SEBIVO 600mg tablets medication leaflet

Sebivo 600 mg film-coated tablets

Each film-coated tablet contains 600 mg telbivudine.

For the full list of excipients, see section 6.1.

Film-coated tablet

White to slightly yellowish, oval film-coated tablet, imprinted with “LDT” on one side.

Sebivo is indicated for the treatment of chronic hepatitis B in adult patients with compensated liverdisease 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 agentwith 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 isbased.

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

The recommended dose of Sebivo is 600 mg (one tablet) once daily.

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 assurecomplete 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 positivefor 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 asfollows:

- In HBeAg-positive patients without cirrhosis, treatment should be administered for at least6-12 months after HBeAg seroconversion (HBeAg loss and HBV DNA loss with anti-HBedetection) 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 discontinuationto 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 treatmentfor more than 2 years, regular reassessment is recommended to confirm that continuation of theselected therapy remains appropriate for the patient.

If a dose is missed, the patient may take the missed dose only up to 4 hours prior to the next scheduleddose. 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).

No adjustment of the recommended dose of telbivudine is necessary in patients whose creatinineclearance 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 ofthe daily dose using Sebivo oral solution, as detailed in Table 1 below, is recommended. If use of theoral solution is not possible, Sebivo film-coated tablets could be used as an alternative and dosingshould 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

Creatinine clearance Telbivudine 20 mg/ml oral Telbivudine 600 mg film-coated(ml/min) solution tablet

Daily dose adjustment Alternative** dose adjustment withincreased dose intervals 50 600 mg (30 ml) once daily 600 mg once daily30-49 400 mg (20 ml) once daily 600 mg once every 48 hours< 30 (not requiring 200 mg (10 ml) once daily 600 mg once every 72 hoursdialysis)

ESRD* 120 mg (6 ml) once daily 600 mg 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 andeffectiveness 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).

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

The safety and efficacy of Sebivo in the paediatric population have not yet been established. No dataare available.

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

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).

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

Exacerbations of hepatitis have also been reported in patients who have terminated treatment ofhepatitis B. Post-treatment ALT flares are normally associated with increases in serum HBV DNAlevels, and the majority of such cases have proven to be self-limiting. Nonetheless, there have alsobeen 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-upfor at least 6 months after discontinuation of hepatitis B therapy.

Lactic acidosis

Rare post-marketing cases of lactic acidosis have been reported with telbivudine. Cases were moreoften secondary to other serious conditions (e.g. rhabdomyolysis) and/or associated withmuscle-related events (e.g. myopathy, myositis). When secondary to other conditions, some caseswere 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 shouldbe followed closely.

Treatment with telbivudine should be discontinued when metabolic/lactic acidosis of unknownaetiology occurs. Benign digestive symptoms, such as nausea, vomiting and abdominal pain, may beindicative of lactic acidosis development.

Muscular effects

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

Myopathy, defined as persistent unexplained muscle aches and/or muscle weakness regardless of thedegree of increases in creatine kinase (CK) levels, should be considered in any patient with diffuseunexplained myalgias, muscle tenderness, muscle weakness or myositis (defined as myopathy withhistological evidence of muscle damage). Patients should be advised to report promptly any persistentunexplained muscle aches, pain, tenderness or weakness. If any of these symptoms are reported, adetailed muscle examination should be performed in order to evaluate muscle function. Telbivudinetherapy should be discontinued if myopathy is diagnosed.

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

Peripheral neuropathy has been uncommonly reported in telbivudine-treated patients. If peripheralneuropathy 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 whentelbivudine and pegylated interferon alfa-2a were co-administered (see section 4.5). Such increasedrisk cannot be excluded for other interferon alfa (pegylated or standard). Moreover, the benefit of thecombination 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).

Telbivudine is eliminated primarily by renal excretion, therefore dose interval adjustment isrecommended 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 (seesections 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 beused with particular caution in cirrhotic patients. These patients should be closely monitored forclinical, biochemical and virological parameters associated with hepatitis B during treatment and aftertreatment 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 rtM204Imutations (see section 5.1). Telbivudine monotherapy is not an option for patients with establishedlamivudine-resistant hepatitis B virus infection. Patients who failed to achieve virological responsefollowing treatment with lamivudine for more than 24 weeks are unlikely to benefit from telbivudinemonotherapy. There is currently no clinical data to properly assess the benefit and risk of switching totelbivudine 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 Bvirus single mutations of rtN236T or A181V. Results from cell-based assays showed that the adefovirresistance-associated substitution A181V had 1.5- to approximately 4-fold reduced susceptibility totelbivudine.

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

Clinical studies of telbivudine did not include sufficient numbers of patients  65 years of age todetermine whether they respond differently from younger subjects. In general, caution must beexercised when prescribing Sebivo to older patients in view of the greater frequency of decreasedrenal function due to concomitant disease or concomitant use of other medicinal products.

Sebivo has not been investigated in co-infected hepatitis B patients (e.g. patients co-infected withhuman immunodeficiency virus [HIV], hepatitis C virus [HCV] or hepatitis D virus [HDV]).

Patients should be advised that treatment with Sebivo has not been shown to reduce the risk oftransmission 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 treatmentresponse observed with combination therapy of telbivudine and lamivudine was lower than withtelbivudine alone.

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

Since telbivudine is eliminated primarily by renal excretion, co-administration of Sebivo withsubstances 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 usedwith caution. The steady-state pharmacokinetics of telbivudine were unaltered following multiple doseadministration in combination with lamivudine, adefovir dipivoxil, tenofovir disoproxil fumarate,ciclosporin or pegylated interferon alfa-2a. In addition, telbivudine does not alter the pharmacokineticsof lamivudine, adefovir dipivoxil, tenofovir disoproxil fumarate or ciclosporin. No definitiveconclusion could be drawn regarding the effects of telbivudine on the pharmacokinetics of pegylatedinterferon due to high interindividual variability of pegylated interferon alfa-2a concentrations. Aclinical trial investigating the combination of telbivudine, 600 mg daily, with pegylated interferonalfa-2a, 180 micrograms once weekly by subcutaneous administration, indicates that this combinationis associated with an increased risk of developing peripheral neuropathy. The mechanism behind theseevents 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 islow.

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

Limited clinical data (less than 300 pregnancy outcomes) after exposure to telbivudine during the firsttrimester of pregnancy indicate no malformative toxicity and a large amount of data (more than 1000pregnancy outcomes) after exposure during the second and third trimesters indicate no foetal/neonataltoxicity.

Sebivo should be used during pregnancy only if the benefit to the mother outweighs the potential riskto the foetus.

Literature shows that exposure to telbivudine in the second and/or third trimester of pregnancy hasbeen shown to reduce the risk of HBV transmission from mother to infant if telbivudine is given inaddition to Hepatitis B immune globulin and Hepatitis B vaccine.

Telbivudine is excreted in the milk of rats. It is not known whether telbivudine is excreted in humanmilk. Women should not breastfeed if they are taking Sebivo.

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

Sebivo has minor influence on the ability to drive and use machines.

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 telbivudine600 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 ormoderate in severity. The most common adverse reactions were grade 3 or 4 blood creatine kinaseelevations (6.8%), fatigue (4.4%), headache (3.0%) and nausea (2.6%).

Table 2 lists the adverse reactions according to MedDRA system organ class and frequency using thefollowing 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 theavailable data). Within each frequency grouping, adverse reactions are presented in order ofdecreasing seriousness.

Table 2 Adverse reactions

Rare* Lactic acidosis

Common Dizziness, headache

Uncommon Peripheral neuropathy, dysgeusia, hypoaesthesia,paresthesia, sciatica

Respiratory, thoracic and mediastinaldisorders

Common Cough

Common Diarrhoea, blood lipase increased, nausea,abdominal pain

Common Rash

Musculoskeletal and connective tissuedisorders

Uncommon Myopathy/myositis, arthralgia, myalgia, pain inthe extremities, back pain, muscle spasm, neckpain, flank pain

Rare* Rhabdomyolysis

General disorders and administration siteconditions

Common Fatigue

Uncommon Malaise

Common Blood creatine phosphokinase increased, bloodalanine aminotransferase increased, bloodamylase increased

Uncommon Aspartate aminotransferase increased

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

Creatine kinase elevation

In the pooled analysis from NV-02B-007 (GLOBE) and NV-02B-015, by 104 weeks of treatmentgrade 3 or4 CK elevations (> 7x ULN) occurred in 12.6% of telbivudine-treated patients (n = 847) and4.0% of lamivudine-treated patients (n = 846). Most CK elevations were asymptomatic and CK valuestypically decreased by the next visit on continued treatment.

ALT flares

The incidence of on treatment alanine aminotransferase (ALT) flares in the two treatment armsaccording to AASLD (American Association for the Study of Liver Diseases) definition (ALTelevation > 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: Lamivudine Telbivudine

ALT elevation > 2x baseline and n/N (%) n/N (%)> 10x ULN

Overall 67/852 (7.9) 41/847 (4.8)

Baseline to week 24 25/852 (2.9) 25/847 (3.0)

Week 24 to end of study 44/837 (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 (see section 4.4).

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

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

Lamivudine Telbivudine

ALT flare n/N (%) n/N (%)

ALT elevation > 2x baseline and > 10x ULN 10/180 (5.6) 9/154 (5.8)

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 safetypopulation 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 for208 weeks. Most grade 3 or 4 CK elevations were asymptomatic and transient.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

Pharmacotherapeutic group: Antivirals for systemic use, nucleoside and nucleotide reversetranscriptase inhibitors, ATC code: J05AF11

Telbivudine is a synthetic thymidine nucleoside analogue with activity against HBV DNApolymerase. It is efficiently phosphorylated by cellular kinases to the active triphosphate form, whichhas 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, resultingin inhibition of HBV replication.

Telbivudine is an inhibitor of both HBV first strand (EC50 = 0.4-1.3 M) and second strand(EC50 = 0.12-0.24 M) synthesis, and shows a distinct preference for inhibiting second strandproduction. By contrast, telbivudine-5'-triphosphate at concentrations up to 100 M did not inhibitcellular DNA polymerases , , or . In assays relating to mitochondrial structure, function and DNAcontent, telbivudine lacked appreciable toxic effect at concentrations up to at 10 M and did notincrease lactic acid production in vitro.

The in vitro antiviral activity of telbivudine was assessed in the HBV-expressing human hepatoma cellline 2.2.15. The concentration of telbivudine that effectively inhibited 50% of viral synthesis (EC50)was approximately 0.2 M. The antiviral activity of telbivudine is specific to the hepatitis B virus andrelated hepadnaviruses. Telbivudine was not active against HIV in vitro. The absence of activity oftelbivudine against HIV has not been evaluated in clinical trials. Transient reductions in HIV-1 RNAhave been reported in a small number of patients after administration of telbivudine in the absence ofantiretroviral therapy. The clinical significance of these reductions has not been determined.

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)

The NV-02B-007 (GLOBE) study is a randomised, double-blind, multinational phase III study oftelbivudine compared to lamivudine for a treatment period of 104 weeks in 1,367 nucleoside-naïvechronic hepatitis B HBeAg-positive and HBeAg-negative patients. The majority of the populationenrolled 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 wasconducted 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 compositeserological endpoint requiring suppression of HBV DNA to < 5 log10 copies/ml in conjunction witheither 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 > 2x ULN andbaseline 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 hadoptimal responses to treatment; conversely patients with HBV DNA levels > 4 log10 copies/ml at24 weeks had less favourable outcomes at week 52.

In HBeAg-positive patients, telbivudine was superior to lamivudine in therapeutic response (75.3% vs67.0% responders; p = 0.0047). In HBeAg-negative patients, telbivudine was non-inferior tolamivudine (75.2% and 77.2% responders; p = 0.6187). Caucasian ethnicity was associated with lowertreatment 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% exhibitedresistance 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 andhistological response in Table 6.

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

HBeAg-positive (n = 921) HBeAg-negative (n = 446)

Response parameter Telbivudine Lamivudine Telbivudine Lamivudine600 mg 100 mg 600 mg 100 mg(n = 458) (n = 463) (n = 222) (n = 224)

Mean HBV DNA -6.45 (0.11) * -5.54 (0.11) -5.23 (0.13) * -4.40 (0.13)reduction frombaseline (log101,2,3copies/ml) ± SEM% Patients HBV 60%* 40% 88%* 71%

DNA undetectable by

PCR

ALT normalisation 77% 75% 74% 79%

HBeAg 23% 22% - -seroconversion

HBeAg loss 26% 23% - -

SEM: Standard error of mean2 ®

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

HBeAg-positive n = 443 and 444, HBeAg-negative n = 219 and 219, for both telbivudine andlamivudine groups, respectively. The difference in populations is due to patient discontinuation fromthe study and missing HBV DNA assessment at week 52.

HBeAg-positive n = 440 and 446, HBeAg-negative n = 203 and 207, for telbivudine and lamivudinegroups, respectively. ALT normalisation assessed only in patients with ALT > ULN at baseline.n = 432 and 442, for telbivudine and lamivudine groups, respectively. HBeAg seroconversion andloss 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 Lamivudine Telbivudine Lamivudine600 mg 100 mg 600 mg 100 mg1 1 1 1(n = 384) (n = 386) (n = 199) (n = 207)

Histological response

Improvement 71%* 61% 71% 70%

No improvement 17% 24% 21% 24%

Ishak Fibrosis Score

Improvement 42% 47% 49% 45%

No change 39% 32% 34% 43%

Worsening 8% 7% 9% 5%

Missing week 52 biopsy 12% 15% 9% 7%

Patients with ≥ one dose of study drug with evaluable baseline liver biopsies and baseline

Knodell Histological Activity Index (HAI) score > 3.

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

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

*p = 0.0024

Clinical results at week 104

Overall, clinical results at week 104 in telbivudine-treated patients were consistent with those atweek 52, demonstrating durability of efficacy responses for telbivudine-treated patients with continuedtreatment.

Among HBeAg-positive patients, therapeutic response (63% vs 48%; p < 0.0001) and key secondaryendpoints (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 differenceat week 104 between telbivudine and lamivudine, respectively. A trend towards higher rates of HBeAgloss (35% vs 29%) and seroconversion (30% vs 25%) was also observed for telbivudine. Moreover, inthe subgroup of patients with baseline ALT levels ≥ 2x ULN (320), a significantly higher proportionof 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 keysecondary 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 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 subjectsachieved undetectable HBV DNA levels.

For both HBeAg-positive and HBeAg-negative patients, week 24 HBV DNA results were a predictorof long-term favourable outcomes. Telbivudine-treated patients who achieved undetectable HBV

DNA by PCR by week 24 had the highest rates of HBV DNA undetectability and HBeAgseroconversion (in HBeAg-positive patients), and the lowest overall rates of virological breakthroughat 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

Outcome for key efficacy end points at 104 weeks based on week 24 results

Therapeutic HBV DNA HBeAg ALT Virological

HBV DNA atresponse undetectability seroconversion normalisation breakthrough*week 24n/N (%) n/N (%) n/N (%) n/N (%) n/N (%)

HBeAg-positive< 300 copies/ml 172/203 (85) 166/203 (82) 84/183 (46) 160/194 (82) 22/203 (11)300 copies/ml to 36/57 (63) 35/57 (61) 21/54 (39) 40/54 (74) 18/57 (32)< 3 log10 copies/ml≥ 3 log10 copies/ml 82/190 (43) 54/190 (28) 23/188 (12) 106/184 (58) 90/190 (47)

HBeAg-negative< 300 copies/ml 146/177 (82) 156/177 (88) N/A 131/159 (82) 11/177 (6)300 copies/ml to 13/18 (72) 14/18 (78) N/A 13/17 (76) 4/18 (22)< 3 log10 copies/ml≥ 3 log10 copies/ml 13/26 (50) 12/26 (46) N/A 14/26 (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 600 mg once dailycompared 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 compensatedchronic hepatitis B who were previously treated with telbivudine for 2 years including patients fromstudies NV-02B-007 (GLOBE) and NV-02B-015, providing efficacy and safety data after 156 and208 weeks of continuous telbivudine therapy. Patients with undetectable HBV DNA at week 24 hadbetter 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 52 Week 104 Week 156 Week 208

HBeAg-positive patients (n = 293*)

Maintained undetectable HBV DNA 70.3% 77.3% 75.0% 76.2%(< 300 copies/ml) (206/293) (218/282) (198/264) (163/214)

Maintained undetectable HBV DNA 99.4% 94.9% 86.7% 87.9%(< 300 copies/ml) with undetectable (161/162) (150/158) (130/150) (109/124)

HBV DNA at week 24

Cumulative HBeAg seroconversion 27.6% 41.6% 48.5% 53.2%rates (%) (81/293) (122/293) (142/293) (156/293)

Cumulative HBeAg seroconversion 40.1% 52.5% 59.3% 65.4%rates in patients with undetectable HBV (65/162) (85/162) (96/162) (106/162)

DNA at week 24 (%)

Maintained ALT normalisation 81.4% 87.5% 82.9% 86.4%(228/280) (237/271) (209/252) (178/106)

HBeAg-negative patients (n = 209*)

Maintained undetectable HBV DNA 95.2% 96.5% 84.7% 86.0%(< 300 copies/ml) (199/209) (195/202) (160/189) (141/164)

Maintained undetectable HBV DNA 97.8% 96.5% 86.7% 87.5%(< 300 copies/ml) with undetectable (175/179) (166/172) (143/165) (126/144)

HBV DNA at week 24

Maintained ALT normalisation 80.3% 89.0% 83.5% 89.6%(151/188) (161/181) (142/170) (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 aftermean treatment of 260.8 weeks were evaluated for changes in liver histology (38 HBeAg-positive and19 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 (noor 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 amean change of -1.3 (SD 1.3). Ishak fibrosis score ≤ 1 (no or minimal fibrosis) was observed in84.2% (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 telbivudinetreatment, and had exhibited HBeAg loss for ≥ 24 weeks with HBV DNA < 5 log10 copies/ml at thelast on-treatment visit. The median treatment duration was 104 weeks. After a median off-treatmentfollow-up period of 120 weeks, the majority of HBeAg-positive telbivudine treated-patients showedsustained HBeAg loss (83.3%; 25/30), and sustained HBeAg seroconversion (79.2%; 19/24). Patientswith 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 withvirological 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 ITTpopulation and included all patients who continued treatment until 4 years, regardless of HBV DNAlevels. 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 upto 208 weeks. Out of these 517 patients 159 patients (HBeAg-positive=135, HBeAg-negative=24) haddetectable HBV DNA.

The cumulative genotypic rates by week 104 were 25.1% (115/458) for HBeAg-positive patients and10.8% (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 whereonly 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 rateof 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/mlat week 24, resistance was 1% (3/203) at 48 weeks and 9% (18/203) at week 104, whilst in patientswith HBV DNA ≥ 300 copies/ml resistance was 8% (20/247) at 48 weeks and 39% (97/247) atweek 104. In HBeAg-negative patients with HBV DNA < 300 copies/ml at week 24, resistance was0% (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 telbivudineresistance was rtM204I, often associated with mutations rtL180M and rtL80I/V and infrequently withrtV27A, rtL82M, rtV173L, rtT184I and rtA200V. Baseline factors associated with development ofgenotypic drug resistance included: lamivudine treatment, higher baseline HBV DNA, lower baselineserum ALT, and increased body weight/BMI. On-treatment response parameters at week 24 thatpredicted emergence of drug resistant virus by week 104 were HBV DNA > 300 copies/ml andelevation 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 atposition 80, 180 and polymorphic positions 91, 229 were always detected in sequences that harbouredthe M204I mutation that confers genotypic resistance. These mutations most likely are compensatorymutations. One isolated rtM204V mutation and two rtM204I/V/M mutations were reported intelbivudine-treated patients experiencing viral breakthrough up to week 208. No novel mutation wasreported.

Cross-resistance has been observed among HBV nucleoside analogues (see section 4.4). In cell-basedassays, lamivudine-resistant HBV strains containing either the rtM204I mutation or thertL180M/rtM204V double mutation had ≥ 1,000-fold reduced susceptibility to telbivudine. HBVencoding 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).

The single- and multiple-dose pharmacokinetics of telbivudine were evaluated in healthy subjects andin patients with chronic hepatitis B. The pharmacokinetics of telbivudine were not evaluated with therecommended dose of 600 mg in patients with chronic hepatitis B. However telbivudinepharmacokinetics are similar between both populations.

Following oral administration of a 600 mg single dose of telbivudine to healthy subjects (n = 42), thepeak plasma concentration (Cmax) of telbivudine was 3.2  1.1 g/ml (mean  SD) and occurred atmedian 3.0 hours post dose. The telbivudine area under the plasma concentration-time curve (AUC0-∞)was 28.0  8.5 gh/ml (mean  SD). Inter-subject variability (CV%) for measures of systemicexposures (Cmax, AUC) was typically approximately 30%.

Telbivudine absorption and exposure were unaffected when a single 600 mg dose was administeredwith food.

In vitro binding of telbivudine to human plasma proteins is low (3.3%).

No metabolites of telbivudine were detected following administration of C-telbivudine in humans.

Telbivudine is not a substrate, inhibitor or inducer of the cytochrome P450 (CYP450) enzyme system.

After reaching peak concentration, plasma disposition of telbivudine declined in a bi-exponentialmanner with a terminal elimination half-life (t1/2) of 41.8 ± 11.8 hours. Telbivudine is eliminatedprimarily by urinary excretion of unchanged substance. The renal clearance of telbivudine approachesnormal 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 600 mg oraldose of telbivudine. As renal excretion is the predominant route of elimination, patients with moderateto severe renal dysfunction and those undergoing haemodialysis require a dose interval adjustment(see section 4.2).

Telbivudine pharmacokinetics are dose proportional over the range of 25 to 1,800 mg. Steady statewas achieved after 5 to 7 days of once-daily administration with an approximate 1.5-fold accumulationin systemic exposure, suggesting an effective accumulation half-life of approximately 15 hours.

Following once-daily administration of telbivudine 600 mg, steady-state trough plasma concentrationswere approximately 0.2-0.3 g/ml.

There are no significant gender-related differences in telbivudine pharmacokinetics.

There are no significant race-related differences in telbivudine pharmacokinetics.

Paediatrics and elderly (65 years age and above)

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

The single-dose pharmacokinetics of telbivudine (200, 400 and 600 mg) have been evaluated inpatients (without chronic hepatitis B) with various degrees of renal impairment (as assessed bycreatinine clearance). Based on the results shown in Table 9, adjustment of the dose interval fortelbivudine is recommended in patients with creatinine clearance of  50 ml/min (see sections 4.2 and4.4).

Table 9 Pharmacokinetic parameters (mean  SD) of telbivudine in subjects with variousdegrees of renal function

Renal function (creatinine clearance in ml/min)

Normal Mild (50-80) Moderate Severe (< 30) ESRD/(> 80) (n = 8) (30-49) (n = 6) Haemodialysis(n = 8) 600 mg (n = 8) 200 mg (n = 6)600 mg 400 mg 200 mg

Cmax (g/ml) 3.4 ± 0.9 3.2 ± 0.9 2.8 ± 1.3 1.6 ± 0.8 2.1 ± 0.9

AUC0-∞ 28.5 ± 9.6 32.5 ± 10.1 36.0 ± 13.2 32.5 ± 13.2 67.4 ± 36.9(g*h/ml)

CLRENAL 126.7 ± 48.3 83.3 ± 20.0 43.3 ± 20.0 11.7 ± 6.7 -(ml/min)

Renally impaired patients on haemodialysis

Haemodialysis (up to 4 hours) reduces systemic telbivudine exposure by approximately 23%.

Following dose interval adjustment for creatinine clearance, no additional dose modification isnecessary during routine haemodialysis (see section 4.2). Telbivudine should be administered afterhaemodialysis.

The pharmacokinetics of telbivudine have been studied in patients (without chronic hepatitis B) withvarious degrees of hepatic impairment and in some patients with decompensated liver disease. Therewere no significant changes in telbivudine pharmacokinetics in hepatically impaired subjectscompared to unimpaired subjects. Results of these studies indicate that no dosage adjustment isnecessary for patients with hepatic impairment (see section 4.2).

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity and genotoxicity. Telbivudine did not show any carcinogenicpotential. No evidence of a direct toxic effect of telbivudine was seen in standard tests of reproductiontoxicology. In rabbits doses of telbivudine providing exposure levels of 37 times those observed inhumans at the therapeutic dose (600 mg) were associated with an increased incidence of abortion andearly 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 juveniletoxicology study.

In adult rats, fertility was reduced when both male and female rats were treated with telbivudine atdoses of 500 or 1000 mg/kg/day (lower fertility index compared to concurrent controls). There wereno abnormalities in sperm morphology or function, and the testes and ovaries were histologicallyunremarkable.

No evidence of impaired fertility was seen in other studies when either male or female rats weretreated at doses up to 2000 mg/kg/day and mated with untreated rats (systemic exposure levelsapproximately 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 matedwith rats receiving the same treatment (no sibling mating). Fertility was reduced in pairs given≥ 1000 mg/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 amountedto 250 mg/kg/day, which provided exposure levels 2.5 to 2.8 times higher than those achieved inhumans with normal renal function at the therapeutic dose.

Cellulose microcrystalline

Povidone

Sodium starch glycolate

Silica, colloidal anhydrous

Magnesium stearate

Titanium dioxide (E171)

Macrogol

Talc

Hypromellose

Not applicable.

3 years

This medicinal product does not require any special storage conditions.

PVC/aluminium blisters

Pack sizes: 28 or 98 film-coated tablets

Not all pack sizes may be marketed.

No special requirements for disposal.

Novartis Europharm Limited

Frimley Business Park

Camberley GU16 7SR

United Kingdom

EU/1/07/388/001

EU/1/07/388/002

Date of first authorisation: 24 April 2007

Date of latest renewal: 16 December 2016

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu