Appformin-D

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描述
盐酸二甲双胍（USP）是一种口服抗高血糖药，用于治疗2型糖尿病。盐酸二甲双胍（N，N-二甲基亚氨基二碳二酰亚胺基二酰胺盐酸盐）与任何其他类别的口服降糖药没有化学或药理关系。结构式如下所示：

盐酸二甲双胍是一种白色至类白色结晶化合物，分子式为C4H11N5-HCl，分子量为165.63。盐酸二甲双胍USP易溶于水，几乎不溶于丙酮，乙醚和氯仿。二甲双胍的pKa为12.4。 USP 1％盐酸二甲双胍水溶液的pH值为6.68。盐酸二甲双胍片USP包含500 mg，850 mg和1000 mg盐酸二甲双胍。每片含有非活性成分聚维酮，聚乙二醇和硬脂酸镁。另外，用于500 mg，850 mg和1000 mg的包衣包含：一水乳糖，羟丙甲纤维素，二氧化钛，三醋精。

临床药理学
作用机理
二甲双胍是一种降糖药，可改善2型糖尿病患者的糖耐量，降低基础和餐后血浆葡萄糖。其药理作用机制与其他类型的口服降糖药不同。盐酸二甲双胍可通过增加外周葡萄糖的摄取和利用来降低肝脏葡萄糖的产生，降低肠道对葡萄糖的吸收并提高胰岛素敏感性。与磺脲类药物不同，二甲双胍在2型糖尿病患者或正常受试者中均不会产生低血糖症（特殊情况除外，请参见注意事项），并且不会引起高胰岛素血症。使用二甲双胍治疗时，胰岛素的分泌保持不变，而空腹的胰岛素水平和为期一天的血浆胰岛素反应实际上可能会降低。

药代动力学

吸收和生物利用度

在禁食条件下给予的盐酸二甲双胍500 mg片剂的绝对生物利用度约为50-60％。使用单次口服二甲双胍盐酸盐片（USP为500 mg至1500 mg和850 mg至2550 mg）进行的研究表明，剂量增加时缺乏剂量比例，这是由于吸收减少而不是消除消除。食物会降低二甲双胍的吸收程度，并稍微延迟其吸收，具体表现为平均峰值血浆浓度（Cmax）降低约40％，血浆浓度与时间的关系曲线下面积（AUC）降低约25％，延长35分钟与空腹服用相同片剂强度相比，与食物一起服用一剂850 mg二甲双胍片剂后达到峰值血浆浓度（Tmax）的时间。这些减少的临床相关性未知。

分配

单次口服850毫克后，二甲双胍的表观分布体积（V / F）平均为654±358L。与磺酰脲类蛋白的结合率超过90％相比，二甲双胍与血浆蛋白的结合率可忽略不计。二甲双胍最有可能是时间的函数，分配为红细胞。在盐酸二甲双胍片的常规临床剂量和给药方案下，二甲双胍的USP稳态血浆浓度在24-48小时内达到，通常低于1 µg / mL。在二甲双胍的对照临床试验中，即使在最大剂量下，二甲双胍的最大血浆水平也不超过5 µg / mL。

代谢与消除

正常受试者的静脉单剂量研究表明，二甲双胍在尿液中原样排泄，并且没有进行肝代谢（在人体中未发现代谢物）或胆汁排泄。肾清除率（见表1）约为肌酐清除率的3.5倍，这表明肾小管分泌物是消除二甲双胍的主要途径。口服后，在最初的24小时内通过肾脏途径消除了约90％的吸收药物，血浆消除半衰期约为6.2小时。在血液中，消除半衰期约为17.6小时，表明红细胞块可能是分布区室。

特殊人群

2型糖尿病患者

在肾功能正常的情况下，2型糖尿病患者和正常受试者之间的二甲双胍单次或多次剂量药代动力学之间没有差异（见表1），在正常临床剂量下，两组中的二甲双胍均无任何蓄积。

肾功能不全

在肾功能降低的患者（基于测得的肌酐清除率）中，二甲双胍的血浆和血液半衰期延长，并且肾清除率与肌酐清除率降低成比例降低（见表1；另请参见警告）。

肝功能不全

肝功能不全的患者尚未进行二甲双胍的药代动力学研究。

老年医学
在健康的老年受试者中进行二甲双胍的受控药代动力学研究的有限数据表明，与健康的年轻受试者相比，二甲双胍的总血浆清除率降低，半衰期延长，Cmax升高。从这些数据可以看出，二甲双胍药代动力学随年龄的变化主要是由肾功能的变化引起的（见表1）。除非肌酐清除率的测量结果表明肾功能没有降低，否则不应在≥80岁的患者中开始二甲双胍治疗。 （请参阅警告和用法用量）。

儿科

服用含食物的口服口服二甲双胍盐酸盐500 mg片后，小儿2型糖尿病患者（12至16岁）与性别和体重相匹配的健康成人（20岁）的几何平均二甲双胍Cmax和AUC差异小于5％。至45岁），所有肾功能均正常。

性别

根据性别（男性= 19，女性= 16）进行分析时，正常受试者与2型糖尿病患者之间的二甲双胍药代动力学参数无显着差异。同样，在2型糖尿病患者的对照临床研究中，盐酸二甲双胍片的抗高血糖作用在男性和女性中均相当。

种族

尚未根据种族对二甲双胍药代动力学参数进行研究。在2型糖尿病患者中盐酸二甲双胍片USP的对照临床研究中，白人（n = 249），黑人（n = 51）和西班牙裔（n = 24）的降血糖作用相当。

临床研究
在一项双盲，安慰剂对照，多中心美国临床试验中，该试验涉及肥胖的2型糖尿病患者，仅通过饮食管理（基线空腹血糖[FPG]约为240 mg / dL）不能充分控制高血糖，使用盐酸二甲双胍治疗USP（最高2550 mg /天）片剂持续29周的结果是，禁食和餐后血浆葡萄糖（PPG）和血红蛋白A1c（HbA1c）的平均净降低分别为59 mg / dL，83 mg / dL和1.8％，分别与安慰剂组比较（见表2）。

对肥胖和2型糖尿病患者进行了为期29周，双盲，安慰剂对照的二甲双胍和格列本脲研究，这些患者在最大剂量的格列本脲（血糖FPG）未达到适当的血糖控制的情况下约250 mg / dL）（见表3）。随机分组的患者开始接受盐酸二甲双胍500 mg和格列本脲20 mg的治疗。在试验的前四个星期的每个星期结束时，如果未能达到目标空腹血糖，则这些患者的盐酸二甲双胍剂量会增加500 mg。第四周后，每月进行此类剂量调整，尽管不允许任何患者超过2500 mg盐酸二甲双胍。仅使用盐酸二甲双胍组（二甲双胍加安慰剂）的患者遵循相同的滴定时间表。在试验结束时，组合组中约70％的患者正在服用盐酸二甲双胍2000 mg /格列本脲20 mg或盐酸二甲双胍2500 mg /格列本脲20 mg。随机分组继续使用格列本脲的患者血糖控制恶化，FPG，PPG和HbA1c的平均升高分别为14 mg / dL，3 mg / dL和0.2％。相比之下，随机分组服用二甲双胍的患者（最高2500 mg / d）则略有​​改善，FPG，PPG和HbA1c的平均降低分别为1 mg / dL，6 mg / dL和0.4％。二甲双胍和格列本脲的组合可有效将FPG，PPG和HbA1c水平分别降低63 mg / dL，65 mg / dL和1.7％。与单独使用格列本脲治疗的结果相比，联合治疗的净差异分别为-77 mg / dL，-68 mg / dL和-1.9％（参见表3）。

服用盐酸二甲双胍片，USP治疗后，空腹血糖浓度下降的幅度与空腹高血糖水平成正比。空腹血糖浓度较高的2型糖尿病患者血浆葡萄糖和糖基化血红蛋白的下降幅度更大。在临床研究中，二甲双胍单独或与磺脲类药物合用，可降低平均空腹血清甘油三酸酯，总胆固醇和LDL胆固醇水平，并且对其他脂质水平无不利影响（见表4）。

与磺脲类药物相比，二甲双胍个体的体重趋于保持稳定甚至有所下降（见表2和3）。

对2型糖尿病患者进行了一项为期24周，双盲，安慰剂对照的盐酸二甲双胍片，USP加胰岛素与胰岛素加安慰剂对照的研究，这些患者仅靠胰岛素就无法获得足够的血糖控制（见表5）。随机接受盐酸二甲双胍加胰岛素治疗的患者HbA1c降低了2.10％，而胰岛素加安慰剂使HbA1c降低了1.56％。在最后的研究拜访中，血糖控制得到了改善，胰岛素减少了16％，分别为93.0 U /天和110.6 U /天，盐酸二甲双胍片，USP加胰岛素与胰岛素加安慰剂相比，p = 0.04。

第二项双盲，安慰剂对照研究（n = 51），进行了16周的随机治疗，证明在2型糖尿病患者中，胰岛素控制8周，平均HbA1c为7.46±0.97％，盐酸二甲双胍片，USP维持相似的血糖控制（盐酸二甲双胍片，USP加胰岛素和安慰剂加胰岛素分别为HbA1C 7.15±0.61和6.97±0.62），胰岛素比基线减少19％（减少23.68±30.22与增加盐酸二甲双胍片，USP加胰岛素和安慰剂加胰岛素的浓度为0.43±25.20单位（小于0.01）。此外，这项研究表明，盐酸二甲双胍片，USP加胰岛素的组合可减轻体重3.11±4.30 lbs，而安慰剂加胰岛素增加1.30±6.08 lbs，p = 0.01。

儿科临床研究
在一项对10至16岁2型糖尿病（平均FPG 182.2 mg / dL）的儿科患者进行的双盲，安慰剂对照研究中，使用盐酸二甲双胍片，USP（最高2000 mg /天）治疗最多16次与安慰剂相比，治疗2周（平均治疗时间11周）可导致FPG的平均平均净降低显着，为64.3 mg / dL（参见表6）。

适应症和用途
盐酸二甲双胍片（USP）可作为饮食和运动的辅助剂，以改善成年人和2型糖尿病儿童的血糖控制。

禁忌症
盐酸二甲双胍片禁用于以下患者：
1.肾脏疾病或肾功能不全（例如，血清肌酐水平大于或等于1.5 mg / dL [男性]，大于或等于1.4 mg / dL [女性]或肌酐清除率异常）诸如心血管衰竭（休克），急性心肌梗塞和败血病等疾病（请参阅警告和注意事项）。
2.已知对USP盐酸二甲双胍片过敏。
3.急性或慢性代谢性酸中毒，包括糖尿病性酮症酸中毒，有或没有昏迷。糖尿病酮症酸中毒应用胰岛素治疗。
在接受影像学检查的患者中，涉及血管内给药碘化造影剂的患者应暂时停用二甲双胍，因为使用此类产品可能会导致肾功能的急性改变。 （另请参见注意事项。）

预防措施

一般

大血管结局
尚无临床研究确定使用二甲双胍或任何其他抗糖尿病药可降低大血管风险的确凿证据。

监测肾功能
已知二甲双胍基本上被肾脏排泄，二甲双胍积累和乳酸性酸中毒的风险随肾功能损害的程度而增加。因此，血清肌酐水平高于正常年龄上限的患者不应接受二甲双胍治疗。在高龄患者中，应谨慎滴定二甲双胍以建立足够的降糖作用的最小剂量，因为衰老与肾功能下降有关。在老年患者中，尤其是≥80岁的老年患者，应定期监测肾功能，并且一般不应将二甲双胍滴定至最大剂量（请参阅“警告和用法用量”）。

在开始二甲双胍治疗之前和之后至少每年一次，应评估并确认肾功能正常。在预期会出现肾功能不全的患者中，应更频繁地评估肾功能，如果存在肾功能不全的证据，则应停用二甲双胍。

使用可能会影响肾功能或二甲双胍治疗的辅助药物
应谨慎使用可能会影响肾功能或导致明显的血流动力学改变或可能干扰二甲双胍治疗的伴随药物，例如通过肾小管分泌物消除的阳离子药物（请参阅预防措施：药物相互作用）。

涉及使用血管内碘化造影剂的放射学研究（例如，静脉内尿路造影，静脉内胆道造影，血管造影和使用血管内造影剂的CT扫描）
含碘物质的血管内对比研究可导致肾功能急性改变，并与接受二甲双胍的患者发生乳酸性酸中毒有关（见禁忌症）。因此，对于计划进行任何此类研究的患者，二甲双胍应在手术时或手术前暂时停药，并在手术后48小时内停药，仅在重新评估肾功能并发现肾功能不佳后才重新开始正常。

缺氧状态
各种原因引起的心血管衰竭（休克），急性充血性心力衰竭，急性心肌梗塞和其他以低氧血症为特征的疾病都与乳酸性酸中毒有关，也可能导致肾前性氮质血症。当二甲双胍治疗的患者发生此类事件时，应立即停药。

外科手术
二甲双胍治疗应暂时暂停任何外科手术（除与限制摄入食物和液体无关的小手术外），除非患者口服摄入恢复并且肾功能评估为正常，否则不得重新开始二甲双胍治疗。

饮酒量
已知酒精可增强二甲双胍对乳酸代谢的作用。因此，在服用二甲双胍时，应警告患者不要过量摄入酒精，无论是急性还是慢性的。

肝功能受损
由于肝功能受损与某些乳酸性酸中毒有关，因此在有肝病临床或实验室证据的患者中通常应避免服用二甲双胍。

维生素B12含量
在为期29周的盐酸二甲双胍的对照临床试验中，大约7％的患者观察到先前的正常血清维生素B12水平降至亚正常水平，没有临床表现。但是，这种减少可能是由于干扰了B12-内在因子复合物对B12的吸收所致，但很少与贫血相关，并且在中止盐酸二甲双胍片，USP或补充维生素B12后似乎可以迅速逆转。
建议使用二甲双胍的患者每年测量一次血液学参数，任何明显的异常都应进行适当的调查和处理（请参阅预防措施：实验室检查）。

某些人（维生素B12不足或钙摄入或吸收不足的人）似乎倾向于发展出低于正常水平的维生素B12。在这些患者中，以两到三年为间隔的常规血清维生素B12测量可能是有用的。

先前控制过的2型糖尿病患者的临床状况变化先前曾接受盐酸二甲双胍片治疗的USP患有实验室异常或临床疾病（尤其是模糊和定义不明确的疾病）的USP，应立即进行评估，以发现酮症酸中毒的证据或乳酸性酸中毒。评估应包括血清电解质和酮，血糖以及血液pH值，乳酸，丙酮酸和二甲双胍的水平（如果指示）。如果发生任何一种酸中毒，则必须立即停止二甲双胍的治疗，并采取其他适当的纠正措施（另请参见警告）。

低血糖症
通常情况下，仅接受二甲双胍治疗的患者不会发生低血糖症，但是当热量摄入不足，剧烈运动无法通过热量补充来弥补时，或者与其他降糖药（如磺脲类药物和胰岛素）同时使用时，可能发生低血糖症。 ）或乙醇。

老年人，虚弱或营养不良的患者，以及肾上腺或垂体功能不全或酒精中毒的患者特别容易发生降血糖作用。低血糖症在老年人和服用β-肾上腺素阻断药的人群中可能难以识别。

血糖失控
当在任何糖尿病治疗方案中稳定下来的患者暴露于诸如发烧，创伤，感染或手术之类的压力下时，可能会暂时失去血糖控制。在这种情况下，可能有必要停用二甲双胍并暂时服用胰岛素。急性发作缓解后，可重新使用二甲双胍。

在一段时间内，许多患者的口服降糖药将血糖降低至目标水平的有效性下降。 This phenomenon, which may be due to progression of the underlying disease or to diminished responsiveness to the drug, is known as secondary failure, to distinguish it from primary failure in which the drug is ineffective during initial therapy. Should secondary failure occur with metformin or sulfonylurea monotherapy, combined therapy with metformin and sulfonylurea may result in a response. Should secondary failure occur with combined metformin/sulfonylurea therapy, it may be necessary to consider therapeutic alternatives including initiation of insulin therapy.

给患者的信息
Patients should be informed of the potential risks and benefits of metformin and of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of blood glucose, glycosylated hemoglobin, renal function and hematologic parameters.
The risks of lactic acidosis, its symptoms, and conditions that predispose to its development, as noted in the WARNINGS and PRECAUTIONS sections should be explained to patients. Patients should be advised to discontinue metformin immediately and to promptly notify their health practitioner if unexplained hyperventilation, myalgia, malaise, unusual somnolence or other nonspecific symptoms occur. Once a patient is stabilized on any dose level of metformin, gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.
Patients should be counseled against excessive alcohol intake, either acute or chronic, while receiving metformin.
Metformin hydrochloride tablets, USP alone does not usually cause hypoglycemia, although it may occur when metformin is used in conjunction with oral sulfonylureas and insulin. When initiating combination therapy, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members. (See Patient Information Printed Below.)

实验室测试
Response to all diabetic therapies should be monitored by periodic measurements of fasting blood glucose and glycosylated
hemoglobin levels, with a goal of decreasing these levels toward the normal range. During initial dose titration, fasting glucose
can be used to determine the therapeutic response. Thereafter, both glucose and glycosylated hemoglobin should be monitored.
Measurements of glycosylated hemoglobin may be especially useful for evaluating long-term control (see also DOSAGE AND
ADMINISTRATION).
Initial and periodic monitoring of hematologic parameters (eg, hemoglobin/hematocrit and red blood cell indices) and renal function
(serum creatinine) should be performed, at least on an annual basis. While megaloblastic anemia has rarely been seen with metformin
therapy, if this is suspected, vitamin B12 deficiency should be excluded.

Drug Interactions (Clinical Evaluation of Drug Interactions Conducted with metformin)

格列本脲
In a single-dose interaction study in type 2 diabetes patients, co-administration of metformin and glyburide did not result in any changes in either metformin pharmacokinetics or pharmacodynamics. Decreases in glyburide AUC and Cmax were observed, but were highly variable. The single-dose nature of this study and the lack of correlation between glyburide blood levels and pharmacodynamic effects, makes the clinical significance of this interaction uncertain (see DOSAGE AND ADMINISTRATION: Concomitant Metformin Hydrochloride Tablets, USP and Oral Sulfonylurea Therapy in Adult Patients).

速尿
A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by co-administration. Furosemide increased the metformin plasma and blood Cmax by 22% and blood AUC by 15%, without any significant change in metformin renal clearance. When administered with metformin, the Cmax and AUC of furosemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life was decreased by 32%, without any significant change in furosemide renal clearance. No information is available about the interaction of metformin and furosemide when co-administered chronically.

硝苯地平
A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that co-administration of nifedipine increased plasma metformin Cmax and AUC by 20% and 9%, respectively, and increased the amount excreted in the urine. Tmax half-life were unaffected.硝苯地平似乎可以增强二甲双胍的吸收。 Metformin had minimal effects on nifedipine.

Cationic Drugs
Cationic drugs (eg, amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, and vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Such interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose, metformin-cimetidine drug interaction studies, with a 60% increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma and whole blood metformin AUC. There was no change in elimination half-life in the single-dose study. Metformin had no effect on cimetidine pharmacokinetics. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of metformin and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.

其他
某些药物倾向于产生高血糖症，并可能导致血糖控制丧失。 These drugs include thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving metformin, the patient should be observed closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin, the patient should be observed closely for hypoglycemia. In healthy volunteers, the pharmacokinetics of metformin and propranolol and metformin and ibuprofen were not affected when coadministered in single-dose interaction studies. Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid, as compared to the sulfonylureas, which are extensively bound to serum proteins.

致癌，诱变，生育力受损
Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively. These doses are both approximately four times the maximum recommended human daily dose of 2000 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day.
There was no evidence of a mutagenic potential of metformin in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative.
Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately three times the maximum recommended human daily dose based on body surface area comparisons.

怀孕

Teratogenic Effects: Pregnancy Category B.
Recent information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities. Most experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible. Because animal reproduction studies are not always predictive of human response, metformin should not be used during pregnancy unless clearly needed.

There are no adequate and well-controlled studies in pregnant women with metformin. Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about two and six times the maximum recommended human daily dose of 2000 mg based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.

NURSING MOTHERS
Studies in lactating rats show that metformin is excreted into milk and reaches levels comparable to those in plasma. Similar studies have not been conducted in nursing mothers. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If metformin is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.

小儿使用
The safety and effectiveness of metformin hydrochloride tablets, USP for treatment of type 2 diabetes have been established in pediatric patients ages 10 to 16 years (studies have not been conducted in pediatric patients below the age of 10 years). Use of metformin hydrochloride tablets, USP in this age group is supported by evidence from adequate and well-controlled studies of Metformin in adults with additional data from a controlled clinical study in pediatric patients ages 10-16 years with type 2 diabetes, which demonstrated a similar response in glycemic control to that seen in adults. (See CLINICAL PHARMACOLOGY: Pediatric Clinical Studies.) In this study, adverse effects were similar to those described in adults. (See ADVERSE REACTIONS: Pediatric Patients.) A maximum daily dose of 2000 mg is recommended. (See DOSAGE AND ADMINISTRATION: Recommended Dosing Schedule: Pediatrics.)

老年使用
Controlled clinical studies of metformin hydrochloride tablets, USP did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and younger patients. Metformin is known to be substantially excreted by the kidney and because the risk of serious adverse reactions to the drug is greater in patients with impaired renal function, it should only be used in patients with normal renal function (see CONTRAINDICATIONS, WARNINGS, and CLINICAL PHARMACOLOGY: Pharmacokinetics). Because aging is associated with reduced renal function, metformin should be used with caution as age increases. Care should be taken in dose selection and should be based on careful and regular monitoring of renal function. Generally, elderly patients should not be titrated to the maximum dose of metformin (see also WARNINGS and DOSAGE AND ADMINISTRATION).

不良反应
In a US double-blind clinical study of metformin in patients with type 2 diabetes, a total of 141 patients received metformin therapy (up to 2550 mg per day) and 145 patients received placebo. Adverse reactions reported in greater than 5% of the metformin patients, and that were more common in metformin than placebotreated patients, are listed in Table 7.

Diarrhea led to discontinuation of study medication in 6% of patients treated with metformin.
Additionally, the following adverse reactions were reported in greater than or equal to 1.0- less than or equal to 5.0% of metformin patients and were more commonly reported with metformin than placebo: abnormal stools, hypoglycemia, myalgia, lightheaded, dyspnea, nail disorder, rash, sweating increased, taste disorder, chest discomfort, chills, flu syndrome, flushing, palpitation.

小儿患者
In clinical trials with metformin hydrochloride tablets, USP in pediatric patients with type 2 diabetes, the profile of adverse reactions was similar to that observed in adults.

过量
Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases (see WARNINGS). Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

剂量和给药
There is no fixed dosage regimen for the management of hyperglycemia in patients with type 2 diabetes with metformin or any other pharmacologic agent. Dosage of metformin must be individualized on the basis of both effectiveness and tolerance, while not exceeding the maximum recommended daily dose. The maximum recommended daily dose of metformin hydrochloride tablets, USP is 2550 mg in adults and 2000 mg in pediatric patients (10-16 years of age).
Metformin should be given in divided doses with meals and should be started at a low dose, with gradual dose escalation, both to reduce gastrointestinal side effects and to permit identification of the minimum dose required for adequate glycemic control of the patient.
During treatment initiation and dose titration (see Recommended Dosing Schedule), fasting plasma glucose should be used to determine the therapeutic response to metformin and identify the minimum effective dose for the patient. Thereafter, glycosylated hemoglobin should be measured at intervals of approximately three months. The therapeutic goal should be to decrease both fasting plasma glucose and glycosylated hemoglobin levels to normal or near normal by using the lowest effective dose of metformin hydrochloride tablets, USP either when used as monotherapy or in combination with sulfonylureas or insulin.
Monitoring of blood glucose and glycosylated hemoglobin will also permit detection of primary failure, ie, inadequate lowering of blood glucose at the maximum recommended dose of medication, and secondary failure, ie, loss of an adequate blood glucose lowering response after an initial period of effectiveness.
Short-term administration of metformin may be sufficient during periods of transient loss of control in patients usually well-controlled on diet alone.

Recommended Dosing Schedule

大人
In general, clinically significant responses are not seen at doses below 1500 mg per day. However, a lower recommended starting dose and gradually increased dosage is advised to minimize gastrointestinal symptoms.

The usual starting dose of metformin hydrochloride tablets, USP is 500 mg twice a day or 850 mg once a day, given with meals. Dosage increases should be made in increments of 500 mg weekly or 850 mg every 2 weeks, up to a total of 2000 mg per day, given in divided doses. Patients can also be titrated from 500 mg twice a day to 850 mg twice a day after 2 weeks. For those patients requiring additional glycemic control, metformin may be given to a maximum daily dose of 2550 mg per day. Doses above 2000 mg may be better tolerated given three times a day with meals.

儿科
The usual starting dose of metformin hydrochloride tablets, USP is 500 mg twice a day, given with meals. Dosage increases should be made in increments of 500 mg weekly up to a maximum of 2000 mg per day, given in divided doses.

Transfer from Other Antidiabetic Therapy
When transferring patients from standard oral hypoglycemic agents other than chlorpropamide to metformin, no transition period generally is necessary. When transferring patients from chlorpropamide, care should be exercised during the first two weeks because of the prolonged retention of chlorpropamide in the body, leading to overlapping drug effects and possible hypoglycemia.

Concomitant Metformin Hydrochloride Tablets, USP and Oral Sulfonylurea Therapy in Adult Patients
If patients have not responded to four weeks of the maximum dose of metformin hydrochloride tablets, USP monotherapy, consideration should be given to gradual addition of an oral sulfonylurea while continuing metformin hydrochloride tablets, USP at the maximum dose, even if prior primary or secondary failure to a sulfonylurea has occurred. Clinical and pharmacokinetic drug-drug interaction data are currently available only for metformin plus glyburide (glibenclamide). With concomitant metformin hydrochloride tablets, USP and sulfonylurea therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug. In a clinical trial of patients with type 2 diabetes and prior failure on glyburide, patients started on metformin 500 mg and glyburide 20 mg were titrated to 1000/20 mg, 1500/20 mg, 2000/20 mg or 2500/20 mg of metformin and glyburide, respectively, to reach the goal of glycemic control as measured by FPG, HbA1c and plasma glucose response (see CLINICAL PHARMACOLOGY:Clinical Studies). However, attempts should be made to identify the minimum effective dose of each drug to achieve this goal. With concomitant metformin hydrochloride tablets, USP and sulfonylurea therapy, the risk of hypoglycemia associated with sulfonylurea
therapy continues and may be increased. Appropriate precautions should be taken. (See Package Insert of the respective sulfonylurea.) If patients have not satisfactorily responded to one to three months of concomitant therapy with the maximum dose of metformin and the maximum dose of an oral sulfonylurea, consider therapeutic alternatives including switching to insulin with or without metformin hydrochloride tablets, USP.

Concomitant Metformin Hydrochloride Tablets, USP and Insulin Therapy in Adult Patients
The current insulin dose should be continued upon initiation of metformin hydrochloride tablets, USP therapy. Metformin hydrochloride tablets, USP therapy should be initiated at 500 mg once daily in patients on insulin therapy. For patients not responding adequately, the dose of metformin hydrochloride tablets, USP should be increased by 500 mg after approximately 1 week and by 500 mg every week thereafter until adequate glycemic control is achieved. The maximum recommended daily dose is 2500 mg for metformin hydrochloride tablets, USP. It is recommended that the insulin dose be decreased by 10% to 25% when fasting plasma glucose concentrations decrease to less than 120 mg/dL in patients receiving concomitant insulin and metformin hydrochloride tablets, USP. Further adjustment should be individualized based on glucose-lowering response.

Specific Patient Populations
Metformin is not recommended for use in pregnancy.
Metformin hydrochloride tablets, USP are not recommended in patients below the age of 10 years.
The initial and maintenance dosing of metformin hydrochloride tablets, USP should be conservative in patients with advanced age, due to the potential for decreased renal function in this population. Any dosage adjustment should be based on a careful assessment of renal function. Generally, elderly, debilitated, and malnourished patients should not be titrated to the maximum dose of metformin hydrochloride tablets, USP.
Monitoring of renal function is necessary to aid in prevention of lactic acidosis, particularly in the elderly. （请参阅警告。）

供应方式
Metformin hydrochloride tablets, USP
500 mg Bottles of 90 NDC 57664-397-59
500 mg Bottles of 100 NDC 57664-397-51
500 mg Bottles of 500 NDC 57664-397-53
500 mg Bottles of 1000 NDC 57664-397-58
850 mg Bottles of 90 NDC 57664-435-59
850 mg Bottles of 100 NDC 57664-435-51
850 mg Bottles of 500 NDC 57664-435-53
850 mg Bottles of 1000 NDC 57664-435-58
1000 mg Bottles of 90 NDC 57664-474-59
1000 mg Bottles of 100 NDC 57664-474-51
1000 mg Bottles of 500 NDC 57664-474-53
1000 mg Bottles of 1000 NDC 57664-474-58

Metformin hydrochloride 500 mg tablets, USP are round, white to off-white, film coated tablets debossed with “397” on one side and
plain on the other side.
Metformin hydrochloride 850 mg tablets, USP are round, white to off-white, film coated tablets debossed with “435” on one side and
plain on the other side.
Metformin hydrochloride 1000 mg tablets, USP are white to off-white colored, oval shaped, film coated tablets debossed with “C” and
“474” on one side and scored on both sides.

存储
Store at controlled room temperature 15degree-30degreeC (59 degree - 86 degree F).
Dispense in tight, light resistant container as defined in the USP.

患者信息
METFORMIN HYDROCHLORIDE TABLETS, USP
Read this information carefully before you start taking this medicine and each time you refill your prescription.可能有新的信息。 This information does not take the place of your doctor's advice. Ask your doctor or pharmacist if you do not understand some of this information or if you want to know more about this medicine.

What is Metformin?
Metformin is used to treat type 2 diabetes. This is also known as non-insulin-dependent diabetes mellitus. People with type 2 diabetes are not able to make enough insulin or respond normally to the insulin their bodies make. When this happens, sugar (glucose) builds up in the blood. This can lead to serious medical problems including kidney damage, amputations, and blindness. Diabetes is also closely linked to heart disease. The main goal of treating diabetes is to lower your blood sugar to a normal level. High blood sugar can be lowered by diet and exercise, by a number of medicines taken by mouth, and by insulin shots. Before you take metformin, try to control your diabetes by exercise and weight loss. While you take your diabetes medicine, continue to exercise and follow the diet advised for your diabetes. No matter what your recommended diabetes management plan is, studies have shown that maintaining good blood sugar control can prevent or delay complications of diabetes, such as blindness.
Metformin helps control your blood sugar in a number of ways. These include helping your body respond better to the insulin it mak