Sebivo

1.

NAME OF THE MEDICINAL PRODUCT

Sebivo 600 mg film-coated tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 600 mg telbivudine.

For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Film-coated tablet

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

4.

CLINICAL PARTICULARS

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. 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.

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.

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 HBe seroconversion (HBeAg loss and HBV DNA loss with anti-HBe

detection) is confirmed or until HBs 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

HBs 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.

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Renal impairment

No adjustment of the recommended dose of telbivudine is necessary in patients whose creatinine

clearance is  50 ml/min. Adjustment of the dose is required in patients with creatinine clearance

< 50 ml/min, including those with end-stage renal disease (ESRD) on haemodialysis. A reduction of

the daily dose using 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

Creatinine clearance

(ml/min)

Telbivudine 20 mg/ml oral

solution

Daily dose adjustment

Telbivudine 600 mg film-coated

tablet

Alternative** dose adjustment with

increased dose intervals

 50

600 mg (30 ml) once daily

600 mg once daily

30-49

400 mg (20 ml) once daily

600 mg once every 48 hours

< 30 (not requiring

dialysis)

200 mg (10 ml) once daily

600 mg once every 72 hours

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 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).

Children and adolescents

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.

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

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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 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).

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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. 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  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

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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, pregnancy 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%).

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Table 2 lists the adverse reactions according to MedDRA system organ class and frequency using the

following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to

<1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from

the available data). Within each frequency grouping, adverse reactions are presented in order of

decreasing seriousness.

Table 2

Adverse reactions

Metabolism and nutrition disorders

Not known*

Lactic acidosis as a secondary event often

associated with serious conditions (e.g. multi-

organ failure or sepsis)

Nervous system disorders

Common

Dizziness, headache

Uncommon

Peripheral neuropathy, dysgeusia, hypoaesthesia,

paresthesia, sciatica

Respiratory, thoracic and mediastinal

disorders

Common

Cough

Gastrointestinal disorders

Common

Blood amylase increased, diarrhoea, blood lipase

increased, nausea, abdominal pain

Hepatobiliary disorders

Common

Blood alanine aminotransferase increased

Uncommon

Aspartate aminotransferase increased

Skin and subcutaneous tissue disorders

Common

Rash

Musculoskeletal and connective tissue

disorders

Common

Blood creatine phosphokinase increased

Uncommon

Arthralgia, myalgia, myopathy/myositis, pain in

the extremities, back pain, muscle spasm, neck

pain, flank pain

Not known*

Rhabdomyolysis

General disorders and administration site

conditions

Common

Fatigue

Uncommon

Malaise

*

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”.

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).

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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

ALT flare:

ALT elevation > 2x baseline and

> 10x ULN

Lamivudine

n/N (%)

Telbivudine

n/N (%)

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 are

further described in Table 4 below.

Table 4

Summary of post-treatment ALT flares – Pooled NV-02B-007/NV-02B-015

Lamivudine

Telbivudine

ALT flare

n/N (%)

ALT elevation > 2x baseline and > 10x ULN

10/180 (5.6)

9/154 (5.8)

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

(EC 50 = 0.4-1.3 M) and second strand (EC 50 = 0.12-0.24 M) synthesis, and shows a distinct

preference for inhibiting second strand production. By contrast, telbivudine-5'-triphosphate at

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concentrations up to 100 M did not inhibit cellular DNA polymerases , , or . In assays relating to

mitochondrial structure, function and DNA content, telbivudine lacked appreciable toxic effect at

concentrations up to at 10 M 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 (EC 50 )

was approximately 0.2 M. 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 log 10 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 log 10 copies/ml were associated with higher rates of eAg seroconversion in

HBeAg-positive patients. Patients who achieve HBV DNA levels < 3 log 10 copies/ml by week 24 had

optimal responses to treatment; conversely patients with HBV DNA levels > 4 log 10 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 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.

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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)

HBeAg-positive (n = 921)

HBeAg-negative (n = 446)

Response parameter

Telbivudine

600 mg

(n = 458)

Lamivudine

100 mg

(n = 463)

Telbivudine

600 mg

(n = 222)

Lamivudine

100 mg

(n = 224)

Mean HBV DNA

reduction from

baseline (log 10

copies/ml) ± SEM 1,2,3

-6.45 (0.11) *

-5.54 (0.11)

-5.23 (0.13) *

-4.40 (0.13)

% Patients HBV

DNA negative by

PCR

60%*

40%

88%*

71%

ALT normalisation 4

77%

75%

74%

79%

HBeAg

seroconversion 4

23%

22%

-

HBeAg loss 5

26%

23%

-

1 SEM: Standard error of mean

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

3 HBeAg-positive n = 443 and 444, HBeAg-negative n = 219 and 219, for both telbivudine and

lamivudine groups, respectively. The difference in populations is due to patient discontinuation from

the study and missing HBV DNA assessment at week 52.

4 HBeAg-positive n = 440 and 446, HBeAg-negative n = 203 and 207, for telbivudine and lamivudine

groups, respectively. ALT normalisation assessed only in patients with ALT > ULN at baseline.

5 n = 432 and 442, for telbivudine and lamivudine groups, respectively. HBeAg seroconversion and

loss assessed only in patients with detectable HBeAg at baseline.

*p < 0.0001

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

007 GLOBE study)

HBeAg-positive (n = 921)

HBeAg-negative (n = 446)

Telbivudine

600 mg

(n = 384) 1

Lamivudine

100 mg

(n = 386) 1

Telbivudine

600 mg

(n = 199) 1

Lamivudine

100 mg

(n = 207) 1

Histological response 2

Improvement

71%*

61%

71%

70%

No improvement

17%

24%

21%

24%

Ishak Fibrosis Score 3

Improvement 42% 47% 49% 45%

No change 39% 32% 34% 43%

Worsening 8% 7% 9% 5%

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

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

Knodell Histological Activity Index (HAI) score > 3.

2 Histological response defined as a ≥ 2 point decrease in Knodell Necroinflammatory Score from

baseline with no worsening of the Knodell Fibrosis Score.

3 For Ishak Fibrosis Score, improvement measured as ≥ 1 point reduction in Ishak Fibrosis Score

from baseline to week 52.

*p = 0.0024

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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 log 10 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 log 10 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)

HBV DNA at

week 24

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

Therapeutic

response

n/N (%)

PCR-negative

HBV DNA

n/N (%)

HBeAg

seroconversion

n/N (%)

ALT

normalisation

n/N (%)

Virological

breakthrough*

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

< 3 log 10 copies/ml

36/57 (63)

35/57 (61)

21/54 (39)

40/54 (74)

18/57 (32)

≥ 3 log 10 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

< 3 log 10 copies/ml

13/18 (72)

14/18 (78)

N/A

13/17 (76)

4/18 (22)

≥ 3 log 10 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

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Study NV-02B-015

The efficacy and safety results of the 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.

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 log 10 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 visits.

Clinical resistance

Analysis of patients with virological rebound (confirmed increase of ≥ 1 log 10 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 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. 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)

GLOBE study patients - ITT

(n = 680)

Study 2303 patients - ITT

(n = 517)

HBeAg

status

Virologic

breakthrough

% (n)

Genotypic

resistance

% (n)

HBeAg

status

Virologic

breakthrough

% (n)

Genotypic

resistance

% (n)

Positive

(n = 458)

41.0 (188)

34.7 (159) Positive

(n = 321)

47.4 (152)

40.8 (131)

Negative

(n = 222)

26.1 (58)

19.8 (44)

Negative

(n = 196)

25.5 (50)

18.9 (37)

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.

12

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, 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.

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).

5.2 Pharmacokinetic properties

The single- and multiple-dose pharmacokinetics of telbivudine were evaluated in healthy subjects and

in patients with chronic hepatitis B. The pharmacokinetics of telbivudine were not evaluated with the

recommended dose of 600 mg in patients with chronic hepatitis B. However telbivudine

pharmacokinetics are similar between both populations.

Absorption

Following oral administration of a 600 mg single dose of telbivudine to healthy subjects (n = 42), the

peak plasma concentration (C max ) of telbivudine was 3.2  1.1 g/ml (mean  SD) and occurred at

median 3.0 hours post dose. The telbivudine area under the plasma concentration-time curve (AUC 0-∞ )

was 28.0  8.5 g  h/ml (mean  SD). Inter-subject variability (CV%) for measures of systemic

exposures (C max , AUC) was typically approximately 30%.

Effect of food on oral absorption

Telbivudine absorption and exposure were unaffected when a single 600 mg dose was administered

with food.

Distribution

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

13

Biotransformation

No metabolites of telbivudine were detected following administration of 14 C-telbivudine in humans.

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

Elimination

After reaching peak concentration, plasma disposition of telbivudine declined in an bi-exponential

manner with a terminal elimination half-life (t 1/2 ) of 41.8 ± 11.8 hours. Telbivudine is eliminated

primarily by urinary excretion of unchanged substance. The renal clearance of telbivudine approaches

normal glomerular filtration rate, suggesting that filtration is the main mechanism of excretion.

Approximately 42% of the dose is recovered in the urine over 7 days following a single 600 mg oral

dose of telbivudine. As renal excretion is the predominant route of elimination, patients with moderate

to severe renal dysfunction and those undergoing haemodialysis require a dose interval adjustment

(see section 4.2).

Linearity / non-linearity

Telbivudine pharmacokinetics are dose proportional over the range of 25 to 1,800 mg. Steady state

was achieved after 5 to 7 days of once-daily administration with an approximate 1.5-fold accumulation

in systemic exposure, suggesting an effective accumulation half-life of approximately 15 hours.

Following once-daily administration of telbivudine 600 mg, steady-state trough plasma concentrations

were approximately 0.2-0.3 g/ml.

Special populations

Gender

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

Race

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

Paediatrics and geriatrics

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

Renal impairment

The single-dose pharmacokinetics of telbivudine (200, 400 and 600 mg) have been evaluated in

patients (without chronic hepatitis B) with various degrees of renal impairment (as assessed by

creatinine clearance). Based on the results shown in Table 9, adjustment of the dose interval for

telbivudine is recommended in patients with creatinine clearance of  50 ml/min (see sections 4.2 and

4.4).

Table 9 Pharmacokinetic parameters (mean  SD) of telbivudine in subjects with various

degrees of renal function

Renal function (creatinine clearance in ml/min)

Normal

(> 80)

(n = 8)

600 mg

Mild (50-80)

(n = 8)

600 mg

Moderate

(30-49)

(n = 8)

400 mg

Severe (< 30)

(n = 6)

200 mg

ESRD/

Haemodialysis

(n = 6)

200 mg

C max (g/ml)

3.4 ± 0.9

3.2 ± 0.9

2.8 ± 1.3

1.6 ± 0.8

2.1 ± 0.9

AUC 0-∞

(g•h/ml)

28.5 ± 9.6

32.5 ± 10.1

36.0 ± 13.2

32.5 ± 13.2

67.4 ± 36.9

CL RENAL

(ml/min)

126.7 ± 48.3

83.3 ± 20.0

43.3 ± 20.0

11.7 ± 6.7

-

14

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 is

necessary during routine haemodialysis (see section 4.2). Telbivudine should be administered after

haemodialysis.

Hepatic impairment

The pharmacokinetics of telbivudine have been studied in patients (without chronic hepatitis B) with

various degrees of hepatic impairment and in some patients with decompensated liver disease. There

were no significant changes in telbivudine pharmacokinetics in hepatically impaired subjects

compared to unimpaired subjects. Results of these studies indicate that no dosage adjustment is

necessary for patients with hepatic impairment (see section 4.2).

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety

pharmacology, repeated dose toxicity and genotoxicity. Telbivudine did not show any carcinogenic

potential. No evidence of a direct toxic effect of telbivudine was seen in standard tests of reproduction

toxicology. In rabbits doses of telbivudine providing exposure levels of 37 times those observed in

humans at the therapeutic dose (600 mg) were associated with an increased incidence of abortion and

early delivery. This effect was considered to be secondary to maternal toxicity.

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

toxicology study.

In adult rats, fertility was reduced when both male and female rats were treated with telbivudine at

doses of 500 or 1000 mg/kg/day (lower fertility index compared to concurrent controls). There were

no abnormalities in sperm morphology or function, and the testes and ovaries were histologically

unremarkable.

No evidence of impaired fertility was seen in other studies when either male or female rats were

treated at doses up to 2000 mg/kg/day and mated with untreated rats (systemic exposure levels

approximately 6-14 times higher than those achieved in humans).

In the juvenile toxicology study, rats were treated from day 14 to day 70 post-partum and were mated

with rats receiving the same treatment (no sibling mating). Fertility was reduced in pairs given

≥ 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 amounted

to 250 mg/kg/day, which provided exposure levels 2.5 to 2.8 times higher than those achieved in

humans with normal renal function at the therapeutic dose.

6.

PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core

Cellulose microcrystalline

Povidone

Sodium starch glycolate

Silica, colloidal anhydrous

Magnesium stearate

15

Tablet film coat

Titanium dioxide (E171)

Macrogol

Talc

Hypromellose

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

PVC/aluminium blisters

Pack sizes: 28 or 98 film-coated tablets

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7.

MARKETING AUTHORISATION HOLDER

Novartis Europharm Limited

Wimblehurst Road

Horsham

West Sussex, RH12 5AB

United Kingdom

8.

MARKETING AUTHORISATION NUMBER(S)

EU/1/07/388/001

EU/1/07/388/002

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

24.04.2007

10. DATE OF REVISION OF THE TEXT

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

http://www.ema.europa.eu

16

1.

NAME OF THE MEDICINAL PRODUCT

Sebivo 20 mg/ml oral solution

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

One ml contains 20 mg telbivudine.

Excipient: A 600 mg dose (30 ml) of oral solution contains approximately 47 mg sodium.

For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Oral solution

Clear, colourless to pale yellow solution.

4.

CLINICAL PARTICULARS

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. 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.

Adults

The recommended dose of Sebivo is 30 ml, providing a dose equivalent to 600 mg, once daily, taken

orally, with or without food.

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 HBe seroconversion (HBeAg loss and HBV DNA loss with anti-HBe

detection) is confirmed or until HBs 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

HBs 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.

17

Renal impairment

No adjustment of the recommended dose of telbivudine is necessary in patients whose creatinine

clearance is  50 ml/min. Adjustment of the dose is required in patients with creatinine clearance

< 50 ml/min, including those with end-stage renal disease (ESRD) on haemodialysis. A reduction of

the daily dose using 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

Creatinine clearance

(ml/min)

Telbivudine 20 mg/ml oral

solution

Daily dose adjustment

Telbivudine 600 mg film-coated tablet

Alternative** dose adjustment with

increased dose intervals

 50

600 mg (30 ml) once daily

600 mg once daily

30-49

400 mg (20 ml) once daily

600 mg once every 48 hours

< 30 (not requiring

dialysis)

200 mg (10 ml) once daily

600 mg once every 72 hours

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 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).

Children and adolescents

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.

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

18