|[March 14, 2014]
FDA Approves Merck's NOXAFIL® (posaconazole) Injection (18 mg/mL) for Intravenous Use
WHITEHOUSE STATION, N.J. --(Business Wire)--
Merck (NYSE: MRK), known as MSD outside the United States and Canada,
today announced that the U.S. Food and Drug Administration has approved
NOXAFIL® (posaconazole) injection (18 mg/ mL), a new
formulation of NOXAFIL for intravenous (IV) use. Merck's antifungal
agent is also marketed as NOXAFIL (100 mg) delayed-release tablets and
NOXAFIL (40 mg/mL) oral suspension. NOXAFIL injection, delayed-release
tablets and oral suspension are indicated for prophylaxis of invasive Aspergillus
and Candida infections in patients 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 injection is indicated in patients 18 years of age
and older. NOXAFIL delayed-release tablets and oral suspension are
indicated in patients 13 years of age and older. With this approval,
Merck now provides an IV formulation and two oral formulations of
NOXAFIL for prophylaxis against invasive Aspergillus and Candida
infections in high-risk patients.
NOXAFIL should not be administered to persons allergic to posaconazole
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 in 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 (posaconazole). (See
Selected Safety Information below.)
"Merck is pleased to add NOXAFIL injection to the NOXAFIL family of
products. The availability of a NOXAFIL formulation for intravenous
administration is particularly important for those patients who may
benefit from or require intravenous therapy, or who, for a variety of
reasons, might not be able to take an oral formulation. In addition,
patients have the possibility to start on NOXAFIL injection and
transition to oral NOXAFIL," said Dr. Nicholas Kartsonis, executive
director, Infectious Disease, Merck Research Laboratories.
NOXAFIL injection offers patients once-daily maintenance dosing
following a twice-daily loading dose on the first day of NOXAFIL
therapy. NOXAFIL injection is administered with a loading dose of 300 mg
(one 300 mg vial) twice a day on the first day of NOXAFIL therapy, then
300 mg (one 300 mg vial) once a day thereafter. Once combined with a
mixture of intravenous solution (150 mL of 5% dextrose in water or
sodium chloride 0.9%), NOXAFIL injection should be immediately
administered through an in-line filter. Administer NOXAFIL through a
central venous line by slow IV infusion over approximately 90 minutes.
If not used immediately, the solution can be stored up to 24 hours
refrigerated at 2-8 degrees C (36-46 degrees F). Coadministration of
drugs that can decrease the plasma concentration 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.
In clinical trials, the adverse reactions reported for NOXAFIL IV
injection were generally similar in type to that reported in trials of
NOXAFIL oral suspension. The most frequently reported adverse reactions
with an onset during the posaconazole intravenous phase of dosing 300 mg
once-daily therapy were diarrhea (32%), hypokalemia (22%), fever (21%)
and nausea (19%).
NOXAFIL injection is expected to be available at wholesalers in
Selected Safety Information
NOXAFIL is contraindicated in persons with known hypersensitivity to
posaconazole 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 (posaconazole) 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 nd 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 if clinical signs and symptoms consistent with liver disease
develop that may be attributable to NOXAFIL.
Due to the variability in exposure with NOXAFIL delayed-release tablets
and oral suspension, patients with severe renal impairment should be
monitored closely for breakthrough fungal infections. NOXAFIL
(posaconazole) injection should be avoided in patients with moderate or
severe renal impairment (estimated glomerular filtration rate [eGFR] <50
mL/min), unless an assessment of the benefit/risk to the patient
justifies the use of NOXAFIL injection. In patients with moderate or
severe renal impairment (eGFR <50 mL/min), receiving the NOXAFIL
injection, accumulation of the intravenous vehicle, Betadex Sulfobutyl
Ether Sodium (SBECD), is expected to occur. Serum creatinine levels
should be closely monitored in these patients, and, if increases occur,
consideration should be given to changing to oral NOXAFIL therapy.
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 these 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 (News - Alert) glucuronosyltransferase
and is a substrate of p-glycoprotein (P-gp) 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 (posaconazole) 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 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 injection in patients below the
age of 18 years old have not been established. NOXAFIL injection should
not be used in pediatric patients because of non-clinical safety
The safety and effectiveness of NOXAFIL delayed-release tablets and oral
suspension in pediatric patients below the age of 13 years old have not
No dose adjustment in NOXAFIL is needed in patients with mild to severe
hepatic insufficiency (Child-Pugh Class A, B, and C). Discontinuation of
NOXAFIL must be considered in patients who experience clinical signs and
symptoms consistent with liver disease that may be attributable to
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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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. If underlying
assumptions prove inaccurate or risks or uncertainties materialize,
actual results may differ materially from those set forth in the
Risks and uncertainties include but are not limited to, general industry
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Merck undertakes no obligation to publicly update any forward-looking
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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) IV
injection, 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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