Telbivudine Other names: Epavudine L-deoxythymidine Beta-l-thymidine

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 telbivudine oral solution, as detailed in the table below, is recommended. If use of the oral solution is not possible, telbivudine film-coated tablets could be used as an alternative and dosing should be adjusted by increasing the time interval between doses, as detailed in the following table.

Dosing regimen adjustment of telbivudine in patients with renal impairment:

* 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, telbivudine should be administered after haemodialysis.

Since telbivudine is eliminated primarily by renal excretion, co-administration of telbivudine 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.

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.

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.

Cases of myopathy and myalgia have been reported with telbivudine use several weeks to months after starting therapy. Cases of rhabdomyolysis have been reported during post-marketing use of telbivudine.

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 has been uncommonly reported in telbivudine-treated patients. If peripheral neuropathy is suspected, treatment with telbivudine should be reconsidered.

An increased risk of developing peripheral neuropathy has been observed in one study when telbivudine and pegylated interferon alfa-2a were co-administered. 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.

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.

Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. 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.

Telbivudine 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.

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 telbivudine.

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.

Telbivudine 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%).

List of adverse reactions

The following list shows 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.

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 or 4 CK elevations (>7 x 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 x baseline and >10 x ULN) are further described in table below.

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.

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 below.

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 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.