Posaconazole 40 mg / ml · Oral suspension

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

General Pharmacokinetic Characteristics — Dose-proportional increases in plasma exposure (AUC) to posaconazole oral suspension were observed following single oral doses from 50 mg to 800 mg and following multiple-dose administration from 50 mg twice daily to 400 mg twice daily in healthy volunteers. No further increases in exposure were observed when the dose of the oral suspension increased from 400 mg twice daily to 600 mg twice daily in febrile neutropenic patients or those with refractory invasive fungal infections.

The mean (%CV) [min-max] posaconazole oral suspension average steady-state plasma concentrations (Cavg) and steady-state pharmacokinetic parameters in patients following administration of 200 mg three times a day and 400 mg twice daily of the oral suspension are provided in Table 22.

Absorption: — Posaconazole oral suspension is absorbed with a median Tmax of ~3 to 5 hours. Steady-state plasma concentrations are attained at 7 to 10 days following multiple-dose administration.

Following single-dose administration of 200 mg, the mean AUC and Cmax of posaconazole are approximately 3 times higher when the oral suspension is administered with a nonfat meal and approximately 4 times higher when administered with a high-fat meal (~50 gm fat) relative to the fasted state. Following single-dose administration of posaconazole oral suspension 400 mg, the mean AUC and Cmax of posaconazole are approximately 3 times higher when administered with a liquid nutritional supplement (14 gm fat) relative to the fasted state (see Table 24). In addition, the effects of varying gastric administration conditions on the Cmax and AUC of posaconazole oral suspension in healthy volunteers have been investigated and are shown in Table 25.

To assure attainment of adequate plasma concentrations, it is recommended to administer posaconazole oral suspension during or immediately following a full meal. In patients who cannot eat a full meal, posaconazole oral suspension should be taken with a liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale).

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 posaconazole 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 oral suspension is eliminated with a mean half-life (t½) of 35 hours (range: 20 to 66 hours).

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

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 posaconazole oral suspension to those with eGFR >80 mL/minute/1.73 m2 treated with posaconazole 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%).