Viread HBV Label Update

肝胆速递

Viread HBV Label Update

Viread labeling updates expand pediatric indication and add 240 week data

from the FDA Aug 27 2012

The Viread label was recently updated to include dosing information for the treatment of chronic hepatitis B infection in patients 12 years of age and older, and to add 240 week data in adults to the package insert.

The following revisions were made with respect to the pediatric information:

Section 2 Dosage and Administration was revised, stating the recommended dose for the treatment of chronic hepatitis B in pediatric patients 12 years of age and older (35 kg or more) is 300 mg once daily taken orally without regard to food.  In addition this section states the safety and efficacy in pediatric patients with chronic hepatitis B weighing less than 35 kg and in patients younger than 12 years of age have not been established.

Section 5.6 Decreases in Bone Mineral Density was updated with the following text:

In a clinical trial (Study 115) conducted in pediatric subjects 12 to less than 18 years of age with chronic hepatitis B infection, both the VIREAD and placebo treatment arms experienced an overall increase in mean lumbar spine BMD (bone mineral density) over 72 weeks, as expected for an adolescent population.  The BMD gains from baseline to Week 72 in lumbar spine and total body BMD in VIREAD-treated subjects (+5% and +3%, respectively) were less than the BMD gains observed in placebo-treated subjects (+8% and +5%, respectively).  Three subjects in the VIREAD group and two subjects in the placebo group had significant (greater than 4%) lumbar spine BMD loss at Week 72.  At baseline, mean BMD Z-scores in subjects randomized to VIREAD were −0.43 for lumbar spine and −0.20 for total body, and mean BMD Z-scores in subjects randomized to placebo were −0.28 for lumbar spine and −0.26 for total body.  In subjects receiving VIREAD for 72 weeks, the mean change in BMD Z-score was −0.05 for lumbar spine and −0.15 for total body compared to +0.07 and +0.06, respectively, in subjects receiving placebo.  As observed in pediatric studies of HIV-infected patients, skeletal growth (height) appeared to be unaffected.

Section 6.1 Adverse Reactions from Clinical Trials Experience was updated as follows:

Clinical Trials in Pediatric Subjects 12 Years of Age and Older with Chronic Hepatitis B

Assessment of adverse reactions is based on one randomized study (Study GS‑US‑174‑0115) in 106 pediatric subjects (12 to less than 18 years of age) infected with chronic hepatitis B receiving treatment with VIREAD (N = 52) or placebo (N = 54) for 72 weeks. The adverse reactions observed in pediatric subjects who received treatment with VIREAD were consistent with those observed in clinical trials of VIREAD in adults.

The mean rate of bone mineral density gain was less in VIREAD-treated subjects compared to placebo.

The following text was added to Section 8.4 Pediatric Use:

Pediatric Patients 12 Years of Age and Older with Chronic Hepatitis B
In Study 115, 106 HBeAg negative (9%) and positive (91%) subjects aged 12 to less than 18 years with chronic HBV infection were randomized to receive blinded treatment with VIREAD 300 mg (N = 52) or placebo (N = 54) for 72 weeks. At study entry, the mean HBV DNA was 8.1 log10 copies/mL and mean ALT was 101 U/L.  Of 52 subjects treated with VIREAD, 20 subjects were nucleos(t)ide-naïve and 32 subjects were nucleos(t)ide-experienced.  Thirty-one of the 32 nucleos(t)ide-experienced subjects had prior lamivudine experience. At Week 72, 88% (46/52) of subjects in the VIREAD group and 0% (0/54) of subjects in the placebo group had HBV DNA <400 copies/mL. Among subjects with abnormal ALT at baseline, 74% (26/35) of subjects receiving VIREAD had normalized ALT at Week 72 compared to 31% (13/42) in the placebo group. One VIREAD-treated subject experienced sustained HBsAg-loss and seroconversion to anti-HBs during the first 72 weeks of study participation.

Safety and effectiveness of VIREAD in pediatric patients younger than 12 years of age or less than 35 kg with chronic hepatitis B have not been established.

Section 12.3 Pharmacokinetics was updated to include the following information in pediatric subjects:

Tenofovir exposures in 52 HBV-infected pediatric subjects (12 to less than 18 years of age) receiving oral once-daily doses of VIREAD 300 mg tablet were comparable to exposures achieved in HIV-1-infected adults and adolescents receiving once-daily doses of 300 mg.

The following information was added regarding with 240 week data in adults:

Section 12.4, Microbiology Table 17 Amino Acid Substitutions in Viremic Subjects across HBV Trials of VIREAD was updated.

Section 14.2, Clinical Efficacy in Adults with Chronic Hepatitis B, the following changes were made:

Treatment Beyond 48 Weeks

In Studies 0102 (HBeAg-negative) and 0103 (HBeAg-positive), subjects who completed double-blind treatment (389 and 196 subjects who were originally randomized to VIREAD and HEPSERA, respectively) were eligible to roll over to open-label VIREAD with no interruption in treatment.

In Study 0102, 304 of 375 subjects (81%) continued in the study through Week 240. Among subjects randomized to VIREAD followed by open-label treatment with VIREAD, 82% had HBV DNA < 400 copies/mL, and 69% had ALT normalization at Week 240. Among subjects randomized to HEPSERA followed by open-label treatment with VIREAD, 88% had HBV DNA < 400 copies/mL and 76% had ALT normalization through Week 240. No subject in either treatment group experienced HBsAg loss/seroconversion through Week 240.

In Study 0103, 185 of 266 subjects (69%) continued in the study through Week 240. Among subjects randomized to VIREAD, 63% had HBV DNA < 400 copies/mL, 44% had ALT normalization, and 34% had HBeAg loss (26% seroconversion to anti-HBe antibody) through Week 240. Among subjects randomized to HEPSERA followed by up to 192 weeks of open-label treatment with VIREAD, 64% had HBV DNA < 400 copies/mL, 54% had ALT normalization, and 34% had HBeAg loss (29% seroconversion to anti-HBe antibody) through Week 240. At Week 240, HBsAg loss was 9% in both treatment groups, and seroconversion to anti-HBs was 7% for the subjects initially randomized to VIREAD and 9% for subjects initially randomized to HEPSERA.

Of the originally randomized and treated 641 subjects in the two studies, liver biopsy data from 328 subjects who received continuing open-label treatment with VIREAD monotherapy were available for analysis at baseline, Week 48 and Week 240. There were no apparent differences between the subset of subjects who had liver biopsy data at Week 240 and those subjects remaining on open-label VIREAD without biopsy data that would be expected to affect histological outcomes at Week 240. Among the 328 subjects evaluated, the observed histological response rates were 80% and 88% at Week 48 and Week 240, respectively. In the subjects without cirrhosis at baseline (Ishak fibrosis score 0-4), 92% (216/235) and 95% (223/235) had either improvement or no change in Ishak fibrosis score at Week 48 and Week 240, respectively. In subjects with cirrhosis at baseline (Ishak fibrosis score 5-6), 97% (90/93) and 99% (92/93) had either improvement or no change in Ishak fibrosis score at Week 48 and Week 240, respectively. Twenty-nine percent (27/93) and 72% (67/93) of subjects with cirrhosis at baseline experienced regression of cirrhosis by Week 48 and Week 240, respectively, with a reduction in Ishak fibrosis score of at least 2 points. No definitive conclusions can be established about the remaining study population who were not part of this subset analysis.

Across the combined HBV treatment trials, the number of subjects with lamivudine-or adefovir-resistance associated substitutions at baseline was too small to establish efficacy in this subgroup.

The complete revised label may be viewed at Drugs@FDA.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

肝胆速递

VIREAD的的HBV标签更新

VIREAD的标签更新扩大儿童的适应症和240周的数据

美国食品药品管理局2012年8月27日

最近更新VIREAD的标签，包括用于治疗慢性乙肝病毒感染患者12岁及以上的剂量信息，并增加成人240周的数据包插入。

的儿科信息进行了以下修改：

第2剂量和给药方法进行了修订，说​​明在儿童患者中12岁及以上（35公斤以上）用于治疗慢性乙型肝炎的推荐剂量是300毫克，每天一次口服，而不考虑到食品。此外，本节阐述小儿慢性乙型肝炎患者体重小于35公斤的患者年龄超过12岁还没有建立的安全性和有效性。

第5.6节的骨矿物质密度减少更新了下面的文字：

在12日至小于18岁的慢性B型肝炎感染在儿科的主题进行的一项临床试验（研究115），VIREAD和安慰剂治疗组经历了总体增长超过72周的平均腰椎骨矿物质密度（BMD） ，如预期的青少年人口。 BMD基准收益72周VIREAD治疗的患者（分别为5％和3％，），腰椎和全身骨密度均小于BMD安慰剂治疗的患者中观察到的收益（+8％和+5 ％，分别）。 72周时，三科VIREAD组和两个主题，而安慰剂组有显着性（大于4％），腰椎骨密度损失。在基线时，平均BMD Z-值随机分配到VIREAD共体，腰椎分别为-0.43和-0.20，平均腰椎BMD Z-分数受试者随机分为安慰剂组分别为-0.28和-0.26，身体总。在接受VIREAD 72周的BMD Z-得分的平均变化为-0.05，腰椎和-0.15总体相比，分别为0.07和0.06，在接受安慰剂。观察在儿科研究HIV感染的患者，骨骼生长（高）出现不会受到影响。

第6.1节的不良反应临床试验的经验，更新如下：

12岁及以上的慢性乙型肝炎的临床试验在儿科的主题

对不良反应的评估是基于一个随机对照研究（研究GS-US-174-0115），在106 VIREAD（N = 52）或安慰剂治疗慢性乙型肝炎感染的儿童受试者（12至小于18岁） （N = 54）72周。与VIREAD接受治疗的儿童主题中观察到的不良反应是与VIREAD在成人临床试验中观察到的一致。

平均骨密度收益率VIREAD治疗的患者相比，服用安慰剂。

下面的文本添加到第8.4儿童使用：

小儿12岁及以上的慢性乙型肝炎患者
在研究115，106 HBeAg阴性（9％）和阳性（91％）受试者年龄在12至小于18岁慢性HBV感染者随机接受双盲治疗VIREAD 300毫克（N = 52）或安慰剂（N = 54 ）72周。研究开始时，平均HBV DNA为8.1 log10拷贝/ mL，平均ALT为101 U / L。与VIREAD治疗的52例中，20名受试者核苷（酸）IDE的天真和32例核苷（酸）IDE经验的。三十一的32个核苷（酸）IDE经验丰富的主题之前接受过拉米夫定治疗的经验。 VIREAD组和0％（0/54），而安慰剂组的受试者科目有88％（46/52）72周时，HBV DNA <400拷贝/ ml。在基线ALT异常的受试者中，有74％（26/35）接受VIREAD有31％（13/42），而安慰剂组相比，在72周ALT复常。在第72周，参与研究的一个VIREAD治疗对象经历了持续损失的HBsAg和抗-HBs的血清转换。

VIREAD儿科患者年龄超过12岁或小于35公斤慢性乙型肝炎中的安全性和有效性尚未确立。

第12.3节药代动力学进行了更新，在儿科的主题包括以下信息：

HBV感染的婴幼儿在52例（12小于18岁）接受VIREAD 300毫克的片剂，每日一次口服剂量的替诺福韦风险与风险，实现在HIV-1感染的成年人和青少年接受每日一次的剂量300毫克。

240周的数据在成人中增加了关于以下信息：

微生物表第12.4节，17种氨基酸替换跨HBV试验VIREAD病毒血症的主题进行了更新。

第14.2节，成人慢性乙型肝炎的临床疗效，进行了以下更改：

治疗超过48周

0102（HBeAg阴性）和0103（HBeAg阳性）的研究中，受试者完成的双盲治疗（389和196谁是最初随机分配到VIREAD和阿德福韦酯，分别）可翻转到开放标签VIREAD在不中断治疗。

在研究0102，304 375人（81％）继续在研究中通过周240。在随机分配到VIREAD开放标签治疗VIREAD，82％有HBV DNA <400拷贝/ ml，69％有ALT正常化周240。在受试者随机分配到开放标签治疗VIREAD的HEPSERA其次，88％的HBV DNA <400拷贝/ ml和76％的240周，ALT正常化。两个治疗组的无主题经历了乙肝表面抗原血清周，240 /损失。

在研究0103，185，266例（69％）继续在研究中通过周240。随机分配到VIREAD，63％的HBV DNA <400拷贝/ ml，44％ALT复常，34％的HBeAg转阴周，240（26％抗-HBe抗体的血清学转换）。在高达192周的开放标签治疗VIREAD受试者随机分为阿德福韦酯后，64％的HBV DNA <400拷贝/毫升，54％的ALT正常化，和34％的HBeAg消失（29％抗-HBe血清转换抗体）通过一周240。在240周，HBsAg消失在两个治疗组，分别为9％和抗-HBs的血清转换的科目最初随机VIREAD和9％的受试者最初随机阿德福韦酯为7％。

最初随机和治疗的641科目在这两项研究中，肝活检继续开放标签的与VIREAD单药治疗的328谁收到的数据可供分析，在基线，48周和周240。周240，这些科目上剩余的开放标签VIREAD没有活检的数据，预计将影响组织的成果，在本周240科目谁了肝活检数据的子集，无显着差异。在评估328名，所观察到的组织学应答率分别为80％和88％，分别在第48周和周240。受试者在基线时无肝硬化（Ishak纤维化评分0-4），92％（216/235）和95％（223/235），无论是改善或Ishak纤维化评分没有改变，在第48周和周240。受试者在基线肝硬化（Ishak纤维化评分5-6），97％（90/93）和99％（92/93），无论是改善或Ishak纤维化评分没有改变，在第48周和周240。百分之二十九（27/93）和72％（67/93），在的基线有经验的回归肝硬化肝硬化周的主题48和周240，分别减少Ishak纤维化评分的至少2个点。没有明确的结论可以成立的其他研究人口不属于这个子集分析。

在整个的合并HBV治疗试验，受试者在基线拉米夫定或阿德福韦耐药相关替代品的数量太小，无法建立在这一亚组的疗效。

@ FDA在药物标签可以被看作完整的修订。

理查德•克莱因
办公室的特殊健康问题
食品和药物管理局（FDA）

金佰利斯特鲁布尔
抗病毒药物产品部
食品和药物管理局（FDA）

MP4

既然是中文，标题最好换成中文

咬牙硬挺

感谢分享