默沙东（Merck & Co）2月28日宣布，Noxafil缓释片（posaconazole，泊沙康唑，100 mg）获得了欧洲药品管理局（EMA）人用医药产品委员会（CHMP）建议批准的积极意见。
在美国，Noxafil缓释片已于2013年11月获FDA批准，该药是一种新配方的posaconazole，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，该药每天给药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。
Friday, February 28, 2014 8:30 am EST
WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--Merck (NYSE:MRK), known as MSD outside the United States and Canada, announced today that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending approval of a new, investigational tablet formulation of NOXAFIL? (posaconazole).
The CHMP positive opinion will be reviewed by the European Commission, which if approved, grants a centralized marketing authorization with unified labeling that is valid in the 28 countries that are members of the European unio, as well as European Economic Area members Iceland, Liechtenstein and Norway.
NOXAFIL in the U.S.
In the U.S., NOXAFIL delayed-release tablets 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.
Selected Safety Information
NOXAFIL is contraindicated in persons with known hypersensitivity to posaconazole, any component of NOXAFIL, or other azole antifungal agents.
NOXAFIL (posaconazole) is contraindicated with sirolimus. Concomitant administration of NOXAFIL with sirolimus increases the sirolimus blood concentrations by approximately 9-fold and can result in sirolimus toxicity.
NOXAFIL is contraindicated with CYP3A4 substrates that prolong the QT interval. Concomitant administration of NOXAFIL with the CYP3A4 substrates, pimozide and quinidine may result in increased plasma concentrations of these drugs, leading to QT prolongation and cases of torsades de pointes.
NOXAFIL is contraindicated with HMG-CoA reductase inhibitors that are primarily me-tabolized through CYP3A4 (e.g., atorvastatin, lovastatin and simvastatin) as increased plasma concentration of these drugs can lead to rhabdomyolysis.
NOXAFIL is contraindicated with ergot alkaloids. NOXAFIL may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism.
Concomitant administration of NOXAFIL with cyclosporine or tacrolimus increases the whole blood trough concentrations of these calcineurin inhibitors. Nephrotoxicity and leukoencephalopathy (including deaths) have been reported in clinical efficacy studies in patients with elevated cyclosporine or tacrolimus concentrations. Frequent monitoring of cyclosporine or tacrolimus whole blood trough concentrations should be performed during and at discontinuation of NOXAFIL treatment and the tacrolimus or cyclosporine dose adjusted accordingly.
Some azoles, including NOXAFIL, have been associated with prolongation of the QT interval on the electrocardiogram. In addition, cases of torsades de pointes have been reported in patients taking NOXAFIL. NOXAFIL should be administered with caution to patients with potentially proarrhythmic conditions. Do not administer with drugs that are known to prolong the QT interval and are me-tabolized through CYP3A4. Rigorous attempts to correct potassium, magnesium and calcium should be made in these patients before starting NOXAFIL.
Hepatic reactions (e.g., mild to moderate elevations in ALT, AST, alkaline phosphatase, total bilirubin and/or clinical hepatitis) have been reported in clinical trials. The elevations in liver function tests were generally reversible on discontinuation of therapy, and in some instances these tests normalized without drug interruption. Cases of more severe hepatic reactions including cholestasis or hepatic failure including deaths have been reported in patients with serious underlying medical conditions (e.g., hematologic malignancy) during treatment with NOXAFIL. Liver function tests should be eva1uated at the start of and during the course of therapy. Patients who develop abnormal liver function tests during posaconazole therapy should be monitored for the development of more severe hepatic injury. Consider discontinuation of NOXAFIL (posaconazole) if clinical signs and symptoms consistent with liver disease develop that may be attributable to NOXAFIL.
Concomitant administration of NOXAFIL with midazolam increases the midazolam plasma concentrations by approximately 5-fold which could potentiate and prolong hypnotic and sedative effects. Concomitant use of NOXAFIL and other benzodiazepines me-tabolized by CYP3A4 (e.g., alprazolam, triazolam) could result in increased plasma concentrations of theses benzodiazepines. Patients must be monitored closely for adverse effects associated with high plasma concentrations of midazolam and other benzodiazepines me-tabolized by CYP3A4. In addition, benzodiazepine receptor antagonists must be available to reverse these effects.
The most frequently reported adverse reactions (>25%) with posaconazole delayed-release tablets (300 mg) were diarrhea, fever, and nausea.
Posaconazole is primarily me-tabolized via UDP glucuronidation and is a substrate of p-glycoprotein efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. 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. Posaconazole is also a strong inhibitor of CYP3A4. Therefore, plasma concentrations of drugs predominantly me-tabolized by CYP3A4 may be increased by posaconazole.
Coadministration of NOXAFIL with rifabutin, phenytoin and efavirenz should be avoided unless the benefit outweighs the risk. Monitoring for toxicity and/or adverse events is recommended when tacrolimus, cyclosporine, benzodiazepines, ritonavir, atazanavir, vinca alkaloids and calcium channel blockers and rifabutin are coadministered with NOXAFIL. Dosage adjustments should also be considered when tacrolimus, cyclosporine, vinca alkaloids, calcium channel blockers and phenytoin are administered with NOXAFIL. Monitor plasma concentrations when coadministering digoxin, phenytoin, tacrolimus and cyclosporine with NOXAFIL. Although no dosage adjustment of glipizide is required, it is recommended to monitor glucose concentrations when coadministering glipizide with NOXAFIL. Monitor for breakthrough fungal infections when coadministering fosamprenavir, rifabutin and phenytoin with NOXAFIL.
No clinically relevant effects on the pharmacokinetics of posaconazole delayed-release tablets were observed when concomitantly administered with drugs affecting gastric pH (i.e., antacids, H2-receptor antagonists, proton pump inhibitors). Concomitant administration of metoclopramide with posaconazole delayed-release tablets did not affect the pharmacokinetics of posaconazole.
The safety and effectiveness of NOXAFIL in patients below the age of 13 years old have not been established.
Patients weighing greater than 120 kg may have lower posaconazole plasma drug exposures. It is therefore, suggested to closely monitor for breakthrough fungal infections.
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