Savient Pharmaceuticals

Pharmacological Class:

PEGylated uric acid ­specific enzyme.

Active Ingredient(s):

Pegloticase 8mg/mL (as uricase protein) in phosphate buffered saline; for IV ­infusion after dilution.

Indication(s):

Chronic gout in adult patients ­refractory to conventional therapy.

Pharmacology:

Pegloticase is a recombinant, modified mammalian urate oxidase conjugated to a form of polyethylene glycol. Pegloticase catalyzes the oxidation of uric acid to allantoin, thereby lowering serum uric acid. It is indicated for use in patients who have failed to normalize serum uric acid and whose signs and symptoms are inadequately controlled with xanthine ­oxidase inhibitors or in those for whom these drugs are contraindicated.

Pegloticase should not be given to patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency because they are at an ­increased risk of hemolysis and methemoglobinemia. To better manage gout flares, patients should be started on therapy with an NSAID or colchicine at least one week before treatment with pegloticase, continuing for at least 6 months when feasible. It is not necessary to discontinue treatment with pegloticase in the event of a gout flare.

Clinical Trials:

Two double-blind, placebo-­controlled 6-month trials were conducted to ­assess the efficacy and safety of pegloticase (­given once every 2 weeks or once every 4 weeks) in treating adults with chronic, refractory gout. Patients were pretreated with an oral antihistamine, intravenous corticosteroid, and aceta­min­ophen, and they also received NSAIDs and/or colchicine beginning one week before treatment, unless contraindicated, to prevent gout flares. The primary endpoint in both ­studies was the proportion of patients who achieved plasma uric acid levels <6mg/dL for at least 80% of the time during months 3 and 6. Baseline criteria included serum uric acid ≥8mg/dL and at least 3 gout flares in the previous 18months or at least one gout tophus or gouty arthritis. A significantly greater proportion of patients treated biweekly with pegloticase achieved urate lowering to <6mg/dL than those given placebo. The benefit: risk profile was ­better with biweekly dosing.

Pegloticase effect on tophi was a secondary endpoint. The biweekly regimen was significantly better than placebo for the rate of tophus complete response (100% resolution of ≥1 ­target tophus with no new or progressive tophi).

Legal Classification:

Rx

Adults:

>18 years: Premedicate with antihistamines and corticosteroids. Give by IV infusion over at least 2 hours. 8mg once every 2 weeks. Slow rate, or stop and restart at lower rate, if ­infusion reaction occurs; observe at least 1hour post-infusion.

Children:

<18 years: not recommended.

Contraindication(s):

G6PD deficiency.

Warnings/Precautions:

Not for treating asymptomatic hyperuricemia. Screen patients at risk for G6PD deficiency (African or Mediterranean descent). Administer in healthcare setting by clinician prepared to manage infusion reactions and anaphylaxis. Monitor closely for anaphylaxis/ infusion reactions, esp. in patients receiving ­retreatment after a drug-free interval >4 weeks. CHF. Monitor serum uric acid levels before each infusion; consider discontinuing when ­levels >6mg/dL, particularly with 2 consecutive levels >6mg/dL (increased risk of anaphylaxis and infusion reactions). Pregnancy (Cat.C). Nursing mothers: not recommended.

Adverse Reaction(s):

Gout flares (prophylax with NSAIDs or colchicine), infusion reactions, GI upset, contusion, ecchymosis, nasopharyngitis, constipation, chest pain, anaphylaxis, CHF ­exacerbation, antibody formation.

How Supplied:

Single-use vial—1

研究证明:新型痛风药Krystexxa(Pegloticase)治疗难治性痛风有效

Pegloticase是一种新近批准的降尿酸药物，用于常规治疗无效或常规治疗无法耐受的成年痛风患者。

杜克大学医学中心的John S. Sundy博士和同事报告了两项研究pegloticase对难治性痛风患者临床疗效及耐受性的随机安慰剂对照试验结果，试验为期6个月。这两项试验(C0405和C0406)于2006年6月至2007年10月在在美国、加拿大和墨西哥的56家风湿病学研究机构开展，以罹患严重痛风且对别嘌呤醇不耐受或缺乏反应、血清尿酸浓度为8.0 mg/dl或更高的患者为研究对象。参加试验的患者共有225例，接受每两周一次的静脉输注，共12次：双周治疗组每次给予8 mg Pegloticase；月治疗组Pegloticase与安慰剂交替给药；安慰剂组每次给予安慰剂。主要测量结果为在3个月和6个月时血浆尿酸水平低于6.0 mg/dl。

汇集2项试验的数据发现，每两周治疗组的85例患者中36例达到主要终点(42％)，每月治疗组84例患者中有29例达到主要终点(35％)，安慰剂组的43例患者均未达到主要终点。在整个6个月的治疗期间，应答者的平均血浆UA显著低于6.0 mg/dl。研究人员还发现，与安慰剂相比，两个Pegloticase治疗组患者的身体机能和QOL生活质量显著改善。与安慰剂相比，双周治疗组患者报告疼痛显著减轻。

每个治疗组中均有超过90％的受试者发生一个或多个不良事件(AE)。双周治疗组(24％)和月治疗组(23％)的严重不良事件发生率为24％和23％，与安慰剂(12％)相比更加频繁。痛风发作是最常见的AE，在3个研究小组中约有80％的患者报告。

试验证明，相当大比例的对常规降尿酸盐治疗不耐受或缺乏反应的慢性痛风症患者显示持续性的尿酸下降和重大临床改善。每两周给予1次Pegloticase，在6个月内可显示出明显的改善疾病益处。