1. Name Of The Medicinal Product
2. Qualitative And Quantitative Composition
Each film-coated tablet contains 600 mg telbivudine.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Film-coated tablet
White to slightly yellowish, oval film-coated tablet, imprinted with “LDT” on one side.
4. Clinical Particulars
4.1 Therapeutic Indications
Sebivo is indicated for the treatment of chronic hepatitis B in adult patients with compensated liver disease and evidence of viral replication, persistently elevated serum alanine aminotransferase (ALT) levels and histological evidence of active inflammation and/or fibrosis. See section 5.1 for details of the study and specific patient characteristics on which this indication is based.
4.2 Posology And Method Of Administration
Therapy must be initiated by a physician experienced in the management of chronic hepatitis B infection.
Adults
The recommended dose of Sebivo is 600 mg (one tablet) once daily, taken orally, with or without food.
Sebivo oral solution may be considered for patients who have difficulties swallowing tablets.
Duration of therapy
The optimal treatment duration is unknown. Treatment discontinuation should be considered as follows:
• In HBeAg-positive patients without cirrhosis, treatment should be administered for at least 6-12 months after HBe seroconversion (HBeAg loss and HBV DNA loss with anti-HBe detection) is confirmed or until HBs seroconversion or there is evidence of loss of efficacy. Serum ALT and HBV DNA levels should be followed regularly after treatment discontinuation to detect any late virological relapse.
• In HBeAg-negative patients without cirrhosis, treatment should be administered at least until HBs seroconversion or until there is evidence of loss of efficacy. With prolonged treatment for more than 2 years, regular reassessment is recommended to confirm that continuation of the selected therapy remains appropriate for the patient.
On-treatment response at week 24 has been shown to be predictive of longer-term response (see Table 7 in section 5.1) and might be useful for driving the management of patients treated with telbivudine monotherapy.
Renal impairment
No adjustment of the recommended dose of telbivudine is necessary in patients whose creatinine clearance is
Table 1 Dosing regimen adjustment of Sebivo in patients with renal impairment
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* End stage renal disease
** In case use of the oral solution is not possible
The proposed dose modifications are based on extrapolation and may not be optimal. The safety and effectiveness of these dosing adjustment guidelines have not been clinically evaluated. Therefore, close clinical monitoring is recommended in these patients.
End-stage renal disease patients
For patients with ESRD, Sebivo should be administered after haemodialysis (see section 5.2).
Hepatic impairment
No adjustment to the recommended dose of Sebivo is necessary in patients with hepatic impairment (see section 5.2).
Children and adolescents
Sebivo is not recommended for use in children and adolescents below 16 years of age due to a lack of data on safety and efficacy.
Elderly patients (age above 65 years)
No data are available to support a specific dose recommendation for patients over the age of 65 years (see section 4.4).
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients.
Combination of telbivudine with pegylated or standard interferon alfa (see sections 4.4 and 4.5).
4.4 Special Warnings And Precautions For Use
Severe acute exacerbations of chronic hepatitis B are relatively frequent, and are characterised by transient elevation of serum ALT. Following initiation of antiviral treatment, serum ALT may rise in some patients while serum levels of HBV DNA fall (see section 4.8). On average, 4-5 weeks elapsed prior to the occurrence of an exacerbation in patients treated with telbivudine. Overall, ALT flares occurred more frequently in HBeAg-positive patients than in HBeAg-negative patients. In patients with compensated liver disease, this elevation of serum ALT is generally not accompanied by elevated levels of serum bilirubin or by other signs of hepatic decompensation. The risk of hepatic decompensation – and of a subsequent exacerbation of hepatitis – may be elevated in patients with cirrhosis. Such patients should therefore be closely monitored.
Exacerbations of hepatitis have also been reported in patients who have terminated treatment of hepatitis B. Post-treatment ALT flares are normally associated with increases in serum HBV DNA levels, and the majority of such cases have proven to be self-limiting. Nonetheless, there have also been reports of severe – and sometimes fatal – post-treatment disease exacerbations. Therefore, hepatic function should be monitored at regular intervals with both clinical and laboratory follow-up for at least 6 months after discontinuation of hepatitis B therapy.
Occurrence of lactic acidosis (in the absence of hypoxaemia) sometimes fatal, and usually associated with severe hepatomegaly with steatosis have been reported with the use of nucleoside/nucleotide analogues. As telbivudine is a nucleoside analogue, this risk cannot be excluded. Treatment with nucleoside analogues should be discontinued when rapidly elevating aminotransferase levels, progressive hepatomegaly or metabolic/lactic acidosis of unknown aetiology occur. Benign digestive symptoms, such as nausea, vomiting and abdominal pain, may be indicative of lactic acidosis development. Severe cases, sometimes with fatal outcome, were associated with pancreatitis, liver failure/hepatic steatosis, renal failure and higher levels of serum lactate. Caution should be exercised when prescribing nucleoside analogues to any patient (particularly obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease. These patients should be followed closely.
Muscular effects
Cases of myopathy and myalgia have been reported with telbivudine use several weeks to months after starting therapy (see section 4.8). Cases of rhabdomyolysis have been reported during post-marketing use of telbivudine (see section 4.8).
Myopathy, defined as persistent unexplained muscle aches and/or muscle weakness regardless of the degree of increases in creatine kinase levels, should be considered in any patient with diffuse unexplained myalgias, muscle tenderness, muscle weakness or myositis (defined as myopathy with histological evidence of muscle damage). Patients should be advised to report promptly any persistent unexplained muscle aches, pain, tenderness or weakness. If any of these symptoms are reported, a detailed muscle examination should be performed in order to evaluate muscle function. Telbivudine therapy should be discontinued if myopathy is diagnosed.
It is not known whether the risk of myopathy during treatment with telbivudine is increased with concurrent administration of other medicinal products associated with myopathy (e.g. statins, fibrates, or ciclosporin). Physicians considering concomitant treatment with other agents associated with myopathy should weigh carefully the potential benefits and risks and should monitor patients for any signs or symptoms suggestive of myopathy.
Peripheral neuropathy
Peripheral neuropathy has been uncommonly reported in telbivudine-treated patients. If peripheral neuropathy is suspected, treatment with telbivudine should be reconsidered (see section 4.8).
An increased risk of developing peripheral neuropathy has been observed in one study when telbivudine and pegylated interferon alfa-2a were co-administered (see section 4.5). Such increased risk cannot be excluded for other interferon alfa (pegylated or standard). Moreover, the benefit of the combination of telbivudine with interferon alfa (pegylated or standard) is not currently established. Therefore, the combination of telbivudine with pegylated or standard interferon alfa is contraindicated (see section 4.3).
Renal function
Telbivudine is eliminated primarily by renal excretion, therefore dose interval adjustment is recommended in patients with creatinine clearance < 50 ml/min, including patients on haemodialysis. The effectiveness of dosing interval adjustment has not been clinically evaluated. Therefore, virological response should be closely monitored in patients with increased dosage interval (see sections 4.2 and 5.2).
Patients with cirrhosis without decompensation
Due to the limited data available (about 3% of patients enrolled had cirrhosis), telbivudine should be used with particular caution in cirrhotic patients. These patients should be closely monitored for clinical, biochemical and virological parameters associated with hepatitis B during treatment and after treatment is discontinued.
Patients with cirrhosis with decompensation
There are no efficacy and safety data in patients with decompensated cirrhosis.
Patients with previous exposure to nucleoside/nucleotide analogs
In vitro, telbivudine was not active against the HBV strains containing rtM204V/rtL180M or rtM204I mutations (see section 5.1). Telbivudine monotherapy is not an option for patients with established lamivudine-resistant hepatitis B virus infection. Patients who failed to achieve virological response following treatment with lamivudine for more than 24 weeks are unlikely to benefit from telbivudine monotherapy. There is currently no clinical data to properly assess the benefit and risk of switching to telbivudine for lamivudine-treated patients who achieve complete viral suppression on lamivudine.
There are no data on telbivudine treatment in patients with established adefovir-resistant hepatitis B virus single mutations of rtN236T or A181V. Results from cell-based assays showed that the adefovir resistance-associated substitution A181V had 1.5- to approximately 4- fold reduced susceptibility to telbivudine.
Liver transplant recipients
The safety and efficacy of telbivudine in liver transplant recipients are unknown.
Elderly patients
Clinical studies of telbivudine did not include sufficient numbers of patients
Other special populations
Sebivo has not been investigated in co-infected hepatitis B patients (e.g. patients co-infected with human immunodeficiency virus [HIV], hepatitis C virus [HCV] or hepatitis D virus [HDV]).
General
Patients should be advised that treatment with Sebivo has not been shown to reduce the risk of transmission of HBV to others through sexual contact or blood contamination.
Telbivudine is not recommended to be used with lamivudine because in a phase II study, the treatment response observed with combination therapy of telbivudine and lamivudine was lower than with telbivudine alone.
There are currently no efficacy and safety data for other antiviral combinations with telbivudine.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Since telbivudine is eliminated primarily by renal excretion, co-administration of Sebivo with substances that affect renal function (such as aminoglycosides, loop diuretics, platinum compounds, vancomycin, amphotericin B) may affect plasma concentrations of telbivudine and/or the co-administered substance. The combination of telbivudine with these medicinal products should be used with caution. The steady-state pharmacokinetics of telbivudine were unaltered following multiple dose administration in combination with lamivudine, adefovir dipivoxil, tenofovir disoproxil fumarate, ciclosporin or pegylated interferon alfa-2a. In addition, telbivudine does not alter the pharmacokinetics of lamivudine, adefovir dipivoxil, tenofovir disoproxil fumarate or ciclosporin. No definitive conclusion could be drawn regarding the effects of telbivudine on the pharmacokinetics of pegylated interferon due to high interindividual variability of pegylated interferon alfa-2a concentrations. A clinical trial investigating the combination of telbivudine, 600 mg daily, with pegylated interferon alfa-2a, 180 micrograms once weekly by subcutaneous administration, indicates that this combination is associated with an increased risk of developing peripheral neuropathy. The mechanism behind these events is not known (see section 4.4). The combination of telbivudine with any interferon alfa-containing product is contraindicated (see section 4.3).
Telbivudine is not a substrate, inhibitor or inducer of the cytochrome P450 (CYP450) enzyme system (see section 5.2).Therefore, the potential for CYP450-mediated drug interactions involving Sebivo is low.
4.6 Pregnancy And Lactation
For telbivudine no clinical data on exposed pregnancies are available. Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). Studies in pregnant rats and rabbits showed that telbivudine crosses the placenta. Studies in pregnant rabbits showed early delivery and/or abortion secondary to maternal toxicity. Sebivo should be used during pregnancy only if the benefit to the mother outweighs the potential risk to the foetus.
There are no data on the effect of telbivudine on transmission of HBV from mother to infant. Therefore, appropriate interventions should be used to prevent neonatal acquisition of HBV infection.
Telbivudine is excreted in the milk of rats. It is not known whether telbivudine is excreted in human milk. Women should not breast-feed if they are taking Sebivo.
There are no clinical data on the effects of telbivudine on male or female fertility. In reproductive toxicology studies in adult animals, fertility was slightly reduced when both male and female rats received telbivudine. The adverse effects on fertility were greater in a separate study in juvenile animals when both sexes received telbivudine (see section 5.3).
4.7 Effects On Ability To Drive And Use Machines
No studies on the effects on the ability to drive and use machines have been performed.
4.8 Undesirable Effects
Assessment of adverse reactions is mainly based on two studies (NV-02B-007 “GLOBE” and NV-02B-015) in which 1,699 patients with chronic hepatitis B received double-blind treatment with telbivudine 600 mg/day (n = 847) or lamivudine (n = 852) for 104 weeks.
In the 104-week clinical studies, reported adverse reactions were usually classified as mild or moderate in severity. The most common adverse events with at least a possible relation to telbivudine were grade 3/4 blood creatine kinase elevations (6.8%), fatigue (4.4%), headache (3.0%) and nausea (2.6%).
Table 2 lists the adverse reactions according to MedDRA system organ class and frequency using the following convention: very common (
Table 2 Adverse reactions
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Not known* |
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Not known* |
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Based on post-marketing reports. Since these reports are from a population of uncertain size it is not possible to reliably estimate their frequency and therefore the frequency is classed as “not known”,
Creatine Kinase
In the pooled analysis, by 104 weeks of treatment Grade 3/4 creatine kinase elevations (> 7x ULN) occurred in 12.6% of telbivudine-treated patients and 4.0% of lamivudine-treated patients. Most creatine kinase elevations were asymptomatic and creatine kinase values typically decreased by the next visit on continued treatment. In the pivotal study NV-02B-007 (GLOBE), higher pre-treatment CK values and Caucasian race were identified in both treatment groups as predictive factors for Grade 3/4 elevations by 104 weeks (see section 4.4).
ALT flares
The incidence of on treatment alanine aminotransferase (ALT) flares in the two treatment arms according to AASLD (American Association for the Study of Liver Diseases) definition (ALT elevation> 2x baseline and> 10x ULN) are further described in Table 3 below.
Table 3 Summary of on treatment ALT (IU/L) flare – Pooled NV-02B-007/NV-02B-015
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Periodic monitoring of hepatic function is recommended during treatment (see section 4.4).
Exacerbations of hepatitis B after discontinuation of treatment
Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy including telbivudine (see section 4.4).
The incidence of post-treatment alanine aminotransferase (ALT) flares in the two treatment arms are further described in Table 4 below.
Table 4 Summary of post-treatment ALT flares – Pooled NV-02B-007/NV-02B-015
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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: Nucleoside and nucleotide reverse transcriptase inhibitors, ATC code: J05AF11
Telbivudine is a synthetic thymidine nucleoside analogue with activity against HBV DNA polymerase. It is efficiently phosphorylated by cellular kinases to the active triphosphate form, which has an intracellular half-life of 14 hours. Telbivudine-5'-triphosphate inhibits HBV DNA polymerase (reverse transcriptase) by competing with the natural substrate, thymidine 5'-triphosphate. Incorporation of telbivudine-5'-triphosphate into viral DNA causes DNA chain termination, resulting in inhibition of HBV replication. Telbivudine is an inhibitor of both HBV first strand (EC50 = 0.4-1.3 μM) and second strand (EC50 = 0.12-0.24 μM) synthesis, and shows a distinct preference for inhibiting second strand production. By contrast, telbivudine-5'-triphosphate at concentrations up to 100 μM did not inhibit cellular DNA polymerases α, β, or γ. In assays relating to mitochondrial structure, function and DNA content, telbivudine lacked appreciable toxic effect at concentrations up to at 10 μM 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 μM. The antiviral activity of telbivudine is specific to the hepatitis B virus and related hepadnaviruses. Telbivudine was not active against HIV in vitro. The absence of activity of telbivudine against HIV has not been evaluated in clinical trials.
Clinical experience
The safety and efficacy of long-term (104 weeks) Sebivo treatment were evaluated in two active-controlled clinical studies that included 1,699 patients with chronic hepatitis B (NV-02B-007 GLOBE and NV-02B-015).
NV-02B- 007 GLOBE study
The NV-02B-007 GLOBE study is a randomised, double-blind, multinational phase III study of telbivudine compared to lamivudine for a treatment period of 104 weeks in 1,367 nucleoside-naïve chronic hepatitis B HBeAg-positive and HBeAg-negative patients. The majority of the population enrolled was Asian. The most common HBV genotypes were B (26%) and C (51%). A small number (total of 98) of Caucasian patients were treated with telbivudine. The primary data analysis was conducted after all patients had reached week 52.
HBeAg-positive patients: The mean age of patients was 32 years, 74% were male, 82% were Asian, 12% were Caucasian, and 6% had previously received alfa-interferon therapy.
HBeAg-negative patients: The mean age of patients was 43 years, 79% were male, 65% were Asian, 23% were Caucasian, and 11% had previously received alfa-interferon therapy.
Clinical results at week 52
Clinical and virological efficacy endpoints were evaluated separately in the HBeAg-positive and HBeAg-negative patient populations. The primary endpoint of therapeutic response was a composite serological endpoint requiring suppression of HBV DNA to < 5 log10 copies/ml in conjunction with either loss of serum HBeAg or ALT normalised. Secondary endpoints included histological response, ALT normalisation, and various measures of antiviral efficacy.
Regardless of baseline characteristics, the majority of patients taking Sebivo showed histological, virological, biochemical, and serological responses to treatment. Baseline ALT levels> 2 x ULN and baseline HBV DNA < 9 log10 copies/ml were associated with higher rates of eAg seroconversion in HBeAg-positive patients. Patients who achieve HBV DNA levels < 3 log10 copies/ml by week 24 had optimal responses to treatment; conversely patients with HBV DNA levels> 4 log10 copies/ml at 24 weeks had less favourable outcomes at week 52.
In HBeAg-positive patients, telbivudine was superior to lamivudine in therapeutic response (75.3% vs 67.0% responders; p = 0.0047). In HBeAg-negative patients, telbivudine was non-inferior to lamivudine (75.2% and 77.2% responders; p = 0.6187). Caucasian ethnicity was associated with lower treatment response to both antiviral agents used in the GLOBE trial; however the Caucasian patient population was very limited (n = 98).
At week 24, 203 HBeAg-positive and 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 (NV-02B-007 GLOBE study)
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Table 6 Histological improvement and change in Ishak Fibrosis Score at week 52 (NV-02B-007 GLOBE study)
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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, PCR negativity: 56% vs 39%; p < 0.0001 and ALT normalisation of 70% vs 62%) demonstrated a widening difference at week 104 between telbivudine and lamivudine, respectively. A trend towards higher rates of HBeAg loss (35% vs 29%) and seroconversion (30% vs 25%) was also observed for telbivudine. Moreover, in the subgroup of patients with baseline ALT levels
Among HBeAg-negative patients, differences in therapeutic response (78% vs 66%) and key secondary endpoints (mean log10 HBV DNA reduction: -5.00 vs -4.17, and PCR negativity: 82% vs 57%; p < 0.0001) were higher for telbivudine up to week 104. ALT normalisation rates (78% vs 70%) continued to be higher by week 104.
Predictability at week 24
At week 24, 203 HBeAg-positive (44%) and 177 HBeAg-negative (80%) telbivudine-treated subjects achieved non-detectable HBV DNA levels.
For both HBeAg positive and negative patients, week 24 HBV DNA results were a predictor of long-term favourable outcomes. Telbivudine-treated patients who achieved PCR negativity by week 24 had the highest rates of PCR negativity and HBeAg seroconversion (in HBeAg-positive patients), and the lowest overall rates of virological breakthrough at week 104.
Outcome results at week 104, based on level of HBV DNA at week 24, for either HBeAg-positive or HBeAg-negative patients are presented in Table 7.
Table 7 Key efficacy endpoints at week 104 by serum HBV DNA levels at week 24, telbivudine patients (NV-02B-007 GLOBE)
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