FDA批准了修订的Tyzeka（替比夫定） 标示为主题的长期安全性

StephenW

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

StephenW

2013年1月28日，FDA批准了修订的Tyzeka（替比夫定）
标示为主题的长期安全性和有效性的数据，包括以前
就读于原来的两个GLOB和的NV02B-015试验谁继续
替比夫定治疗至208周。 Tyzeka是HBV的核苷
类逆转录酶抑制剂，用于治疗所示
慢性乙型肝炎成年患者病毒复制的证据
无论是血清转氨酶持续升高的证据
（ALT或AST）或组织学活动性病变。变化的主要标签
总结如下。
第6不良反应结果在208周
经过104周双盲治疗在临床试验中007 GLOBE和NV-02B-015，667
收到Tyzeka在开放标记延伸试验，CLDT600A2303。
那些最初随机Tyzeka治疗，78％的受试者（六百八十〇分之五百三十〇）
从试验007 GLOBE和82％的从试验的受试者NV-02B-015（137/167）
入选的扩展试验，并继续到Tyzeka治疗
208周。的长期Tyzeka的安全在试验CLDT600A2303人口
包括655名，包括518科007 GLOBE试验和
137试验受试者NV-02B-015。从整体安全性
汇总分析多达104个和208周是类似的。 3/4级肌酸
激酶（CK）升高发生在16％的患者（104/655）治疗
Tyzeka在试验CLDT600A2303。大多数3/4级CK升高
无症状（74％的受试者没有任何肌肉相关不良反应）
和短暂的（98％的发作持续了一两次访问（参观间隔2  -
12周）和87％的受试者有一个或两个集）。 3/4级CK
升高（93％）自发缓解或恢复至基线水平。二
在655例肌病和2案件肌炎的
Tyzeka治疗的受试者。在队列的655科目继续Tyzeka
至208周在试验CLDT600A2303，包括亚组
轻度肾功能不全的患者（n = 223）与表皮生长因子受体（EGFR每分钟60〜90毫升）
MDRD评估基线，平均估计肾小球滤过率（GFR）
并没有下降。
第12.4节微生物：
HIV-1 RNA的抗病毒活性瞬态减少已经出现在某些患者用药后的替比夫定抗逆转录病毒治疗的情况下。 “
这些减少的临床意义尚未确定。
阻力位：
2年的Tyzeka单药治疗的试用CLDT600A2303：
007 GLOBE试验的受试者中，77％（505/656）进入开放标签
CLDT600A2303继续Tyzeka长达2个额外的扩展试验
年，包括349个科目谁了HBV DNA检测不到的水平，
156谁是病毒血症在入境。 rtM204I / V替代
检测到的病毒的科目失去病毒83％（39/47）
抑制和评估的基因型数据。评估的病毒血症
进入延长的主题，25/33（76％）开发rtM204I / V
换人。总体而言，64开发的基因型耐药
Tyzeka在2年​​的新兴rtM204I / V替换的证据
在此扩展试验Tyzeka治疗。主题较高的基准
病毒载量的基因型耐药率较高，而到Tyzeka
谁取得第24周时HBV DNA水平小于300拷贝每毫升
拥有较低的利率基因型耐药Tyzeka的。所累积的
频率基因型耐药（rtM204I / V替代的出现）
IDE Tyzeka核苷（酸）治疗初治的主题分别为7％和22％
周受控007 GLOBE试验52和104，以及30％和35％的
156和208周的开放标签扩展的试验（CLDT600A2303）
（表5）。一百年67例（25％的人在
根据现有计量的007 GLOBE试验）处理Tyzeka，
建议[见适应症和用法（1.1）]。 84％
（140/167），这些科目资格在24周的持续Tyzeka
治疗（HBV DNA小于300拷贝每毫升）。追溯计算
此亚组的累积率的基因型耐药Tyzeka的
的受试者为0％，3％，12％，和16％周52，104，156，和208，
分别。

@ FDA在药物标签可以查看完整的修订。 Tyzeka
是诺华公司的产品。理查德•克莱因的特殊健康问题办公室
食品和药物管理局金佰利斯特鲁布尔部的抗病毒药物
产品食品和药物管理局（FDA）