近日，美国FDA批准反义寡核苷酸药物Tegsedi（inotersen）上市，用于治疗遗传性转甲状腺素蛋白淀粉样变性（hATTR）患者的多发性神经病（polyneuropathy）。
hATTR是一种致命的进行性遗传病，它是由于患者体内转甲状腺素蛋白（TTR）折叠异常，导致淀粉样TTR在身体的各种组织和器官中沉积而造成的。TTR沉积的组织包括外周神经、心脏、肠道，眼睛，肾脏，中枢神经系统，甲状腺和骨髓。TTR在这些组织和器官中的沉积造成多种感觉，运动和植物性功能异常，最终会导致患者在症状出现后3-5年内去世。
Tegsedi是一种抑制人类TTR合成的反义寡核苷酸药物，它通过与编码TTR蛋白的mRNA相结合，能够导致mRNA的降解，从而降低TTR蛋白（野生型和突变型）的水平。它是一种每周一次的皮下注射针剂，患者在家中就可以自我给药。
批准日期：2018年10月6日  公司：Akcea Therapeutics, Inc.
TEGSEDI（inotersen）注射液，用于皮下注射
美国最初批准：2018年
警告：
血栓形成和GLOMERULONEPHRITIS查看完整的BOXED警告的完整预定信息。
血小板减少
TEGSEDI导致血小板计数减少，可能导致突发性和不可预测的血小板减少症，这可能危及生命。
需要在治疗前进行测试和治疗期间的监测。
肾小球肾炎
TEGSEDI可引起可能需要免疫抑制治疗的肾小球肾炎，并可能导致透析依赖性肾功能衰竭。
需要在治疗前进行测试和治疗期间的监测。
TEGSEDI只能通过名为TEGSEDI REMS计划的限制分发计划获得。
作用机制
Inotersen是一种反义寡核苷酸，通过与TTR mRNA结合导致突变体和野生型TTR mRNA的降解，这导致组织中血清TTR蛋白和TTR蛋白沉积物的减少。
适应症和用法
TEGSEDI是一种经转甲状腺素蛋白定向的反义寡核苷酸，用于治疗成人遗传性转甲状腺素介导的淀粉样变性的多发性神经病。
剂量和给药
推荐剂量为284mg，每周一次皮下注射。
必须在治疗前测量实验室测试，在治疗开始后继续监测，并在停止治疗后按照指示进行8周。
剂量形式和强度
注射：单剂量预充式注射器中284mg/1.5mL。
禁忌症
血小板计数小于100x109/L.
TEGSEDI引起急性肾小球肾炎的病史。
对TEGSEDI有过敏反应史的患者。
警告和注意事项
中风和颈头动脉解剖：这些不良事件发生在首次给药后2天内，并伴有细胞因子释放症状。教育患者中风和中枢神经系统动脉夹层症状。
炎症和免疫效应：严重的神经系统不良反应与炎症和免疫效应一致。
肝脏影响：在治疗期间每4个月监测丙氨酸氨基转移酶，天冬氨酸氨基转移酶和总胆红素以及肝功能障碍症状。
超敏反应：如果发生这些反应，请停止并开始适当的治疗。
无法解释的血小板计数：抗血小板抗体与乙二胺四乙酸之间的反应：血小板聚集可导致无法解释的血小板测量;如果怀疑这是重复测试。
降低血清维生素A水平和推荐补充：补充维生素A的建议每日允许量。如果出现提示维生素A缺乏的眼部症状，请咨询眼科医生。
不良反应
最常见的不良反应（至少20％的TEGSEDI治疗患者，比安慰剂更常见）是注射部位反应，恶心，头痛，疲劳，血小板减少和发烧。
包装提供/存储和处理
TEGSEDI是一种透明，无色至淡黄色的溶液，在带有SSD的单剂量预装注射器中提供。填充TEGSEDI的每个预填充注射器以递送1.5mL含有284mg inotersen的溶液（相当于300mg inotersen钠盐）。
TEGSEDI有纸箱包含1或4个预装注射器。
一包1个预装注射器：NDC 72126-007-03
一包4个预装注射器：NDC 72126-007-01
单个托盘包含NDC 72126-007-02
药店
在原装容器中冷藏至2°C至8°C（36°F至46°F），避免直射光线。不要冻结。
对于患者/看护人
在原始容器中冷藏至2°C至8°C（36°F至46°F）。不要冻结。 TEGSEDI可在原始容器中保持室温（最高30°C [86°F]），最长可达6周;如果在6周内没有使用，请丢弃TEGSEDI。
使用前至少30分钟从冷藏室（2°C至8°C [36°F至46°F]）中取出。[TEGSEDI]预充式注射器应在注射前达到室温。
避免暴露在高于30°C（86°F）的温度下。
完整说明附件：https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8513207e-b55f-417b-9473-af785146a543
TEGSEDI(inotersen) injection, for subcutaneous use
INDICATION
TEGSEDI is indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults.
IMPORTANT SAFETY INFORMATION
WARNING: THROMBOCYTOPENIA AND GLOMERULONEPHRITIS
Thrombocytopenia
TEGSEDI causes reductions in platelet count that may result in sudden and unpredictable thrombocytopenia, which can be life-threatening. One clinical trial patient died from intracranial hemorrhage
TEGSEDI is contraindicated in patients with a platelet count below 100 x 109/L
Prior to starting TEGSEDI, obtain a platelet count. During treatment, monitor platelet counts weekly if values are 75x109/L or greater, and more frequently if values are less than 75x109/L
If a patient develops signs or symptoms of thrombocytopenia, obtain a platelet count as soon as possible. The patient should not receive additional TEGSEDI unless a platelet count is determined to be interpretable and acceptable by a medical professional
Following discontinuation of treatment for any reason, continue to monitor platelet count for 8 weeks, or longer if platelet counts are less than normal, to verify that platelet counts remain above 75x109/L
Glomerulonephritis
TEGSEDI can cause glomerulonephritis that may require immunosuppressive treatment and may result in dialysis-dependent renal failure. One clinical trial patient who developed glomerulonephritis and did not receive immunosuppressive treatment remained dialysis-dependent. In clinical trials, cases of glomerulonephritis were accompanied by nephrotic syndrome, which can have manifestations of edema, hypercoagulability with venous or arterial thrombosis, and increased susceptibility to infection
TEGSEDI should generally not be initiated in patients with urinary protein to creatinine ratio (UPCR) of 1000 mg/g or higher
Prior to starting TEGSEDI, measure the serum creatinine, estimated glomerular filtration rate (eGFR), urine protein to creatinine ratio (UPCR), and perform a urinalysis. During treatment, monitor serum creatinine, eGFR urinalysis, and UPCR every 2 weeks. TEGSEDI should not be given to patients who develop a UPCR of 1000 mg/g or higher or eGFR below 45 mL/minute/1.73 m2, pending further eva luation of the cause
If a dose is held, once eGFR increases to ≥45 mL/minute/1.73 m2, UPCR decreases to below 1000 mg/g, or the underlying cause of the decline in renal function is corrected, weekly dosing may be reinitiated. In patients with UPCR of 2000 mg/g or higher, perform further eva luation for acute glomerulonephritis, as clinically indicated. If acute glomerulonephritis is confirmed, TEGSEDI should be permanently discontinued
TEGSEDI REMS Program
Because of the risks of serious bleeding caused by severe thrombocytopenia and because of glomerulonephritis, both of which require frequent monitoring, TEGSEDI is available only through a restricted distribution program under a Risk eva luation and Mitigation Strategy (REMS) called the TEGSEDI REMS Program
CONTRAINDICATIONS
TEGSEDI is contraindicated in patients with
Platelet count below 100 x109/L
History of acute glomerulonephritis caused by TEGSEDI
History of a hypersensitivity reaction to TEGSEDI
WARNINGS AND PRECAUTIONS
Thrombocytopenia
TEGSEDI causes reductions in platelet count that may result in sudden and unpredictable thrombocytopenia that can be life-threatening. In Study 1, platelet counts below 100 x 109/L occurred in 25% of TEGSEDI-treated patients compared with 2% of patients on placebo. Platelet counts below 75 x 109/L occurred in 14% of TEGSEDI-treated patients compared with no patients on placebo. One patient in a clinical trial experienced a fatal intracranial hemorrhage. Do not initiate TEGSEDI in patients with a platelet count below 100 x 109/L. Follow recommended monitoring and treatment recommendations for platelet count.
Symptoms of thrombocytopenia can include unusual or prolonged bleeding (eg, petechiae, easy bruising, hematoma, subconjunctival bleeding, gingival bleeding, epistaxis, hemoptysis, irregular or heavier than normal menstrual bleeding, hematemesis, hematuria, hematochezia, melena), neck stiffness, or atypical severe headache. Patients and caregivers should be instructed to be vigilant for symptoms of thrombocytopenia and seek immediate medical help if they have concerns.
Glomerulonephritis and Renal Toxicity
TEGSEDI can cause glomerulonephritis that may result in dialysis-dependent renal failure. In Study 1, glomerulonephritis occurred in 3 (3%) TEGSEDI-treated patients compared with no patients on placebo. One patient did not receive immunosuppressive treatment and remained dialysis-dependent. If glomerulonephritis is suspected, pursue prompt diagnosis and initiate immunosuppressive treatment as soon as possible. Follow recommended monitoring and treatment recommendations for renal parameters. TEGSEDI should generally not be initiated in patients with a UPCR of 1000 mg/g or greater. If acute glomerulonephritis is confirmed, TEGSEDI should be permanently discontinued.
TEGSEDI is available only through a restricted program under a Risk eva luation and Mitigation Strategy (REMS) called the TEGSEDI REMS Program because of risks of serious bleeding caused by severe thrombocytopenia and because of glomerulonephritis.
Stroke and Cervicocephalic Arterial Dissection
TEGSEDI may cause stroke and cervicocephalic arterial dissection. In clinical studies, 1 of 161 (0.6%) TEGSEDI-treated patients experienced carotid artery dissection and stroke. Educate patients on the symptoms of stroke and central nervous system arterial dissection. Instruct patients to seek help as soon as possible if symptoms of stroke or arterial dissection occur.
Inflammatory and Immune Effects
Inflammatory and immune changes are an effect of some antisense oligonucleotide drugs, including TEGSEDI. In clinical studies, serious inflammatory and immune adverse reactions occurred in TEGSEDI-treated patients, including immune thrombocytopenia and glomerulonephritis, as well as a single case of antineutrophil cytoplasmic autoantibody (ANCA)–positive systemic vasculitis.
Liver Effects
In clinical studies, 8% of TEGSEDI-treated patients had an increased alanine aminotransferase (ALT) at least 3 times the upper limit of normal (ULN) compared with 3% of patients on placebo; 3% of TEGSEDI-treated patients had an ALT at least 8 times the ULN compared with no patients on placebo. Monitor ALT, aspartate aminotransferase, and total bilirubin at baseline and every 4 months during treatment with TEGSEDI. If a patient develops clinical signs or symptoms suggestive of hepatic dysfunction, promptly measure serum transaminases and total bilirubin and interrupt or discontinue treatment with TEGSEDI, as appropriate.
Hypersensitivity Reactions/Antibody Formation
TEGSEDI can cause hypersensitivity reactions. In clinical studies, 6 of 161 (4%) TEGSEDI-treated patients stopped treatment because of a hypersensitivity reaction. These reactions generally occurred within 2 hours of administration of TEGSEDI. Antibodies to TEGSEDI were present when the reactions occurred. If a hypersensitivity reaction occurs, discontinue administration of TEGSEDI and initiate appropriate therapy. Do not use in patients who have a history of hypersensitivity reactions to TEGSEDI.
Uninterpretable Platelet Counts: Reaction Between Antiplatelet Antibodies and Ethylenediaminetetraacetic acid (EDTA)
In Study 1, 23% of TEGSEDI-treated patients had at least 1 uninterpretable platelet count caused by platelet clumping compared with 13% of patients on placebo. If there is suspicion of EDTA-mediated platelet clumping, perform a repeat platelet count using a different anticoagulant (eg, sodium citrate, heparin) in the blood collection tube. Recheck the platelet count as soon as possible if a platelet measurement is uninterpretable. Hold TEGSEDI dosing until an acceptable platelet count is confirmed with an interpretable blood sample.
Reduced Serum Vitamin A Levels and Recommended Supplementation
TEGSEDI treatment leads to a decrease in serum vitamin A levels. Supplementation at the recommended daily allowance of vitamin A is advised for patients taking TEGSEDI. Patients should be referred to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (eg, night blindness).
ADVERSE REACTIONS
The most common adverse reactions that occurred in at least 20% of TEGSEDI-treated patients and more frequently than in those on placebo were injection site reactions, nausea, headache, fatigue, thrombocytopenia, and fever. Serious adverse reactions were more frequent in TEGSEDI-treated patients (32%) than in patients on placebo (21%).
DRUG INTERACTIONS
Because of the risk of thrombocytopenia, caution should be used when using antiplatelet drugs (including nonprescription products that affect platelets) or anticoagulants concomitantly with TEGSEDI. Because of the risk of glomerulonephritis and renal toxicity, caution should be used when using nephrotoxic drugs and other drugs that may impair renal function concomitantly with TEGSEDI.