On January 28, 2013, FDA approved revisions to the Tyzeka
(telbivudine) label to include long-term safety and efficacy data for
subjects previously enrolled in the original two year GLOB and NV02B-015
trials who continued telbivudine treatment for up to 208 weeks.
Tyzeka is an HBV nucleoside analogue reverse transcriptase inhibitor
indicated for the treatment of chronic hepatitis B in adult patients
with evidence of viral replication and either evidence of persistent
elevations in serum aminotransferases (ALT or AST) or histologically
active disease.
The major label changes are summarized below.
Section 6 Adverse Reactions
Results at 208 Weeks
After 104 weeks of blinded therapy in trials 007 GLOBE and
NV-02B-015, 667 subjects received Tyzeka in an open-label extension
trial, CLDT600A2303. Of those initially randomized to Tyzeka therapy,
78% of subjects (530/680) from trial 007 GLOBE and 82% (137/167) of
subjects from trial NV-02B-015 enrolled into the extension trial and
continued Tyzeka treatment for up to 208 weeks. The long-term Tyzeka
safety population in trial CLDT600A2303 consisted of 655 subjects,
including 518 subjects from trial 007 GLOBE and 137 subjects from trial
NV-02B-015.
The overall safety profile from the pooled analysis up to 104 and 208
weeks was similar. Grade 3/4 creatine kinase (CK) elevations occurred
in 16% of subjects (104/655) treated with Tyzeka in trial CLDT600A2303.
Most grade 3/4 CK elevations were asymptomatic (74% of subjects without
any muscle related adverse reaction) and transient (98% of episodes
lasted one or two visits (visit interval 2 - 12 weeks) and 87% of
subjects had one or two episodes). Most grade 3/4 CK elevations (93%)
resolved spontaneously or returned to baseline levels. Two cases of
myopathy and two cases of myositis were reported in the 655
Tyzeka-treated subjects.
Among the cohort of 655 subjects continuing Tyzeka for up to 208
weeks in trial CLDT600A2303, including the subgroup of patients (n=223)
with mild renal impairment (eGFR 60-90 mL per min) at baseline, mean
estimated Glomerular filtration rate (GFR) assessed by MDRD did not decline.
Section 12.4 Microbiology: Antiviral Activity
Transient reductions in HIV-1 RNA have been seen in some patients
after administration of telbivudine in the absence of antiretroviral
therapy. The clinical significance of these reductions has not been
determined.
Resistance:
Trial CLDT600A2303: After 2 years of Tyzeka monotherapy in the
007 GLOBE trial, 77% (505/656) of subjects entered the open-label
CLDT600A2303 extension trial to continue Tyzeka for up to 2 additional
years, including 349 subjects who had undetectable levels of HBV DNA and
156 subjects who were viremic at entry. The rtM204I/V substitution was
detectable in the virus from 83% (39/47) of the subjects losing viral
suppression and having evaluable genotypic data. Of evaluable viremic
subjects entering the extension, 25/33 (76%) developed rtM204I/V
substitutions. Overall, 64 subjects developed genotypic resistance to
Tyzeka with evidence of emerging rtM204I/V substitutions during the 2
years of Tyzeka treatment in this extension trial.
Subjects with higher baseline viral load had higher rates of
genotypic resistance to Tyzeka, while subjects who achieved HBV DNA
levels less than 300 copies per mL at Week 24 had lower rates of
genotypic resistance to Tyzeka. The cumulative frequency of genotypic
resistance (emergence of the rtM204I/V substitution) to Tyzeka in
nucleos(t)ide treatment-naïve subjects was 7% and 22% at Weeks 52 and
104 of the controlled 007 GLOBE trial, and 30% and 35% at Weeks 156 and
208 of the open-label extension trial (CLDT600A2303), respectively
(Table 5).
One-hundred-sixty-seven subjects (25% of those in the 007 GLOBE
trial) were treated with Tyzeka according to current dosing
recommendations [see Indications and Usage (1.1)]. Eighty-four
percent (140/167) of these subjects qualified at 24 weeks for continued
Tyzeka treatment (HBV DNA less than 300 copies per mL). Retrospective
calculation of the cumulative rate of genotypic resistance to Tyzeka for
this subgroup of subjects was 0%, 3%, 12%, and 16% at Weeks 52, 104,
156, and 208, respectively.
The complete revised label can be viewed at Drugs@FDA.
Tyzeka is a product of Novartis.
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
No comments:
Post a Comment