Merck Announces FDA Acceptance of New Drug Application for an Investigational Tablet Formulation of the Antifungal NOXAFIL® (posaconazole)


April 10, 2013 7:30 am ET

Merck (NYSE: MRK), known as MSD outside the United States and Canada,
today announced that its New Drug Application for an investigational,
tablet formulation of the company’s antifungal agent, NOXAFIL®
(posaconazole), has been accepted for review by the U.S. Food and Drug
Administration (FDA).

Merck currently markets NOXAFIL Oral Suspension 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.

“Invasive fungal infections are a significant cause of illness and death
among severely immunocompromised patients,” said Robin Isaacs, M.D.,
vice president, infectious disease clinical research, Merck Research
Laboratories. “This filing for a tablet formulation of NOXAFIL is an
example of Merck’s ongoing commitment to developing new therapy options
for patients in the hospital setting.”

Merck is seeking FDA approval of NOXAFIL tablets for once-daily
administration (following a twice-a-day loading dose on the first day of
therapy). The company has filed a marketing authorization application
for NOXAFIL tablets with the European Medicines Agency (EMA) and plans
to seek regulatory approval for the tablet formulation in other
countries around the world.

Selected safety information about NOXAFIL (posaconazole) Oral

NOXAFIL is contraindicated in persons with known hypersensitivity to
posaconazole, any component of NOXAFIL, 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 the 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
(posaconazole). 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 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

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.

About Merck

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Forward-Looking Statement

This news release includes “forward-looking statements” within the
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
commercially successful. If underlying assumptions prove inaccurate or
risks or uncertainties materialize, actual results may differ materially
from those set forth in the forward-looking statements.

Risks and uncertainties include but are not limited to, general industry
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rate and currency exchange rate fluctuations; the impact of
pharmaceutical industry regulation and health care legislation in the
United States and internationally; global trends toward health care cost
containment; technological advances, new products and patents attained
by competitors; challenges inherent in new product development,
including obtaining regulatory approval; Merck’s ability to accurately
predict future market conditions; manufacturing difficulties or delays;
financial instability of international economies and sovereign risk;
dependence on the effectiveness of Merck’s patents and other protections
for innovative products; and the exposure to litigation, including
patent litigation, and/or regulatory actions.

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 (

Please see Prescribing Information for NOXAFIL (posaconazole) at
and Patient Information for NOXAFIL at

Pam Eisele, (908) 423-5042
Robert Consalvo, (908) 423-6595
Carol Ferguson, (908) 423-4465
Justin Holko, (908) 423-5088

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