Merck to Initiate Proof-of-Concept Study of Posaconazole for Chronic Chagas Disease, Recognized by WHO as One of the World`s Neglected Tropical Diseases
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WHITEHOUSE STATION, N.J.--(Business Wire)--
Merck today announced plans to initiate a Phase II investigational
proof-of-concept clinical study to evaluate its oral antifungal agent
posaconazole for the treatment of chronic Chagas disease. Chagas disease results
from infection with the parasite Trypanosoma cruzi that is spread by biting
insects. The disease is estimated to affect approximately eight million people
in Latin America, of whom approximately 30-40 percent will develop serious
cardiac disease, digestive disease, or both as a result of this infection.
Recognized by the World Health Organization (WHO) as a neglected tropical
disease, Chagas disease also is becoming an emerging health problem in
non-endemic areas through migration of infected populations from endemic areas.
Currently, only two drugs are approved for treatment: benznidazole and
nifurtimox.
"While significant progress has been made in recent years in the prevention of
the transmission of this potentially life-threatening disease, no new drugs have
been approved for the treatment of chronic Chagas disease in over three
decades," said Roger J. Pomerantz, M.D., F.A.C.P., global franchise head for
infectious diseases and senior vice president, Merck Research Laboratories.
In planning the study to evaluate posaconazole, Merck has consulted with
international agencies and research organizations to identify the current
medical needs and reach consensus on a study design for posaconazole in
asymptomatic chronic Chagas disease. The proposed study is a randomized,
placebo-controlled Phase II study of posaconazole oral suspension (400 mg twice
daily) given for 60 days, either as monotherapy or concomitantly with
benznidazole. Benznidazole monotherapy will serve as an active control. The
study is planned to enroll 160 adult patients with chronic Chagas disease at
several sites in South America and follow them for a total of 360 days. The
study will utilize polymerase chain reaction (PCR) to evaluate the levels of
Trypanosoma cruzi in blood samples as the primary endpoint for response to
treatment. Safety will be monitored by an external independent Data and Safety
Monitoring Board (DSMB) on an ongoing basis and the DSMB will make
recommendations as appropriate. Results from the study are expected in 2012. If
successful, Phase III clinical studies with posaconazole would follow. Merck
looks forward to working with interested partners to facilitate access if
posaconazole is shown to be beneficial in the treatment of chronic Chagas
disease.
About Chagas Disease
Chagas disease is caused by the protozoan parasite Trypanosoma cruzi, and was
discovered in 1909 by the Brazilian physician Carlos Chagas (1879-1934). It
continues to represent a serious social and economic problem in many Latin
American countries, with approximately 20,000 deaths each year attributed to
Chagas disease. Chagas disease is transmitted to humans mainly by insect bites,
but also can be transmitted via blood transfusion, transplantation and
vertically from mother to infant. Rarely, it can be contracted by ingestion of
contaminated food or liquid. The initial phase of acute infection lasts for
four-to-eight weeks and the chronic phase persists for the person`s lifespan. In
most individuals, irrespective of the mode of transmission, acute Chagas
infection is usually asymptomatic. The clinical outcome of the chronic phase of
Chagas disease ranges from the absence of signs and symptoms of disease to
severe illness and premature death. Typical clinical manifestations of the
chronic phase are related to the pathological involvement of the heart,
esophagus, colon, or a combination, and are grouped into three major forms:
cardiac, digestive, and cardiodigestive. It may take more than 20 years from the
time of the original infection to develop serious heart or digestive disease.
Benznidazole and nifurtimox are the only drugs with proven efficacy against
Chagas disease. Benznidazole is usually used for first-line treatment.
Merck`s Ongoing Commitment to Improving Global Health
Merck has a long history of engaging in public-private partnerships and research
initiatives to develop and foster access to its medicines and vaccines
worldwide. These efforts include:
* Working with the Drugs for Neglected Diseases initiative (DNDi), Medicines for
Malaria Venture (MMV) and other partners to advance the discovery and
development of novel treatments for malaria, Chagas disease and other Neglected
Tropical Diseases;
* Fighting onchocerciasis (river blindness) and lymphatic filariasis
(elephantiasis) through the MECTIZAN Donation Program, a diverse global
partnership;
* Partnering with the Government of Botswana and the Bill and Melinda Gates
Foundation to support Botswana`s comprehensive national response to HIV and AIDS
through the African Comprehensive HIV/AIDS Partnerships;
* Collaborating with the Government of Nicaragua to demonstrate the feasibility
and impact of rotavirus vaccine introduction in a GAVI-eligible country;
and,Developing new and improved vaccines to address unmet medical needs in
low-income countries by establishing, through a novel joint venture with the
Wellcome Trust, the MSD Wellcome Trust Hilleman Laboratories.
About Posaconazole
Posaconazole is approved and marketed in the United States, European Union and
several other countries as NOXAFIL® (posaconazole) oral suspension. In the U.S.,
NOXAFIL 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 (HSCT) recipients with graft-versus-host
disease (GVHD) or those with hematologic malignancies with prolonged neutropenia
from chemotherapy. NOXAFIL also is indicated for the treatment of oropharyngeal
candidiasis (OPC), including OPC refractory to itraconazole and/or fluconazole.
Selected Safety Information for NOXAFIL (posaconazole) Oral Suspension
Use in patients with hypersensitivity to the active substance or to any of the
excipients is contraindicated. Coadministration with sirolimus or ergot
alkaloids is contraindicated. Coadministration with the CYP3A4 substrates
terfenadine, astemizole, cisapride, pimozide, halofantrine, or quinidine, is
also contraindicated since this may result in increased plasma concentrations of
these medicinal products, leading to QTc prolongation and rare occurrences of
torsades de pointes.
NOXAFIL has been shown to interact with several medications, including drugs
that suppress the immune system, and these reactions may be serious. The product
label should be consulted when other drugs are prescribed with NOXAFIL.
Serious and rare fatal toxicity from cyclosporine has occurred when taken in
combination with NOXAFIL and therefore reduction of the dose of drugs like
cyclosporine or tacrolimus and frequent monitoring of drug levels of these
medications are necessary when taking them in combination with NOXAFIL.
In clinical trials, there were infrequent cases of hepatic reactions (e.g., mild
to moderate elevations in ALT, AST, alkaline phosphatase, total bilirubin,
and/or clinical hepatitis). Rarely, more severe hepatic reactions including
cholestasis or hepatic failure including fatalities were reported in patients
with serious underlying medical conditions (e.g., hematologic malignancies)
during treatment with posaconazole. Liver function tests should be monitored at
the start of and during the course of therapy. Discontinuation of NOXAFIL must
be considered in patients who experience symptoms consistent with liver disease
that may be attributable to NOXAFIL. The safety and effectiveness of NOXAFIL in
patients below the age of 13 years old have not been established.
The most common treatment-related serious adverse events (1% each) in the
combined prophylaxis studies were bilirubinemia, increased hepatic enzymes,
hepatocellular damage, nausea, and vomiting.
In the pooled prophylaxis safety analysis, fever, headache, anemia, diarrhea,
nausea, vomiting, abdominal pain, hypokalemia, and thrombocytopenia were
frequently reported treatment-emergent adverse events.
In clinical studies of OPC and refractory OPC, adverse events were reported more
frequently in the pool of patients with refractory OPC. The most commonly
reported serious adverse events in refractory OPC patients included fever (13%)
and neutropenia (10%).
U.S. prescribing information for NOXAFIL is attached and also is available at
http://www.spfiles.com/pinoxafil.pdf.
About Merck
Today's Merck is working to help the world be well. Through our medicines,
vaccines, biologic therapies, and consumer and animal products, we work with
customers and operate in more than 140 countries to deliver innovative health
solutions. We also demonstrate our commitment to increasing access to healthcare
through far-reaching programs that donate and deliver our products to the people
who need them. Merck. Be Well. For more information, visit www.merck.com.
Forward-Looking Statement
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. Such statements may include, but are not limited to,
statements about the benefits of the merger between Merck and Schering-Plough,
including future financial and operating results, the combined company`s plans,
objectives, expectations and intentions and other statements that are not
historical facts. Such statements are based upon the current beliefs and
expectations of Merck`s management and are subject to significant risks and
uncertainties. Actual results may differ from those set forth in the
forward-looking statements.
The following factors, among others, could cause actual results to differ from
those set forth in the forward-looking statements: the possibility that the
expected synergies from the merger of Merck and Schering-Plough will not be
realized, or will not be realized within the expected time period; the impact of
pharmaceutical industry regulation and health care legislation; the risk that
the businesses will not be integrated successfully; disruption from the merger
making it more difficult to maintain business and operational relationships;
Merck`s ability to accurately predict future market conditions; dependence on
the effectiveness of Merck`s patents and other protections for innovative
products; the risk of new and changing regulation and health policies in the
U.S. and internationally and the exposure to 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 2009 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).
# # #
31153620T
PRODUCT INFORMATION
NOXAFIL®
(posaconazole) ORAL SUSPENSION
DESCRIPTION
NOXAFIL® (posaconazole) is a triazole antifungal agent available as a suspension
for oral administration.
Posaconazole is designated chemically as 4-[4-[4-[4-[[ (3R,5R)-5-
(2,4-difluorophenyl)tetrahydro-5-
(1H-1,2,4-triazol-1-ylmethyl)-3-furanyl]methoxy]phenyl]-1-piperazinyl]phenyl]-2-[
(1S,2S)-1-ethyl-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one with an
empirical formula of C37H42F2N8O4 and a molecular weight of 700.8. The
structural formula is:
(Graphic Omitted)
Posaconazole is a white powder and is insoluble in water.
NOXAFIL Oral Suspension is a white, cherry-flavored immediate-release suspension
containing 40 mg of posaconazole per mL and the following inactive ingredients:
polysorbate 80, simethicone, sodium benzoate, sodium citrate dihydrate, citric
acid monohydrate, glycerin, xanthan gum, liquid glucose, titanium dioxide,
artificial cherry flavor, and purified water.
CLINICAL PHARMACOLOGY
Pharmacokinetics
Absorption
Posaconazole is absorbed with a median Tmax of ~3 to 5 hours. Dose proportional
increases in plasma exposure (AUC) to posaconazole were observed following
single oral doses from 50 mg to 800 mg and following multiple-dose
administration from 50 mg BID to 400 mg BID. No further increases in exposure
were observed when the dose was increased from 400 mg BID to 600 mg BID in
febrile neutropenic patients or those with refractory invasive fungal
infections. Steady-state plasma concentrations are attained at 7 to 10 days
following multiple-dose administration.
Following single-dose administration of 200 mg, the mean AUC and Cmax of
posaconazole are approximately 3 times higher when administered with a nonfat
meal and approximately 4 times higher when administered with a high-fat meal
(~50 gm fat) relative to the fasted state. Following single-dose administration
of 400 mg, the mean AUC and Cmax of posaconazole are approximately 3 times
higher when administered with a liquid nutritional supplement (14 gm fat)
relative to the fasted state (see Table 1). In order to assure attainment of
adequate plasma concentrations, it is recommended to administer posaconazole
with food or a nutritional supplement (see DOSAGE AND ADMINISTRATION).
TABLE 1: The Mean (%CV) [min-max] Posaconazole Pharmacokinetic Parameters Following Single-
Dose Suspension Administration of 200 mg and 400 mg Under Fed and Fasted Conditions
Dose (mg) Cmax Tmaxa AUC (I) CL/F t½
(ng/mL) (hr) (ng·hr/mL) (L/hr) (hr)
200 mg fasted 132 (50) 3.50 4179 (31) 51 (25) 23.5 (25)
(n=20)c [45-267] [1.5-36b] [2705-7269] [28-74] [15.3-33.7]
200 mg nonfat 378 (43) 4 [3-5] 10,753 (35) 21 (39) 22.2 (18)
(n=20) c [131-834] [4579-17,092] [12-44] [17.4-28.7]
200 mg high-fat 512 (34) 5 [4-5] 15,059 (26) 14 (24) 23.0 (19)
(54 gm fat) [241-1016] [10,341-24,476] [8.2-19] [17.2-33.4]
(n=20) c
400 mg fasted 121 (75) 4 [2-12] 5258 (48) 91 (40) 27.3 (26)
(n=23) d [27-366] [2834-9567] [42-141] [16.8-38.9]
400 mg with liquid nutritional supplement 355 (43) 5 [4-8] 11,295 (40) 43 (56) 26.0 (19)
(14 gm fat) [145-720] [3865-20,592] [19-103] [18.2-35.0]
(n=23) d
a Median [min-max]
b The subject with Tmax of 36 hrs had relatively constant plasma levels over 36 hrs (1.7 ng/mL difference between 4 hrs and 36 hrs)
c n=15 for AUC (I), CL/F and t1/2
d n=10 for AUC (I), CL/F and t1/2
In 12 healthy volunteers who received a single 400 mg dose of NOXAFIL Oral
Suspension in the fasted state, 5 minutes before, during, and 20 minutes after a
high-fat meal in a 4-way crossover design, the coadministration of NOXAFIL with
a high fat meal significantly increased the extent of absorption of posaconazole
compared to in the fasted state. However, the magnitude of the food effect
varied with timing of the meals. When NOXAFIL was administered during a high-fat
meal, the mean Cmax and AUC increased by 339% and 382% compared to in the fasted
state, respectively. When NOXAFIL was administered 20 minutes after a high-fat
meal, the mean Cmax and AUC also increased by 333% and 387% compared to in the
fasted state, respectively. When NOXAFIL was administered 5 minutes before a
high-fat meal, the mean Cmax
and AUC increased by 96% and 111% compared to in the fasted state,
respectively (See DOSAGE AND ADMINISTRATION).
In 12 healthy volunteers who received 400 mg BID and 200 mg QID of NOXAFIL Oral
Suspension for 7 days in the fasted state and with liquid nutritional supplement
(BOOST® Drink) in a 4-way crossover design, the administration of NOXAFIL 400 mg
BID with BOOST increased the mean Cmax and AUC by 65% and 66%, respectively,
compared to NOXAFIL 400 mg BID in the fasted state. However, when NOXAFIL 200 mg
QID was administered with BOOST, the mean Cmax and AUC were not affected
compared to NOXAFIL 200 mg QID in the fasted state.
In 12 healthy volunteers who received 400 mg BID and 200 mg QID of NOXAFIL Oral
Suspension for 7 days in the fasted state and with liquid nutritional supplement
(BOOST Drink) in a 4-way crossover design, the absorption of posaconazole was
significantly increased when NOXAFIL was administered by dividing the total
daily dose from 400 mg BID to 200 mg QID regardless of under fasted conditions
or with liquid nutritional supplement. In the fasted state, the mean Cmax and
AUC increased by 136% and 161%, respectively, when NOXAFIL was administered as
200 mg QID compared to 400 mg BID. When NOXAFIL was administered as 200 mg QID
with BOOST, the mean Cmax and AUC increased by 44% and 54%, respectively,
compared to 400 mg BID with BOOST.
In 12 healthy volunteers who received a single 400 mg dose of NOXAFIL Oral
Suspension alone, or with ginger ale, or with esomeprazole, or both ginger ale
and esomeprazole in the fasted state in a 4-way crossover design, the
coadministration of NOXAFIL with ginger ale (carbonated acidic beverage)
increased the mean Cmax and AUC by 92% and 70% compared to NOXAFIL alone,
respectively. The coadministration of NOXAFIL with esomeprazole (proton pump
inhibitor) decreased the mean Cmax and AUC by 46% and 32% compared to NOXAFIL
alone, respectively. The coadministration of NOXAFIL with both ginger ale and
esomeprazole decreased the mean Cmax and AUC by 33% and 21% compared to NOXAFIL
alone, respectively (See CLINICAL PHARMACOLOGY, Drug Interactions, PRECAUTIONS,
Drug Interactions, and DOSAGE AND ADMINISTRATION.
In 12 subjects who received single 400 mg dose of NOXAFIL Oral Suspension with
BOOST, or with a prokinetic agent (metoclopramide 10 mg TID for 2 days) and
BOOST, or with an anti-kinetic agent (loperamide 4 mg single dose) and BOOST in
a 3-way crossover design, the coadministration of NOXAFIL with metoclopramide
decreased the mean Cmax
and AUC by 21% and 19%, respectively, compared to NOXAFIL alone. When
NOXAFIL was coadministered with loperamide, the mean Cmax and AUC were decreased
by 3% and increased by 11%, respectively, compared to NOXAFIL alone (See
CLINICAL PHARMACOLOGY, Drug Interactions and PRECAUTIONS, Drug Interactions).
In 16 healthy volunteers who received a single 400 mg dose of NOXAFIL either
orally or via an NG tube in a crossover design, the mean Cmax and AUC decreased
by 19% and 23%, respectively, when NOXAFIL was administered via an NG tube
compared to when POS was administered orally. In 5 subjects, the Cmax and AUC
decreased substantially (range -27% to -53% and -33% to -51%, respectively) when
NOXAFIL was administered via an NG tube compared to when NOXAFIL was
administered orally. It is recommended to closely monitor patients for
breakthrough fungal infections when NOXAFIL is administered via an NG tube
because a lower plasma exposure may be associated with an increase risk of
treatment failure (See CLINICAL PHARMACOLOGY, Exposure Response Relationship).
Distribution
Posaconazole has an apparent volume of distribution of 1774 L, suggesting
extensive extravascular distribution and penetration into the body tissues.
Posaconazole is highly protein bound (>98%), predominantly to albumin.
Metabolism
Posaconazole primarily circulates as the parent compound in plasma. Of the
circulating metabolites, the majority are glucuronide conjugates formed via UDP
glucuronidation (phase 2 enzymes). Posaconazole does not have any major
circulating oxidative (CYP450 mediated) metabolites. The excreted metabolites in
urine and feces account for ~17% of the administered radiolabeled dose.
Excretion
Posaconazole is eliminated with a mean half-life (t½) of 35 hours (range 20 to
66 hours) and a total body clearance (CL/F) of 32 L/hr. Posaconazole is
predominantly eliminated in the feces (71% of the radiolabeled dose up to 120
hours) with the major component eliminated as parent drug (66% of the
radiolabeled dose). Renal clearance is a minor elimination pathway, with 13% of
the radiolabeled dose excreted in urine up to 120 hours (<0.2% of the
radiolabeled dose is parent drug).
Summary of Pharmacokinetic Parameters
The mean (%CV) [min-max] posaconazole average steady-state plasma concentrations
(Cav) and steady-state pharmacokinetic parameters in patients following
administration of 200 mg TID and 400 mg BID of the oral suspension are provided
in Table 2.
TABLE 2. The Mean (%CV) [min-max] Posaconazole Steady-State Pharmacokinetic Parameters in
Patients Following Oral Administration of Posaconazole 200 mg TID and 400 mg BID
Dosea Cav (ng/mL) AUCe (ng·hr/mL) CL/F (L/hr) V/F (L) t1/2 (hr)
200 mg TIDb 1103 (67) NDf NDf NDf NDf
(n=252) [21.5- 3650]
200 mg TIDc (n=215) 583 (65) 15,900 (62) 51.2 (54) 2425 (39) 37.2 (39)
[89.7-2200] [4100-56,100] [10.7-146] [828-5702] [19.1-148]
400 mg BIDd (n=23) 723 (86) 9093 (80) 76.1 (78) 3088 (84) 31.7 (42)
[6.70-2256] [1564-26,794] [14.9-256] [407-13,140] [12.4-67.3]
Note: Cav based on observed data; other pharmacokinetic parameters based on estimates from population pharmacokinetic analyses
a Oral suspension administration
b Allogeneic hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease
c Neutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia or
myelodysplastic syndromes
d Febrile neutropenic patients or patients with refractory invasive fungal infections, Cav n=24
e AUC (0-24 hr) for 200 mg TID and AUC (0-12 hr) for 400 mg BID
f Not done
The variability in average plasma posaconazole concentrations in patients was
relatively higher than that in healthy subjects.
Exposure Response Relationship
In clinical studies of immunocompromised patients, a wide range of plasma
exposures to posaconazole was noted. A pharmacokinetic-pharmacodynamic analysis
of patient data revealed an apparent association between average posaconazole
concentrations (Cav) and prophylactic efficacy. A lower Cav may be associated
with an increased risk of treatment failure [defined in the study as treatment
discontinuation, use of empiric systemic antifungal therapy (SAF), or invasive
fungal infections (IFI)].
To enhance the oral absorption of posaconazole and optimize plasma
concentrations:
* Each dose of NOXAFIL® Oral Suspension should be administered during or
immediately (i.e. within 20 minutes) following a full meal or liquid nutritional
supplement. For patients who cannot eat a full meal or tolerate an oral
nutritional supplement, alternative antifungal therapy should be considered or
patients should be monitored closely for breakthrough fungal infections.
* Patients who have severe diarrhea or vomiting should be monitored closely for
breakthrough fungal infections.
* Co-administration 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 (see CLINICAL PHARMACOLOGY, Drug Interactions
section).
Pharmacokinetics in Special Populations
Gender
The pharmacokinetics of posaconazole are comparable in men and women. No
adjustment in the dosage of NOXAFIL is necessary based on gender.
Race
The pharmacokinetic profile of posaconazole is not significantly affected by
race. No adjustment in the dosage of NOXAFIL is necessary based on race.
Geriatric
The pharmacokinetics of posaconazole are comparable in young and elderly
subjects (≥65 years of age). No adjustment in the dosage of NOXAFIL is necessary
in elderly patients (≥65 years of age) based on age.
Pediatric
In the prophylaxis studies, the mean steady-state posaconazole average
concentration (Cav) was similar among ten adolescents (13-17 years of age) and
adults (≥18 years of age). This is consistent with pharmacokinetic data from
another study in which mean steady-state posaconazole Cav from 12 adolescent
patients (8-17 years of age) was similar to that in the adults (≥18 years of
age).
Hepatic Insufficiency
After a single oral dose of posaconazole 400 mg, the mean AUC was 43%, 27% and
21% higher in subjects with mild (Child-Pugh Class A, N=6), moderate (Child-Pugh
Class B, N=6), and severe (Child-Pugh Class C, N=6) hepatic insufficiency,
respectively, compared to subjects with normal hepatic function (N=18). Compared
to subjects with normal hepatic function, the mean Cmax was 1% higher, 40%
higher, and 34% lower in subjects with mild, moderate, and severe hepatic
insufficiency, respectively. The mean apparent oral clearance (CL/F) was reduced
by 18%, 36% and 28% in subjects with mild, moderate, and severe hepatic
insufficiency, respectively, compared to subjects with normal hepatic function.
The elimination half-life (t½) was 27 hours, 39 hours, 27 hours, and 43 hours in
subjects with normal hepatic function, mild, moderate, and severe hepatic
insufficiency, respectively.
It is recommended that no dose adjustment of NOXAFIL is needed in patients with
mild to severe hepatic insufficiency (Child-Pugh Class A, B, and C)(See WARNINGS
and DOSAGE AND ADMINISTRATION).
Renal Insufficiency
Following single-dose administration of 400 mg of the oral suspension, there was
no significant effect of mild (CLcr: 50-80 mL/min/1.73m2, n=6) and moderate
(CLcr: 20-49 mL/min/1.73m2, n=6) renal insufficiency on posaconazole
pharmacokinetics; therefore, no dose adjustment is required in patients with
mild to moderate renal impairment. In subjects with severe renal insufficiency
(CLcr: <20 mL/min/1.73m2), the mean plasma exposure (AUC) was similar to that in
patients with normal renal function (CLcr: >80 mL/min/1.73m2); however, the
range of the AUC estimates was highly variable (CV=96%) in these subjects with
severe renal insufficiency as compared to that in the other renal impairment
groups (CV<40%). Due to the variability in exposure, patients with severe renal
impairment should be monitored closely for breakthrough fungal infections (see
DOSAGE AND ADMINISTRATION).
Electrocardiogram Evaluation
Multiple, time-matched ECGs collected over a 12-hour period were recorded at
baseline and steady-state from 173 healthy male and female volunteers (18-85
years of age) administered posaconazole 400 mg BID with a high-fat meal. In this
pooled analysis, the mean QTc (Fridericia) interval change from baseline was -5
msec following administration of the recommended clinical dose. A decrease in
the QTc (F) interval (-3 msec) was also observed in a small number of subjects
(n=16) administered placebo. The placebo-adjusted mean maximum QTc (F) interval
change from baseline was <0 msec (-8 msec). No healthy subject administered
posaconazole had a QTc (F) interval ≥500 msec or an increase ≥60 msec in their
QTc (F) interval from baseline (see PRECAUTIONS).
Drug Interactions
Effect of Other Drugs on Posaconazole
Posaconazole is primarily metabolized via UDP glucuronidation (phase 2 enzymes)
and is a substrate for p-glycoprotein (P-gp) efflux. Therefore, inhibitors or
inducers of these clearance pathways may affect posaconazole plasma
concentrations.A summary of drugs studied clinically, which affect posaconazole
concentrations, is provided in Table3 (see PRECAUTIONS, Drug Interactions
section).
TABLE 3. Summary of the Effect of Co-administered Drugs on Posaconazole in Healthy Volunteers
Co-administered Co-administered Posaconazole Effect on Recommendations
Drug
Drug
Dose/Schedule
Bioavailability of
(Postulated
Dose/Schedule
Posaconazole
Mechanism of
Interaction)
Change Change
in Mean
in Mean
Cmax
AUC
(ratio
(ratio
estimate*
estimate*;
; 90% CI
90% CI of
of the
the ratio
ratio
estimate)
estimate)
Rifabutin 300 mg QD x 17 days 200 mg (tablets) QD × 10 days ↓ 43% (0.57; ↓ 49% (0.51; 0.37-0.71) Avoid concomitant use unless the benefit outweighs the risks.
(UDP-G
0.43-0.75)
Induction)
Phenytoin 200 mg QD x 10 days 200 mg (tablets) QD × 10 days ↓ 41% ↓ 50% Avoid concomitant use unless the benefit outweighs the risks.
(UDP-G
(0.59;
(0.50; 0.36-0.71)
Induction)
0.44-0.79)
Cimetidine 400 mg BID × 10 days 200 mg (tablets) QD × 10 days ↓ 39% ↓ 39% Avoid concomitant use unless the benefit outweighs the risks.
(Alteration of
(0.61; 0.53-0.70)
(0.61; 0.54-0.69)
Gastric pH)
Efavirenz 400 mg QD × 10 and 20 days 400 mg (oral suspension) BID × 10 and 20 days ↓ 45% (0.55; ↓ 50% (0.50; 0.43-0.60) Avoid concomitant use unless the benefit outweighs the risks.
(UDP-G
0.47-0.66)
Induction)
Esomeprazole 40 mg QAM × 3 days 400 mg (oral suspension) single dose ↓ 46% (0.54; 0.43-0.69) ↓ 32% (0.68; 0.57-0.81) Monitor closely for breakthrough fungal infections
(Increase in
gastric pH)
Metoclopramide 10 mg TID × 2 days 400 mg (oral suspension) single dose ↓ 21% (0.79; 0.72-0.87) ↓ 19% (0.81; 0.72-0.91) Monitor closely for breakthrough fungal infections
(Increase in
gastric motility)
*Ratio Estimate is the ratio of co-administered drug plus posaconazole to posaconazole alone for Cmax or AUC.
Co-administration of these drugs listed in Table 3 with posaconazole may result
in lower plasma concentrations of posaconazole.
No clinically relevant effect on posaconazole bioavailability and/or plasma
concentrations was observed when administered with an antacid, glipizide,
ritonavir, loperamide, or H2 receptor antagonists other than cimetidine;
therefore, no posaconazole dose adjustments are required when used concomitantly
with these products.
Effect of Posaconazole on Other Drugs
In vitro studies with human hepatic microsomes and clinical studies indicate
that posaconazole is an inhibitor primarily of CYP3A4. A clinical study in
healthy
volunteers also indicates that posaconazole is a strong CYP3A4 inhibitor as
evidenced by a >5-fold increase in midazolam AUC. Therefore, plasma
concentrations of drugs predominantly metabolized by CYP3A4 may be increased by
posaconazole. A summary of the drugs studied clinically, for which plasma
concentrations were affected by posaconazole, is provided in Table4. (see
CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS, Drug Interactions section).
TABLE 4. Summary of the Effect of Posaconazole on Co-administered Drugs in Healthy Volunteers and Patients
Coadministered Coadministered Posaconazole Dose/ Effect on Bioavailability of Recommendations
Drug (Postulated
Drug Dose/Schedule Schedule Co-administered
Mechanism of Interaction)
Drugs
Change in Change in
Mean
Mean AUC
Cmax
(ratio
(ratio estimate*;
estimate*;
90% CI of the
90% CI of the
ratio
ratio estimate)
estimate)
Sirolimus 2 mg single oral dose 400 mg (oral suspension) BID x 16 days ↑ 572% ↑ 788% Co-administration of
(Inhibition of CYP3A4 by posaconazole)
(6.72; 5.62-8.03)
(8.88; 7.26-10.9)
posaconazole with
sirolimus is
contraindicated (see
CONTRAINDICATIONS).
Cyclosporine Stable maintenance dose in heart transplant recipients 200 mg (tablets) QD x 10 days ↑ cyclosporine whole blood trough concentrations At initiation of
(Inhibition of CYP3A4 by posaconazole)
posaconazole treatment,
Cyclosporine dose reductions of up to 29% were required
reduce the cyclosporine
dose to approximately
three-fourths of the
original dose.
Frequent monitoring of
cyclosporine whole blood
trough concentrations
should be performed
during and at
discontinuation of
posaconazole treatment
and the cyclosporine
dose adjusted
accordingly.
Tacrolimus 0.05 mg/kg single oral dose 400 mg (oral suspension) BID × 7 days ↑ 121% (2.21; 2.01-2.42) ↑ 358% At initiation of
(Inhibition of CYP3A4 by posaconazole)
(4.58; 4.03-5.19)
posaconazole treatment,
reduce the tacrolimus
dose to approximately
one-third of the original
dose.
Frequent monitoring of
tacrolimus whole blood
trough concentrations
should be performed
during and at
discontinuation of
posaconazole treatment
and the tacrolimus dose
adjusted accordingly.
Rifabutin 300 mg QD x 17 days 200 mg (tablets) QD × 10 days ↑ 31% (1.31; 1.10-1.57) ↑ 72% Avoid concomitant use
(Inhibition of CYP3A4 by posaconazole)
(1.72;
unless the benefit
1.51-1.95)
outweighs the risks. If the
drugs are co-
administered, frequent
monitoring of rifabutin
adverse effects (eg,
uveitis, leukopenia)
should be performed.
Midazolam Single 30 min 200 mg NA** ↑ 83% (1.83; Frequent monitoring
(Inhibition of CYP3A4 by posaconazole)
IV infusion of
(tablets) QD x
1.57-2.14)
of adverse effects of
0.05 mg/kg
10 days
benzodiazepines
metabolized by CYP3A4
0.4 mg single IV
200 mg (oral
↑ 30% (1.3;
↑ 362% (4.62;
should be performed and
dosea
suspension)
1.13-1.48)
4.02-5.3)
dose reduction of these
BID x 7 days
benzodiazepines should
be considered during co-
2 mg single oral
200 mg (oral
↑ 126%
↑ 362% (4.59;
administration with
dosea
suspension)
(2.26; 2.02-
4.12-5.11)
posaconazole.
BID x 7 days
2.53)
0.4 mg single IV dosea
400 mg (oral
↑ 62% (1.62;
↑ 524%
suspension)
1.41-1.86)
(6.24; 5.43-
BID x 7 days
7.16)
Phenytoin 200 mg QD PO x 10 days 200 mg (tablets) QD x 10 days ↑ 16% (1.16; 0.85-1.57) ↑ 16% Frequent monitoring of
(Inhibition of CYP3A4 by posaconazole)
(1.16; 0.84-1.59)
phenytoin concentrations
should be performed
while co-administered
with posaconazole and
dose reduction of
phenytoin should be
considered.
Ritonavir 100 mg QD x 400 mg (oral ↑ 49% ↑ 80% Frequent monitoring of
(Inhibition of 14 days suspension)
(1.49;
(1.8;
adverse effects and
CYP3A4 by
BID x 7 days 1.04-2.15)
1.39-2.31)
toxicity of ritonavir should
posaconazole)
be performed during co-
administration with
posaconazole.
Atazanavir (Inhibition of CYP3A4 by posaconazole) 300 mg QD x 400 mg (oral ↑ 155% ↑ 268% Frequent monitoring of
14 days
suspension)
(2.55; 1.89-
(3.68; 2.89-
adverse effects and
BID x 7 days
3.45)
4.70)
toxicity of Atazanavir
Atazanavir/ ritonavir boosted regimen
should be performed
(Inhibition of CYP3A4 by posaconazole)
during co-administration
with posaconazole.
300 mg/100 mg
400 mg (oral
↑ 53% (1.53;
↑ 146%
QD x 14 days
suspension)
1.13-2.07)
(2.46; 1.93-
BID x 7 days
3.13)
*Ratio Estimate is the ratio of co-administered drug plus posaconazole to co-administered drug alone for Cmax or AUC.
**NA: Not applicable if administered as an IV.
a The mean terminal half-life of midazolam was increased from 3 hours to 8 to 10 hours during co-administration with posaconazole.
Additional clinical studies demonstrated that no clinically significant effects
on zidovudine, lamivudine, ritonavir, indinavir, or caffeine were observed when
administered with posaconazole 200 mg QD; therefore, no dose adjustments are
required for these co-administered drugs when co-administered with posaconazole
200 mg QD.
Posaconazole administration with glipizide does not require a dose adjustment in
either drug; however, glucose concentrations decreased in some healthy
volunteers administered the combination. Therefore, glucose concentrations
should be monitored in accordance with the current standard of care for patients
with diabetes when posaconazole is co-administered with glipizide.
MICROBIOLOGY
Mechanism of Action
As a triazole antifungal agent, posaconazole blocks the synthesis of ergosterol,
a key component of the fungal cell membrane, through the inhibition of the
enzyme lanosterol 14α-demethylase and accumulation of methylated sterol
precursors.
Activity in vitro and in vivo
Posaconazole has shown in vitro activity against Aspergillus fumigatus and
Candida albicans, including Candidaalbicans isolates from patients refractory to
itraconazole or fluconazole or both drugs (see CLINICAL STUDIES and INDICATIONS
AND USAGE).
In vitro susceptibility testing was performed according to the Clinical and
Laboratory Standards Institute (CLSI) methods (M27-A2, M27-A, M38-A, M38-P).
However, correlation between the results of susceptibility studies and clinical
outcome has not been established. Posaconazole interpretive criteria/
breakpoints have not been established for any fungi.
In immunocompetent and/or immunocompromised mice and rabbits with pulmonary or
disseminated infection with A. fumigatus, posaconazole administered
prophylactically was effective in prolonging survival and reducing mycological
burden. Prophylactic posaconazole also prolonged survival of immunocompetent
mice challenged with C. albicans or A. flavus (see CLINICAL STUDIES).
Drug Resistance
Clinical isolates of Candida albicans and Candida glabrata with decreases in
posaconazole susceptibility were observed in oral swish samples taken during
prophylaxis with posaconazole and fluconazole, suggesting a potential for
development of resistance. These isolates also showed reduced susceptibility to
other azoles, suggesting cross-resistance between azoles. The clinical
significance of this finding is not known.
CLINICAL STUDIES
Prophylaxis of Aspergillus and Candida Infections
Two randomized, controlled studies were conducted using posaconazole as
prophylaxis for the prevention of invasive fungal infections (IFIs) among
patients at high risk due to severely compromised immune systems.
The first study (Study 1) was a randomized, double-blind trial 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 hematopoietic stem cell transplant (HSCT) recipients with Graft
versus Host Disease (GVHD). Efficacy of prophylaxis was evaluated using a
composite endpoint of proven/probable IFIs, death, or treatment with systemic
antifungal therapy (Patients may have met more than one of these criteria).
Study 1 assessed all patients while on study therapy plus 7 days and at 16 weeks
post-randomization. The mean duration of therapy was comparable between the two
treatment groups (80 days, posaconazole; 77 days, fluconazole). Table 5 contains
the results from Study 1.
TABLE 5. Results from Blinded Clinical Study 1 in Prophylaxis of IFI in All
Randomized Patients with Hematopoietic Stem Cell Transplant (HSCT) and
Graft-vs-Host Disease (GVHD)
Posaconazole Fluconazole
n=301 n=299
On therapy plus 7 days
Clinical Failurea 50 (17%) 55 (18%)
Failure due to:
Proven/Probable IFI 7 (2%) 22 (7%)
(Aspergillus) 3 (1%) 17 (6%)
(Candida) 1 (<1%) 3 (1%)
(Other) 3 (1%) 2 (1%)
All Deaths 22 (7%) 24 (8%)
Proven/probable 2 (1%) 6 (2%)
fungal infection
prior to death
SAFb 27 (9%) 25 (8%)
Through 16 weeks
Clinical Failurea,c 99 (33%) 110 (37%)
Failure due to:
Proven/Probable IFI 16 (5%) 27 (9%)
(Aspergillus) 7 (2%) 21 (7%)
(Candida) 4 (1%) 4 (1%)
(Other) 5 (2%) 2 (1%)
All Deaths 58 (19%) 59 (20%)
Proven/probable 10 (3%) 16 (5%)
fungal infection
prior to death
SAFb 26 (9%) 30 (10%)
Event free lost to follow-upd 24 (8%) 30 (10%)
a Patients may have met more than one criterion defining failure.
b Use of systemic antifungal therapy (SAF) criterion is based on protocol definitions (empiric/IFI usage >4 consecutive days).
c 95% confidence interval (posaconazole-fluconazole) = (-11.5%, +3.7%).
d Patients who are lost to follow-up (not observed for 112 days), and who did not meet another clinical failure endpoint. These patients were considered failures.
The second study (Study 2) was a 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 a
day) as prophylaxis against IFIs in neutropenic patients who were receiving
cytotoxic chemotherapy for acute myelogenous leukemia or myelodysplastic
syndromes. As in Study 1, efficacy of prophylaxis was evaluated using a
composite endpoint of proven/probable IFIs, death, or treatment with systemic
antifungal therapy (Patients might have met more than one of these criteria).
Study 2 assessed patients while on treatment plus 7 days and 100 days
post-randomization. The mean duration of therapy was comparable between the two
treatment groups (29 days, posaconazole; 25 days, fluconazole or itraconazole).
Table 6 contains the results from Study 2.
TABLE 6. Results from Open-Label Clinical Study 2 in Prophylaxis of IFI in All
Randomized Patients with Hematologic Malignancy and Prolonged Neutropenia
Posaconazole Fluconazole/Itraconazole
n=304 n=298
On therapy plus 7 days
Clinical Failurea,b 82 (27%) 126 (42%)
Failure due to:
Proven/Probable IFI 7 (2%) 25 (8%)
(Aspergillus) 2 (1%) 20 (7%)
(Candida) 3 (1%) 2 (1%)
(Other) 2 (1%) 3 (1%)
All Deaths 17 (6%) 25 (8%)
Proven/probable 1 (1%) 2 (1%)
fungal infection
prior to death
SAFc 67 (22%) 98 (33%)
Through 100 days post-randomization
Clinical Failureb 158 (52%) 191 (64%)
Failure due to:
Proven/Probable IFI 14 (5%) 33 (11%)
(Aspergillus) 2 (1%) 26 (9%)
(Candida) 10 (3%) 4 (1%)
(Other) 2 (1%) 3 (1%)
All Deaths 44 (14%) 64 (21%)
Proven/probable 2 (1%) 16 (5%)
fungal infection
prior to death
SAFc 98 (32%) 125 (42%)
Event free lost to follow-upd 34 (11%) 24 (8%)
a 95% confidence interval (posaconazole-fluconazole/itraconazole) = (-22.9%, -7.8%).
b Patients may have met more than one criterion defining failure.
c Use of systemic antifungal therapy (SAF) criterion is based on protocol definitions (empiric/IFI usage >3 consecutive days).
d Patients who are lost to follow-up (not observed for 100 days), and who did not meet another clinical failure endpoint. These patients were considered failures.
In summary, two clinical studies of prophylaxis were conducted. As seen in the
accompanying tables (Tables 5 and 6), clinical failure represented a composite
endpoint of breakthrough IFI, mortality and use of systemic antifungal therapy.
In Study 1 (Table 5), the clinical failure rate of posaconazole (33%) was
similar to fluconazole (37%), (95% CI for the difference posaconazole-comparator
-11.5% to 3.7%) while in Study 2 (Table 6) clinical failure was lower for
patients treated with posaconazole (27%) when compared to patients treated with
fluconazole or itraconazole (42%), (95% CI for the difference
posaconazole-comparator -22.9% to -7.8%).
All-cause mortality was similar at 16 weeks for both treatment arms in Study 1
[POS 58/301 (19%) vs FLU 59/299 (20%)]; all-cause mortality was lower at 100
days for posaconazole-treated patients in Study 2 [POS 44/304 (14%) vs FLU/ITZ
64/298 (21%)]. Both studies demonstrated substantially fewer breakthrough
infections caused by Aspergillus species in patients receiving posaconazole
prophylaxis when compared to patients receiving fluconazole or itraconazole.
For information on a pharmacokinetic/pharmacodynamic analysis of patient data
see CLINICAL PHARMACOLOGY, Exposure Response Relationship section.
Treatment of Oropharyngeal Candidiasis (OPC)
Study 3 was a randomized, controlled, evaluator-blinded study in HIV-infected
patients with oropharyngeal candidiasis. Patients were treated with posaconazole
or fluconazole oral suspension (both posaconazole and fluconazole were given as
follows: 100 mg twice a day for 1 day followed by 100 mg once a day for 13
days).
Clinical and mycological outcomes were assessed after 14 days of treatment and
at 4 weeks after the end of treatment. Patients who received at least one dose
of study medication and had a positive oral swish culture of Candida species at
baseline were included in the analyses (Table 7). The majority of the subjects
had C. albicans as the baseline pathogen.
Clinical success at Day 14 (complete or partial resolution of all ulcers and/or
plaques and symptoms) and clinical relapse rates (recurrence of signs or
symptoms after initial cure or improvement) 4 weeks after the end of treatment
were similar between the treatment arms (Table 7).
Mycologic eradication rates (absence of colony forming units in quantitative
culture at the end of therapy, day 14), as well as mycologic relapse rates (4
weeks after the end of treatment) were also similar between the treatment arms
(see Table 7).
TABLE 7. Clinical Success, Mycological Eradication, and Relapse Rates in Oropharyngeal
Candidiasis
Posaconazole Fluconazole
Clinical Success at End of Therapy (Day 14) 155/169 (91.7%) 148/160 (92.5%)
Clinical Relapse (4 Weeks after End of Therapy) 45/155 (29.0%) 52/148 (35.1%)
Mycological Eradication (absence of CFU) at End of Therapy (Day 14) 88/169 (52.1%) 80/160 (50.0%)
Mycological Relapse (4 Weeks after End of Treatment) 49/88 (55.6%) 51/80 (63.7%)
Mycologic response rates, using a criterion for success as a post-treatment
quantitative culture with ≤20 colony forming units (CFU/mL) were also similar
between the two groups (posaconazole 68.0%, fluconazole 68.1%). The clinical
significance of this finding is unknown.
Treatment of Oropharyngeal Candidiasis Refractory to Treatment with Fluconazole
or Itraconazole
Study 4 was a non-comparative study of posaconazole oral suspension in
HIV-infected subjects with OPC that was refractory to treatment with fluconazole
or itraconazole. An episode of OPC was considered refractory if there was
failure to improve or worsening of OPC after a standard course of therapy with
fluconazole ≥ 100 mg/day for at least 10 consecutive days or itraconazole 200
mg/day for at least 10 consecutive days and treatment with either fluconazole or
itraconazole had not been discontinued for more than 14 days prior to treatment
with posaconazole. Of the 199 subjects enrolled in this study, eighty-nine
subjects met these strict criteria for refractory infection.
Forty-five subjects with refractory OPC were treated with posaconazole 400 mg
BID for three days, followed by 400 mg QD for 25 days with an option for further
treatment during a 3-month maintenance period. Following a dosing amendment, a
further 44 subjects were treated with posaconazole 400 mg BID for twenty-eight
days. The efficacy of posaconazole was assessed by the clinical success (cure or
improvement) rate after 4 weeks of treatment. The clinical success rate was
74.2% (66/89). The clinical success rates for both the original and the amended
dosing regimens were similar (73.3% and 75.0%, respectively).
For information on a pharmacokinetic/pharmacodynamic analysis of patient data
see CLINICAL PHARMACOLOGY, Exposure Response Relationship section.
INDICATIONS AND USAGE
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 (HSCT) recipients
with graft-versus-host disease (GVHD) or those with hematologic malignancies
with prolonged neutropenia from chemotherapy (see MICROBIOLOGY and CLINICAL
STUDIES).
NOXAFIL (posaconazole) is indicated for the treatment of oropharyngeal
candidiasis, including oropharyngeal candidiasis refractory to itraconazole
and/or fluconazole (see MICROBIOLOGY and CLINICAL STUDIES).
CONTRAINDICATIONS
Hypersensitivity to the active substance or to any of the excipients.
Co-administration of NOXAFIL® (posaconazole) with sirolimus is contraindicated.
(see CLINICAL PHARMACOLOGY/Drug Interactions section, and PRECAUTIONS, Drug
Interactions section).
Co-administration with ergot alkaloids (see PRECAUTIONS/DrugInteractions).
Co-administration with the CYP3A4 substrates terfenadine, astemizole, cisapride,
pimozide, halofantrine, or quinidine since this may result in increased plasma
concentrations of these medicinal products, leading to QTc prolongation and rare
occurrences of torsades de pointes (see CLINICAL PHARMACOLOGY/Drug Interactions
and PRECAUTIONS/Drug Interactions).
WARNINGS
Hypersensitivity There is no information regarding cross-sensitivity between
NOXAFIL® and other azole antifungal agents. Caution should be used when
prescribing NOXAFIL to patients with hypersensitivity to other azoles.
Hepatic Toxicity In clinical trials, there were infrequent cases of hepatic
reactions (eg, mild to moderate elevations in ALT, AST, alkaline phosphatase,
total bilirubin, and/or clinical hepatitis). 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. Rarely, more severe hepatic reactions including
cholestasis or hepatic failure including fatalities were reported in patients
with serious underlying medical conditions (eg, hematologic malignancy) during
treatment with posaconazole. These severe hepatic events were seen primarily in
subjects receiving the 800 mg daily (400 mg BID or 200 mg QID) in another
indication.
Monitoring of hepatic function Liver function tests should be evaluated at the
start of and during the course of posaconazole therapy. Patients who develop
abnormal liver function tests during posaconazole therapy should be monitored
for the development of more severe hepatic injury. Patient management should
include laboratory evaluation of hepatic function (particularly liver function
tests and bilirubin). Discontinuation of posaconazole must be considered if
clinical signs and symptoms consistent with liver disease develop that may be
attributable to posaconazole.
Cyclosporine drug interaction Cases of elevated cyclosporine levels resulting in
rare serious adverse events, including nephrotoxicity and leukoencephalopathy,
and death were reported in clinical efficacy studies. Dose reduction and more
frequent clinical monitoring of cyclosporine and tacrolimus, should be performed
when posaconazole therapy is initiated (see PRECAUTIONS, Drug Interactions
section).
PRECAUTIONS
Arrhythmias and QT prolongation Some azoles, including posaconazole, have been
associated with prolongation of the QT interval on the electrocardiogram.
Results from a multiple time-matched ECG analysis in healthy volunteers did not
show any increase in the mean of the QTc interval. During clinical development
there was one case of torsades de pointes in a patient taking posaconazole. This
patient was seriously ill with multiple confounding risk factors including a
history of cardiotoxic chemotherapy, hypokalemia, and concomitant medications
that may have been contributory.
Posaconazole should be administered with caution to patients with potentially
proarrhythmic conditions and should not be administered with drugs that are
known to prolong the QTc interval and are metabolized through CYP3A4 (see
CLINICAL PHARMACOLOGY, ElectrocardiogramEvaluation section;
CONTRAINDICATIONS;and PRECAUTIONS,DrugInteractions section). Rigorous attempts
to correct potassium, magnesium, and calcium should be made before starting
posaconazole.
Information for Patients
Patients should be advised to:
* Take each dose of NOXAFIL® Oral Suspension during or immediately (i.e. within
20 minutes) following a full meal or liquid nutritional supplement in order to
enhance absorption.
* Inform their physician if they develop severe diarrhea or vomiting as these
conditions may decrease the plasma concentrations of posaconazole.
* Inform their physician if they are taking other drugs or before they begin
taking other drugs as certain drugs can decrease the plasma concentrations of
posaconazole (see CLINICAL PHARMACOLOGY, Drug Interactions section).
Drug Interactions
A summary of significant drug interactions with posaconazole that have been
studied clinically are provided in Tables 8 and 9. Appropriate precautions for
the co-administration of these drugs with posaconazole are provided (see
CLINICALPHARMACOLOGY/DrugInteractions section, CONTRAINDICATIONS and WARNINGS).
TABLE 8. Summary of the Effect of Co-administered Drugs on Posaconazole
Co-administered Drug Recommendations
Cimetidine Avoid concomitant use unless the benefit outweighs the risks.
Rifabutin Avoid concomitant use unless the benefit outweighs the risks.
Phenytoin Avoid concomitant use unless the benefit outweighs the risks.
Efavirenz Avoid concomitant use unless the benefit outweighs the risks.
Esomeprazole Monitor closely for breakthrough fungal infections
Metoclopramide Monitor closely for breakthrough fungal infections
Co-administration of these drugs listed in Table 8 with posaconazole may result
in lower plasma concentrations of posaconazole.
TABLE 9. Summary of the Effect of Posaconazole on Co-administered Drugs
Co-administered Drug Recommendations
Sirolimus Co-administration of posaconazole with sirolimus is contraindicated (see CLINICAL PHARMACOLOGY, Drug Interactions sectionand CONTRAINDICATIONS).
Cyclosporine Increased cyclosporine concentrations resulted in cyclosporine dose reductions in heart transplant patients co-administered posaconazole. At initiation of posaconazole treatment, reduce the cyclosporine dose to approximately three-fourths of the original dose. Frequent monitoring of cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the cyclosporine dose adjusted accordingly.
Tacrolimus Posaconazole has been shown to increase Cmax and AUC of tacrolimus significantly. At initiation of posaconazole treatment, reduce the tacrolimus dose to approximately one-third of the original dose. Frequent monitoring of tacrolimus whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus dose adjusted accordingly.
Rifabutin Concomitant use of posaconazole and rifabutin should be avoided unless the benefit to the patient outweighs the risk. However, if concomitant administration is required frequent monitoring of full blood counts and adverse events due to increased rifabutin levels (eg, uveitis, leukopenia) is recommended.
Midazolam Frequent monitoring of adverse effects of benzodiazepines metabolized by CYP3A4 should be performed and dose reduction of these benzodiazepines should be considered during co-administration with posaconazole.
Phenytoin Frequent monitoring of phenytoin concentrations should be performed while co-administered with posaconazole and dose reduction of phenytoin should be considered.
Atazanavir Frequent monitoring of adverse effects and toxicity of atazanavir should be performed during co-administration with posaconazole.
Ritonavir Frequent monitoring of adverse effects and toxicity of ritonavir should be performed during co-administration with posaconazole.
Although not studied in vitro or in vivo, posaconazole may affect the plasma
concentrations of the drugs or drug classes described in Table 10. Appropriate
precautions for the co-administration of these drugs with posaconazole are
provided (see CONTRAINDICATIONS).
TABLE 10. Drugs Not Studied in vitro or in vivo but Likely to Result in Significant Drug Interactions
Drug or Drug Class (CYP3A4 Substrates) Recommendations
Terfenadine, Astemizole, Pimozide, Cisapride, Quinidine, Halofantrine Increased plasma concentrations of these drugs can lead to QT prolongation with rare occurrences of torsade de pointes.Co-administration with posaconazole is contraindicated (see CONTRAINDICATIONS).
Ergot Alkaloids Posaconazole may increase the plasma concentration of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism. Co-administration of posaconazole with ergot alkaloids is contraindicated (see CONTRAINDICATIONS).
Vinca Alkaloids Posaconazole may increase the plasma concentrations of vinca alkaloids (eg, vincristine and vinblastine) which may lead to neurotoxicity. Therefore, it is recommended that the dose adjustment of the vinca alkaloid be considered.
HMG-CoA reductase inhibitors (statins) metabolized through CYP3A4 It is recommended that dose reduction of statins be considered during co-administration. Increased statin concentrations in plasma can be associated with rhabdomyolysis.
Calcium Channel Blockers metabolized through CYP3A4 Frequent monitoring for adverse events and toxicity related to calcium channel blockers is recommended during co-administration. Dose reduction of calcium channel blockers may be needed.
Digoxin Increased plasma concentrations of digoxin have been reported in patients receiving digoxin and posaconazole. Therefore, monitoring of digoxin plasma concentrations is recommended during co-administration.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No drug-related neoplasms were recorded in rats or mice treated with
posaconazole for two years at doses below the maximum tolerated dose. In a
two-year carcinogenicity study, rats were given posaconazole orally at doses up
to 20 mg/kg (females), or 30 mg/kg (males). These doses are equivalent to 3.9 or
3.5 times the exposure achieved with a 400 mg BID regimen, respectively, based
on steady-state AUC in healthy volunteers administered a high-fat meal (400 mg
BID regimen). In the mouse study, mice were treated at oral doses up to 60
mg/kg/day or 4.8 times the exposure achieved with a 400 mg BID regimen.
Posaconazole was not genotoxic or clastogenic when evaluated in bacterial
mutagenicity (Ames), a chromosome aberration study in human peripheral blood
lymphocytes, a Chinese hamster ovary cell mutagenicity study, and a mouse bone
marrow micronucleus study.
Posaconazole had no effect on fertility of male rats at a dose up to 180 mg/kg
(1.7 x the 400 mg BID regimen based on steady-state plasma concentrations in
healthy volunteers) or female rats at a dose up to 45 mg/kg (2.2 x the 400 mg
BID regimen).
Pregnancy
Pregnancy Category C. Posaconazole has been shown to cause skeletal
malformations (cranial malformations and missing ribs) in rats when given in
doses ≥27 mg/kg (≥1.4 times the 400 mg BID regimen based on steady-state plasma
concentrations of drug in healthy volunteers). The no-effect dose for
malformations in rats was 9 mg/kg, which is 0.7 times the exposure achieved with
the 400 mg BID regimen. No malformations were seen in rabbits at doses up to 80
mg/kg. In the rabbit, the no-effect dose was 20 mg/kg, while high doses of 40
mg/kg and 80 mg/kg, 2.9 or 5.2 times the exposure achieved with the 400 mg BID
regimen, caused an increase in resorptions. In rabbits dosed at 80 mg/kg, a
reduction in body weight gain of females and a reduction in litter size was
seen. There are no adequate and well-controlled studies in pregnant women.
Posaconazole should be used in pregnancy only if the potential benefit justifies
the potential risk to the fetus.
Nursing Mothers
Posaconazole is excreted in milk of lactating rats.The excretion of posaconazole
in human breast milk has not been investigated. NOXAFIL should not be used by
nursing mothers unless the benefit to the mother clearly outweighs the potential
risk to the infant.
Pediatric Use
A total of 12 patients 13 to 17 years of age received 600 mg/day (200 mg three
times a day) for prophylaxis of invasive fungal infections. The safety profile
in these patients <18 years of age appears similar to the safety profile
observed in adults. Based on pharmacokinetic data in 10 of these pediatric
patients, the mean steady-state average posaconazole concentration (Cav) was
similar between these patients and adults (≥ 18 years of age).
A total of 16 patients 8 to 17 years of age were treated with 800 mg/day (400 mg
twice a day or 200 mg four times a day) in a study for another indication. Based
on pharmacokinetic data in 12 of these pediatric patients, the mean steady-state
average posaconazole concentration (Cav) was similar between these patients and
adults (≥18 years of age) (see CLINICAL PHARMACOLOGY, Pharmacokinetics in
Special Populations,Pediatric section).
Safety and effectiveness of posaconazole in pediatric patients below the age of
13 years have not been established.
Geriatric Use
Of the 605 patients randomized to posaconazole in the prophylaxis clinical
trials, 63 (10%) were ≥65 years of age. In addition, 48 patients treated with
≥800 mg/day posaconazole in another indication were ≥65 years of age. No overall
differences in safety were observed between the geriatric patients and younger
patients; therefore, no dosage adjustment is recommended for geriatric patients.
(see CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Populations,Geriatric
section).
ADVERSE REACTIONS
The safety of posaconazole therapy has been assessed in 1844 patients. This
includes 605 patients in the prophylaxis studies, 796 in OPC/rOPC studies, and
over 400 patients treated for other indications. Posaconazole therapy was given
to 171 patients for ≥ 6 months, with 58 patients receiving posaconazole therapy
for ≥ 12 months.
Prophylaxis of Aspergillus and Candida
Table 11 presents treatment-emergent adverse events observed at an incidence
>10% in posaconazole prophylaxis studies.
TABLE 11. Study 1 and Study 2. Number (%) of Randomized Subjects Reporting Treatment-Emergent
Adverse Events: Frequency of at Least 10% in the Posaconazole or Fluconazole Treatment
Groups (Pooled Prophylaxis Safety Analysis)
Posaconazole Fluconazole Itraconazole
(n=605) (n=539) (n=58)
Subjects Reporting any Adverse Event 595 (98) 531 (99) 58 (100)
Body as a Whole - General Disorders
Fever 274 (45) 254 (47) 32 (55)
Headache 171 (28) 141 (26) 23 (40)
Rigors 122 (20) 87 (16) 17 (29)
Fatigue 101 (17) 98 (18) 5 (9)
Edema Legs 93 (15) 67 (12) 11 (19)
Anorexia 92 (15) 94 (17) 16 (28)
Dizziness 64 (11) 56 (10) 5 (9)
Edema 54 (9) 68 (13) 8 (14)
Weakness 51 (8) 52 (10) 2 (3)
Cardiovascular Disorders, General
Hypertension 106 (18) 88 (16) 3 (5)
Hypotension 83 (14) 79 (15) 10 (17)
Disorders of Blood and Lymphatic System
Anemia 149 (25) 124 (23) 16 (28)
Neutropenia 141 (23) 122 (23) 23 (40)
Febrile Neutropenia 118 (20) 85 (16) 23 (40)
Disorders of the Reproductive System and Breast
Vaginal Hemorrhagea 24 (10) 20 (9) 3 (12)
Gastrointestinal System Disorders
Diarrhea 256 (42) 212 (39) 35 (60)
Nausea 232 (38) 198 (37) 30 (52)
Vomiting 174 (29) 173 (32) 24 (41)
Abdominal Pain 161 (27) 147 (27) 21 (36)
Constipation 126 (21) 94 (17) 10 (17)
Mucositis NOS 105 (17) 68 (13) 15 (26)
Dyspepsia 61 (10) 50 (9) 6 (10)
Heart Rate and Rhythm Disorders
Tachycardia 72 (12) 75 (14) 3 (5)
Infection and Infestations
Bacteremia 107 (18) 98 (18) 16 (28)
Herpes Simplex 88 (15) 61 (11) 10 (17)
Cytomegalovirus Infection 82 (14) 69 (13) 0
Pharyngitis 71 (12) 60 (11) 12 (21)
Upper Respiratory Tract Infection 44 (7) 54 (10) 5 (9)
Liver and Biliary System Disorders
Bilirubinemia 59 (10) 51 (9) 11 (19)
Metabolic and Nutritional Disorders
Hypokalemia 181 (30) 142 (26) 30 (52)
Hypomagnesemia 110 (18) 84 (16) 11 (19)
Hyperglycemia 68 (11) 76 (14) 2 (3)
Hypocalcemia 56 (9) 55 (10) 5 (9)
Musculoskeletal System Disorders
Musculoskeletal Pain 95 (16) 82 (15) 9 (16)
Arthralgia 69 (11) 67 (12) 5 (9)
Back Pain 63 (10) 66 (12) 4 (7)
Platelet, Bleeding and Clotting Disorders
Thrombocytopenia 175 (29) 146 (27) 20 (34)
Petechiae 64 (11) 54 (10) 9 (16)
Psychiatric Disorders
Insomnia 103 (17) 92 (17) 11 (19)
Anxiety 52 (9) 61 (11) 9 (16)
Respiratory System Disorders
Coughing 146 (24) 130 (24) 14 (24)
Dyspnea 121 (20) 116 (22) 15 (26)
Epistaxis 82 (14) 73 (14) 12 (21)
Skin and Subcutaneous Tissue Disorders
Rash 113 (19) 96 (18) 25 (43)
Pruritus 69 (11) 62 (12) 11 (19)
a Percentages of sex-specific adverse events are based on the number of males/females.
NOS = not otherwise specified.
Tables 12 and 13 present treatment-related adverse events observed at an
incidence ≥2% in the posaconazole prophylaxis studies.
TABLE 12. Study 1. Treatment-Related Adverse Events, Occurring in Greater Than or Equal to 2% of
Patients in Posaconazole or Fluconazole Treatment Group
Posaconazole Fluconazole
N=301 N=299
n (%) n (%)
Body System/Preferred Term
Subjects Reporting Any Adverse Event 107 (36) 115 (38)
Body as a Whole - General Disorders
Drug Level Altered 5 (2) 2 (1)
Dizziness 4 (1) 5 (2)
Fatigue 4 (1) 6 (2)
Anorexia 3 (1) 7 (2)
Headache 3 (1) 8 (3)
Weakness 3 (1) 5 (2)
Cardiovascular Disorders, General
Hypertension 2 (1) 5 (2)
Central and Peripheral Nervous System Disorders
Tremor 4 (1) 6 (2)
Disorders of the Eye
Vision Blurred 3 (1) 5 (2)
Gastrointestinal System Disorders
Nausea 22 (7) 28 (9)
Vomiting 13 (4) 15 (5)
Diarrhea 8 (3) 12 (4)
Abdominal Pain 4 (1) 7 (2)
Dyspepsia 3 (1) 6 (2)
Constipation 1 (<1) 5 (2)
Liver and Biliary System Disorders
SGPT Increased 9 (3) 4 (1)
GGT Increased 9 (3) 7 (2)
Bilirubinemia 8 (3) 5 (2)
Hepatic Enzymes Increased 8 (3) 7 (2)
SGOT Increased 8 (3) 3 (1)
Metabolic and Nutritional Disorders
Phosphatase Alkaline Increased 5 (2) 5 (2)
Renal and Urinary System Disorders
Blood Creatinine Increased 6 (2) 5 (2)
Special Senses, Other Disorders
Taste Perversion 3 (1) 5 (2)
GGT = gamma-glutamyl transpeptidase; SGOT = serum glutamic oxaloacetic transaminase; SGPT = serum glutamic pyruvic transaminase.
TABLE 13. Study 2. Treatment-Related Adverse Events, Occurring in Greater Than or Equal to 2% of
Patients in Posaconazole or Fluconazole/Itraconazole Treatment Group
Number (%) of Patients
Posaconazole Fluconazole/ Fluconazole Itraconazole
(n=304) Itraconazole (n=240) (n=58)
(n=298)
Body System/Preferred Term
Subjects Reporting Any Adverse Event 102 (34) 101 (34) 71 (30) 30 (52)
Body as a Whole -
General Disorders
Headache 5 (2) 1 (<1) 0 1 (2)
Gastrointestinal System Disorders
Nausea 22 (7) 25 (8) 17 (7) 8 (14)
Diarrhea 20 (7) 21 (7) 12 (5) 9 (16)
Vomiting 14 (5) 20 (7) 14 (6) 6 (10)
Abdominal Pain 9 (3) 9 (3) 8 (3) 1 (2)
Mucositis NOS 7 (2) 0 0 0
Dyspepsia 5 (2) 3 (1) 3 (1) 0
Constipation 3 (1) 7 (2) 7 (3) 0
Heart Rate and Rhythm Disorders
QT/QTc Prolongation 12 (4) 9 (3) 5 (2) 4 (7)
Liver and Biliary System Disorders
Bilirubinemia 7 (2) 8 (3) 5 (2) 3 (5)
Hepatic Enzymes Increased 7 (2) 3 (1) 3 (1) 0
SGPT Increased 7 (2) 5 (2) 4 (2) 1 (2)
SGOT Increased 6 (2) 5 (2) 4 (2) 1 (2)
GGT Increased 5 (2) 2 (1) 1 (<1) 1 (2)
Metabolic and Nutritional Disorders
Hypokalemia 9 (3) 6 (2) 5 (2) 1 (2)
Skin and Subcutaneous Tissue Disorders
Rash 9 (3) 11 (4) 10 (4) 1 (2)
GGT = gamma-glutamyl transpeptidase; NOS = not otherwise specified; SGOT = serum glutamic oxaloacetic transaminase; SGPT = serum glutamic pyruvic transaminase.
The most common treatment-related serious adverse events (1% each) in the
combined prophylaxis studies were bilirubinemia, increased hepatic enzymes,
hepatocellular damage, nausea, and vomiting.
Overview of Adverse Events in HIV-infected subjects with OPC
In two randomized comparative studies in OPC, the safety of posaconazole at a
dose of ≤ 400 mg QD in 557 HIV-infected patients was compared to the safety of
fluconazole in 262 HIV-infected patients at a dose of 100 mg QD.
An additional 239 HIV-infected patients with refractory OPC received
posaconazole in 2 non-comparative trials for refractory OPC (rOPC). Of these
subjects, 149 received the 800 mg/day dose and the remainder received the ≤400
mg QD dose.
Table 14 presents Treatment-Emergent Adverse Events of Clinical Significance in
the comparative and non-comparative studies of OPC.
TABLE 14. Treatment-Emergent Adverse Events of Clinical Significance in OPC studies
Number (%) of Subjects
Controlled OPC Pool Refractory OPC Pool
Posaconazole Fluconazole Posaconazole
n=557 n=262 n=239
Subjects Reporting any Adverse Eventa 356 (64) 175 (67) 221 (92)
Body as a Whole - General Disorders
Fever 34 (6) 22 (8) 82 (34)
Headache 44 (8) 23 (9) 47 (20)
Anorexia 10 (2) 4 (2) 46 (19)
Fatigue 18 (3) 12 (5) 31 (13)
Asthenia 9 (2) 5 (2) 31 (13)
Rigors 2 (<1) 4 (2) 29 (12)
Pain 4 (1) 2 (1) 27 (11)
Disorders of Blood and Lymphatic System
Neutropenia 21 (4) 8 (3) 39 (16)
Anemia 11 (2) 5 (2) 34 (14)
Neutropenia Aggravated 0 0 5 (2)
Gastrointestinal System Disorders
Diarrhea 58 (10) 34 (13) 70 (29)
Nausea 48 (9) 30 (11) 70 (29)
Vomiting 37 (7) 18 (7) 67 (28)
Abdominal Pain 27 (5) 17 (6) 43 (18)
Infection and Infestations
Candidiasis, Oral 3 (1) 1 (<1) 28 (12)
Herpes Simplex 16 (3) 8 (3) 26 (11)
Pneumonia 17 (3) 6 (2) 25 (10)
Liver and Biliary System Disorders
Bilirubinemia 6 (1) 2 (1) 6 (3)
Hepatic Enzymes Increased 1 (<1) 1 (<1) 8 (3)
Hepatic Function Abnormal 8 (1) 4 (2) 0
Hepatitis 3 (1) 0 5 (2)
Hepatomegaly 0 0 8 (3)
Jaundice 0 0 4 (2)
SGOT Increased 8 (1) 5 (2) 6 (3)
SGPT Increased 6 (1) 5 (2) 6 (3)
Metabolic and Nutritional Disorders
Weight Decrease 4 (1) 2 (1) 33 (14)
Dehydration 4 (1) 7 (3) 27 (11)
Hypokalemia 6 (1) 3 (1) 15 (6)
Platelet, Bleeding, and Clotting Disorders
Thrombocytopenia 4 (1) 1 (<1) 12 (5)
Psychiatric Disorders
Insomnia 8 (1) 3 (1) 39 (16)
Renal & Urinary System Disorders
Renal Failure Acute 0 0 7 (3)
Respiratory System Disorders
Coughing 18 (3) 11 (4) 60 (25)
Dyspnea 8 (1) 8 (3) 28 (12)
Skin and Subcutaneous Tissue Disorders
Rash 15 (3) 10 (4) 36 (15)
Sweating Increased 13 (2) 5 (2) 23 (10)
OPC=oropharyngeal candidiasis;
SGOT=serum glutamic oxaloacetic transaminase (same as AST); SGPT=serum glutamic pyruvic transaminase (same as ALT).
a Number of subjects reporting treatment-emergent adverse events at least once during the study, without regard to
relationship to treatment. Subjects may have reported more than one event.
Treatment-related, treatment-emergent events observed in patients with OPC at an
incidence of ≥2% are shown in Table 15.
TABLE 15. Treatment-Related Adverse Events (Any Grade) ≥ 2%
Number (%) of Subjects
Controlled OPC Pool Refractory OPC Pool
Posaconazole Fluconazole Posaconazole
Adverse Event n=557 n=262 n=239
Subjects Reporting any Adverse Eventa 150 (27) 70 (27) 135 (56)
Headache 16 (3) 5 (2) 18 (8)
Anorexia 6 (1) 1 (<1) 7 (3)
Asthenia 4 (1) 2 (1) 6 (3)
Dizziness 9 (2) 5 (2) 8 (3)
Fatigue 8 (1) 5 (2) 7 (3)
Fever 10 (2) 1 (<1) 6 (3)
Central and Periph Nerv System
Somnolence 4 (1) 5 (2) 3 (1)
Disorders of Blood and Lymphatic System
Neutropenia 10 (2) 4 (2) 20 (8)
Anemia 2 (<1) 0 6 (3)
Gastrointestinal System Disorders
Diarrhea 19 (3) 13 (5) 26 (11)
Nausea 27 (5) 18 (7) 20 (8)
Vomiting 20 (4) 4 (2) 16 (7)
Abdominal Pain 10 (2) 8 (3) 12 (5)
Flatulence 6 (1) 0 11 (5)
Mouth Dry 7 (1) 6 (2) 5 (2)
Liver and Biliary System Disorders
Hepatic Enzymes Increased 1 (<1) 0 5 (2)
Hepatic Function Abnormal 3 (1) 4 (2) 0
Metabolic and Nutritional Disorders
Phosphatase Alkaline Increased 3 (1) 3 (1) 5 (2)
Musculoskeletal System Disorders
Myalgia 1 (<1) 0 4 (2)
Platelet, Bleeding, and Clotting Disorders
Thrombocytopenia 3 (1) 0 4 (2)
Psychiatric Disorders
Insomnia 3 (1) 0 6 (3)
Skin and Subcutaneous Tissue Disorders
Rash 8 (1) 4 (2) 10 (4)
Pruritus 6 (1) 2 (1) 5 (2)
OPC=oropharyngeal candidiasis;
SGOT=serum glutamic oxaloacetic transaminase (same as AST); SGPT=serum glutamic pyruvic transaminase (same as ALT).
a Number of subjects reporting treatment-related adverse events at least once during the study, without regard to
relationship to treatment. Subjects may have reported more than one event.
Adverse events were reported more frequently in the pool of patients with
refractory OPC. Among these highly immunocompromised patients with advanced HIV
disease, serious adverse events (SAEs) were reported in 55% (132/239). The most
commonly reported SAEs were fever (13%) and neutropenia (10%).
Treatment-related SAEs were reported for 14% (34/239) of these patients and
included neutropenia (5%) and abdominal pain (2%). Posaconazole was discontinued
in two patients who developed neutropenia that was considered serious and
treatment-related. All other reported treatment-related SAEs occurred in ≤ 1% of
subjects on posaconazole.
Uncommon and rare treatment related serious or medically significant adverse
events reported during clinical trials in prophylaxis, OPC/rOPC or other
indications with posaconazole have included adrenal insufficiency, allergic
and/or hypersensitivity reactions.
Rare cases of hemolytic uremic syndrome, thrombotic thrombocytopenic purpura,
and pulmonary embolus have been reported primarily among patients who had been
receiving concomitant cyclosporine or tacrolimus for management of transplant
rejection or graft-vs-host disease.
During clinical development there was a single case of torsade de pointes in a
patient taking posaconazole. This report involved a seriously ill patient with
multiple confounding, potentially contributory risk factors, such as a history
of palpitations, recent cardiotoxic chemotherapy, hypokalemia, and
hypomagnesemia.
Additionally, in another indication, 428 patients were treated with ≥800 mg/day
with a similar AE profile.
Clinical Laboratory Values
In healthy volunteers and patients, elevation of liver function test values did
not appear to be associated with higher plasma concentrations of posaconazole.
The majority of abnormal liver function test results were minor, transient, and
did not lead to discontinuation of therapy.
For the prophylaxis studies, the number of patients with changes in liver
function tests from Common Toxicity Criteria (CTC) Grade 0, 1, or 2 at baseline
to Grade 3 or 4 during the study is presented in Table 16.
TABLE 16. Study 1 and Study 2. Changes in Liver Function Test Results from CTC Grade 0, 1, or 2 at
Baseline to Grade 3 or 4
Number (%) of Patients With Changea
Study 1
Laboratory Parameter Posaconazole Fluconazole
N=301 N=299
AST 11/266 (4) 13/266 (5)
ALT 47/271 (17) 39/272 (14)
Bilirubin 24/271 (9) 20/275 (7)
Alkaline Phosphatase 9/271 (3) 8/271 (3)
Study 2
Posaconazole Fluconazole/Itraconazole
(n=304) (n=298)
AST 9/286 (3) 5/280 (2)
ALT 18/289 (6) 13/284 (5)
Bilirubin 20/290 (7) 25/285 (9)
Alkaline Phosphatase 4/281 (1) 1/276 (<1)
a Change from Grade 0 to 2 at baseline to Grade 3 or 4 during the study. These data are presented in the form X/Y, where X represents the number of patients who met the criterion as indicated, and Y represents the number of patients who had a baseline observation and at least one post-baseline observation.
CTC = Common Toxicity Criteria; AST= Aspartate Aminotransferase; ALT= Alanine Aminotransferase.
The number of patients treated for OPC with clinically significant liver
function test (LFT) abnormalities at any time during the studies is provided in
Table 17 (LFT abnormalities were present in some of these patients prior to
initiation of the study drug).
TABLE 17. Clinically Significant Laboratory Test Abnormalities Without Regard to Baseline Value
Laboratory Test Controlled Refractory
Posaconazole Fluconazole Posaconazole
n= 557 n=262 n=239
ALT > 3.0 x ULN 16/537 (3) 13/254 (5) 25/226 (11)
AST > 3.0 x ULN 33/537 (6) 26/254 (10) 39/223 (17)
Total Bilirubin > 1.5 x ULN 15/536 (3) 5/254 (2) 9/197 (5)
Alkaline Phosphatase > 3.0 x ULN 17/535 (3) 15/253 (6) 24/190 (13)
ALT= Alanine Aminotransferase; AST= Aspartate Aminotransferase.
OVERDOSAGE
During the clinical trials, some patients received posaconazole up to 1600
mg/day with no adverse events noted that were different from the lower doses. In
addition, accidental overdose was noted in one patient who took 1200 mg BID for
3 days. No related adverse events were noted by the investigator.
Posaconazole is not removed by hemodialysis.
DOSAGE AND ADMINISTRATION
Indication Dose and Duration of therapy
Prophylaxis of Invasive Fungal Infections 200 mg (5 mL) three times a day. The duration of therapy is based on recovery from neutropenia or immunosuppression.
Oropharyngeal Candidiasis Loading dose of 100 mg (2.5 mL) twice a day on the first day, then 100 mg (2.5 mL) once a day for 13 days.
Oropharyngeal Candidiasis Refractory to itraconazole and/or fluconazole 400 mg (10 mL) twice a day. Duration of therapy should be based on the severity of the patient`s underlying disease and clinical response.
Each dose of NOXAFIL® should be administered with a full meal or with a liquid
nutritionalsupplement in patients who cannot eat a full meal (see CLINICAL
PHARMACOLOGY).
Alternatively, NOXAFIL may be taken with an acidic carbonated beverage (e.g.
ginger ale).
To enhance the oral absorption of posaconazole and optimize plasma
concentrations:
* Each dose of NOXAFIL Oral Suspension should be administered during or
immediately (i.e. within 20 minutes) following a full meal or liquid nutritional
supplement. For patients who cannot eat a full meal or tolerate an oral
nutritional supplement, alternative antifungal therapy should be considered or
patients should be monitored closely for breakthrough fungal infections.
* Patients who have severe diarrhea or vomiting should be monitored closely for
breakthrough fungal infections.
* Co-administration 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 (see CLINICAL PHARMACOLOGY, Drug Interactions
section).
Shake NOXAFIL® Oral Suspension well before use.
A measured dosing spoon is provided, marked for doses of 2.5 mL and 5 mL.
(Graphic Omitted)
It is recommended that the spoon is rinsed with water after each administration
and before storage.
Renal Insufficiency
No dose adjustment is recommended for patients with renal dysfunction. However,
the range of the posaconazole AUC estimates was highly variable (CV=96%) in
subjects with severe renal insufficiency as compared to that in the other renal
impairment groups (CV<40%). Due to the variability in exposure, patients with
severe renal impairment should be monitored closely for breakthrough IFIs (see
CLINICAL PHARMACOLOGY).
Hepatic Insufficiency
No dose adjustment of NOXAFIL is needed in patients with mild to severe hepatic
insufficiency (Child-Pugh Class A, B, and C). (See CLINICAL
PHARMACOLOGY/Pharmacokinetics in Special Populations).
HOW SUPPLIED
NOXAFIL® (posaconazole) Oral Suspension is available in 4-ounce (123 mL) amber
glass bottles with child-resistant closures (NDC 0085-1328-01) containing 105 mL
of suspension (40 mg of posaconazole per mL).
Supplied with each bottle is a plastic dosing spoon calibrated for measuring
2.5- mL and 5-mL doses.
Store at 25oC (77oF); excursions permitted to 15-30oC (59-86oF) [see USP
Controlled Room Temperature]. DO NOT FREEZE.
Schering-Plough
Kenilworth, NJ 07033 USA
Copyright © 2006, 2008, Schering Corporation. All rights reserved.
U.S. Patent Nos. 5,661,151; 5,703,079; and 6,958,337.
BOOST® Drink is a registered trademark of Nestlé Healthcare Nutrition, Inc.
31153620T
2/09
31157528T
PATIENT INFORMATION
NOXAFIL®
(posaconazole) ORAL SUSPENSION
Read the Patient Information that comes with NOXAFIL® before you start taking it
and each time you get a refill. There may be new information. This information
does not replace talking with your doctor about your condition or treatment.
Only your doctor can prescribe NOXAFIL and determine if it is right for you.
What is NOXAFIL?
- NOXAFIL® is a prescription medicine that is used to prevent invasive fungal infections (infections that can spread throughout the body) caused by Aspergillus or Candida in patients with weak immune systems because of medicines or diseases [such as stem cell transplantation with graft versus host disease or chemotherapy for hematologic malignancy (blood cancers)].
- NOXAFIL is also used to treat fungal infections in the mouth or throat area (known as "thrush") caused by fungi called Candida. NOXAFIL can be used as initial treatment or as a treatment after itraconazole and/or fluconazole have failed.
NOXAFIL is for adults and children over 13 years of age.
What should I tell my doctor before taking NOXAFIL?
Tell your doctor about all your health conditions, including if you:
- are taking certain drugs that suppress your immune system like cyclosporine
(Neoral®), tacrolimus (Prograf®),or sirolimus (Rapamune®). Serious and rare
fatal toxicity from cyclosporine has occurred when taken in combination with
posaconazole and, therefore, reduction of the dose of drugs like cyclosporine,
tacrolimus, or atazanavir and frequent monitoring of drug levels of these
medicines is necessary when taking them in combination with posaconazole.
- have ever had an allergic reaction to other antifungal medicines such as
ketoconazole, fluconazole, itraconazole, or voriconazole.
- are taking any other medicines, including prescription and non-prescription
medicines, vitamins, and herbal supplements.
- have, or have had liver problems. Your doctor may do blood tests to make sure
you should take NOXAFIL®.
- have, or have had an abnormal heart rate or rhythm.
- are, or think you are pregnant. Do not use NOXAFIL during pregnancy unless
specifically advised by your doctor. You should use effective birth control
while you are taking NOXAFIL if you are a woman who could become pregnant.
Contact your doctor immediately if you become pregnant while being treated with
NOXAFIL.
Do not breast-feed while being treated with NOXAFIL, unless specifically advised
by your doctor.
Who should not take NOXAFIL?
- Do NOT take NOXAFIL® if you are taking any of the medicines listed below.
If any of these medicines are taken together with NOXAFIL, serious or life-threatening side effects from these medicines, or a decrease in the effect of NOXAFIL can occur. Tell your doctor right away if you are taking any of these medicines:
* sirolimus
* ergot alkaloids (ergotamine, dihydroergotamine, methylsergide, methylergonovine, ergonovine or bromocriptine)
* terfenadine
* astemizole
* cisapride
* pimozide
* halofantrine
* quinidine
* rifabutin
* phenytoin
* cimetidine
- If you have questions or are uncertain about your medicines, talk with your doctor or pharmacist.
- Do not take NOXAFIL if you are allergic to anything in it. There is a list of what is in NOXAFIL at the end of this leaflet.
Can I take other medicines with NOXAFIL?
NOXAFIL® and many medicines can interact with each other and some must not be
taken together (See "Who should not take NOXAFIL?"). The dose of other medicines
may need to be adjusted when taken with NOXAFIL [for example, cyclosporine
(Neoral®)*, tacrolimus (Prograf®)*, ritonavir, or atazanavir]. (See "What should
I tell my doctor before taking NOXAFIL?")
Knowing the medicines that you are taking is important. Tell your doctor about
all the medicines you take including prescription and non-prescription
medicines, vitamins, and herbal supplements. Keep a list of them with you to
show your doctor or pharmacist. Do not take any new medicine without talking to
your doctor.
What are possible side effects of NOXAFIL?
The most commonly reported side effects related to NOXAFIL® use were nausea,
diarrhea, vomiting, headache, stomach pain, bloating, liver problems, low blood
potassium, and decrease in neutrophils (certain type of white blood cells that
fight infection).
Rarely, NOXAFIL may cause serious or life-threatening side effects.It may also
cause severe drug interactions as discussed above. Call your doctor right away
if you have any of the symptoms listed below.
Changes in heart rate or rhythm. People who have certain heart conditions or who
take certain other medicines have a higher chance for this problem.
Rarely, very serious liver problems were reported in patients with serious
underlying medical conditions. Your doctor may test your liver function while
you are taking NOXAFIL. Call your doctor if you have any of these symptoms, as
these may be signs of liver problems: you have itching, your eyes or skin turn
yellow, you feel more tired than usual or feel like you have the flu, or you
have nausea or vomiting.
Rarely, an increase in blood clots may occur in patients with blood cancers or
post stem cell transplantation. These events may or may not be further increased
in patients also on posaconazole and primarily occurred in patients also
receiving cyclosporine or tacrolimus. If you notice swelling of one leg or
shortness of breath, notify your doctor immediately.
These are not all the side effects associated with NOXAFIL. For more
information, ask your doctor or pharmacist. If you experience any unusual
effects while taking NOXAFIL, contact your doctor immediately.
How do I take NOXAFIL?
* NOXAFIL® comes in cherry-flavored liquid form. Shake NOXAFIL Oral Suspension
well before use.
* Take NOXAFIL for as long as your doctor tells you. Take each dose of NOXAFIL
during or immediately (i.e. within 20 minutes) following a full meal, or with a
liquid nutritional supplement if you are unable to eat a full meal.
Alternatively, NOXAFIL may be taken with an acidic carbonated beverage (e.g.
ginger ale).
* Follow your doctor`s instructions on when and how much of NOXAFIL you should
take.
If you miss a dose of NOXAFIL, take it as soon as you remember.
* If you take too much NOXAFIL, call your doctor or poison control center
immediately.
* Tell your doctor right away if you develop severe diarrhea or vomiting.
A measured dosing spoon is provided, marked for doses of 2.5 mL and 5 mL.
(Graphic Omitted)
It is recommended that the spoon is rinsed with water after each administration
and before storage.
How do I store NOXAFIL?
* Store at 25oC (77oF); excursions permitted to 15-30oC (59-86oF) [see USP
Controlled Room Temperature]. DO NOT FREEZE. Keep all containers tightly closed.
* Keep NOXAFIL®, as well as other medicines, out of the reach of children.
General information about NOXAFIL
Doctors can prescribe medicines for conditions that are not in this leaflet. Use
NOXAFIL® only as directed by your doctor. Do not give it to other people, even
if they have the same symptoms as you. It may harm them.
This leaflet gives the most important information about NOXAFIL. For more
information, talk to your doctor. You can ask your doctor or pharmacist for
information about NOXAFIL that is written for health care professionals.
What is in NOXAFIL?
Active ingredient: posaconazole
Inactive ingredients: polysorbate 80, simethicone, sodium benzoate, sodium
citrate dihydrate, citric acid monohydrate, glycerin, xanthan gum, liquid
glucose, titanium dioxide, artificial cherry flavor, and purified water.
Schering Corporation
Kenilworth, NJ 07033 USA
Rx only
*Trademarks are the property of their respective owners.
Copyright © 2006, 2008 Schering Corporation. All rights reserved.
U.S. Patents 5,661,151; 5,703,079; and 6,958,337.
31157528T
Rev 02/09
Merck
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Ian McConnell, 908-423-3046
Robert Consalvo, 908-423-6595
or
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