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

Wed Apr 10, 2013 8:30am EDT

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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, 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 Suspension

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 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
(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 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. 

About Merck

Today's Merck is a global healthcare leader working to help the world be well.
Merck is known as MSD outside of the United States and Canada. Through our
prescription medicines, vaccines, biologic therapies, and consumer care and
animal health products, we work with customers and operate in more than 140
countries to deliver innovative health solutions. We also demonstrate our
commitment to increasing access to healthcare through far-reaching policies,
programs and partnerships. For more information, visit www.merck.com and connect
with us on Twitter, Facebook and YouTube. 

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
conditions and competition; general economic factors, including interest 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 (www.sec.gov). 

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.

Merck
Media:
Pam Eisele, (908) 423-5042
Robert Consalvo, (908) 423-6595
or
Investor:
Carol Ferguson, (908) 423-4465
Justin Holko, (908) 423-5088 



Copyright Business Wire 2013

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