Pharmacy & Therapeutics- July 2008 - (Page 395) DRUG FORECAST Table 2 Treatment-Related Adverse Effects in Patients Treated with Posaconazole (Noxafil) Adverse Event Fever Diarrhea Nausea Hypokalemia Vomiting Thrombocytopenia Headache Abdominal pain Anemia Percent (%) 45 42 38 30 29 29 28 27 25 200 mg three times a day, and the duration of treatment is based on the recovery of neutropenia or immunosuppression. The dose for patients with orophar yngeal candidiasis is 100 mg twice a day for the first day, followed by 100 mg daily for 13 days. Oropharyngeal candidiasis that is unresponsive to fluconazole or itraconazole should be treated with 400 mg twice daily. The duration of therapy is based on the severity of the patient’s disease and clinical response. profile in shor t-term and long-term experimental studies. Although posaconazole has promising clinical efficacy against life-threatening fungal infections that are often refractor y to the other antifungal agents, it is still considered an alternative option, because potential cost savings are associated with currently available antifungal therapies. REFERENCES 1. Greer ND. Posaconazole (Noxafil): A new triazole antifungal agent. Proc (Bayl Univ Med Center) 2007;20:188–196. 2. Carrillo-Munoz AJ, Giusiano G, Ezkurra PA, et al. Antifungal agents: Mode of action in yeast cells. Rev Esp Quimioter 2006;19:130–139. 3. Noxafil (posaconazole) oral suspension, package insert. Kenilworth, NJ: Schering; 2006. 4. Clinical Pharmacology. Posaconazole drug monograph. Accessed March 2007. 5. Sabatelli F, Patel R, Mann PA, et al. In vitro activities of posaconazole, fluconazole, itraconazole, voriconazole, and amphotericin B against a large collection of clinically important molds and yeasts. Antimicrob Agents Chemother 2006;50: 2009–2015. 6. Courtney R, Wexler D, Radwanski E, et al. Effect of food on the relative bioavailability of two oral formulations of posaconazole in healthy adults. Br J Clin Pharmacol 2004;57:218–222. 7. Ezzet F, Wexler D, Courtney R, et al. Oral bioavailability of posaconazole in fasted healthy subjects: Comparison between three regimens and basis for clinical dosage recommendations. Clin Pharmacokinet 2005;44:211–220. 8. Sansone-Parsons A, Krishna G, Calzetta A, et al. Effect of a nutritional supplement on posaconazole pharmacokinetics following oral administration to healthy volunteers. Antimicrob Agents Chemother 2006;50:1881–1883. 9. Torres-Narbona M, Guinea J, MartínezAlarcón J, et al. In vitro activities of amphotericin B, caspofungin, itraconazole, posaconazole, and voriconazole against 45 clinical isolates of zygomycetes: Comparison of CLSI M38-A, Sensititre Yeast One, and the Etest. Antimicrob Agents Chemother 2007;51: 1126–1129. 10. Cacciapuoti A, Halpern J, Mendrick C, et al. Interaction between posaconazole and caspofungin in concomitant treatment of mice with systemic Aspergillus infection. Antimicrob Agents Chemother 2006;50:2587–2590. 11. Barchiesi F, Spreghini E, Santinelli A, et al. Posaconazole prophylaxis in experimental systemic zygomycosis. Anti microb Agents Chemother 2007;51:73–77. 12. Ullmann AJ, Cornely OA, Burchardt A, et al. Pharmacokinetics, safety, and efficacy of posaconazole in patients with persistent febrile neutropenia or refractory continued on page 426 Vol. 33 No. 7 • July 2008 • COST The average daily cost of posaconazole for prophylaxis of IFI is approximately $84, compared with generic fluconazole ($20) and itraconazole ($40), making it the least cost-effective option based on this comparison. However, formal pharmacoeconomic studies must be performed to assess the difference in cost effeciveness. mouth, headache, and fatigue (Table 2). 12–26 Some of the less common but more notable events reported with posaconazole administration included hypokalemia, rash, anemia, thrombo cytopenia, and QTc prolongation.12–26 In rare instances, severe adverse events have also been reported, including cholestasis, hepatic failure, adrenal insufficiency, allergic or hypersensitivity reactions, hemolytic–uremic syndrome, thrombotic thrombocytopenia purpura, pulmonary embolism, and torsades de pointes.1,3,4 Posaconazole is an inhibitor of CYP 3A4 hepatic enzymes.1,3,4 Drugs undergoing metabolism by the CYP 3A4 pathway may be associated with significant drug–drug interactions with posaconazole. In one study, concentrations of tacrolimus (Prograf, Astellas) were double what they were when taken with posaconazole.1 Another report noted a 30% increase in cyclosporine concentrations with posaconazole administration.1 Concomitant posaconazole administration is contraindicated with terfenadine (Seldane, Hoechst), astemizole (Hismanal, Janssen), pimozide (Orap, Gate), cisapride (Propulsid, Janssen), quinidine, and ergot alkaloids because of their increased potential for QT prolongation.1 (Seldane, Hismanal, and Propulsid are no longer on the market.) During clinical trials, only one case of torsades de pointes was reported in a patient who had other multiple confounding factors.3 It is important to closely monitor patients’ cardiac status when initiating therapy. CONCLUSION Posaconazole is the newest triazole antifungal agent approved for the management of resistant and difficult-to-eradicate fungal infections. It is available as an oral suspension. The daily dose must be divided and administered with a nutritional supplement to improve absorption. For patients who cannot take an oral suspension, posaconazole may be given via nasogastric tubes. In case reports and series, in vitro studies, and clinical trials, posaconazole was active against common as well as emerging, resistant, and rare fungal pathogens, including Candida, Aspergillus, Coccidioides, Rhizopus, Cryptococcus, Fusarium, Mucor, Scedosporium, and Absidia species, among others. Posaconazole is approved by the FDA for preventing invasive Aspergillus and Candida infections in patients at high risk for these opportunistic infections, including stem-cell recipients with graftversus-host disease or those with chemotherapy-induced FN. It is also approved for treating oropharyngeal candidiasis that is refractor y to itraconazole and fluconazole. Posaconazole can become an important treatment option for patients with resistant opportunistic fungal infections when other antifungal options fail or are not tolerated. It has a favorable safety DOSAGE The recommended daily dose of posaconazole for the prophylaxis of IFIs is P&T® 395
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