Merck's New Drug Application for an Investigational Intravenous (IV) Formulation of NOXAFIL® (posaconazole) Receives FDA Priority Review

PRESS RELEASE

WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced that its New Drug Application for an investigational intravenous (IV) solution formulation of the company's antifungal agent, NOXAFIL® (posaconazole), has been accepted for priority review by the U.S. Food and Drug Administration (FDA).

Priority review designation is assigned to applications for drugs that, if approved, would provide significant improvements in the safety or effectiveness of the treatment, diagnosis or prevention of serious conditions. The company also has filed a marketing authorization application for NOXAFIL IV solution with the European Medicines Agency (EMA) and plans to seek regulatory approval for the IV formulation in other countries around the world.

Merck currently markets NOXAFIL Oral Suspension in the U.S. for 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 patients who have received hematopoietic stem cell transplants and have graft-versus-host disease, or patients with cancers of the blood who are experiencing prolonged low white blood cell counts (neutropenia) as a result of chemotherapy.

In April, Merck announced that it had filed new drug applications for an investigational, tablet formulation of NOXAFIL with both the FDA and EMA. These applications are currently under review.

Selected safety information about NOXAFIL Oral Suspension

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 QTc prolongation and rare occurrences of torsades de pointes.

NOXAFIL 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 isolated deaths) have been reported in clinical efficacy studies in patients with elevated cyclosporine 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, rare cases of torsades de pointes have been reported in patients taking NOXAFIL. NOXAFIL should be administered with caution to patients with potentially proarrhythmic conditions. 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 and rarely required drug discontinuation. Isolated 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. Discontinuation of NOXAFIL must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to NOXAFIL.

Concomitant administration of NOXAFIL (posaconazole) with midazolam increases the midazolam plasma concentrations by approximately 5-fold. Increased plasma midazolam concentrations could potentiate and prolong hypnotic and sedative effects. Patients must be monitored closely for adverse effects associated with high plasma concentrations of midazolam and benzodiazepine receptor antagonists must be available to reverse these effects.

NOXAFIL has been shown to interact with several medications, including drugs that suppress the immune system, and these reactions may be serious. NOXAFIL is also a strong inhibitor of CYP3A4. Therefore, plasma concentrations of drugs predominantly metabolized by CYP3A4 may be increased by NOXAFIL. The product label should be consulted when other drugs are prescribed with NOXAFIL.

Co-administration of NOXAFIL with rifabutin, phenytoin, efavirenz, cimetidine and esomeprazole should be avoided unless the benefit outweighs the risk. Monitoring for toxicity and adverse events is recommended when tacrolimus, cyclosporine, ritonavir, atazanavir, vinca alkaloids, and calcium channel blockers and rifabutin are co-administered 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 co-administering digoxin, phenytoin, tacrolimus and cyclosporine with NOXAFIL. Monitor for breakthrough fungal infections when co-administering metoclopramide, fosamprenavir, rifabutin, phenytoin, cimetidine and esomeprazole with NOXAFIL.

The safety and effectiveness of NOXAFIL in patients below the age of 13 years old have not been established.

The most common adverse reactions (>30%) in the prophylaxis clinical studies were fever, diarrhea, and nausea.