Sebivo

1 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 



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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 the 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. 

 

Initiation of Sebivo treatment should only be considered when the use of an alternative antiviral agent 

with a higher genetic barrier to resistance is not available or appropriate. 
 

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

based. 

 

4.2 Posology and method of administration 

 

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

infection. 

 

Posology 

 

Adults 

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

 

Sebivo oral solution may be considered for patients who have difficulties swallowing tablets. 

 

Monitoring during treatment 

On-treatment response at week 24 has been shown to be predictive of longer-term response (see 

Table 7 in section 5.1). HBV DNA levels should be monitored at 24 weeks of treatment to assure 

complete viral suppression (HBV DNA less than 300 copies/ml). For patients with detectable HBV 

DNA after 24 weeks of therapy, treatment modification should be considered. 

 

HBV DNA should be monitored every 6 months to assure continued response. If patients test positive 

for HBV DNA at any time after their initial response, treatment modification should be considered. 

Optimal therapy should be guided by resistance testing. 



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Duration of therapy 

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

follows: 

 In HBeAg-positive patients without cirrhosis, treatment should be administered for at least 
6-12 months after HBeAg seroconversion (HBeAg loss and HBV DNA loss with anti-HBe 

detection) is confirmed or until HBsAg seroconversion or there is evidence of loss of efficacy. 

Serum ALT and HBV DNA levels should be followed regularly after treatment discontinuation 

to detect any late virological relapse. 

 In HBeAg-negative patients without cirrhosis, treatment should be administered at least until 
HBsAg seroconversion or until there is evidence of loss of efficacy. With prolonged treatment 

for more than 2 years, regular reassessment is recommended to confirm that continuation of the 

selected therapy remains appropriate for the patient. 

 

Missed doses 

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

dose. The next dose should be taken at the usual time. 

 

Elderly (age above 65 years) 

No data are available to support a specific dose recommendation for patients over the age of 65 years 

(see section 4.4). 

 

Renal impairment 

No adjustment of the recommended dose of telbivudine 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). 



4 

 

Paediatric population 

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

are available. 

 

Method of administration 

 

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

 
4.3 Contraindications 
 

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

 

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

 

4.4 Special warnings and precautions for use 
 

Severe acute exacerbations of chronic hepatitis B are relatively frequent, and are characterised by 

transient elevation of serum ALT. Following initiation of antiviral treatment, serum ALT may rise in 

some patients while serum levels of HBV DNA fall (see section 4.8). On average, 4-5 weeks elapsed 

prior to the occurrence of an exacerbation in patients treated with telbivudine. Overall, ALT flares 

occurred more frequently in HBeAg-positive patients than in HBeAg-negative patients. In patients 

with compensated liver disease, this elevation of serum ALT is generally not accompanied by elevated 

levels of serum bilirubin or by other signs of hepatic decompensation. The risk of hepatic 

decompensation – and of a subsequent exacerbation of hepatitis – may be elevated in patients with 

cirrhosis. Such patients should, therefore, be closely monitored. 

 

Exacerbations of hepatitis have also been reported in patients who have terminated treatment of 

hepatitis B. Post-treatment ALT flares are normally associated with increases in serum HBV DNA 

levels, and the majority of such cases have proven to be self-limiting. Nonetheless, there have also 

been reports of severe – and sometimes fatal – post-treatment disease exacerbations. Therefore, 

hepatic function should be monitored at regular intervals with both clinical and laboratory follow-up 

for at least 6 months after discontinuation of hepatitis B therapy. 

 

Lactic acidosis 

 

Rare post-marketing cases of lactic acidosis have been reported with telbivudine. Cases were more 

often secondary to other serious conditions (e.g. rhabdomyolysis) and/or associated with 

muscle-related events (e.g. myopathy, myositis). When secondary to other conditions, some cases 

were also associated with pancreatitis, liver failure/hepatic steatosis and renal failure. In some cases, 

fatal outcomes were reported when lactic acidosis was secondary to rhabdomyolysis. Patients should 

be followed closely. 

 

Treatment with telbivudine should be discontinued when metabolic/lactic acidosis of unknown 

aetiology occurs. Benign digestive symptoms, such as nausea, vomiting and abdominal pain, may be 

indicative of lactic acidosis development. 

 

Muscular effects 

 

Cases of myopathy and myalgia have been reported with telbivudine 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). 

 



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Myopathy, defined as persistent unexplained muscle aches and/or muscle weakness regardless of the 

degree of increases in creatine kinase (CK) levels, should be considered in any patient with diffuse 

unexplained myalgias, muscle tenderness, muscle weakness or myositis (defined as myopathy with 

histological evidence of muscle damage). Patients should be advised to report promptly any persistent 

unexplained muscle aches, pain, tenderness or weakness. If any of these symptoms are reported, a 

detailed muscle examination should be performed in order to evaluate muscle function. Telbivudine 

therapy should be discontinued if myopathy is diagnosed. 

 

It is not known whether the risk of myopathy during treatment with telbivudine is increased with 

concurrent administration of other medicinal products associated with myopathy (e.g. statins, fibrates, 

or ciclosporin). Physicians considering concomitant treatment with other agents associated with 

myopathy should weigh carefully the potential benefits and risks and should monitor patients for any 

signs or symptoms suggestive of myopathy. 

 

Peripheral neuropathy 

 

Peripheral neuropathy has been uncommonly reported in telbivudine-treated patients. If peripheral 

neuropathy is suspected, treatment with telbivudine should be reconsidered (see section 4.8). 

 

An increased risk of developing peripheral neuropathy has been observed in one study when 

telbivudine and pegylated interferon alfa-2a were co-administered (see section 4.5). Such increased 

risk cannot be excluded for other interferon alfa (pegylated or standard). Moreover, the benefit of the 

combination of telbivudine with interferon alfa (pegylated or standard) is not currently established. 

Therefore, the combination of telbivudine with pegylated or standard interferon alfa is contraindicated 

(see section 4.3). 

 

Renal function 

 

Telbivudine is eliminated primarily by renal excretion, therefore dose interval adjustment is 

recommended in patients with creatinine clearance < 50 ml/min, including patients on haemodialysis. 

The effectiveness of dosing interval adjustment has not been clinically evaluated. Therefore, 

virological response should be closely monitored in patients with increased dosage interval (see 

sections 4.2 and 5.2). 

 

Patients with cirrhosis without decompensation 

 

Due to the limited data available (about 3% of patients enrolled had cirrhosis), telbivudine should be 

used with particular caution in cirrhotic patients. These patients should be closely monitored for 

clinical, biochemical and virological parameters associated with hepatitis B during treatment and after 

treatment is discontinued. 

 

Patients with cirrhosis with decompensation 

 

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

 

Patients with previous exposure to nucleoside/nucleotide analogues 

 

In vitro, telbivudine was not active against the HBV strains containing rtM204V/rtL180M or rtM204I 

mutations (see section 5.1). Telbivudine monotherapy is not an option for patients with established 

lamivudine-resistant hepatitis B virus infection. Patients who failed to achieve virological response 

following treatment with lamivudine for more than 24 weeks are unlikely to benefit from telbivudine 

monotherapy. There is currently no clinical data to properly assess the benefit and risk of switching to 

telbivudine for lamivudine-treated patients who achieve complete viral suppression on lamivudine. 

 



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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 

 

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 older patients in view of the greater frequency of decreased 

renal function due to concomitant disease or concomitant use of other medicinal products. 

 

Other special populations 

 

Sebivo has not been investigated in co-infected hepatitis B patients (e.g. patients co-infected with 

human immunodeficiency virus [HIV], hepatitis C virus [HCV] or hepatitis D virus [HDV]). 

 

General 

 

Patients should be advised that treatment with Sebivo has not been shown to reduce the risk of 

transmission of HBV to others through sexual contact or blood contamination. 

 

Telbivudine is not recommended to be used with lamivudine because in a phase II study, the treatment 

response observed with combination therapy of telbivudine and lamivudine was lower than with 

telbivudine alone. 

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

 

4.5 Interaction with other medicinal products and other forms of interaction 
 

Since telbivudine is eliminated primarily by renal excretion, co-administration of Sebivo with 

substances that affect renal function (such as aminoglycosides, loop diuretics, platinum compounds, 

vancomycin, amphotericin B) may affect plasma concentrations of telbivudine and/or the co-

administered substance. The combination of telbivudine with these medicinal products should be used 

with caution. The steady-state pharmacokinetics of telbivudine were unaltered following multiple dose 

administration in combination with lamivudine, adefovir dipivoxil, tenofovir disoproxil fumarate, 

ciclosporin or pegylated interferon alfa-2a. In addition, telbivudine does not alter the pharmacokinetics 

of lamivudine, adefovir dipivoxil, tenofovir disoproxil fumarate or ciclosporin. No definitive 

conclusion could be drawn regarding the effects of telbivudine on the pharmacokinetics of pegylated 

interferon due to high interindividual variability of pegylated interferon alfa-2a concentrations. A 

clinical trial investigating the combination of telbivudine, 600 mg daily, with pegylated interferon 

alfa-2a, 180 micrograms once weekly by subcutaneous administration, indicates that this combination 

is associated with an increased risk of developing peripheral neuropathy. The mechanism behind these 

events is not known (see section 4.4). The combination of telbivudine with any interferon alfa-

containing product is contraindicated (see section 4.3). 

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

(see section 5.2). Therefore, the potential for CYP450-mediated drug interactions involving Sebivo is 

low. 



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4.6 Fertility, pregnancy and lactation 
 

Pregnancy 

 

Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal 

development, parturition or postnatal development (see section 5.3). Studies in pregnant rats and 

rabbits showed that telbivudine crosses the placenta. Studies in pregnant rabbits showed early delivery 

and/or abortion secondary to maternal toxicity. 

 

Limited clinical data (less than 300 pregnancy outcomes) after exposure to telbivudine during the first 

trimester of pregnancy indicate no malformative toxicity and a large amount of data (more than 1000 

pregnancy outcomes) after exposure during the second and third trimesters indicate no foetal/neonatal 

toxicity. 

 

Sebivo should be used during pregnancy only if the benefit to the mother outweighs the potential risk 

to the foetus. 

 

Literature shows that exposure to telbivudine in the second and/or third trimester of pregnancy has 

been shown to reduce the risk of HBV transmission from mother to infant if telbivudine is given in 

addition to Hepatitis B immune globulin and Hepatitis B vaccine. 

 

Breast-feeding 

 

Telbivudine is excreted in the milk of rats. It is not known whether telbivudine is excreted in human 

milk. Women should not breastfeed if they are taking Sebivo. 

 

Fertility 

 

There are no clinical data on the effects of telbivudine on male or female fertility. In reproductive 

toxicology studies in adult animals, fertility was slightly reduced when both male and female rats 

received telbivudine. The adverse effects on fertility were greater in a separate study in juvenile 

animals when both sexes received telbivudine (see section 5.3). 

 

4.7 Effects on ability to drive and use machines 

 

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

 

4.8 Undesirable effects 

 

Summary of the safety profile 

 

Assessment of adverse reactions is mainly based on two studies, NV-02B-007 (GLOBE) and NV-02B-

015, in which 1,699 patients with chronic hepatitis B received double-blind treatment with telbivudine 

600 mg/day (n = 847) or lamivudine (n = 852) for 104 weeks. 

 

In the 104-week clinical studies, reported adverse reactions were usually classified as mild or 

moderate in severity. The most common adverse reactions were grade 3 or 4 blood creatine kinase 

elevations (6.8%), fatigue (4.4%), headache (3.0%) and nausea (2.6%). 

 



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Tabulated list of adverse reactions 

 

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

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

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

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

decreasing seriousness. 

 

Table 2 Adverse reactions 

 

Metabolism and nutrition disorders  

 Rare* Lactic acidosis 

Nervous system disorders  

 Common Dizziness, headache 

 Uncommon Peripheral neuropathy, dysgeusia, hypoaesthesia, 

paresthesia, sciatica 

Respiratory, thoracic and mediastinal 

disorders 

 

 Common Cough 

Gastrointestinal disorders  

 Common Diarrhoea, blood lipase increased, nausea, 

abdominal pain 

Skin and subcutaneous tissue disorders  

 Common Rash 

Musculoskeletal and connective tissue 

disorders 

 

 Uncommon Myopathy/myositis, arthralgia, myalgia, pain in 

the extremities, back pain, muscle spasm, neck 

pain, flank pain 

 Rare* Rhabdomyolysis 

General disorders and administration site 

conditions 

 

 Common Fatigue 

 Uncommon Malaise 

Investigations  

 Common Blood creatine phosphokinase increased, blood 

alanine aminotransferase increased, blood 

amylase increased 

 Uncommon Aspartate aminotransferase increased 

* This adverse reaction was identified through post-marketing surveillance but not observed in 

controlled clinical trials. The frequency category was estimated from a statistical calculation 

based on the total number of patients exposed to telbivudine in clinical trials (n = 8,914). 

 

Description of selected adverse reactions 

 

Creatine kinase elevation 

In the pooled analysis from NV-02B-007 (GLOBE) and NV-02B-015, by 104 weeks of treatment 

grade 3 or4 CK elevations (> 7x ULN) occurred in 12.6% of telbivudine-treated patients (n = 847) and 

4.0% of lamivudine-treated patients (n = 846). Most CK elevations were asymptomatic and CK values 

typically decreased by the next visit on continued treatment. 



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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 flares – Pooled NV-02B-007 (GLOBE) and NV-02B-

015 studies 

 

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 (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 safety 

population consisted of 655 patients including 518 from NV-02B-007 (GLOBE) and 137 from NV-

02B-015. The overall safety profile from the pooled analysis up to 104 and 208 weeks was similar. 

Grade 3 or 4 CK elevations newly occurred in 15.9% of patients treated with telbivudine for 

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

 

Reporting of suspected adverse reactions 

 

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 

allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 

professionals are asked to report any suspected adverse reactions via the national reporting system 

listed in Appendix V. 

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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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: Antivirals for systemic use, nucleoside and nucleotide reverse 

transcriptase inhibitors, ATC code: J05AF11 

 

Mechanism of action 

 

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. 

 

Pharmacodynamic effects 

 

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 strand 

production. By contrast, telbivudine-5'-triphosphate at 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 (EC50) 

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. Transient reductions in HIV-1 RNA 

have been reported in a small number of patients after administration of telbivudine in the absence of 

antiretroviral therapy. The clinical significance of these reductions has not been determined. 

 

Clinical experience 

 

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



11 

 

HBeAg-positive patients: The mean age of patients was 32 years, 74% were male, 82% were Asian, 

12% were Caucasian, and 6% had previously received alfa-interferon therapy. 

 

HBeAg-negative patients: The mean age of patients was 43 years, 79% were male, 65% were Asian, 

23% were Caucasian, and 11% had previously received alfa-interferon therapy. 

 

Clinical results at week 52 

Clinical and virological efficacy endpoints were evaluated separately in the HBeAg-positive and 

HBeAg-negative patient populations. The primary endpoint of therapeutic response was a composite 

serological endpoint requiring suppression of HBV DNA to < 5 log10 copies/ml in conjunction with 

either loss of serum HBeAg or ALT normalised. Secondary endpoints included histological response, 

ALT normalisation, and various measures of antiviral efficacy. 

 

Regardless of baseline characteristics, the majority of patients taking Sebivo showed histological, 

virological, biochemical, and serological responses to treatment. Baseline ALT levels > 2x ULN and 

baseline HBV DNA < 9 log10 copies/ml were associated with higher rates of HBeAg seroconversion in 

HBeAg-positive patients. Patients who achieve HBV DNA levels < 3 log10 copies/ml by week 24 had 

optimal responses to treatment; conversely patients with HBV DNA levels > 4 log10 copies/ml at 

24 weeks had less favourable outcomes at week 52. 

 

In HBeAg-positive patients, telbivudine was superior to lamivudine in therapeutic response (75.3% vs 

67.0% responders; p = 0.0047). In HBeAg-negative patients, telbivudine was non-inferior to 

lamivudine (75.2% and 77.2% responders; p = 0.6187). Caucasian ethnicity was associated with lower 

treatment response to both antiviral agents used in the NV-02B-007 (GLOBE) study; however the 

Caucasian patient population was very limited (n = 98). 

 

At week 24, 203 HBeAg-positive and 177 HBeAg-negative subjects achieved non-detectable HBV 

DNA levels. Of those HBeAg-positive subjects, 95% achieved non-detectable HBV DNA, 39% 

achieved HBeAg seroconversion, 90% achieved ALT normalisation at week 52 and 0.5% exhibited 

resistance at week 48. Similarly of those HBeAg-negative subjects, 96% achieved non-detectable 

HBV DNA, 79% achieved ALT normalisation at week 52 and 0% exhibited resistance at week 48. 



12 

 

Selected virological, biochemical and serological outcome measures are shown in Table 5 and 

histological response in Table 6. 

 

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

(GLOBE) study 

 

 

Response parameter  

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

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 (log10 

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 undetectable 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 in 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 log10 HBV DNA reduction: -5.74 vs -4.42; p < 0.0001, HBV DNA undetectability: 

56% vs 39%; p < 0.0001 and ALT normalisation of 70% vs 62%) demonstrated a widening difference 

at week 104 between telbivudine and lamivudine, respectively. A trend towards higher rates of HBeAg 

loss (35% vs 29%) and seroconversion (30% vs 25%) was also observed for telbivudine. Moreover, in 

the subgroup of patients with baseline ALT levels ≥ 2x ULN (320), a significantly higher proportion 

of telbivudine patients than lamivudine patients achieved HBeAg seroconversions at week 104 (36% 

vs 28%, respectively). 

 

Among HBeAg-negative patients, differences in therapeutic response (78% vs 66%) and key 

secondary endpoints (mean log10 HBV DNA reduction: -5.00 vs -4.17, and HBV DNA 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 subjects 

achieved undetectable HBV DNA levels. 

 

For both HBeAg-positive and HBeAg-negative patients, week 24 HBV DNA results were a predictor 

of long-term favourable outcomes. Telbivudine-treated patients who achieved undetectable HBV 

DNA by PCR by week 24 had the highest rates of HBV DNA undetectability and HBeAg 

seroconversion (in HBeAg-positive patients), and the lowest overall rates of virological breakthrough 

at week 104. 

 

Outcome results at week 104, based on level of HBV DNA at week 24, for either HBeAg-positive or 

HBeAg-negative patients are presented in Table 7. 

 

Table 7 Key efficacy endpoints at week 104 by serum HBV DNA levels at week 24, 

telbivudine-treated patients in NV-02B-007 (GLOBE) study 

 

 

 

HBV DNA at 

week 24 

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

Therapeutic 

response 

n/N (%) 

HBV DNA 

undetectability 

n/N (%) 

HBeAg 

seroconversion 

n/N (%) 

ALT 

normalisation  

n/N (%) 

Virological 

breakthrough* 

n/N (%) 

HBeAg-positive      

< 300 copies/ml 172/203 (85) 166/203 (82) 84/183 (46) 160/194 (82) 22/203 (11) 

300 copies/ml to 

< 3 log10 copies/ml 

36/57 (63) 35/57 (61) 21/54 (39) 40/54 (74) 18/57 (32) 

≥ 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 

< 3 log10 copies/ml 

13/18 (72) 14/18 (78) N/A 13/17 (76) 4/18 (22) 

≥ 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 



14 

 

Study NV-02B-015 

The efficacy and safety results of the NV-02B-007 (GLOBE) study were confirmed in study NV-02B-

015. This study is a phase III, randomised, double-blind study of telbivudine 600 mg once daily 

compared to lamivudine 100 mg once daily for a treatment period of 104 weeks in 332 nucleoside-

naïve chronic hepatitis B HBeAg-positive and HBeAg-negative Chinese patients. 

 

Study CLDT600A2303 - Clinical results over 208 weeks 

Study CLDT600A2303 was an open-label 104-week extension study in patients with compensated 

chronic hepatitis B who were previously treated with telbivudine for 2 years including patients from 

studies NV-02B-007 (GLOBE) and NV-02B-015, providing efficacy and safety data after 156 and 

208 weeks of continuous telbivudine therapy. Patients with undetectable HBV DNA at week 24 had 

better outcomes at 156 and 208 weeks (Table 8). 

 

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

CLDT600A2303 studies 

 

 Week 52 Week 104 Week 156 Week 208 

HBeAg-positive patients (n = 293*) 

Maintained undetectable HBV DNA 

(< 300 copies/ml) 

70.3% 

(206/293) 

77.3% 

(218/282) 

75.0% 

(198/264) 

76.2% 

(163/214) 

Maintained undetectable HBV DNA 

(< 300 copies/ml) with undetectable 

HBV DNA at week 24 

99.4% 

(161/162) 

94.9% 

(150/158) 

86.7% 

(130/150) 

87.9% 

(109/124) 

Cumulative HBeAg seroconversion 

rates (%) 

27.6% 

(81/293) 

41.6% 

(122/293) 

48.5% 

(142/293) 

53.2% 

(156/293) 

Cumulative HBeAg seroconversion 

rates in patients with undetectable HBV 

DNA at week 24 (%) 

40.1% 

(65/162) 

52.5% 

(85/162) 

59.3% 

(96/162) 

65.4% 

(106/162) 

Maintained ALT normalisation 81.4% 

(228/280) 

87.5% 

(237/271) 

82.9% 

(209/252) 

86.4% 

(178/106) 

HBeAg-negative patients (n = 209*) 

Maintained undetectable HBV DNA 

(< 300 copies/ml) 

95.2% 

(199/209) 

96.5% 

(195/202) 

84.7% 

(160/189) 

86.0% 

(141/164) 

Maintained undetectable HBV DNA 

(< 300 copies/ml) with undetectable 

HBV DNA at week 24 

97.8% 

(175/179) 

96.5% 

(166/172) 

86.7% 

(143/165) 

87.5% 

(126/144) 

Maintained ALT normalisation 80.3% 

(151/188) 

89.0% 

(161/181) 

83.5% 

(142/170) 

89.6% 

(129/144) 

* The population without viral resistance at entry into study CLDT600A2303 consisted of 502 patients 

(293 HBeAg-positive and 209 HBeAg-negative). 



15 

 

Study CLDT600ACN04E1 - Impact of treatment on liver histology 

In study CLDT600ACN04E1, 57 patients with available paired liver biopsies at baseline and after 

mean treatment of 260.8 weeks were evaluated for changes in liver histology (38 HBeAg-positive and 

19 HBeAg-negative patients). 

 The mean Knodell necroinflammatory score of 7.6 (SD 2.9) at baseline improved (p < 0.0001) 
to 1.4 (SD 0.9) with a mean change of -6.3 (SD 2.8). Knodell necroinflammatory score ≤ 3 (no 

or minimal necroinflammation) was observed in 98.2% (56/57) of patients. 

 The mean Ishak score of 2.2 (SD 1.1) at baseline improved (p < 0.0001) to 0.9 (SD 1.0) with a 
mean change of -1.3 (SD 1.3). Ishak fibrosis score ≤ 1 (no or minimal fibrosis) was observed in 

84.2% (48/57) of patients. 

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

HBeAg-negative patients. 

 

CLDT600A2303 - Off-treatment durability of HBeAg responses 

Study CLDT600A2303 included HBeAg-positive patients from studies NV-02B-007 (GLOBE) or 

NV-02B-015 for off-treatment follow up. These patients had completed ≥ 52 weeks of telbivudine 

treatment, and had exhibited HBeAg loss for ≥ 24 weeks with HBV DNA < 5 log10 copies/ml at the 

last on-treatment visit. The median treatment duration was 104 weeks. After a median off-treatment 

follow-up period of 120 weeks, the majority of HBeAg-positive telbivudine treated-patients showed 

sustained HBeAg loss (83.3%; 25/30), and sustained HBeAg seroconversion (79.2%; 19/24). Patients 

with sustained HBeAg seroconversion had a mean HBV DNA of 3.3 log10 copies/ml; and 73.7% had 

HBV DNA < 4 log10 copies/ml. 

 
Clinical resistance 

 

Genotypic resistance test was performed in study NV-02B-007 (GLOBE; n = 680) in patients with 

virological rebound (confirmed increase of ≥ 1 log10 copies/ml HBV DNA from nadir). 

 

At week 48 among HBeAg-positive and HBeAg-negative patients, 5% (23/458) and 2% (5/222), 

respectively, had virological rebound with detectable HBV resistance mutations. 

 

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

The original analysis for cumulative genotypic resistance at week 104 and 208 was based on the ITT 

population and included all patients who continued treatment until 4 years, regardless of HBV DNA 

levels. Out of the 680 telbivudine-treated patients initially included in the pivotal study NV-02B-007 

(GLOBE), 517 (76%) enrolled into study CLDT600A2303 for continued telbivudine treatment for up 

to 208 weeks. Out of these 517 patients 159 patients (HBeAg-positive=135, HBeAg-negative=24) had 

detectable HBV DNA. 

 

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

10.8% (24/222) for HBeAg-negative patients. 

 

In the overall ITT population the cumulative resistance rates at year 4 for HBeAg-positive and 

HBeAg-negative patients, was 40.8% (131/321) and 18.9% (37/196), respectively. 

 

Cumulative genotypic resistance rates were also assessed by applying a mathematical model where 

only patients with undetectable HBV DNA at the beginning of the respective year are considered. 

Cumulative resistance rates at year 4 were 22.3% for HBeAg-positive patients and 16.0% for HBeAg-

negative patients in this analysis. 

 



16 

When considering patients with viral breakthrough by 104 weeks in NV-02B-007 (GLOBE), the rate 

of resistance was lower in patients with HBV DNA < 300 copies/ml at week 24 than in patients with 

HBV DNA ≥ 300 copies/ml at week 24. In HBeAg-positive patients with HBV DNA < 300 copies/ml 

at week 24, resistance was 1% (3/203) at 48 weeks and 9% (18/203) at week 104, whilst in patients 

with HBV DNA ≥ 300 copies/ml resistance was 8% (20/247) at 48 weeks and 39% (97/247) at 

week 104. In HBeAg-negative patients with HBV DNA < 300 copies/ml at week 24, resistance was 

0% (0/177) at 48 weeks and 5% (9/177) at week 104, whilst in patients with HBV DNA 

≥ 300 copies/ml resistance was 11% (5/44) at 48 weeks and 34% (15/44) at week 104. 

 

Genotypic mutation pattern and cross-resistance 

 

Genotypic analysis of 203 evaluable sample pairs with HBV DNA ≥ 1,000 copies/ml at week 104 

(NV-02B-007 (GLOBE)) demonstrated that the primary mutation associated with telbivudine 

resistance was rtM204I, often associated with mutations rtL180M and rtL80I/V and infrequently with 

rtV27A, rtL82M, rtV173L, rtT184I and rtA200V. Baseline factors associated with development of 

genotypic drug resistance included: lamivudine treatment, higher baseline HBV DNA, lower baseline 

serum ALT, and increased body weight/BMI. On-treatment response parameters at week 24 that 

predicted emergence of drug resistant virus by week 104 were HBV DNA > 300 copies/ml and 

elevation of serum ALT. 

 

Genotypic analysis of 50 HBV isolates from telbivudine-treated patients at week 208 

(CLDT600A2303) revealed a similar resistance profile as reported at week 104. Conversions at 

position 80, 180 and polymorphic positions 91, 229 were always detected in sequences that harboured 

the M204I mutation that confers genotypic resistance. These mutations most likely are compensatory 

mutations. One isolated rtM204V mutation and two rtM204I/V/M mutations were reported in 

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

reported. 

 

Cross-resistance 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 (Cmax) 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 (AUC0-∞) 

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

exposures (Cmax, AUC) was typically approximately 30%. 

 

Effect of food on oral absorption 

Telbivudine 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%). 

 



17 

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 a bi-exponential 

manner with a terminal elimination half-life (t1/2) 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 elderly (65 years age and above) 

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

 

Renal impairment 

The single-dose pharmacokinetics of telbivudine (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 

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

AUC0-∞ 
(g•h/ml) 

28.5 ± 9.6 32.5 ± 10.1 36.0 ± 13.2 32.5 ± 13.2 67.4 ± 36.9 

CLRENAL 

(ml/min) 

126.7 ± 48.3 83.3 ± 20.0 43.3 ± 20.0 11.7 ± 6.7 - 

 



18 

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. 

 

 



19 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 
 

Tablet core 

 

Cellulose microcrystalline 

Povidone 

Sodium starch glycolate 

Silica, colloidal anhydrous 

Magnesium stearate 

 
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 for disposal. 

 

 

7. MARKETING AUTHORISATION HOLDER 
 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 



20 

 

8. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/07/388/001 

EU/1/07/388/002 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 

Date of first authorisation: 24 April 2007 

Date of latest renewal: 16 December 2016 

 

 

10. DATE OF REVISION OF THE TEXT 

 

 

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

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



21 

1. NAME OF THE MEDICINAL PRODUCT 
 

Sebivo 20 mg/ml oral solution 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 

One ml contains 20 mg telbivudine. 

 

Excipient with known effect: A 600 mg dose (30 ml) of oral solution contains approximately 47 mg 

sodium. 

 

For the 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. 

 

Initiation of Sebivo treatment should only be considered when the use of an alternative antiviral agent 

with a higher genetic barrier to resistance is not available or appropriate. 
 

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

based. 

 

4.2 Posology and method of administration 

 

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

infection. 

 

Posology 

 

Adults 

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

 

Monitoring during treatment 

On-treatment response at week 24 has been shown to be predictive of longer-term response (see 

Table 7 in section 5.1). HBV DNA levels should be monitored at 24 weeks of treatment to assure 

complete viral suppression (HBV DNA less than 300 copies/ml). For patients with detectable HBV 

DNA after 24 weeks of therapy, treatment modification should be considered. 

 

HBV DNA should be monitored every 6 months to assure continued response. If patients test positive 

for HBV DNA at any time after their initial response, treatment modification should be considered. 

Optimal therapy should be guided by resistance testing. 



22 

 

Duration of therapy 

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

follows: 

 In HBeAg-positive patients without cirrhosis, treatment should be administered for at least 
6-12 months after HBeAg seroconversion (HBeAg loss and HBV DNA loss with anti-HBe 

detection) is confirmed or until HBsAg seroconversion or there is evidence of loss of efficacy. 

Serum ALT and HBV DNA levels should be followed regularly after treatment discontinuation 

to detect any late virological relapse. 

 In HBeAg-negative patients without cirrhosis, treatment should be administered at least until 
HBsAg seroconversion or until there is evidence of loss of efficacy. With prolonged treatment 

for more than 2 years, regular reassessment is recommended to confirm that continuation of the 

selected therapy remains appropriate for the patient. 

 

Missed doses 

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

dose. The next dose should be taken at the usual time. 

 

Elderly (age above 65 years) 

No data are available to support a specific dose recommendation for patients over the age of 65 years 

(see section 4.4). 

 

Renal impairment 

No adjustment of the recommended dose of telbivudine 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). 

 

Paediatric population 

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

are available. 



23 

 

Method of administration 

 

Sebivo is to be taken orally, with or without food. 

 

4.3 Contraindications 
 

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

 

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

 

4.4 Special warnings and precautions for use 
 

Severe acute exacerbations of chronic hepatitis B are relatively frequent, and are characterised by 

transient elevation of serum ALT. Following initiation of antiviral treatment, serum ALT may rise in 

some patients while serum levels of HBV DNA fall (see section 4.8). On average, 4-5 weeks elapsed 

prior to the occurrence of an exacerbation in patients treated with telbivudine. Overall, ALT flares 

occurred more frequently in HBeAg-positive patients than in HBeAg-negative patients. In patients 

with compensated liver disease, this elevation of serum ALT is generally not accompanied by elevated 

levels of serum bilirubin or by other signs of hepatic decompensation. The risk of hepatic 

decompensation – and of a subsequent exacerbation of hepatitis – may be elevated in patients with 

cirrhosis. Such patients should, therefore, be closely monitored. 

 

Exacerbations of hepatitis have also been reported in patients who have terminated treatment of 

hepatitis B. Post-treatment ALT flares are normally associated with increases in serum HBV DNA 

levels, and the majority of such cases have proven to be self-limiting. Nonetheless, there have also 

been reports of severe – and sometimes fatal – post-treatment disease exacerbations. Therefore, 

hepatic function should be monitored at regular intervals with both clinical and laboratory follow-up 

for at least 6 months after discontinuation of hepatitis B therapy. 

 

Lactic acidosis 

 

Rare post-marketing cases of lactic acidosis have been reported with telbivudine. Cases were more 

often secondary to other serious conditions (e.g. rhabdomyolysis) and/or associated with 

muscle-related events (e.g. myopathy, myositis). When secondary to other conditions, some cases 

were also associated with pancreatitis, liver failure/hepatic steatosis and renal failure. In some cases, 

fatal outcomes were reported when lactic acidosis was secondary to rhabdomyolysis. Patients should 

be followed closely. 

 

Treatment with telbivudine should be discontinued when metabolic/lactic acidosis of unknown 

aetiology occurs. Benign digestive symptoms, such as nausea, vomiting and abdominal pain, may be 

indicative of lactic acidosis development. 

 

Muscular effects 

 

Cases of myopathy and myalgia have been reported with telbivudine use several weeks to months after 

starting therapy (see section 4.8). Cases of rhabdomyolysis have been reported during post-marketing 

use of telbivudine (see section 4.8). 

 

Myopathy, defined as persistent unexplained muscle aches and/or muscle weakness regardless of the 

degree of increases in creatine kinase (CK) levels, should be considered in any patient with diffuse 

unexplained myalgias, muscle tenderness, muscle weakness or myositis (defined as myopathy with 

histological evidence of muscle damage). Patients should be advised to report promptly any persistent 

unexplained muscle aches, pain, tenderness or weakness. If any of these symptoms are reported, a 

detailed muscle examination should be performed in order to evaluate muscle function. Telbivudine 

therapy should be discontinued if myopathy is diagnosed. 

 



24 

It is not known whether the risk of myopathy during treatment with telbivudine is increased with 

concurrent administration of other medicinal products associated with myopathy (e.g. statins, fibrates, 

or ciclosporin). Physicians considering concomitant treatment with other agents associated with 

myopathy should weigh carefully the potential benefits and risks and should monitor patients for any 

signs or symptoms suggestive of myopathy. 

 

Peripheral neuropathy 

 

Peripheral neuropathy has been uncommonly reported in telbivudine-treated patients. If peripheral 

neuropathy is suspected, treatment with telbivudine should be reconsidered (see section 4.8). 

 

An increased risk of developing peripheral neuropathy has been observed in one study when 

telbivudine and pegylated interferon alfa-2a were co-administered (see section 4.5). Such increased 

risk cannot be excluded for other interferon alfa (pegylated or standard). Moreover, the benefit of the 

combination of telbivudine with interferon alfa (pegylated or standard) is not currently established. 

Therefore, the combination of telbivudine with pegylated or standard interferon alfa is contraindicated 

(see section 4.3). 

 

Renal function 

 

Telbivudine is eliminated primarily by renal excretion, therefore dose interval adjustment is 

recommended in patients with creatinine clearance < 50 ml/min, including patients on haemodialysis. 

The effectiveness of dosing interval adjustment has not been clinically evaluated. Therefore, 

virological response should be closely monitored in patients with increased dosage interval (see 

sections 4.2 and 5.2). 

 

Patients with cirrhosis without decompensation 

 

Due to the limited data available (about 3% of patients enrolled had cirrhosis), telbivudine should be 

used with particular caution in cirrhotic patients. These patients should be closely monitored for 

clinical, biochemical and virological parameters associated with hepatitis B during treatment and after 

treatment is discontinued. 

 

Patients with cirrhosis with decompensation 

 

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

 

Patients with previous exposure to nucleoside/nucleotide analogues 

 

In vitro, telbivudine was not active against the HBV strains containing rtM204V/rtL180M or rtM204I 

mutations (see section 5.1). Telbivudine monotherapy is not an option for patients with established 

lamivudine-resistant hepatitis B virus infection. Patients who failed to achieve virological response 

following treatment with lamivudine for more than 24 weeks are unlikely to benefit from telbivudine 

monotherapy. There is currently no clinical data to properly assess the benefit and risk of switching to 

telbivudine for lamivudine-treated patients who achieve complete viral suppression on lamivudine. 

 

There are no data on telbivudine treatment in patients with established adefovir-resistant hepatitis B 

virus single mutations of rtN236T or A181V. Results from cell-based assays showed that the adefovir 

resistance-associated substitution A181V had 1.5- to approximately 4-fold reduced susceptibility to 

telbivudine. 



25 

 

Liver transplant recipients 

 

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

 

Elderly 

 

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 older patients in view of the greater frequency of decreased 

renal function due to concomitant disease or concomitant use of other medicinal products. 

 

Other special populations 

 

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. 

 

Excipients 

 

Sebivo oral solution contains approximately 47 mg sodium per 600 mg dose (30 ml), which should be 

taken into consideration by patients on a controlled sodium diet. 

 

4.5 Interaction with other medicinal products and other forms of interaction 
 

Since telbivudine is eliminated primarily by renal excretion, co-administration of Sebivo with 

substances that affect renal function (such as aminoglycosides, loop diuretics, platinum compounds, 

vancomycin, amphotericin B) may affect plasma concentrations of telbivudine and/or the co-

administered substance. The combination of telbivudine with these medicinal products should be used 

with caution. The steady-state pharmacokinetics of telbivudine were unaltered following multiple dose 

administration in combination with lamivudine, adefovir dipivoxil, tenofovir disoproxil fumarate, 

ciclosporin or pegylated interferon alfa-2a. In addition, telbivudine does not alter the pharmacokinetics 

of lamivudine, adefovir dipivoxil, tenofovir disoproxil fumarate or ciclosporin. No definitive 

conclusion could be drawn regarding the effects of telbivudine on the pharmacokinetics of pegylated 

interferon due to high interindividual variability of pegylated interferon alfa-2a concentrations. A 

clinical trial investigating the combination of telbivudine, 600 mg daily, with pegylated interferon 

alfa-2a, 180 micrograms once weekly by subcutaneous administration, indicates that this combination 

is associated with an increased risk of developing peripheral neuropathy. The mechanism behind these 

events is not known (see section 4.4). The combination of telbivudine with any interferon alfa-

containing product is contraindicated (see section 4.3). 

 

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

(see section 5.2). Therefore, the potential for CYP450-mediated drug interactions involving Sebivo is 

low. 

 



26 

4.6 Fertility, pregnancy and lactation 
 

Pregnancy 

 

Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal 

development, parturition or postnatal development (see section 5.3). Studies in pregnant rats and 

rabbits showed that telbivudine crosses the placenta. Studies in pregnant rabbits showed early delivery 

and/or abortion secondary to maternal toxicity. 

 

Limited clinical data (less than 300 pregnancy outcomes) after exposure to telbivudine during the first 

trimester of pregnancy indicate no malformative toxicity and a large amount of data (more than 1000 

pregnancy outcomes) after exposure during the second and third trimesters indicate no foetal/neonatal 

toxicity. 

 

Sebivo should be used during pregnancy only if the benefit to the mother outweighs the potential risk 

to the foetus. 

 

Literature shows that exposure to telbivudine in the second and/or third trimester of pregnancy has 

been shown to reduce the risk of HBV transmission from mother to infant if telbivudine is given in 

addition to Hepatitis B immune globulin and Hepatitis B vaccine. 

 

Breast-feeding 

 

Telbivudine is excreted in the milk of rats. It is not known whether telbivudine is excreted in human 

milk. Women should not breastfeed if they are taking Sebivo. 

 

Fertility 

 

There are no clinical data on the effects of telbivudine on male or female fertility. In reproductive 

toxicology studies in adult animals, fertility was slightly reduced when both male and female rats 

received telbivudine. The adverse effects on fertility were greater in a separate study in juvenile 

animals when both sexes received telbivudine (see section 5.3). 

 

4.7 Effects on ability to drive and use machines 

 

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

 

4.8 Undesirable effects 

 

Summary of the safety profile 

 

Assessment of adverse reactions is mainly based on two studies, NV-02B-007 (GLOBE) and NV-02B-

015, in which 1,699 patients with chronic hepatitis B received double-blind treatment with telbivudine 

600 mg/day (n = 847) or lamivudine (n = 852) for 104 weeks. 

 

In the 104-week clinical studies, reported adverse reactions were usually classified as mild or 

moderate in severity. The most common adverse reactions were grade 3 or 4 blood creatine kinase 

elevations (6.8%), fatigue (4.4%), headache (3.0%) and nausea (2.6%). 



27 

 

Tabulated list of adverse reactions 

 

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

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

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

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

decreasing seriousness. 

 

Table 2 Adverse reactions 

 

Metabolism and nutrition disorders  

 Rare* Lactic acidosis 

Nervous system disorders  

 Common Dizziness, headache 

 Uncommon Peripheral neuropathy, dysgeusia, hypoaesthesia, 

paresthesia, sciatica 

Respiratory, thoracic and mediastinal 

disorders 

 

 Common Cough 

Gastrointestinal disorders  

 Common Diarrhoea, blood lipase increased, nausea, 

abdominal pain 

Skin and subcutaneous tissue disorders  

 Common Rash 

Musculoskeletal and connective tissue 

disorders 

 

 Uncommon Myopathy/myositis, arthralgia, myalgia, pain in 

the extremities, back pain, muscle spasm, neck 

pain, flank pain 

 Rare* Rhabdomyolysis 

General disorders and administration site 

conditions 

 

 Common Fatigue 

 Uncommon Malaise 

Investigations  

 Common Blood creatine phosphokinase increased, blood 

alanine aminotransferase increased, blood 

amylase increased 

 Uncommon Aspartate aminotransferase increased 

* This adverse reaction was identified through post-marketing surveillance but not observed in 

controlled clinical trials. The frequency category was estimated from a statistical calculation 

based on the total number of patients exposed to telbivudine in clinical trials (n = 8,914). 
 

Description of selected adverse reactions 
 

Creatine kinase elevation 

In the pooled analysis from NV-02B-007 (GLOBE) and NV-02B-015, by 104 weeks of treatment 

grade 3 or4 CK elevations (> 7x ULN) occurred in 12.6% of telbivudine-treated patients (n = 847) and 

4.0% of lamivudine-treated patients (n = 846). Most CK elevations were asymptomatic and CK values 

typically decreased by the next visit on continued treatment. 



28 

 

ALT flares 
The incidence of on treatment alanine aminotransferase (ALT) flares in the two treatment arms 

according to AASLD (American Association for the Study of Liver Diseases) definition (ALT 

elevation > 2x baseline and > 10x ULN) are further described in Table 3 below. 

 

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

015 studies 

 

ALT flare: 

ALT elevation > 2x baseline and 

> 10x ULN 

Lamivudine 

n/N (%) 

Telbivudine 

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 (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 safety 

population consisted of 655 patients including 518 from NV-02B-007 (GLOBE) and 137 from NV-

02B-015. The overall safety profile from the pooled analysis up to 104 and 208 weeks was similar. 

Grade 3 or 4 CK elevations newly occurred in 15.9% of patients treated with telbivudine for 

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

 

Reporting of suspected adverse reactions 

 

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 

allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 

professionals are asked to report any suspected adverse reactions via the national reporting system 

listed in Appendix V. 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


29 

 

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: Antivirals for systemic use, nucleoside and nucleotide reverse 

transcriptase inhibitors, ATC code: J05AF11 

 

Mechanism of action 

 

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. 

 

Pharmacodynamic effects 

 

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 strand 

production. By contrast, telbivudine-5'-triphosphate at 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 (EC50) 

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. Transient reductions in HIV-1 RNA 

have been reported in a small number of patients after administration of telbivudine in the absence of 

antiretroviral therapy. The clinical significance of these reductions has not been determined. 

 

Clinical experience 

 

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



30 

 

Study NV-02B-007 (GLOBE) 

The NV-02B-007 (GLOBE) study is a randomised, double-blind, multinational phase III study of 

telbivudine compared to lamivudine for a treatment period of 104 weeks in 1,367 nucleoside-naïve 

chronic hepatitis B HBeAg-positive and HBeAg-negative patients. The majority of the population 

enrolled was Asian. The most common HBV genotypes were B (26%) and C (51%). A small number 

(total of 98) of Caucasian patients were treated with telbivudine. The primary data analysis was 

conducted after all patients had reached week 52. 

 

HBeAg-positive patients: The mean age of patients was 32 years, 74% were male, 82% were Asian, 

12% were Caucasian, and 6% had previously received alfa-interferon therapy. 

 

HBeAg-negative patients: The mean age of patients was 43 years, 79% were male, 65% were Asian, 

23% were Caucasian, and 11% had previously received alfa-interferon therapy. 

 

Clinical results at week 52 

Clinical and virological efficacy endpoints were evaluated separately in the HBeAg-positive and 

HBeAg-negative patient populations. The primary endpoint of therapeutic response was a composite 

serological endpoint requiring suppression of HBV DNA to < 5 log10 copies/ml in conjunction with 

either loss of serum HBeAg or ALT normalised. Secondary endpoints included histological response, 

ALT normalisation, and various measures of antiviral efficacy. 

 

Regardless of baseline characteristics, the majority of patients taking Sebivo showed histological, 

virological, biochemical, and serological responses to treatment. Baseline ALT levels > 2x ULN and 

baseline HBV DNA < 9 log10 copies/ml were associated with higher rates of HBeAg seroconversion in 

HBeAg-positive patients. Patients who achieve HBV DNA levels < 3 log10 copies/ml by week 24 had 

optimal responses to treatment; conversely patients with HBV DNA levels > 4 log10 copies/ml at 

24 weeks had less favourable outcomes at week 52. 

 

In HBeAg-positive patients, telbivudine was superior to lamivudine in therapeutic response (75.3% vs 

67.0% responders; p = 0.0047). In HBeAg-negative patients, telbivudine was non-inferior to 

lamivudine (75.2% and 77.2% responders; p = 0.6187). Caucasian ethnicity was associated with lower 

treatment response to both antiviral agents used in the NV-02B-007 (GLOBE) study; however the 

Caucasian patient population was very limited (n = 98). 

 

At week 24, 203 HBeAg-positive and 177 HBeAg-negative subjects achieved non-detectable HBV 

DNA levels. Of those HBeAg-positive subjects, 95% achieved non-detectable HBV DNA, 39% 

achieved HBeAg seroconversion, 90% achieved ALT normalisation at week 52 and 0.5% exhibited 

resistance at week 48. Similarly of those HBeAg-negative subjects, 96% achieved non-detectable 

HBV DNA, 79% achieved ALT normalisation at week 52 and 0% exhibited resistance at week 48. 

 



31 

Selected virological, biochemical and serological outcome measures are shown in Table 5 and 

histological response in Table 6. 

 

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

(GLOBE) study 
 

 

Response parameter  

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

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 (log10 

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 undetectable 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 in 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 

 



32 

Clinical results at week 104 

Overall, clinical results at week 104 in telbivudine-treated patients were consistent with those at 

week 52, demonstrating durability of efficacy responses for telbivudine-treated patients with continued 

treatment. 

 

Among HBeAg-positive patients, therapeutic response (63% vs 48%; p < 0.0001) and key secondary 

endpoints (mean log10 HBV DNA reduction: -5.74 vs -4.42; p < 0.0001, HBV DNA undetectability: 

56% vs 39%; p < 0.0001 and ALT normalisation of 70% vs 62%) demonstrated a widening difference 

at week 104 between telbivudine and lamivudine, respectively. A trend towards higher rates of HBeAg 

loss (35% vs 29%) and seroconversion (30% vs 25%) was also observed for telbivudine. Moreover, in 

the subgroup of patients with baseline ALT levels ≥ 2x ULN (320), a significantly higher proportion 

of telbivudine patients than lamivudine patients achieved HBeAg seroconversions at week 104 (36% 

vs 28%, respectively). 

 

Among HBeAg-negative patients, differences in therapeutic response (78% vs 66%) and key 

secondary endpoints (mean log10 HBV DNA reduction: -5.00 vs -4.17, and HBV DNA 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 subjects 

achieved undetectable HBV DNA levels. 

 

For both HBeAg-positive and HBeAg-negative patients, week 24 HBV DNA results were a predictor 

of long-term favourable outcomes. Telbivudine-treated patients who achieved undetectable HBV 

DNA by PCR by week 24 had the highest rates of HBV DNA undetectability and HBeAg 

seroconversion (in HBeAg-positive patients), and the lowest overall rates of virological breakthrough 

at week 104. 

 

Outcome results at week 104, based on level of HBV DNA at week 24, for either HBeAg-positive or 

HBeAg-negative patients are presented in Table 7. 

 

Table 7 Key efficacy endpoints at week 104 by serum HBV DNA levels at week 24, 

telbivudine-treated patients in NV-02B-007 (GLOBE) study 

 

 

 

HBV DNA at 

week 24 

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

Therapeutic 

response 

n/N (%) 

HBV DNA 

undetectability 

n/N (%) 

HBeAg 

seroconversion 

n/N (%) 

ALT 

normalisation  

n/N (%) 

Virological 

breakthrough* 

n/N (%) 

HBeAg-positive      

< 300 copies/ml 172/203 (85) 166/203 (82) 84/183 (46) 160/194 (82) 22/203 (11) 

300 copies/ml to 

< 3 log10 copies/ml 

36/57 (63) 35/57 (61) 21/54 (39) 40/54 (74) 18/57 (32) 

≥ 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 

< 3 log10 copies/ml 

13/18 (72) 14/18 (78) N/A 13/17 (76) 4/18 (22) 

≥ 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 

 



33 

Study NV-02B-015 

The efficacy and safety results of the NV-02B-007 (GLOBE) study were confirmed in study NV-02B-

015. This study is a phase III, randomised, double-blind study of telbivudine 600 mg once daily 

compared to lamivudine 100 mg once daily for a treatment period of 104 weeks in 332 nucleoside-

naïve chronic hepatitis B HBeAg-positive and HBeAg-negative Chinese patients. 

 

Study CLDT600A2303 - Clinical results over 208 weeks 

Study CLDT600A2303 was an open-label 104-week extension study in patients with compensated 

chronic hepatitis B who were previously treated with telbivudine for 2 years including patients from 

studies NV-02B-007 (GLOBE) and NV-02B-015, providing efficacy and safety data after 156 and 

208 weeks of continuous telbivudine therapy. Patients with undetectable HBV DNA at week 24 had 

better outcomes at 156 and 208 weeks (Table 8). 

 

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

CLDT600A2303 studies 

 

 Week 52 Week 104 Week 156 Week 208 

HBeAg-positive patients (n = 293*) 

Maintained undetectable HBV DNA 

(< 300 copies/ml) 

70.3% 

(206/293) 

77.3% 

(218/282) 

75.0% 

(198/264) 

76.2% 

(163/214) 

Maintained undetectable HBV DNA 

(< 300 copies/ml) with undetectable 

HBV DNA at week 24 

99.4% 

(161/162) 

94.9% 

(150/158) 

86.7% 

(130/150) 

87.9% 

(109/124) 

Cumulative HBeAg seroconversion 

rates (%) 

27.6% 

(81/293) 

41.6% 

(122/293) 

48.5% 

(142/293) 

53.2% 

(156/293) 

Cumulative HBeAg seroconversion 

rates in patients with undetectable HBV 

DNA at week 24 (%) 

40.1% 

(65/162) 

52.5% 

(85/162) 

59.3% 

(96/162) 

65.4% 

(106/162) 

Maintained ALT normalisation 81.4% 

(228/280) 

87.5% 

(237/271) 

82.9% 

(209/252) 

86.4% 

(178/106) 

HBeAg-negative patients (n = 209*) 

Maintained undetectable HBV DNA 

(< 300 copies/ml) 

95.2% 

(199/209) 

96.5% 

(195/202) 

84.7% 

(160/189) 

86.0% 

(141/164) 

Maintained undetectable HBV DNA 

(< 300 copies/ml) with undetectable 

HBV DNA at week 24 

97.8% 

(175/179) 

96.5% 

(166/172) 

86.7% 

(143/165) 

87.5% 

(126/144) 

Maintained ALT normalisation 80.3% 

(151/188) 

89.0% 

(161/181) 

83.5% 

(142/170) 

89.6% 

(129/144) 

* The population without viral resistance at entry into study CLDT600A2303 consisted of 502 patients 

(293 HBeAg-positive and 209 HBeAg-negative). 

 

Study CLDT600ACN04E1 - Impact of treatment on liver histology 

In study CLDT600ACN04E1, 57 patients with available paired liver biopsies at baseline and after 

mean treatment of 260.8 weeks were evaluated for changes in liver histology (38 HBeAg-positive and 

19 HBeAg-negative patients). 

 The mean Knodell necroinflammatory score of 7.6 (SD 2.9) at baseline improved (p < 0.0001) 
to 1.4 (SD 0.9) with a mean change of -6.3 (SD 2.8). Knodell necroinflammatory score ≤ 3 (no 

or minimal necroinflammation) was observed in 98.2% (56/57) of patients. 

 The mean Ishak score of 2.2 (SD 1.1) at baseline improved (p < 0.0001) to 0.9 (SD 1.0) with a 
mean change of -1.3 (SD 1.3). Ishak fibrosis score ≤ 1 (no or minimal fibrosis) was observed in 

84.2% (48/57) of patients. 

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

HBeAg-negative patients. 



34 

 

CLDT600A2303 - Off-treatment durability of HBeAg responses 

Study CLDT600A2303 included HBeAg-positive patients from studies NV-02B-007 (GLOBE) or 

NV-02B-015 for off-treatment follow up. These patients had completed ≥ 52 weeks of telbivudine 

treatment, and had exhibited HBeAg loss for ≥ 24 weeks with HBV DNA < 5 log10 copies/ml at the 

last on-treatment visit. The median treatment duration was 104 weeks. After a median off-treatment 

follow-up period of 120 weeks, the majority of HBeAg-positive telbivudine treated-patients showed 

sustained HBeAg loss (83.3%; 25/30), and sustained HBeAg seroconversion (79.2%; 19/24). Patients 

with sustained HBeAg seroconversion had a mean HBV DNA of 3.3 log10 copies/ml; and 73.7% had 

HBV DNA < 4 log10 copies/ml. 

 
Clinical resistance 

 

Genotypic resistance test was performed in study NV-02B-007 (GLOBE; n = 680) in patients with 

virological rebound (confirmed increase of ≥ 1 log10 copies/ml HBV DNA from nadir). 

 

At week 48 among HBeAg-positive and HBeAg-negative patients, 5% (23/458) and 2% (5/222), 

respectively, had virological rebound with detectable HBV resistance mutations. 

 

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

The original analysis for cumulative genotypic resistance at week 104 and 208 was based on the ITT 

population and included all patients who continued treatment until 4 years, regardless of HBV DNA 

levels. Out of the 680 telbivudine-treated patients initially included in the pivotal study NV-02B-007 

(GLOBE), 517 (76%) enrolled into study CLDT600A2303 for continued telbivudine treatment for up 

to 208 weeks. Out of these 517 patients 159 patients (HBeAg-positive=135, HBeAg-negative=24) had 

detectable HBV DNA. 

 

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

10.8% (24/222) for HBeAg-negative patients. 

 

In the overall ITT population the cumulative resistance rates at year 4 for HBeAg-positive and 

HBeAg-negative patients, was 40.8% (131/321) and 18.9% (37/196), respectively. 

 

Cumulative genotypic resistance rates were also assessed by applying a mathematical model where 

only patients with undetectable HBV DNA at the beginning of the respective year are considered. 

Cumulative resistance rates at year 4 were 22.3% for HBeAg-positive patients and 16.0% for HBeAg-

negative patients in this analysis. 

 

When considering patients with viral breakthrough by 104 weeks in NV-02B-007 (GLOBE), the rate 

of resistance was lower in patients with HBV DNA < 300 copies/ml at week 24 than in patients with 

HBV DNA ≥ 300 copies/ml at week 24. In HBeAg-positive patients with HBV DNA < 300 copies/ml 

at week 24, resistance was 1% (3/203) at 48 weeks and 9% (18/203) at week 104, whilst in patients 

with HBV DNA ≥ 300 copies/ml resistance was 8% (20/247) at 48 weeks and 39% (97/247) at 

week 104. In HBeAg-negative patients with HBV DNA < 300 copies/ml at week 24, resistance was 

0% (0/177) at 48 weeks and 5% (9/177) at week 104, whilst in patients with HBV DNA 

≥ 300 copies/ml resistance was 11% (5/44) at 48 weeks and 34% (15/44) at week 104. 

 

Genotypic mutation pattern and cross-resistance 

 

Genotypic analysis of 203 evaluable sample pairs with HBV DNA ≥ 1,000 copies/ml at week 104 

(NV-02B-007 (GLOBE)) demonstrated that the primary mutation associated with telbivudine 

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. 



35 

 

Genotypic analysis of 50 HBV isolates from telbivudine-treated patients at week 208 

(CLDT600A2303) revealed a similar resistance profile as reported at week 104. Conversions at 

position 80, 180 and polymorphic positions 91, 229 were always detected in sequences that harboured 

the M204I mutation that confers genotypic resistance. These mutations most likely are compensatory 

mutations. One isolated rtM204V mutation and two rtM204I/V/M mutations were reported in 

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

reported. 

 

Cross-resistance 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 (Cmax) 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 (AUC0-∞) 

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

exposures (Cmax, AUC) was typically approximately 30%. Film-coated tablets containing 600 mg 

telbivudine are bioequivalent to 30 ml telbivudine oral solution (20 mg/ml). 

 

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%). 

 

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 a bi-exponential 

manner with a terminal elimination half-life (t1/2) 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). 

 



36 

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 elderly (65 years age and above) 

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

 

Renal impairment 

The single-dose pharmacokinetics of telbivudine (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 

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

AUC0-∞ 
(g•h/ml) 

28.5 ± 9.6 32.5 ± 10.1 36.0 ± 13.2 32.5 ± 13.2 67.4 ± 36.9 

CLRENAL 

(ml/min) 

126.7 ± 48.3 83.3 ± 20.0 43.3 ± 20.0 11.7 ± 6.7 - 

 

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). 

 



37 

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 
 

Benzoic acid (E210) 

Sodium saccharin 

Passion fruit flavouring 

Sodium hydroxide 

Citric acid anhydrous 

Water, purified 
 

6.2 Incompatibilities 
 

Not applicable. 

 

6.3 Shelf life 
 

3 years 

 

Use within 2 months of opening the bottle. 

 

6.4 Special precautions for storage 
 

Do not store above 30°C. Do not freeze. 



38 

 

6.5 Nature and contents of container 

 

300 ml brown glass bottle with a child-resistant closure, including a polyethylene sealing disc and a 

guarantee ring, a polypropylene dosing cup with embossed graduations from 5 to 30 ml in 5 ml 

increments, and a polypropylene oral syringe with graduations of 1 ml to 10 ml in 0.5 ml increments. 

 

6.6 Special precautions for disposal 
 

No special requirements for disposal. 

 

 

7. MARKETING AUTHORISATION HOLDER 
 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

8. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/07/388/003 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 

Date of first authorisation: 24 April 2007 

Date of latest renewal: 16 December 2016 

 

 

10. DATE OF REVISION OF THE TEXT 

 

 

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

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



39 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX II 

 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 

PRODUCT 

 



40 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 
Name and address of the manufacturer responsible for batch release 

 

Novartis Pharma GmbH 

Roonstrasse 25 

90429 Nuremberg 

Germany 

 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 

Characteristics, section 4.2). 

 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 

 Periodic Safety Update Reports 
 

The requirements for submission of periodic safety update reports for this medicinal product are set 

out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 

2001/83/EC and any subsequent updates published on the European medicines web-portal. 

 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 

 Risk Management plan (RMP) 

 

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 

agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 

updates of the RMP. 

 

An updated RMP should be submitted: 

 At the request of the European Medicines Agency; 

 Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 

an important (pharmacovigilance or risk minimisation) milestone being reached. 

 

 

 



41 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 



42 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 



43 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Sebivo 600 mg film-coated tablets 

telbivudine 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

One tablet contains 600 mg telbivudine. 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Film-coated tablet 

 

28 film-coated tablets 

98 film-coated tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use. 

Do not chew, split or crush the tablet. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 
 

9. SPECIAL STORAGE CONDITIONS 

 



44 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/07/388/001 28 film-coated tablets 

EU/1/07/388/002 98 film-coated tablets 
 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Sebivo 600 mg 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included 

 

 

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 



45 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTERS 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Sebivo 600 mg film-coated tablets 

telbivudine 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. OTHER 

 

Monday 

Tuesday 

Wednesday 

Thursday 

Friday 

Saturday 

Sunday 

 



46 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 

PACKAGING 

 

FOLDING BOX AND BOTTLE LABEL 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Sebivo 20 mg/ml oral solution 

telbivudine 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each ml contains 20 mg telbivudine. 

 

 

3. LIST OF EXCIPIENTS 

 

Also contains sodium. See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Oral solution 

 

1 bottle containing 300 ml oral solution [folding box only] 

1 cup + 1 oral syringe [folding box only] 

 

300 ml [bottle label only] 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

Use within 2 months of opening the bottle. 

 



47 

 

9. SPECIAL STORAGE CONDITIONS 

 

Do not store above 30C. 

Do not freeze. 
 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/07/388/003 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Sebivo 20 mg/ml [folding box only] 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE [folding box only] 

 

2D barcode carrying the unique identifier included 

 

 

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA [folding box only] 

 

PC: 

SN: 

NN: 



48 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. PACKAGE LEAFLET 
 



49 

Package leaflet: Information for the user 

 

Sebivo 600 mg film-coated tablets 

Telbivudine 

 

 

Read all of this leaflet carefully before you start taking this medicine because it contains 

important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 

- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 
effects not listed in this leaflet. See section 4. 

 

What is in this leaflet 
1. What Sebivo is and what it is used for 

2. What you need to know before you take Sebivo 

3. How to take Sebivo 

4. Possible side effects 

5. How to store Sebivo 

6. Contents of the pack and other information 

 

 

1. What Sebivo is and what it is used for 

 

Sebivo contains the active substance telbivudine. Sebivo belongs to a group of medicines called 

antiviral medicines, which are used to treat infections caused by viruses. 

 

Sebivo is used to treat adults with chronic hepatitis B. Starting treatment with Sebivo should only be 

considered when it is not possible or appropriate to use an alternative medicine to which the hepatitis 

B virus is less likely to develop resistance. Your doctor will decide which treatment is most 

appropriate for you. 

 

Hepatitis B is caused by infection with the hepatitis B virus, which multiplies in the liver and causes 

liver damage. Treatment with Sebivo reduces the amount of hepatitis B virus in the body by blocking 

its growth, resulting in less liver damage and improved liver function. 

 

 

2. What you need to know before you take Sebivo 

 

Do not take Sebivo 
- if you are allergic to telbivudine or any of the other ingredients of this medicine (listed in 

section 6). 

- if you are being treated with pegylated or standard interferon alfa (see “Taking other 
medicines”). 

If this applies to you, do not take Sebivo. Talk to your doctor. 

 



50 

Warnings and precautions 

Talk to your doctor before taking Sebivo: 

- if you have or have had any kidney problems. Your doctor may order laboratory tests to check 
your kidneys are working properly before and during treatment. Depending on the results of 

these tests your doctor may advise you to change how often you take Sebivo. 

- if you suffer from cirrhosis of the liver (a serious condition which causes liver “scarring”). In 
this case your doctor will want to monitor you more closely. 

- if you have had a liver transplant. 
- if you are taking any medicines that may cause muscle problems (talk to your doctor or 

pharmacist if you are unsure). 

- if you are infected with HIV, hepatitis C or D, or are being treated with any antiviral medicines. 
If any of these applies to you, tell your doctor before you take Sebivo. 

 

During the treatment with Sebivo: 

- Sebivo can cause persistent unexplained muscle weakness or muscle pain (myopathy). Muscle 
symptoms may progress and become serious, sometimes leading to muscle breakdown 

(rhabdomyolysis) which can cause kidney damage. 

- Uncommonly Sebivo can induce numbness, tingling, pain and/or burning sensations in the arms 
and/or legs (peripheral neuropathy). 

If you experience any of these symptoms during your treatment with Sebivo, call your doctor 

immediately. 

 

Other side effects of this type of medicine 

Sebivo can cause an excess of lactic acid in the blood (lactic acidosis) which is usually associated with 

an enlargement of the liver (hepatomegaly). Lactic acidosis is a rare but serious side effect which can 

occasionally be fatal. Your doctor will monitor you regularly while you are receiving Sebivo. If you 

experience muscle pain, severe and persistent stomach pain with nausea and vomiting, severe and 

persistent trouble breathing, tiredness or abdominal discomfort while taking Sebivo, call your doctor 

immediately. 

 

Some people may get very serious hepatitis symptoms when they stop taking medicines like Sebivo. 

Your doctor will monitor your health and do regular blood tests to check your liver after you stop 

treatment with Sebivo. Tell your doctor immediately about any new or unusual symptoms that you 

notice after stopping treatment (see “If you stop taking Sebivo” in section 3 of this leaflet). 

 

Take care not to infect other people 

Even if you take Sebivo, you may still infect others with hepatitis B virus (HBV) through sexual 

contact or exposure to contaminated blood or other body fluids. If you have sexual intercourse with a 

partner who is not immune against hepatitis B, always use condoms and avoid any other exchange of 

body fluids. Never share needles. Do not share personal items that could have blood or body fluids on 

them, such as toothbrushes or razor blades. A vaccine is available to prevent infection with HBV. 

 

Children and adolescents 

Sebivo is not recommended for use in children and adolescents. 

 

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

medicines. 

 

Your doctor or pharmacist needs to know about other medicines because some medicines could affect 

your kidneys and because Sebivo mainly leaves the body via the kidneys in the urine. 

 

Do not take Sebivo if you are using pegylated or standard interferon alfa (see “Do not take Sebivo”), 

because the combination of these medicines may increase your risk of developing peripheral 

neuropathy (numbness, tingling, and/or burning sensations in the arms and/or legs). Tell your doctor 

or pharmacist if you are being treated with interferon. 

 



51 

Pregnancy and breast-feeding 

- Do not use Sebivo during pregnancy unless your doctor recommends it. If you are pregnant, 
think you may be pregnant or are planning to have a baby, ask your doctor for advice before 

taking this medicine. Your doctor will discuss with you the potential risks of taking Sebivo 

during pregnancy. 

 

- If you have hepatitis B and become pregnant, talk to your doctor about how you can best protect 
your baby. Sebivo may reduce the risk of passing your hepatitis B virus on to your unborn baby 

if taken in combination with Hepatitis B immune globulin and Hepatitis B vaccine. 

 

- Do not breast-feed during treatment with Sebivo. Tell your doctor if you are breast- feeding. 
 

Driving and using machines 
Sebivo has minor influence on the ability to drive and use machines. If you feel dizzy while taking this 

medicine, do not drive a vehicle or use any tools or machines. 

 

 

3. How to take Sebivo 

 

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 

or pharmacist if you are not sure. 

 

How much Sebivo to take 

The recommended dose of Sebivo is one 600 mg tablet once a day. Take the tablet at about the same 

time each day. 

 

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

crush it. 

 

You may need to take Sebivo less frequently if you have kidney problems. Tell your doctor if you 

have, or have ever had, any kidney problems. 

 

How long to take Sebivo 

Continue taking Sebivo every day for as long as your doctor tells you. Do not change your dose or 

stop taking Sebivo without talking to your doctor. This medicine is intended for long-term treatment, 

possibly lasting for months or years. Your doctor will regularly monitor your condition to check that 

the treatment is having the desired effect. 

 

If you take more Sebivo than you should 

If you have taken too much Sebivo, or if someone else accidentally takes your tablets, go to your 

doctor or hospital for advice straight away. Take the pack of tablets with you and show it to your 

doctor. 

 

If you forget to take Sebivo 

- If you forget to take Sebivo, take it as soon as you remember and then take your next dose at its 
regular time. 

- However, if it is within 4 hours before your next dose, skip the dose you missed and take the 
next one at the usual time. 

 

Do not take a double dose to make up for a forgotten tablet. This may increase the chance of you 

getting unwanted side effects. Ask your doctor or pharmacist if you are not sure what to do. 

 

If you stop taking Sebivo 

Stopping treatment with Sebivo may result in a worsening of your hepatitis B infection i.e. progression 

of the disease and abnormal test results (increase of viral load, ALT increase). Do not stop Sebivo 

unless your doctor tells you to. While you are taking Sebivo, make sure you do not run out of Sebivo. 

 



52 

Your doctor will monitor your health and do regular blood tests to check your liver after you stop 

treatment with Sebivo since your hepatitis B infection may get worse or become very serious after 

stopping treatment. Tell your doctor immediately about any new or unusual symptoms that you notice 

after stopping treatment. 

 

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

 

 

4. Possible side effects 
 

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

 

Some side effects could be serious: 

- Persistent muscle weakness or muscle pain 
- Numbness, tingling, pain and/or burning sensation in the arms and/or legs 
If you experience any of these, call your doctor immediately. 

 

Sebivo may also cause other side effects: 

Common (may affect up to 1 in 10 people) 

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

creatine kinase 

 

Uncommon (may affect up to 1 in 100 people) 

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

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

- Excess of lactic acid in the blood (lactic acidosis) 

- Muscle breakdown (rhabdomyolysis) 

 

Reporting of side effects 

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 

not listed in this leaflet. You can also report side effects directly via the national reporting system 

listed in Appendix V. By reporting side effects you can help provide more information on the safety of 

this medicine. 

 

 

5. How to store Sebivo 
 

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

 

Do not use this medicine after the expiry date which is stated on the carton after EXP. The expiry date 

refers to the last day of that month. 

 

This medicinal product does not require any special storage conditions. 

 

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

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


53 

 

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 

throw away medicines you no longer use. These measures will help to protect the environment. 

 

 

6. Contents of the pack and other information 

 

What Sebivo contains 

- The active substance is telbivudine. Each tablet contains 600 mg telbivudine. 
- The other ingredients are: cellulose, microcrystalline; povidone; sodium starch glycolate; silica, 

colloidal anhydrous; magnesium stearate; hypromellose; titanium dioxide (E171); talc; 

macrogol. 

 

What Sebivo looks like and contents of the pack 

Sebivo film-coated tablets are white to slightly yellowish, oval, film-coated tablets with “LDT” 

imprinted on one side. 

 

Sebivo film-coated tablets are supplied in packs of 28 or 98 tablets. Not all pack sizes may be 

marketed in your country. 

 

Marketing Authorisation Holder 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

Manufacturer 

Novartis Pharma GmbH 

Roonstrasse 25 

90429 Nuremberg 
Germany 

 

For any information about this medicine, please contact the local representative of the Marketing 

Authorisation Holder: 

 

België/Belgique/Belgien 

Novartis Pharma N.V. 

Tél/Tel: +32 2 246 16 11 

 

Lietuva 

Novartis Pharma Services Inc. 

Tel: +370 5 269 16 50 

 

България 

Novartis Pharma Services Inc. 

Тел.: +359 2 489 98 28 

 

Luxembourg/Luxemburg 

Novartis Pharma N.V. 

Tél/Tel: +32 2 246 16 11 

 

Česká republika 

Novartis s.r.o. 

Tel: +420 225 775 111 

 

Magyarország 

Novartis Hungária Kft. Pharma 

Tel.: +36 1 457 65 00 

Danmark 

Novartis Healthcare A/S 

Tlf: +45 39 16 84 00 

 

Malta 

Novartis Pharma Services Inc. 

Tel: +356 2122 2872 

Deutschland 

Novartis Pharma GmbH 

Tel: +49 911 273 0 

 

Nederland 

Novartis Pharma B.V. 

Tel: +31 26 37 82 111 



54 

 

Eesti 

Novartis Pharma Services Inc. 

Tel: +372 66 30 810 

 

Norge 

Novartis Norge AS 

Tlf: +47 23 05 20 00 

Ελλάδα 

Novartis (Hellas) A.E.B.E. 

Τηλ: +30 210 281 17 12 

 

Österreich 

Novartis Pharma GmbH 

Tel: +43 1 86 6570 

España 

Novartis Farmacéutica, S.A. 

Tel: +34 93 306 42 00 

 

Polska 

Novartis Poland Sp. z o.o. 

Tel.: +48 22 375 4888 

France 

Novartis Pharma S.A.S. 

Tél: +33 1 55 47 66 00 

 

Portugal 

Novartis Farma - Produtos Farmacêuticos, S.A. 

Tel: +351 21 000 8600 

Hrvatska 

Novartis Hrvatska d.o.o. 

Tel. +385 1 6274 220 

 

România 

Novartis Pharma Services Romania SRL 

Tel: +40 21 31299 01 

Ireland 

Novartis Ireland Limited 

Tel: +353 1 260 12 55 

 

Slovenija 

Novartis Pharma Services Inc. 

Tel: +386 1 300 75 50 

Ísland 

Vistor hf. 

Sími: +354 535 7000 

 

Slovenská republika 

Novartis Slovakia s.r.o. 

Tel: +421 2 5542 5439 

 

Italia 

Novartis Farma S.p.A. 

Tel: +39 02 96 54 1 

Suomi/Finland 

Novartis Finland Oy 

Puh/Tel: +358 (0)10 6133 200 

 

Κύπρος 

Novartis Pharma Services Inc. 

Τηλ: +357 22 690 690 

 

Sverige 

Novartis Sverige AB 

Tel: +46 8 732 32 00 

 

Latvija 

Novartis Pharma Services Inc. 

Tel: +371 67 887 070 

 

United Kingdom 

Novartis Pharmaceuticals UK Ltd. 

Tel: +44 1276 698370 

 

 

This leaflet was last revised in 
 

Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency website: 

http://www.ema.europa.eu 



55 

Package leaflet: Information for the user 

 

Sebivo 20 mg/ml oral solution 

Telbivudine 

 

 

Read all of this leaflet carefully before you start taking this medicine because it contains 

important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 

- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 
effects not listed in this leaflet. See section 4. 

 

What is in this leaflet 
1. What Sebivo is and what it is used for 

2. What you need to know before you take Sebivo 

3. How to take Sebivo 

4. Possible side effects 

5. How to store Sebivo 

6. Contents of the pack and other information 

 

 

1. What Sebivo is and what it is used for 

 

Sebivo contains the active substance telbivudine. Sebivo belongs to a group of medicines called 

antiviral medicines, which are used to treat infections caused by viruses. 

 

Sebivo is used to treat adults with chronic hepatitis B. Starting treatment with Sebivo should only be 

considered when it is not possible or appropriate to use an alternative medicine to which the hepatitis 

B virus is less likely to develop resistance. Your doctor will decide which treatment is most 

appropriate for you. 

 

Hepatitis B is caused by infection with the hepatitis B virus, which multiplies in the liver and causes 

liver damage. Treatment with Sebivo reduces the amount of hepatitis B virus in the body by blocking 

its growth, resulting in less liver damage and improved liver function. 

 

 

2. What you need to know before you take Sebivo 

 

Do not take Sebivo 
- if you are allergic to telbivudine or any of the other ingredients of this medicine (listed in 

section 6). 

- if you are being treated with pegylated or standard interferon alfa (see “Taking other 
medicines”). 

If this applies to you, do not take Sebivo. Talk to your doctor. 

 



56 

Warnings and precautions 

Talk to your doctor before taking Sebivo: 

- if you have or have had any kidney problems. Your doctor may order laboratory tests to check 
your kidneys are working properly before and during treatment. Depending on the results of 

these tests your doctor may advise you to change how often you take Sebivo. 

- if you suffer from cirrhosis of the liver (a serious condition which causes liver “scarring”). In 
this case your doctor will want to monitor you more closely. 

- if you have had a liver transplant. 
- if you are taking any medicines that may cause muscle problems (talk to your doctor or 

pharmacist if you are unsure). 

- if you are infected with HIV, hepatitis C or D, or are being treated with any antiviral medicines. 
If any of these applies to you, tell your doctor before you take Sebivo. 

 

During the treatment with Sebivo: 

- Sebivo can cause persistent unexplained muscle weakness or muscle pain (myopathy). Muscle 
symptoms may progress and become serious, sometimes leading to muscle breakdown 

(rhabdomyolysis) which can cause kidney damage. 

- Uncommonly Sebivo can induce numbness, tingling, pain and/or burning sensations in the arms 
and/or legs (peripheral neuropathy). 

If you experience any of these symptoms during your treatment with Sebivo, call your doctor 

immediately. 

 

Other side effects of this type of medicine 

Sebivo can cause an excess of lactic acid in the blood (lactic acidosis) which is usually associated with 

an enlargement of the liver (hepatomegaly). Lactic acidosis is a rare but serious side effect which can 

occasionally be fatal. Your doctor will monitor you regularly while you are receiving Sebivo. If you 

experience muscle pain, severe and persistent stomach pain with nausea and vomiting, severe and 

persistent trouble breathing, tiredness or abdominal discomfort while taking Sebivo, call your doctor 

immediately. 

 

Some people may get very serious hepatitis symptoms when they stop taking medicines like Sebivo. 

Your doctor will monitor your health and do regular blood tests to check your liver after you stop 

treatment with Sebivo. Tell your doctor immediately about any new or unusual symptoms that you 

notice after stopping treatment (see “If you stop taking Sebivo” in section 3 of this leaflet). 

 

Take care not to infect other people 

Even if you take Sebivo, you may still infect others with hepatitis B virus (HBV) through sexual 

contact or exposure to contaminated blood or other body fluids. If you have sexual intercourse with a 

partner who is not immune against hepatitis B, always use condoms and avoid any other exchange of 

body fluids. Never share needles. Do not share personal items that could have blood or body fluids on 

them, such as toothbrushes or razor blades. A vaccine is available to prevent infection with HBV. 

 

Children and adolescents 

Sebivo is not recommended for use in children and adolescents. 

 

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

medicines. 

 

Your doctor or pharmacist needs to know about other medicines because some medicines could affect 

your kidneys and because Sebivo mainly leaves the body via the kidneys in the urine. 

 

Do not take Sebivo if you are using pegylated or standard interferon alfa (see “Do not take Sebivo”), 

because the combination of these medicines may increase your risk of developing peripheral 

neuropathy (numbness, tingling, and/or burning sensations in the arms and/or legs). Tell your doctor 

or pharmacist if you are being treated with interferon. 

 



57 

Pregnancy and breast-feeding 

- Do not use Sebivo during pregnancy unless your doctor recommends it. If you are pregnant, 
think you may be pregnant or are planning to have a baby, ask your doctor for advice before 

taking this medicine. Your doctor will discuss with you the potential risks of taking Sebivo 

during pregnancy. 

 

- If you have hepatitis B and become pregnant, talk to your doctor about how you can best protect 
your baby. Sebivo may reduce the risk of passing your hepatitis B virus on to your unborn baby 

if taken in combination with Hepatitis B immune globulin and Hepatitis B vaccine. 

 

- Do not breast-feed during treatment with Sebivo. Tell your doctor if you are breast- feeding. 
 

Driving and using machines 
Sebivo has minor influence on the ability to drive and use machines. If you feel dizzy while taking this 

medicine, do not drive a vehicle or use any tools or machines. 

 

Sebivo contains sodium 

Sebivo oral solution contains approximately 47 mg of sodium per 600 mg dose (30 ml). If you are on a 

controlled sodium diet, ask your doctor for advice. 

 

 

3. How to take Sebivo 

 

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 

or pharmacist if you are not sure. 

 

How much Sebivo to take 

The recommended dose of Sebivo is 30 ml of oral solution (600 mg telbivudine) once a day. Take 

Sebivo at about the same time each day. It can be taken with or without food. 

 

For full instructions on how to take Sebivo, see section “Instructions for use” at the end of this leaflet. 

 

Remove the dosing cup and open the bottle. Slowly and carefully pour the solution from the bottle into 

the dosing cup until it reaches the prescribed amount. Swallow the entire contents of the dosing cup 

immediately. 

 

If you cannot measure the prescribed amount precisely using the dosing cup alone, you should use the 

oral syringe. Detailed instructions on how to use this are given in the section “Instructions for use”. 

 

Your dose may be reduced if you have kidney problems. Tell your doctor if you have, or have ever 

had, any kidney problems. 

 

How long to take Sebivo 

Continue taking Sebivo every day for as long as your doctor tells you. Do not change your dose or 

stop taking Sebivo without talking to your doctor. This medicine is intended for long-term treatment, 

possibly lasting for months or years. Your doctor will regularly monitor your condition to check that 

the treatment is having the desired effect. 

 

If you take more Sebivo than you should 

If you have taken too much Sebivo, or if someone else accidentally takes your oral solution, go to your 

doctor or hospital for advice straight away. Take the pack with you and show it to the doctor. 

 



58 

If you forget to take Sebivo 

- If you forget to take Sebivo, take it as soon as you remember and then take your next dose at its 
regular time. 

- However, if it is within 4 hours before your next dose, skip the dose you missed and take the 
next one at the usual time. 

 

Do not take a double dose to make up for a forgotten dose. This may increase the chance of you 

getting unwanted side effects. Ask your doctor or pharmacist if you are not sure what to do. 

 

If you stop taking Sebivo 

Stopping treatment with Sebivo may result in a worsening of your hepatitis B infection i.e. progression 

of the disease and abnormal test results (increase of viral load, ALT increase). Do not stop Sebivo 

unless your doctor tells you to. While you are taking Sebivo, make sure you do not run out of Sebivo. 

 

Your doctor will monitor your health and do regular blood tests to check your liver after you stop 

treatment with Sebivo since your hepatitis B infection may get worse or become very serious after 

stopping treatment. Tell your doctor immediately about any new or unusual symptoms that you notice 

after stopping treatment. 

 

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

 

 

4. Possible side effects 
 

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

 

Some side effects could be serious: 

- Persistent muscle weakness or muscle pain 
- Numbness, tingling, pain and/or burning sensation in the arms and/or legs 
If you experience any of these, call your doctor immediately. 

 

Sebivo may also cause other side effects: 

Common (may affect up to 1 in 10 people) 

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

creatine kinase 

 

Uncommon (may affect up to 1 in 100 people) 

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

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

- Excess of lactic acid in the blood (lactic acidosis) 

- Muscle breakdown (rhabdomyolysis) 

 



59 

Reporting of side effects 

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 

not listed in this leaflet. You can also report side effects directly via the national reporting system 

listed in Appendix V. By reporting side effects you can help provide more information on the safety of 

this medicine. 

 

 

5. How to store Sebivo 
 

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

 

Do not use this medicine after the expiry date which is stated on the carton and bottle label. The expiry 

date refers to the last day of that month. 

 

Do not store above 30C. Do not freeze. 

 

Use within 2 months of opening the bottle. 

 

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 

throw away medicines you no longer use. These measures will help to protect the environment. 

 

 

6. Contents of the pack and other information 

 

What Sebivo contains 

- The active substance is telbivudine. 30 ml oral solution contain 600 mg telbivudine. 
- The other ingredients are: benzoic acid, sodium saccharin, passion fruit flavouring, sodium 

hydroxide, citrc acid anhydrous, water. 

 

What Sebivo looks like and contents of the pack 

Sebivo 20 mg/ml oral solution is supplied as 300 ml of a clear, colourless to pale yellow solution in an 

brown glass bottle with a child-resistant white polypropylene closure, including a polyethylene sealing 

disc and a guarantee ring. The pack contains an oral dosing cup made of polypropylene with embossed 

graduations from 5 to 30 ml in 5 ml increments and a polypropylene oral syringe with graduations of 

1 ml to 10 ml in 0.5 ml increments. 

 

Marketing Authorisation Holder 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

Manufacturer 

Novartis Pharma GmbH 

Roonstrasse 25 

90429 Nuremberg 
Germany 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


60 

 

For any information about this medicine, please contact the local representative of the Marketing 

Authorisation Holder: 

 

België/Belgique/Belgien 

Novartis Pharma N.V. 

Tél/Tel: +32 2 246 16 11 

 

Lietuva 

Novartis Pharma Services Inc. 

Tel: +370 5 269 16 50 

 

България 

Novartis Pharma Services Inc. 

Тел.: +359 2 489 98 28 

 

Luxembourg/Luxemburg 

Novartis Pharma N.V. 

Tél/Tel: +32 2 246 16 11 

 

Česká republika 

Novartis s.r.o. 

Tel: +420 225 775 111 

 

Magyarország 

Novartis Hungária Kft. Pharma 

Tel.: +36 1 457 65 00 

Danmark 

Novartis Healthcare A/S 

Tlf: +45 39 16 84 00 

 

Malta 

Novartis Pharma Services Inc. 

Tel: +356 2122 2872 

Deutschland 

Novartis Pharma GmbH 

Tel: +49 911 273 0 

 

Nederland 

Novartis Pharma B.V. 

Tel: +31 26 37 82 111 

Eesti 

Novartis Pharma Services Inc. 

Tel: +372 66 30 810 

 

Norge 

Novartis Norge AS 

Tlf: +47 23 05 20 00 

Ελλάδα 

Novartis (Hellas) A.E.B.E. 

Τηλ: +30 210 281 17 12 

 

Österreich 

Novartis Pharma GmbH 

Tel: +43 1 86 6570 

España 

Novartis Farmacéutica, S.A. 

Tel: +34 93 306 42 00 

 

Polska 

Novartis Poland Sp. z o.o. 

Tel.: +48 22 375 4888 

France 

Novartis Pharma S.A.S. 

Tél: +33 1 55 47 66 00 

 

Portugal 

Novartis Farma - Produtos Farmacêuticos, S.A. 

Tel: +351 21 000 8600 

Hrvatska 

Novartis Hrvatska d.o.o. 

Tel. +385 1 6274 220 

 

România 

Novartis Pharma Services Romania SRL 

Tel: +40 21 31299 01 

Ireland 

Novartis Ireland Limited 

Tel: +353 1 260 12 55 

 

Slovenija 

Novartis Pharma Services Inc. 

Tel: +386 1 300 75 50 

Ísland 

Vistor hf. 

Sími: +354 535 7000 

 

Slovenská republika 

Novartis Slovakia s.r.o. 

Tel: +421 2 5542 5439 

 

Italia 

Novartis Farma S.p.A. 

Tel: +39 02 96 54 1 

Suomi/Finland 

Novartis Finland Oy 

Puh/Tel: +358 (0)10 6133 200 

 

Κύπρος Sverige 



61 

Novartis Pharma Services Inc. 

Τηλ: +357 22 690 690 

 

Novartis Sverige AB 

Tel: +46 8 732 32 00 

 

Latvija 

Novartis Pharma Services Inc. 

Tel: +371 67 887 070 

 

United Kingdom 

Novartis Pharmaceuticals UK Ltd. 

Tel: +44 1276 698370 

 

 

This leaflet was last revised in 
 

Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency website: 

http://www.ema.europa.eu 

 



62 

INSTRUCTIONS FOR USE 

 

Please read these instructions carefully so that you know how to use the solution correctly. 
 

 

 

 

1. Bottle containing the oral solution. 

2. Child-resistant screw cap with a guarantee-ring. 

Always close the bottle with the cap after use. 

3. Oral dosing cup for measuring out the dose. 

Always put the dosing cup back onto the cap 

after use and cleaning. 

4. Oral syringe for measuring out doses that cannot 

be precisely measured using the cup. 

 

 

 

Preparing a dose of medicine using the dosing cup 
 

 

1. Remove the dosing cup. 
2. Simultaneously press down (2a) and turn the child-resistant 

cap (2b) to the left to open the bottle. 

 

 

 

 

3. Before pouring any solution into the cup, please check the 
position of the appropriate graduation to avoid any potential 

waste or spillage. 

Holding the cup at eye level, carefully and slowly pour the 

prescribed amount of solution from the bottle into the dosing 

cup until the solution reaches the top of the appropriate 

graduation. 

 

Note: If the amount poured into the cup exceeds the required dose, 

discard the excess in the sink. Do not pour it back into the bottle. 

 

 

 

 

4. Drink the solution or administer it to the patient immediately. 
5. Close the bottle by screwing the cap back on tightly. 

 

 



63 

 

 

6. Immediately rinse the dosing cup with water. 
7. Remove the water from the dosing cup, wipe it with a clean 

tissue and place it back on top of the cap. 

 

 

Preparing a 6 ml dose of medicine using the oral syringe 
 

 

1. Remove the dosing cup. 
2. Simultaneously press down (2a) and turn the child-

resistant cap (2b) to the left to open the bottle. 

 

3. Before pouring any solution into the cup, please 
check the position of the 5 and 10 ml marks to avoid 

any potential waste or spillage. 

Holding the cup at eye level, carefully and slowly 

pour the solution from the bottle into the cup until it 

comes to about halfway between the 5 ml and 10 ml 

marks. 

 

4. Withdraw all the solution from the cup into the 
syringe. 

 

5. Turn the syringe to the upright position and incline it 
slightly so that the air bubbles rise to the top. 

6. Push the plunger carefully and slowly to remove the 
air until a droplet of solution appears. 



64 

 

 

7. Hold the syringe above the cup. 
8. Push the plunger slowly and carefully until the 

solution reaches the 6 ml mark. 

 

9. Immediately swallow the solution direct from the 
syringe. 

10. Discard the solution left in the cup into the sink. Do 
not pour it back into the bottle as this could cause 

contamination. 

11. Close the bottle firmly. 
12. Rinse the cup and syringe with clean water. 
13. Dry the cup with a clean tissue and place it back over 

the cap of the bottle. 

14. Allow the syringe to air-dry and store with the bottle. 

 

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET