藥物警訊

Metformin-containing Drugs: Drug Safety Communication - Revised Warnings for Certain Patients With Reduced Kidney Function

AUDIENCE: Pharmacy, Nephrology, Internal Medicine, Patient

ISSUE: FDA is requiring labeling changes regarding the recommendations for metformin-containing medicines for diabetes to expand metformin's use in certain patients with reduced kidney function. The current labeling strongly recommends against use of metformin in some patients whose kidneys do not work normally. FDA was asked to review numerous medical studies regarding the safety of metformin use in patients with mild to moderate impairment in kidney function, and to change the measure of kidney function in the metformin drug labeling that is used to determine whether a patient can receive metformin.

FDA concluded, from the review of studies published in the medical literature, that metformin can be used safely in patients with mild impairment in kidney function and in some patients with moderate impairment in kidney function. FDA is requiring changes to the metformin labeling to reflect this new information and provide specific recommendations on the drug's use in patients with mild to moderate kidney impairment.

FDA is also requiring manufacturers to revise the labeling to recommend that the measure of kidney function used to determine whether a patient can receive metformin be changed from one based on a single laboratory parameter (blood creatinine concentration) to one that provides a better estimate of renal function (i.e., glomerular filtration rate estimating equation (eGFR)). This is because in addition to blood creatinine concentration, the glomerular filtration rate takes into account additional parameters that are important, such as the patient's age, gender, race and/or weight.

BACKGROUND: Metformin-containing medicines are available by prescription only and are used along with diet and exercise to lower blood sugar levels in patients with type 2 diabetes. When untreated, type 2 diabetes can lead to serious problems, including blindness, nerve and kidney damage, and heart disease. Metformin-containing medicines are available as single-ingredient products and also in combination with other drugs used to treat diabetes. The current drug labeling strongly recommends against metformin use in some patients whose kidneys do not work normally because use of metformin in these patients can increase the risk of developing a serious and potentially deadly condition called lactic acidosis, in which too much lactic acid builds up in the blood.

RECOMMENDATION: Healthcare professionals should follow the latest recommendations when prescribing metformin-containing medicines to patients with impaired kidney function. Patients should talk to their health care professionals if they have any questions or concerns about taking metformin.

The labeling recommendations on how and when kidney function is measured in patients receiving metformin will include the following information:

‧ Before starting metformin, obtain the patient's eGFR.

‧ Metformin is contraindicated in patients with an eGFR below 30 mL/minute/1.73 m2.

‧ Starting metformin in patients with an eGFR between 30-45 mL/minute/1.73 m2 is not recommended.

‧ Obtain an eGFR at least annually in all patients taking metformin. In patients at increased risk for the development of renal impairment such as the elderly, renal function should be assessed more frequently.

‧ In patients taking metformin whose eGFR later falls below 45 mL/minute/1.73 m2, assess the benefits and risks of continuing treatment. Discontinue metformin if the patient's eGFR later falls below 30 mL/minute/1.73 m2.

‧ Discontinue metformin at the time of or before an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/minute/1.73 m2; in patients with a history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart metformin if renal function is stable.

Read the MedWatch safety alert, including a link to the full Drug Safety Communication, at:

http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm494829.htm

Metformin過去不建議用於腎功能不佳之病人。美國FDA經評估多篇有關metformin用於輕中度腎功能不全病人之安全性研究，將更新病人使用含metformin成分藥品之腎功能評估方式並提供輕中度腎功能不全病人之使用建議。

評估病人是否適用metformin原為依據病人之血清肌酸酐濃度(blood creatinine concentration)來判定，而現在建議改使用將病人年齡、性別及/或體重等其它重要參數納入考量，能提供更佳的腎功能評估，例如腎絲球廓清率eGFR(glomerular filtration rate estimating equation)。

含metformin成分藥品適用於第二型糖尿病人搭配飲食及運動來達到血糖控制作用。第二型糖尿病若未接受治療，可能會導致嚴重併發症，如失明、神經及腎臟受損或心臟疾病。含metformin成分藥品目前上市品項有單方藥品及與其它降血糖用藥合併之複方製劑。過去的藥品仿單中禁止metformin用於腎功能不全之病人，因為可能增加發生乳酸中毒的風險。

美國FDA建議醫療人員當需處方此藥品予腎功能不佳之病人時，應依循最新的處方建議。正在服用此藥之病人，若有任何問題，應向醫療人員諮詢及討論。

此藥仿單中有關腎功能調整之建議更新如下：

1. 在開始服用metformin治療之前，應先計算病人的eGFR。

2. eGFR低於30 mL/min/1.73 m2者禁用metformin。

3. eGFR為30-45mL/min/1.73 m2之間者不建議使用metformin。

4. 服用metformin期間應至少每年一次定期追蹤病人之eGFR。若病人為腎功能不全高風險族群（例如年長者），應更頻繁監測腎功能。

5. 若病人服藥後eGFR低於45 mL/min/1.73 m2，應重新評估利弊是否繼續治療；若低於30 mL/min/1.73 m2，則應停用。

6. 病人若eGFR在30-60 mL/min/1.73 m2之間，曾有肝臟疾病、酗酒或心衰竭病史、即將接受含碘顯影劑造影檢查時/ 前，應停用metformin；在檢查完畢48小時後，應再次評估病人eGFR，若腎功能正常，則可恢復使用metformin。

相關訊息與連結請參考FDA網址：

http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm494829.htm

[Posted 04/09/2016]

資料來源：美國FDA之藥物安全警訊

資料提供：台大醫院藥劑部