新型注射设备OTREXUP（氨甲蝶呤 methotrexate）通过美国FDA批准
近日，美国食品和药物管理局FDA批准一次性自动注射器Otrexup（甲氨蝶呤 methotrexate）用于成年人的活动性类风湿性关节炎。
Otrexup是一种针对类风湿关节炎（RA）和牛皮癣，以及与多关节幼年特发性关节炎（pJIA）治疗儿童的成人甲氨蝶呤的皮下（SC）每周一次施用（MTX）的自注射装置。
另外，FDA批准也被授予对严重顽固的症状控制成人使用Otrexup的，禁用银屑病是不充分响应于其他形式的治疗。
Otrexup自称是第一个专利产品为特色的Vibex的Medi-喷射技术，自动进样器。
本剂七个剂量强度可供选择：7.5毫克，10毫克，12.5毫克，15毫克，20毫克，22.5毫克，25毫克
注意：本品对口服甲氨蝶呤无效者切换到Otrexup与小瓶和注射器的决定性因素。
批准日期：2014年1月15日  公司：Antares Pharma, Inc
OTREXUP（甲氨蝶呤 methotrexate）注射剂，皮下使用
最初美国批准：1953年
警告：
严重毒性反应，包括胚胎-胎儿毒性和完整的黑框警告DEATHSee完整处方信息。
•严重毒性反应和死亡已报告的使用甲氨蝶呤。患者应严密监测骨髓，肝，肺，皮肤和肾毒性。
•甲氨蝶呤有报道引起胎儿死亡和/或先天性异常和妊娠禁忌。
•不料严重（有时是致命的）骨髓抑制，再生障碍性贫血，和胃肠道毒性，已报告有一些非甾体抗炎药（NSAIDs）一起同时给予甲氨蝶呤（通常在高剂量）。
•肝毒性，可以长期使用后发生纤维化和肝硬化。
•甲氨蝶呤可以治疗期间的任何时间引起间质性肺炎，并已在低剂量的报道。肺部症状（特别是干燥，干咳）可能需要治疗和精心的调查中断。
•腹泻，可发生口腔溃疡，出血性肠炎和死亡的肠穿孔。
•严重，据报道偶尔会致命，皮肤反应也。
•可能发生潜在的致命性机会性感染。
目前的主要变化
用法与用量 3/2016
作用机理
氨甲蝶呤抑制二氢叶酸还原酶。Dihydrofolates必须通过此酶减至tetrahydrofolates才可以被用作在嘌呤核苷酸和胸苷酸合成一碳基团的载体。因此，甲氨蝶呤与DNA合成，修复和细胞复制干扰。活跃增殖的组织，如恶性细胞，骨髓，胎儿细胞，颊和肠粘膜和膀胱细胞在一般甲氨蝶呤的这种影响更为敏感。
在类风湿关节炎的作用机制是未知的;它可能会影响免疫功能。
适应症和用法
Otrexup对于叶酸类似物代谢抑制剂表示：
•重症患者，活动性类风湿关节炎（RA）和多关节幼年特发性关节炎（pJIA），谁是不能容忍或有一个应对不力一线治疗管理。
•严重的，顽固的，禁用牛皮癣症状的控制，成年人谁没有充分反映其他形式的治疗
使用限制
Otrexup没有为肿瘤性疾病的治疗中显示。
用法用量
Otrexup仅用于每周一次皮下注射使用。在腹部或大腿施用Otrexup。
用氨甲喋呤的另一种制剂用于需要口服，肌内，静脉内，动脉内，或鞘内给药的病人，剂量每周少于7.5毫克，剂量高于每周25毫克，高剂量治疗方案，或剂量小于5毫克的调整增量
起始剂量甲氨蝶呤：
RA：7.5毫克每周一次
pJIA：10毫克/米2，每周一次
银屑病：10至25毫克，一次口服，肌内，皮下每周，或静脉内制剂。
调整剂量逐渐达到最佳的反应。
剂型和规格
注射：
单剂量自动注射器递送0.4毫升甲氨蝶呤在下列剂量浓度：7.5毫克，10毫克，12.5毫克，15毫克，17.5毫克，20毫克，22.5mg和25毫克。
禁忌症
怀孕
乳母
酒精中毒或肝脏疾病
免疫缺陷综合征
预存血液恶液质
过敏甲氨蝶呤
警告和注意事项
器官系统毒性：潜在的严重毒性。仅适用于由医生使用经验丰富的抗代谢药物治疗。
胚胎 - 胎儿毒性：治疗前排除妊娠。避免怀孕，如果任何一方接收Otrexup。劝男性避免怀孕最少治疗三个月后，女性避免怀孕对治疗后的至少一个排卵周期。
对生殖的影响：可能引起生育，少精症和月经功能紊乱的损害
实验室检查：监测全血细胞计数，肾功能和肝功能检查。
从剂量不当的风险：误日常使用已经导致致命的毒性
患者肾功能受损，腹水或胸腔积液：
消除被降低。
头晕和疲劳：影响驾车和机械操作能力
不良反应
常见的不良反应有：恶心，腹痛，消化不良，口腔炎/口腔溃疡，皮疹，鼻咽炎，腹泻，肝功能试验异常，呕吐，头痛，支气管炎，血小板减少，脱发，白细胞减少，全血细胞减少，头晕，光敏性，而“燃烧皮肤损伤“。
药物相互作用
阿司匹林的NSAIDs和类固醇：同时使用可提高并延长甲氨蝶呤血清水平，导致增加毒性
质子泵抑制剂：同时使用可提高并延长甲氨蝶呤血清水平，导致增加毒性。
特殊人群中使用
儿童用药：安全和甲氨蝶呤疗效，包括Otrexup，尚未确定在儿童牛皮癣患者。 Otrexup的安全性和有效性尚未确定在儿科患者恶性肿瘤。
老年用药：在剂量选择谨慎使用。
包装规格/储存与处理
Otrexup包含在单次皮下注射一个不含防腐剂的无菌溶液甲氨蝶呤。 Otrexup是在以下的长处和配置。
注：本品每一个规格1支和4支包装可供选择
7.5毫克/0.4毫升
10毫克/0.4毫升
12.5毫克/0.4毫升
15毫克/0.4毫升
17.5毫克/0.4毫升
20毫克/0.4毫升
22.5毫克/0.4毫升
25毫克/ 0.4毫升
存储在控制室温，25°C（77°F）;游览允许15°到30°C（59°至86°F）。避光。
处理和处置
手柄和与细胞毒性drugs.1的处理和处置建议Otrexup一致的处理

完整处方来源：https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9ab8ce16-f7de-41d4-a4c8-1c742621b6d5
Otrexup (methotrexate) injection
Indications and Important Safety Information Including Boxed Warning
INDICATIONS:
Otrexup is indicated in:
•the management of selected adults with severe, active rheumatoid arthritis (RA) (ACR criteria), or children with active polyarticular juvenile idiopathic arthritis (pJIA), who have had an insufficient therapeutic response to, or are intolerant of, an adequate trial of first-line therapy including full dose non-steroidal anti-inflammatory agents (NSAIDs).
•in adults for the symptomatic control of severe, recalcitrant, disabling psoriasis that is not adequately responsive to other forms of therapy, but only when the diagnosis has been established, as by biopsy and/or after dermatologic consultation. It is important to ensure that a psoriasis “flare” is not due to an undiagnosed concomitant disease affecting immune response.
Otrexup should not be used for the treatment of cancer.
Otrexup should not be used for the treatment of children with psoriasis.
This product includes the following Black Box Warning:
WARNING:
SEVERE TOXIC REACTIONS, INCLUDING EMBRYO-FETAL TOXICITY AND DEATH
Otrexup should be used only by physicians whose knowledge and experience include the use of antimetabolite therapy. Because of the possibility of serious toxic reactions (which can be fatal), Otrexup should be used only in patients with psoriasis or rheumatoid arthritis with severe, recalcitrant, disabling disease which is not adequately responsive to other forms of therapy. Deaths have been reported with the use of methotrexate in the treatment of malignancy, psoriasis, and rheumatoid arthritis. Patients should be closely monitored for bone marrow, liver, lung, skin, and kidney toxicities. Patients should be informed by their physician of the risks involved and be under a physician’s care throughout therapy.
1.Methotrexate has been reported to cause fetal death and/or congenital anomalies. Therefore, Otrexup is not recommended for females of childbearing potential unless there is clear medical evidence that the benefits can be expected to outweigh the considered risks.
2.Methotrexate elimination is reduced in patients with impaired renal functions, ascites, or pleural effusions. Such patients require especially careful monitoring for toxicity, and require dose reduction or, in some cases, discontinuation of Otrexup administration.
3.Unexpectedly severe (sometimes fatal) bone marrow suppression, aplastic anemia, and gastrointestinal toxicity have been reported with concomitant administration of methotrexate (usually in high dosage) along with some nonsteroidal anti-inflammatory drugs (NSAIDs).
4.Methotrexate causes hepatotoxicity, fibrosis and cirrhosis, but generally only after prolonged use. Acutely, liver enzyme elevations are frequently seen. These are usually transient and asymptomatic, and also do not appear predictive of subsequent hepatic disease. Liver biopsy after sustained use often shows histologic changes, and fibrosis and cirrhosis have been reported; these latter lesions may not be preceded by symptoms or abnormal liver function tests in the psoriasis population. For this reason, periodic liver biopsies are usually recommended for psoriatic patients who are under long-term treatment. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in the rheumatoid arthritis population.
5.Methotrexate-induced lung disease, including acute or chronic interstitial pneumonitis, is a potentially dangerous lesion, which may occur acutely at any time during therapy and has been reported at low doses. It is not always fully reversible and fatalities have been reported. Pulmonary symptoms (especially a dry, nonproductive cough) may require interruption of treatment and careful investigation.
6.Diarrhea and ulcerative stomatitis require interruption of therapy: otherwise, hemorrhagic enteritis and death from intestinal perforation may occur.
7.Malignant lymphomas, which may regress following withdrawal of methotrexate, may occur in patients receiving low-dose methotrexate and, thus, may not require cytotoxic treatment. Discontinue Otrexup first and, if the lymphoma does not regress, appropriate treatment should be instituted
8.Like other cytotoxic drugs, methotrexate may induce “tumor lysis syndrome” in patients with rapidly growing tumors.
9.Severe, occasionally fatal, skin reactions have been reported following single or multiple doses of methotrexate. Reactions have occurred within days of oral, intramuscular, intravenous, or intrathecal methotrexate administration. Recovery has been reported with discontinuation of therapy.
10.Potentially fatal opportunistic infections, especially Pneumocystis jiroveci pneumonia, may occur with methotrexate therapy.
11.Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.
Otrexup is contraindicated in the following:
•Females and Males of Reproductive Potential: Contraception should be used by both females and males while taking Otrexup. Pregnancy should be avoided if either partner is receiving Otrexup:
•for a minimum of 3 months after treatment with Otrexup for males.
•during and for at least 1 menstrual cycle after treatment with Otrexup for females.
•Pregnancy: Otrexup can cause fetal death or teratogenic effects when administered to a pregnant woman. Otrexup is contraindicated in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
•Nursing Mothers: Because of the potential for serious adverse reactions from methotrexate in breast fed infants, Otrexup is contraindicated in nursing mothers.
•Alcoholism or Liver Disease: Patients with alcoholism, alcoholic liver disease or other chronic liver disease.
•Immunodeficiency Syndromes: Patients who have overt or laboratory evidence of immunodeficiency syndromes.
•Preexisting Blood Dyscrasias: Patients who have preexisting blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anemia.
•Hypersensitivity: Patients with a known hypersensitivity to methotrexate. Severe hypersensitivity reactions have been observed with methotrexate use.
Warnings and Precautions:
•Organ system toxicity: Potential for serious toxicity. Only for use by physicians experienced in antimetabolite therapy.
•Embryo-fetal toxicity: Exclude pregnancy before treatment. Avoid pregnancy if either partner is receiving Otrexup. Advise males to avoid pregnancy for a minimum of three months after therapy and females to avoid pregnancy for at least one ovulatory cycle after therapy.
•Effects on reproduction: May cause impairment of fertility, oligospermia and menstrual dysfunction.
•Laboratory tests: Monitor complete blood counts, renal function and liver function tests.
•Risks from improper dosing: Mistaken daily use has led to fatal toxicity.
•Patients with impaired renal function, ascites, or pleural effusions: Elimination is reduced.
•Dizziness and fatigue: May impair ability to drive or operate machinery.
Adverse Reactions
Common adverse reactions are: nausea, abdominal pain, dyspepsia, stomatitis/mouth sores, rash, nasopharyngitis, diarrhea, liver function test abnormalities, vomiting, headache, bronchitis, thrombocytopenia, alopecia, leucopenia, pancytopenia, dizziness, photosensitivity, and “burning of skin lesions”.
Drug Interactions
•Aspirin, NSAIDs, and steroids: concomitant use may elevate and prolong serum methotrexate levels and cause increased toxicity.
•Proton pump inhibitors: concomitant use may elevate and prolong serum methotrexate levels and cause increased toxicity.
Use in Special Populations
•Pregnancy: Methotrexate has been reported to cause embryotoxicity, fetal death, congenital anomalies, and abortion in humans and is contraindicated in pregnant women.
•Nursing Mothers: Because of the potential for serious adverse reactions from methotrexate in breast fed infants, Otrexup is contraindicated in nursing mothers.
•Females and Males of Reproductive Potential: Contraception should be used by both females and males while taking Otrexup. Pregnancy should be avoided if either partner is receiving Otrexup:
•for a minimum of 3 months after treatment with Otrexup for males.
•during and for at least 1 menstrual cycle after treatment with Otrexup for females.
•Pediatric use: Safety and efficacy of methotrexate, including Otrexup, have not been established in pediatric patients with psoriasis. Safety and efficacy of Otrexup have not been established in pediatric patients with malignancy.
•Geriatric use: Use caution in dose selection.
Dosage and Administration
Otrexup is for once weekly subcutaneous use only.
Administer Otrexup in the abdomen or thigh.