Merck’s New Drug Application for an Investigational Intravenous (IV) Formulation of NOXAFIL® (posaconazole) Receives FDA Priority Review
November 18, 2013 8:30 am ET
Marketing Authorization Application also Filed with the European Medicines Agency
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
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
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
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
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.
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meaning of the safe harbor provisions of the United States Private
Securities Litigation Reform Act of 1995. These statements are based
upon the current beliefs and expectations of Merck’s management and are
subject to significant risks and uncertainties. There can be no
guarantees with respect to pipeline products that the products will
receive the necessary regulatory approvals or that they will prove to be
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Merck undertakes no obligation to publicly update any forward-looking
statement, whether as a result of new information, future events or
otherwise. Additional factors that could cause results to differ
materially from those described in the forward-looking statements can be
found in Merck’s 2012 Annual Report on Form 10-K and the company’s other
filings with the Securities and Exchange Commission (SEC) available at
the SEC’s Internet site (www.sec.gov).
NOXAFIL® is a registered trademark of Merck
Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse
Station, N.J., USA.
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Please see Prescribing Information for NOXAFIL (posaconazole) at http://www.spfiles.com/pinoxafil.pdf
and Patient Information for NOXAFIL at http://www.spfiles.com/ppinoxafil.pdf.
Pam Eisele, 908-423-5042
Robert Consalvo, 908-423-6595
Carol Ferguson, 908-423-4465
Justin Holko, 908-423-5088