CHMP Issues Positive Opinion for Tablet Formulation of Merck’s NOXAFIL® (posaconazole)

  CHMP Issues Positive Opinion for Tablet Formulation of Merck’s NOXAFIL®
  (posaconazole)

Business Wire

WHITEHOUSE STATION, N.J. -- February 28, 2014

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) 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
chemotherapy.

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 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.

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 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, H[2]-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

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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
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internationally; global trends toward health care cost containment;
technological advances, new products and patents attained by competitors;
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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) 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.

Contact:

Merck
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Pam Eisele, 267-305-3558
or
Robert Consalvo, 908-423-6595
or
Investor:
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or
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