.6187). Caucasian ethnicity was associated with lower treatment response to both antiviral agents used in the NV-02B-007 (GLOBE) study; however the Caucasian patient population was very limited (n = 98).

At week 24, 203 HBeAg-positive and 177 HBeAg-negative subjects achieved non-detectable HBV DNA levels. Of those HBeAg-positive subjects, 95% achieved non-detectable HBV DNA, 39% achieved HBeAg seroconversion, 90% achieved ALT normalisation at week 52 and 0.5% exhibited resistance at week 48. Similarly of those HBeAg-negative subjects, 96% achieved non-detectable HBV DNA, 79% achieved ALT normalisation at week 52 and 0% exhibited resistance at week 48.

Selected virological, biochemical and serological outcome measures are shown in Table 5 and histological response in Table 6.

Table 5 Virological, biochemical and serological endpoints at week 52 in NV-02B-007 (GLOBE) study

Response parameterHBeAg-positive (n = 921)HBeAg-negative (n = 446)
Telbivudine Taj Pharma 600mg

(n = 458)

Lamivudine 100mg

(n = 463)

Telbivudine Taj Pharma 600mg

(n = 222)

Lamivudine 100mg

(n = 224)

Mean HBV DNA reduction from baseline (log10 copies/ml) ± SEM1,2,3-6.45 (0.11) *-5.54 (0.11)-5.23 (0.13) *-4.40 (0.13)
% Patients HBV DNA undetectable by PCR60%*40%88%*71%
ALT normalisation477%75%74%79%
HBeAg seroconversion423%22%
HBeAg loss526%23%
1 SEM: Standard error of mean

2 Roche COBAS Amplicor PCR Assay (lower limit of quantification ≤ 300 copies/ml).

3 HBeAg-positive n = 443 and 444, HBeAg-negative n = 219 and 219, for both Telbivudine Taj Pharma and lamivudine groups, respectively. The difference in populations is due to patient discontinuation from the study and missing HBV DNA assessment at week 52.

4 HBeAg-positive n = 440 and 446, HBeAg-negative n = 203 and 207, for Telbivudine Taj Pharma and lamivudine groups, respectively. ALT normalisation assessed only in patients with ALT > ULN at baseline.

5 n = 432 and 442, for Telbivudine Taj Pharma and lamivudine groups, respectively. HBeAg seroconversion and loss assessed only in patients with detectable HBeAg at baseline.

*p < 0.0001

Table 6 Histological improvement and change in Ishak Fibrosis Score at week 52 in NV-02B-007 (GLOBE) study

HBeAg-positive (n = 921)HBeAg-negative (n = 446)
Telbivudine Taj Pharma 600mg

(n = 384)1

Lamivudine 100mg
(n = 386)1
Telbivudine Taj Pharma 600mg

(n = 199)1

Lamivudine 100mg
(n = 207)1
Histological response2
Improvement71%*61%71%70%
No improvement17%24%21%24%
Ishak Fibrosis Score3
Improvement42%47%49%45%
No change39%32%34%43%
Worsening8%7%9%5%
Missing week 52 biopsy12%15%9%7%
1 Patients with ≥ one dose of study drug with evaluable baseline liver biopsies and baseline Knodell Histological Activity Index (HAI) score > 3.

2 Histological response defined as a ≥ 2 point decrease in Knodell Necroinflammatory Score from baseline with no worsening of the Knodell Fibrosis Score.

3 For Ishak Fibrosis Score, improvement measured as ≥ 1 point reduction in Ishak Fibrosis Score from baseline to week 52.

*p = 0.0024

Clinical results at week 104

Overall, clinical results at week 104 in Telbivudine Taj Pharma-treated patients were consistent with those at week 52, demonstrating durability of efficacy responses for Telbivudine Taj Pharma-treated patients with continued treatment.

Among HBeAg-positive patients, therapeutic response (63% vs 48%; p < 0.0001) and key secondary endpoints (mean log10 HBV DNA reduction: -5.74 vs -4.42; p < 0.0001, HBV DNA undetectability: 56% vs 39%; p < 0.0001 and ALT normalisation of 70% vs 62%) demonstrated a widening difference at week 104 between Telbivudine Taj Pharma and lamivudine, respectively. A trend towards higher rates of HBeAg loss (35% vs 29%) and seroconversion (30% vs 25%) was also observed for Telbivudine Taj Pharma. Moreover, in the subgroup of patients with baseline ALT levels ≥ 2x ULN (320), a significantly higher proportion of Telbivudine Taj Pharma patients than lamivudine patients achieved HBeAg seroconversions at week 104 (36% vs 28%, respectively).

Among HBeAg-negative patients, differences in therapeutic response (78% vs 66%) and key secondary endpoints (mean log10 HBV DNA reduction: -5.00 vs -4.17, and HBV DNA undetectability: 82% vs 57%; p < 0.0001) were higher for Telbivudine Taj Pharma up to week 104. ALT normalisation rates (78% vs 70%) continued to be higher by week 104.

Predictability at week 24

At week 24, 203 HBeAg-positive (44%) and 177 HBeAg-negative (80%) Telbivudine Taj Pharma-treated subjects achieved undetectable HBV DNA levels.

For both HBeAg-positive and HBeAg-negative patients, week 24 HBV DNA results were a predictor of long-term favourable outcomes. Telbivudine Taj Pharma-treated patients who achieved undetectable HBV DNA by PCR by week 24 had the highest rates of HBV DNA undetectability and HBeAg seroconversion (in HBeAg-positive patients), and the lowest overall rates of virological breakthrough at week 104.

Outcome results at week 104, based on level of HBV DNA at week 24, for either HBeAg-positive or HBeAg-negative patients are presented in Table 7.

Table 7 Key efficacy endpoints at week 104 by serum HBV DNA levels at week 24, Telbivudine Taj Pharma-treated patients in NV-02B-007 (GLOBE) study

HBV DNA at week 24Outcome for key efficacy end points at 104 weeks based on week 24 results
Therapeutic response

n/N (%)

HBV DNA undetectability

n/N (%)

HBeAg seroconversion

n/N (%)

ALT normalisation

n/N (%)

Virological breakthrough*

n/N (%)

HBeAg-positive
< 300 copies/ml172/203 (85)166/203 (82)84/183 (46)160/194 (82)22/203 (11)
300 copies/ml to < 3 log10 copies/ml36/57 (63)35/57 (61)21/54 (39)40/54 (74)18/57 (32)
≥ 3 log10 copies/ml82/190 (43)54/190 (28)23/188 (12)106/184 (58)90/190 (47)
HBeAg-negative
< 300 copies/ml146/177 (82)156/177 (88)N/A131/159 (82)11/177 (6)
300 copies/ml to < 3 log10 copies/ml13/18 (72)14/18 (78)N/A13/17 (76)4/18 (22)
≥ 3 log10 copies/ml13/26 (50)12/26 (46)N/A14/26 (54)12/26 (46)

N/A = not applicable

* Virological breakthrough: “1 log above nadir” definition assessed at week 104

Study NV-02B-015

The efficacy and safety results of the NV-02B-007 (GLOBE) study were confirmed in study NV-02B-015. This study is a phase III, randomised, double-blind study of Telbivudine Taj Pharma 600mg once daily compared to lamivudine 100mg once daily for a treatment period of 104 weeks in 332 nucleoside-naïve chronic hepatitis B HBeAg-positive and HBeAg-negative Chinese patients.

Study CLDT600A2303 – Clinical results over 208 weeks

Study CLDT600A2303 was an open-label 104-week extension study in patients with compensated chronic hepatitis B who were previously treated with Telbivudine Taj Pharma for 2 years including patients from studies NV-02B-007 (GLOBE) and NV-02B-015, providing efficacy and safety data after 156 and 208 weeks of continuous Telbivudine Taj Pharma therapy. Patients with undetectable HBV DNA at week 24 had better outcomes at 156 and 208 weeks (Table 8).

Table 8 Efficacy analysis in pooled data from NV-02B-007 (GLOBE), NV-02B-015 and CLDT600A2303 studies

Week 52Week 104Week 156Week 208
HBeAg-positive patients (n = 293*)
Maintained undetectable HBV DNA (< 300 copies/ml)70.3%

(206/293)

77.3%

(218/282)

75.0%

(198/264)

76.2%

(163/214)

Maintained undetectable HBV DNA (< 300 copies/ml) with undetectable HBV DNA at week 2499.4%

(161/162)

94.9%

(150/158)

86.7%

(130/150)

87.9%

(109/124)

Cumulative HBeAg seroconversion rates (%)27.6%

(81/293)

41.6%

(122/293)

48.5%

(142/293)

53.2%

(156/293)

Cumulative HBeAg seroconversion rates in patients with undetectable HBV DNA at week 24 (%)40.1%

(65/162)

52.5%

(85/162)

59.3%

(96/162)

65.4%

(106/162)

Maintained ALT normalisation81.4%

(228/280)

87.5%

(237/271)

82.9%

(209/252)

86.4%

(178/106)

HBeAg-negative patients (n = 209*)
Maintained undetectable HBV DNA (< 300 copies/ml)95.2%

(199/209)

96.5%

(195/202)

84.7%

(160/189)

86.0%

(141/164)

Maintained undetectable HBV DNA (< 300 copies/ml) with undetectable HBV DNA at week 2497.8%

(175/179)

96.5%

(166/172)

86.7%

(143/165)

87.5%

(126/144)

Maintained ALT normalisation80.3%

(151/188)

89.0%

(161/181)

83.5%

(142/170)

89.6%

(129/144)

* The population without viral resistance at entry into study CLDT600A2303 consisted of 502 patients (293 HBeAg-positive and 209 HBeAg-negative).

Study CLDT600ACN04E1 – Impact of treatment on liver histology

In study CLDT600ACN04E1, 57 patients with available paired liver biopsies at baseline and after mean treatment of 260.8 weeks were evaluated for changes in liver histology (38 HBeAg-positive and 19 HBeAg-negative patients).

  • The mean Knodell necroinflammatory score of 7.6 (SD 2.9) at baseline improved (p < 0.0001) to 1.4 (SD 0.9) with a mean change of -6.3 (SD 2.8). Knodell necroinflammatory score ≤ 3 (no or minimal necroinflammation) was observed in 98.2% (56/57) of patients.
  • The mean Ishak score of 2.2 (SD 1.1) at baseline improved (p < 0.0001) to 0.9 (SD 1.0) with a mean change of -1.3 (SD 1.3). Ishak fibrosis score ≤ 1 (no or minimal fibrosis) was observed in 84.2% (48/57) of patients.

Changes in Knodell necroinflammatory and Ishak scores were similar for HBeAg-positive and HBeAg-negative patients.

CLDT600A2303 – Off-treatment durability of HBeAg responses

Study CLDT600A2303 included HBeAg-positive patients from studies NV-02B-007 (GLOBE) or NV-02B-015 for off-treatment follow up. These patients had completed ≥ 52 weeks of Telbivudine Taj Pharma treatment, and had exhibited HBeAg loss for ≥ 24 weeks with HBV DNA < 5 log10 copies/ml at the last on-treatment visit. The median treatment duration was 104 weeks. After a median off-treatment follow-up period of 120 weeks, the majority of HBeAg-positive Telbivudine Taj Pharma treated-patients showed sustained HBeAg loss (83.3%; 25/30), and sustained HBeAg seroconversion (79.2%; 19/24). Patients with sustained HBeAg seroconversion had a mean HBV DNA of 3.3 log10 copies/ml; and 73.7% had HBV DNA < 4 log10 copies/ml.

Clinical resistance

Genotypic resistance test was performed in study NV-02B-007 (GLOBE; n = 680) in patients with virological rebound (confirmed increase of ≥ 1 log10 copies/ml HBV DNA from nadir).

At week 48 among HBeAg-positive and HBeAg-negative patients, 5% (23/458) and 2% (5/222), respectively, had virological rebound with detectable HBV resistance mutations.

Studies NV-02B-007 (GLOBE) and CLDT600A2303 – cumulative genotypic resistance rates

The original analysis for cumulative genotypic resistance at week 104 and 208 was based on the ITT population and included all patients who continued treatment until 4 years, regardless of HBV DNA levels. Out of the 680 Telbivudine Taj Pharma-treated patients initially included in the pivotal study NV-02B-007 (GLOBE), 517 (76%) enrolled into study CLDT600A2303 for continued Telbivudine Taj Pharma treatment for up to 208 weeks. Out of these 517 patients 159 patients (HBeAg-positive=135, HBeAg-negative=24) had detectable HBV DNA.

The cumulative genotypic rates by week 104 were 25.1% (115/458) for HBeAg-positive patients and 10.8% (24/222) for HBeAg-negative patients.

In the overall ITT population the cumulative resistance rates at year 4 for HBeAg-positive and HBeAg-negative patients, was 40.8% (131/321) and 18.9% (37/196), respectively.

Cumulative genotypic resistance rates were also assessed by applying a mathematical model where only patients with undetectable HBV DNA at the beginning of the respective year are considered. Cumulative resistance rates at year 4 were 22.3% for HBeAg-positive patients and 16.0% for HBeAg-negative patients in this analysis.

When considering patients with viral breakthrough by 104 weeks in NV-02B-007 (GLOBE), the rate of resistance was lower in patients with HBV DNA < 300 copies/ml at week 24 than in patients with HBV DNA ≥ 300 copies/ml at week 24. In HBeAg-positive patients with HBV DNA < 300 copies/ml at week 24, resistance was 1% (3/203) at 48 weeks and 9% (18/203) at week 104, whilst in patients with HBV DNA ≥ 300 copies/ml resistance was 8% (20/247) at 48 weeks and 39% (97/247) at week 104. In HBeAg-negative patients with HBV DNA < 300 copies/ml at week 24, resistance was 0% (0/177) at 48 weeks and 5% (9/177) at week 104, whilst in patients with HBV DNA ≥ 300 copies/ml resistance was 11% (5/44) at 48 weeks and 34% (15/44) at week 104.

Genotypic mutation pattern and cross-resistance

Genotypic analysis of 203 evaluable sample pairs with HBV DNA ≥ 1,000 copies/ml at week 104 (NV-02B-007 (GLOBE)) demonstrated that the primary mutation associated with Telbivudine Taj Pharma resistance was rtM204I, often associated with mutations rtL180M and rtL80I/V and infrequently with rtV27A, rtL82M, rtV173L, rtT184I and rtA200V. Baseline factors associated with development of genotypic drug resistance included: lamivudine treatment, higher baseline HBV DNA, lower baseline serum ALT, and increased body weight/BMI. On-treatment response parameters at week 24 that predicted emergence of drug resistant virus by week 104 were HBV DNA > 300 copies/ml and elevation of serum ALT.

Genotypic analysis of 50 HBV isolates from Telbivudine Taj Pharma-treated patients at week 208 (CLDT600A2303) revealed a similar resistance profile as reported at week 104. Conversions at position 80, 180 and polymorphic positions 91, 229 were always detected in sequences that harboured the M204I mutation that confers genotypic resistance. These mutations most likely are compensatory mutations. One isolated rtM204V mutation and two rtM204I/V/M mutations were reported in Telbivudine Taj Pharma-treated patients experiencing viral breakthrough up to week 208. No novel mutation was reported.

Cross-resistance has been observed among HBV nucleoside analogues (see section 4.4). In cell-based assays, lamivudine-resistant HBV strains containing either the rtM204I mutation or the rtL180M/rtM204V double mutation had ≥ 1,000-fold reduced susceptibility to Telbivudine Taj Pharma. HBV encoding the adefovir resistance-associated substitutions rtN236T or rtA181V had around 0.3- and 4-fold change in susceptibility to Telbivudine Taj Pharma in cell culture, respectively (see section 4.4).

  • Pharmacokinetic properties

The single- and multiple-dose pharmacokinetics of Telbivudine Taj Pharma were evaluated in healthy subjects and in patients with chronic hepatitis B. The pharmacokinetics of Telbivudine Taj Pharma were not evaluated with the recommended dose of 600mg in patients with chronic hepatitis B. However Telbivudine Taj Pharma pharmacokinetics are similar between both populations.

Absorption

Following oral administration of a 600mg single dose of Telbivudine Taj Pharma to healthy subjects (n = 42), the peak plasma concentration (Cmax) of Telbivudine Taj Pharma was 3.2 ± 1.1 μg/ml (mean ± SD) and occurred at median 3.0 hours post dose. The Telbivudine Taj Pharma area under the plasma concentration-time curve (AUC0-∞) was 28.0 ± 8.5 μg•h/ml (mean ± SD). Inter-subject variability (CV%) for measures of systemic exposures (Cmax, AUC) was typically approximately 30%.

Effect of food on oral absorption

Telbivudine Taj Pharma absorption and exposure were unaffected when a single 600mg dose was administered with food.

Distribution

In vitro binding of Telbivudine Taj Pharma to human plasma proteins is low (3.3%).

Biotransformation

No metabolites of Telbivudine Taj Pharma were detected following administration of 14C-Telbivudine Taj Pharma in humans. Telbivudine Taj Pharma is not a substrate, inhibitor or inducer of the cytochrome P450 (CYP450) enzyme system.

Elimination

After reaching peak concentration, plasma disposition of Telbivudine Taj Pharma declined in a bi-exponential manner with a terminal elimination half-life (t1/2) of 41.8 ± 11.8 hours. Telbivudine Taj Pharma is eliminated primarily by urinary excretion of unchanged substance. The renal clearance of Telbivudine Taj Pharma approaches normal glomerular filtration rate, suggesting that filtration is the main mechanism of excretion. Approximately 42% of the dose is recovered in the urine over 7 days following a single 600mg oral dose of Telbivudine Taj Pharma. As renal excretion is the predominant route of elimination, patients with moderate to severe renal dysfunction and those undergoing haemodialysis require a dose interval adjustment (see section 4.2).

Linearity/non-linearity

Telbivudine Taj Pharma pharmacokinetics are dose proportional over the range of 25 to 1,800mg. Steady state was achieved after 5 to 7 days of once-daily administration with an approximate 1.5-fold accumulation in systemic exposure, suggesting an effective accumulation half-life of approximately 15 hours. Following once-daily administration of Telbivudine Taj Pharma 600mg, steady-state trough plasma concentrations were approximately 0.2-0.3 μg/ml.

Special populations

Gender

There are no significant gender-related differences in Telbivudine Taj Pharma pharmacokinetics.

Race

There are no significant race-related differences in Telbivudine Taj Pharma pharmacokinetics.

Paediatrics and elderly (65 years age and above)

Pharmacokinetic studies have not been conducted in paediatric or elderly subjects.

Renal impairment

The single-dose pharmacokinetics of Telbivudine Taj Pharma (200, 400 and 600mg) have been evaluated in patients (without chronic hepatitis B) with various degrees of renal impairment (as assessed by creatinine clearance). Based on the results shown in Table 9, adjustment of the dose interval for Telbivudine Taj Pharma is recommended in patients with creatinine clearance of < 50 ml/min (see sections 4.2 and 4.4).

Table 9 Pharmacokinetic parameters (mean ± SD) of Telbivudine Taj Pharma in subjects with various degrees of renal function

Renal function (creatinine clearance in ml/min)
Normal (> 80)

(n = 8)

600mg

Mild (50-80)

(n = 8)

600mg

Moderate (30-49)

(n = 8)

400mg

Severe (< 30)

(n = 6)

200mg

ESRD/ Haemodialysis

(n = 6)

200mg

Cmax (μg/ml)3.4 ± 0.93.2 ± 0.92.8 ± 1.31.6 ± 0.82.1 ± 0.9
AUC0-∞ (μg•h/ml)28.5 ± 9.632.5 ± 10.136.0 ± 13.232.5 ± 13.267.4 ± 36.9
CLRENAL (ml/min)126.7 ± 48.383.3 ± 20.043.3 ± 20.011.7 ± 6.7

Renally impaired patients on haemodialysis

Haemodialysis (up to 4 hours) reduces systemic Telbivudine Taj Pharma exposure by approximately 23%. Following dose interval adjustment for creatinine clearance, no additional dose modification is necessary during routine haemodialysis (see section 4.2). Telbivudine Taj Pharma should be administered after haemodialysis.

Hepatic impairment

The pharmacokinetics of Telbivudine Taj Pharma have been studied in patients (without chronic hepatitis B) with various degrees of hepatic impairment and in some patients with decompensated liver disease. There were no significant changes in Telbivudine Taj Pharma pharmacokinetics in hepatically impaired subjects compared to unimpaired subjects. Results of these studies indicate that no dosage adjustment is necessary for patients with hepatic impairment (see section 4.2).

  • Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity. Telbivudine Taj Pharma did not show any carcinogenic potential. No evidence of a direct toxic effect of Telbivudine Taj Pharma was seen in standard tests of reproduction toxicology. In rabbits doses of Telbivudine Taj Pharma providing exposure levels of 37 times those observed in humans at the therapeutic dose (600mg) were associated with an increased incidence of abortion and early delivery. This effect was considered to be secondary to maternal toxicity.

Fertility was assessed in conventional studies performed in adult rats, and as part of a juvenile toxicology study.

In adult rats, fertility was reduced when both male and female rats were treated with Telbivudine Taj Pharma at doses of 500 or 1000mg/kg/day (lower fertility index compared to concurrent controls). There were no abnormalities in sperm morphology or function, and the testes and ovaries were histologically unremarkable.

No evidence of impaired fertility was seen in other studies when either male or female rats were treated at doses up to 2000mg/kg/day and mated with untreated rats (systemic exposure levels approximately 6-14 times higher than those achieved in humans).

In the juvenile toxicology study, rats were treated from day 14 to day 70 post-partum and were mated with rats receiving the same treatment (no sibling mating). Fertility was reduced in pairs given ≥ 1000mg/kg/day as shown by decreases in fertility and mating indices, and reduced conception rate. However the ovarian and uterine parameters of those females mating successfully were unaffected.

The no observed adverse effect level (NOAEL) for effects on fertility or mating parameters amounted to 250mg/kg/day, which provided exposure levels 2.5 to 2.8 times higher than those achieved in humans with normal renal function at the therapeutic dose.

  1. Pharmaceutical particulars
  • List of excipients

Tablet core

Cellulose microcrystalline

Povidone

Sodium starch glycolate

Silica, colloidal anhydrous

Magnesium stearate

Tablet film coat

Titanium dioxide

Macrogol

Talc

Hypromellose

  • Incompatibilities

Not applicable.

  • Shelf life

3 years

  • Special precautions for storage

This medicinal product does not require any special storage conditions.

  • Nature and contents of container

PVC/aluminium blisters

Pack Size:

Telbivudine Taj Pharma film-coated tablets are supplied in packs of 5, 7, 14, 20, 28, 30, 40, 50, 56, 60, 98, 120, 240, 360 and 500 tablets.

Not all pack sizes may be marketed in your country.

  • Special precautions for disposal and other handling

No special requirements for disposal.

Manufactured in India by:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at: Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

Telbivudine Tablet 600mg Taj Pharma

Package leaflet: Information for the user

Telbivudine 600mg film-coated tablets Taj Pharma

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

  • Keep this leaflet. You may need to read it again.
  • If you have any further questions, ask your doctor or pharmacist.
  • This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
  • If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

  1. What Telbivudine Taj Pharma is and what it is used for
  2. What you need to know before you take Telbivudine Taj Pharma
  3. How to take Telbivudine Taj Pharma
  4. Possible side effects
  5. How to store Telbivudine Taj Pharma
  6. Contents of the pack and other information

1. What Telbivudine Taj Pharma is and what it is used for

Telbivudine Taj Pharma contains the active substance Telbivudine Taj Pharma. Telbivudine Taj Pharma belongs to a group of medicines called antiviral medicines, which are used to treat infections caused by viruses.

Telbivudine Taj Pharma is used to treat adults with chronic hepatitis B. Starting treatment with Telbivudine Taj Pharma should only be considered when it is not possible or appropriate to use an alternative medicine to which the hepatitis B virus is less likely to develop resistance. Your doctor will decide which treatment is most appropriate for you.

Hepatitis B is caused by infection with the hepatitis B virus, which multiplies in the liver and causes liver damage. Treatment with Telbivudine Taj Pharma reduces the amount of hepatitis B virus in the body by blocking its growth, resulting in less liver damage and improved liver function.

  1. What you need to know before you take Telbivudine Taj Pharma

Do not take Telbivudine Taj Pharma

  • if you are allergic to Telbivudine Taj Pharma or any of the other ingredients of this medicine (listed in section 6).
  • if you are being treated with pegylated or standard interferon alfa (see “Taking other medicines”).

If this applies to you, do not take Telbivudine Taj Pharma. Talk to your doctor.

Warnings and precautions

Talk to your doctor before taking Telbivudine Taj Pharma:

  • if you have or have had any kidney problems. Your doctor may order laboratory tests to check your kidneys are working properly before and during treatment. Depending on the results of these tests your doctor may advise you to change how often you take Telbivudine Taj Pharma.
  • if you suffer from cirrhosis of the liver (a serious condition which causes liver “scarring”). In this case your doctor will want to monitor you more closely.
  • if you have had a liver transplant.
  • if you are taking any medicines that may cause muscle problems (talk to your doctor or pharmacist if you are unsure).
  • if you are infected with HIV, hepatitis C or D, or are being treated with any antiviral medicines.

If any of these applies to you, tell your doctor before you take Telbivudine Taj Pharma.

During the treatment with Telbivudine Taj Pharma:

– Telbivudine Taj Pharma can cause persistent unexplained muscle weakness or muscle pain (myopathy). Muscle symptoms may progress and become serious, sometimes leading to muscle breakdown (rhabdomyolysis) which can cause kidney damage.

– Uncommonly Telbivudine Taj Pharma can induce numbness, tingling, pain and/or burning sensations in the arms and/or legs (peripheral neuropathy).

If you experience any of these symptoms during your treatment with Telbivudine Taj Pharma, call your doctor immediately.

Other side effects of this type of medicine

Telbivudine Taj Pharma can cause an excess of lactic acid in the blood (lactic acidosis) which is usually associated with an enlargement of the liver (hepatomegaly). Lactic acidosis is a rare but serious side effect which can occasionally be fatal. Your doctor will monitor you regularly while you are receiving Telbivudine Taj Pharma. If you experience muscle pain, severe and persistent stomach pain with nausea and vomiting, severe and persistent trouble breathing, tiredness or abdominal discomfort while taking Telbivudine Taj Pharma, call your doctor immediately.

Some people may get very serious hepatitis symptoms when they stop taking medicines like Telbivudine Taj Pharma.

Your doctor will monitor your health and do regular blood tests to check your liver after you stop treatment with Telbivudine Taj Pharma. Tell your doctor immediately about any new or unusual symptoms that you notice after stopping treatment (see “If you stop taking Telbivudine Taj Pharma” in section 3 of this leaflet).

Take care not to infect other people

Even if you take Telbivudine Taj Pharma, you may still infect others with hepatitis B virus (HBV) through sexual contact or exposure to contaminated blood or other body fluids. If you have sexual intercourse with a partner who is not immune against hepatitis B, always use condoms and avoid any other exchange of body fluids. Never share needles. Do not share personal items that could have blood or body fluids on them, such as toothbrushes or razor blades. A vaccine is available to prevent infection with HBV.

Children and adolescents

Telbivudine Taj Pharma is not recommended for use in children and adolescents.

Other medicines and Telbivudine Taj Pharma

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

Your doctor or pharmacist needs to know about other medicines because some medicines could affect your kidneys and because Telbivudine Taj Pharma mainly leaves the body via the kidneys in the urine.

Do not take Telbivudine Taj Pharma if you are using pegylated or standard interferon alfa (see “Do not take Telbivudine Taj Pharma”), because the combination of these medicines may increase your risk of developing peripheral neuropathy (numbness, tingling, and/or burning sensations in the arms and/or legs). Tell your doctor or pharmacist if you are being treated with interferon.

Pregnancy and breast-feeding

  • Do not use Telbivudine Taj Pharma during pregnancy unless your doctor recommends it. If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. Your doctor will discuss with you the potential risks of taking Telbivudine Taj Pharma during pregnancy.
  • If you have hepatitis B and become pregnant, talk to your doctor about how you can best protect your baby. Telbivudine Taj Pharma may reduce the risk of passing your hepatitis B virus on to your unborn baby if taken in combination with Hepatitis B immune globulin and Hepatitis B vaccine.
  • Do not breast-feed during treatment with Telbivudine Taj Pharma. Tell your doctor if you are breast-feeding.

Driving and using machines

Telbivudine Taj Pharma has minor influence on the ability to drive and use machines. If you feel dizzy while taking this medicine, do not drive a vehicle or use any tools or machines.

  1. How to take Telbivudine Taj Pharma

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

How much Telbivudine Taj Pharma to take

The recommended dose of Telbivudine Taj Pharma is one 600mg tablet once a day. Take the tablet at about the same time each day.

The tablet can be taken with or without food. Swallow it whole with some water. Do not chew, split or crush it.

You may need to take Telbivudine Taj Pharma less frequently if you have kidney problems. Tell your doctor if you have, or have ever had, any kidney problems.

How long to take Telbivudine Taj Pharma

Continue taking Telbivudine Taj Pharma every day for as long as your doctor tells you. Do not change your dose or stop taking Telbivudine Taj Pharma without talking to your doctor. This medicine is intended for long-term treatment, possibly lasting for months or years. Your doctor will regularly monitor your condition to check that the treatment is having the desired effect.

If you take more Telbivudine Taj Pharma than you should

If you have taken too much Telbivudine Taj Pharma, or if someone else accidentally takes your tablets, go to your doctor or hospital for advice straight away. Take the pack of tablets with you and show it to your doctor.

If you forget to take Telbivudine Taj Pharma

  • If you forget to take Telbivudine Taj Pharma, take it as soon as you remember and then take your next dose at its regular time.
  • However, if it is within 4 hours before your next dose, skip the dose you missed and take the next one at the usual time.

Do not take a double dose to make up for a forgotten tablet. This may increase the chance of you getting unwanted side effects. Ask your doctor or pharmacist if you are not sure what to do.

If you stop taking Telbivudine Taj Pharma

Stopping treatment with Telbivudine Taj Pharma may result in a worsening of your hepatitis B infection i.e. progression of the disease and abnormal test results (increase of viral load, ALT increase). Do not stop Telbivudine Taj Pharma unless your doctor tells you to. While you are taking Telbivudine Taj Pharma, make sure you do not run out of Telbivudine Taj Pharma.

Your doctor will monitor your health and do regular blood tests to check your liver after you stop treatment with Telbivudine Taj Pharma since your hepatitis B infection may get worse or become very serious after stopping treatment. Tell your doctor immediately about any new or unusual symptoms that you notice after stopping treatment.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

  1. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Some side effects could be serious:

  • Persistent muscle weakness or muscle pain
  • Numbness, tingling, pain and/or burning sensation in the arms and/or legs

If you experience any of these, call your doctor immediately.

Telbivudine Taj Pharma may also cause other side effects:

Common (may affect up to 1 in 10 people)

  • Dizziness, headache
  • Cough
  • Diarrhoea, feeling sick (nausea), stomach (abdominal) pain
  • Skin rash
  • Tiredness (fatigue)
  • Blood test results show higher levels of some liver enzymes (e.g. ALT, AST), amylase, lipase or creatine kinase

Uncommon (may affect up to 1 in 100 people)

  • Joint pain
  • Persistent muscle weakness or muscle pain (myopathy/myositis), muscle cramp
  • Back, neck and flank pain
  • Numbness, tingling, pain and/or burning sensation in the arms and/or legs or around the mouth
  • Pain in lower back or hip that may radiate into the leg (sciatica)
  • Taste disturbance
  • Feeling unwell (malaise)

Rare (may affect up to 1 in 1,000 people)

  • Excess of lactic acid in the blood (lactic acidosis)
  • Muscle breakdown (rhabdomyolysis)

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. By reporting side effects you can help provide more information on the safety of this medicine.

  1. How to store Telbivudine Taj Pharma

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton after EXP. The expiry date refers to the last day of that month. This medicinal product does not require any special storage conditions.

Do not use this medicine if the pack is damaged or shows signs of tampering.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help to protect the environment.

  1. Contents of the pack and other information

What Telbivudine Taj Pharma contains

  • The active substance is Telbivudine Taj Pharma. Each tablet contains 600mg Telbivudine Taj Pharma.
  • The other ingredients are: Cellulose, Microcrystalline; Povidone; Sodium Starch Glycolate; Silica, Colloidal Anhydrous; Magnesium Stearate; Hypromellose; Titanium Dioxide; Talc; Macrogol.

What Telbivudine Taj Pharma looks like and contents of the pack

Telbivudine Taj Pharma film-coated tablets are white to slightly yellowish, oval, film-coated tablets.

Pack Size:

Telbivudine Taj Pharma film-coated tablets are supplied in packs of 5, 7, 14, 20, 28, 30, 40, 50, 56, 60, 98, 120, 240, 360 and 500 tablets.

Not all pack sizes may be marketed in your country.

Manufactured in India by:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at: Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com