瑞格列奈二甲双胍片说明书.docx

药品说明书
此说明书说不包括安全并有效使用PrandiMet的所有信息。请参阅PrandiMet完整的处方信息。

PrandiMet (瑞格列奈盐酸二甲双胍片) Tablets
Initial U.S. Approval: 2008

警告: 乳酸性酸中毒
请参阅黑框警告完整处方信息

•由于二甲双胍蓄积可造成乳酸酸中毒，增加脓毒病、脱水、过量摄入酒精、肝损伤、肾损伤和充血性心力衰竭的危险。
• 症状表现为不适。肌痛、呼吸抑制、嗜睡增加和非特异性腹部不适。
实验室检查出现pH值降低和血中乳酸盐增加。 (5.1)
• 若疑有酸中毒，应停用Prandimet，并立即住院治疗。

·······································适应症和使用·········································
• PrandiMet is a meglitinide and biguanide combination product indicated as an
adjunct to diet and exercise to improve glycemic control in adults with type 2
diabetes mellitus who are already treated with a meglitinide and metformin HCl or who have inadequate glycemic control on a meglitinide alone or metformin
HCl alone. (1)

重要限制使用:
• 不要用来治疗1型糖尿病或糖尿病酮酸症。 (1)

··································用法与用量·································
• PrandiMet 的用量应根据个人调整剂量 (2)
• 从每日两次1mg/500mg剂量开始服用，除非患者已经高剂量服用瑞格列奈和二甲双胍联合使用。(2)
• 不超过10mg盐酸二甲双胍/瑞格列奈/2500mg每天或4mg瑞格列奈/1000mg盐酸二甲双胍每顿饭。(2)
• 分剂量在饭前15分钟内给予。(2)
• 跳过一顿饭的病人应跳过那顿饭对应的Prandmet的剂量。(2)

······························剂型和强度·································
片剂:
• 1 mg repaglinide/500 mg metformin HCl (3)
• 2 mg repaglinide/500 mg metformin HCl (3)

········································禁忌症··············································
不适用于以下患者:
• 肾损伤. (4, 5.2)
• 代谢性酸中毒，包括糖尿病酮症酸中毒. (4, 5.1)
• 同时接受二甲苯氧庚酸和伊曲康唑. (4, 5.7, 7.2, 12.3)

··································警告和预防措施··································
• 盐酸二甲双胍禁止适用于肾损伤患者。在使用Prandimet之前和以后每年一次肾功能检查应正常。(4, 5.2)
• 在接受放射性碘造影的患者暂时停止使用Prandimet (5.3)
• 乳酸性酸中毒与肝损害有关。建议肝损害患者不要使用 (5.4)
• 酒精能增强二甲双胍对乳酸的代谢。警告患者不要过量饮酒(5.5 )
• PrandiMet 不应与NPH胰岛素结合使用. (5.6)
• 吉非贝奇可以大大增加瑞格列奈在体内的暴露时间。不建议Prandimet和吉非贝奇何用(4, 5.7, 7.2, 12.3)
• 瑞格列奈成分可以导致低血糖。 (5.8)
• 二甲双胍可导致维生素B12缺乏症。应当每年对血液指标进行测量. (5.9)
• 如果血糖控制能力或者在减少摄入的流体和食物（如感染、手术）期间恶化，可能需要停止使用Prandimet 并暂时使用胰岛素。(5.10)
• 没有临床研究证明Prandimet或其他口服抗糖尿病药物能够减少大血管病变的风险。(5.15)

······································不良反应·············································.
• 低血糖和头痛是最常见的不良反应（≥ 10% ），据报道瑞格列奈和盐酸二甲双胍联合使用发生的不良反应事件比患者单独使用瑞格列奈或盐酸二甲双胍的多(6.2)
• 盐酸二甲双胍治疗的最常见的不良反应是胃肠道反应（如腹泻、恶心和呕吐），在较高剂量盐酸二甲双胍时发生更频繁。 (6.1, 6.2)

可疑不良反应报告, 联系诺和诺德公司
1-888-NOVO-444 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

········································药物相互作用·············································
• 阳离子药物通过肾小管代谢可能会干扰二甲双胍消除：谨慎使用。 (7.1)
• 瑞格列奈会部分代谢CYP2C8和CYP3A4.在病人服用抑制剂或CYP2C8和CYP3A4的诱导剂时要谨慎使用。(7.2)

患者信息咨询请参阅17

修订: 6/2008

1

全处方信息：内容
* 警告-乳酸酸性中毒
1 适应症和用途
2 剂量和用法
3 剂型和优势
4 禁忌症
5 警告和预防措施
5.1 乳酸酸中毒
5.2 肾功能评价
5.3 血管内碘对比材料与放射性研究
5.4 肝功能受损
5.5 酒精摄入
5.6 与NPH-胰岛素联用
5.7 药物相互作用
5.8 低血糖症
5.9 维生素B12 水平
5.10 外科治疗
5.11 控制血糖失败
5.12 使用相应的药物影响肾功能或二甲双胍的代谢
5.13 缺氧状态
5.14 患者以前控制2型糖尿病的临床状态
5.15 Macrovascular Outcomes
6 不良反应
6.1 最常见的不良反应
6.2 临床试验经验
6.3 上市后的经验
7 药物相互作用
7.1 阳离子药物
7.2 CYP2C8和CYP3A4抑制剂/诱导剂
8 特殊人群使用
8.1 孕妇
8.3 哺乳期母亲
8.4 儿童使用
8.5 老年人使用
10 过量使用
11 描述
12 临床药理学
12.1 作用机制
12.3 药物代谢动力学
13 临床前毒理学
13.1 致癌致突变，生育能力损害
14 临床研究
14.1 二甲双胍治疗患者血糖控制不足
16 如何储存和处理
17 病人咨询信息
17.1 医生指示
17.2 实验室检验
*部分或一小部分的完整的处方信息省略未列出

15

全处方信息

警告：乳酸性酸中毒
由于二甲双胍蓄积可造成乳酸酸中毒，增加脓毒病、脱水、过量摄入酒精、肝损伤、肾损伤和充血性心力衰竭的危险。
• 症状表现为不适。肌痛、呼吸抑制、嗜睡增加和非特异性腹部不适。
实验室检查出现pH值降低和血中乳酸盐增加。 (5.1)
• 若疑有酸中毒，应停用Prandimet，并立即住院治疗。

1 适应症和用途

PrandiMet is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus who are already treated with a meglitinide and metformin HCl or who have inadequate glycemic control on a meglitinide alone or metformin HCl alone.
使用的重要限制:
PrandiMet 不应该使用在1型糖尿病或糖尿病酮症酸中毒的病人治疗中，因为它在这种情况下是无效的.

2 剂量和用法
推荐剂量
PrandiMet的剂量应在病人当前病情、有效性和耐受性的基础上个体化给药。PrandiMet 每天给药两到三次，每日最大剂量不超过10mg瑞格列奈/2500mg盐酸二甲双胍. 每顿饭不多于4mg瑞格列奈/1000mg盐酸二甲双胍。PrandiMet 的治疗和维持应根据个体差异进行联合治疗，并且听从医务人员的处理.应执行动态血糖监测，以确定PrandiMet的治疗反应.

PrandiMet 通常应采取餐前15分钟内给药，但时间可以最早提前改变至这顿饭前30分钟. 跳过一顿饭的病人应相应的跳过那顿饭对应的PrandiMet的剂量.

用盐酸二甲双胍单独治疗的病人病情未能充分控制
如果用瑞格列奈和盐酸二甲双胍联合使用可以作为那些单独使用盐酸二甲双胍不能控制2型糖尿病患者的治疗方案, 推荐PrandiMet 剂量是饭时每天两次1mg瑞格列奈/500mg盐酸二甲双胍，剂量逐渐增加（基于血糖反应）以减少瑞格列奈与低血糖的风险。
单独使用美各里替尼未能充分控制的病人

目前同时使用瑞格列奈和盐酸二甲双胍的病人
For patients switching from repaglinide co-administered with metformin HCl, PrandiMet can be initiated at the dose of repaglinide and metformin HCl similar to (but not exceeding) the patient’s current doses, then may be titrated to the maximum daily dose as necessary to achieve targeted glycemic control.

No studies have been performed examining the safety and efficacy of PrandiMet in patients previously treated with other oral antihyperglycemic agents and switched to PrandiMet. Any change in therapy should be undertaken with care and with appropriate monitoring as changes in glycemic control can occur.

3 DOSAGE FORMS AND STRENGTHS
• 1 mg repaglinide /500mg metformin HCl tablets are yellow, biconvex, debossed with Novo Nordisk
(Apis) bull symbol on one side, and strength indicated on the other side
• 2 mg repaglinide /500mg metformin HCl tablets are pink, biconvex, debossed with Novo Nordisk
(Apis) bull symbol on one side, and strength indicated on the other side

4 CONTRAINDICATIONS
PrandiMet is contraindicated in:
• Renal impairment (e.g., serum creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL [females], or
abnormal creatinine clearance). [see Warnings and Precautions (5.2)].
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be
treated with insulin [see Warnings and Precautions (5.1)].
• Patients receiving both gemfibrozil and itraconazole [see Warnings and Precautions (5.7), Drug
Interactions (7.2), Clinical Pharmacology (12.3)].
• Patients with known hypersensitivity to repaglinide, metformin HCl or any inactive ingredients in
PrandiMet.

5 WARNINGS AND PRECAUTIONS
5.1 Lactic Acidosis
Metformin hydrochloride
Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with PrandiMet; when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels >5 µg/mL are generally found.
The reported incidence of lactic acidosis in patients receiving metformin HCl is very low (approximately 0.03 cases/1,000 patient-years of exposure, with approximately 0.015 fatal cases/1,000 patient-years of exposure). In more than 20,000 patient-years exposure to metformin HCl in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal impairment, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or

acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal impairment and the patient's age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking PrandiMet and by use of the minimum effective dose of PrandiMet. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Treatment with PrandiMet should not be initiated in patients ≥80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition, PrandiMet should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, PrandiMet should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking PrandiMet, since alcohol potentiates the effects of metformin on lactate metabolism. In addition, PrandiMet should be temporarily discontinued prior to any
intravascular radiocontrast study and for any surgical procedure [see Warnings and Precautions (5.3), (5.5)
and (5.10)].
The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis. The patient and the patient's physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur (see also Warnings and Precautions). PrandiMet should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose and, if indicated, blood pH, lactate levels, and even blood metformin levels may be useful. Once a patient is stabilized on any dose level of PrandiMet, 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.
Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking PrandiMet do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity or technical problems in sample handling [see Warnings and Precautions (5.11), (5.14)].
Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).
Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking PrandiMet, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery [see Contraindication (4)].
5.2 Assessment of Renal Function
Metformin is substantially excreted by the kidney and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Therefore, patients with renal impairment should not receive PrandiMet. [see Warnings and Precautions (5.1), Contraindications (4)].
Before initiation of therapy with PrandiMet and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal impairment is anticipated, renal function should be assessed more frequently and PrandiMet discontinued if evidence of renal impairment
is present. [see Clinical Pharmacology (12.3)].
5.3 Radiologic Studies with Intravascular Iodinated 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 HCl [see Contraindications(4)]. Therefore, in patients in whom any such study is planned, PrandiMet 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.
5.4 Impaired Hepatic Function
Hepatic impairment has been associated with some cases of lactic acidosis. Therefore, PrandiMet should generally be avoided in patients with hepatic impairment. [see Clinical Pharmacology (12.3)]
5.5 Alcohol Intake
Alcohol potentiates the effect of metformin on lactate metabolism. Patients should be warned against
excessive alcohol intake while receiving PrandiMet.
5.6 Combination with NPH-insulin

Repaglinide
Repaglinide is not indicated for use in combination with NPH-insulin.
Across seven controlled clinical trials, there were six serious adverse events (1.4%) of myocardial ischemia with repaglinide in combination with NPH-insulin compared to one event (0.3%) in patients using insulin alone [see Adverse Reactions (6.2)]
5.7 Drug Interactions
Gemfibrozil increases exposures to repaglinide, one of the components of PrandiMet, which may
enhance and prolong the blood glucose lowering effects of repaglinide. Postmarketing events of serious hypoglycemia have been reported in patients taking both repaglinide and gemfibrozil. Administration of PrandiMet and gemfibrozil to the same patient is not recommended. [see Drug Interactions (7.2) and Clinical Pharmacology (12.3)].
Repaglinide exposures are increased more than 20-fold in patients taking both gemfibrozil and itraconazole. Therefore, do not use PrandiMet in patients taking both gemfibrozil and itraconazole [see Contraindications (4), Drug Interactions (7.2), and Clinical Pharmacology (12.3)].
5.8 Hypoglycemia
Most blood glucose-lowering drugs, including repaglinide, can cause hypoglycemia. Patients who have not previously been treated with a meglitinide should be started on the lowest available repaglinide component of PrandiMet to reduce the risk of hypoglycemia. Elderly, debilitated or malnourished patients and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemia. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking β­ adrenergic blocking drugs [see Adverse Reactions (6.1)].
5.9 Vitamin B12 Levels
In controlled clinical trials of metformin HCl 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. This finding, possibly due to interference with B12 absorption from the B12­ intrinsic factor complex, is rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin HCl or vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on PrandiMet and any apparent abnormalities should be appropriately investigated and managed.