文档库

最新最全的文档下载
当前位置:文档库 > 注射用美曲普汀(metreleptin for injection)说明书翻译对照

注射用美曲普汀(metreleptin for injection)说明书翻译对照

FULL PRESCRIBING INFORMATION

注射用美曲普汀(metreleptin for injection)说明书翻译对照

1.1 Patients with Generalized Lipodystrophy 全身性脂肪代谢障碍患者

MYALEPT (metreleptin for injection) is indicated as an adjunct to diet as replacement therapy to treat the complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy.

本药用于辅助饮食,用作补充疗法治疗先天性或获得性全身性脂肪代谢障碍患者瘦素缺乏的并发症。

Limitations of Use 使用限制

The safety and effectiveness of MYALEPT for the treatment of complications of partial lipodystrophy have not been established.

本药用于治疗局部脂肪代谢障碍的安全性及有效性尚未建立。

The safety and effectiveness of MYALEPT for the treatment of liver disease, including nonalcoholic steatohepatitis (NASH), have not been established.

本药用于治疗肝病,包括非酒精性脂肪肝炎(NASH)的安全性及有效性尚未建立。MYALEPT is not indicated for use in patients with HIV-related lipodystrophy.

本药不用于HIV感染相关的脂肪代谢障碍。

MYALEPT is not indicated for use in patients with metabolic disease, including diabetes mellitus and hypertriglyceridemia, without concurrent evidence of congenital or acquired generalized lipodystrophy.

在没有并发先天性或获得性全身脂肪代谢障碍证据时,本药不用于代谢疾病,包括糖尿病和高三酰甘油血症。

2 DOSAGE AND ADMINISTRATION 用法用量

2.1 Recommended Dosing 推荐剂量

See Table 1 for the recommended daily dose and maximum recommended daily dose in adults and pediatric patients.

表1中列出成人及儿童日推荐剂量及日推荐最大剂量。

Based on clinical response (e.g., inadequate metabolic control) or other considerations (e.g., tolerability issues, excessive weight loss [especially in pediatric patients]), MYALEPT dosage may be decreased or increased to the maximum dosage listed in Table 1.

依照临床反应(如代谢控制不充分)及其他注意事项[如耐受性、体重急剧下降(尤其是儿童)],本药剂量应按照表1所列减量或增量至最大剂量。

注射用美曲普汀(metreleptin for injection)说明书翻译对照

administered any time of day without regard to the timing of meals.

本药应在每日同一时间给药,一日1次。可不考虑进餐时间,于任意时间给药。

Instruct patients that if a dose is missed, administer the dose as soon as noticed, and resume the normal dosing schedule the next day.

如患者漏用一剂,应在记起时尽快补用,次日应按平常时间给药。

2.2 MYALEPT Preparation and Storage 制备和贮存

Healthcare practitioners should provide proper training to patients and caregivers regarding how to prepare and administer the correct dose of MYALEPT prior to self-use. The patients and caregivers should prepare and administer the first dose of MYALEPT under the supervision of a qualified healthcare professional.

医生应在患者自行用药前,训练患者及监护人如何配置和使用正确剂量。患者及监护人第一次配置和使用药物时应有医生监护。

Instruct patients to store the vials of lyophilized powder in their carton in the refrigerator as soon as received [see How Supplied/Storage and Handling (16.2)].

患者在领取本药后应尽快储存至冰箱。

MYALEPT can be reconstituted aseptically with 2.2 mL of sterile Bacteriostatic Water for Injection (BWFI), USP (0.9% benzyl alcohol), or with 2.2 mL of sterile Water for Injection (WFI).

本药可用2.2ml无菌注射用水(BWFI)、0.9%苯甲醇(USP)或2.2ml无菌注射用水(WFI)配置。

When reconstituted in BWFI, MYALEPT solution can be used within 3 days when stored in the

refrigerator between 36°F and 46°F (2°C and 8°C) and protected from light [see How

Supplied/Storage and Handling (16.2)]. Discard unused reconstituted solution after 3 days. Attach the supplied sticker to the vial and enter the discard date.

使用BWFI配置时,本药于2℃-8℃避光储存时应于3日内使用。3日后丢弃未使用的溶液。应在小瓶上贴上使用和废弃日期的标签。

For use in neonates and infants, reconstitute with preservative-free sterile WFI [see Warnings and Precautions (5.7) and Use in Specific Populations (8.4)]. When reconstituted in sterile WFI, MYALEPT should be administered immediately. Unused reconstituted solution cannot be saved for later use and should be discarded.

用于新生儿及婴幼儿时,应使用无防腐剂的无菌WFI配制。当使用无菌WFI配制时,本药应立即使用。未使用的溶液不可储存稍后使用,应丢弃。

Reconstitution of the Lyophilized Powder 冻干粉末配制

Instruct patients to follow the directions below for reconstitution of the lyophilized powder:

患者应按下列指示配制冻干粉末:

a) Remove the vial containing the MYALEPT lyophilized powder from the refrigerator and allow the vial to warm to room temperature prior to use.

使用前应将含本药冻干粉末的小瓶从冰箱中取出,置于室温下。

b) Visually inspect the vial containing MYALEPT. The cake of lyophilized powder should be intact and white in color.

观察小瓶,冻干粉末块应完整且为白色。

c) Using a 3-mL syringe with a 22-gauge or smaller diameter needle withdraw 2.2 mL of sterile Bacteriostatic Water for Injection (BWFI) or preservative-free sterile Water for Injection (WFI). Do not reconstitute MYALEPT with other diluents.

使用口径22-ga以下的3ml注射器抽取2.2ml BWFI或无防腐剂的WFI,不要使用其他稀释剂配制。

d) Inject the BWFI or WFI into the vial containing the lyophilized powder of MYALEPT, slowly injecting down the side of the vial. It is normal for some bubbles to form.

将BWFI或WFI注入含本药粉末的小瓶中,缓慢注入小瓶一侧,出现起泡是正常现象。e) Remove the needle and syringe from the vial and gently swirl the contents to reconstitute. Do not shake or vigorously agitate. When properly mixed, the MYALEPT reconstituted solution should be clear and free of clumps or dry powder, bubbles or foam. Do not use the solution if discolored or cloudy, or if particulate matter remains.

移除针头,缓慢旋转混合,不得摇晃或剧烈搅动。完全混合后,配制好的溶液应清澈且无冻干块状物或粉末、起泡、白沫。不要使用变色或混浊或有颗粒物的溶液。

f) Regarding the compatibility of MYALEPT reconstituted solution with other solutions:

本药配制后的溶液与其他溶液的兼容性:

Do not mix with, or transfer into, the contents of another vial of MYALEPT.

不得与含本药的另一小瓶混合或倒入含本药的另一小瓶。

Do not add other medications, including insulin. Use a separate syringe for insulin injections.

不得添加其他药物,包括胰岛素。使用单独的注射器注射胰岛素。

See the MYALEPT Instructions for Use for complete administration instructions. The instructions can also be found at http://www.wendangku.net/doc/f733bdab4b35eefdc9d33375.html.

见本药说明书中完整的给药说明。

2.3 Administration Instructions 给药说明

Healthcare practitioners should instruct patients and caregivers on the proper subcutaneous injection technique with care to avoid intramuscular injection in patients with minimal subcutaneous adipose tissue. Never administer MYALEPT intravenously or intramuscularly.

医生应指导患者及监护人皮下注射的技巧,避免于患者皮下最小的脂肪组织中肌内注射。不得静脉注射或肌内注射。

Instruct patients to follow the recommended injection technique:

患者应按下列推荐注射技巧注射:

a) Using a 1-mL syringe with a needle appropriate for subcutaneous injection, withdraw the prescribed dose of MYALEPT reconstituted solution.

使用适用于皮下注射的1ml注射器,从配置好的溶液中抽取规定剂量。

b) Remove any large air pockets or large bubbles from the filled syringe prior to administration. Some small bubbles may remain in the syringe.

注射前去除填装后的注射器中的大气泡或大泡沫,一些小泡沫可留在注射器中。

c) Administer MYALEPT into the subcutaneous tissue of the abdomen, thigh or upper arm. Advise patients to use a different injection site each day when injecting in the same region. After choosing an injection site, pinch the skin and at a 45-degree angle, inject the MYALEPT reconstituted solution subcutaneously. Avoid intramuscular injection, especially in patients with minimal subcutaneous adipose tissue.

于腹部、大腿、上皮的皮下注射。在注射同一区域时,每日注射部位应不同。确定注射部位后,以45°捏起皮肤,经皮下注射溶液。应避免肌内注射,尤其是有皮下最小的脂肪组织的患者。

d) Doses exceeding 1 mL can be administered as two injections (the total daily dose divided equally) to minimize potential injection-site discomfort due to injection volume. When dividing doses due to volume, doses can be administered one after the other.

剂量超过1ml可分2次注射(日剂量均分)以降低因注射剂量所致的注射部位不适。当分为2剂时。可于前一剂注射后注射。

Do not mix MYALEPT with insulin. Use a separate syringe for each medication. If MYALEPT and insulin are administered at the same time of day, they may be injected in the same body area using two different injection sites.

本药不得与胰岛素混合。药物皆使用单独的注射器。如本药与胰岛素在同一时间用药,可于同一区域不同注射部位注射。

See the MYALEPT Instructions for Use for complete administration instructions. The instructions can also be found at http://www.wendangku.net/doc/f733bdab4b35eefdc9d33375.html.

2.4 Dosage Adjustments of Medications Known to Cause Hypoglycemia 可引起低血糖药物的剂量调整

Dosage adjustments, including possible large reductions, of insulin or insulin secretagogue (e.g., sulfonylurea) may be necessary in some patients to minimize the risk of hypoglycemia [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)]. Closely monitor blood glucose in patients on concomitant insulin therapy, especially those on high doses, or insulin secretagogue (e.g., sulfonylurea) when treating with MYALEPT.

某些使用胰岛素或胰岛素促分泌素(如磺酰脲类药)的患者可能需要调整剂量(包括大量减量)以最小化低血糖风险。接受本药治疗期间,如与胰岛素(尤其是高剂量)或胰岛素促分泌素(如磺酰脲类药)合用应密切监测血糖。

2.5 Discontinuation in Patients at Risk for Pancreatitis 有胰腺炎风险患者应停药

When discontinuing MYALEPT therapy in patients with risk factors for pancreatitis (e.g., history of pancreatitis, severe hypertriglyceridemia), tapering of the dose over a one-week period is recommended. During tapering, monitor triglyceride levels and consider initiating or adjusting the dose of lipid-lowering medications as needed. Signs and/or symptoms consistent with pancreatitis should prompt an appropriate clinical evaluation.

有胰腺炎风险(如胰腺炎史、严重高三酰甘油血症)患者停止本药治疗时,推荐1周的缓慢

减量期。减量阶段,应监测三酰甘油水平,如有需要,可考虑开始或调整降脂药的剂量。胰腺炎体征和/或症状持续应进行适当的临床评估。

3 DOSAGE FORMS AND STRENGTHS 剂型和规格

For Injection: 11.3 mg of metreleptin supplied in a vial as a sterile, white, solid, lyophilized cake (delivers 5 mg per mL of metreleptin when reconstituted with 2.2 mL of BWFI or WFI).

冻干粉针11.3mg每小瓶。

4 CONTRAINDICATIONS 禁忌症

4.1 General Obesity 普通肥胖

MYALEPT is contraindicated in patients with general obesity not associated with congenital leptin deficiency. MYALEPT has not been shown to be effective in treating general obesity, and the development of anti-metreleptin antibodies with neutralizing activity has been reported in obese patients treated with MYALEPT [see Warnings and Precautions (5.1)].

本药禁用于与先天性瘦素缺乏无关的普通肥胖。本药用于普通肥胖时无效,且接受本药治疗的肥胖患者出现有中和作用的抗美曲普汀抗体。

4.2 Hypersensitivity 超敏性

MYALEPT is contraindicated in patients with prior severe hypersensitivity reactions to metreleptin or to any of the product components. Known hypersensitivity reactions have included urticaria and generalized rash [see Warnings and Precautions (5.6)].

本药禁用于先前对美曲普汀或本药任一成分有严重超敏反应者。已知的超敏反应包括荨麻疹和全身性皮疹。

5 WARNINGS AND PRECAUTIONS 警告和注意事项

5.1 Risk for Development of Antibodies that Neutralize Endogenous Leptin and/or MYALEPT

出现中和内源性瘦素和/或本药的抗体风险

Anti-metreleptin antibodies with in vitro neutralizing activity to leptin associated with adverse events consistent with loss of endogenous leptin activity and/or loss of efficacy have been identified in two patients with generalized lipodystrophy treated with MYALEPT (severe infections, increases in HbA1c and triglycerides), and in three patients without lipodystrophy who received MYALEPT in clinical studies (excessive weight gain, development of glucose intolerance or diabetes mellitus).

抗美曲普汀抗体在体外中和瘦素活性所致不良事件与在临床研究中,2名全身性脂肪代谢障碍患者(严重感染、糖化血红蛋白及三酰甘油升高)及3名无脂肪代谢障碍患者(体重急剧增加、葡萄糖不耐受及糖尿病)接受本药治疗出现内源性瘦素活性降低和/或疗效降低相一致。

The clinical implications associated with development of antimetreleptin antibodies with neutralizing activity are not well characterized at this time due to the small number of reports. Test for anti-metreleptin antibodies with neutralizing activity in patients who develop severe infections or show signs suspicious for loss of MYALEPT efficacy during treatment. Contact Bristol

Myers-Squibb at 1-866-216-1526 for neutralizing antibody testing of clinical samples [see Adverse Reactions (6.2)].

因报告数量少,这些中和抗体的影响特征不明。患者在治疗过程中有本药疗效降低的可疑体征或出现严重感染应检测有中和作用的抗美曲普汀抗体。

5.2 Lymphoma 淋巴瘤

Three cases of T-cell lymphoma have been reported in the MYALEPT lipodystrophy program; all three patients had acquired generalized lipodystrophy. Two of these patients were diagnosed with peripheral T-cell lymphoma while receiving MYALEPT. Both had immunodeficiency and significant hematologic abnormalities including severe bone marrow abnormalities before the start

of MYALEPT treatment. A separate case of anaplastic large cell lymphoma was reported in a patient receiving MYALEPT who did not have hematological abnormalities before treatment.

本药用于脂肪代谢障碍时有3例T细胞淋巴瘤报道,3名患者皆为获得性全身性脂肪代谢障碍。其中2名在接受本药治疗时诊断为外周T细胞淋巴瘤,治疗前2者皆有免疫缺陷及显著的血液学异常(包括严重骨髓异常)。另一名患者治疗前无血液学异常,出现间变性大细胞淋巴瘤。

Lymphoproliferative disorders, including lymphomas, have been reported in patients with acquired generalized lipodystrophy not treated with MYALEPT. A causal relationship between MYALEPT treatment and the development and/or progression of lymphoma has not been established. Acquired lipodystrophies are associated with autoimmune disorders, and autoimmune disorders are associated with an increased risk of malignancies including lymphomas.

淋巴组织增生病,包括淋巴瘤,在未接受本药治疗的获得性脂肪代谢障碍患者中也有报道。尚未建立接受本药治疗和出现淋巴瘤和/或淋巴瘤进展的因果关系。获得性脂肪代谢障碍与自体免疫性疾病有关,而自体免疫性疾病又与恶性肿瘤(包括淋巴瘤)风险增加有关。The benefits and risks of MYALEPT treatment should be carefully considered in patients with acquired generalized lipodystrophy and/or those with significant hematologic abnormalities (including leukopenia, neutropenia, bone marrow abnormalities, lymphoma, and/or lymphadenopathy).

有获得性全身性脂肪代谢障碍和/或明显血液学异常(包括白细胞减少、中性粒细胞减少、骨髓异常、淋巴瘤和/或淋巴结病)的患者应仔细权衡用药利弊。

5.3 MYALEPT REMS Program REMS项目

MYALEPT is available only through a restricted distribution program under a REMS, called the MYALEPT REMS Program, because of the risks associated with the development of antimetreleptin antibodies that neutralize endogenous leptin and/or MYAELPT and the risk for lymphoma [see Warnings and Precautions (5.1, 5.2)].

本药仅在通过REMS时才可使用,因有出现可中和内源性瘦素和/或本药的抗美曲普汀抗体和淋巴瘤风险。

Notable requirements of the MYALEPT REMS Program include the following:

REMS项目注意点包括:

Prescribers must be certified with the program by enrolling and completing training.

开处方者必须通过登记和完成训练进行认证。

Pharmacies must be certified with the program and only dispense MYALEPT after receipt of the MYALEPT REMS Prescription Authorization Form for each new prescription.

Further information is available at http://www.wendangku.net/doc/f733bdab4b35eefdc9d33375.html or 1-855-6MYALEPT.

药房必须进行认证且仅在收到处方的处方授权书后才可发药。

5.4 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues

本药与胰岛素及胰岛素促分泌素合用时的低血糖风险

Dosage adjustments, including possible large reductions, of insulin or insulin secretagogue (e.g., sulfonylurea) may be necessary in some patients to minimize the risk of hypoglycemia [see Dosage and Administration (2.4) and Adverse Reactions (6.1)]. Closely monitor blood glucose in patients on concomitant insulin therapy, especially those on high doses, or insulin secretagogue (e.g., sulfonylurea), when treating with MYALEPT.

某些使用胰岛素或胰岛素促分泌素(如磺酰脲类药)的患者可能需要调整剂量(包括大量减量)以最小化低血糖风险。接受本药治疗期间,如与胰岛素(尤其是高剂量)或胰岛素促分泌素(如磺酰脲类药)合用应密切监测血糖。

5.5 Autoimmunity 自身免疫性

Leptin plays a role in immune system homeostasis. Acquired lipodystrophies are associated with

autoimmune disorders including autoimmune hepatitis and membranoproliferative glomerulonephritis. Cases of progression of autoimmune hepatitis and membranoproliferative glomerulonephritis (associated with massive proteinuria and renal failure) were observed in some patients with acquired generalized lipodystrophy treated with MYALEPT. A causal relationship between MYALEPT treatment and the development and/or progression of autoimmune disease has not been established. The potential benefits and risks of MYALEPT treatment should be carefully considered in patients with autoimmune disease.

瘦素在免疫系统平衡中发挥着作用。获得性脂肪代谢障碍与自体免疫性疾病有关,包括自身免疫性肝炎及膜性增生性肾小球肾炎。在某些接受本药治疗的获得性脂肪代谢患者中可见自身免疫性肝炎进展及膜性增生性肾小球肾炎(与大量蛋白尿和肾衰竭有关)。尚未建立接受本药治疗和出现自体免疫性疾病和/或自体免疫性疾病进展的因果关系。有自体免疫性疾病着应权衡用药利弊。

5.6 Hypersensitivity超敏性

There have been reports of generalized hypersensitivity (e.g., urticaria or generalized rash) in patients taking MYALEPT. If a hypersensitivity reaction occurs, instruct the patient to promptly seek medical advice regarding discontinuation of MYALEPT.

接受本药治疗的患者有全身性超敏反应(如荨麻疹或全身性皮疹)报道,如出现超敏反应,应立即就医以了解停用本药的建议。

5.7 Benzyl Alcohol Toxicity 苯甲醇的毒性

MYALEPT contains benzyl alcohol when reconstituted with BWFI. MYALEPT contains no preservative when reconstituted with sterile Water for Injection (WFI). Preservative-free WFI is recommended for use in neonates and infants. The preservative benzyl alcohol has been associated with serious adverse events and death in pediatric patients, particularly in neonates and premature infants [see Use in Specific Populations (8.4)].

本药使用BWFI配制时包含苯甲醇,使用WFI配制时不含防腐剂。新生儿及婴幼儿建议使用不含防腐剂的WFI配制。含防腐剂苯甲醇可致儿童严重不良事件及死亡,尤其是新生儿及早产儿。

6 ADVERSE REACTIONS 不良反应

6.1 Clinical Trials Experience 临床试验经验

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

因临床试验是在广泛的不同情况下进行,临床试验观察到的不良反应率不能与另一种药临床试验发生率直接比较,而且可能不能反映临床实践中观察到的发生率。

Open-Label, Single-Arm Study 开放性、单臂试验

The safety of MYALEPT was evaluated in 48 patients with generalized lipodystrophy in a

single-arm, open-label study [see Clinical Studies (14.1)]. The median duration of exposure in this trial was 2.7 years with a range of 3.6 months to 10.9 years. The most frequent adverse reactions are summarized in Table 2.

本药的安全性通过一项在48名全身性脂肪代谢障碍患者中进行的单臂、开放性试验证明,中位暴露持续时间为2.7年(范围为3.6个月-10.9年)。表2总结了发生率最高的不良反应。Table 2: Adverse Reactions of 5% or Greater Incidence in Patients with Generalized Lipodystrophy Receiving MYALEPT in an Open-Label, Single-Arm Study

表2:试验中发生率≥5%的不良反应

注射用美曲普汀(metreleptin for injection)说明书翻译对照

注射用美曲普汀(metreleptin for injection)说明书翻译对照

protocol specified definitions: Mild: Documentation of low plasma glucose values with no symptoms; Moderate: Presence of clinical symptoms requiring ingestion of glucose,

self-alleviated; Severe: Presence of neuroglycopenic symptoms requiring assistance from others for alleviation; Life threatening: Loss of consciousness and/or requiring intervention by administration of intravenous glucose or intramuscular glucagon.

按草案规定的定义,低血糖事件被分为轻度、中度、中度或危及生命。轻度:资料证明血糖水平低但无症状;中度:有临床症状,需补充葡萄糖,可自行缓解;重度:有神经性低血糖症状需别人的帮助来缓解;危及生命:失去意识和/或需要通过静脉输注葡萄糖或肌内注射葡萄糖进行干预。

In patients with generalized lipodystrophy receiving MYALEPT in this study, less common adverse reactions included injection-site erythema and urticaria (N=2 [4%]).

在本项试验中,不太常见的不良反应包括注射部位红斑或荨麻疹。

Six patients (13%) had 7 adverse reactions of hypoglycemia, 6 of which occurred in the setting of concomitant insulin use, with or without oral antihyperglycemic agents.

6名患者出现7例低血糖,其中6例与痛胰岛素合用,伴或不伴口服降糖药有关。

Two patients (4%) had events of pancreatitis, both of whom had a medical history of pancreatitis. 2名患者出现胰腺炎,2者皆有胰腺炎病史。

6.2 Immunogenicity 免疫原性

As with all therapeutic proteins, there is potential for immunogenicity. Anti-metreleptin antibodies were detected in 84% (36/43) of generalized lipodystrophy patients studied in the MYALEPT trials. Total anti-metreleptin antibody titers ranged between 1:5 and 1:1,953,125. The incompleteness of the current immunogenicity database precludes understanding of the magnitude and persistence of the observed anti-drug antibody responses.

与其他治疗性蛋白质一样,本药有潜在的免疫原性。试验中有84%全身性脂肪代谢障碍患者检测出抗美曲普汀抗体。抗美曲普汀抗体总滴定范围为1:5和1:1953125。因当前免疫原性数据库的不完整妨碍了对所观察到的抗药物抗体反应的重要性和持续性理解。

Anti-metreleptin antibodies with neutralizing activity associated with adverse events consistent with loss of endogenous leptin activity and/or loss of MYALEPT efficacy were observed in 6% (2/33) of the patients with generalized lipodystrophy tested. Adverse events reported in these two

patients included severe infections and worsening of metabolic control (increases in HbA1c and/or triglycerides). Test for anti-metreleptin antibodies with neutralizing activity in patients who develop severe infections or show signs suspicious for loss of MYALEPT efficacy during treatment. Contact Bristol Myers-Squibb at 1-866-216-1526 for testing of clinical samples.

抗美曲普汀抗体中和瘦素活性所致不良事件与接受本药治疗出现内源性瘦素活性降低和/或

疗效降低相一致,在6%全身性脂肪代谢障碍患者中可见。2名全身性脂肪代谢障碍患者有

严重感染和代谢控制恶化(化血红蛋白及三酰甘油升高)。治疗过程中,应检测出现严重感染或疑似本药疗效降低迹象患者抗美曲普汀抗体。

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. The immunogenicity assays utilized in clinical trials lacked sensitivity, resulting in potential underestimation of the number of samples positive for anti-metreleptin antibodies with neutralizing activity. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to metreleptin with the incidence of antibodies to other products may be misleading.

抗体生成的检测主要依靠检验方法的敏感性和特异性。试验所用的免疫原性的检测方法如缺乏敏感性可能导致对具中和作用的抗美曲普汀抗体阳性样本数量低估。此外,检验方法中,抗体阳性发生率(包括中和抗体)可受多个因素影响,包括检测方法的方法学、样本的处理、收集样本的时间、合用药物、基础疾病。因为上述原因,比较美曲普汀抗体发生率与其他产品的抗体发生率可能有误导性。

7 DRUG INTERACTIONS 药物相互作用

No formal drug interaction studies were performed. 尚未进行正式的药物相互作用研究

Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450

(CYP450) enzymes. This should be taken into account when prescribing concomitant drugs metabolized by CYP450 (e.g., oral contraceptives and drugs with a narrow therapeutic index).

瘦素是一种细胞因子,可能改变细胞色素P450(CYP)酶的形成。当给予经CYP代谢的药

物(如:口服避孕药及药物)与本药合用时应考虑这一点。

The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with narrow therapeutic index, where the dose is individually adjusted. Upon initiation or discontinuation of MYALEPT, in patients being treated with these types of agents, therapeutic monitoring of effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) should be performed and the individual dose of the agent adjusted as needed.

美曲普汀对CYP酶的影响与适应症狭窄的CYP底物有临床相关性,需要单独调整剂量。根据使用或停用本药,接受这些类型药物治疗的患者应对疗效(如华法林)或药物浓度(如环孢素或茶碱)进行监测并按需要调整这些药物的剂量。

8 USE IN SPECIFIC POPULATIONS 特殊人群用药

8.1 Pregnancy 妊娠期妇女

Pregnancy Category C 妊娠分级:C级

There is a program that monitors outcomes in women exposed to MYALEPT during pregnancy. Women who become pregnant during MYALEPT treatment are encouraged to enroll. Patients or their physicians should call 1-855-6MYALEPT to enroll.

有一项项目监测妊娠期妇女暴露于本药的结果。接受本药治疗期间妊娠的妇女鼓励进行登记。Risk Summary 风险概述

There are no adequate and well-controlled studies of MYALEPT in pregnant women. All pregnancies, regardless of drug exposure, have a background rate of 2% to 4% for major

malformations and 15% to 20% for pregnancy loss. In a pre-and postnatal development study in mice, administration of metreleptin caused prolonged gestation and dystocia resulting in maternal death during parturition and lower survival of offspring in the immediate postnatal period at doses starting approximately at the maximum recommended clinical dose. Because animal reproduction studies are not always predictive of human response, MYALEPT should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

本药尚无在妊娠期妇女中适当且对照良好的研究。所有妊娠,不管是否为药物暴露,皆有

2-4%的致畸率,15-20%的流产率。在一项小鼠产前产后研究中,给予美曲普汀约为临床用

量最大推荐剂量的剂量时,可致妊娠期延长和难产,导致母体分娩时死亡和产后阶段子代存活率低。因为动物生殖研究不能完全预测人体反应,妊娠期妇女仅在利大于弊时用药。Clinical Considerations 临床注意事项

Disease-Associated Maternal and Fetal Risk 疾病相关的妊娠期妇女及胎儿风险

The contribution of MYALEPT to obstetrical risks and complications is unknown compared with those already documented in the lipodystrophy patient population (e.g., gestational diabetes, macrosomia, eclampsia, intrauterine growth retardation, intrauterine death, and miscarriage).

与已在脂肪代谢障碍患者中备案的风险(如妊娠期糖尿病、巨婴、子痫、胎儿宫内发育迟缓、宫内死亡及流产)相比,本药对产科的风险及并发症尚不明确。

Labor and Delivery 分娩

The effects of MYALEPT on labor and delivery in pregnant women are unknown. In an in vitro study of human myometrial tissue exposed to a recombinant leptin, human uterine contractility

was inhibited. Furthermore, prolonged gestation and dystocia were observed in animal studies

with metreleptin (see below).

本药对妊娠期妇女分娩的影响尚不明确,在一项体外研究中,人子宫肌层组织暴露于重组瘦素中,子宫收缩性受抑制。此外,动物试验中可见妊娠期延长和难产。

Animal Data 动物数据

Metreleptin administered to pregnant mice during the period of organogenesis was not teratogenic at doses ranging between 7-and 15-fold the maximum recommended clinical dose, based on body surface area of a 20-and 60-kg patient, respectively.

在器官形成期给予小鼠临床最大推荐剂量的7倍和15倍,分别以20kg和60kg患者体表面积计,未见致畸作用。

In a pre-and postnatal development study in mice, metreleptin administered at doses of 3, 10, and 30 mg/kg (approximately 1-, 5-, and 15-fold the clinical dose for a 60-kg subject, based on body surface area) from gestation day 6 to lactation day 21 caused prolonged gestation and dystocia at

all doses, starting at approximately the maximum recommended clinical dose. Prolonged gestation resulted in the death of some females during parturition and lower survival of offspring within the immediate postnatal period. Consistent with metreleptin pharmacology, decreased maternal body weight was observed from gestation throughout lactation at all doses and resulted in reduced weight of offspring at birth, which persisted into adulthood. However, no developmental abnormalities were observed and reproductive performance of the first or second generations was not affected at any dose.

在一项小鼠产前产后研究中,从妊娠期第6日至哺乳期21日给予美曲普汀3 mg/kg、10 mg/kg、30mg/kg(分别约为60kg患者临床剂量的1、5、15倍,以体表面积计),从临床最大推荐剂量起,所有剂量皆可致妊娠期延长和难产。妊娠期延长导致母体分娩时死亡和产后阶段子代存活率低。与美曲普汀药理学抑制,所有剂量皆可致母体从妊娠期至整个哺乳期体重下降一级子代出生体重降低,并且可持续至成熟期。但未见发育异常以及对第1代及第2代子代的生育力无影响。

Placental transfer of metreleptin into the fetus was low (approximately 1%) following

subcutaneous dosing.

皮下注射美曲普汀透过胎盘率低(约1%)。

8.3 Nursing Mothers 哺乳期妇女

It is not known if MYALEPT is present in human milk. Endogenous leptin is present in human milk. Because of the potential for serious adverse reactions (including possible adverse reactions related to passage of anti-metreleptin antibodies) in nursing infants from MYALEPT a decision should be made whether to discontinue nursing or discontinue the drug, taking into account importance of drug to the mother [see Adverse Reactions (6.2) and Nonclinical Toxicology (13.1)].

尚不明确本药是否随人乳排泄。内源性瘦素可随人乳排泄。因为本药可致乳儿严重不良反应(包括通过抗美曲普汀抗体可能导致的不良反应),哺乳期妇女用药应权衡利弊。

8.4 Pediatric Use 儿童用药

The MYALEPT study included a total of 35 pediatric patients (73%) with an age range from 1 to 17 years [see Clinical Studies (14.1)]. No clinically meaningful differences were observed in the efficacy and safety of MYALEPT between pediatric and adult patients.

本药的试验包括35名年龄1-17岁儿童。本药用于儿童和成人的安全性及有效性无临床有意义差异。

MYALEPT contains benzyl alcohol when reconstituted with BWFI. MYALEPT contains no preservative when reconstituted with WFI. Preservative-free WFI is recommended for use in neonates and infants. The preservative benzyl alcohol has been associated with serious adverse events and death, particularly in pediatric patients. The "gasping syndrome" (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth weight infants. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse.

本药使用BWFI配制时包含苯甲醇,使用WFI配制时不含防腐剂。新生儿及婴幼儿建议使用不含防腐剂的WFI配制。含防腐剂苯甲醇可致儿童严重不良事件及死亡,尤其是新生儿及早产儿。新生儿及低出生体重儿一日苯甲醇剂量超过99mg/kg可能出现喘息综合症(以中枢神经系统受抑、代谢性酸中毒、喘气呼吸及血液和尿液中苯甲醇及其代谢物水平高为特征)。其他症状包括进行性神经功能退化、癫痫发作、颅内出血、血液学异常、皮肤破裂、肝肾衰竭、低血压、心动过缓及心血管性虚脱。

Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the "gasping syndrome," the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and

low-birthweight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources. When reconstituted with 2.2 mL of BWFI, MYALEPT contains 1.76 mg of benzyl alcohol per mg of metreleptin or 9 mg of benzyl alcohol per mL of reconstituted product.

虽然本药治疗剂量所含苯甲醇远远低于引起喘息综合症报道的剂量,但苯甲醇毒性的最低剂量尚不明确。早产儿、低出生体重而以及接受高剂量的患者出现毒性作用的可能性更高。医生在给予本药及其他含有苯甲醇药物时应考虑所有来源的苯甲醇的代谢负荷。使用2.2ml BWFI配制时,本药每毫克美曲普汀含1.76ng苯甲醇或配制后的溶液每毫升含9mg苯甲醇。

8.5 Geriatric Use 老人用药

Clinical trials of MYALEPT did not include sufficient numbers of subjects aged 65 and over (n=1)

to determine whether they respond differently from younger subjects. In general, dose selection

for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

本药的临床试验未包含足够的年龄大于等于65岁的受试者用以确定这些受试者的反应是否与年轻受试者有差别。一般而言,老年患者因肝功能、肾功能及心脏功能减退以及共患病和使用其他药物的频率更高,用药应谨慎,常从剂量范围的低限开始用药。

10 OVERDOSAGE 药物过量

There were no reports of overdose in the lipodystrophy clinical trial program of MYALEPT. In

the event of an overdose, patients should be monitored and appropriate supportive treatment be initiated as dictated by the patient’s clinical status.

本药临床试验中无用药过量报道。如用药过量,应按患者口述的临床状态进行监测和进行适当的支持性治疗。

12 CLINICAL PHARMACOLOGY 临床药理学

12.1 Mechanism of Action 作用机制

Adipocytes store lipids to meet the fuel requirements of non-adipose tissues during fasting. In patients with generalized lipodystrophy, the deficiency of adipose tissue leads to hypertriglyceridemia and ectopic deposition of fat in non-adipose tissues such as liver and muscle, contributing to metabolic abnormalities including insulin resistance. Native leptin is a hormone predominantly secreted by adipose tissue that informs the central nervous system of the status of energy stores in the body. In patients with generalized lipodystrophy, leptin deficiency, resulting from the loss of adipose tissue, contributes to excess caloric intake, which exacerbates the metabolic abnormalities.

脂肪细胞储存脂质以满足空腹时非脂肪组织对能量的需求。在全身性脂肪代谢障碍的患者中,脂肪组织的缺乏导致高三酰甘油血症及脂肪在非脂肪组织中异位沉积,如肝脏和肌肉中,可致代谢异常,包括胰岛素抵抗。本体瘦素是一种主要经脂肪组织分泌的激素,可告知中枢神经系统身体能力储存状态。全身性脂肪代谢障碍患者缺乏瘦素(脂肪组织减少所致),可致能量过度摄入,使代谢障碍恶化。

MYALEPT (metreleptin for injection) exerts its function by binding to and activating the human leptin receptor (ObR), which belongs to the Class I cytokine family of receptors that signals through the JAK/STAT transduction pathway.

本药通过与人瘦素受体结合并激活瘦素受体起效,瘦素受体属Ⅰ型细胞因子受体家族,通过JAK/STAT转导通路释放信号。

12.2 Pharmacodynamics 药效学

Clinical studies in patients with generalized lipodystrophy suggest that MYALEPT increases insulin sensitivity and reduces food intake. Improvements in insulin sensitivity and reductions in food intake are consistent with lower HbA1c, fasting glucose, and fasting triglyceride values that were seen in the MYALEPT clinical trial [see Clinical Studies (14)].

临床试验显示全身性脂肪代谢障碍患者使用本药可增加胰岛素敏感性及减少食物摄入。胰岛素敏感性增加及食物摄入减少与临床试验中观察到的糖化血红蛋白、空腹血糖、口服三酰甘油值一致。

12.3 Pharmacokinetics 药动学

There are limited data on the pharmacokinetics of metreleptin in patients with generalized lipodystrophy, and therefore, no formal exposure-response analysis has been performed. It should be noted that the leptin assay measures both endogenous leptin as well as exogenously administered metreleptin.

美曲普汀用于全身性脂肪代谢障碍患者的药动学数据有限,所以无已完成的暴露-反应分析。值得指出的是对瘦素的分析分析了内源性瘦素及外源性给予美曲普汀。

Absorption 吸收

Peak serum leptin concentration (Cmax) occurred approximately 4.0 to 4.3 hours after subcutaneous administration of single doses ranging from 0.1 to 0.3 mg/kg in healthy subjects. In

a supportive trial in lipodystrophy patients, the median Tmax of metreleptin was 4 hours (range: 2 to 8 hours; N=5) following single-dose administration of metreleptin.

健康受试者皮下注射美曲普汀0.1-0.3mg/kg后,血清中瘦素峰浓度(C max)约于4-4.3小时

出现。在一项在脂肪代谢障碍患者中进行的支持性试验中,给予美曲普汀单剂后,美曲普汀达峰时间(T max)约为4小时。

Distribution 分布

In studies of healthy adult subjects, following intravenous administration of metreleptin, leptin volume of distribution was approximately 4 to 5 times plasma volume; volumes (Vz) (mean ± SD) were 370 ± 184 mL/kg, 398 ± 92 mL/kg, and 463 ± 116 mL/kg for 0.3, 1.0, and 3.0 mg/kg/day doses, respectively.

在健康受试者中,静脉注射美曲普汀后,瘦素分布量约为血清量的4-5倍,一日给予0.3 mg/kg、1.0 mg/kg、3mg/kg分布量分别为370 ± 184 mL/kg、398 ± 92 mL/kg、463 ± 116 mL/kg。Metabolism and Elimination代谢和排泄

No formal metabolism studies have been conducted with metreleptin. Nonclinical data indicate renal clearance is the major route of metreleptin elimination, with no apparent contribution of systemic metabolism or degradation. Following single subcutaneous doses of 0.01 to 0.3 mg/mL metreleptin in healthy subjects, the half-life was 3.8 to 4.7 hours. The clearance of metreleptin is expected to be delayed in the presence of leptin antibodies [see Adverse Reactions (6.2)].

美曲普汀未进行正式的代谢研究。非临床数据显示肾清除为美曲普汀的主要排泄途径,全身性代谢或降解无明显作用。健康受试者皮下注射美曲普汀0.01-0.3mg/ml,半衰期为3.8-4.7

小时。存在瘦素抗体时,美曲普汀清除时间可延长。

Drug Interactions 药物相互作用

No drug interaction studies have been conducted in lipodystrophy patients [see Drug Interactions (7)].未在脂肪代谢障碍患者中进行药物相互作用研究。

Specific Populations 特殊人群用药

Renal Impairment 肾功能损害

No formal pharmacokinetic studies were conducted in patients with renal impairment. Nonclinical data indicate renal clearance is the major route of metreleptin elimination, with no apparent contribution of systemic metabolism or degradation. Hence, the pharmacokinetics of metreleptin may be altered in subjects with renal impairment.

未在肾损害患者中进行正式的药动学研究。非临床数据显示肾清除为美曲普汀的主要排泄途径,全身性代谢或降解无明显作用。因此,肾损伤患者美曲普汀的药动学可能改变。Hepatic Impairment 肝功能损害

No formal pharmacokinetic studies were conducted in patients with hepatic impairment.

未在肝损害患者中进行正式的药动学研究。

Age, Gender, Race, Body Mass Index 年龄、性别、种族、体重指数

Specific clinical studies have not been conducted to assess the effect of age, gender, race, or body mass index on the pharmacokinetics of metreleptin in patients with generalized lipodystrophy.

未在全身性脂肪代谢障碍患者中进行年龄、性别、种族或体重指数对药动学影响的特异性研究。

13 NONCLINICAL TOXICOLOGY 非临床毒性

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 致癌、致突变、生育力损害Two-year carcinogenicity studies in rodents have not been conducted with metreleptin. No proliferative or preneoplastic lesions were observed in mice or dogs following treatment up to six months. However, leptin is reported in the literature to promote cell proliferation in vitro and tumor progression in some mouse models of cancer.

美曲普汀未在啮齿类动物中进行2年致癌性研究。治疗6个月,在小鼠和犬类中未见增生性组织或癌前病变。但是,在文献中报道瘦素在体外可促进细胞增殖和在一些小肿瘤模型中可促进肿瘤进展。

Metreleptin was not mutagenic in the Ames bacterial mutagenicity assay or clastogenic in an in vitro chromosomal aberration assay in Chinese hamster ovary cells and human peripheral blood lymphocytes. Metreleptin was not mutagenic or clastogenic in an in vivo mouse micronucleus assay.

在中国仓鼠卵巢细胞和人外周血淋巴细胞中,Ames细菌诱变测试中,美曲普汀未见致突变;体外染色体畸变测试中,美曲普汀不致染色体断裂。在小鼠体内微核测试中,美曲普汀无致突变或致染色体断裂作用。

In a fertility study in mice, metreleptin had no adverse effects on mating, fertility, or early embryonic development at doses ranging between 7 and 15 times the maximum recommended clinical dose based on body surface area of a 20-and 60-kg patient, respectively.

在一项小鼠生育力研究中,给予美曲普汀临床最大推荐剂量的7倍到15倍时(分别以20kg 患者和60kg患者体表面积计),对小鼠交配、繁殖或早期胚胎形成无不良影响。

16 HOW SUPPLIED/STORAGE AND HANDLING 如何供应/储存/处理

16.2 Storage and Handling 储存

MYALEPT should be stored in the refrigerator at 36°F to 46°F (2°C to 8°C) and protected from light until preparing for use. Keep MYALEPT vials in the carton when not in use.

MYALEPT should not be used past the expiration date.

Do not freeze MYALEPT.

Do not use if the white lyophilized cake is discolored.

Use with BWFI: when MYALEPT is reconstituted with BWFI, the vial can be used for multiple doses within 3 days when stored in the refrigerator at 36°F to 46°F (2°C to 8°C) and protected from light.

Use with WFI: when MYALEPT is reconstituted with WFI, the vial can be used for a single dose should be administered immediately. Unused reconstituted solution cannot be saved for later use and should be discarded.

After reconstitution, the vials should not be frozen (below 0°C) or shaken vigorously. If the reconstituted product is inadvertently frozen, it should be thrown away.

After reconstitution, the mixture should be clear and colorless. Do not use if visible particulates are present in the solution.

Keep out of the reach of children.

本药于2℃-8℃避光储存于冰箱,不得冷冻。

采用BWFI配制时:于2℃-8℃避光储存于冰箱,应于3日内使用。

采用WFI配制时:立即使用。

配制好的溶液不得冷冻或用力摇晃。

置于儿童不能接触的地方。