默沙东Noxafil缓释片获FDA批准

默沙东（Merck & Co）11月26日宣布，Noxafil（posaconazole，泊沙康唑，100 mg）缓释片获FDA批准。Noxafil缓释片是一种新的配方，在治疗第一天的负荷剂量（loading dose）为300mg（即3片100mg缓释片），一天2次；从治疗的第二天开始，维持剂量（maintenance dose）为300mg（即3片100mg缓释片），一天1次。

同时，默沙东还销售Noxafil（40mg/mL）口服混悬液，剂量为每天给药3次。

Noxafil缓释片和口服混悬液，适应症为用于因免疫功能严重低下而具有高风险的侵袭性曲霉菌和念珠菌感染的13岁及以上患者，如患有移植物抗宿主病（GVHD）的造血干细胞移植（HSCT）受者，或那些因化疗导致长期的中性粒细胞减少（低白细胞计数）的恶性血液病患者。

Noxafil缓释片的获批，是基于一项药代动力学研究。该项研究是一项非对照、多中心临床研究，在已发生或预期将发生显著中性粒细胞减少（neutropenia）的急性髓性系白血病（AML）或骨髓增生异常综合症（MDS）患者、以及已接受造血干细胞移植（HSCT）同时正接受免疫抑制治疗以预防移植物抗宿主病（GVHD）的患者中开展中，评价了Noxafil缓释片的药代动力学、安全性和耐受性。

英文原文：FDA Approves Merck’s NOXAFIL® (posaconazole) Delayed-Release Tablets

WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has approved NOXAFIL® (posaconazole) 100 mg delayed-release tablets. NOXAFIL delayed-release tablets are a new formulation with a loading dose of 300 mg (three 100 mg delayed-release tablets) twice daily on the first day, followed by a once-daily maintenance dose of 300 mg (three 100 mg delayed-release tablets) starting on the second day of therapy. Merck also markets NOXAFIL (40 mg/mL) oral suspension, which is dosed three times daily.

NOXAFIL delayed-release tablets and oral suspension are indicated for the prophylaxis of invasive Aspergillus and Candida infections in patients, 13 years of age and older, who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia (low white blood cell counts) from chemotherapy.

NOXAFIL should not be administered to persons allergic to posaconazole, any ingredients of NOXAFIL, or other azole antifungal medicines. The administration of NOXAFIL with sirolimus, pimozide, quinidine, atorvastatin, lovastatin, simvastatin and ergot alkaloids must be avoided. When administered with NOXAFIL, some drugs such as cyclosporine and tacrolimus required dosage adjustments and frequent monitoring of their levels in the blood as serious side effects of the kidney (nephrotoxicity) or brain (leukoencephalopathy) including deaths have been reported in patients with increased cyclosporine or tacrolimus blood levels. NOXAFIL should be administered with caution to patients who may develop an irregular heart rhythm as NOXAFIL has been shown to prolong the QT interval and cases of potentially fatal irregular heart rhythm (torsades de pointes) have been reported in patients taking NOXAFIL. (See Selected Safety Information below.)

“Prophylaxis against invasive Aspergillus and Candida infections plays a key role in the management of severely immunocompromised patients with hematologic malignancies or hematopoietic stem cell transplant recipients who are at high risk for these life-threatening fungal infections," said Daniel Couriel, M.D., professor of internal medicine and clinical program director, adult blood and marrow transplantation program, University of Michigan Comprehensive Cancer Center. “Posaconazole delayed-release tablets offer physicians a way to help protect these critically ill patients against invasive Aspergillus and Candida infections while they are in the hospital and once they return home.”

FDA approval of NOXAFIL (posaconazole) delayed-release tablets based on a pharmacokinetic study in patients

A non-comparative, multicenter study was performed to evaluate the pharmacokinetic properties, safety and tolerability of NOXAFIL delayed-release tablets in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who had developed or were anticipated to develop significant neutropenia, and in patients who had undergone HSCT and were receiving immunosuppressive therapy for prevention or treatment of GVHD. In the study, exposures of posaconazole within a pre-specified range were attained. The exposure levels achieved support a 300 mg (three 100 mg delayed-release tablets) once-daily dose of NOXAFIL delayed-release tablets, following a 300 mg (three 100 mg delayed-release tablets) twice-a-day loading dose on the first day of therapy. The most frequently reported adverse reactions (>25%) with NOXAFIL delayed-release tablets were diarrhea, fever and nausea. The type of adverse reactions reported for NOXAFIL delayed-release tablets were generally similar to that reported in trials of NOXAFIL oral suspension. (See Selected Safety Information below.)

The effect of food intake on the oral bioavailability of posaconazole following administration of NOXAFIL delayed-release tablets is not known. However, since the oral bioavailability of posaconazole is significantly increased when NOXAFIL oral suspension is administered with food or a nutritional supplement, or an acidic carbonated beverage (e.g., ginger ale) in patients who cannot eat a full meal, it is also recommended that NOXAFIL delayed-release tablets be taken with food. For patients who cannot eat a full meal, NOXAFIL delayed-release tablets should be used instead of NOXAFIL oral suspension for the prophylaxis indication. NOXAFIL delayed-release tablets provide higher plasma drug exposures than NOXAFIL oral suspension under fasted conditions.

NOXAFIL delayed-release tablets should be swallowed whole, and not be divided, crushed or chewed. Coadministration of drugs that can decrease the plasma concentrations of posaconazole should generally be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections. Patients who have severe diarrhea or vomiting should be monitored closely for breakthrough fungal infections.

Clinical experience with NOXAFIL (posaconazole) oral suspension for antifungal prophylaxis

Two clinical studies of prophylaxis against invasive fungal infections were conducted with NOXAFIL oral suspension. Both studies demonstrated substantially fewer breakthrough infections caused by Aspergillus species in patients receiving posaconazole prophylaxis when compared to patients receiving fluconazole or itraconazole.

In one randomized, open-label study that compared posaconazole oral suspension (200 mg three times a day) with fluconazole suspension (400 mg once daily) or itraconazole oral solution (200 mg twice daily) as prophylaxis against invasive fungal infections in neutropenic patients receiving cytotoxic chemotherapy for AML or MDS (n=602), clinical failure in patients while receiving antifungal prophylaxis and for seven days following the last dose of therapy was lower for posaconazole (27% [82/304]) compared to fluconazole or itraconazole (42% [126/298]), (95% CI for the difference posaconazole-comparator -22.9% to -7.8%). Clinical failure at 100 days post-randomization was 52% (158/304]) for posaconazole compared to 64% (191/298) for fluconazole or itraconazole. All-cause mortality was lower at 100 days for patients receiving posaconazole (14% [44/304]) vs. fluconazole or itraconazole (21% [64/298]).

In a randomized, double-blind study that compared posaconazole oral suspension (200 mg three times a day) with fluconazole capsules (400 mg once daily) as prophylaxis against invasive fungal infections in allogeneic HSCT recipients with GVHD (n=600), the clinical failure rate on therapy plus 7 days was 17% (50/301) for posaconazole and 18% (55/299) for fluconazole. Clinical failure through 16 weeks post-randomization was similar for posaconazole (33% [99/301]) and fluconazole (37% [110/299]), (95% CI for the difference posaconazole-comparator -11.5% to 3.7%). All-cause mortality was similar at 16 weeks for both treatment arms 19% ([58/301] vs. 20% [59/299]), respectively.

Clinical failure in these studies represented a composite endpoint of breakthrough invasive fungal infections, mortality and use of systemic antifungal therapy.

The most frequently reported adverse reactions (>30%) in these prophylaxis studies with NOXAFIL oral suspension were fever, diarrhea and nausea.

NOXAFIL delayed-release tablets and oral suspension are not to be used interchangeably due to the differences in the dosing of each formulation.