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Drug Details

SEBIVO Film-Coated Tablets

• Drug Class Description
  Antiviral for systemic use
• Generic Name
  Telbivudine
• Presentation
  Film-coated tablet White to slightly yellowish, oval film-coated tablet, imprinted with “LDT” on one side.
• Description
  Each film-coated tablet contains 600 mg telbivudine.
• 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.

• Adult Dosage
  

  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 612 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 50 ml/min. Adjustment of the dose is required in patients with creatinine clearance < 50 ml/min, including those with end-stage renal disease (ESRD) on haemodialysis. A reduction of the daily dose using Sebivo oral solution, as detailed in Table 1 below, is recommended. If use of the oral solution is not possible, Sebivo film-coated tablets could be used as an alternative and dosing should be adjusted by increasing the time interval between doses, as detailed in Table 1.

  Table 1 Dosing regimen adjustment of Sebivo in patients with renal impairment

  Creatinine clearance (ml/min)	Telbivudine 20 mg/ml oral solution Daily dose adjustment	Telbivudine 600 mg film-coated tablet Alternative** dose adjustment with increased dose intervals
  50	600 mg (30 ml) once daily	600 mg once daily
  30-49	400 mg (20 ml) once daily	600 mg once every 48 hours
  < 30 (not requiring dialysis)	200 mg (10 ml) once daily	600 mg once every 72 hours
  ESRD*	120 mg (6 ml) once daily	600 mg once every 96 hours

  * End stage renal disease

  ** In case use of the oral solution is not possible

  The proposed dose modifications are based on extrapolation and may not be optimal. The safety and effectiveness of these dosing adjustment guidelines have not been clinically evaluated. Therefore, close clinical monitoring is recommended in these patients.

  End-stage renal disease patients

  For patients with ESRD, Sebivo should be administered after haemodialysis.

  Hepatic impairment

  No adjustment to the recommended dose of Sebivo is necessary in patients with hepatic impairment.

• Child Dosage
  

  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 Dosage
  No data are available to support a specific dose recommendation for patients over the age of 65 years (See Special Precautions).
• Contra Indications
  

  Hypersensitivity to the active substance or to any of the excipients.

• Special Precautions
  

  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. On average, 45 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.

  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.

  An increased risk of peripheral neuropathy has been observed when telbivudine and pegylated interferon alfa-2a are co-administered. Such increased risk cannot be excluded for other interferons alfa (pegylated or standard). Moreover, the benefit of this combination of telbivudine with interferon alfa (pegylated or standard) is not currently established.

  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.

  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 antiviral resistant HBV infection

  Available evidence does not support the use of telbivudine monotherapy in patients with established lamivudine-resistant hepatitis B virus infection. In vitro, telbivudine was not active against the HBV strains containing rtM204V/rtL180M or rtM204I mutations. The efficacy of telbivudine against HBV harbouring the M204V mutation has not been established in clinical trials.

  There are no data on telbivudine treatment in patients with established adefovir-resistant hepatitis B virus single mutations of rtN236T or A181V. The preliminary results from the cell-based assay showed that the adefovir resistance-associated substitution A181V had 3.7 fold reduced susceptibility to telbivudine.

  The rate of genotypically confirmed telbivudine resistance in the pivotal study at 48 weeks was 2.7%.

  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 65 years of age to determine whether they respond differently from younger subjects. In general, caution must be exercised when prescribing Sebivo to elderly 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.

• Interactions
  

  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.

  Telbivudine is not a substrate, inhibitor or inducer of the cytochrome P450 (CYP450) enzyme system.Therefore, the potential for CYP450-mediated drug interactions involving Sebivo is low.

• Adverse Drug Reactions
  

  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 recorded in the pooled 104-week NV-02B-007 GLOBE and NV-02B-015 studies by system organ class and by 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). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

  Table 2 Clinical adverse reactions in patients with chronic hepatitis B, treated with telbivudine 600 mg in the pooled 104-week NV-02B-007 (GLOBE) and NV-02B-015 studies*

  Nervous system disorders
  Common	Dizziness, headache
  Uncommon	Peripheral neuropathy, dysgeusia, hypoaesthesia, paresthesia, sciatica
  Respiratory, thoracic and mediastinal disorders
  Common	Cough
  Gastrointestinal disorders
  Common	Blood amylase increased, diarrhoea, blood lipase increased, nausea, abdominal pain
  Skin and subcutaneous tissue disorders
  Common	Rash
  Musculoskeletal and connective tissue disorders
  Common	Blood creatine phosphokinase increased
  Uncommon	Arthralgia, myalgia, myopathy/myositis, pain in the extremities, back pain, muscle spasm, neck pain, flank pain
  General disorders and administration site conditions
  Common	Fatigue
  Uncommon	Malaise
  Hepatobiliary disorders
  Common	Blood alanine aminotransferase increased
  Uncommon	Aspartate aminotransferase increased

  * Due to the sample size of the pooled analysis (NV-02B-007 [GLOBE] and NV-02B-015), there are insufficient numbers of telbivudine-treated patients to detect rare and very rare events.

  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.

  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

  ALT flare: ALT elevation> 2x baseline and > 10x ULN	Lamivudine n/N (%)	Telbivudinen/N (%)
  Overall	7/852 (7.9)	41/847 (4.8)
  Baseline to week 24	25/852 (2.9)	25/847 (3.0)
  Week 24 to end of study	44/837 (5.3)">	17/834 (2.0)

  Periodic monitoring of hepatic function is recommended during treatment (see section 4.4).

   

  Exacerbations of hepatitis B after discontinuation of treatment

  Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy including telbivudine.

  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

  	Lamivudine	Telbivudine
  ALT flare	n/N (%)	n/N (%)
  ALT elevation> 2x baseline and> 10x ULN	10/180 (5.6)	9/154 (5.8)