FDA Approves Merck’s NOXAFIL® (posaconazole) Delayed-Release Tablets

  FDA Approves Merck’s NOXAFIL® (posaconazole) Delayed-Release Tablets

Business Wire

WHITEHOUSE STATION, N.J. -- November 26, 2013

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 H[2]-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
H[2]-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, 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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Additional factors that could cause results to differ materially from those
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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.

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