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November 26, 2013 9:00 am ET

Merck (NYSE:MRK), known as MSD outside the United States and Canada,
today announced that the U.S. Food and Drug Administration (FDA) has
approved NOXAFIL^® (posaconazole) 100 mg delayed-release
tablets. NOXAFIL delayed-release tablets are a new formulation with a
loading dose of 300 mg (three 100 mg delayed-release tablets) twice
daily on the first day, followed by a once-daily maintenance dose of 300
mg (three 100 mg delayed-release tablets) starting on the second day of
therapy. Merck also markets NOXAFIL (40 mg/mL) oral suspension, which is
dosed three times daily.

NOXAFIL delayed-release tablets and oral suspension are indicated for
the 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 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 should not be administered to persons allergic to posaconazole,
any ingredients of NOXAFIL, 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 of 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. (See Selected Safety Information below.)

“Prophylaxis against invasive Aspergillus and Candida infections
plays a key role in the management of severely immunocompromised
patients with hematologic malignancies or hematopoietic stem cell
transplant recipients who are at high risk for these life-threatening
fungal infections,” said Daniel Couriel, M.D., professor of internal
medicine and clinical program director, adult blood and marrow
transplantation program, University of Michigan Comprehensive Cancer
Center. “Posaconazole delayed-release tablets offer physicians a way to
help protect these critically ill patients against invasive Aspergillus
and Candida infections while they are in the hospital and
once they return home.”

FDA approval of NOXAFIL (posaconazole) delayed-release tablets based
on a pharmacokinetic study in patients

A non-comparative, multicenter study was performed to evaluate the
pharmacokinetic properties, safety and tolerability of NOXAFIL
delayed-release tablets in patients with acute myeloid leukemia (AML) or
myelodysplastic syndrome (MDS) who had developed or were anticipated to
develop significant neutropenia, and in patients who had undergone HSCT
and were receiving immunosuppressive therapy for prevention or treatment
of GVHD. In the study, exposures of posaconazole within a pre-specified
range were attained. The exposure levels achieved support a 300 mg
(three 100 mg delayed-release tablets) once-daily dose of NOXAFIL
delayed-release tablets, following a 300 mg (three 100 mg
delayed-release tablets) twice-a-day loading dose on the first day of
therapy. The most frequently reported adverse reactions (>25%) with
NOXAFIL delayed-release tablets were diarrhea, fever and nausea. The
type of adverse reactions reported for NOXAFIL delayed-release tablets
were generally similar to that reported in trials of NOXAFIL oral
suspension. (See Selected Safety Information below.)

The effect of food intake on the oral bioavailability of posaconazole
following administration of NOXAFIL delayed-release tablets is not
known. However, since the oral bioavailability of posaconazole is
significantly increased when NOXAFIL oral suspension is administered
with food or a nutritional supplement, or an acidic carbonated beverage
(e.g., ginger ale) in patients who cannot eat a full meal, it is also
recommended that NOXAFIL delayed-release tablets be taken with food. For
patients who cannot eat a full meal, NOXAFIL delayed-release tablets
should be used instead of NOXAFIL oral suspension for the prophylaxis
indication. NOXAFIL delayed-release tablets provide higher plasma drug
exposures than NOXAFIL oral suspension under fasted conditions.

NOXAFIL delayed-release tablets should be swallowed whole, and not be
divided, crushed or chewed. Coadministration of drugs that can decrease
the plasma concentrations 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.
Patients who have severe diarrhea or vomiting should be monitored
closely for breakthrough fungal infections.

Clinical experience with NOXAFIL (posaconazole) oral suspension for
antifungal prophylaxis

Two clinical studies of prophylaxis against invasive fungal infections
were conducted with NOXAFIL oral suspension. Both studies demonstrated
substantially fewer breakthrough infections caused by Aspergillus
species in patients receiving posaconazole prophylaxis when compared to
patients receiving fluconazole or itraconazole.

In one randomized, open-label study that compared posaconazole oral
suspension (200 mg three times a day) with fluconazole suspension (400
mg once daily) or itraconazole oral solution (200 mg twice daily) as
prophylaxis against invasive fungal infections in neutropenic patients
receiving cytotoxic chemotherapy for AML or MDS (n=602), clinical
failure in patients while receiving antifungal prophylaxis and for seven
days following the last dose of therapy was lower for posaconazole (27%
[82/304]) compared to fluconazole or itraconazole (42% [126/298]), (95%
CI for the difference posaconazole-comparator -22.9% to -7.8%). Clinical
failure at 100 days post-randomization was 52% (158/304]) for
posaconazole compared to 64% (191/298) for fluconazole or itraconazole.
All-cause mortality was lower at 100 days for patients receiving
posaconazole (14% [44/304]) vs. fluconazole or itraconazole (21%
[64/298]).

In a randomized, double-blind study that compared posaconazole oral
suspension (200 mg three times a day) with fluconazole capsules (400 mg
once daily) as prophylaxis against invasive fungal infections in
allogeneic HSCT recipients with GVHD (n=600), the clinical failure rate
on therapy plus 7 days was 17% (50/301) for posaconazole and 18%
(55/299) for fluconazole. Clinical failure through 16 weeks
post-randomization was similar for posaconazole (33% [99/301]) and
fluconazole (37% [110/299]), (95% CI for the difference
posaconazole-comparator -11.5% to 3.7%). All-cause mortality was similar
at 16 weeks for both treatment arms 19% ([58/301] vs. 20% [59/299]),
respectively.

Clinical failure in these studies represented a composite endpoint of
breakthrough invasive fungal infections, mortality and use of systemic
antifungal therapy.

The most frequently reported adverse reactions (>30%) in these
prophylaxis studies with NOXAFIL oral suspension were fever, diarrhea
and nausea.

NOXAFIL delayed-release tablets and oral suspension are not to be used
interchangeably due to the differences in the dosing of each formulation.

Selected Safety Information

NOXAFIL (posaconazole) 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 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 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 (posaconazole) 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 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 theses 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 glucuronidation and is a
substrate of p-glycoprotein efflux. Therefore, inhibitors or inducers of
these clearance pathways may affect posaconazole plasma concentrations.
Coadministration of drugs that can decrease the plasma concentrations 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. Posaconazole is also a
strong inhibitor of CYP3A4. Therefore, plasma concentrations of drugs
predominantly metabolized by CYP3A4 may be increased by posaconazole.

Coadministration of NOXAFIL with rifabutin, phenytoin and efavirenz
should be avoided unless the benefit outweighs the risk. Monitoring for
toxicity and/or adverse events is recommended when tacrolimus,
cyclosporine, benzodiazepines, ritonavir, atazanavir, vinca alkaloids
and calcium channel blockers and rifabutin are coadministered 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
coadministering digoxin, phenytoin, tacrolimus and cyclosporine with
NOXAFIL. Although no dosage adjustment of glipizide is required, it is
recommended to monitor glucose concentrations when coadministering
glipizide with NOXAFIL. Monitor for breakthrough fungal infections when
coadministering fosamprenavir, rifabutin and phenytoin with NOXAFIL.

Coadministration of NOXAFIL oral suspension with cimetidine (an H₂-receptor
antagonist) and esomeprazole (a proton pump inhibitor) results in lower
posaconazole plasma concentrations and should be avoided unless the
benefit outweighs the risk. No clinically relevant effects were observed
when posaconazole oral suspension is concomitantly used with antacids
and H₂-receptor antagonists other than cimetidine.

Coadministration of NOXAFIL oral suspension with metoclopramide
decreases posaconazole plasma concentrations; however loperamide does
not affect posaconazole plasma concentrations. Monitor for
breakthrough fungal infections when coadministering cimetidine,
esomeprazole and metoclopramide with NOXAFIL (posaconazole) oral
suspension.

No clinically relevant effects on the pharmacokinetics of posaconazole
delayed-release tablets were observed when concomitantly administered
with drugs affecting gastric pH (i.e., antacids, H₂-receptor
antagonists, proton pump inhibitors). Concomitant administration of
metoclopramide with posaconazole delayed-release tablets did not affect
the pharmacokinetics of posaconazole.

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

Patients weighing greater than 120 kg may have lower posaconazole plasma
drug exposures. It is therefore, suggested to closely monitor for
breakthrough fungal infections.

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
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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
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 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)
delayed-release tablets and oral suspension at http://www.spfiles.com/pinoxafil.pdf
and Patient Information for NOXAFIL at http://www.spfiles.com/ppinoxafil.pdf.

NOXAFIL^® is a registered trademark of Merck
Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse
Station, N.J., USA.

Merck
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