|[February 28, 2014]
CHMP Issues Positive Opinion for Tablet Formulation of Merck's NOXAFIL® (posaconazole)
WHITEHOUSE STATION, N.J. --(Business Wire)--
Merck (NYSE:MRK), known as MSD outside the United States and Canada,
announced today that the Committee for Medicinal Products for Human Use
(CHMP) of the European Medicines Agency (EMA (News - Alert)) has adopted a positive
opinion recommending approval of a new, investigational tablet
formulation of NOXAFIL® (posaconazole).
The CHMP positive opinion will be reviewed by the European Commission,
which if approved, grants a centralized marketing authorization with
unified labeling that is valid in the 28 countries that are members of
the European Union, as well as European Economic Area members Iceland,
Liechtenstein and Norway.
NOXAFIL in the U.S.
In the U.S., NOXAFIL delayed-release tablets 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
Selected Safety Information
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 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
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 terapy 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
The most frequently reported adverse reactions (>25%) with posaconazole
delayed-release tablets (300 mg) were diarrhea, fever, and nausea.
Posaconazole is primarily metabolized via UDP (News - Alert) 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.
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.
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more information, visit www.merck.com
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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 2013 Annual Report on Form 10-K and the company's other
filings with the Securities and Exchange Commission (SEC (News - Alert)) 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 (News - Alert) & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse
Station, N.J., USA.
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