Study Description
AML and MDS patients with neutropenia need protection6,25
Objective6
To determine the efficacy and safety of NOXAFIL® versus standard azole therapy* for prophylaxis against IFIs in patients at high risk due to anticipated neutropenia.
Overview6
* Fluconazole or itraconazole.
† Prophylaxis was temporarily discontinued during anthracycline-based chemotherapy. Therapy was initiated 24 hours after last dose of anthracycline.
Patients had similar characteristics6,7
| Number (%) of Subjects | ||
| NOXAFIL® (n=304) | Fluconazole/Itraconazole (n=298) | |
| Primary diagnosis at study entry | ||
| AML (new diagnosis) | 213 (70) | 222 (74) |
| AML (first relapse) | 42 (14) | 38 (13) |
| MDS | 49 (16) | 38 (13) |
| Severity of neutropenia at baseline | ||
| Neutropenic | 192 (63) | 189 (63) |
| Severe neutropenia (ANC ≤100 cells/mm3) | 73 (24) | 71 (24) |
| Non-severe neutropenia (ANC >100 cells/mm3 to ≤500 cells/mm3) | 119 (39) | 118 (40) |
| Non-neutropenic (ANC >500 cells/mm3) | 98 (32) | 94 (32) |
| Missing or unknown | 14 (5) | 15 (5) |
| Neutropenia during the treatment phase | ||
| ANC ≤100 cells/mm3 | 264 (87) | 261 (88) |
| ANC ≤500 cells/mm3 | 298 (98) | 290 (97) |
| Mucositis score on or before first date of study drug‡ | ||
| No mucositis | 164 (54) | 154 (52) |
| CTC§ Grade 1–2 | 93 (31) | 97 (33) |
| CTC§ Grade 3–4 | 7 (2) | 3 (1) |
| Missing or unknown | 40 (13) | 44 (15) |
‡ For subjects who were randomized but not treated, result obtained on or before date of randomization is reported.
§ CTC=Common Toxicity Criteria.
Study description6,7
Randomized, open-label, evaluator-blinded, active-control, parallel-group, multicenter study
- NOXAFIL® oral suspension 200 mg TID
- Standard azole therapy
- Fluconazole oral suspension 400 mg QD
- Itraconazole oral solution 200 mg BID
- A blinded panel of external experts (Data Review Committee) determined if patients had proven, probable, or possible IFIs on the basis of European Organisation for Research and Treatment of Cancer/Mycosis Study Group (EORTC-MSG) criteria
- Primary efficacy endpoint was proven/probable IFIs during oral treatment phase (from randomization to 7 days after last dose)
- Select secondary endpoints evaluated at 100 days post-randomization
- Treatment continued until recovery from neutropenia, complete remission, occurrence of an IFI, or other protocol-specified endpoints were reached, up to a maximal time period of 84 days after randomization
Select inclusion criteria6
- Patients ≥13 years of age
- Anticipated neutropenia (ANC ≤500 cells/mm3 [0.5 x 109 cells/L]) for ≥7 days due to chemotherapy for:
- New diagnosis of AML
- AML in first relapse
- MDS or other diagnosis of secondary AML
Select exclusion criteria6
- Treatment with amphotericin B, fluconazole, or itraconazole for a proven or probable IFI within 30 days of enrollment
- Clinically significant hepatic/renal dysfunction
- Treatment with medications having a potential for adverse interactions with azoles
- Known or suspected invasive or systemic fungal infection at randomization
- History of acute lymphoblastic leukemia or chronic myelogenous leukemia
- History of allogeneic hematopoietic stem cell or bone marrow transplantation for any diagnosis, or autologous stem cell transplantation for the underlying diagnosis
- ECG with a prolonged QTc interval by manual reading: QTc >450 msec for men and QTc >470 msec for women
Important Safety Information
NOXAFIL® has been shown to interact with several medications, including drugs that suppress the immune system, and these reactions may be serious. The product label should be consulted when other drugs are prescribed with NOXAFIL®.
Coadministration with sirolimus or ergot alkaloids is contraindicated. Coadministration with the CYP3A4 substrates terfenadine, astemizole, cisapride, pimozide, halofantrine, or quinidine, is also contraindicated since this may result in increased plasma concentrations of these medicinal products, leading to QTc prolongation and rare occurrences of torsades de pointes.
Serious and rare fatal toxicity from cyclosporine has occurred when taken in combination with NOXAFIL® and therefore reduction of the dose of drugs like cyclosporine or tacrolimus and frequent monitoring of drug levels of these medications are necessary when taking them in combination with NOXAFIL®.
In clinical trials, there were infrequent cases of hepatic reactions (eg, mild to moderate elevations in ALT, AST, alkaline phosphatase, total bilirubin, and/or clinical hepatitis). Rarely, more severe hepatic reactions including cholestasis or hepatic failure including fatalities were reported in patients with serious underlying medical conditions (eg, hematologic malignancies) during treatment with posaconazole. Liver function tests should be monitored at the start of and during the course of therapy. Discontinuation of NOXAFIL® must be considered in patients who experience symptoms consistent with liver disease that may be attributable to NOXAFIL®.
The safety and effectiveness of NOXAFIL® in patients below the age of 13 years old have not been established.
The most common treatment-related serious adverse events (1% each) in the combined prophylaxis studies were bilirubinemia, increased hepatic enzymes, hepatocellular damage, nausea, and vomiting.
In the pooled prophylaxis safety analysis, fever, headache, anemia, diarrhea, nausea, vomiting, abdominal pain, hypokalemia, and thrombocytopenia were frequently reported treatment-emergent adverse events.
In clinical studies of OPC and refractory OPC, adverse events were reported more frequently in the pool of patients with refractory OPC. The most commonly reported serious adverse events in refractory OPC patients included fever (13%) and neutropenia (10%).
