1、FDA Drug Safety Communication: Low magnesium levels can be associated with long-term use of Proton Pump Inhibitor drugs(PPIs)美国食品药品监督管理局（FDA）药物安全通讯：长期使用质子泵抑制剂（PPIs）可能导致低镁血症Safety Announcement 安全通告3-2-2011 The U.S. Food and Drug Administration (FDA) is informing the public that prescription proton pu
2、mp inhibitor (PPI) drugs may cause low serum magnesium levels (hypomagnesemia) if taken for prolonged periods of time (in most cases, longer than one year). In approximately one-quarter of the cases reviewed, magnesium supplementation alone did not improve low serum magnesium levels and the PPI had
3、to be discontinued.2011 年 3 月 2 日 美国食品药品监督管理局告知公众，长期（大多数情况下，指超过 1 年）使用处方药类质子泵抑制剂（PPIs）可能导致血清镁水平降低(低镁血症)。其中约 1/4 的病例，单纯进行补充镁无法对血镁水平有明显改善，必须停止使用相关的质子泵抑制剂。PPIs work by reducing the amount of acid in the stomach and are used to treat conditions such as gastroesophageal reflux disease (GERD), stomach and
4、 small intestine ulcers, and inflammation of the esophagus. In 2009, approximately 21 million patients filled PPI prescriptions at outpatient retail pharmacies in the United States.2 Patients who take prescription PPIs usually stay on therapy for an average of about 180 days (6 months).3质子泵抑制剂可降低胃酸水
5、平，用于胃食管反流症（GERD） 、胃和小肠溃疡以及食管炎等疾病的治疗。2009 年，美国大约有 2100 万患者通过门诊零售药房调配了质子泵抑制剂 2。患者接受质子泵抑制剂治疗的平均治疗时间为 180 天（6 个月） 3。Prescription PPIs include Nexium (esomeprazole magnesium), Dexilant (dexlansoprazole), Prilosec (omeprazole), Zegerid (omeprazole and sodium bicarbonate), Prevacid (lansoprazole), Protonix
6、 (pantoprazole sodium), and AcipHex (rabeprazole sodium). Vimovo is a prescription combination drug product that contains a PPI (esomeprazole magnesium and naproxen). Over-the-counter (OTC) PPIs include Prilosec OTC (omeprazole), Zegerid OTC (omeprazole and sodium bicarbonate), and Prevacid 24HR (la
7、nsoprazole).处方药类质子泵抑制剂包括 Nexium (埃索美拉唑镁)、Dexilant（右旋兰索拉唑） 、Prilosec（奥美拉唑） 、Zegerid（奥美拉唑+碳酸氢钠） 、Prevacid（兰索拉唑） 、Protonix（泮托拉唑钠） 、以及 AcipHex（雷贝拉唑钠） 。Vimovo 的成分为埃索美拉唑镁和萘普生，是含有一种质子泵抑制剂的复方处方药。非处方药类质子泵抑制剂包括 Prilosec OTC (奥美拉唑) 、Zegerid OTC (奥美拉唑 +碳酸氢钠)和 Prevacid 24HR (兰索拉唑 )。In contrast to prescription PP
8、Is, OTC PPIs are marketed at low doses and are only intended for a 14 day course of treatment up to 3 times per year. FDA believes that there is very little risk of hypomagnesemia when OTC PPIs are used according to the directions on the OTC label.相比于处方药类质子泵抑制剂，市场销售的非处方类质子泵抑制剂的含量较低，仅仅用于每年不超过 3 个疗程，每
9、个疗程为 14 天的疾病治疗。FDA 相信非处方药类质子泵抑制剂如果按照其标签上标注的用法使用，引发低镁血症的风险很低。Low serum magnesium levels can result in serious adverse events including muscle spasm (tetany), irregular heartbeat (arrhythmias), and convulsions (seizures); however, patients do not always have these symptoms. Treatment of hypomagnesemia
10、 generally requires magnesium supplements. Treatment in patients taking a PPI and who have hypomagnesemia may also require stopping the PPI.低镁血症可能导致肌肉痉挛（手足抽搐） 、心跳不规则(心律失常) 和抽搐（癫痫发作） ，但是症状并非在患者中经常出现。低镁血症的治疗一般采用补镁治疗，对于正在使用质子泵抑制剂的患者，可能需要停止使用相关质子泵抑制剂。Healthcare professionals should consider obtaining se
11、rum magnesium levels prior to initiation of prescription PPI treatment in patients expected to be on these drugs for long periods of time, as well as patients who take PPIs with medications such as digoxin, diuretics or drugs that may cause hypomagnesemia. For patients taking digoxin, a heart medici
12、ne, this is especially important because low magnesium can increase the likelihood of serious side effects. Healthcare professionals should consider obtaining magnesium levels periodically in these patients.如果患者接受的质子泵抑制剂治疗可能持续很长一段时间，或者患者同时有服用地高辛、利尿剂以及其它可能导致低镁血症的药物，医疗保健专业人员在给患者质子泵抑制剂之前应先获取患者血镁水平的信息。对
13、于服用心脏病治疗药地高辛的患者，这点尤其重要，因为低镁血症可能增加一些严重副作用的发生率。医疗保健专业人员应定期收集这些患者血镁水平的信息。Information about the potential risk of low serum magnesium levels from PPIs will be added to the WARNINGS AND PRECAUTIONS sections of the labels for all the prescription PPIs.这些处方药类质子泵抑制剂标签 WARNINGS AND PRECAUTIONS 部分将增加这类药物引发低镁血
14、症风险的信息。Todays communication is in keeping with FDAs commitment to inform the public about its ongoing safety review of drugs. FDA is continuing to review reports of possible adverse events and drug interactions with PPI drugs submitted to our Adverse Event Reporting System. FDA 本着将进行的药物安全评价信息及时告知公众的
15、承诺进行了今天的通讯，FDA 还将对不良事件报告系统收集的可能不良事件和药物相互作用的报告进行进一步的评价。Additional Information for Patients致患者的额外信息Seek immediate care if you (or your child) experience an abnormal heart rate or rhythm, or symptoms such as a racing heartbeat, palpitations, muscle spasm, tremor or convulsions while taking a PPI drug.
16、In children, abnormal heart rates may cause fatigue, upset stomach, dizziness and lightheadedness.如果您或您的孩子服用质子泵抑制剂后出现心跳或心律失常，或者出现心跳加快、心悸、肌肉痉挛、震颤或者癫痫发作等症状，请及时就医。对于儿童，心律失常还可能导致疲劳、胃部不适、头晕和头晕等症状。Tell your healthcare professional if you have ever been told you have low magnesium levels in your blood, or
17、if you take the drug digoxin, diuretics, or other drugs that may cause hypomagnesemia.如果您曾获知血镁水平偏低，或者您正在服用地高辛、利尿剂或其它可能导致低镁血症的药物，请告诉您的医疗保健专业人员。Your healthcare professional may occasionally check your serum magnesium level (a blood test) while you are taking your prescription PPI drug.如果您正在服用这些处方药类质子泵
18、抑制剂，您的医疗保健专业人员可能会不时对您的血镁水平进行抽血检查。Do not stop taking your prescription PPI drug without talking to your healthcare professional.在没和您的医疗保健专业人员沟通之前，请不要停止使用您的处方药类质子泵抑制剂。Discuss any questions or concerns about your PPI drug with your healthcare professional.请与您的医疗保健专业人员讨论您对使用的处方药类质子泵抑制剂的疑惑和关切。If you take
19、 an over-the-counter (OTC) PPI drug, follow the directions on the package carefully.如果您服用的是非处方药类质子泵抑制剂，请认真按照包装上标注的使用方法使用。Make sure your healthcare professional knows if you have been taking an OTC PPI drug for a long period of time.如果您长期使用非处方药类质子泵抑制剂，请务必告知您的医疗保健专业人员。Report any side effects you exper
20、ience to the FDA MedWatch program using the information in the “Contact Us“ box at the bottom of the page.您可以通过本页面底端“Contact Us”框提到的方式向 FDA MedWatch 项目汇报您曾经历的任何副作用。 Additional Information for Healthcare Professionals至医疗保健专业人员的额外信息Consider obtaining serum magnesium levels prior to initiation of presc
21、ription PPI treatment and checking levels periodically thereafter for patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics).如果患者接受的质子泵抑制剂治疗可能需持续很长一段时间，或者患者有同时服用地高辛以及其它可能导致低镁血症的药物（如,利尿剂） ，在给患者质子泵抑制剂之前应
22、先获取患者血镁水平的信息并在此后定期收集该患者血镁水平的信息。Hypomagnesemia occurs with both loop diuretics (furosemide, bumetanide, torsemide, and ethacrynic acid) and thiazide diuretics (chlorothiazide, hydrochlorothiazide, indapamide, and metolazone). These agents can cause hypomagnesemia when used as a single agent or when c
23、ombined with other anti-hypertensives (e.g., beta-blockers, angiotensin receptor blockers and/or ACE inhibitors).亨利氏环利尿剂（呋塞米、布美他尼、托拉塞米和依他尼酸）和噻嗪类利尿剂（氯噻嗪、氢氯噻嗪、吲达帕胺和美托拉宗）使用时都可能发生低镁血症。这些利尿剂单独使用或者与其它抗高血压药物（如， 受体阻滞剂、血管紧缩素受体阻滞剂和 /或血管紧张素转换酶抑制剂）合用时均可引起低镁血症。Advise patients to seek immediate care from a health
24、care professional if they experience arrhythmias, tetany, tremors, or seizures while taking PPIs. These may be signs of hypomagnesemia.应建议患者服用质子泵抑制剂后如果出现心律失常、抽搐、或者癫痫等症状应及时就医。这些症状可能是低镁血症的征兆。Consider PPIs as a possible cause of hypomagnesemia, particularly in patients who are clinically symptomatic.对于
25、低镁血症，尤其是对有明显临床症状的患者，应注意询问其使用质子泵抑制剂的情况。Patients who develop hypomagnesemia may require PPI discontinuation in addition to magnesium replacement.发生低镁血症的患者，应停止使用质子泵抑制剂并进行镁的补充Be aware that consumers either on their own, or based on a healthcare professionals recommendation, may take OTC PPIs for periods
26、 of time that exceed the directions on the OTC label. This is considered an off-label (unapproved) use. Healthcare professionals should communicate the risk of hypomagnesemia to patients if they are recommending prolonged use of an OTC PPIs.需要注意到，患者可能会自行决定或者根据医疗保健专业人员的推荐，延长非处方类质子泵抑制剂使用的时间（超过非处方药标签中标
27、注的使用时间） ，这种情况被视为“标示外”使用。如果医疗保健专业人员建议患者如此延长非处方类质子泵抑制剂使用的时间，应当与患者沟通由此可能发生的低镁血症的风险。Report adverse events involving PPIs to the FDA MedWatch program, using the information in the “Contact Us“ box at the bottom of the page.通过本页面底端“Contact Us”框提到的方式向 FDA MedWatch 项目汇报质子泵抑制剂使用相关的不良事件。Data Summary数据总结FDA ha
28、s reviewed reports from the Adverse Event Reporting System (AERS), medical literature, and periodic safety update reports for cases of hypomagnesemia in patients undergoing prolonged treatment with PPI medications. FDAs review focused on 38 cases in AERS and 23 cases reported in the literature (whic
29、h include at least 8 cases of the identified AERS cases).4,5,6,7,8,9,10,11 The AERS case series excluded patients who were on diuretics. The cases from the literature included patients on diuretics when either (a) change in diuretic was not associated with an improvement in serum magnesium level, or
30、 (b) when increase in serum magnesium level occurred with documented PPI discontinuation. The FDA review suggests an association between hypomagnesemia-related serious adverse events and prolonged PPI use. However, because hypomagnesemia is likely under-recognized and under-reported, the available d
31、ata are insufficient to quantify an incidence rate for hypomagnesemia with PPI therapy.FDA 已经对来自于不良事件报告系统、医学文献以及长期使用质子泵抑制剂患者低镁血症定期安全更新等方面的病例报告进行了评估，重点评估了不良事件报告系统报告的 38 例以及医学文献 4-11中报道的 23 例低镁血症不良事件。其中来自不良事件报告系统的为未使用利尿剂的病例；来自文献报道的有合用利尿剂的病例，主要包括（1）改变利尿剂对患者血镁水平没有改善，或（2）停用相关质子泵抑制剂后血镁水平上升这两种情况。FDA 评估报告显示
32、低镁血症相关的不良事件和长期使用质子泵抑制剂有关。由于低镁血症可能会被漏诊和漏报，现有数据还不能对接受质子泵抑制剂治疗后低镁血症的发生率进行准确评估。Hypomagnesemia has been reported in adult patients taking PPIs for at least three months, but most cases occurred after a year of treatment. Approximately one-quarter of these cases required discontinuation of PPI treatment i
33、n addition to magnesium supplementation. Some cases cited both positive dechallenge as well as positive rechallenge (i.e., resolution of hypomagnesemia with PPI cessation and recurrent hypomagnesemia with PPI resumption). After discontinuing the PPI, the median time required for the magnesium to nor
34、malize was one week. After restarting the PPI, the median time to develop hypomagnesemia again was two weeks. In most cases reviewed the patients did not continue on PPIs after the hypomagnesemia was treated.已有成年人使用质子泵抑制剂超过 3 个月时发生低镁血症的报道，但是大多数的低镁血症病例都发生在使用质子泵抑制剂超过 1 年以后。大约有 1/4 的病例除了进行镁的补充，还必须得停止质子
35、泵抑制剂治疗。一部分病例去激发和再激发试验的结果均为阳性（如，考察停止质子泵抑制后低镁血症是否恢复及恢复使用质子泵抑制后低镁血症是否复发） ，在这些病例中，停止使用质子泵抑制剂后，血镁水平恢复到正常水平的平均时间为 1 周。再次使用质子泵抑制剂后，低镁血症再次复发的的平均时间为 2 周。大多数病例在低镁血症得到治疗后没有继续使用质子泵抑制剂。Examples of positive dechallenge in two patients include a 63-year-old woman and a 67-year-old man who were both treated with PP
36、Is for 6 and 11 years, respectively. Both patients presented with seizures and hypomagnesemia. Although both patients hypomagnesemia partially resolved with intravenous replacement, in both cases discontinuation of PPI treatment was necessary to stop ongoing symptoms and to stop magnesium loss.在 2 例
37、病例中中去激发试验结果为阳性，包括 1 位 63 岁女性和 1 位 67 岁男性，分别接受过 6 年和 11 年质子泵抑制剂治疗，且均出现过癫痫发作和低镁血症症状。尽管通过静脉补充镁后低镁血症有部分缓解，这两例病例还是需要停止了质子泵抑制剂的治疗以消除相关症状以及镁的丢失。Clinically serious adverse events were consistent with commonly reported signs and symptoms of hypomagnesemia, which are similar to the signs and symptoms reported
38、 with hypocalcemia. The serious events included tetany, seizures, tremors, carpo-pedal spasm, atrial fibrillation, supraventricular tachycardia, and abnormal QT interval. Hypomagnesemia also produces impaired parathyroid hormone secretion which may lead to hypocalcemia. In cases where comprehensive
39、clinical laboratory data were available, most patients had concomitant hypocalcemia and normal parathyroid hormone levels. Therefore, these findings confirm hypomagnesemia as the primary deficit.临床发现的严重不良事件符合低镁血症常见的症状和体征，和低钙血症的症状和体征比较相似。这些严重不良事件包括手足抽搐、癫痫发作、震颤、腕足痉挛、房颤、室上性心动过速和 QT 间期异常。低镁血症还能导致甲状旁腺激素分
40、泌受损，引发低钙血症。对于临床实验室检查数据比较齐全的病例，大多数患者同时表现出低钙血症和甲状旁腺激素异常。这些发现说明低镁血症是这些症状发生的首要原因。The mechanism responsible for hypomagnesemia associated with long term PPI use is unknown; however, long term use of PPIs may be associated with changes in intestinal absorption of magnesium.5目前，还不清楚长期使用质子泵抑制剂导致低镁血症的确切作用机制，
41、但是，现在认为长期使用质子泵抑制剂可能改变肠道对镁的吸收水平 5。OTC PPIs are marketed for the treatment of frequent heartburn under the brand names Prilosec OTC, Zegerid OTC, and Prevacid 24 HR. OTC PPIs are labeled for 14 days of use, and this treatment course may be repeated every 4 months, up to 3 times per year. FDA acknowled
42、ges that consumers, either on their own, or based on a healthcare professionals recommendation, may take these products for periods of time that exceed the directions on the OTC label. This is considered an off-label (unapproved) use, based on the directions of use for OTC PPIs. Healthcare professio
43、nals should be aware of the risk of hypomagnesemia if they are recommending use of OTC PPIs for longer periods of time than in the OTC PPI label. FDA believes that OTC PPIs carry very little risk of hypomagnesemia when used according to the package directions, and therefore the Drug Facts box for th
44、e OTC PPIs will not be changed to include the risk of hypomagnesemia.目前市场上销售的非处方药类质子泵抑制剂包括 Prilosec OTC、Zegerid OTC 和 Prevacid 24 HR 等，主要用于频发烧心症状治疗。处方药类质子泵抑制剂标示的使用疗程是 2 周，每4 个月可重复一个疗程，一年最多 3 个疗程。FDA 认识到，一些患者可能会自行决定或者根据医疗保健专业人员的推荐，使用质子泵抑制剂的时间超过标签上使用方法规定的时间，这种情况被视为“标示外” 使用。医疗保健专业人员应意识到如果推荐使用质子泵抑制剂的时间超过处方药质子泵抑制剂标签规定的时间，可能增加低镁血症的风险。FDA 相信如果严格按照说明规定的用法，非处方类质子泵抑制剂引发低镁血症的风险较低，因此这类药物的说明书 Drug Facts 部分目前不需要加入低镁血症风险的内容。
