Summary of medicine characteristics - Sebivo
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 i disease and evidence of viral replication, persistently elevat levels and histological evidence of active inflammation
Initiation of Sebivo treatment should only be consi with a higher genetic barrier to resistance is not av atients with compensated liver alanine aminotransferase (ALT)
use of an alternative antiviral agent or appropriate.
See section 5.1 for details of the study and specific patient characteristics on which this indication is based.
Posology
Adults
The recom
4.2 Posology and method of
is 600 mg (one tablet) once daily.
ation
Therapy must be initiated by infection.
ician experienced in the management of chronic hepatitis B lution may be considered for patients who have difficulties swallowing tablets.
Sebiv
toring during treatment
eatment response at week 24 has been shown to be predictive of longer-term response (see able 7 in section 5.1). HBV DNA levels should be monitored at 24 weeks of treatment to assure complete viral suppression (HBV DNA less than 300 copies/ml). For patients with detectable HBV DNA after 24 weeks of therapy, treatment modification should be considered.
HBV DNA should be monitored every 6 months to assure continued response. If patients test positive for HBV DNA at any time after their initial response, treatment modification should be considered. Optimal therapy should be guided by resistance testing.
Duration of therapy
The optimal treatment duration is unknown. Treatment discontinuation should be considered as follows:
- • In HBeAg-positive patients without cirrhosis, treatment should be administered for at least
6–12 months after HBeAg seroconversion (HBeAg loss and HBV DNA loss with anti-HBe
detection) is confirmed or until HBsAg seroconversion or there is evidence of loss of efficacy.
Serum ALT and HBV DNA levels should be followed regularly after treatment discontinuation to detect any late virological relapse.
In HBeAg-negative patients without cirrhosis, treatment should be administered at least until HBsAg seroconversion or until there is evidence of loss of efficacy. With prolonged treatment for more than 2 years, regular reassessment is recommended to confirm that continuation o 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 th dose. The next dose should be taken at the usual time.
led
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
clearance is > 50 ml/min. Adjustment of the dose is required i < 50 ml/min, including those with end-stage renal disease ( the daily dose using Sebivo oral solution, as detailed in Tab oral solution is not possible, Sebivo film-coated tablets cou
tients whose creatinine th creatinine clearance
on haemodialysis. A reduction of 1 below, is recommended. If use of the e used as an alternative and dosing
should be adjusted by increasing the time interval between doses, as detailed in Table 1.
4.3 Contraindications
4.3 ContraindicationsHypersensitivity 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 chara
transient elevation of serum ALT. Following initiation of antiviral treatment, se some patients while serum levels of HBV DNA fall (see section 4.8). On avera
prior to the occurrence of an exacerbation in patients treated with telbivudi occurred more frequently in HBeAg-positive patients than in HBeAg-n with compensated liver disease, this elevation of serum ALT is gener levels of serum bilirubin or by other signs of hepatic decompensation.
weeks elapsed
rised by may rise in
decompensation – and of a subsequent exacerbation of hepatiti cirrhosis. Such patients should, therefore, be closely monitored
. Overall, ALT flares e patients. In patients accompanied by elevated
risk of hepatic elevated in patients with
who have terminated treatment of d with increases in serum HBV DNA imiting. Nonetheless, there have also
t-treatment disease exacerbations. Therefore,
Exacerbations of hepatitis have also been reported in patie hepatitis B. Post-treatment ALT flares are normally levels, and the majority of such cases have prov been reports of severe – and sometimes fatal – p 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
Treatme
Rare post-marketing cases o often secondary to other s
muscle-related events were also associated fatal outcomes be followed c
is have been reported with telbivudine. Cases were more s conditions (e.g. rhabdomyolysis) and/or associated with
. myopathy, myositis). When secondary to other conditions, some cases
ith pancreatitis, liver failure/hepatic steatosis and renal failure. In some cases, ed when lactic acidosis was secondary to rhabdomyolysis. Patients should
elbivudine should be discontinued when metabolic/lactic acidosis of unknown
Cases of myopathy and myalgia have been reported with telbivudine use several weeks to months after starting therapy (see section 4.8). Cases of rhabdomyolysis have been reported during post-marketing use of telbivudine (see section 4.8).
Myopathy, defined as persistent unexplained muscle aches and/or muscle weakness regardless of the degree of increases in creatine kinase (CK) levels, should be considered in any patient with diffuse unexplained myalgias, muscle tenderness, muscle weakness or myositis (defined as myopathy with histological evidence of muscle damage). Patients should be advised to report promptly any persistent unexplained muscle aches, pain, tenderness or weakness. If any of these symptoms are reported, a
detailed muscle examination should be performed in order to evaluate muscle function. Telbivudine therapy should be discontinued if myopathy is diagnosed.
It is not known whether the risk of myopathy during treatment with telbivudine is increased with
concurrent administration of other medicinal products associated with myopathy (e.g. statins, fibrates,
or ciclosporin). Physicians considering concomitant treatment with other agents associated with myopathy should weigh carefully the potential benefits and risks and should monitor patients for any signs or symptoms suggestive of myopathy.
Peripheral neuropathy
Peripheral neuropathy has been uncommonly reported in telbivudine-treated patients. If peripheral neuropathy is suspected, treatment with telbivudine should be reconsidered (see section 4.8
An increased risk of developing peripheral neuropathy has been observed in one stu telbivudine and pegylated interferon alfa-2a were co-administered (see section 4.5). risk cannot be excluded for other interferon alfa (pegylated or standard). Moreover, combination of telbivudine with interferon alfa (pegylated or standard) is not cu Therefore, the combination of telbivudine with pegylated or (see section 4.3).
Renal function
ased of the hed. contraindicated
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
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 adequat
Patients with
mutati
y and safety data in patients with decompensated cirrhosis.
exposure to nucleoside/nucleotide analogues
In vitro , t
ine was not active against the HBV strains containing rtM204V/rtL180M or rtM204I section 5.1). Telbivudine monotherapy is not an option for patients with established ivudine-resistant hepatitis B virus infection. Patients who failed to achieve virological response g treatment with lamivudine for more than 24 weeks are unlikely to benefit from telbivudine therapy. There is currently no clinical data to properly assess the benefit and risk of switching to ivudine for lamivudine-treated patients who achieve complete viral suppression on lamivudine.
There are no data on telbivudine treatment in patients with established adefovir-resistant hepatitis B virus single mutations of rtN236T or A181V. Results from cell-based assays showed that the adefovir resistance-associated substitution A181V had 1.5– to approximately 4-fold reduced susceptibility to telbivudine.
Liver transplant recipients
The safety and efficacy of telbivudine in liver transplant recipients are unknown.
Elderly
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
e risk of
Sebivo has not been investigated in co-infected hepatitis B patients (e.g. patients co-in human immunodeficiency virus [HIV], hepatitis C virus [HCV] or hepatitis D virus [
General
Patients should be advised that treatment with Sebivo has not been shown to re transmission of HBV to others through sexual contact or blood contamination.
Telbivudine is not recommended to be used with lamivudine because in se 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
ther 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 coadministered substance. The combinati of telbivudine with these medicinal products should be used
with caution. The steady-state p administration in combination ciclosporin or pegylated inte
cokinetics of telbivudine were unaltered following multiple dose ivudine, adefovir dipivoxil, tenofovir disoproxil fumarate, fa-2a. In addition, telbivudine does not alter the pharmacokinetics
of lamivudine, adefovir ipivoxil, tenofovir disoproxil fumarate or ciclosporin. No definitive conclusion could be d garding the effects of telbivudine on the pharmacokinetics of pegylated
interferon due to hig terindividual variability of pegylated interferon alfa-2a concentrations. A clinical trial investigating the combination of telbivudine, 600 mg daily, with pegylated interferon
is associat events i cont
alfa-2a, 180 mi
ms once weekly by subcutaneous administration, indicates that this combination increased risk of developing peripheral neuropathy. The mechanism behind these
wn (see section 4.4). The combination of telbivudine with any interferon alfa-duct is contraindicated (see section 4.3).
dine is not a substrate, inhibitor or inducer of the cytochrome P450 (CYP450) enzyme system ction 5.2). Therefore, the potential for CYP450-mediated drug interactions involving Sebivo is ow.
4.6 Fertility, pregnancy and lactation
4.6 Fertility, pregnancy and lactationPregnancy
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.
k
Limited clinical data (less than 300 pregnancy outcomes) after exposure to telbivudine during the trimester of pregnancy indicate no malformative toxicity and a large amount of data (more than 1 pregnancy outcomes) after exposure during the second and third trimesters indicate no foetal/neo toxicity.
Sebivo should be used during pregnancy only if the benefit to the mother outweighs the pote to the foetus.
dine is excreted in human
Literature shows that exposure to telbivudine in the second and/or third trimeste been shown to reduce the risk of HBV transmission from mother to infant if tel addition to Hepatitis B immune globulin and Hepatitis B vaccine.
ancy has e is given in
Breast-feeding
Telbivudine is excreted in the milk of rats. It is not known whe milk. Women should not breastfeed if they are taking Sebivo.
Fertility
There are no clinical data on the effects of telbivud toxicology studies in adult animals, fertility was sli
received telbivudine. The adverse effects animals when both sexes received telbiv
Sebivo has minor influence
Summary of theSafc
4.8 Undesirable e
4.7 Effects on ability to driv
ee section 5.3).
ility to drive and use machines.
male or female fertility. In reproductive htly reduced when both male and female rats were greater in a separate study in juvenile
015, in which
erse reactions is mainly based on two studies, NV-02B-007 (GLOBE) and NV-02B-9 patients with chronic hepatitis B received double-blind treatment with telbivudine = 847) or lamivudine (n = 852) for 104 weeks.
Assessmen
600
4-week clinical studies, reported adverse reactions were usually classified as mild or rate in severity. The most common adverse reactions were grade 3 or 4 blood creatine kinase ), fatigue (4.4%), headache (3.0%) and nausea (2.6%).
Tabulated list of adverse reactions
Table 2 lists the adverse reactions according to MedDRA system organ class and frequency using the following convention: very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Lactic acidosis
Dizziness, headache ___________
Peripheral neuropathy, dysgeusi paresthesia, sciatica
Cough
Table 2 Adverse reactions
Metabolism and nutrition disorders
Rare*
Nervous system disorders
____Common _______ Uncommon
thesia,
Diarrhoea, blood l abdominal pain
creased, nausea,
Rash
Respiratory, thoracic and mediastinal disorders ____________________________
____Common ________________ Gastrointestinal disorders ___________
Common
Skin and subcutaneous tissue disorders
____Common _________________
Musculoskeletal and connective tissue disorders _____________________________
Uncommon
pathy/myositis, arthralgia, myalgia, pain in xtremities, back pain, muscle spasm, neck
^ain, flank pain _______________________________
Rhabdomyolysis
Fatigue
Malaise
Blood creatine phosphokinase increased, blood alanine aminotransferase increased, blood amylase increased __________________________
Aspartate aminotransferase increased
_____Rare* _______________________
General disorders and administratio
conditions _______
____Common
____Uncommon
Investigations
Common
_____Uncomi
* This adl
erse reaction was identified through post-marketing surveillance but not observed in d clinical trials. The frequency category was estimated from a statistical calculation the total number of patients exposed to telbivudine in clinical trials (n = 8,914).
ion of selected adverse reactions
eatine kinase elevation
the pooled analysis from NV-02B-007 (GLOBE) and NV-02B-015, by 104 weeks of treatment grade 3 or4 CK elevations (> 7× 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.
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 > 2× baseline and > 10× 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 > 2× baseline and > 10× 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) _ V) |
| Week 24 to end of study | 44/837 (5.3) | 17/834 (2MRV"’r |
Periodic monitoring of hepatic function is recommended during treatment (see section
Exacerbations of hepatitis B after discontinuation of treatment
Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued antihepatitis B therapy including telbivudine (see section 4.4).
The incidence of post-treatment alanine aminotransferase (ALT) further described in Table 4 below.
the two treatment arms are
Table 4 Summary of post-treatment ALT flares 02B-015 studies
ALT flare
ALT elevation > 2× baseline and > 10×
NV-02B-007 (GLOBE) and NV-
Lamivudine
n/N (%) 10/180 (5.6)
Results at 208 weeks
Telbivudine
n/N (%) 9/154 (5.8)
and 82% (137/16 CLDT600A2303 population consis 02B-015. The ov Grade 3 or 4 CK 208 week
After 104 weeks of telbivud
erapy, 78% of patients (530/680) from study NV-02B-007 (GLOBE) m study NV-02B-015 enrolled into the extension study
Rep
5.1) to continue treatment for up to 208 weeks. The long-term safety ed of 655 patients including 518 from NV-02B-007 (GLOBE) and 137 from NV-all safety profile from the pooled analysis up to 104 and 208 weeks was similar. levations newly occurred in 15.9% of patients treated with telbivudine for rade 3 or 4 CK elevations were asymptomatic and transient.
suspected adverse reactions
ing suspected adverse reactions after authorisation of the medicinal product is important. It 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
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 PROPERTIES5.1 Pharmacodynamic properties
5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic propertiesPharmacotherapeutic 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 has an intracellular half-life of 14 hours. Telbivudine-5'-triphosphate inhibits HBV DNA poly (reverse transcriptase) by competing with the natural substrate, thymidine 5'-triphosphat Incorporation of telbivudine-5'-triphosphate into viral DNA causes DNA chain termin in inhibition of HBV replication.
, resulting
Pharmacodynamic effects
and second strand ibiting second strand uP^to 100 pM did not inhibit ructure, function and DNA
Telbivudine is an inhibitor of both HBV first strand (EC50 = 0.4–1.3 pF (EC50 = 0.12–0.24 pM) synthesis, and shows a distinct preference forj production. By contrast, telbivudine-5'-triphosphate at concentratio cellular DNA polymerases a, p, or y. In assays relating to mitocho
content, telbivudine lacked appreciable toxic effect at conc increase lactic acid production in vitro.
s up to at 10 pM and did not
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 pM. 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 ev d in clinical trials. Transient reductions in HIV-1 RNA
have been reported in a small number nts after administration of telbivudine in the absence of
antiretroviral therapy. The clinic
ance of these reductions has not been determined.
Clinical experience
The safety and efficac controlled clinical studi (GLOBE
g-term (104 weeks) Sebivo treatment were evaluated in two active-at included 1,699 patients with chronic hepatitis B (NV-02B-007
5).
Study NV-02B-0O7GLOBE)
The NV-02B-007 (GLOBE) study is a randomised, double-blind, multinational phase III study of teibivUdine^Compared to lamivudine for a treatment period of 104 weeks in 1,367 nucleoside-naive ic hepatitis B HBeAg-positive and HBeAg-negative patients. The majority of the population ed was Asian. The most common HBV genotypes were B (26%) and C (51%). A small number of 98) of Caucasian patients were treated with telbivudine. The primary data analysis was ucted 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 wit either loss of serum HBeAg or ALT normalised. Secondary endpoints included histological respon 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 > baseline HBV DNA < 9 log10 copies/ml were associated with higher rates of HBeAg ser 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 l pies/ml at
d ersion in
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.
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) z | |
| Mean HBV DNA reduction from baseline (log10 copies/ml) ± SEM1,2,3 | –6.45 (0.11) | –5.54 (0.11) | –5.23 (0.13) | –4.40 (0.13)C |
| % Patients HBV DNA undetectable by PCR | 60%* | 40% | 88%* « | "Xf HkP/ />% |
| ALT normalisation4 | 77% | 75% | 74VJV | 7 79% |
seroconversion | 23% | 22% | ,–pS | – |
| HBeAg loss5 | 26% | 23% | – | |
-
1 SEM: Standard error of mean
-
2 Roche COBAS Amplicor® PCR Assay (lower limit of quantifiaation^30O 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 = 44O and 446, HBeAg-negative n = 2O3 and 2O7, 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.
hange in Ishak Fibrosis Score at week 52 in NV-02B-
Table 6 Histological improve 007 (GLOBE) study
| -----------------y | HBeAg-positive (n = 921) | HBeAg-negative (n = 446) | ||
| ^k | ^telbivudine | Lamivudine | Telbivudine | Lamivudine |
| 600 mg | 100 mg | 600 mg | 100 mg | |
| (n = 384) 1 | (n = 386) 1 | (n = 199) 1 | (n = 207) 1 | |
| Histological response 2 | ||||
| Improvement | 71% | 61% | 71% | 70% |
| ♦ No improvement | 17% | 24% | 21% | 24% |
| IshakFibrosis Score 3 | ||||
| ^Improvement | 42% | 47% | 49% | 45% |
| AMo change | 39% | 32% | 34% | 43% |
| k, Worsening | 8% | 7% | 9% | 5% |
| pissing week 52 biopsy | 12% | 15% | 9% | 7% |
| 1Patients with > one dose of study drug with evaluable baseline liver biopsies and | baseline | |||
| Knodell Histological Activity Index (HAI) score > 3. | ||||
| 2Histological response defined as a > 2 point decrease in Knodell Necroinflammatory Score from | ||||
| baseline with no worsening of the Knodell Fibrosis Score. | ||||
| 3For Ishak Fibrosis Score, improvement measured as > 1 point reduction in Ishak Fibrosis Score | ||||
| from baseline to week 52. *p = 0.0024 | ||||
Clinical results at week 104
Overall, clinical results at week 104 in telbivudine-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 > 2× 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% secondary endpoints (mean log10 HBV DNA reduction: –5.00 vs –4.17, and HBV DN 82% vs 57%; p < 0.0001) were higher for telbivudine up to week 104. ALT normalis 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% achieved undetectable HBV DNA levels.
ability:
dine-treated subjects
A results were a predictor o achieved undetectable HBV
For both HBeAg-positive and HBeAg-negative patients, week of long-term favourable outcomes. Telbivudine-treated patient 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 le HBeAg-negative patients are presented in
DNA at week 24, for either HBeAg-positive or
104 by serum HBV DNA levels at week 24, in NV-02B-007 (GLOBE) study
Table 7 Key efficacy endpoint telbivudine-treated pa
| Outcomefor | key efficacy end points at 104 weeks based on week 24 results | ||||
| HBV DNA at week 24 | ThOutic ^response n/n (%) | HBV DNA undetectability n/N (%) | HBeAg seroconversion n/N (%) | ALT normalisation n/N (%) | Virological breakthrough n/N (%) |
| HBeAg-positiv®^ | |||||
| < 300 copigs/m^P | 172/203 (85) | 166/203 (82) | 84/183 (46) | 160/194 (82) | 22/203 (11) |
| 300 copigS/ml to <3 logi0 fopies/ml | 36/57 (63) | 35/57 (61) | 21/54 (39) | 40/54 (74) | 18/57 (32) |
| S3loglQ£opics/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 logio copies/ml | 13/18 (72) | 14/18 (78) | N/A | 13/17 (76) | 4/18 (22) |
| > 3 logi0 copies/ml | 13/26 (50) | 12/26 (46) | N/A | 14/26 (54) | 12/26 (46) |
N/A = not applicable
* Virological breakthrough: “1 log above nadir” definition assessed at week 104
Study NV-02B-015
The efficacy and safety results of the NV-02B-007 (GLOBE) study were confirmed in study NV-02B-015. This study is a phase III, randomised, double-blind study of telbivudine 600 mg once daily compared to lamivudine 100 mg once daily for a treatment period of 104 weeks in 332 nucleosidenaive 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 h better outcomes at 156 and 208 weeks (Table 8).
Efficacy analysis in pooled data from NV-02B-007 (GLOBE), NV-02B-015 and CLDT600A2303 studies
Table 8
| Week 52 | Week 104 | Week ^6\j | **\Veek 208 | |
| HBeAg-positivepatients (n = 293) | ||||
| Maintained undetectable HBV DNA (< 300 copies/ml) | 70.3% (206/293) | 77.3% (218/282) | > 75.1%’ A98/264) | 76.2% (163/214) |
| Maintained undetectable HBV DNA (< 300 copies/ml) with undetectable HBV DNA at week 24 | 99.4% (161/162) | 94.9%^V (150/®8\ | ¿Z 86.7%. (130/150) | 87.9% (109/124) |
| Cumulative HBeAg seroconversion rates (%) | 27.6% (81/293) \ | Cr° V2/293) | 48.5% (142/293) | 53.2% (156/293) |
| Cumulative HBeAg seroconversion rates in patients with undetectable HBV DNA at week 24 (%) | 40.1%"X (65/^)^ | * 52.5% (85/162) | 59.3% (96/162) | 65.4% (106/162) |
| Maintained ALT normalisation | V 81S% "2(228/280) | 87.5% (237/271) | 82.9% (209/252) | 86.4% (178/106) |
| HBeAg-negative patients (n = 209) | ||||
| Maintained undetectable HBV DN^^^ (< 300 copies/ml) __ | ” 95.2% (199/209) | 96.5% (195/202) | 84.7% (160/189) | 86.0% (141/164) |
| Maintained undetectable HBVDNA (< 300 copies/ml) with^ndetectable HBV DNA at week MJ | 97.8% (175/179) | 96.5% (166/172) | 86.7% (143/165) | 87.5% (126/144) |
| Maintained ALT\orm;msition | 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 sitive and 209 HBeAg-negative).
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 logw 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 pat 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 respectively, had virological rebound with detectable HBV resistance mutation
22),
Studies NV-02B-007 (GLOBE) and CLDT600A2303 – cumulative genot The original analysis for cumulative genotypic resistance at week 104 a population and included all patients who continued treatment until 4 levels. Out of the 680 telbivudine-treated patients initially included
(GLOBE), 517 (76%) enrolled into study CLDT600A2303 for to 208 weeks. Out of these 517 patients 159 patients (HBe detectable HBV DNA.
The cumulative genotypic rates by week 104 were 10.8% (24/222) for HBeAg-negative patients.
208was based on the ITT regardless of HBV DNA ivotal study NV-02B-007 elbivudine treatment for up
itive=135, HBeAg-negative=24) had
(115/458) for HBeAg-positive patients and
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 resistanc only patients with undetectable Cumulative resistance rates negative patients in this ana
re also assessed by applying a mathematical model where A at the beginning of the respective year are considered. e 22.3% for HBeAg-positive patients and 16.0% for HBeAg-
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 48weeks and 9% (18/203) at week 104, whilst in patients with HBV DNA > 300 copies/ml resistance was 8% (20/247) at 48weeks and 39% (97/247) at wee In HBeAg-negative patients with HBV DNA < 300 copies/ml at week 24, resistance was
) at 48weeks and 5% (9/177) at week 104, whilst in patients with HBV DNA ies/ml resistance was 11% (5/44) at 48weeks and 34% (15/44) at week 104.
enotypic 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-base 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– an 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 i
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 telb
peak plasma concentration (Cmax) of telbivudine was 3.
median 3.0 hours post dose. The telbivudine area under th was 28.0 ± 8.5 pg*h/ml (mean ± SD). Inter-subject exposures (Cmax, AUC) was typically approximatel
ility (CV%) for measures of systemic
ine to healthy subjects (n = 42), the /ml (mean ± SD) and occurred at sma concentration-time curve (AUC0-v)
Effect of food on oral absorption Telbivudine absorption and exposure w with food.
ected when a single 600 mg dose was administered
Distribution
In vitro binding
Biotransformation
uman plasma proteins is low (3.3%).
No metabolite
Telbivudine
Elimi
ivudine were detected following administration of 14C-telbivudine in humans. substrate, inhibitor or inducer of the cytochrome P450 (CYP450) enzyme system.
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 pg/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 subjec
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 ent (as assessed by
creatinine clearance). Based on the results shown in Table 9, adjust he dose interval for
telbivudine is recommended in patients with creatinine clearan /min (see sections 4.2 and
4.4).
Table 9 Pharmacokinetic parameters (mean ± SD) ortelbivudme in subjects with various degrees of renal function
| Renal function ^Creatinine clearance in ml/min) | |||||
| Normal (> 80) (n = 8) 600 mg | Mild (50–80) ' SmT | * Moderate (30–49) (n = 8) 400 mg | Severe (< 30) (n = 6) 200 mg | ESRD/ Haemodialysis (n = 6) 200 mg | |
| Cmax (Mg/ml) | 3.4 ± 0.9 ( | 0.9 | 2.8 ± 1.3 | 1.6 ± 0.8 | 2.1 ± 0.9 |
| AUC , (pg*h/ml) | 28.5 ± 9/*> | S32.5 ± 10.1 | 36.0 ± 13.2 | 32.5 ± 13.2 | 67.4 ± 36.9 |
| CLRENAL (ml/min) , | 126|7±^83 | 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 nece during routine haemodialysis (see section 4.2). Telbivudine should be administered after
ysis.
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
5.3 Preclinical safety dataNon-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 telbivudi doses of 500 or 1000 mg/kg/day (lower fertility index compared to concurrent controls). There we no abnormalities in sperm morphology or function, and the testes and ovaries were histo 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 da with rats receiving the same treatment (no sibling mating). Fertility > 1000 mg/kg/day as shown by decreases in fertility and matin However the ovarian and uterine parameters of those females
70 post-partum and were mated as reduced in pairs given es, and reduced conception rate. 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 humans with normal renal function at the
2.8 times higher than those achieved in
Tablet core
Cellulose microcrystal
Povidone
Sodium starch glycolat Silica, colloidal anhydrous Magnesium stearate
6. PHARMACEUTICAL PARTI
6.1 List of excipients
Tablee
>at
ypromellose
6.2 Incompatibilities
itanium dioxide (E171) acrogol
Not applicable.
6.3 Shelf life
6.4 Special precautions for storage
6.4 Special precautions for storageThis medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
6.6 Special precautions for disposal
7. MARKETING AUTHORISATION HOLDER
7. MARKETING AUTHORISATION HOLDERNovartis Europharm Limited Frimley Business Park Camberley GU16 7SR United Kingdom
EU/1/07/388/001
EU/1/07/388/002
Detailed Agency
Date of first authorisation: 24 A
Date of latest renewal: 16 D
10. DATE OF R
8. MARKETING AUTHORISATION NUMBER(
8. MARKETING AUTHORISATION NUMBER(9. DATE OF FIRST AUTHOR
016
OF THE TEXT
on this medicinal product is available on the website of the European Medicines ww.ema.europa.eu