Novartis Pharmaceuticals UK Ltd

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 600 mg telbivudine.

For a the full list of excipients, see section 6.1.

4.1     Therapeutic indications

Sebivo 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 Sebivo 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.

4.2       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 Sebivo is 600 mg (one tablet) once daily, taken orally, with or without food.

Sebivo 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.

On-treatment response at week 24 has been shown to be predictive of longer-term response (see Table 7 in section 5.1) and might be useful for driving the management of patients treated with telbivudine monotherapy.

Paediatric population

The safety and efficacy of Sebivo in the paediatric population have not yet been established.

Elderly patients (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 is necessary in patients whose creatinine clearance is ³ 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 Sebivo oral solution, as detailed in Table 1 below, is recommended. If use of the oral solution is not possible, Sebivo 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 Sebivo in patients with renal impairment

* 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, Sebivo should be administered after haemodialysis (see section 5.2).

Hepatic impairment

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

Method of administration

Sebivo is to be taken orally, with or without food. Do not chew, split or crush the tablet.

Children and adolescents

The safety and efficacy of Sebivo in children aged 0 to 16 years have not yet been established. No data are available.Sebivo is not recommended for use in children and adolescents below 16 years of age due to a lack of data on safety and efficacy.

Elderly patients (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).

4.3     Contraindications

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

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

4.4     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. 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

Occurrences of lactic acidosis (in the absence of hypoxaemia) sometimes fatal, and usually associated with severe hepatomegaly with steatosis have been reported with the use of nucleoside/nucleotide analogues. As telbivudine is a nucleoside analogue, this risk cannot be excluded. Treatment with nucleoside analogues should be discontinued when rapidly elevating aminotransferase levels, progressive hepatomegaly or metabolic/lactic acidosis of unknown aetiology occur. Benign digestive symptoms, such as nausea, vomiting and abdominal pain, may be indicative of lactic acidosis development. Severe cases, sometimes with fatal outcome, were associated with pancreatitis, liver failure/hepatic steatosis, renal failure and higher levels of serum lactate. Caution should be exercised when prescribing nucleoside analogues to any patient (particularly obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease. These patients should be followed closely.

Muscular effects

Cases of myopathy and myalgia have been reported with telbivudine use several weeks to months after starting therapy (see section 4.8). Cases of rhabdomyolysis have been reported during post-marketing use of telbivudine (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 therapy should be discontinued if myopathy is diagnosed.

It is not known whether the risk of myopathy during treatment with telbivudine 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-treated patients. If peripheral neuropathy is suspected, treatment with telbivudine should be reconsidered (see section 4.8).

An increased risk of developing peripheral neuropathy has been observed in one study when telbivudine 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 with interferon alfa (pegylated or standard) is not currently established. Therefore, the combination of telbivudine with pegylated or standard interferon alfa is contraindicated (see section 4.3).

Renal function

Telbivudine 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 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 was not active against the HBV strains containing rtM204V/rtL180M or rtM204I mutations (see section 5.1). Telbivudine 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 monotherapy. There is currently no clinical data to properly assess the benefit and risk of switching to telbivudine for lamivudine-treated patients who achieve complete viral suppression on lamivudine.

There are no data on telbivudine 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.

Liver transplant recipients

The safety and efficacy of telbivudine in liver transplant recipients are unknown.

Elderly patients

Clinical studies of telbivudine did not include sufficient numbers of patients ³ 65 years of age to determine whether they respond differently from younger subjects. In general, caution must be exercised when prescribing Sebivo to elderly 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

Sebivo 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 Sebivo has not been shown to reduce the risk of transmission of HBV to others through sexual contact or blood contamination.

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

There are currently no efficacy and safety data for other antiviral combinations with telbivudine.

4.6     Fertility, pregnancy and lactation

Pregnancy

For telbivudine no clinical data on exposed pregnancies are available. 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 crosses the placenta. Studies in pregnant rabbits showed early delivery and/or abortion secondary to maternal toxicity. Sebivo should be used during pregnancy only if the benefit to the mother outweighs the potential risk to the foetus.

There are no data on the effect of telbivudine on transmission of HBV from mother to infant. Therefore, appropriate interventions should be used to prevent neonatal acquisition of HBV infection.

Breast-feeding

Telbivudine is excreted in the milk of rats. It is not known whether telbivudine is excreted in human milk. Women should not breast-feed if they are taking Sebivo.

Fertility

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

4.8       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 600 mg/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 events reactions with at least a possible relation to telbivudine 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

*        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 in clinical trials (n = 8,914).Based on post-marketing reports. Since these reports are from a population of uncertain size it is not possible to reliably estimate their frequency and therefore the frequency is classed as “not known”

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 Ggrade 3 or/4 creatine kinase  CK elevations (> 7x ULN) occurred in 12.6% of telbivudine-treated patients (n = 847) and 4.0% of lamivudine-treated patients (n = 846). Most CK creatine kinase elevations were asymptomatic and CKcreatine kinase values typically decreased by the next visit on continued treatment. In the pivotal study NV-02B-007 (GLOBE), higher pre-treatment CK values and Caucasian race were identified in both treatment groups as predictive factors for Grade 3/4 elevations by 104 weeks (see section 4.4).

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 (IU/L) flares – Pooled NV-02B-007 (GLOBE) and/ NV-02B-015 studies

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 (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

Results at 208 weeks

After 104 weeks of telbivudine 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 for 208 weeks. Most grade 3 or 4 CK elevations were asymptomatic and transient.

5.1     Pharmacodynamic properties

Pharmacotherapeutic group: Antivirals for systemic use, Nnucleoside and nucleotide reverse transcriptase inhibitors, ATC code: J05AF11

Telbivudine 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-5'-triphosphate inhibits HBV DNA polymerase (reverse transcriptase) by competing with the natural substrate, thymidine 5'-triphosphate. Incorporation of telbivudine-5'-triphosphate into viral DNA causes DNA chain termination, resulting in inhibition of HBV replication. Telbivudine is an inhibitor of both HBV first strand (EC₅₀ = 0.4‑1.3 mM) and second strand (EC₅₀ = 0.12‑0.24 mM) synthesis, and shows a distinct preference for inhibiting second strand production. By contrast, telbivudine-5'-triphosphate at concentrations up to 100 mM did not inhibit cellular DNA polymerases a, b, or g. In assays relating to mitochondrial structure, function and DNA content, telbivudine lacked appreciable toxic effect at concentrations up to at 10 mM and did not increase lactic acid production in vitro.

The in vitro antiviral activity of telbivudine was assessed in the HBV-expressing human hepatoma cell line 2.2.15. The concentration of telbivudine that effectively inhibited 50% of viral synthesis (EC₅₀) was approximately 0.2 mM. The antiviral activity of telbivudine is specific to the hepatitis B virus and related hepadnaviruses. Telbivudine was not active against HIV in vitro. The absence of activity of telbivudine against HIV has not been evaluated in clinical trials.

Clinical experience

The safety and efficacy of long-term (104 weeks) Sebivo 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) study

The NV-02B-007 (GLOBE) study is a randomised, double-blind, multinational phase III study of telbivudine 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. 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 Sebivo showed histological, virological, biochemical, and serological responses to treatment. Baseline ALT levels > 2 x 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 was superior to lamivudine in therapeutic response (75.3% vs 67.0% responders; p = 0.0047). In HBeAg-negative patients, telbivudine 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) trialstudy; 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)

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

Clinical results at week 104

Overall, clinical results at week 104 in telbivudine-treated patients were consistent with those at week 52, demonstrating durability of efficacy responses for telbivudine-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 undetectabilityPCR negativity: 56% vs 39%; p < 0.0001 and ALT normalisation of 70% vs 62%) demonstrated a widening difference at week 104 between telbivudine and lamivudine, respectively. A trend towards higher rates of HBeAg loss (35% vs 29%) and seroconversion (30% vs 25%) was also observed for telbivudine. Moreover, in the subgroup of patients with baseline ALT levels ≥ 2x ULN (320), a significantly higher proportion of telbivudine 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 undetectabilityPCR negativity: 82% vs 57%; p < 0.0001) were higher for telbivudine 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-treated subjects achieved undetectable non-detectable 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-treated patients who achieved PCR negativityundetectable HBV DNA by PCR by week 24 had the highest rates of HBV DNA undetectabilityPCR negativity 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-treated patients (in NV-02B-007 (GLOBE) study

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 600 mg once daily compared to lamivudine 100 mg 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 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 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

* 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 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 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.

Durability of HBeAg-seroconversion

Durability of HBeAg-seroconversion was assessed from pooled data from studies NV-02B-007 and NV-02B-015. The Kaplan-Meier estimates of the proportion of patients who maintained HBeAg seroconversion for at least 52 weeks following treatment discontinuation were 86.2% for telbivudine and 92.8% for lamivudine. Patients included in this analysis had completed ≥ 52 weeks of study drug treatment and exhibited HBeAg loss for ≥ 24 weeks, with HBV DNA < 5 log₁₀ copies/ml at the last visit, or, if they were HBeAg-negative at entry, completed ≥ 52 weeks of study drug treatment AND had HBsAg loss documented on ≥ 2 consecutive study visit

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-treated patients initially included in the pivotal study NV-02B-007 (GLOBE), 517 (76%) enrolled into study CLDT600A2303 for continued telbivudine treatment for up to 208 weeks. Out of these 517 patients 159 patients (HBeAg-positive=135, HBeAg-negative=24) had detectable HBV DNA.

Analysis of patients with virological rebound (confirmed increase of ≥ 1 log₁₀ copies/ml HBV DNA from nadir) in the pivotal study (NV-02B-007) at week 48 indicated that, among HBeAg-positive and HBeAg-negative patients, 5% (23/458) and 2% (5/222), of telbivudine recipients, respectively, had virological rebound with detectable HBV resistance mutations. The cumulative genotypic rates of genotypically confirmed telbivudine resistance by week 104 were 25.1% (115/458) for HBeAg-positive patients and 10.8% (24/222) for HBeAg-negative patients.

Out of the 680 telbivudine patients initially included in the pivotal study (NV-02B-007, 517 (76%) enrolled into study CLDT600A2303 for continued telbivudine treatment for up to 208 weeks.

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.

Among HBeAg-positive patients enrolled into study CLDT600A2303, the 3^rd and 4^th year resistance rate was 7.8% (25/321) and 5.9% (19/321), respectively. Similarly in all of the HBeAg-negative patients, the 3^rd and 4^th year resistance rate was 6.1% (12/196) and 4.1% (8/196), respectively.

Table 8       Cumulative virologic breakthrough and genetic resistance by HBeAg status in the GLOBE study and in study 2303 (year 1 to 4)

ITT = Intent to treat

The GLOBE ITT population included patients who were randomised in the 2-year GLOBE study, received at least one dose of study treatment and had at least one post-baseline HBV DNA assessment. The 2303 ITT population included GLOBE study patients who subsequently enrolled into study 2303 for continued telbivudine treatment and had at least one post-baseline HBV DNA assessment in study 2303.

Cumulative calculation: Two different denominators were used to calculate cumulative rates: 1) Using the 680 ITT patients in the GLOBE study 2) Using the number of GLOBE patients who continued into extension study 2303 - 517 ITT patients. The nominators included all patients who were identified with viral breakthrough/genotypic resistance over 4 years corresponding to each denominator above.

Patients included in study 2303 have detectable (n = 159, HBeAg-postive=135, HBeAg-negative=24) or undetectable HBV DNA (n = 358). From the 159 patients with detectable HBV DNA, 27 (HBeAg-positive=23, HBeAg-negative=4) patients developed new resistance mutations during 3^rd and 4^th year of telbivudine treatment.

Genotypic analysis of 203 evaluable sample pairs with HBV DNA ≥ 1,000 copies/ml at week 104 demonstrated that the primary mutation associated with telbivudine 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-treated patients at week 208 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-treated patients experiencing viral breakthrough up to week 208. No novel mutation was reported.

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 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-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-treated patients experiencing viral breakthrough up to week 208. No novel mutation was reported.

Cross-resistance

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. HBV encoding the adefovir resistance-associated substitutions rtN236T or rtA181V had around 0.3- and 4-fold change in susceptibility to telbivudine in cell culture, respectively (see section 4.4).

6.6     Special precautions for disposal

No special requirements for disposal.

9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 24 April .04.2007

Date of latest renewal: 20 April 2012

10.     DATE OF REVISION OF THE TEXT

20 April 2012

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu

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 600 mg/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 events with at least a possible relation to telbivudine were grade 3/4 blood creatine kinase elevations (6.8%), fatigue (4.4%), headache (3.0%) and nausea (2.6%).

Table 2 lists the adverse reactions according to MedDRArecorded in the pooled 104-week NV-02B-007 GLOBE and NV-02B-015 studies by system organ class and by 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       AClinical adverse reactions in patients with chronic hepatitis B, treated with telbivudine 600 mg in the pooled 104-week NV-02B-007 (GLOBE) and NV-02B-015 studies*

*        Based on post-marketing reports. Since these reports are from a population of uncertain size it is not possible to reliably estimate their frequency and therefore the frequency is classed as “not known”Due to the sample size of the pooled analysis (NV-02B-007 [GLOBE] and NV-02B-015), there are insufficient numbers of telbivudine-treated patients to detect rare and very rare events.

Creatine kinase

In the pooled analysis, by 104 weeks of treatment Grade 3/4 creatine kinase elevations (> 7x ULN) occurred in 12.6% of telbivudine-treated patients and 4.0% of lamivudine-treated patients. Most creatine kinase elevations were asymptomatic and creatine kinase values typically decreased by the next visit on continued treatment. In the pivotal study NV-02B-007 (GLOBE), higher pre-treatment CK values and Caucasian race were identified in both treatment groups as predictive factors for Grade 3/4 elevations by 104 weeks (see section 4.4).

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 (IU/L) flare – Pooled NV-02B-007/NV-02B-015

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 (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/NV-02B-015

Post-marketing experience

The following adverse drug reactions have been identified based on post-marketing spontaneous reports and are organised by body system organ classes. Since these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency and therefore the frequency is “not known”.

Metabolism and nutrition disorders

Cases of lactic acidosis as a secondary event often associated with serious conditions (e.g. multi-organ failure or sepsis) have been reported.

Musculoskeletal, connective tissue and bone disorders

Cases of rhabdomyolysis have been reported.

At week 24, 203 HBeAg-positive and 1778 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.

Out of the 680 telbivudine patients initially included in the pivotal study (NV-02B-007), 517 (76%) enrolled into study CLDT600A2303 for continued telbivudine treatment for up to 208 weeks. Among HBeAg-positive patients enrolled into study CLDT600A2303, the 3^rd and 4^th year resistance rate was 7.8% (25/321) and 5.9% (19/321), respectively. Similarly in the HBeAg-negative patients, the 3^rd and 4^th year resistance rate was 6.1% (12/196) and 4.1% (8/196), respectively.

Table 8       Cumulative virologic breakthrough and genetic resistance by HBeAg status in the GLOBE study and in study 2303 (year 1 to 4)

ITT = Intent to treat

The GLOBE ITT population included patients who were randomised in the 2-year GLOBE study, received at least one dose of study treatment and had at least one post-baseline HBV DNA assessment. The 2303 ITT population included GLOBE study patients who subsequently enrolled into study 2303 for continued telbivudine treatment and had at least one post-baseline HBV DNA assessment in study 2303.

Cumulative calculation: Two different denominators were used to calculate cumulative rates: 1) Using the 680 ITT patients in the GLOBE study 2) Using the number of GLOBE patients who continued into extension study 2303 - 517 ITT patients. The nominators included all patients who were identified with viral breakthrough/genotypic resistance over 4 years corresponding to each denominator above.

Patients included in study 2303 have detectable (n = 159, HBeAg-postive=135, HBeAg-negative=24) or undetectable HBV DNA (n = 358). From the 159 patients with detectable HBV DNA, 27 (HBeAg-positive=23, HBeAg-negative=4) patients developed new resistance mutations during 3^rd and 4^th year of telbivudine treatment.

Genotypic analysis of 203 evaluable sample pairs with HBV DNA ≥ 1,000 copies/ml at week 104 demonstrated that the primary mutation associated with telbivudine 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-treated patients at week 208 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-treated patients experiencing viral breakthrough up to week 208. No novel mutation was reported.

4.3     Contraindications

Hypersensitivity to the active substance or to any of the excipients.

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

4.4     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. 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.

Occurrence of lactic acidosis (in the absence of hypoxaemia) sometimes fatal, and usually associated with severe hepatomegaly with steatosis have been reported with the use of nucleoside/nucleotide analogues. As telbivudine is a nucleoside analogue, this risk cannot be excluded. Treatment with nucleoside analogues should be discontinued when rapidly elevating aminotransferase levels, progressive hepatomegaly or metabolic/lactic acidosis of unknown aetiology occur. Benign digestive symptoms, such as nausea, vomiting and abdominal pain, may be indicative of lactic acidosis development. Severe cases, sometimes with fatal outcome, were associated with pancreatitis, liver failure/hepatic steatosis, renal failure and higher levels of serum lactate. Caution should be exercised when prescribing nucleoside analogues to any patient (particularly obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease. These patients should be followed closely.

Muscular effects

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

Myopathy, defined as persistent unexplained muscle aches and/or muscle weakness regardless of the degree of increases in creatine kinase 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 therapy should be discontinued if myopathy is diagnosed.

It is not known whether the risk of myopathy during treatment with telbivudine 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-treated patients. If peripheral neuropathy is suspected, treatment with telbivudine should be reconsidered (see section 4.8).

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

Renal function

Telbivudine 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 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 efficacy and safety data in patients with decompensated cirrhosis.

Patients with previous exposure to nucleoside/nucleotide analogs

In vitro, telbivudine was not active against the HBV strains containing rtM204V/rtL180M or rtM204I mutations (see section 5.1). Telbivudine 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 monotherapy. There is currently no clinical data to properly assess the benefit and risk of switching to telbivudine for lamivudine-treated patients who achieve complete viral suppression on lamivudine.

There are no data on telbivudine treatment in patients with established adefovir-resistant hepatitis B virus single mutations of rtN236T or A181V. The preliminary rResults from the cell-based assays showed that the adefovir resistance-associated substitution A181V had 1.5- to approximately 4-3.7 fold reduced susceptibility to telbivudine.

Liver transplant recipients

The safety and efficacy of telbivudine in liver transplant recipients are unknown.

Elderly patients

Clinical studies of telbivudine did not include sufficient numbers of patients ³ 65 years of age to determine whether they respond differently from younger subjects. In general, caution must be exercised when prescribing Sebivo to elderly 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

Sebivo 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 Sebivo has not been shown to reduce the risk of transmission of HBV to others through sexual contact or blood contamination.

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

There are currently no efficacy and safety data for other antiviral combinations with telbivudine.

4.5     Interaction with other medicinal products and other forms of interaction

Since telbivudine is eliminated primarily by renal excretion, co-administration of Sebivo with substances that affect renal function (such as aminoglycosides, loop diuretics, platinum compounds, vancomycin, amphotericin B) may affect plasma concentrations of telbivudine and/or the co-administered substance. The combination of telbivudine with these medicinal products should be used with caution. The steady-state pharmacokinetics of telbivudine were unaltered following multiple dose administration in combination with lamivudine, adefovir dipivoxil, tenofovir disoproxil fumarate, ciclosporin or pegylated interferon alfa-2a. In addition, telbivudine 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 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, 600 mg 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 with any interferon alfa-containing product is contraindicated (see section 4.3).

Telbivudine 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 Sebivo is low.

4.6     Fertility, pPregnancy and lactation

For telbivudine no clinical data on exposed pregnancies are available. 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 crosses the placenta. Studies in pregnant rabbits showed early delivery and/or abortion secondary to maternal toxicity. Sebivo should be used during pregnancy only if the benefit to the mother outweighs the potential risk to the foetus.

There are no data on the effect of telbivudine on transmission of HBV from mother to infant. Therefore, appropriate interventions should be used to prevent neonatal acquisition of HBV infection.

Telbivudine is excreted in the milk of rats. It is not known whether telbivudine is excreted in human milk. Women should not breast-feed if they are taking Sebivo.

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

4.7     Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8       Undesirable effects

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 600 mg/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 events with at least a possible relation to telbivudine were grade 3/4 blood creatine kinase elevations (6.8%), fatigue (4.4%), headache (3.0%) and nausea (2.6%).

Table 2 lists the adverse reactions recorded in the pooled 104-week NV-02B-007 GLOBE and NV-02B-015 studies by system organ class and by 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       Clinical adverse reactions in patients with chronic hepatitis B, treated with telbivudine 600 mg in the pooled 104-week NV-02B-007 (GLOBE) and NV-02B-015 studies*

*        Due to the sample size of the pooled analysis (NV-02B-007 [GLOBE] and NV-02B-015), there are insufficient numbers of telbivudine-treated patients to detect rare and very rare events.

In the pooled analysis, by 104 weeks of treatment Grade 3/4 creatine kinase elevations (> 7x ULN) occurred in 12.6% of telbivudine-treated patients and 4.0% of lamivudine-treated patients. Most creatine kinase elevations were asymptomatic and creatine kinase values typically decreased by the next visit on continued treatment. In the pivotal study NV-02B-007 (GLOBE), higher pre-treatment CK values and Caucasian race were identified in both treatment groups as predictive factors for Grade 3/4 elevations by 104 weeks.

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 (IU/L) flare – Pooled NV-02B-007/NV-02B-015

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 (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/NV-02B-015

Post-marketing experience

The following adverse drug reactions have been identified based on post-marketing spontaneous reports and are organised by body system organ classes. Since these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency and therefore the frequency is “not known”.

Metabolism and nutrition disorders

Cases of lactic acidosis as a secondary event often associated with serious conditions (e.g. multi-organ failure or sepsis) have been reported.

Musculoskeletal, connective tissue and bone disorders

Cases of rhabdomyolysis have been reported.

4.9     Overdose

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

5.       PHARMACOLOGICAL PROPERTIES

5.1     Pharmacodynamic properties

Pharmacotherapeutic group: Nucleoside and nucleotide reverse transcriptase inhibitors, ATC code: J05AF11

Telbivudine 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-5'-triphosphate inhibits HBV DNA polymerase (reverse transcriptase) by competing with the natural substrate, thymidine 5'-triphosphate. Incorporation of telbivudine-5'-triphosphate into viral DNA causes DNA chain termination, resulting in inhibition of HBV replication. Telbivudine is an inhibitor of both HBV first strand (EC₅₀ = 0.4‑1.3 mM) and second strand (EC₅₀ = 0.12‑0.24 mM) synthesis, and shows a distinct preference for inhibiting second strand production. By contrast, telbivudine-5'-triphosphate at concentrations up to 100 mM did not inhibit cellular DNA polymerases a, b, or g. In assays relating to mitochondrial structure, function and DNA content, telbivudine lacked appreciable toxic effect at concentrations up to at 10 mM and did not increase lactic acid production in vitro.

The in vitro antiviral activity of telbivudine was assessed in the HBV-expressing human hepatoma cell line 2.2.15. The concentration of telbivudine that effectively inhibited 50% of viral synthesis (EC₅₀) was approximately 0.2 mM. The antiviral activity of telbivudine is specific to the hepatitis B virus and related hepadnaviruses. Telbivudine was not active against HIV in vitro. The absence of activity of telbivudine against HIV has not been evaluated in clinical trials.

Clinical experience

The safety and efficacy of long-term (104 weeks) Sebivo 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).

NV-02B-007 GLOBE study

The NV-02B-007 GLOBE study is a randomised, double-blind, multinational phase III study of telbivudine 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. 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 Sebivo showed histological, virological, biochemical, and serological responses to treatment. Baseline ALT levels > 2 x ULN and baseline HBV DNA < 9 log₁₀ copies/ml were associated with higher rates of eAg 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 was superior to lamivudine in therapeutic response (75.3% vs 67.0% responders; p = 0.0047). In HBeAg-negative patients, telbivudine 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 GLOBE trial; however the Caucasian patient population was very limited (n = 98).

At week 24, 203 HBeAg-positive and 178 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 (NV-02B-007 GLOBE study)

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

Clinical results at week 104

Overall, clinical results at week 104 in telbivudine-treated patients were consistent with those at week 52, demonstrating durability of efficacy responses for telbivudine-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, PCR negativity: 56% vs 39%; p < 0.0001 and ALT normalisation of 70% vs 62%) demonstrated a widening difference at week 104 between telbivudine and lamivudine, respectively. A trend towards higher rates of HBeAg loss (35% vs 29%) and seroconversion (30% vs 25%) was also observed for telbivudine. Moreover, in the subgroup of patients with baseline ALT levels ≥ 2x ULN (320), a significantly higher proportion of telbivudine 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 PCR negativity: 82% vs 57%; p < 0.0001) were higher for telbivudine 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-treated subjects achieved non-detectable HBV DNA levels.

For both HBeAg positive and negative patients, week 24 HBV DNA results were a predictor of long-term favourable outcomes. Telbivudine-treated patients who achieved PCR negativity by week 24 had the highest rates of PCR negativity 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 patients (NV-02B-007 GLOBE)