General Information

Noxafil (posaconazole) is a triazole antifungal agent. It blocks the synthesis of ergosterol, a key component of the fungal cell membrane, through the inhibition of the enzyme lanosterol 14a-demethylase and accumulation of methylated sterol precursors.

Noxafil is specifically indicated for the prophylaxis of invasive Aspergillus and Candida infections in subjects, 13 years of age and older, who are at high risk of developing these infections due to being severely immunocompromised.

Noxafil is supplied as a 4-ounce (123 mL) suspension designed for oral administration. The recommended initial dose of the drug is 200 mg (5 mL) three times a day with a full meal.

Clinical Results

FDA approval
FDA approval of Noxafil was based on the results of two clinical trials.

Study 1 This randomized, double-blind trial compared 200 mg of posaconazole oral suspension, given three times a day, with 400 mg of fluconazole, given once a day, as prophylaxis against invasive fungal infections in allogeneic hematopoietic stem cell transplant (HSCT) recipients with Graft versus Host Disease (GVHD). Treatment duration was 80 days for posaconazole and 77 days for fluconazole. The primary endpoint was efficacy, evaluated using a composite endpoint of proven/probable invasive fungal infections, death, or treatment with systemic anti-fungal therapy. In this study the clinical failure rate of posaconazole (33%) was similar to fluconazole (37%). Cause mortality was similar at 16 weeks for the posaconazole group (19%) and the fluconazole group (20%).

Study 2 This was a randomized, open-label study that compared 200 mg of posaconazole oral suspension (three times a day), with 400 mg of fluconazole suspension (once daily) or 200 mg itraconazole oral solution (twice a day), as prophylaxis against IFIs in neutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia or myelodysplastic syndromes. Subjects were assessed for 107 days post-treatment. The primary endpoint was the same as study 1. In this study clinical failure was lower for patients treated with posaconazole (27%) when compared to patients treated with fluconazole or itraconazole (42%). Cause mortality was lower at 100 days for the posaconazole treated group (14%) versus the fluconazole and itraconazole groups (21%).

In both study groups subjects receiving posaconazole prophylaxis experienced substantially lower breakthrough infections caused by Aspergillus species when compared to subjects receiving fluconazole or itraconazole.

Ongoing Study Commitments

• Schering has agreed to a deferred pediatric study under PREA for prophylaxis of invasive fungal infections in pediatric patients ages zero months to twelve years of age who are at high risk for developing these infections.
  Final Report Submission: September 15, 2011
  
• Schering has agreed to a post approval study to be conducted among patients receiving antifungal prophylaxis. The study will enroll patients who are at risk for low absorption. Different dosing strategies including the use of therapeutic drug monitoring to increase plasma concentrations will be explored.
  Protocol Submission: by January 2007
  Study Start: by January 2008
  Final Report Submission: by March 2011

Side Effects

Adverse reactions associated with the use of Noxafil may include, but are not limited to, the following:

• fever
• hypokalemia
• thrombocytopenia
• anemia
• diarrhea
• nausea
• insomnia
• abdominal pain
• coughing

In addition, Noxafil has been associated with prolongation of the QT interval on the electrocardiogram. It should be administered with caution to patients with potentially proarrhythmic conditions and should not be administered with drugs that are known to prolong the QTc interval and are metabolized through CYP3A4.

Mechanism of Action

Noxafil is a triazole antifungal agent. It blocks the synthesis of ergosterol, a key component of the fungal cell membrane, through the inhibition of the enzyme lanosterol 14a-demethylase and accumulation of methylated sterol precursors.

Literature References

Notheis G, Tarani L, Costantino F, Jansson A, Rosenecker J, Friederici D, Belohradsky BH, Reinhardt D, Seger R, Schweinitz DV, Wintergerst U Posaconazole for treatment of refractory invasive fungal disease. Mycoses 2006;49 Suppl 1:37-41.

Groll AH, Walsh TJ Antifungal efficacy and pharmacodynamics of posaconazole in experimental models of invasive fungal infections. Mycoses 2006;49 Suppl 1:7-16.

Dodds Ashley ES, Alexander BD Posaconazole. Drugs of today 2005 Jun;41(6):393-400.

Carrillo-Munoz AJ, Quindos G, Ruesga M, Alonso R, del Valle O, Hernandez-Molina JM, McNicholas P, Loebenberg D, Santos P Antifungal activity of posaconazole compared with fluconazole and amphotericin B against yeasts from oropharyngeal candidiasis and other infections. The Journal of antimicrobial chemotherapy 2005 Mar;55(3):317-9. Epub 2005 Feb 10.

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. Antimicrobial Agents and Chemotherapy 2003 Sep;47(9):2788-95.

Additional Information

For additional information regarding Noxafil or fungal infections, please vist the Schering web page.