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 suppled as an injection, delayed-release tablets, and oral suspension, specifically for prophylaxis of invasive Aspergillus and Candida infections in patients who are at high risk of developing these infections due to being severely immunocompromised, such as HSCT recipients with GVHD or those with hematologic malignancies with prolonged neutropenia from chemotherapy.

Noxafil Oral suspension only is specifically indicated for the treatment of oropharyngeal candidiasis (OPC), including OPC refractory (rOPC) to itraconazole and/or fluconazole.

Noxafil delayed-release tablets and oral suspension are not interchangeable due to the differences in the dosing of each formulation. Therefore, follow the specific dosage recommendations for each of the formulations.

Noxafil injection must be administered through an in-line filter. Administer by intravenous infusion over approximately 90 minutes via a central venous line. Never give Noxafil injection as an intravenous bolus injection.

Noxafil delayed-release tablets should be taken with food.

Noxafil oral suspension should be taken with a full meal.

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.

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.

Clinical Trial Results

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.