英文药名: Glucophage XR(Metformin Extended Release Tablets)

中文药名: 格华止（盐酸二甲双胍缓释片）

生产厂家: Not available

药品介绍；

格华止是盐酸二甲双胍是双胍类降糖药的一个商品名称。用于单纯饮食控制不满意得2型糖尿病患者，尤其是肥胖和伴高胰岛素血症者，用本品不但有降血糖作用，还是减轻体重和高胰岛素血症的效果。对某些磺酰脲类疗效差的患者可奏效，如与磺酰脲类降血糖药、小肠糖苷酶抑制剂或噻唑烷二酮类降糖药合用，较分别单用的效果更好。亦可用于胰岛素治疗的患者，以减少胰岛素的用量。

药品名称

通用名：盐酸二甲双胍片
商品名：格华止(Glucophage)
英文名：Metformin Hydrochloride Tablets
性 状: 盐酸二甲双胍片为薄膜衣片，除去包衣后显白色或类白色。
规 格

(1)0.5g，(2)0.85g，(3)1g
药理毒理

药理作用：
1．盐酸二甲双胍片为双胍类降糖药。不是通过刺激胰岛β细胞增加胰岛素的浓度，而是直接作用于糖的代谢过程，促进糖的无氧酵解，增加肌肉、脂肪等外周组织对葡萄糖的摄取和利用，从而保护已受损的胰岛β细胞功能免受进一步损害，有利于糖尿病的长期控制。
2．盐酸二甲双胍片抑制肠道吸收葡萄糖，并抑制肝糖原异生，减少肝糖输出，可使糖尿病患者血糖及糖化血红蛋白降低。
3．本品无促使脂肪合成的作用，对正常人无明显降血糖作用。
4．盐酸二甲双胍片与磺酰脲类降糖药比较，不刺激胰岛素分泌，甚少引起低血糖症，而两者合用时可起到协同作用，以提高降血糖的疗效。
毒理研究：
动物实验提示，本品无致癌、致突变作用，对生育能力无影响。
药代动力学

口服二甲双胍主要在小肠吸收。空腹状态下口服二甲双胍0.5克的绝对生物利用度为50-60%。同时进食略减少药物的吸收速度和吸收程度。国内口服本品药代动力学试验结果表明，口服后中位达血药浓度时间为2小时，平均血浆药物清除半衰期约为4小时。二甲双胍几乎不与血浆蛋白结合，按照常用临床剂量和给药方案口服本品，可在24-48小时内达到稳态血浆浓度。本品主要经肾脏排泄，口服本品24小时内肾脏排泄90%。
适应症

1．盐酸二甲双胍片首选用于单纯饮食控制及体育锻炼治疗无效的2型糖尿病，特别是肥胖的2型糖尿病。
2．对于1型或2型糖尿病，本品与胰岛素合用，可增加胰岛素的降血糖作用，减少胰岛素用量，防止低血糖发生；
3．本品也可与磺脲类口服降糖药合用，具协同作用。
用法用量

应遵医嘱服药。本品应从小剂量开始使用，根据病人状况，逐渐增加剂量。通常本品的起始剂量为0.5克，每日二次；或0.85克，每日一次；随餐服用。可每周增加0.5克，或每2周增加0.85克，逐渐加至每日2克，分次服用。
成人最大推荐剂量为每日2550毫克。对需进一步控制血糖患者，剂量可以加至每日2550毫克(即每次0.85克，每天三次)。每日剂量超过2克时，为了更好的耐受，药物最好随三餐分次服用。
不良反应

盐酸二甲双胍片常见不良反应包括腹泻、恶心、呕吐、胃胀、乏力、消化不良、腹部不适及头痛。其他少见者为大便异常、低血糖、肌痛、头昏、头晕、指甲异常、皮疹、出汗增加、味觉异常、胸部不适、寒战、流感症状、潮热、心悸、体重减轻等。二甲双胍可减少维生素B12的吸收，但极少引起贫血。本品在治疗剂量范围内，引起乳酸性酸中毒罕见。
禁 忌

1．肾脏疾病或下列情况禁用本品：心力衰竭(休克)、急性心肌梗塞和败血症等引起的肾功能障碍(血清肌酐水平＞1.5毫克/分升(男性)，≥1.4毫克/分升(女性)或肌酐清除异常)。
2．需要药物治疗的充血性心衰，和其他严重心、肺疾患。
3．严重感染和外伤，外科大手术，临床有低血压和缺氧等。
4．已知对盐酸二甲双胍过敏。
5．急性或慢性代谢性酸中毒，包括有或无昏迷的糖尿病酮症酸中毒，和糖尿病酮症酸中毒需要用胰岛素治疗。
6．酗酒者。
7．接受血管内注射碘化造影剂者，可以暂时停用本品。
8．维生素B12、叶酸缺乏未纠正者。
注意事项

1．口服本品期间，定期检查肾功能，可以减少乳酸中毒的发生，尤其是老年患者更应定期检查肾功能。接受外科手术和碘剂X射线摄影检查前患者暂时停止口服本品。
2．肝功能不良：某些乳酸性酸中毒患者合并有肝功能损害，因此有肝脏疾病者应避免使用本品。
3．应激状态：在发热、感染和外科手术时，服用口服降糖药患者易发生血糖暂时控制不良，此时必须暂时停用本品，改用胰岛素。待应激状态缓解后恢复使用。
4．对1型糖尿病患者，不宜单独使用本品，而应与胰岛素合用。
5．应定期进行血液学检查。本品治疗引起巨幼红细胞性贫血罕见。如发生应排除维生素B12缺乏。
6．即往服用盐酸二甲双胍片治疗，血糖控制良好的2型糖尿病患者出现实验室化验异常或临床异常 (特别是乏力或难于言表的不适)，应当迅速寻找酮症酸中毒或乳酸酸中毒的证据，测定包括血清电解质、酮体、血糖、血酸碱度，乳酸盐、丙酮酸二甲双胍水平，存在任何类型的酸中毒都应立即停用，开始其他恰当的治疗方法。
7．单独接受盐酸二甲双胍片治疗的患者正常情况下不会产生低血糖，但当进食过少，或大运动量后没有补充足够的热量，与其他降糖药联合使用(如磺脲类药物和胰岛素)，饮酒等情况下会出现低血糖，须注意。
8．老年、衰弱或营养不良的患者，以及肾上腺和垂体功能低减、酒精中毒的患者更易发生低血糖。老年患者和服用β-肾上腺阻滞剂的患者的低血糖很难辨认，须注意。
9．患者应当了解盐酸二甲双胍片治疗的潜在危险和益处，以及选择治疗的方式。他们也应知道同时控制饮食、规律运动的重要性，以及规律检测血糖、糖化血红蛋白、肾脏功能和血液学参数的重要性。
10．须向患者解释乳酸酸中毒的危险性、症状和容易发生乳酸酸中毒的情况。当出现不能解释的过度呼气、肌痛、乏力、嗜睡或其他非特异性的症状时，应立即停药，及时医生。在二甲双胍治疗的初期常出现胃肠道症状，一旦患者坚持某一剂量治疗后出现胃肠道症状，通常与药物本身无关，随后出现的胃肠道症状可能是由于乳酸酸中毒或其他严重的疾病造成的。
孕妇及哺乳期妇女用药

不推荐孕妇使用本品。哺乳期妇女应慎用本品，必须使用本品时，应停止哺乳。
儿童用药

10-16岁2型糖尿病患者使用本品的每日最高剂量为2000毫克。不推荐10岁以下儿童使用本品。
老年患者用药

65岁以上老年患者使用本品时应谨慎，并定期检查肾功能。通常不用最大剂量。不推荐80岁以上的患者使用本品，除非其肌酐清除率检查表明其肾功能未降低。
药物相互作用

1．单剂联合使用二甲双胍和格列苯脲未发现二甲双胍的药代动力学参数改变。
2．二甲双胍与呋塞米(速尿)合用，二甲双胍的AUC增加，但肾清除无变化；同时呋塞米的Cmax和AUC均下降，终末半衰期缩短, 肾清除无改变。
3．经肾小管排泌的阳离子药物(例如氨氯吡咪、地高辛、吗啡、普鲁卡因胺、奎尼丁、奎宁、雷尼替丁、氨苯喋啶、甲氧苄氨嘧啶和万古霉素)理论上可能与二甲双胍竞争肾小管转运系统，发生相互作用，因此建议密切监测、调整本品及/或相互作用药物的剂量。
4．二甲双胍与西咪替丁合用，二甲双胍的血浆和全血AUC增加，但两药单剂合用，未见二甲双胍清除半衰期改变。西咪替丁的药代动力学未见变化。
5．如同时服用某些可引起血糖升高的药物，如噻嗪类药物或其他利尿剂、糖皮质激素、酚噻嗪、甲状腺制剂、雌激素、口服避孕药、苯妥英、烟碱酸、拟交感神经药、离子通道阻滞剂和异烟肼等时要密切监测血糖，而在这些药物停用后，要密切注意低血糖的发生。
6．二甲双胍不与血浆蛋白结合，因此与蛋白高度结合的药物例如水杨酸盐、氨苯磺胺、氯霉素、丙磺舒等与磺脲类药物相比不易发生相互作用，后者主要与血清蛋白结合。
7．除氯磺丙脲，患者从其他的口服降糖药转为用本品治疗时，通常不需要转换期。服用氯磺丙脲的患者在换用本品的最初2周要密切注意，因为氯磺丙脲在体内有较长滞留，易导致药物作用过量，发生低血糖。
8．二甲双胍有增加华法令的抗凝血倾向。
9．树脂类药物与本品同服，可减少二甲双胍吸收。
药物过量

即使二甲双胍服药量达到85克都没有发生低血糖，但在这种情况下会发生乳酸中毒。在良好的血液动力学的状况下二甲双胍可以以170毫升/分的速度透析清除。因此怀疑二甲双胍过量的患者，血透可以清除蓄积的药物。

包装规格：
·1000mg *84片（Merck生产）
·500mg *84 片（Merck 生产）
·750mg*84 片（Merck 生产）
·1000mg*90 片
·500mg*90 片
·850mg*100 片
·500mg *60片（法国）有现货

Glucophage®

(metformin hydrochloride) Tablets
Glucophage® XR
(metformin hydrochloride) Extended-Release Tablets
Glucophage Description
Glucophage® (metformin hydrochloride) Tablets and Glucophage® XR (metformin hydrochloride) Extended-Release Tablets are oral antihyperglycemic drugs used in the management of type 2 diabetes. Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. The structural formula is as shown:

Metformin hydrochloride is a white to off-white crystalline compound with a molecular formula of C4H11N5 • HCl and a molecular weight of 165.63. Metformin hydrochloride is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68.

Glucophage tablets contain 500 mg, 850 mg, or 1000 mg of metformin hydrochloride. Each tablet contains the inactive ingredients povidone and magnesium stearate. In addition, the coating for the 500 mg and 850 mg tablets contains hypromellose and the coating for the 1000 mg tablet contains hypromellose and polyethylene glycol.

Glucophage XR contains 500 mg or 750 mg of metformin hydrochloride as the active ingredient.

Glucophage XR 500 mg tablets contain the inactive ingredients sodium carboxymethyl cellulose, hypromellose, microcrystalline cellulose, and magnesium stearate.

Glucophage XR 750 mg tablets contain the inactive ingredients sodium carboxymethyl cellulose, hypromellose, and magnesium stearate.

System Components and Performance–Glucophage XR comprises a dual hydrophilic polymer matrix system. Metformin hydrochloride is combined with a drug release controlling polymer to form an "inner" phase, which is then incorporated as discrete particles into an "external" phase of a second polymer. After administration, fluid from the gastrointestinal (GI) tract enters the tablet, causing the polymers to hydrate and swell. Drug is released slowly from the dosage form by a process of diffusion through the gel matrix that is essentially independent of pH. The hydrated polymer system is not rigid and is expected to be broken up by normal peristalsis in the GI tract. The biologically inert components of the tablet may occasionally remain intact during GI transit and will be eliminated in the feces as a soft, hydrated mass.

Glucophage - Clinical Pharmacology

Mechanism of Action

Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal subjects (except in special circumstances, see PRECAUTIONS) and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.

Pharmacokinetics

Absorption and Bioavailability

The absolute bioavailability of a Glucophage 500 mg tablet given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of Glucophage 500 to 1500 mg, and 850 to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. Food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration (Cmax), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35-minute prolongation of time to peak plasma concentration (Tmax) following administration of a single 850 mg tablet of metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.

Following a single oral dose of Glucophage XR, Cmax is achieved with a median value of 7 hours and a range of 4 to 8 hours. Peak plasma levels are approximately 20% lower compared to the same dose of Glucophage, however, the extent of absorption (as measured by AUC) is similar to Glucophage.

At steady state, the AUC and Cmax are less than dose proportional for Glucophage XR within the range of 500 to 2000 mg administered once daily. Peak plasma levels are approximately 0.6, 1.1, 1.4, and 1.8 µg/mL for 500, 1000, 1500, and 2000 mg once-daily doses, respectively. The extent of metformin absorption (as measured by AUC) from Glucophage XR at a 2000 mg once-daily dose is similar to the same total daily dose administered as Glucophage tablets 1000 mg twice daily. After repeated administration of Glucophage XR, metformin did not accumulate in plasma.

Within-subject variability in Cmax and AUC of metformin from Glucophage XR is comparable to that with Glucophage.

Although the extent of metformin absorption (as measured by AUC) from the Glucophage XR tablet increased by approximately 50% when given with food, there was no effect of food on Cmax and Tmax of metformin. Both high and low fat meals had the same effect on the pharmacokinetics of Glucophage XR.

Distribution

The apparent volume of distribution (V/F) of metformin following single oral doses of Glucophage 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of Glucophage, steady state plasma concentrations of metformin are reached within 24 to 48 hours and are generally <1 µg/mL. During controlled clinical trials of Glucophage, maximum metformin plasma levels did not exceed 5 µg/mL, even at maximum doses.

Metabolism and Elimination

Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. Renal clearance (see Table 1) is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.

Special Populations

Patients with Type 2 Diabetes

In the presence of normal renal function, there are no differences between single- or multiple-dose pharmacokinetics of metformin between patients with type 2 diabetes and normal subjects (see Table 1), nor is there any accumulation of metformin in either group at usual clinical doses.

The pharmacokinetics of Glucophage XR in patients with type 2 diabetes are comparable to those in healthy normal adults.

Renal Insufficiency

In patients with decreased renal function (based on measured creatinine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance (see Table 1; also see WARNINGS).

Hepatic Insufficiency

No pharmacokinetic studies of metformin have been conducted in patients with hepatic insufficiency.

Geriatrics

Limited data from controlled pharmacokinetic studies of Glucophage in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and Cmax is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (see Table 1). Glucophage (metformin hydrochloride) Tablets and Glucophage XR (metformin hydrochloride) Extended-Release Tablets treatment should not be initiated in patients ≥80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced (see WARNINGS and DOSAGE AND ADMINISTRATION).

Table 1: Select Mean (±S.D.) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of Glucophage

Subject Groups: Glucophage dosea (number of subjects)	Cmaxb (µg/mL)	Tmaxc (hrs)	Renal Clearance (mL/min)
a All doses given fasting except the first 18 doses of the multiple dose studies
b Peak plasma concentration
c Time to peak plasma concentration
d Combined results (average means) of five studies: mean age 32 years (range 23-59 years)
e Kinetic study done following dose 19, given fasting
f Elderly subjects, mean age 71 years (range 65-81 years)
g CLcr = creatinine clearance normalized to body surface area of 1.73 m2
Healthy, nondiabetic adults:
500 mg single dose (24)	1.03 (±0.33)	2.75 (±0.81)	600 (±132)
850 mg single dose (74)d	1.60 (±0.38)	2.64 (±0.82)	552 (±139)
850 mg three times daily for 19 dosese (9)	2.01 (±0.42)	1.79 (±0.94)	642 (±173)
Adults with type 2 diabetes:
850 mg single dose (23)	1.48 (±0.5)	3.32 (±1.08)	491 (±138)
850 mg three times daily for 19 dosese (9)	1.90 (±0.62)	2.01 (±1.22)	550 (±160)
Elderlyf, healthy nondiabetic adults:
850 mg single dose (12)	2.45 (±0.70)	2.71 (±1.05)	412 (±98)
Renal-impaired adults:
850 mg single dose
Mild (CLcrg 61-90 mL/min) (5)	1.86 (±0.52)	3.20 (±0.45)	384 (±122)
Moderate (CLcr 31-60 mL/min) (4)	4.12 (±1.83)	3.75 (±0.50)	108 (±57)
Severe (CLcr 10-30 mL/min) (6)	3.93 (±0.92)	4.01 (±1.10)	130 (±90)

After administration of a single oral Glucophage 500 mg tablet with food, geometric mean metformin Cmax and AUC differed less than 5% between pediatric type 2 diabetic patients (12-16 years of age) and gender- and weight-matched healthy adults (20-45 years of age), all with normal renal function.

Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender (males = 19, females = 16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of Glucophage was comparable in males and females.

No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of Glucophage in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51), and Hispanics (n=24).

Clinical Studies

In a double-blind, placebo-controlled, multicenter US clinical trial involving obese patients with type 2 diabetes whose hyperglycemia was not adequately controlled with dietary management alone (baseline fasting plasma glucose [FPG] of approximately 240 mg/dL), treatment with Glucophage (up to 2550 mg/day) for 29 weeks resulted in significant mean net reductions in fasting and postprandial plasma glucose (PPG) and hemoglobin A1c (HbA1c) of 59 mg/dL, 83 mg/dL, and 1.8%, respectively, compared to the placebo group (see Table 2).

A 29-week, double-blind, placebo-controlled study of Glucophage and glyburide, alone and in combination, was conducted in obese patients with type 2 diabetes who had failed to achieve adequate glycemic control while on maximum doses of glyburide (baseline FPG of approximately 250 mg/dL) (see Table 3). Patients randomized to the combination arm started therapy with Glucophage 500 mg and glyburide 20 mg. At the end of each week of the first 4 weeks of the trial, these patients had their dosages of Glucophage increased by 500 mg if they had failed to reach target fasting plasma glucose. After week 4, such dosage adjustments were made monthly, although no patient was allowed to exceed Glucophage 2500 mg. Patients in the Glucophage only arm (metformin plus placebo) followed the same titration schedule. At the end of the trial, approximately 70% of the patients in the combination group were taking Glucophage 2000 mg/glyburide 20 mg or Glucophage 2500 mg/glyburide 20 mg. Patients randomized to continue on glyburide experienced worsening of glycemic control, with mean increases in FPG, PPG, and HbA1c of 14 mg/dL, 3 mg/dL, and 0.2%, respectively. In contrast, those randomized to Glucophage (up to 2500 mg/day) experienced a slight improvement, with mean reductions in FPG, PPG, and HbA1c of 1 mg/dL, 6 mg/dL, and 0.4%, respectively. The combination of Glucophage and glyburide was effective in reducing FPG, PPG, and HbA1c levels by 63 mg/dL, 65 mg/dL, and 1.7%, respectively. Compared to results of glyburide treatment alone, the net differences with combination treatment were –77 mg/dL, –68 mg/dL, and –1.9%, respectively (see Table 3).

The magnitude of the decline in fasting blood glucose concentration following the institution of Glucophage (metformin hydrochloride) Tablets therapy was proportional to the level of fasting hyperglycemia. Patients with type 2 diabetes with higher fasting glucose concentrations experienced greater declines in plasma glucose and glycosylated hemoglobin.

In clinical studies, Glucophage, alone or in combination with a sulfonylurea, lowered mean fasting serum triglycerides, total cholesterol, and LDL cholesterol levels, and had no adverse effects on other lipid levels (see Table 4).

In contrast to sulfonylureas, body weight of individuals on Glucophage tended to remain stable or even decrease somewhat (see Tables 2 and 3).

A 24-week, double-blind, placebo-controlled study of Glucophage plus insulin versus insulin plus placebo was conducted in patients with type 2 diabetes who failed to achieve adequate glycemic control on insulin alone (see Table 5). Patients randomized to receive Glucophage plus insulin achieved a reduction in HbA1c of 2.10%, compared to a 1.56% reduction in HbA1c achieved by insulin plus placebo. The improvement in glycemic control was achieved at the final study visit with 16% less insulin, 93.0 U/day vs 110.6 U/day, Glucophage plus insulin versus insulin plus placebo, respectively, p=0.04.

A second double-blind, placebo-controlled study (n=51), with 16 weeks of randomized treatment, demonstrated that in patients with type 2 diabetes controlled on insulin for 8 weeks with an average HbA1c of 7.46 ± 0.97%, the addition of Glucophage maintained similar glycemic control (HbA1c 7.15 ± 0.61 vs 6.97 ± 0.62 for Glucophage plus insulin and placebo plus insulin, respectively) with 19% less insulin versus baseline (reduction of 23.68 ± 30.22 vs an increase of 0.43 ± 25.20 units for Glucophage plus insulin and placebo plus insulin, p<0.01). In addition, this study demonstrated that the combination of Glucophage plus insulin resulted in reduction in body weight of 3.11 ± 4.30 lbs, compared to an increase of 1.30 ± 6.08 lbs for placebo plus insulin, p=0.01.

A 24-week, double-blind, placebo-controlled study of Glucophage XR, taken once daily with the evening meal, was conducted in patients with type 2 diabetes who had failed to achieve glycemic control with diet and exercise (HbA1c 7.0%-10.0%, FPG 126-270 mg/dL). Patients entering the study had a mean baseline HbA1c of 8.0% and a mean baseline FPG of 176 mg/dL. After 12 weeks treatment, mean HbA1c had increased from baseline by 0.1% and mean FPG decreased from baseline by 2 mg/dL in the placebo group, compared with a decrease in mean HbA1c of 0.6% and a decrease in mean FPG of 23 mg/dL in patients treated with Glucophage XR 1000 mg once daily. Subsequently, the treatment dose was increased to 1500 mg once daily if HbA1c was ≥7.0% but <8.0% (patients with HbA1c ≥8.0% were discontinued from the study). At the final visit (24-week), mean HbA1c had increased 0.2% from baseline in placebo patients and decreased 0.6% with Glucophage XR.

A 16-week, double-blind, placebo-controlled, dose-response study of Glucophage XR, taken once daily with the evening meal or twice daily with meals, was conducted in patients with type 2 diabetes who had failed to achieve glycemic control with diet and exercise (HbA1c 7.0%-11.0%, FPG 126-280 mg/dL). Changes in glycemic control and body weight are shown in Table 6.

Compared with placebo, improvement in glycemic control was seen at all dose levels of Glucophage XR (metformin hydrochloride) Extended-Release Tablets and treatment was not associated with any significant change in weight (see DOSAGE AND ADMINISTRATION for dosing recommendations for Glucophage and Glucophage XR).

A 24-week, double-blind, randomized study of Glucophage XR, taken once daily with the evening meal, and Glucophage (metformin hydrochloride) Tablets, taken twice daily (with breakfast and evening meal), was conducted in patients with type 2 diabetes who had been treated with Glucophage 500 mg twice daily for at least 8 weeks prior to study entry. The Glucophage dose had not necessarily been titrated to achieve a specific level of glycemic control prior to study entry. Patients qualified for the study if HbA1c was ≤8.5% and FPG was ≤200 mg/dL. Changes in glycemic control and body weight are shown in Table 7.

After 12 weeks of treatment, there was an increase in mean HbA1c in all groups; in the Glucophage XR 1000 mg group, the increase from baseline of 0.23% was statistically significant (see DOSAGE AND ADMINISTRATION).

Changes in lipid parameters in the previously described placebo-controlled dose-response study of Glucophage XR are shown in Table 8.

Changes in lipid parameters in the previously described study of Glucophage and Glucophage XR are shown in Table 9.

Pediatric Clinical Studies

In a double-blind, placebo-controlled study in pediatric patients aged 10 to 16 years with type 2 diabetes (mean FPG 182.2 mg/dL), treatment with Glucophage (up to 2000 mg/day) for up to 16 weeks (mean duration of treatment 11 weeks) resulted in a significant mean net reduction in FPG of 64.3 mg/dL, compared with placebo (see Table 10).

Indications and Usage for Glucophage

Glucophage (metformin hydrochloride) Tablets is indicated as an adjunct to diet and exercise to improve glycemic control in adults and children with type 2 diabetes mellitus.

Glucophage XR (metformin hydrochloride) Extended-Release Tablets is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Contraindications

Glucophage and Glucophage XR are contraindicated in patients with:

1. Renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL [females] or abnormal creatinine clearance) which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia (see WARNINGS and PRECAUTIONS).
2. Known hypersensitivity to metformin hydrochloride.
3. Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.

Glucophage and Glucophage XR should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function. (See also PRECAUTIONS.)

Warnings

Macrovascular Outcomes—There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Glucophage or Glucophage XR or any other antidiabetic drug.

Monitoring of renal function—Metformin is known to be substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive Glucophage or Glucophage XR. In patients with advanced age, Glucophage and Glucophage XR should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging is associated with reduced renal function. In elderly patients, particularly those ≥80 years of age, renal function should be monitored regularly and, generally, Glucophage and Glucophage XR should not be titrated to the maximum dose (see WARNINGS and DOSAGE AND ADMINISTRATION).

Before initiation of Glucophage or Glucophage XR therapy and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated, renal function should be assessed more frequently and Glucophage or Glucophage XR discontinued if evidence of renal impairment is present.

Use of concomitant medications that may affect renal function or metformin disposition—Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin, such as cationic drugs that are eliminated by renal tubular secretion (see PRECAUTIONS: Drug Interactions), should be used with caution.

Radiologic studies involving the use of intravascular iodinated contrast materials (for example, intravenous urogram, intravenous cholangiography, angiography, and computed tomography (CT) scans with intravascular contrast materials)—Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin (see CONTRAINDICATIONS). Therefore, in patients in whom any such study is planned, Glucophage or Glucophage XR should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal.

Hypoxic states—Cardiovascular collapse (shock) from whatever cause, acute congestive heart failure, acute myocardial infarction and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on Glucophage or Glucophage XR therapy, the drug should be promptly discontinued.

Surgical procedures—Glucophage or Glucophage XR therapy should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient's oral intake has resumed and renal function has been evaluated as normal.

Alcohol intake—Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving Glucophage or Glucophage XR.

Impaired hepatic function—Since impaired hepatic function has been associated with some cases of lactic acidosis, Glucophage and Glucophage XR should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.

Vitamin B12 levels—In controlled clinical trials of Glucophage of 29 weeks duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of Glucophage or vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on Glucophage or Glucophage XR and any apparent abnormalities should be appropriately investigated and managed (see PRECAUTIONS: Laboratory Tests).

Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 measurements at 2- to 3-year intervals may be useful.

Change in clinical status of patients with previously controlled type 2 diabetes—A patient with type 2 diabetes previously well controlled on Glucophage or Glucophage XR who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. 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, Glucophage or Glucophage XR must be stopped immediately and other appropriate corrective measures initiated (see also WARNINGS).

Hypoglycemia—Hypoglycemia does not occur in patients receiving Glucophage or Glucophage XR alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol.

Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking beta-adrenergic blocking drugs.

Loss of control of blood glucose—When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold Glucophage or Glucophage XR and temporarily administer insulin. Glucophage or Glucophage XR may be reinstituted after the acute episode is resolved.

The effectiveness of oral antidiabetic drugs in lowering blood glucose to a targeted level decreases in many patients over a period of time. 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 either Glucophage or Glucophage XR or sulfonylurea monotherapy, combined therapy with Glucophage or Glucophage XR and sulfonylurea may result in a response. Should secondary failure occur with combined Glucophage/sulfonylurea therapy or Glucophage XR/sulfonylurea therapy, it may be necessary to consider therapeutic alternatives including initiation of insulin therapy.

Information for Patients

Patients should be informed of the potential risks and benefits of Glucophage or Glucophage XR 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 Glucophage or Glucophage XR 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 Glucophage or Glucophage XR, 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.

Patients should be counselled against excessive alcohol intake, either acute or chronic, while receiving Glucophage or Glucophage XR.

Glucophage or Glucophage XR alone does not usually cause hypoglycemia, although it may occur when Glucophage or Glucophage XR 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.)

Patients should be informed that Glucophage XR must be swallowed whole and not crushed or chewed, and that the inactive ingredients may occasionally be eliminated in the feces as a soft mass that may resemble the original tablet.

Laboratory Tests

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 (e.g., 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 Glucophage therapy, if this is suspected, vitamin B12 deficiency should be excluded.

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

Glyburide—In a single-dose interaction study in type 2 diabetes patients, coadministration 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 Glucophage or Glucophage XR and Oral Sulfonylurea Therapy in Adult Patients).

Furosemide—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 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 coadministered chronically.

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

Cationic drugs—Cationic drugs (e.g., 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 Glucophage or Glucophage XR and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.

Other—Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the 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 Glucophage or Glucophage XR, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving Glucophage or Glucophage XR, the patient should be observed cl