Schering-Plough Corp's Noxafil

Noxafil (posaconazole) oral suspensionis a triazole antifungal manufactured bySchering-Plough that was approved bythe FDA on September 15, 2006, for prophylaxisof Aspergillus and Candidainfections in patients aged 13 years andolder whose immune system has beenseverely weakened.¹ Patients who becomeseverely immunocompromised asa consequence of chemotherapy orhematopoietic stem cell transplantrecipients with graft-versus-host diseaseare at high risk for developingthese infections.^1,2

Since the introduction of oral triazoleantifungal agents in the 1980s, thespecies of Candida has changed.³ Thischange has led to the emergence ofresistant Candida strains and new fungaldiseases.³ Invasive fungal infections (IFIs)are the leading cause of death in immunocompromisedand critically ill hospitalizedpatients.¹ Older triazole compoundsare limited in their ability to treatthese infections, which justifies the needfor more potent and broad-spectrumtherapeutic options, such as posaconazole.On October 23, 2006, the FDAapproved posaconazole for the treatmentof oropharyngeal candidiasis (OPC)including infections refractory to itraconazoleand/or fluconazole.⁴

Pharmacology/Pharmacokinetics

Posaconazole exerts its mechanism ofaction in the fungal cell wall by blockingthe enzyme lanosterol 14a-demethylaseand accumulation of methylated sterolprecursors. This mechanism inhibits thesynthesis of ergosterol, critical for fungalgrowth.²

Posaconazole has extensive extravasculardistribution and is highly proteinbound(>98%).² Renal excretion is minimal,and dosage adjustments are notnecessary for mild-to-moderate renalimpairment.^2,5 It is suggested that patientswith severe renal impairment beclosely monitored for breakthrough fungalinfections.²

Limited pharmacokinetic data are availablefor posaconazole in patients withhepatic insufficiency. Liver function testsshould be obtained at baseline and duringtherapy. Liver function should return tonormal upon discontinuation of therapy.²

Posaconazole is metabolized primarilyby glucuronidation in the liver, and it hasinactive metabolites. In vitro studies haveshown that posaconazole inhibitsCYP3A4; therefore, concentrations ofdrugs metabolized by this enzyme willincrease.² Some of these includecyclosporine, tacrolimus, rifabutin, benzodiazepines,and phenytoin. Posaconazoleincreases concentrations of pimozide,quinidine, cisapride, and astemizole thatlead to QT prolongation.

Clinical Trials

Two trials evaluated the efficacy ofposaconazole for the prophylaxis of Aspergillusand Candida infections inimmunocompromised patients.² In a randomized,double-blind study (Study #1),patients received posaconazole 200 mgTID or fluconazole 400 mg QD. In a randomized,open-label study (Study #2),patients received either posaconazole200 mg TID with fluconazole suspension400 mg QD or itraconazole solution 200mg PO BID. Both studies confirmed fewerbreakthrough Aspergillus species infectionsin posaconazole-treated patients.²

Two separate studies evaluated the efficacyof posaconazole for the treatment ofOPC in HIV-infected patients. Both studiesreported cure or improvement of OPCwith posaconazole treatment.²

Clinical studies showed a higherabsorption rate when taken with a nutritionalsupplement or a high-fat meal.

Conclusion

The prophylaxis dose for IFIs is 200 mgTID, and the duration of therapy should bedependent on recovery from neutropeniaor immunosuppression. OPC should betreated with a loading dose of 100 mg BIDon day 1, then 100 mg QD for 13 days. Forthe treatment of OPC refractory to itraconazoleand/or fluconazole, a dose of400 mg BID is recommended.

Cherry-flavored Noxafil is available in a105-mL amber glass bottle and should beshaken well before each use.

Adverse effects include headache,fever, diarrhea, bloating, and vomiting.Noxafil is in pregnancy category C, anddata on excretion in breast milk areinconclusive.

Ms. Domenici and Dr. Patel areboth pharmacists at Brigham andWomen's Hospital, Boston, Mass.Ms. Tortora is a sixth-year PharmDcandidate from MassachusettsCollege of Pharmacy currentlyon clinical clerkship in theInvestigational Drug Service atBrigham and Women's Hospital.

References

1. Schering-Plough News Release. Available at: www.schering-plough.com/schering_plough/news/release.jsp?releaseID=906202. AccessedNovember 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 oforal posaconazole administered in single and multiple doses in healthy adults. Antimicrob AgentsChemother. 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-spectrumtriazole antifungal. Lancet Infect Dis. 2005;5:775-785.