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Noxafil

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Noxafil

CLINICAL PHARMACOLOGY

Mechanism Of Action

Posaconazole is an azole antifungal agent.

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 10). 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 10: 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‡ (%)
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
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

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 11.

Table 11: 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) t½ (hr) CL (L/hr)
Healthy 200 9 35400 (50) 8840 (20) 2250 (29) 23.6 (23) 6.5 (32)
Volunteers 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
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

Table 12 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 12: 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)
10/14 49 3280 (74) 1.5 (0.98-4.0) 36100 (35) 1500 (35) 1090 (44)
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)

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 13.

Table 13: 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) T max‡ (hr) t½ (hr) CL/F (L/hr)
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)
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)

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 14.

Table 14: 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)
200 mg TID‡(n=252) 1103 (67) [21.5-3650] ND§ ND§ ND§ ND§
200 mg TID¶(n=215) 583 (65) 15,900 (62) 51.2 (54) 2425 (39) 37.2 (39)
[89.7-2200] [4100-56,100] [10.7-146] [828-5702] [19.1-148]
400 mg BID#(n=23) 723 (86) 9093 (80) 76.1 (78) 3088 (84) 31.7 (42)
[6.70-2256] [1564-26,794] [14.9-256] [407-13,140] [12.4-67.3]
Cavg = the average posaconazole concentration when measured at steady state
* 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
The variability in average plasma posaconazole concentrations in patients was relatively higher than that in healthy subjects

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 effect of food intake on the oral bioavailability of posaconazole following administration of posaconazole delayed-release tablets is not known. However, since the oral bioavailability of posaconazole is significantly increased when the oral suspension is administered with food or a nutritional supplement (see below), it is also recommended that posaconazole delayed-release tablets be taken with food.

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 15).

Table 15: 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)
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)
* Ratio Estimate is the ratio of coadministered drug plus posaconazole to posaconazole alone for Cmax or AUC0-last.

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 16). 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 17.

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 16: 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)
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]
* Median [min-max].
† n=15 for AUC (I), CL/F, and t ½
‡ 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 t ½

Table 17: 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)
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)
* 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

Concomitant administration of posaconazole oral suspension with drugs affecting gastric pH or gastric motility results in lower posaconazole exposure. (See Table 18.)

Table 18: 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 Mean Cmax (ratio estimate*; 90% CI of the ratio estimate) Change in Mean AUC (ratio estimate*; 90% CI of the ratio estimate)
Cimetidine (Alteration of gastric pH) 400 mg BID x 10 days 200 mg (tablets) QD x 10 days† ↓39%
(0.61; 0.53-0.70)
↓39%
(0.61; 0.54-0.69)
Esomeprazole (Increase in gastric pH)‡ 40 mg QAM x 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 x 2 days 400 mg (oral suspension) single dose ↓21%
(0.79; 0.72-0.87)
↓19%
(0.81; 0.72-0.91)
* 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.

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 19.

Table 19: 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 Mean Cmax (ratio estimate*; 90% CI of the ratio estimate) Change in Mean AUC (ratio estimate*; 90% CI of the ratio estimate)
Efavirenz (UDP-G Induction) 400 mg QD x 10 and 20 days 400 mg (oral suspension) BID x 10 and 20 days ↓45%
(0.55; 0.47-0.66)
↓50%
(0.50; 0.43-0.60)
Fosamprenavir (unknown mechanism) 700 mg BID x 10 days 200 mg QD on the 1st day, 200 mg BID on the 2nd day, then 400 mg BID x 8 Days ↓21% 0.79
(0.71-0.89)
↓23% 0.77
(0.68-0.87)
Rifabutin (UDP-G Induction) 300 mg QD x 17 days 200 mg (tablets) QD x 10 days† ↓43%
(0.57; 0.43-0.75)
↓49%
(0.51; 0.37-0.71)
Phenytoin (UDP-G Induction) 200 mg QD x 10 days 200 mg (tablets) QD x 10 days† ↓ 41%
(0.59; 0.44-0.79)
↓50%
(0.50; 0.36-0.71)
* 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.

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 20 [see CONTRAINDICATIONS and DRUG INTERACTIONS including recommendations].

Table 20: Summary of the Effect of Posaconazole on Coadministered Drugs in Healthy Volunteers and Patients

Coadministered Drug (Postulated Mechanism of Interaction is Inhibition of CYP3A4by 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)
Sirolimus 2-mg single oral dose 400 mg
(oral suspension) BID x 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 x 10 days1 ↑ cyclosporine whole blood trough concentrations Cyclosporine dose reductions of up to 29% were required
Tacrolimus 0.05-mg/kg single oral dose 400 mg (oral suspension) BID x 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 x 13 days Simvastatin ↑ 841%
(9.41, 7.13-12.44)
Simvastatin ↑931%
(10.31, 8.40-12.67)
Simvastatin Acid ↑817%
(9.17, 7.36-11.43)
Simvastatin Acid ↑634%
(7.34, 5.82-9.25)
200 mg (oral suspension) QD x 13 days Simvastatin ↑1041%
(11.41, 7.99-16.29)
Simvastatin ↑960%
(10.60, 8.63-13.02)
Simvastatin Acid ↑851%
(9.51, 8.15-11.10)
Simvastatin Acid ↑748%
(8.48, 7.04-10.23)
  0.4-mg single intravenous dose‡ 200 mg (oral suspension) BID x 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 x 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 x 7 days ↑169%
(2.69; 2.46-2.93)
↑ 470%
(5.70; 4.82-6.74)
Midazolam 2-mg single oral dose‡ 400 mg (oral suspension) BID x 7 days ↑ 138%
(2.38; 2.13-2.66)
↑397%
(4.97; 4.46-5.54)
Rifabutin 300 mg QD x 17 days 200 mg (tablets) QD x 10 days† ↑31%
(1.31; 1.10-1.57)
↑72%
(1.72;1.51-1.95)
Phenytoin 200 mg QD PO x 10 days 200 mg (tablets) QD x 10 days† ↑16%
(1.16; 0.85-1.57)
↑16%
(1.16; 0.84-1.59)
Ritonavir 100 mg QD x 14 days 400 mg (oral suspension) BID x 7 days ↑49%
(1.49; 1.04-2.15)
↑ 80%
(1.8;1.39-2.31)
Atazanavir 300 mg QD x 14 days 400 mg (oral suspension) BID x 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 x 14 days 400 mg (oral suspension) BID x 7 days ↑53%
(1.53; 1.13-2.07)
↑146%
(2.46; 1.93-3.13)
* 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

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: 2066 hours).

Microbiology

Mechanism of Action

Posaconazole blocks the synthesis of ergosterol, a key component of the fungal cell membrane, through the inhibition of cytochrome P-450 dependent enzyme lanosterol 14α-demethylase responsible for the conversion of lanosterol to ergosterol in the fungal cell membrane. This results in an accumulation of methylated sterol precursors and a depletion of ergosterol within the cell membrane thus weakening the structure and function of the fungal cell membrane. This may be responsible for the antifungal activity of posaconazole.

Activity in vitro

Posaconazole has in vitro activity against Aspergillus fumigatus and Candida albicans, including Candida albicans isolates from patients refractory to itraconazole or fluconazole or both drugs [see Clinical Studies, INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION]. However, correlation between the results of susceptibility tests and clinical outcome has not been established. Posaconazole interpretive criteria (breakpoints) have not been established for any fungus.

Drug Resistance

Clinical isolates of Candida albicans and Candida glabrata with decreased susceptibility to posaconazole were observed in oral swish samples taken during prophylaxis with posaconazole and fluconazole, suggesting a potential for development of resistance. These isolates also showed reduced susceptibility to other azoles, suggesting cross-resistance between azoles. The clinical significance of this finding is not known.

Animal Toxicology And/Or Pharmacology

In a nonclinical study using intravenous administration of posaconazole in very young dogs (dosed from 2 to 8 weeks of age), an increase in the incidence of brain ventricle enlargement was observed in treated animals as compared with concurrent control animals. No difference in the incidence of brain ventricle enlargement between control and treated animals was observed following the subsequent 5month treatment-free period. There were no neurologic, behavioral or developmental abnormalities in the dogs with this finding, and a similar brain finding was not seen with oral posaconazole administration to juvenile dogs (4 days to 9 months of age).

The clinical significance of this finding is unknown; therefore, the use of posaconazole injection to patients under 18 years of age is not recommended.

Clinical Studies

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 evaluated 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 21 contains the results from Oral Suspension Study 1.

Table 21: 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
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%)
* 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.

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 evaluated using a composite endpoint of proven/probable IFIs, death, or treatment with systemic antifungal therapy (Patients might have met more than one of these criteria). This study assessed patients while on treatment plus 7 days and 100 days postrandomization. The mean duration of therapy was comparable between the 2 treatment groups (29 days, posaconazole; 25 days, fluconazole or itraconazole). Table 22 contains the results from Oral Suspension Study 2.

Table 22: Results from Open-Label Clinical Study 2 in Prophylaxis of IFI in All Randomized Patients with Hematologic Malignancy and Prolonged Neutropenia: Oral Suspension Study 2

  Posaconazole
n=304
Fluconazole/It raconazole
n=298
On therapy plus 7 days
Clinical Failure*,† 82 (27%) 126 (42%)
Failure due to:
Proven/Probable IFI 7 (2%) 25 (8%)
  (Aspergillus) 2 (1%) 20 (7%)
  (Candida) 3 (1%) 2 (1%)
  (Other) 2 (1%) 3 (1%)
All Deaths 17 (6%) 25 (8%)
  Proven/probable fungal infection prior to death 1 ( < 1%) 2 (1%)
SAF‡ 67 (22%) 98 (33%)
Through 100 days postrandomization
Clinical Failure† 158 (52%) 191 (64%)
Failure due to:
Proven/Probable IFI 14 (5%) 33 (11%)
  (Aspergillus) 2 (1%) 26 (9%)
  (Candida 10 (3%) 4 (1%)
  (Other) 2 (1%) 3 (1%)
All Deaths 44 (14%) 64 (21%)
  Proven/probable fungal infection prior to death 2 (1%) 16 (5%)
SAF‡ 98 (32%) 125 (42%)
Event free lost to follow-up§ 34 (11%) 24 (8%)
* 95% confidence interval (posaconazole-fluconazole/itraconazole) = (-22.9%, -7.8%).
† 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 > 3 consecutive days).
§ Patients who are lost to follow-up (not observed for 100 days), and who did not meet another clinical failure endpoint. These patients were considered failures.

In summary, 2 clinical studies of prophylaxis were conducted with the posaconazole oral suspension. As seen in the accompanying tables (Tables 21 and 22), clinical failure represented a composite endpoint of breakthrough IFI, mortality and use of systemic antifungal therapy. In Oral Suspension Study 1 (Table 21), the clinical failure rate of posaconazole (33%) was similar to fluconazole (37%), (95% CI for the difference posaconazole–comparator -11.5% to 3.7%) while in Oral Suspension Study 2 (Table 22) clinical failure was lower for patients treated with posaconazole (27%) when compared to patients treated with fluconazole or itraconazole (42%), (95% CI for the difference posaconazole–comparator -22.9% to 7.8%).

All-cause mortality was similar at 16 weeks for both treatment arms in Oral Suspension Study 1 [POS 58/301 (19%) vs. FLU 59/299 (20%)]; all-cause mortality was lower at 100 days for posaconazole-treated patients in Oral Suspension Study 2 [POS 44/304 (14%) vs. FLU/ITZ 64/298 (21%)]. Both studies demonstrated substantially fewer breakthrough infections caused by Aspergillus species in patients receiving posaconazole prophylaxis when compared to patients receiving fluconazole or itraconazole.

Treatment Of Oropharyngeal Candidiasis With Posaconazole Oral Suspension

Posaconazole Oral Suspension Study 3 was a randomized, controlled, evaluator-blinded study in HIV-infected patients with oropharyngeal candidiasis. Patients were treated with posaconazole or fluconazole oral suspension (both posaconazole and fluconazole were given as follows: 100 mg twice a day for 1 day followed by 100 mg once a day for 13 days).

Clinical and mycological outcomes were assessed after 14 days of treatment and at 4 weeks after the end of treatment. Patients who received at least 1 dose of study medication and had a positive oral swish culture of Candida species at baseline were included in the analyses (see Table 23). The majority of the subjects had C. albicans as the baseline pathogen.

Clinical success at Day 14 (complete or partial resolution of all ulcers and/or plaques and symptoms) and clinical relapse rates (recurrence of signs or symptoms after initial cure or improvement) 4 weeks after the end of treatment were similar between the treatment arms (see Table 23).

Mycologic eradication rates (absence of colony forming units in quantitative culture at the end of therapy, Day 14), as well as mycologic relapse rates (4 weeks after the end of treatment) were also similar between the treatment arms (see Table 23).

Table 23: Posaconazole Oral Suspension Clinical Success, Mycological Eradication, and Relapse Rates in Oropharyngeal Candidiasis

  Posaconazole Fluconazole
Clinical Success at End of Therapy (Day 14) 155/169 (91.7%) 148/160 (92.5%)
Clinical Relapse (4 Weeks after End of Therapy) 45/155 (29.0%) 52/148 (35.1%)
Mycological Eradication (absence of CFU) at End of Therapy (Day 14) 88/169 (52.1%) 80/160 (50.0%)
Mycological Relapse (4 Weeks after End of Treatment) 49/88 (55.6%) 51/80 (63.7%)

Mycologic response rates, using a criterion for success as a posttreatment quantitative culture with ≤ 20 colony forming units (CFU/mL) were also similar between the two groups (posaconazole 68.0%, fluconazole 68.1%). The clinical significance of this finding is unknown.

Posaconazole Oral Suspension Treatment Of Oropharyngeal Candidiasis Refractory To Treatment With Fluconazole Or Itraconazole

Posaconazole Oral Suspension Study 4 was a noncomparative study of posaconazole oral suspension in HIV-infected subjects with OPC that was refractory to treatment with fluconazole or itraconazole. An episode of OPC was considered refractory if there was failure to improve or worsening of OPC after a standard course of therapy with fluconazole greater than or equal to 100 mg/day for at least 10 consecutive days or itraconazole 200 mg/day for at least 10 consecutive days and treatment with either fluconazole or itraconazole had not been discontinued for more than 14 days prior to treatment with posaconazole. Of the 199 subjects enrolled in this study, 89 subjects met these strict criteria for refractory infection.

Forty-five subjects with refractory OPC were treated with posaconazole oral suspension 400 mg BID for 3 days, followed by 400 mg QD for 25 days with an option for further treatment during a 3-month maintenance period. Following a dosing amendment, a further 44 subjects were treated with posaconazole 400 mg BID for 28 days. The efficacy of posaconazole was assessed by the clinical success (cure or improvement) rate after 4 weeks of treatment. The clinical success rate was 74.2% (66/89). The clinical success rates for both the original and the amended dosing regimens were similar (73.3% and 75.0%, respectively).

Last reviewed on RxList: 4/1/2014
This monograph has been modified to include the generic and brand name in many instances.

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