ST LOUIS (MD Consult) - On May 21, 2009, Otsuka Pharmaceutical Co announced that the US Food and Drug Administration (FDA) approved Samsca (tolvaptan) for the treatment of patients with clinically significant hypervolemic and euvolemic hyponatremia (ie, with serum sodium levels <125 mEq/L, or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction). Patients who may benefit from this drug include those with heart failure, cirrhosis, or the syndrome of inappropriate antidiuretic hormone (SIADH).

Samsca acts by selectively blocking the binding of vasopressin to the V2 receptors in the collecting duct of the kidney. By inhibiting the effects of vasopressin at the V2 receptor, Samsca increases the excretion of free water while not directly affecting the excretion of sodium and other electrolytes.

In 2 double-blind, placebo-controlled, multicenter studies, a total of 424 patients with euvolemic or hypervolemic hyponatremia were treated for 30 days with either Samsca or placebo. The patients were followed up for an additional 7 days after treatment withdrawal. The primary end point of these studies was the average daily area-under-the-curve change in serum sodium levels from baseline to Day 4 and baseline to Day 30 in patients with a serum sodium level of <135 mEq/L. Compared with placebo, Samsca caused a statistically greater increase in serum sodium levels (P < .0001) during both periods in both studies. For patients with a serum sodium level of <130 mEq/L or <125 mEq/L, the effects at Day 4 and Day 30 remained significant. This effect was seen across all disease etiology subsets (eg, congestive heart failure, cirrhosis, SIADH/other). Seven days after treatment withdrawal, serum sodium levels in patients treated with Samsca decreased to levels approximately equivalent to those of patients treated with placebo.

In the aforementioned trials, the most common adverse reactions observed in patients receiving Samsca (occurring ≥5% more frequently than in patients receiving placebo) were thirst, dry mouth, asthenia, constipation, pollakiuria or polyuria, and hyperglycemia. In these studies, 10% of patients receiving Samsca discontinued therapy as a result of adverse reactions compared with 12% of placebo-treated patients.

In clinical trials, treatment with Samsca was shown to significantly raise serum sodium concentrations in as early as 8 hours after drug administration, and this change in concentration was maintained for 30 days. Exposure and response to Samsca appear to be similar in patients with creatinine clearance levels of 10 to79 mL/min and in patients without renal impairment. However, the use of Samsca has not been evaluated in patients with creatinine clearance levels of <10 mL/min or in patients undergoing dialysis.

Because treatment with Samsca may provide an overly rapid correction of hyponatremia, the drug should only be initiated and reinitiated in patients in a hospital, where their serum sodium levels can be monitored closely. Overly rapid correction of hyponatremia (ie, a serum sodium level increase of >12 mEq/L in 24 hours) can cause osmotic demyelination syndrome, resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma, and death. In susceptible patients, including those with severe malnutrition, alcoholism, or advanced liver disease, a slower rate of serum sodium correction may be advisable.

Patients requiring urgent treatment to raise serum sodium levels to prevent or to treat serious neurologic deficits should not be treated with Samsca. Additionally, it has not been established that raising serum sodium levels with Samsca provides a symptomatic benefit to patients.

圣路易斯(MD Consult)——2009年5月21日，大冢制药有限公司(Otsuka Pharmaceutical Co)宣布，美国食品药品管理局(FDA)已批准Samsca(替伐普坦)治疗临床上严重的高容量性和等容量性低钠血症(即，血清钠水平<125 mEq/L，或有症状且通过限制输液进行了持续性校正的较不明显的低钠血症)。该药可能对患有心力衰竭、肝硬化或抗利尿激素分泌异常综合征(SIADH)等疾病的患者有益。

Samsca通过选择性阻断肾集合管中血管加压素与V2受体结合而发挥作用。通过抑制V2受体上血管加压素的作用，Samsca可增加自由水的排泄，但对钠和其他电解质的排泄无直接影响。

在2项双盲、安慰剂对照、多中心研究中，总共纳入了424例高容量性和等容量性低钠血症患者，应用Samsca或安慰剂对其进行治疗或处置。停止治疗后对这些患者又额外随访了7d。这两项研究的主要终点为血清钠水平<135 mEq/L的患者基线至研究第4d和基线至研究第30d的血清钠水平的曲线下面积日平均变化值。在这两项研究中，无论在哪一期，与安慰剂相比，应用Samsca治疗均导致血清钠水平在统计学上显著升高(P < 0.0001)。在研究的第4d和第30d，该药对血清钠水平低于130 mEq/L或125 mEq/L的患者仍有显著疗效。这种疗效在各种疾病病因学亚组(如充血性心力衰竭，肝硬化，SIADH或其他)中均可见。停止治疗后7d，Samsca治疗组患者的血清钠水平降至与安慰剂处置组患者大致相等的水平。

在前面提到的试验中，接受Samsca治疗的患者最常见的不良反应(发生率较接受安慰剂处置的患者高5%或以上)为口渴、嘴干、体虚、便秘、尿频或多尿，以及高血糖症。在这些研究中，Samsca治疗组患者因不良反应中断治疗者占10%，而安慰剂处置组为12%。

临床试验结果显示，Samsca治疗早在给药后8h即可显著升高血清钠的水平，此浓度改变可持续30d。在肌酐清除率为10至79 ml/min的患者和无肾功能损害的患者中，应用Samsca可获得相同的疗效。然而，在肌酐清除率<10 ml/min的患者及进行透析的患者中尚未对Samsca的应用进行评估。

鉴于Samsca治疗可能会对低钠血症产生快速的过校正，因此该药应仅用于对医院中的患者进行治疗，这样方能密切监测血清钠的水平。低钠血症的快速过校正可导致渗透性脱髓鞘综合征，产生构音障碍、缄默症、吞咽困难、昏睡、情感变化、痉挛性四肢瘫痪、惊厥、昏迷以及死亡。在患有中毒营养不良、酒精中毒或晚期肝病等疾病的疑似患者中，最好缓慢进行血清钠校正。

有些患者需要紧急治疗以提高血清钠的水平，进而预防或治疗严重的神经功能缺失，对这类患者禁止采用Samsca治疗。此外，应用Samsca提高血清钠水平是否有益于改善患者的症状，这尚未得到证实。

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