Sebivo

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.

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. Medicinal product no longer authorised 3 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. 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. 2). Medicinal product no longer authorised 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.

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. Medicinal product no longer authorised 8 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). 0% of lamivudine-treated patients (n = 846). Medicinal product no longer authorised 9 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.

4). 4). The incidence of post-treatment alanine aminotransferase (ALT) flares in the two treatment arms are further described in Table 4 below. 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. 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.

Severe acute exacerbations of chronic hepatitis B are relatively frequent, and are characterised by transient elevation of serum ALT. 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.

g. 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.

8). 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, aMedicinal product no longer authorised 5 detailed muscle examination should be performed in order to evaluate muscle function.

Telbivudine therapy should be discontinued if myopathy is diagnosed. 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. 8). 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.

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.

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. 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 […]

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