Noxafil (posaconazole) oral suspension
is a triazole antifungal manufactured by
Schering-Plough that was approved by
the FDA on September 15, 2006, for prophylaxis
of Aspergillus and Candida
infections in patients aged 13 years and
older whose immune system has been
severely weakened.1 Patients who become
severely immunocompromised as
a consequence of chemotherapy or
hematopoietic stem cell transplant
recipients with graft-versus-host disease
are at high risk for developing
these infections.1,2
Since the introduction of oral triazole
antifungal agents in the 1980s, the
species of Candida has changed.3 This
change has led to the emergence of
resistant Candida strains and new fungal
diseases.3 Invasive fungal infections (IFIs)
are the leading cause of death in immunocompromised
and critically ill hospitalized
patients.1 Older triazole compounds
are limited in their ability to treat
these infections, which justifies the need
for more potent and broad-spectrum
therapeutic options, such as posaconazole.
On October 23, 2006, the FDA
approved posaconazole for the treatment
of oropharyngeal candidiasis (OPC)
including infections refractory to itraconazole
and/or fluconazole.4
Pharmacology/Pharmacokinetics
Posaconazole exerts its mechanism of
action in the fungal cell wall by blocking
the enzyme lanosterol 14a-demethylase
and accumulation of methylated sterol
precursors. This mechanism inhibits the
synthesis of ergosterol, critical for fungal
growth.2
Posaconazole has extensive extravascular
distribution and is highly proteinbound
(>98%).2 Renal excretion is minimal,
and dosage adjustments are not
necessary for mild-to-moderate renal
impairment.2,5 It is suggested that patients
with severe renal impairment be
closely monitored for breakthrough fungal
infections.2
Limited pharmacokinetic data are available
for posaconazole in patients with
hepatic insufficiency. Liver function tests
should be obtained at baseline and during
therapy. Liver function should return to
normal upon discontinuation of therapy.2
Posaconazole is metabolized primarily
by glucuronidation in the liver, and it has
inactive metabolites. In vitro studies have
shown that posaconazole inhibits
CYP3A4; therefore, concentrations of
drugs metabolized by this enzyme will
increase.2 Some of these include
cyclosporine, tacrolimus, rifabutin, benzodiazepines,
and phenytoin. Posaconazole
increases concentrations of pimozide,
quinidine, cisapride, and astemizole that
lead to QT prolongation.
Clinical Trials
Two trials evaluated the efficacy of
posaconazole for the prophylaxis of Aspergillus
and Candida infections in
immunocompromised patients.2 In a randomized,
double-blind study (Study #1),
patients received posaconazole 200 mg
TID or fluconazole 400 mg QD. In a randomized,
open-label study (Study #2),
patients received either posaconazole
200 mg TID with fluconazole suspension
400 mg QD or itraconazole solution 200
mg PO BID. Both studies confirmed fewer
breakthrough Aspergillus species infections
in posaconazole-treated patients.2
Two separate studies evaluated the efficacy
of posaconazole for the treatment of
OPC in HIV-infected patients. Both studies
reported cure or improvement of OPC
with posaconazole treatment.2
Clinical studies showed a higher
absorption rate when taken with a nutritional
supplement or a high-fat meal.
Conclusion
The prophylaxis dose for IFIs is 200 mg
TID, and the duration of therapy should be
dependent on recovery from neutropenia
or immunosuppression. OPC should be
treated with a loading dose of 100 mg BID
on day 1, then 100 mg QD for 13 days. For
the treatment of OPC refractory to itraconazole
and/or fluconazole, a dose of
400 mg BID is recommended.
Cherry-flavored Noxafil is available in a
105-mL amber glass bottle and should be
shaken well before each use.
Adverse effects include headache,
fever, diarrhea, bloating, and vomiting.
Noxafil is in pregnancy category C, and
data on excretion in breast milk are
inconclusive.
Ms. Domenici and Dr. Patel are
both pharmacists at Brigham and
Women's Hospital, Boston, Mass.
Ms. Tortora is a sixth-year PharmD
candidate from Massachusetts
College of Pharmacy currently
on clinical clerkship in the
Investigational Drug Service at
Brigham and Women's Hospital.
References
1. Schering-Plough News Release. Available at:
www.schering-plough.com/schering_plough/news/release.jsp?releaseID=906202. Accessed
November 6, 2006.
2. Noxafil Product Information. Kenilworth, NJ: Schering-Plough; 2006.
3. Courtney R, Pai S, Laughlin M, Lim J, Batra V. Pharmacokinetics, safety, and tolerability of
oral posaconazole administered in single and multiple doses in healthy adults. Antimicrob Agents
Chemother. 2003;47(9):2788-2795.
4. Schering-Plough News Release. Available at:
http://www.schering-plough.com/schering_plough/
news/release.jsp?releaseID=919520.
Accessed November 6, 2006.
5. Torres H, Hachem R, Chemaly R, Kontoyiannos DP, Raad II. Posaconazole: a broad-spectrum
triazole antifungal. Lancet Infect Dis. 2005;5:775-785.
