默沙东Noxafil静脉注射剂获FDA批准

关键词:默沙东,Noxafil,泊沙康唑,posaconazole

2014年3月15日讯 /生物谷BIOON/ --默沙东(Merck & Co)3月14日宣布,Noxafil(posaconazole,泊沙康唑)静脉注射剂(intravenous,IV,18mg/ml)获FDA批准,这是一种新配方Noxafil。FDA于2013年11月授予Noxafil IV新药申请(NDA)优先审查资格。此外,Noxafil(posaconazole,100 mg)缓释片于2013年11月获FDA批准,同时默沙东还销售Noxafil(40mg/mL)口服混悬液。

Noxafil注射液、缓释片及口服混悬液,均适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注射液适用于18岁及以上患者,Noxafil缓释片和口服混悬液适用于13岁及以上患者。这些药物均用于高危患者预防侵袭性曲霉菌和念珠菌感染。

默沙东计划在4月中旬将Noxafil静脉注射剂推向市场。(生物谷Bioon.com)

英文原文:FDA Approves Merck’s NOXAFIL® (posaconazole) Injection (18 mg/mL) for Intravenous Use

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 has approved NOXAFIL® (posaconazole) injection (18 mg/ mL), a new formulation of NOXAFIL for intravenous (IV) use. Merck’s antifungal agent is also marketed as NOXAFIL (100 mg) delayed-release tablets and NOXAFIL (40 mg/mL) oral suspension. NOXAFIL injection, delayed-release tablets and oral suspension are indicated for prophylaxis of invasive Aspergillus and Candida infections in patients 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 injection is indicated in patients 18 years of age and older. NOXAFIL delayed-release tablets and oral suspension are indicated in patients 13 years of age and older. With this approval, Merck now provides an IV formulation and two oral formulations of NOXAFIL for prophylaxis against invasive Aspergillus and Candida infections in high-risk patients.

NOXAFIL should not be administered to persons allergic to posaconazole 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 in 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 (posaconazole). (See Selected Safety Information below.)

“Merck is pleased to add NOXAFIL injection to the NOXAFIL family of products. The availability of a NOXAFIL formulation for intravenous administration is particularly important for those patients who may benefit from or require intravenous therapy, or who, for a variety of reasons, might not be able to take an oral formulation. In addition, patients have the possibility to start on NOXAFIL injection and transition to oral NOXAFIL,” said Dr. Nicholas Kartsonis, executive director, Infectious Disease, Merck Research Laboratories.

NOXAFIL injection offers patients once-daily maintenance dosing following a twice-daily loading dose on the first day of NOXAFIL therapy. NOXAFIL injection is administered with a loading dose of 300 mg (one 300 mg vial) twice a day on the first day of NOXAFIL therapy, then 300 mg (one 300 mg vial) once a day thereafter. Once combined with a mixture of intravenous solution (150 mL of 5% dextrose in water or sodium chloride 0.9%), NOXAFIL injection should be immediately administered through an in-line filter. Administer NOXAFIL through a central venous line by slow IV infusion over approximately 90 minutes. If not used immediately, the solution can be stored up to 24 hours refrigerated at 2-8 degrees C (36-46 degrees F). Coadministration of drugs that can decrease the plasma concentration 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.

In clinical trials, the adverse reactions reported for NOXAFIL IV injection were generally similar in type to that reported in trials of NOXAFIL oral suspension. The most frequently reported adverse reactions with an onset during the posaconazole intravenous phase of dosing 300 mg once-daily therapy were diarrhea (32%), hypokalemia (22%), fever (21%) and nausea (19%).

NOXAFIL injection is expected to be available at wholesalers in mid-April.

Selected Safety Information

NOXAFIL is contraindicated in persons with known hypersensitivity to posaconazole or other azole antifungal agents.

NOXAFIL 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 (posaconazole) is contraindicated with HMG-CoA reductase inhibitors that are primarily metabolized 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 metabolized 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 evaluated 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 if clinical signs and symptoms consistent with liver disease develop that may be attributable to NOXAFIL.

Due to the variability in exposure with NOXAFIL delayed-release tablets and oral suspension, patients with severe renal impairment should be monitored closely for breakthrough fungal infections. NOXAFIL (posaconazole) injection should be avoided in patients with moderate or severe renal impairment (estimated glomerular filtration rate [eGFR] <50 mL/min), unless an assessment of the benefit/risk to the patient justifies the use of NOXAFIL injection. In patients with moderate or severe renal impairment (eGFR <50 mL/min), receiving the NOXAFIL injection, accumulation of the intravenous vehicle, Betadex Sulfobutyl Ether Sodium (SBECD), is expected to occur. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral NOXAFIL therapy.

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 metabolized by CYP3A4 (e.g., alprazolam, triazolam) could result in increased plasma concentrations of these benzodiazepines. Patients must be monitored closely for adverse effects associated with high plasma concentrations of midazolam and other benzodiazepines metabolized by CYP3A4. In addition, benzodiazepine receptor antagonists must be available to reverse these effects.

Posaconazole is primarily metabolized via UDP glucuronosyltransferase and is a substrate of p-glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways m

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