NOXAFIL (Page 6 of 10)

8.6 Renal Impairment

Following single-dose administration of 400 mg of the oral suspension, there was no significant effect of mild (eGFR: 50-80 mL/min/1.73 m2 , n=6) or moderate (eGFR: 20-49 mL/min/1.73 m2 , n=6) renal impairment on posaconazole pharmacokinetics; therefore, no dose adjustment is required in patients with mild to moderate renal impairment. In subjects with severe renal impairment (eGFR: <20 mL/min/1.73 m2), the mean plasma exposure (AUC) was similar to that in patients with normal renal function (eGFR: >80 mL/min/1.73 m2); however, the range of the AUC estimates was highly variable (CV=96%) in these subjects with severe renal impairment as compared to that in the other renal impairment groups (CV<40%). Due to the variability in exposure, patients with severe renal impairment should be monitored closely for breakthrough fungal infections [see Dosage and Administration (2)]. Similar recommendations apply to posaconazole delayed-release tablets; however, a specific study has not been conducted with the delayed-release tablets.

Noxafil injection should be avoided in patients with moderate or severe renal impairment (eGFR <50 mL/min), unless an assessment of the benefit/risk to the patient justifies the use of Noxafil injection. In patients with moderate or severe renal impairment (eGFR <50 mL/min), receiving the Noxafil injection, accumulation of the intravenous vehicle, SBECD, is expected to occur. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral Noxafil therapy [see Dosage and Administration (2.6) and Warnings and Precautions (5.5)].

8.7 Hepatic Impairment

After a single oral dose of posaconazole 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. The mean apparent oral clearance (CL/F) was reduced by 18%, 36%, and 28% in subjects with mild, moderate, or severe hepatic impairment, respectively, compared to subjects with normal hepatic function. The elimination half-life (t½ ) was 27 hours, 39 hours, 27 hours, and 43 hours in subjects with normal hepatic function and mild, moderate, or severe hepatic impairment, respectively.

It is recommended that no dose adjustment of Noxafil is needed in patients with mild to severe hepatic impairment (Child-Pugh Class A, B, or C) [see Dosage and Administration (2) and Warnings and Precautions (5.4)]. Similar recommendations apply to posaconazole delayed-release tablets; however, a specific study has not been conducted with the delayed-release tablets.

Similar recommendations apply to posaconazole injection; however, a specific study has not been conducted with the posaconazole injection.

8.8 Gender

The pharmacokinetics of posaconazole are comparable in men and women. No adjustment in the dosage of Noxafil is necessary based on gender.

8.9 Race

The pharmacokinetic profile of posaconazole is not significantly affected by race. No adjustment in the dosage of Noxafil is necessary based on race.

8.10 Weight

Pharmacokinetic modeling suggests that patients weighing greater than 120 kg may have lower posaconazole plasma drug exposure. It is, therefore, suggested to closely monitor for breakthrough fungal infections.

10 OVERDOSAGE

There is no experience with overdosage of posaconazole injection and delayed-release tablets.

During the clinical trials, some patients received posaconazole oral suspension up to 1600 mg/day with no adverse reactions noted that were different from the lower doses. In addition, accidental overdose was noted in one patient who took 1200 mg BID posaconazole oral suspension for 3 days. No related adverse reactions were noted by the investigator.

Posaconazole is not removed by hemodialysis.

11 DESCRIPTION

Noxafil is an azole antifungal agent available as concentrated solution to be diluted before intravenous administration, delayed-release tablet, or suspension for oral administration.

Posaconazole is designated chemically as 4-[4-[4-[4-[[ (3R ,5R)-5- (2,4-difluorophenyl)tetrahydro-5- (1H -1,2,4-triazol-1-ylmethyl)-3-furanyl]methoxy]phenyl]-1-piperazinyl]phenyl]-2-[(1S ,2S)-1-ethyl-2-hydroxypropyl]-2,4-dihydro-3H -1,2,4-triazol-3-one with an empirical formula of C37 H42 F2 N8 O4 and a molecular weight of 700.8. The chemical structure is:

Chemical Structure
(click image for full-size original)

Posaconazole is a white powder with a low aqueous solubility.

Noxafil injection is available as a clear colorless to yellow, sterile liquid essentially free of foreign matter. Each vial contains 300 mg of posaconazole and the following inactive ingredients: 6.68 g Betadex Sulfobutyl Ether Sodium (SBECD), 0.003 g edetate disodium, hydrochloric acid and sodium hydroxide to adjust the pH to 2.6, and water for injection.

Noxafil delayed-release tablet is a yellow, coated, oblong tablet containing 100 mg of posaconazole. Each delayed-release tablet contains the inactive ingredients: hypromellose acetate succinate, microcrystalline cellulose, hydroxypropylcellulose, silicon dioxide, croscarmellose sodium, magnesium stearate, and Opadry® II Yellow (consists of the following ingredients: polyvinyl alcohol partially hydrolyzed, Macrogol/PEG 3350, titanium dioxide, talc, and iron oxide yellow).

Noxafil oral suspension is a white, cherry-flavored immediate-release suspension containing 40 mg of posaconazole per mL and the following inactive ingredients: polysorbate 80, simethicone, sodium benzoate, sodium citrate dihydrate, citric acid monohydrate, glycerin, xanthan gum, liquid glucose, titanium dioxide, artificial cherry flavor, and purified water.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

Exposure Response Relationship: In clinical studies of neutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia (AML) or myelodysplastic syndromes (MDS) or hematopoietic stem cell transplant (HSCT) recipients with Graft versus Host Disease (GVHD), a wide range of plasma exposures to posaconazole was noted following administration of Noxafil oral suspension. A pharmacokinetic-pharmacodynamic analysis of patient data revealed an apparent association between average posaconazole concentrations (Cavg) and prophylactic efficacy (Table 12). A lower Cavg may be associated with an increased risk of treatment failure, defined as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or occurrence of breakthrough invasive fungal infections.

Table 12: Noxafil Oral Suspension Exposure Analysis (Cavg) in Prophylaxis Trials
Prophylaxis in AML/MDS * Prophylaxis in GVHD
Cavg Range (ng/mL) Treatment Failure (%) Cavg Range (ng/mL) Treatment Failure (%)
Cavg = the average posaconazole concentration when measured at steady state
*
Neutropenic patients who were receiving cytotoxic chemotherapy for AML or MDS
HSCT recipients with GVHD
Defined as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or occurrence of breakthrough invasive fungal infections
Quartile 1 90-322 54.7 22-557 44.4
Quartile 2 322-490 37.0 557-915 20.6
Quartile 3 490-734 46.8 915-1563 17.5
Quartile 4 734-2200 27.8 1563-3650 17.5

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