Merck Highlights Ongoing Commitment to Developing Medicines Targeting Infectious Disease at 52nd Annual ICAAC


September 12, 2012 7:08 am ET

Merck (NYSE: MRK), known outside the United States and Canada as MSD,
today reaffirmed its longstanding commitment to discovering and
developing novel medicines in the global fight against infectious
disease, and highlighted scientific data presented by researchers at the
52nd Annual Interscience Conference on Antimicrobial Agents and
Chemotherapy (ICAAC) being held in San Francisco.

Building on its rich heritage, Merck scientists and their collaborators
will present results from early-phase studies of novel investigational
anti-infective drug candidates and new investigational formulations of a
currently marketed product. Researchers will also present the latest
findings from the Merck-sponsored Study for Monitoring Antimicrobial
Resistance Trends (SMART), which has been tracking trends in antibiotic
susceptibility of bacterial isolates collected from patients in
different regions of the world since 2002.

“Infectious disease remains one of the most urgent global public health
challenges we face, and growing resistance to some current therapies
underscores the critical need for continued innovation in developing new
medicines,” said Robin Isaacs, M.D., vice president, infectious disease
clinical research, Merck Research Laboratories. “At the same time, we
must also look for ways to extend the utility of the therapies we have

At ICAAC, pharmacokinetic and safety data will be presented for two new
investigational formulations of Merck’s antifungal agent posaconazole: a
once-daily solid oral tablet formulation and a once-daily intravenous
(IV) formulation. Phase III studies with these new formulations are
ongoing. NOXAFIL® (posaconazole) Oral Suspension is indicated for
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 recipients with
graft-versus-host disease or those with hematologic malignancies with
prolonged neutropenia from chemotherapy. NOXAFIL also is indicated for
the treatment of oropharyngeal candidiasis, including oropharyngeal
candidiasis refractory to itraconazole and/or fluconazole.

In addition, researchers will present data for MK-7655, an
investigational beta-lactamase inhibitor currently in Phase II
development in combination with a marketed antibiotic. This combination
has shown activity against bacterial isolates with class A and class C
beta-lactamase-producing capabilities; such isolates, which are
routinely resistant to many different classes of antibiotics, are
increasing in prevalence worldwide.

Researchers will also present data from the SMART (Study for Monitoring
Antimicrobial Resistance Trends) program. SMART was initiated by Merck
in 2002 to monitor the in vitro susceptibility of clinical
isolates to 12 commonly used antibiotics in different regions of the
world to monitor changing trends in antibiotic susceptibility. SMART
currently monitors antibiotic activity against gram-negative bacteria
isolated from two common types of infection: intra-abdominal and urinary
tract infections. Isolates have been collected from patients with
complicated intra-abdominal infections since 2002 and from patients with
complicated urinary tract infections since 2010. Among the new findings
presented at ICAAC, researchers have found that there has been an
increase in the percentage of common bacteria that produce enzymes
called extended-spectrum beta-lactamases, or ESBLs. ESBL-producing
bacteria are often less susceptible to the activity of many of the
currently available antibiotics.

Key data presentations at ICAAC 2012


A-1934 Phase 1B Study of the Pharmacokinetics and Safety of
Posaconazole (POS) Solid Oral Tablet in Patients at Risk for Invasive
Fungal Infection (IFI); Duarte, RF et al.; poster session Halls A-C;
Wednesday, Sept. 12, 2012, 9:15 AM – 11:15 AM

A-1935 Effect of Concomitant Medications Affecting Gastric pH and
Motility on Posaconazole (POS) Tablet Pharmacokinetics (PK); Kraft, WK
et al.; poster session Halls A-C; Wednesday, Sept. 12, 2012, 9:15 AM –
11:15 AM

A-1946a Phase 1B Study of the Pharmacokinetics (PK) and Safety of
Posaconazole (POS) IV in Patients (Pts) at Risk for Invasive Fungal
Infection (IFI); Maertens, J et al.; poster session Halls A-C;
Wednesday, Sept. 12, 2012, 9:15 AM – 11:15 AM


A-008 MK-7655, A Novel β-lactamase Inhibitor (bLI), Elicits a
Prolonged Post-Inhibitor Effect in P. Aeruginosa; Young, K et
al.; poster session Halls A-C; Sunday, Sept. 9, 11:30 AM – 1:30 PM

A-009 A Phase I Study Evaluating the Single-Dose Safety,
Tolerability and Pharmacokinetics of an Intravenous Beta-Lactamase
Inhibitor in Healthy Elderly Male, Elderly Female and Young Female
Volunteers; Jumes, P et al.; poster session Halls A-C; Sunday, Sept. 9,
11:30 AM – 1:30 PM

A-010 Pharmacokinetics of MK-7655, a Novel Beta-lactamase
Inhibitor (BLI), in Combination with Imipenem/Cilastatin (IPM/CIL) in
Subjects with Impaired Renal Function; Rizk, ML et al.; poster session
Halls A-C; Sunday, Sept. 9, 11:30 AM – 1:30 PM

D-767 Broth Microdilution Quality Control Ranges for Testing the
Imipenem/MK-7655 Combination (IMK) Against Key Organism Groups; Deane, J
et al.; poster session Halls A-C; Monday, Sept. 10, 2012, 11:15 AM –
1:15 PM

E-192 Activity of MK-7655 with Imipenem vs. β-Lactamase
Producers; Livermore, DM et al.; poster session Halls A-C; Sunday, Sept.
9, 2012, 11:30 AM – 1:30 PM


C2-100 Trends in Susceptibility and ESBL Production for Escherichia
from Intra-abdominal Infections; SMART 2002-2011; Lob, S et al;
poster session Halls A-C; Sunday, Sept. 9, 11:30 AM – 1:30 PM

C2-120 Global Susceptibility and ESBL+ Rates of K. pneumoniae
from Intra-abdominal Infections – SMART 2011; Badal, R et al.; poster
session Halls A-C; Sunday, Sept. 9, 11:30 AM – 1:30 PM

C2-688 Regional Differences in Susceptibility of E. coli
in Community-acquired versus Hospital-associated Intra-abdominal
Infections: SMART 2010/2011; Badal, R et al.; poster session Halls A-C;
Monday, Sept. 10, 11:15 AM – 1:15 PM

C2-702 In Vitro Susceptibilities of E. coli and K.
Isolated from Patients with Intra-abdominal Infections in
China: Data from the Study for Monitoring Antimicrobial Resistance
Trends (SMART) 2002-2011; Wang, W et al.; poster session Halls A-C;
Monday, Sept. 10, 11:15 AM – 1:15 PM

L2-2107 Surveillance of Antimicrobial Susceptibility of Aerobic
and Facultative Gram-Negative Bacilli Isolated from Patients with
Urinary-Tract Infections in China: the 2010-2011 Study for Monitoring
Antimicrobial Resistance Trends (SMART); Yang, Q et al; poster session
Halls A-C; Wednesday, Sept. 12, 9:15 AM – 11:15 AM

Selected safety information about NOXAFIL


NOXAFIL 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 the 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 QTc prolongation and rare
occurrences 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.

Warnings and Precautions

Concomitant administration of NOXAFIL with cyclosporine or tacrolimus
increases the whole blood trough concentrations of these calcineurin
inhibitors. Nephrotoxicity and leukoencephalopathy (including isolated
deaths) have been reported in clinical efficacy studies in patients with
elevated cyclosporine 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, rare cases of
torsades de pointes have been reported in patients taking NOXAFIL.
NOXAFIL should be administered with caution to patients with potentially
proarrhythmic conditions. Rigorous attempts to correct potassium,
magnesium, and calcium should be made in these patients before starting

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 and rarely
required drug discontinuation. Isolated 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. Discontinuation of NOXAFIL must be considered 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. Increased
plasma midazolam concentrations could potentiate and prolong hypnotic
and sedative effects. Patients must be monitored closely for adverse
effects associated with high plasma concentrations of midazolam and
benzodiazepine receptor antagonists must be available to reverse these

NOXAFIL has been shown to interact with several medications, including
drugs that suppress the immune system, and these reactions may be
serious. NOXAFIL is also a strong inhibitor of CYP3A4. Therefore, plasma
concentrations of drugs predominantly metabolized by CYP3A4 may be
increased by NOXAFIL. The product label should be consulted when other
drugs are prescribed with NOXAFIL.

Co-administration of NOXAFIL with rifabutin, phenytoin, efavirenz,
cimetidine and esomeprazole should be avoided unless the benefit
outweighs the risk. Monitoring for toxicity and adverse events is
recommended when tacrolimus, cyclosporine, ritonavir, atazanavir, vinca
alkaloids, and calcium channel blockers and rifabutin are
co-administered 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 co-administering digoxin, phenytoin,
tacrolimus and cyclosporine with NOXAFIL. Monitor for breakthrough
fungal infections when co-administering metoclopramide, fosamprenavir,
rifabutin, phenytoin, cimetidine and esomeprazole with NOXAFIL.

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

Adverse Reactions

The most common adverse reactions (>30%) in the prophylaxis clinical
studies were fever, diarrhea, and nausea.

In clinical studies of OPC and refractory OPC (rOPC), the adverse
reactions were more common in the pool of patients with rOPC. The most
common adverse reactions (>5%) in the controlled OPC pool were diarrhea,
nausea, headache, vomiting, and fever. The most common adverse reactions
(>20%) in the rOPC pool were fever, diarrhea, nausea, vomiting, and
coughing. The most common serious adverse reactions in rOPC patients
included fever (13%) and neutropenia (10%).

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subsidiary of Merck & Co., Inc., Whitehouse Station, N.J., USA.

Please see Prescribing Information for NOXAFIL at
and Patient Information for NOXAFIL at

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