NOXAFIL: Package Insert and Label Information (Page 4 of 7)

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

12.3 Pharmacokinetics

General Pharmacokinetic Characteristics

Posaconazole Injection

Posaconazole injection exhibits dose proportional pharmacokinetics after single doses between 200 and 300 mg in healthy volunteers and patients. The mean pharmacokinetic parameters after single doses with posaconazole injection in healthy volunteers and patients are shown in Table 13.

Table 13: Summary of Mean Pharmacokinetic Parameters (%CV) in Healthy Volunteers (30 minute infusion via peripheral venous line) and Patients (90 minute infusion via central venous line) after Dosing with Posaconazole Injection on Day 1
Dose (mg) n AUC0-∞ (ng∙hr/mL) AUC0-12 (ng∙hr/mL) Cmax (ng/mL) t1/2 (hr) CL(L/hr)
AUC0-∞ = Area under the plasma concentration-time curve from time zero to infinity; AUC0-12 = Area under the plasma concentration-time curve from time zero to 12 hr after the first dose on Day 1; Cmax = maximum observed concentration; t½ = terminal phase half-life; CL = total body clearance; N/D = Not Determined
Healthy Volunteers 200 9 35400 (50) 8840 (20) 2250 (29) 23.6 (23) 6.5 (32)
300 9 46400 (26) 13000 (13) 2840 (30) 24.6 (20) 6.9 (27)
Patients 200 30 N/D 5570 (32) 954 (44) N/D N/D
300 22 N/D 8240 (26) 1590 (62) N/D N/D

Table 14 displays the pharmacokinetic parameters of posaconazole in patients following administration of posaconazole injection 300 mg taken once a day for 10 or 14 days following BID dosing on Day 1.

Table 14: Arithmetic Mean (%CV) of PK Parameters in Serial PK-Evaluable Patients Following Dosing of Posaconazole Injection (300 mg)*
Day N Cmax (ng/mL) Tmax (hr) AUC0-24 (ng*hr/mL) Cav(ng/mL) Cmin (ng/mL)
AUC0-24 = area under the concentration-time curve over the dosing interval (i.e. 24 hours); Cav= time-averaged concentrations (i.e., AUC0-24h /24hr);
Cmin = POS trough level immediately before a subject received the dose of POS on the day specified in the protocol; Cmax = observed maximum plasma concentration; CV = coefficient of variation, expressed as a percent (%); Day = study day on treatment; Tmax = time of observed maximum plasma concentration.
*
300 mg dose administered over 90 minutes once a day following BID dosing on Day 1
Median (minimum-maximum)
10/14 49 3280 (74) 1.5 (0.98-4.0) 36100 (35) 1500 (35) 1090 (44)

Posaconazole Delayed-Release Tablets

Noxafil 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 Noxafil delayed-release tablets 300 mg twice daily (BID) on Day 1, then 300 mg once daily (QD) 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 15.

Table 15: Arithmetic Mean (%CV) of Steady State PK Parameters in Healthy Volunteers and Patients Following Administration of Posaconazole Delayed-Release Tablets (300 mg)*
N AUC0-24 hr (ng∙hr/mL) Cav (ng/mL) Cmax (ng/mL) Cmin (ng/mL) Tmax (hr) t1/2 (hr) CL/F(L/hr)
CV = coefficient of variation expressed as a percentage (%CV); AUC0-T = Area under the plasma concentration-time curve from time zero to 24 hr; Cmax = maximum observed concentration; Cmin = minimum observed plasma concentration; Tmax = time of maximum observed concentration; t½ = terminal phase half-life; CL /F = Apparent total body clearance
*
300 mg BID on Day 1, then 300 mg QD thereafter
Cav = time-averaged concentrations (i.e., AUC0-24 hr /24hr)
Median (minimum-maximum)
Healthy Volunteers 12 51618(25) 2151(25) 2764(21) 1785(29) 4(3-6) 31(40) 7.5(26)
Patients 50 37900(42) 1580(42) 2090(38) 1310(50) 4 (1.3-8.3) - 9.39(45)

Posaconazole Oral Suspension

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 BID to 400 mg BID in healthy volunteers. No further increases in exposure were observed when the dose of the oral suspension increased from 400 mg BID to 600 mg BID 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 TID and 400 mg BID of the oral suspension are provided in Table 16.

Table 16: The Mean (%CV) [min-max] Posaconazole Steady-State Pharmacokinetic Parameters in Patients Following Oral Administration of Posaconazole Oral Suspension 200 mg TID and 400 mg BID
Dose * Cavg (ng/mL) AUC (ng∙hr/mL) CL/F (L/hr) V/F (L) t½ (hr)
Cavg = the average posaconazole concentration when measured at steady state
The variability in average plasma posaconazole concentrations in patients was relatively higher than that in healthy subjects.
*
Oral suspension administration
AUC (0-24 hr) for 200 mg TID and AUC (0-12 hr) for 400 mg BID
HSCT recipients with GVHD
§
Not done
Neutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia or myelodysplastic syndromes
#
Febrile neutropenic patients or patients with refractory invasive fungal infections, Cavg n=24
200 mg TID (n=252) 1103 (67)[21.5-3650] ND § ND § ND § ND §
200 mg TID (n=215) 583 (65)[89.7-2200] 15,900 (62)[4100-56,100] 51.2 (54)[10.7-146] 2425 (39)[828-5702] 37.2 (39)[19.1-148]
400 mg BID # (n=23) 723 (86)[6.70-2256] 9093 (80)[1564-26,794] 76.1 (78)[14.9-256] 3088 (84)[407-13,140] 31.7 (42)[12.4-67.3]

Absorption:

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 (QD after BID 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 is increased 16% and 51%, respectively, when given with a high fat meal compared to a fasted state (see Table 17). In order to enhance the oral absorption of posaconazole and optimize plasma concentrations, posaconazole delayed-release tablets should be administered with food.

Table 17: Statistical Comparison of Plasma Pharmacokinetics of Posaconazole Following Single Oral Dose Administration of 300 mg Posaconazole Delayed-Release Tablet to Healthy Subjects under Fasting and Fed Conditions
Fasting Conditions Fed Conditions (High Fat Meal)* Fed/Fasting
Pharmacokinetic Parameter N Mean (%CV) N Mean (%CV) GMR (90% CI)
GMR=Geometric least-squares mean ratio; CI=Confidence interval
*
48.5 g fat
Median (Min, Max) reported for Tmax
Cmax (ng/mL) 14 935 (34) 16 1060 (25) 1.16 (0.96, 1.41)
AUC0-72hr (hr∙ng/mL) 14 26200 (28) 16 38400 (18) 1.51 (1.33, 1.72)
Tmax (hr) 14 5.00 (3.00, 8.00) 16 6.00 (5.00, 24.00) N/A

Concomitant administration of posaconazole delayed-release tablets with drugs affecting gastric pH or gastric motility did not demonstrate any significant effects on posaconazole pharmacokinetic exposure (see Table 18).

Table 18: The Effect of Concomitant Medications that Affect the Gastric pH and Gastric Motility on the Pharmacokinetics of Posaconazole Delayed-Release Tablets in Healthy Volunteers
Coadministered Drug Administration Arms Change in Cmax (ratio estimate *;90% CI of the ratio estimate) Change in AUC0-last (ratio estimate *;90% CI of the ratio estimate)
*
Ratio Estimate is the ratio of coadministered drug plus posaconazole to posaconazole alone for Cmax or AUC0-last .
Mylanta® Ultimate strength liquid (Increase in gastric pH) 25.4 meq/5 mL, 20 mL ↑6%(1.06; 0.90 -1.26)↑ ↑4%(1.04; 0.90 -1.20)
Ranitidine (Zantac®) (Alteration in gastric pH) 150 mg (morning dose of 150 mg Ranitidine BID) ↑4%(1.04; 0.88 -1.23)↑ ↓3%(0.97; 0.84 -1.12)
Esomeprazole (Nexium®) (Increase in gastric pH) 40 mg (QAM 5 days, day -4 to 1) ↑2%(1.02; 0.88-1.17)↑ ↑5%(1.05; 0.89 -1.24)
Metoclopramide (Reglan®) (Increase in gastric motility) 15 mg four times daily during 2 days (Day -1 and 1) ↓14%(0.86, 0.73,1.02) ↓7%(0.93, 0.803,1.07)

Posaconazole Oral Suspension

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 19). 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 20.

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

Table 19: The Mean (%CV) [min-max] Posaconazole Pharmacokinetic Parameters Following Single-Dose Oral Suspension Administration of 200 mg and 400 mg Under Fed and Fasted Conditions
Dose (mg) Cmax (ng/mL) Tmax *(hr) AUC (I)(ng∙hr/mL) CL/F(L/hr) t½ (hr)
*
Median [min-max].
n=15 for AUC (I), CL/F, and t½
The subject with Tmax of 36 hrs had relatively constant plasma levels over 36 hrs (1.7 ng/mL difference between 4 hrs and 36 hrs).
§
n=10 for AUC (I), CL/F, and t½
200 mg fasted(n=20) 132 (50)[45-267] 3.50[1.5-36] 4179 (31)[2705-7269] 51 (25)[28-74] 23.5 (25)[15.3-33.7]
200 mg nonfat(n=20) 378 (43)[131-834] 4 [3-5] 10,753 (35)[4579-17,092] 21 (39)[12-44] 22.2 (18)[17.4-28.7]
200 mg high fat(54 gm fat)(n=20) 512 (34)[241-1016] 5 [4-5] 15,059 (26)[10,341-24,476] 14 (24)[8.2-19] 23.0 (19)[17.2-33.4]
400 mg fasted(n=23)§ 121 (75)[27-366] 4 [2-12] 5258 (48)[2834-9567] 91 (40)[42-141] 27.3 (26)[16.8-38.9]
400 mg with liquid nutritional supplement(14 gm fat)(n=23)§ 355 (43)[145-720] 5 [4-8] 11,295 (40)[3865-20,592] 43 (56)[19-103] 26.0 (19)[18.2-35.0]
Table 20: The Effect of Varying Gastric Administration Conditions on the Cmax and AUC of Posaconazole Oral Suspension in Healthy Volunteers *
Study Description Administration Arms Change in Cmax (ratio estimate ;90% CI of the ratio estimate) Change in AUC(ratio estimate ;90% CI of the ratio estimate)
*
In 5 subjects, the Cmax and AUC decreased substantially (range: -27% to -53% and -33% to -51%, respectively) when Noxafil was administered via an NG tube compared to when Noxafil was administered orally. It is recommended to closely monitor patients for breakthrough fungal infections when Noxafil is administered via an NG tube because a lower plasma exposure may be associated with an increased risk of treatment failure.
Ratio Estimate is the ratio of coadministered drug plus posaconazole to coadministered drug alone for Cmax or AUC.
NG = nasogastric
400-mg single dose with a high-fat meal relative to fasted state (n=12) 5 minutes before high-fat meal ↑96%(1.96; 1.48-2.59) ↑111%(2.11; 1.60-2.78)
During high-fat meal ↑339%(4.39; 3.32-5.80) ↑382%(4.82; 3.66-6.35)
20 minutes after high-fat meal ↑333%(4.33; 3.28-5.73) ↑387%(4.87; 3.70-6.42)
400 mg BID and 200 mg QID for 7 days in fasted state and with liquid nutritional supplement (BOOST®) (n=12) 400 mg BID with BOOST ↑65%(1.65; 1.29-2.11) ↑66%(1.66; 1.30-2.13)
200 mg QID with BOOST No Effect No Effect
Divided daily dose from 400 mg BID to 200 mg QID for 7 days regardless of fasted conditions or with BOOST (n=12) Fasted state ↑136%(2.36; 1.84-3.02) ↑161%(2.61; 2.04-3.35)
With BOOST ↑137%(2.37; 1.86-3.04) ↑157%(2.57; 2.00-3.30)
400-mg single dose with carbonated acidic beverage (ginger ale) and/or proton pump inhibitor (esomeprazole) (n=12) Ginger ale ↑92%(1.92; 1.51-2.44) ↑70%(1.70; 1.43-2.03)
Esomeprazole ↓32%(0.68; 0.53-0.86) ↓30%(0.70; 0.59-0.83)
400-mg single dose with a prokinetic agent (metoclopramide 10 mg TID for 2 days) + BOOST or an antikinetic agent (loperamide 4-mg single dose) + BOOST (n=12) With metoclopramide + BOOST ↓21%(0.79; 0.72-0.87) ↓19%(0.81; 0.72-0.91)
With loperamide + BOOST ↓3%(0.97; 0.88-1.07) ↑11%(1.11; 0.99-1.25)
400-mg single dose either orally with BOOST or via an NG tube with BOOST (n=16) Via NG tube ↓19%(0.81; 0.71-0.91) ↓23%(0.77; 0.69-0.86)

Concomitant administration of posaconazole oral suspension with drugs affecting gastric pH or gastric motility results in lower posaconazole exposure. (See Table 21.)

Table 21: The Effect of Concomitant Medications that Affect the Gastric pH and Gastric Motility on the Pharmacokinetics of Posaconazole Oral Suspension in Healthy Volunteers
Coadministered Drug (Postulated Mechanism of Interaction) Coadministered Drug Dose/Schedule Posaconazole Dose/Schedule Effect on Bioavailability of Posaconazole
Change in MeanCmax (ratio estimate *; 90% CI of the ratio estimate) Change in Mean AUC(ratio estimate *; 90% CI of the ratio estimate)
*
Ratio Estimate is the ratio of coadministered drug plus posaconazole to coadministered drug alone for Cmax or AUC.
The tablet refers to a non-commercial tablet formulation without polymer.
The drug interactions associated with the oral suspension are also relevant for the delayed-release tablet with the exception of Esomeprazole and Metoclopramide.
Cimetidine(Alteration of gastric pH) 400 mg BID × 10 days 200 mg (tablets) QD × 10 days ↓ 39%(0.61; 0.53-0.70) ↓ 39%(0.61; 0.54-0.69)
Esomeprazole (Increase in gastric pH) 40 mg QAM × 3 days 400 mg (oral suspension) single dose ↓ 46%(0.54; 0.43-0.69) ↓ 32%(0.68; 0.57-0.81)
Metoclopramide (Increase in gastric motility) 10 mg TID × 2 days 400 mg (oral suspension) single dose ↓ 21%(0.79; 0.72-0.87) ↓ 19%(0.81; 0.72-0.91)

Distribution:

The mean volume of distribution of posaconazole after intravenous solution administration was 261 L and ranged from 226-295 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 primarily metabolized via UDP glucuronidation (phase 2 enzymes) and is a substrate for p-glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. A summary of drugs studied clinically with the oral suspension or an early tablet formulation, which affect posaconazole concentrations, is provided in Table 22.

Table 22: Summary of the Effect of Coadministered Drugs on Posaconazole in Healthy Volunteers
Coadministered Drug (Postulated Mechanism of Interaction) Coadministered Drug Dose/Schedule Posaconazole Dose/Schedule Effect on Bioavailability of Posaconazole
Change in MeanCmax (ratio estimate *; 90% CI of the ratio estimate) Change in Mean AUC(ratio estimate *; 90% CI of the ratio estimate)
*
Ratio Estimate is the ratio of coadministered drug plus posaconazole to posaconazole alone for Cmax or AUC.
The tablet refers to a non-commercial tablet formulation without polymer.
Efavirenz(UDP-G Induction) 400 mg QD × 10 and 20 days 400 mg (oral suspension) BID × 10 and 20 days ↓45%(0.55; 0.47-0.66) ↓ 50%(0.50; 0.43-0.60)
Fosamprenavir (unknown mechanism) 700 mg BID × 10 days 200 mg QD on the 1st day, 200 mg BID on the 2nd day, then 400 mg BID × 8 Days ↓21%0.79 (0.71-0.89) ↓23%0.77 (0.68-0.87)
Rifabutin(UDP-G Induction) 300 mg QD × 17 days 200 mg (tablets) QD × 10 days ↓ 43%(0.57; 0.43-0.75) ↓ 49%(0.51; 0.37-0.71)
Phenytoin(UDP-G Induction) 200 mg QD × 10 days 200 mg (tablets) QD × 10 days ↓ 41%(0.59; 0.44-0.79) ↓ 50%(0.50; 0.36-0.71)

In vitro studies with human hepatic microsomes and clinical studies indicate that posaconazole is an inhibitor primarily of CYP3A4. A clinical study in healthy volunteers also indicates that posaconazole is a strong CYP3A4 inhibitor as evidenced by a >5-fold increase in midazolam AUC. Therefore, plasma concentrations of drugs predominantly metabolized by CYP3A4 may be increased by posaconazole. A summary of the drugs studied clinically, for which plasma concentrations were affected by posaconazole, is provided in Table 23 [see Contraindications (4) and Drug Interactions (7.1) including recommendations].

Table 23: Summary of the Effect of Posaconazole on Coadministered Drugs in Healthy Volunteers and Patients
Coadministered Drug(Postulated Mechanism of Interaction is Inhibition of CYP3A4 by posaconazole) Coadministered Drug Dose/Schedule Posaconazole Dose/Schedule Effect on Bioavailability of Coadministered Drugs
Change in Mean Cmax (ratio estimate *; 90% CI of the ratio estimate) Change in Mean AUC(ratio estimate *; 90% CI of the ratio estimate)
*
Ratio Estimate is the ratio of coadministered drug plus posaconazole to coadministered drug alone for Cmax or AUC.
The tablet refers to a non-commercial tablet formulation without polymer.
The mean terminal half-life of midazolam was increased from 3 hours to 7 to 11 hours during coadministration with posaconazole.
Sirolimus 2-mg single oral dose 400 mg (oral suspension) BID × 16 days ↑ 572%(6.72; 5.62-8.03) ↑ 788%(8.88; 7.26-10.9)
Cyclosporine Stable maintenance dose in heart transplant recipients 200 mg (tablets) QD × 10 days ↑ cyclosporine whole blood trough concentrationsCyclosporine dose reductions of up to 29% were required
Tacrolimus 0.05-mg/kg single oral dose 400 mg (oral suspension) BID × 7 days ↑ 121%(2.21; 2.01-2.42) ↑ 358%(4.58; 4.03-5.19)
Simvastatin 40-mg single oral dose 100 mg (oral suspension) QD × 13 days Simvastatin↑ 841%(9.41, 7.13-12.44)Simvastatin Acid↑ 817%(9.17, 7.36-11.43) Simvastatin↑ 931%(10.31, 8.40-12.67)Simvastatin Acid↑634%(7.34, 5.82-9.25)
200 mg (oral suspension) QD × 13 days Simvastatin↑ 1041%(11.41, 7.99-16.29)Simvastatin Acid↑851%(9.51, 8.15-11.10) Simvastatin↑ 960%(10.60, 8.63-13.02)Simvastatin Acid↑748%(8.48, 7.04-10.23)
Midazolam 0.4-mg single intravenous dose 200 mg (oral suspension) BID × 7 days ↑ 30%(1.3; 1.13-1.48) ↑ 362%(4.62; 4.02-5.3)
0.4-mg single intravenous dose 400 mg (oral suspension) BID × 7 days ↑62%(1.62; 1.41-1.86) ↑524%(6.24; 5.43-7.16)
2-mg single oral dose 200 mg (oral suspension) QD × 7 days ↑ 169%(2.69; 2.46-2.93) ↑ 470%(5.70; 4.82-6.74)
2-mg single oral dose 400 mg (oral suspension) BID × 7 days ↑ 138%(2.38; 2.13-2.66) ↑ 397%(4.97; 4.46-5.54)
Rifabutin 300 mg QD × 17 days 200 mg (tablets) QD × 10 days ↑ 31%(1.31; 1.10-1.57) ↑ 72%(1.72;1.51-1.95)
Phenytoin 200 mg QD PO × 10 days 200 mg (tablets) QD × 10 days ↑ 16%(1.16; 0.85-1.57) ↑ 16%(1.16; 0.84-1.59)
Ritonavir 100 mg QD × 14 days 400 mg (oral suspension)BID × 7 days ↑ 49%(1.49; 1.04-2.15) ↑ 80%(1.8;1.39-2.31)
Atazanavir 300 mg QD × 14 days 400 mg (oral suspension) BID × 7 days ↑ 155%(2.55; 1.89-3.45) ↑ 268%(3.68; 2.89-4.70)
Atazanavir/ ritonavir boosted regimen 300 mg/100 mg QD × 14 days 400 mg (oral suspension) BID × 7 days ↑ 53%(1.53; 1.13-2.07) ↑ 146%(2.46; 1.93-3.13)

Additional clinical studies demonstrated that no clinically significant effects on zidovudine, lamivudine, indinavir, or caffeine were observed when administered with posaconazole 200 mg QD; therefore, no dose adjustments are required for these coadministered drugs when coadministered with posaconazole 200 mg QD.

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 injection is eliminated with a mean terminal half-life (t½ ) of 27 hours and a total body clearance (CL) of 7.3 L/h.

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

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

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