Metaglip

Metaglip说明

Metaglip ™ （格列吡嗪和盐酸二甲双胍）片剂含有2种用于治疗2型糖尿病的口服降糖药，格列吡嗪和盐酸二甲双胍。

格列吡嗪是磺酰脲类的口服降糖药。格列吡嗪的化学名称为1-环己基-3-[[ p- [2-（5-（甲基吡嗪甲酰胺基）乙基]苯基]磺酰基]脲。格列吡嗪是一种白色的无味粉末，分子式为C 21 H 27 N 5 O 4 S，分子量为445.55，pK a为5.9。不溶于水和醇，但溶于0.1 N NaOH。可自由溶于二甲基甲酰胺。结构式如下所示。

盐酸二甲双胍是用于治疗2型糖尿病的口服降糖药。盐酸二甲双胍（ N ， N-N-二甲基亚氨基二碳酰亚胺二酰胺一盐酸盐）与磺酰脲类，噻唑烷二酮或α-葡萄糖苷酶抑制剂在化学或药理上均不相关。它是白色至类白色晶体化合物，分子式为C 4 H 12 ClN 5 （一盐酸盐），分子量为165.63。盐酸二甲双胍可自由溶于水，而实际上不溶于丙酮，乙醚和氯仿。二甲双胍的pK a为12.4。 1％盐酸二甲双胍水溶液的pH值为6.68。结构式如下所示：

Metaglip可在含有2.5 mg格列吡嗪和250 mg盐酸二甲双胍，2.5 mg格列吡嗪和500 mg盐酸二甲双胍以及5 mg格列吡嗪和500 mg盐酸二甲双胍的片剂中口服给药。此外，每片含有以下非活性成分：微晶纤维素，聚维酮，交联羧甲基纤维素钠和硬脂酸镁。片剂被薄膜包衣，提供了颜色差异。

Metaglip-临床药理学

作用机理

Metaglip结合了格列吡嗪和盐酸二甲双胍（两种具有互补作用机制的降糖药），以改善2型糖尿病患者的血糖控制。

格列吡嗪似乎可通过刺激胰脏中胰岛素的释放而急剧降低血糖，这种作用取决于胰岛中功能性的β细胞。胰外作用可能在口服磺酰脲降糖药的作用机理中起作用。长期服用格列吡嗪降低血糖的机制尚未明确。在人中，毫无疑问，格列吡嗪响应餐后刺激胰岛素分泌至关重要。即使长期服用格列吡嗪，空腹胰岛素水平也不会升高，但是在至少治疗6个月后，餐后胰岛素反应仍会继续增强。

盐酸二甲双胍是一种降糖药，可提高2型糖尿病患者的糖耐量，同时降低基础和餐后血浆葡萄糖。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。

药代动力学

Metaglip

在健康受试者的单剂量研究中，Metaglip 5毫克/ 500毫克格列吡嗪和二甲双胍组分是生物等效的共施用GLUCOTROL®和GLUCOPHAGE®。在健康受试者中将单一的Metaglip 5 mg / 500 mg片剂与20％葡萄糖溶液或20％葡萄糖溶液和食物一起服用后，食物对峰值血浆浓度（C max ）的影响很小，而对格列吡嗪成分的曲线下（AUC）上的食物。与在20％葡萄糖溶液中禁食相同片剂强度的食物相比，格列吡嗪组分的血浆峰浓度峰值时间（T max ）延迟了1小时。食物可降低二甲双胍成分的C max约14％，而AUC则不受影响。食物后1小时，二甲双胍成分的T max延迟。

格列吡嗪

格列吡嗪在胃肠道的吸收是均匀的，快速的，并且基本上是完全的。单次口服后1至3小时，血浆峰值浓度就会出现。重复口服后格列吡嗪不会积聚在血浆中。在正常志愿者中，食物的总吸收和口服剂量的设置不受食物的影响，但是吸收被延迟了约40分钟。

盐酸二甲双胍

在禁食条件下给予的500 mg盐酸二甲双胍片剂的绝对生物利用度约为50％至60％。使用500 mg和1500 mg以及850 mg至2550 mg单次口服二甲双胍片剂的研究表明，剂量增加时缺乏剂量比例性，这是由于吸收减少而不是消除的改变所致。食物会降低二甲双胍的吸收程度，并会稍微延迟其吸收，这表现为单次服用850毫克后血浆中的峰值浓度降低约40％，血浆AUC降低25％，血浆血浆浓度达到峰值的时间延长了35分钟片剂与食物一起服用的二甲双胍，与空腹时服用同一片片剂的强度相比。这些减少的临床相关性未知。

格列吡嗪

研究了接受口服或静脉注射格列吡嗪的志愿者血清中的蛋白结合，发现两种给药途径均在1小时后达到98％至99％。静脉给药后格列吡嗪的表观分布体积为11升，表明在细胞外液室内定位。在小鼠中，在雄性或雌性的大脑或脊髓中，或在妊娠雌性的胎儿中，放射自显影均未检出格列吡嗪或代谢产物。但是，在另一项研究中，在使用标记药物的大鼠的胎儿中检测到非常少量的放射性。

盐酸二甲双胍

单次口服850 mg后，二甲双胍的表观分布体积（V / F）平均为654±358L。二甲双胍与血浆蛋白的结合可忽略不计。二甲双胍最有可能是时间的函数，分配为红细胞。在二甲双胍的常规临床剂量和给药方案下，二甲双胍的稳态血浆浓度在24至48小时内达到，通常<1 µg / mL。在对照临床试验中，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。

格列吡嗪

格列吡嗪的代谢广泛且主要发生在肝脏中。主要代谢物是非活性羟基化产物和极性结合物，主要从尿中排泄。在尿液中发现少于10％的未变格列吡嗪。正常受试者的消除半衰期为2-4小时，无论是静脉内还是口服。代谢和排泄方式与两种给药途径相似，表明首过代谢并不重要。

盐酸二甲双胍

在正常受试者中进行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

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剂量或多剂量药代动力学没有差异（见表1 ），在通常的临床情况下，两组中的二甲双胍均无任何积累剂量。

肝功能受损的患者中格列吡嗪的代谢和排泄可能会减慢（请参阅注意事项）。肝功能不全的二甲双胍患者尚未进行药代动力学研究。

肾功能不全的患者中格列吡嗪的代谢和排泄可能会减慢（请参阅注意事项）。

在肾功能下降（基于肌酐清除率）的患者中，二甲双胍的血浆和血液半衰期延长，并且与肌酐清除率降低成比例地降低肾清除率（见表1 ；另请参见警告）。

没有关于格列吡嗪在老年患者中药代动力学的信息。

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，与健康的青年受试者相比，血浆总清除率降低，半衰期延长，C max升高。从这些数据看来，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≥80岁的患者不应开始二甲双胍治疗。

格列吡嗪尚无儿科受试者药代动力学研究的数据。

服用含食物的单次口服GLUCOPHAGE 500 mg片剂后，小儿2型糖尿病患者（12-16岁）与性别和体重相匹配的健康成人（20岁至20岁）之间的几何平均二甲双胍C max和AUC差异小于5％。 45岁），所有肾功能均正常。

没有关于性别对格列吡嗪药代动力学影响的信息。

根据性别进行分析时，无论是否患有2型糖尿病，二甲双胍的药代动力学参数均无显着差异（男性= 19，女性= 16）。同样，在2型糖尿病患者的对照临床研究中，二甲双胍的降血糖作用在男性和女性中均相当。

没有关于格列吡嗪药代动力学中种族差异的信息。

尚未根据种族对二甲双胍药代动力学参数进行研究。在二甲双胍对2型糖尿病患者的对照临床研究中，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

在一项为期24周，双盲，主动控制，多中心的国际临床试验中，仅通过饮食和运动不能充分控制高血糖的2型糖尿病患者（血红蛋白A 1c [HbA 1c ]> 7.5％且≤12随机分配空腹血糖（FPG）<300 mg / dL）接受格列吡嗪5 mg，二甲双胍500 mg，Metaglip 2.5 mg / 250 mg或Metaglip 2.5 mg / 500 mg的初始治疗。 2周后，根据需要逐渐增加剂量（最多12周就诊），每天最多4片，以达到目标每日平均葡萄糖（MDG）≤130 mg / dL的目标。表2总结了24周的试验数据。

24周后，与格列吡嗪和二甲双胍治疗相比，用Metaglip 2.5 mg / 250 mg和2.5 mg / 500 mg Metablip治疗可显着降低HbA 1c 。同样，与二甲双胍治疗相比，Metaglip 2.5 mg / 250 mg治疗可导致FPG显着降低。

在基线和最终研究访视时，通过测量标准混合流食后3小时的血浆葡萄糖和胰岛素来确定空腹血糖和胰岛素水平以上的升高。与基线相比，用Metaglip进行的治疗可降低餐后3小时的葡萄糖AUC，其幅度要比格列吡嗪和二甲双胍的治疗显着更大。与基线相比，Metaglip增强了餐后胰岛素反应，但并未显着影响空腹胰岛素水平。

在Metaglip治疗与二甲双胍治疗或格列吡嗪治疗之间，所有脂质参数的基线变化均无临床上有意义的变化。与体重相比，基线的调整后平均变化为：Metaglip 2.5 mg / 250 mg，-0.4 kg； Metaglip 2.5 mg / 500 mg，-0.5 kg；格列吡嗪，-0.2千克;和二甲双胍-1.9公斤。与二甲双胍相比，二甲双胍的体重减轻更大。

在一个18周的，双盲的，主动控制的美国临床试验中，共有247例2型糖尿病没有得到充分控制（HbA1c水平≥7.5％和≤12％，和FPG <300毫克/分升），同时用最大标记剂量的磺脲类药物（例如格列本脲10 mg，格列吡嗪20 mg）治疗至少一半的患者被随机分配接受格列吡嗪（固定剂量30 mg），二甲双胍（500 mg）或Metaglip 5 mg / 500毫克为了达到MDG≤130mg / dL的需要，每天（最多连续8周）将二甲双胍和Metaglip的剂量滴定至最多4片。表3总结了18周的试验数据。

18周后，与格列吡嗪和二甲双胍治疗相比，每天以高达20 mg / 2000 mg的剂量使用Metaglip进行治疗的结果是，平均最终HbA 1c明显降低，FPG的平均降低量也明显更大。与基线相比，用Metaglip进行的治疗可降低餐后3小时的葡萄糖AUC，其幅度要比格列吡嗪和二甲双胍的治疗显着更大。 Metaglip并没有显着影响空腹胰岛素水平。

在Metaglip治疗与二甲双胍治疗或格列吡嗪治疗之间，所有脂质参数的基线变化均无临床上有意义的变化。与基线相比，校正后的平均体重变化为：Metaglip 5 mg / 500 mg，-0.3 kg；格列吡嗪，-0.4千克;和二甲双胍，-2.7公斤。与二甲双胍相比，二甲双胍的体重减轻更大。

Metaglip的适应症和用法

Metaglip（格列吡嗪和盐酸二甲双胍）片剂可作为饮食和运动的辅助手段，以改善2型糖尿病成年人的血糖控制。

禁忌症

患有以下情况的患者禁用Metaglip药物：

1. 肾病或肾功能不全（例如，血清肌酐水平≥1.5mg / dL [男性]，≥1.4mg / dL [女性]或肌酐清除率异常），也可能是由于心血管衰竭（休克）引起的，急性心肌梗塞和败血病（请参阅警告和注意事项）。
2. 已知对格列吡嗪或盐酸二甲双胍过敏。
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。

对于正在进行放射学研究的患者，应予停用Metaglip，这些患者需要在血管内施用碘化造影剂，因为这些产品的使用可能会导致肾功能的急性改变。 （另请参见注意事项。）

警告事项

盐酸二甲双胍

特别警告增加心血管死亡率的风险

据报道，与单纯饮食或饮食加胰岛素治疗相比，口服降糖药的服用会增加心血管死亡率。此警告基于大学集团糖尿病计划（UGDP）进行的研究，该研究是一项长期的前瞻性临床试验，旨在评估降糖药物在预防或延迟非胰岛素依赖型糖尿病患者血管并发症中的有效性。 。该研究涉及823名患者，这些患者被随机分配到4个治疗组中的1个中（ Diabetes 19（Suppl。2）：747-830，1970）。

UGDP报告称，饮食加固定剂量的甲苯磺丁酰胺（每天1.5克）治疗5至8年的患者，其心血管死亡率约为仅饮食治疗的患者的2.5倍。没有观察到总死亡率的显着增加，但是基于心血管疾病死亡率的增加，停止使用甲苯磺丁酰胺，因此限制了研究显示总体死亡率增加的机会。尽管对这些结果的解释存在争议，但UGDP研究的结果为这一警告提供了充分的依据。应告知患者格列吡嗪的潜在风险和益处以及其他治疗方式。

尽管本研究仅包括一种磺脲类药物（甲苯磺丁酰胺），但出于安全考虑，考虑到该警告也可能适用于该类别的其他降血糖药物，因此谨慎起见是谨慎的，因为它们的作用方式非常相似和化学结构。

预防措施

一般

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

低血糖症

Metaglip能够产生低血糖症；因此，正确的患者选择，剂量和用法说明对避免潜在的降血糖事件很重要。当热量摄入不足，剧烈运动无法通过热量补充来补偿时，或者在与其他降糖药或乙醇同时使用时，发生低血糖的风险会增加。肾功能不全可能导致格列吡嗪和盐酸二甲双胍的药物水平升高。肝功能不全可能会增加格列吡嗪的药物水平，也可能降低糖原异生能力，这两者都会增加降糖反应的风险。老年，虚弱或营养不良的患者以及患有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。

肾和肝病

肾和/或肝功能受损的患者中格列吡嗪的代谢和排泄可能会减慢。如果此类患者应发生低血糖症，则应延长血糖并应采取适当的治疗措施。

溶血性贫血

用磺酰脲类药物治疗葡萄糖-6-磷酸脱氢酶（G6PD）缺乏症患者可导致溶血性贫血。因为Metaglip属于磺酰脲类药物，在G6PD缺乏症患者中应谨慎行事，应考虑使用非磺酰脲类替代药物。在上市后的报告中，还曾报道过不存在G6PD缺乏症的患者发生溶血性贫血。

监测肾功能

已知二甲双胍基本上被肾脏排泄，二甲双胍蓄积和乳酸性酸中毒的风险随着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Metaglip。在高龄患者中，应谨慎地调整Metaglip的剂量以建立起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，并且通常不应将Metaglip滴定至最大剂量（请参阅“警告和用法用量” ）。在开始进行Metaglip治疗之前以及之后至少每年一次，应评估并验证肾功能是否正常。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Metaglip。

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（请参见预防措施：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，对于计划进行此类研究的患者，应在手术时或手术前暂时停用Metaglip，并在手术后48小时内停用该药，仅在重新评估肾功能并确定其正常后才恢复使用。 。

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。当在Metaglip治疗的患者中发生此类事件时，应立即停药。

外科手术

对于任何外科手术，均应暂时停用Metaglip疗法（与无限制进食和进水有关的小手术除外），并且应在患者口服摄入恢复并且肾功能评估为正常之前重新开始。

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Metaglip时应警告患者不要过量摄入酒精，无论是急性还是慢性的。由于其对肝脏的糖原异生能力的影响，酒精还可能增加低血糖的风险。

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使用Metaglip。

维生素B12含量

在二甲双胍持续29周的对照临床试验中，约有7％的患者观察到先前的正常血清维生素B 12降至亚正常水平，而无临床表现。这样降低，可能是由于与从B 12 -intrinsic因子络合物B 12吸收的干扰，然而，很少有贫血症和相关联的出现是与二甲双胍或维生素B 12补充停药迅速可逆的。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B 12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B 12 。在这些患者中，以2至3年为间隔进行常规血清维生素B 12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

先前对二甲双胍进行良好控制的2型糖尿病患者，如果出现实验室异常或临床疾病（尤其是模糊和定义不明确的疾病），应立即进行评估，以评估是否有酮症酸中毒或乳酸性酸中毒。 Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis of either form occurs, Metaglip must be stopped immediately and other appropriate corrective measures initiated (see also WARNINGS ).

给患者的信息

Patients should be informed of the potential risks and benefits of Metaglip and alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions; a regular exercise program; and regular testing of blood glucose, glycosylated hemoglobin, renal function, and hematologic parameters.

The risks of lactic acidosis associated with metformin therapy, 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 Metaglip immediately and 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 Metaglip, gastrointestinal symptoms, which are common during initiation of metformin therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.

The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members.

Patients should be counseled against excessive alcohol intake, either acute or chronic, while receiving Metaglip. (See Patient Information printed below.)

实验室测试

Periodic fasting blood glucose (FBG) and HbA 1c measurements should be performed to monitor therapeutic response.

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 B 12 deficiency should be excluded.

药物相互作用

Certain drugs tend to produce hyperglycemia and may lead to loss of blood glucose control. 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 Metaglip, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving Metaglip, the patient should be observed closely for hypoglycemia. 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 sulfonylureas, which are extensively bound to serum proteins.

The hypoglycemic action of sulfonylureas may be potentiated by certain drugs, including nonsteroidal anti-inflammatory agents, some azoles, and other drugs that are highly protein-bound, salicylates, sulfonamides, chloramphenicol, probenecid, coumarins, monoamine oxidase inhibitors, and beta-adrenergic blocking agents. When such drugs are administered to a patient receiving Metaglip, the patient should be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving Metaglip, the patient should be observed closely for loss of blood glucose control. In vitro binding studies with human serum proteins indicate that glipizide binds differently than tolbutamide and does not interact with salicylate or dicumarol. However, caution must be exercised in extrapolating these findings to the clinical situation and in the use of Metaglip with these drugs.

A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported. Whether this interaction also occurs with the intravenous, topical, or vaginal preparations of miconazole is not known. The effect of concomitant administration of fluconazole and glipizide has been demonstrated in a placebo-controlled crossover study in normal volunteers. All subjects received glipizide alone and following treatment with 100 mg of fluconazole as a single oral daily dose for 7 days, the mean percent increase in the glipizide AUC after fluconazole administration was 56.9% (range: 35%-81%).

速尿

A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by coadministration. Furosemide increased the metformin plasma and blood C max by 22% and blood AUC by 15%, without any significant change in metformin renal clearance. When administered with metformin, the C max 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 coadministered chronically.

硝苯地平

A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that coadministration of nifedipine increased plasma metformin C max and AUC by 20% and 9%, respectively, and increased the amount excreted in the urine. T max and half-life were unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on nifedipine.

Cationic drugs

Cationic drugs (eg, amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or 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 Metaglip 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

In healthy volunteers, the pharmacokinetics of metformin and propranolol and metformin and ibuprofen were not affected when coadministered in single-dose interaction studies.

致癌，诱变，生育力受损

No animal studies have been conducted with the combined products in Metaglip. The following data are based on findings in studies performed with the individual products.

A 20-month study in rats and an 18-month study in mice at doses up to 75 times the maximum human dose revealed no evidence of drug-related carcinogenicity. Bacterial and in vivo mutagenicity tests were uniformly negative. Studies in rats of both sexes at doses up to 75 times the human dose showed no effects on fertility.

Long-term carcinogenicity studies were performed with metformin alone 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 4 times the maximum recommended human daily (MRHD) dose of 2000 mg of the metformin component of Metaglip based on body surface area comparisons. No evidence of carcinogenicity with metformin alone was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin alone in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day of metformin alone.

There was no evidence of a mutagenic potential of metformin alone 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 alone when administered at doses as high as 600 mg/kg/day, which is approximately 3 times the MRHD dose of the metformin component of Metaglip based on body surface area comparisons.

怀孕

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 as close to normal as possible. Because animal reproduction studies are not always predictive of human response, Metaglip should not be used during pregnancy unless clearly needed. (See below.)

There are no adequate and well-controlled studies in pregnant women with Metaglip or its individual components. No animal studies have been conducted with the combined products in Metaglip. The following data are based on findings in studies performed with the individual products.

格列吡嗪

Glipizide was found to be mildly fetotoxic in rat reproductive studies at all dose levels (5-50 mg/kg). This fetotoxicity has been similarly noted with other sulfonylureas, such as tolbutamide and tolazamide. The effect is perinatal and believed to be directly related to the pharmacologic (hypoglycemic) action of glipizide. In studies in rats and rabbits, no teratogenic effects were found.

Metformin Hydrochloride

Metformin alone was not teratogenic in rats or rabbits at doses up to 600 mg/kg/day. This represents an exposure of about 2 and 6 times the MRHD dose of 2000 mg of the metformin component of Metaglip based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.

Prolonged severe hypoglycemia (4-10 days) has been reported in neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery. This has been reported more frequently with the use of agents with prolonged half-lives. It is not recommended that Metaglip be used during pregnancy. However, if it is used, Metaglip should be discontinued at least 1 month before the expected delivery date. (See Pregnancy: Teratogenic Effects: Pregnancy Category C .)

护理母亲

Although it is not known whether glipizide is excreted in human milk, some sulfonylurea drugs are known to be excreted in human milk. 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 Metaglip, taking into account the importance of the drug to the mother. If Metaglip is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.

儿科用

Safety and effectiveness of Metaglip in pediatric patients have not been established.

老人用

Of the 345 patients who received Metaglip 2.5 mg/250 mg and 2.5 mg/500 mg in the initial therapy trial, 67 (19.4%) were aged 65 and older while 5 (1.4%) were aged 75 and older. Of the 87 patients who received Metaglip in the second-line therapy trial, 17 (19.5%) were aged 65 and older while 1 (1.1%) was at least aged 75. No overall differences in effectiveness or safety were observed between these patients and younger patients in either the initial therapy trial or the second-line therapy trial, and other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Metformin hydrochloride is known to be substantially excreted by the kidney and because the risk of serious adverse reactions to the