Posaconazole 300 mg (DR) · Tablets

Posaconazole is an azole antifungal agent [see Clinical Pharmacology (12.4)].

General Pharmacokinetic Characteristics — General Pharmacokinetic Characteristics of Posaconazole Delayed-Release Tablets

Posaconazole delayed-release tablets exhibit dose proportional pharmacokinetics after single and multiple dosing up to 300 mg. The mean pharmacokinetic parameters of posaconazole at steady state following administration of posaconazole delayed-release tablets 300 mg twice daily on Day 1, then 300 mg once daily thereafter in healthy volunteers and in neutropenic patients who are receiving cytotoxic chemotherapy for AML or MDS or HSCT recipients with GVHD are shown in Table 21.

Absorption of Posaconazole Delayed-Release Tablets — When given orally in healthy volunteers, posaconazole delayed-release tablets are absorbed with a median Tmax of 4 to 5 hours. Steady-state plasma concentrations are attained by Day 6 at the 300 mg dose (once daily after twice daily loading dose at Day 1). The absolute bioavailability of the oral delayed-release tablet is approximately 54% under fasted conditions. The Cmax and AUC of posaconazole following administration of posaconazole delayed-release tablets are increased 16% and 51%, respectively, when given with a high fat meal compared to a fasted state (see Table 23).

Distribution: — The mean volume of distribution of posaconazole after intravenous solution administration was 261 L and ranged from 226 to 295 L between studies and dose levels.

Posaconazole is highly bound to human plasma proteins (>98%), predominantly to albumin.

Metabolism: — Posaconazole primarily circulates as the parent compound in plasma. Of the circulating metabolites, the majority are glucuronide conjugates formed via UDP glucuronidation (phase 2 enzymes). Posaconazole does not have any major circulating oxidative (CYP450 mediated) metabolites. The excreted metabolites in urine and feces account for ~17% of the administered radiolabeled dose. Posaconazole is a substrate for p-glycoprotein (P-gp) efflux.

In vitro studies with human hepatic microsomes and clinical studies indicate that posaconazole is an inhibitor primarily of CYP3A4.

Excretion: — Following administration of Noxafil® oral suspension, posaconazole is predominantly eliminated in the feces (71% of the radiolabeled dose up to 120 hours) with the major component eliminated as parent drug (66% of the radiolabeled dose). Renal clearance is a minor elimination pathway, with 13% of the radiolabeled dose excreted in urine up to 120 hours (<0.2% of the radiolabeled dose is parent drug).

Posaconazole delayed-release tablet is eliminated with a mean half-life (t½) ranging between 26 to 31 hours.

Specific Populations: — No clinically significant differences in the pharmacokinetics of posaconazole were observed based on age, sex, renal impairment, and indication (prophylaxis).

Patients with Renal Impairment: — After posaconazole oral administration, there were no significant differences in the posaconazole pharmacokinetics in patients with eGFR 20 mL/minute/1.73 m2 or higher compared to those with eGFR>80 mL/minute/1.73 m2. Although the mean posaconazole plasma exposure (AUC) was similar in patients with eGFR less than 20 mL/minute/1.73 m2 treated with Noxafil ® oral suspension to those with eGFR >80 m L/minute/1.73 m2 treated with Noxafil ® oral suspension, the range of the AUC estimates was highly variable (CV=96%) in patients with eGFR less than 20 mL/minute/1.73 m2 compared to those with eGFR>80 mL/minute/1.73 m2 (CV<40%). Similar posaconazole pharmacokinetic results are expected after administration of posaconazole delayed-release tablets [see Use in Specific Populations (8.6)].

Patients with Hepatic Impairment: — After a single oral dose of Noxafil ® oral suspension 400 mg, the mean AUC was 43%, 27%, and 21% higher in subjects with mild (Child-Pugh Class A, N=6), moderate (Child-Pugh Class B, N=6), or severe (Child-Pugh Class C, N=6) hepatic impairment, respectively, compared to subjects with normal hepatic function (N=18). Compared to subjects with normal hepatic function, the mean Cmax was 1% higher, 40% higher, and 34% lower in subjects with mild, moderate, or severe hepatic impairment, respectively [see Use in Specific Populations (8.7)].