Approximately 760 subjects have been treated with telbivudine in clinical studies at a dose of 600 mg once daily. Assessment of adverse reactions is primarily based on the pivotal 007 GLOBE study in which 1,367 patients with chronic hepatitis B received double-blind treatment with telbivudine 600 mg/day (n=680 patients) or lamivudine (n=687 patients) for up to 104 weeks. Median duration of treatment in the 007 GLOBE study was 60 weeks for telbivudine- and lamivudine-treated patients. The safety profiles of telbivudine and lamivudine were generally comparable in this study.

Clinical Adverse Events

In clinical studies telbivudine was generally well tolerated, with most adverse experiences classified as mild or moderate in severity and not attributed to telbivudine. In the 007 GLOBE study patient discontinuations for adverse events, clinical disease progression or lack of efficacy were 0.6% for telbivudine and 2.0% for lamivudine. Frequently occurring adverse events regardless of attributability to telbivudine were upper respiratory tract infection (14%), fatigue and malaise (12%), abdominal pain (12%), nasopharyngitis (11%), headache (11%), blood CPK increased (9%), cough (7%), nausea and vomiting (7%), influenza and influenza-like symptoms (7%), post-procedural pain (7%), diarrhea and loose stools (7%), pharyngolaryngeal pain (5%), pyrexia (4%), arthralgia (4%), rash (4%), back pain (4%), dizziness (4%), myalgia (3%), insomnia (3%), and dyspepsia (3%).

Frequently occurring adverse events regardless of attributability to lamivudine were headache (14%), upper respiratory tract infection (13%), abdominal pain (13%), fatigue and malaise (11%), nasopharyngitis (10%), influenza and influenza-like symptoms (8%), blood CPK increased (7%), cough (6%), post-procedural pain (6%), nausea and vomiting (6%), dyspepsia (5%), diarrhea and loose stools (5%), dizziness (5%), pharyngolaryngeal pain (4%), rash (4%), hepatic/RUQ pain (4%), arthralgia (4%), back pain (4%), pyrexia (3%), rhinorrhea (3%), ALT increased (3%), and pruritus (3%).

Selected, treatment-emergent, clinical adverse events of moderate to severe intensity, without consideration of study drug causality, during the pivotal 007 GLOBE study clinical trial are presented in Table 4.

Table 4. Selected Treatment-Emergent Clinical Adverse Events^a (Grade 2-4) of Moderate to Severe Intensity Reported in the 007 GLOBE Study

Frequencies of selected treatment-emergent laboratory abnormalities in the 007 GLOBE study are listed in Table 5.

Table 5. Selected Treatment-Emergent Grade 3-4 Laboratory Abnormalities¹ in Patients with Chronic Hepatitis B in the 007 GLOBE Study

Creatine kinase (CK) elevations were more frequent among subjects on telbivudine treatment, as shown above in Table 5. CK elevations occurred in both treatment arms; however median CK levels were higher in telbivudine-treated patients by Week 52. Grade 1-4 CK elevations occurred in 72% of telbivudine-treated patients and 42% of lamivudine-treated patients, whereas Grade 3/4 CK elevations occurred in 9% of telbivudine-treated patients and 3% of lamivudine-treated patients. Most CK elevations were asymptomatic but the mean recovery time was longer for subjects on telbivudine than subjects on lamivudine. While there was not a uniform pattern with regard to the type of adverse event and timing with respect to the CK elevation, 8% of telbivudine-treated patients with Grade 1-4 CK elevations experienced a CK-related adverse event¹ (within a 30-day window) compared to 6% of lamivudine-treated patients. In this subgroup of patients with CK-related adverse events, 9% of telbivudine-treated patients subsequently interrupted or discontinued study drug. These patients recovered after study drug discontinuation or interruption. Less than 1% of telbivudine-subjects overall (n=3/680) were diagnosed with myopathy with muscular weakness; these patients also recovered after study drug discontinuation (See WARNINGS, Skeletal Muscle).

As shown in Table 5, on-treatment ALT elevations were more frequent on lamivudine treatment. Additionally, the overall incidence of on-treatment ALT flares, using AASLD criteria (ALT > 10 x ULN and > 2.0 x baseline), was slightly higher in the lamivudine arm (5.1%) than the telbivudine arm (3.2%). The incidence of ALT flares was similar in the two treatment arms in the first six months. ALT flares occurred less frequently in both arms after Week 24, with a lower incidence in the telbivudine arm (0.4%) compared to the lamivudine arm (2.2%). For both lamivudine and telbivudine subjects, the occurrence of ALT flares was more common in HBeAg positive subjects than in HBeAg negative subjects. Periodic monitoring of hepatic function is recommended during treatment.

Exacerbations of Hepatitis After Discontinuation of Treatment (See WARNINGS) There are insufficient data on post-treatment exacerbations of hepatitis after discontinuation of telbivudine treatment.

Drug Abuse and Dependence

Telbivudine is not a controlled substance and no potential for dependence has been observed.

Telbivudine is excreted mainly by passive diffusion so the potential for interactions between telbivudine and other drugs eliminated by renal excretion is low. However, because telbivudine is eliminated primarily by renal excretion, co-administration of telbivudine with drugs that alter renal function may alter plasma concentrations of telbivudine.

References

¹ Includes preferred terms: back pain, chest wall pain, non-cardiac chest pain, chest discomfort, flank pain, muscle cramp, muscular weakness, MSK pain, MSK chest pain, MSK discomfort, MSK stiffness, myalgia, myofascial pain syndrome, myopathy, myositis, neck pain, non-cardiac chest pain, and pain in extremity.

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