Pharmacy Times

Schering-Plough Corp's Noxafil

Author: Caryn Domenici, RPh; Alka Patel, PharmD; and Lisa Tortora

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.