Invasive fungal infections will have less of a fighting chance now that a new antifungal has been approved by the Food & Drug
Administration. Posaconazole (Noxafil, Schering-Plough), available as an oral suspension, is indicated for the prophylaxis
of invasive Aspergillus and Candida infections in patients 13 years of age and older who are immunocompromised, such as hematopoietic
stem cell transplant recipients with graft-versus-host disease or those with hematologic malignancies with prolonged neutropenia
from chemotherapy.
Peggy L. Carver, Pharm.D., associate professor at the University of Michigan College of Pharmacy, believes the new drug will
prove very useful in this setting. "We will likely use it since it's orally administered and quite effective with a broad
spectrum of activity." She explained that up until now, she'd been using other antifungals, such as fluconazole, and, rarely,
itraconazole (Sporanox, Sandoz), which is effective but poorly tolerated by patients. Micafungin (Mycamine, Astellas) is also
approved for this indication but requires an IV—which can be a problem given the risk of infection in these patients and the
long-term use of prophylaxis, she said.
According to the manufacturer, the triazole antifungal works by blocking the synthesis of ergosterol, a component in the fungal
cell membrane, through the inhibition of the enzyme lanosterol 14a-demethylase and accumulation of methylated sterol precursors.
Posaconazole is primarily metabolized via UDP glucuroni-dation and is a substrate of p-glycoprotein (P-gp) efflux. Since inhibitors
or inducers of these pathways may affect plasma concentrations of the antifungal, concomitant use of rifabutin, phenytoin,
and cimetidine should be avoided unless the benefit outweighs the risks. Posaconazole is also an inhibitor of CYP3A4, meaning
concentrations of drugs predominantly metabolized by CYP3A4 may be increased. When used concurrently with certain immunosuppressant
drugs, the dose of cyclosporine should be reduced to approximately three-fourths the original dose, and tacrolimus should
be reduced to one-third its original dose when given with posaconazole. In addition, dosage reductions of statins and calcium-channel
blockers should also be considered during coadministration. "From a safety standpoint, clinicians should monitor a patient's hepatic function," pointed out Michael E. Klepser, Pharm.D.,
FCCP, professor of pharmacy, Ferris State University in Kalamazoo, Mich. In fact, according to the prescribing information,
liver function tests (LFTs) should be evaluated at the start of and during the course of posaconazole therapy. Patients who
develop abnormal LFTs during treatment should be monitored for the development of more severe hepatic injury. "In addition,
the absorption of the drug can be highly variable and is best when large daily doses are divided and administered with food,"
Klepser added.
Pharmacokinetic studies have shown that the mean AUC and Cmax of posaconazole are substantially higher when the drug is taken with food than in the fasting state. Therefore, it is recommended
to administer the drug with a full meal or a liquid nutritional supplement. Patients who cannot eat or tolerate a nutritional
supplement should be monitored closely for breakthrough fungal infections.
Posaconazole oral suspension is a white, cherry-flavored, immediate-release suspension containing 40 mg posaconazole per ml
and is available in four-oz. glass bottles.
TIPS TO REMEMBER Noxafil Oral Suspension
- Noxafil should be administered as 200 mg (5 ml) three times a day with a full meal.
- The most common adverse effects associated with Noxafil include fever, diarrhea, nausea, hypokalemia, thrombocytopenia, vomiting,
and headache.
- Noxafil should not be coadministered with ergot alkaloids.
- Noxafil has been shown to prolong the QTc interval on an electrocardiogram leading to rare occurrences of torsades de pointes
and should be used with caution in patients with potentially proarrhythmic conditions.
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