ST LOUIS (MD Consult) - On November 2, 2009, the US Food and Drug Administration (FDA) notified health care professionals of revisions to the prescribing informationfor Byetta (exenatide) to include information on postmarketing reports of altered kidney function, including acute renal failure and insufficiency. Byetta, an incretin-mimetic drug, is approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

 

From April 2005 to October 2008, the FDA received reports of 78 cases of altered kidney function (62 cases of acute renal failure and 16 cases of renal insufficiency) in patients treated with Byetta. Some cases occurred in patients with preexisting kidney disease or in patients with one or more risk factors for experiencing kidney problems. From April 2005 to September 2008, more than 6.6 million prescriptions for Byetta were dispensed. With that in mind, the FDA acknowledges that 78 reported cases of altered renal function represent a small percentage of the total number of patients who have received the drug.

Some of the 78 patients who experienced altered kidney function reported nausea, vomiting, and diarrhea, the most common adverse effects associated with Byetta in clinical trials. According to the FDA, these untoward effects may have contributed to the development of altered kidney function in the reported cases.

Revisions to the product label for Byetta include the following recommendations:

 

• Byetta should not be used in patients with severe renal impairment (creatinine clearance values of <30 ml/min) or end-stage renal disease.
• Caution should be applied when initiating or increasing doses of Byetta from 5 µg to 10 µg in patients with moderate renal impairment (creatinine clearance values of 30 to 50 ml/min).
• Patients receiving Byetta should be carefully monitored for the development of kidney dysfunction, and the continued need for Byetta should be reevaluated if a suspicion of kidney dysfunction arises.
• Patients should be provided with the Byetta Medication Guide when they receive their prescription to aid in understanding the benefits and potential risks associated with Byetta use.

 

The discontinuation of Byetta should be considered if a patient's kidney dysfunction cannot be explained by other causes, keeping in mind that altered kidney function can be a consequence of diabetes, independent of any risk associated with Byetta. The FDA also advises health care professionals to inform patients that chronic conditions (eg, hypertension and pancreatitis) as well as medications (eg, nonsteroidal antiinflammatory drugs, diuretics, and antihypertensives) can increase the risk of alterations in renal function.

Patients should be advised to seek medical counsel if they experience any unusual signs or symptoms such as nausea, vomiting, dehydration, lethargy, changes in urination (color, frequency, amount), unexplained swelling in the extremities, increases in blood pressure, changes in appetite or digestion, or dull ache in the middle to lower back.

Also on November 2, 2009, Amylin Pharmaceuticals and Eli Lilly and Company issued the following statement in response to the FDA update on Byetta:

"The FDA update issued today aligns with the Byetta label approved last week. The current label reflects our understanding of postmarketing reports of renal events and provides physicians with updated guidance about appropriate use in patients with renal conditions. There is no evidence from preclinical and clinical studies that Byetta has any direct toxic effect on the kidney," said Orville G. Kolterman, MD, senior vice president of research and development for Amylin Pharmaceuticals. "Postmarketing reports of serious changes in renal function have been rare and usually complicated by other factors that could have contributed to the kidney problems. It is also important to note that diabetes is the leading cause of kidney failure. Information about use of Byetta in patients with impaired renal function was included in the initial product label in 2005 and was updated in 2007. We remain committed to working closely with the FDA to ensure that physicians and patients are provided with accurate information about any potential risks associated with the use of our products."

圣路易斯(MD Consult)——2009年11月2日，美国食品药品管理局(FDA)提醒医务人员注意Byetta (exenatide, 艾塞那肽)的新处方信息，这些信息包括如急性肾功能衰竭或肾功能不全等肾功改变的上市后报告。Byetta，是一种肠降血糖素类药物，已获准作为饮食控制和运动疗法基础上的辅助用药，用于成年2型糖尿病患者控制血糖。

 

从2005年4月至2008年10月，FDA 收到78例应用Byetta的患者出现肾功能改变的报告(62例急性肾功能衰竭，16例肾功能不全)。一些病例发生于原本就有肾脏疾病或者有一个或一个以上引起肾脏问题的风险因素的患者。从2005年4月至2008年9月，一共开出超过660万张用Byetta的处方。考虑到这一点，FDA认为这78例肾功能改变的病例仅占所有使用该药物的病人中的很小的比例。

 

这78例出现肾功能改变的病人中的有些人有恶心、呕吐和腹泻等反应，这些都是在临床试验中服用Byetta最常见的副作用。据FDA所说，在报道的病例中，这些副作用可能与肾功能改变的进展有关。

 

• Byetta禁用于严重的肾脏损害(肌酐清除率<30 ml/min)或终末期肾病患者。
• 对于中度肾脏损害(30 ml/min<肌酐清除率<50 ml/min)的患者来说，当服用量从5 µg增加到10 µg时要慎重。
• 服用Byetta的患者应注意监测肾功异常的改变，一旦怀疑有肾脏功能异常，则需要再评估是否应该继续使用Byetta。
• 当给患者开具Byetta的处方时，应向他们提供服药指南，让其知道服用该药的好处和可能存在的风险。

 

Byetta标签的修订内容包括以下几个方面的建议：

 

如果没有其他原因可以解释患者的肾脏功能异常改变，那么就要考虑停止服用Byetta，但必须注意的是，糖尿病也会引起肾功改变，这与服用Byetta无关。FDA也建议医务工作者要告知患者：一些慢性疾病(如高血压、胰腺炎)以及服用某些药物(如非甾体抗炎药物、利尿剂以及降压药)也会增加发生肾功改变的风险。

 

如果患者出现下述异常症状或体征时，建议尽快就医：恶心、呕吐、脱水、嗜睡、小便异常(包括颜色、频率、量的异常)、无法解释的四肢肿胀、血压升高、食欲或消化改变、腰背部钝痛。

 

也在2009年11月2日，Amylin制药公司和Eli Lilly 公司针对FDA对Byetta标签的更新做了以下声明：

 

“FDA此次更新与上周批准的Byetta标签协调一致。目前的药品标签，反映了我们对肾病事件的上市后报告的理解，也为医生提供了最新信息，指导他们在肾脏疾病患者中合理使用该药。从临床前和临床研究的结果表明，尚无证据显示Byetta有任何直接的肾毒性作用，”Orville G. Kolterman医学博士，Amylin制药公司研究和开发部高级副总裁，说道：“发生肾功能严重改变的上市后报告是罕见的，而且常常并发于其他引起肾脏疾患的病因。同时也必须指出，糖尿病是导致肾衰竭的主要原因。关于使用Byetta的患者肾功能受损的资料载于2005年最初的药品标签中，并于2007年更新。我们将继续致力于同FDA密切合作，确保提供给医生和病人关于服用我们的药物发生任何相关潜在风险的准确资料。”