ST LOUIS (MD Consult) - On September 14, 2010, Savient Pharmaceuticals and the US Food and Drug Administration (FDA) announced the approval of Krystexxa (pegloticase), an intravenous (IV) treatment for chronic gout in adults whose conditions have been refractory to conventional therapy. Krystexxa is a pegylated uric-acid–specific enzyme that lowers uric acid levels by metabolizing the acid into a harmless chemical that is excreted in the urine.

Chronic gout that is refractory to conventional therapy occurs in patients whose serum uric acid levels have failed to normalize and whose signs and symptoms are inadequately controlled with xanthine oxidase inhibitors at the maximum medically appropriate dose—or for whom these drugs are contraindicated. Xanthine oxidase inhibitors that are often prescribed for the treatment of gout include Zyloprim (allopurinol) and Uloric (febuxostat).

The efficacy and safety of Krystexxa were studied in patients with chronic gout refractory to conventional therapy in 2 replicate, multicenter, randomized, double-blind, placebo-controlled clinical studies of 6 months' duration. Patients were randomly assigned to receive Krystexxa every 2 weeks or every 4 weeks or placebo in a 2:2:1 ratio.

Results of both clinical studies showed that a greater proportion of patients treated with Krystexxa every 2 weeks achieved urate lowering to <6 mg/dL than patients receiving placebo. During the first 6 months of treatment, 47% (P < 0.001) and 38% (P < 0.001) of patients in the Krystexxa arms in both studies achieved the primary efficacy end point, compared with 0% of patients in the placebo arm.

Clinical trial results also demonstrated that patients treated with Krystexxa experienced a reduction in deposits of uric acid crystals in joints and soft tissue.

The full prescribing information for Krystexxa contains a boxed warning regarding anaphylaxis and infusion reactions. In clinical trials, 1 of 4 patients experienced severe allergic reactions during Krystexxa infusions. A corticosteroid and an antihistamine should be administered to all patients before a Krystexxa infusion is initiated to minimize the risk of such a reaction.

Other adverse reactions that occurred during the clinical trials include gout flare, nausea, injection-site bruising, irritation of the nasal passages, constipation, chest pain, and vomiting.

Physicians are also being warned to use caution about administering Krystexxa to patients with congestive heart failure because the drug was not studied in this patient population.

Savient plans to conduct a post-approval observational safety study of 500 patients treated for 1 year to further evaluate the frequency and severity of infusion reactions, anaphylaxis, and immune complex-related adverse events, and to identify serious adverse events associated with Krystexxa therapy.

The recommended dose and regimen of Krystexxa is 8 mg given as an IV infusion every 2 weeks. Krystexxa should not be administered by IV push or bolus. The drug should only be administered in a health care setting and by health care providers prepared to manage anaphylaxis.

圣路易斯(MD Consult)——2010年9月14日，美国Savient制药公司(Savient Pharmaceuticals)和美国食品药品管理局(FDA)宣布，批准静脉注射用(IV)药Krystexxa (pegloticase)用于治疗对常规治疗无效的成人慢性痛风。Krystexxa是一种聚乙二醇尿酸特异性酶，通过使酸代谢为无害的化学物随尿排出而降低尿酸水平。

 

对常规治疗无效的慢性痛风患者包括：血清尿酸水平未能复常的患者，以及采用医学上最大适合剂量的黄嘌呤氧化酶抑制剂后症状和体征控制不充分或者不适宜使用这些药物的患者。常用于治疗痛风的黄嘌呤氧化酶抑制剂的处方药有Zyloprim (别嘌呤醇)和Uloric (非布索坦)。

 

两项为期6个月、重复性、多中心、随机、双盲、安慰剂对照临床试验研究了对常规治疗无效的慢性痛风患者应用Krystexxa的疗效和安全性。临床试验以2:2:1的比例将患者随机分配至每2周接受1次Krystexxa治疗组、每4周接受1次Krystexxa治疗组和安慰剂组。

 

两项临床试验结果均表明，与安慰剂组相比，在每2周接受1次Krystexxa治疗组中尿酸降至6 mg/dl以下的患者比例较大。在最初6个月的治疗期间，两项研究的Krystexxa治疗组中分别有47%(P < 0.001)和38%(P <0 .001)的患者达到了主要疗效终点，而对照组为0。

 

临床试验结果还证实，在接受Krystexxa治疗的患者中，沉积于关节和软组织中的尿酸结晶减少。

 

Krystexxa的完整的处方信息中包含一个关于过敏反应和输液反应的黑框警告。在临床试验中，有1/4的患者在注射Krystexxa期间发生了严重的过敏反应。对于所有患者，在开始注射Krystexxa之前均应给予皮质类固醇和抗组胺药，使过敏反应的风险降至最低。

 

在临床试验期间发生的其他不良反应有痛风加剧、恶心、注射部位瘀血、鼻腔刺激、便秘、胸痛和呕吐等。

 

FDA同时提醒内科医生，对于伴有充血性心力衰竭的患者要慎用Krystexxa，因为尚未在此类患者中对该药开展研究。

 

Krystexxa的推荐剂量和用药方案为8 mg，每2周静脉注射1次。Krystexxa不应通过静推或静脉泵给药。此药应仅在医疗保健机构由医护人员给药，并且在给药前应做好处理过敏反应的准备。

   

为了进一步评估输液反应、过敏反应和免疫复合物相关的不良事件的发生频率和严重程度，以及明确Krystexxa 治疗相关的严重不良事件，Savient公司计划进行一项获准后观察性安全性研究，此研究计划纳入500例接受1年Krystexxa治疗的患者。