conazole had no effect on fertility of male rats at a dose up to 180 mg/kg (1.7 × the 400-mg BID oral suspension regimen based on steady-state plasma concentrations in healthy volunteers) or female rats at a dose up to 45 mg/kg (2.2 × the 400-mg BID oral suspension regimen).
14 CLINICAL STUDIES
14.1 Prophylaxis of Aspergillus and Candida Infections with Posaconazole Oral Suspension
Two randomized, controlled studies were conducted using posaconazole as prophylaxis for the prevention of invasive fungal infections (IFIs) among patients at high risk due to severely compromised immune systems.
The first study (Oral Suspension Study 1) was a randomized, double-blind trial that compared posaconazole oral suspension (200 mg three times a day) with fluconazole capsules (400 mg once daily) as prophylaxis against invasive fungal infections in allogeneic hematopoietic stem cell transplant (HSCT) recipients with Graft versus Host Disease (GVHD). Efficacy of prophylaxis was eva luated using a composite endpoint of proven/probable IFIs, death, or treatment with systemic antifungal therapy (patients may have met more than one of these criteria). This assessed all patients while on study therapy plus 7 days and at 16 weeks post-randomization. The mean duration of therapy was comparable between the 2 treatment groups (80 days, posaconazole; 77 days, fluconazole). Table 17 contains the results from Oral Suspension Study 1.
Table 17: Results from Blinded Clinical Study in Prophylaxis of IFI in All Randomized Patients with Hematopoietic Stem Cell Transplant (HSCT) and Graft-vs.-Host Disease (GVHD): Oral Suspension Study 1
Posaconazole
n=301
Fluconazole
n=299
* Patients may have met more than one criterion defining failure.† Use of systemic antifungal therapy (SAF) criterion is based on protocol definitions (empiric/IFI usage >4 consecutive days).‡ 95% confidence interval (posaconazole-fluconazole) = (-11.5%, +3.7%).§ Patients who are lost to follow-up (not observed for 112 days), and who did not meet another clinical failure endpoint. These patients were considered failures.
On therapy plus 7 days
Clinical Failure* 50 (17%) 55 (18%)
Failure due to:
Proven/Probable IFI 7 (2%) 22 (7%)
(Aspergillus) 3 (1%) 17 (6%)
(Candida) 1 (<1%) 3 (1%)
(Other) 3 (1%) 2 (1%)
All Deaths 22 (7%) 24 (8%)
Proven/probable fungal infection prior to death 2 (<1%) 6 (2%)
SAF† 27 (9%) 25 (8%)
Through 16 weeks
Clinical Failure*,‡ 99 (33%) 110 (37%)
Failure due to:
Proven/Probable IFI 16 (5%) 27 (9%)
(Aspergillus) 7 (2%) 21 (7%)
(Candida) 4 (1%) 4 (1%)
(Other) 5 (2%) 2 (1%)
All Deaths 58 (19%) 59 (20%)
Proven/probable fungal infection prior to death 10 (3%) 16 (5%)
SAF† 26 (9%) 30 (10%)
Event free lost to follow-up§ 24 (8%) 30 (10%)
The second study (Oral Suspension Study 2) was a randomized, open-label study that compared posaconazole oral suspension (200 mg 3 times a day) with fluconazole suspension (400 mg once daily) or itraconazole oral solution (200 mg twice a day) as prophylaxis against IFIs in neutropenic patients who were receiving cytotoxic chemotherapy for AML or MDS. As in Oral Suspension Study 1, efficacy of prophylaxis was eva luated using a composite endpoint of proven/probable IFIs, death, or treatment with s
