SEBIVO Film-coated tablet Ref.[8658] Active ingredients: Telbivudine

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.

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.

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.

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.

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).

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

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%).

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.

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:

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:

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.

Not applicable.