Pharmacotherapeutic Group: Antiinfective for Systemic Use, Triazole derivative, J02AC04.
Pharmacology: Pharmacodynamics: Mechanism of action: Posaconazole is a triazole antifungal agent. It is an inhibitor of the enzyme lanosterol 14α-demethylase, which catalyses an essential step in ergosterol biosynthesis. Ergosterol depletion, coupled with the accumulation of methylated sterol precursors, is thought to impair membrane integrity and the function of some membrane-associated proteins. This results in the inhibition of cell growth and/or cell death.
Consequently, posaconazole exhibits broad-spectrum antifungal activity against a variety of yeasts and moulds including species of
Candida (including
C. albicans isolates resistant to fluconazole, voriconazole and itraconazole,
C. krusei and
C. glabrata which are inherently less susceptible to fluconazole, and
C. lusitaniae which is inherently less susceptible to amphotericin B),
Aspergillus (including isolates resistant to fluconazole, voriconazole, itraconazole and amphotericin B) and organisms not previously regarded as being susceptible to azoles such as the zygomycetes (e.g. species of
Absidia, Mucor, Rhizopus and
Rhizomucor).
In vitro posaconazole exhibited fungicidal activity against species of
Aspergillus, dimorphic fungi (
Blastomyces dermatitidis, Histoplasma capsulatum, Penicillium marneffei, and
Coccidioides immitis) and some species of
Candida. In animal infection models posaconazole was active against a wide variety of fungal infections caused by moulds or yeasts. However, there was no consistent correlation between minimum inhibitory concentration and efficacy.
Clinical Trials: Pharmacokinetics and Safety of Posaconazole Modified Release Tablets in Patients: Study 5615 was a non-comparative multi-center study performed to evaluate the pharmacokinetic properties, safety, and tolerability of posaconazole modified release tablet. Study 5615 was conducted in a similar patient population to that previously studied in the pivotal posaconazole oral suspension clinical program. The pharmacokinetics and safety data from Study 5615 were bridged to the existing data (including efficacy data) with the oral suspension.
Study 5615 enrolled a total of 230 subjects. Part 1 of the study was designed to select a dose for further study in Part 2, after first evaluating pharmacokinetics, safety, and tolerability in the neutropenic patient population at high risk of a fungal infection. Part 2 of the study was designed to evaluate posaconazole modified release tablet in a more diverse patient population, and to confirm the exposure of posaconazole modified release tablet in additional subjects at risk of a fungal infection. Posaconazole modified release tablet was administered without regard to food intake in both Part 1 and Part 2 of the study.
The subject population for Part 1 included subjects with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) who had recently received chemotherapy and had developed or were anticipated to develop significant neutropenia. Two different dosing groups were evaluated in Part 1: 200 mg BID on Day 1, followed by 200 mg QD thereafter (Part 1A) and 300 mg BID on Day 1, followed by 300 mg QD thereafter (Part 1B).
The subject population in Part 2 included: patients with AML or MDS who had recently received chemotherapy and had developed or were anticipated to develop significant neutropenia, or patients who had undergone a HSCT and were receiving immunosuppressive therapy for prevention or treatment of GVHD. These types of patients had been previously studied in a pivotal controlled trial of posaconazole oral suspension. Based on the pharmacokinetics and safety results of Part 1, all subjects in Part 2 received 300 mg BID on Day 1, followed by 300 mg QD thereafter.
The total subject population had a mean age of 51 years (range=19-78 years), 93% were White, the major ethnicity was not Hispanic or Latino (84%), and 62% were male. The study treated 110 (48%) subjects with AML (new diagnosis), 20 (9%) subjects with AML (first relapse), 9 (4%) subjects with MDS, and 91 (40%) subjects with HSCT, as the primary diseases at study entry.
Serial PK samples were collected on Day 1 and at steady-state on Day 8 for all Part 1 subjects and a subset of Part 2 subjects. This serial PK analysis demonstrated that 90% of the subjects treated with the 300 mg QD dose attained steady state Cavg between 500-2500 ng/mL. [Cavg was the average concentration of posaconazole at steady state, calculated as AUC/dosing interval (24 hours).] Subjects with AML/MDS with neutropenia following chemotherapy or HSCT subjects receiving immunosuppressive therapy to prevent or treat GVHD who received 300 mg QD achieved a mean Cavg at steady state of 1580 ng/mL. The PK findings from the pivotal study (Study 5615) support a 300-mg daily dose of posaconazole modified release tablet for use in prophylaxis.
Pharmacokinetics and Safety of Posaconazole Oral Suspension in Patients: Invasive Aspergillosis: Efficacy in patients with refractory disease or intolerance to prior therapy: The efficacy and survival benefit of oral posaconazole for the treatment of invasive aspergillosis in patients with disease refractory to amphotericin B (including liposomal formulations), itraconazole or, in a small number of cases, voriconazole or echinocandins, and/or with intolerance to amphotericin B (including liposomal formulations) or itraconazole was demonstrated in 107 patients enrolled in a salvage therapy trial. Patients were administered posaconazole oral suspension 800 mg/day in divided doses for up to 585 days. The median duration of posaconazole therapy was 56 days (1-585 days).
The majority of patients were severely immunocompromised with underlying conditions such as haematologic malignancies, including bone marrow transplantation; solid organ transplantation; solid tumours and/or AIDS. An independent expert panel reviewed all patient data, including diagnosis of invasive aspergillosis, refractoriness and intolerance to previous therapy, and clinical outcome in a parallel and blinded fashion with an external control group of 86 patients treated with standard salvage therapy (e.g. amphotericin B including liposomal formulations, and/or itraconazole) mostly at the same time and at the same sites as the patients enrolled in the posaconazole trial.
A success was defined as either complete resolution (complete response) or a clinically meaningful improvement (partial response) of all signs, symptoms and radiographic findings attributable to the fungal infection. Stable, non-progressive disease and failure were considered to be a non-success. Most of the cases of aspergillosis were considered to be refractory in both the posaconazole group (88%) and in the external control group (79%) while the remaining patients were intolerant to prior antifungal therapy (12%, posaconazole; 21% external control group).
As shown in Table 1, a successful global response at end of treatment was seen in 42% of posaconazole-treated patients compared to 26% of the external group (P=0.006). (See Table 1.)
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Other Serious Fungal Pathogens: Posaconazole oral suspension has been shown to be effective against the following additional pathogens when other therapy had been ineffective or when the patient had developed intolerance of the prior therapy: Zygomycosis: Successful responses to posaconazole oral suspension therapy were noted in 7/13 (54%) of patients with zygomycete infections. Sites of infection included the sinuses, lung, and skin. Organisms included Rhizopus, Mucor and Rhizomucor. Most of the patients had underlying haematological malignancies, half of which required a bone marrow transplant. Half of the patients were enrolled with intolerance to previous therapy and the other half as a result of disease that was refractory to prior therapy. Three patients were noted to have disseminated disease, one of which had a successful outcome after failing amphotericin B therapy.
Fusarium spp.: Successful responses to posaconazole oral suspension therapy were seen in 11 of 24 (46%) of patients with fusariosis. Four of the responders had disseminated disease and one patient had disease localized to the eye; the remainder had a variety of sites of infection. Seven of 24 patients had profound neutropenia at baseline. In addition, 3/5 patients with infection due to
F. solani which is typically resistant to most antifungal agents, were successfully treated.
Chromoblastomycosis/Mycetoma: Successful responses to posaconazole oral suspension therapy were seen in 9 of 11 (82%) of patients with chromoblastomycosis or mycetoma. Five of these patients had chromoblastomycosis due to
Fonsecaea pedrosoi and 4 had mycetoma, mostly due to
Madurella species.
Coccidioidomycosis: The efficacy of posaconazole in the primary treatment of non-meningeal coccidioidomycosis was demonstrated in 15 clinically evaluable patients enrolled in an open-label, non-comparative trial to receive posaconazole 400 mg daily for 6 months. Most patients were otherwise healthy and had infections at a variety of sites. A satisfactory response (defined as an improvement of at least 50% of the Cocci score as defined by the BAMSG Coccidioidomycosis trial group) was seen in 12 of 15 patients (80%) after an average of 4 months of posaconazole treatment. In a separate open-label, non-comparative trial, the safety and efficacy of posaconazole 400 mg twice a day was assessed in 16 patients with coccidioidomycosis infection refractory to standard treatment.
Most had been treated with amphotericin B (including lipid formulations) and/or itraconazole or fluconazole for months to years prior to posaconazole treatment. At the end of treatment with posaconazole, a satisfactory response (complete or partial resolution of signs and symptoms present at baseline) as determined by an independent panel was achieved for 11/16 (69%) of patients. One patient with CNS disease that had failed fluconazole therapy had a successful outcome following 12 months of posaconazole therapy.
Treatment of Azole-Susceptible Oropharyngeal Candidiasis (OPC) in HIV-infected patients: A randomised, double-blind, controlled study was completed in HIV-infected patients with azole-susceptible oropharyngeal candidiasis. The primary efficacy variable was the clinical success rate (defined as cure or improvement) after 14 days of treatment. 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).
The clinical and mycological response rates from the above study are shown in Table 2 as follows. Posaconazole and fluconazole demonstrated equivalent clinical success rates at Day 14 as well as 4 weeks after the end of treatment. However, posaconazole oral suspension demonstrated a significantly better mycological response rate than fluconazole 4 weeks after the end of treatment. (See Table 2.)
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Clinical success rate was defined as the number of cases assessed as having a clinical response (cure or improvement) divided by the total number of cases eligible for analysis.
Mycological response rate was defined as mycological success (≤20 CFU/ml) divided by the total number of cases eligible for analysis.
Treatment of Oropharyngeal Candidiasis refractory to itraconazole and fluconazole (rOPC) in HIV-infected patients: The primary efficacy parameter in the short-term treatment study was the clinical success rate (cure or improvement) after 4 weeks of treatment. HIV-infected patients were treated with posaconazole oral suspension 400 mg twice a day with an option for further treatment during a 3-month maintenance period. A 75% (132/176) clinical success rate and a 36.5% (46/126) mycological response rate (≤20 CFU/ml) were achieved after 4 weeks of posaconazole treatment. Clinical success rates ranged from 71% to 100%, inclusive, for all azole-resistant
Candida species identified at Baseline, including
C. glabrata and
C. krusei.
In the long-term treatment study the primary efficacy endpoint was the clinical success rate (cure or improvement) after 3 months of treatment. A total of 100 HIV-infected patients with OPC and/or EC were treated with posaconazole 400 mg twice a day for up to 15 months. Sixty of these patients had been previously treated in Study 330. An 85.6% (77/90) clinical success rate overall (cure or improvement) was achieved after 3 months of posaconazole treatment; 80.6% (25/31) for previously untreated subjects.
The mean exposure to posaconazole based on the actual days dosed was 102 days (range: 1-544 days). Sixty-seven percent (67%, 10/15) of patients treated with posaconazole for at least 12 months had continued clinical success at the last assessment.
Prophylaxis of Invasive Fungal Infections (IFIs) (Studies 316 and 1899): Two randomised, controlled prophylaxis studies were conducted using posaconazole oral suspension as prophylaxis for the prevention of IFIs among patients at high risk for developing invasive fungal infections.
Study 316 was a randomised, double-blind trial of posaconazole oral suspension (200 mg three times a day) versus fluconazole capsules (400 mg once daily) in allogeneic hematopoietic stem cell transplant recipients with graft-versus-host disease (GVHD). The primary efficacy endpoint was the incidence of proven/probable IFIs at 16 weeks post-randomization as determined by an independent, blinded external expert panel. A key secondary endpoint was the incidence of proven/probable IFIs during the on-treatment period (first dose to last dose of study medicinal product + 7 days). The majority (377/600, [63%]) of patients included had Acute Grade 2 or 3 or chronic extensive (195/600, [32.5%]) GVHD at study start. The mean duration of therapy was 80 days for posaconazole and 77 days for fluconazole.
Study 1899 was a randomised, evaluator-blinded study of posaconazole oral suspension (200 mg three times a day) versus fluconazole suspension (400 mg once daily) or itraconazole oral solution (200 mg twice a day) in neutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia or myelodysplastic syndromes. The primary efficacy endpoint was the incidence of proven/probable IFIs as determined by an independent, blinded external expert panel during the on-treatment period. A key secondary endpoint was the incidence of proven/probable IFIs at 100 days post-randomization. New diagnosis of acute myelogenous leukemia was the most common underlying condition (435/602, [72%]). The mean duration of therapy was 29 days for posaconazole and 25 days for fluconazole/itraconazole.
In both prophylaxis studies, aspergillosis was the most common breakthrough infection. See Tables 3 and 4 for results from both studies. There were fewer breakthrough Aspergillus infections in patients receiving posaconazole prophylaxis when compared to control patients. (See Tables 3 and 4.)
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In Study 1899, a significant decrease in all cause mortality in favour of posaconazole was observed [POS 49/304 (16%) vs. FLU/ITZ 67/298 (22%) p=0.048]. Based on Kaplan-Meier estimates, the probability of survival up to day 100 after randomization, was significantly higher for posaconazole recipients; this survival benefit was demonstrated when the analysis considered all causes of death (P=0.0354) as well as IFI-related deaths (P=0.0209).
In Study 316, overall mortality was similar (POS, 25%; FLU, 28%); however, the proportion of IFI-related deaths was significantly lower in the POS group (4/301) compared with the FLU group (12/299; P=0.0413).
Use in paediatric patients: Sixteen patients 8-17 years of age were treated with up to 800 mg/day in a study for invasive fungal infections. Based on the available data in 16 of these paediatric patients, the safety profile appears to be similar to patients ≥18 years of age.
Additionally, twelve patients 13-17 years of age received 600 mg/day for prophylaxis of invasive fungal infections (Studies 316 and 1899). The safety profile in these patients <18 years of age appears similar to the safety profile observed in adults. Based on pharmacokinetic data in 10 of these paediatric patients, the pharmacokinetic profile appears to be similar to patients ≥18 years of age.
Safety and efficacy in paediatric patients below the age of 18 years have not been established.
Electrocardiogram evaluation: Multiple, time-matched ECGs collected over a 12 hour period were obtained before and during administration of posaconazole oral suspension (400 mg twice daily with high fat meals) from 173 healthy male and female volunteers aged 18 to 85 years. No clinically relevant changes in the mean QTc (Fridericia) interval from baseline were observed.
Pharmacokinetics: Absorption: MR Tablet: When given orally in healthy volunteers, posaconazole modified release tablets are absorbed with a median T
max of 4 to 5 hours. Posaconazole modified release tablets exhibit dose proportional pharmacokinetics after single and multiple dosing up to 300 mg. Steady-state plasma concentrations are attained by Day 6 at the 300 mg dose (QD after BD loading dose at Day 1). The absolute bioavailability of the oral modified release tablet is approximately 54%. Relative bioavailability was investigated between the 100 mg modified release tablet under fasted conditions and the 100 mg oral suspension under fed conditions in healthy adults. Under these conditions, plasma exposure to posaconazole for the two treatments was similar. Under fasted conditions, the exposure of posaconazole after single-dose modified release tablet administration was 3.7-fold higher than the oral suspension.
Oral Suspension: Posaconazole is absorbed with a median T
max of 3 hours (patients) and ~5 hours (healthy volunteers). Intersubject variability in mean AUC and C
max was high in healthy volunteers and patients despite the controlled conditions in pharmacokinetic studies.
The pharmacokinetics of posaconazole are linear following single and multiple dose administration of up to 800 mg. No further increases in exposure are observed above a total daily dose of 800 mg in patients and healthy volunteers. There is no effect of altered pH on the absorption of posaconazole (see Interactions).
Dividing the total posaconazole daily dose (800 mg) as 400 mg twice a day results in a 184% higher exposure relative to once-a-day administration in patients. Exposure further increased when posaconazole was given as 200 mg four times daily.
Effect of food on oral absorption healthy volunteers: MR Tablet: In a single dose study (P112) investigating the effect of a high fat meal on the bioavailability of posaconazole following administration of NOXAFIL modified release tablets 300 mg (3 x 100 mg) in healthy volunteers, the C
max was 16% higher and the AUC
0-72 hours was 51% higher with food relative to fasting. The results of the study are summarised as follows in Table 5. The effect of food on the absorption of NOXAFIL modified release tablets is not considered clinically meaningful. Food effect was taken into consideration at the time of final dose selection of the 300 mg modified release tablet based on data from the pivotal clinical Phase 1b/Phase 3 pharmacokinetic/safety study P5615 in which patients took NOXAFIL modified release tablets without regard to food intake. NOXAFIL modified release tablets can therefore be administered with or without food. Posaconazole modified release tablets can be taken without regard to food. (See Table 5.)
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Oral Suspension: The AUC of posaconazole is about 2.6 times greater when administered with a nonfat meal or nutritional supplement (14 gm fat) and 4 times greater when administered with a high-fat meal (~50 gm fat) relative to the fasted state.
Posaconazole should be administered with food or a nutritional supplement (see Dosage & Administration).
Distribution: Posaconazole is highly protein bound (>98.0%), predominantly to serum albumin.
MR Tablet: Posaconazole, after administration of the modified release tablet, has a mean apparent volume of distribution of 394 L (42%), ranging between 294-583 L among the studies in healthy volunteers.
Oral Suspension: Posaconazole has a large apparent volume of distribution (1774 L) suggesting extensive penetration into the peripheral tissues.
Metabolism: Posaconazole does not have any major circulating metabolites and its concentrations are unlikely to be altered by inhibitors of CYP450 enzymes. Of the circulating metabolites, the majority are glucuronide conjugates of posaconazole with only minor amounts of oxidative (CYP450 mediated) metabolites observed. The excreted metabolites in urine and faeces account for approximately 17% of the administered radio-labelled dose.
Excretion: Posaconazole is predominantly excreted in the faeces (77% of the radio-labelled dose) with the major component eliminated as parent drug (66% of the radio-labelled dose). Renal clearance is a minor elimination pathway, with 14% of the radio-labelled dose excreted in urine (<0.2% of the radio-labelled dose is parent drug).
MR Tablet: Posaconazole modified release tablet is eliminated with a mean half-life (t
1/2) ranging between 26 and 31 hours and a mean apparent clearance ranging from 7.5 to 11 L/hr.
Oral Suspension: Posaconazole is slowly eliminated with a mean half-life (t
1/2) of 35 hours (range 20 to 66 hours) and a total body clearance (Cl/F) of 32 L/hr. Steady-state is attained following 7 to 10 days of multiple-dose administration.
Summary of the mean pharmacokinetic parameters in patients: The general pharmacokinetic findings across the clinical program in both healthy volunteers and patients were consistent, in that posaconazole modified release and oral suspension was slowly absorbed and slowly eliminated with an extensive volume of distribution.
MR Tablet: Exposure following multiple administration of posaconazole tablets (200 or 300 mg) QD was 1.3 times higher in healthy volunteers than in patients.
The mean pharmacokinetic parameters in patients and healthy volunteers following administration of posaconazole modified release tablet 300 mg daily are displayed in Table 6. Patients have approximately 25% lower exposure as compared to healthy volunteers after multiple dosing of posaconazole modified release tablet. The differences in exposure between healthy volunteers and patients are much less than the exposure differences reported for posaconazole oral suspension. (See Table 6.)
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Simulation based on the population pharmacokinetic model was performed in patients receiving posaconazole modified release tablet 300 mg daily (following 300 mg BD on Day 1). Simulated pharmacokinetics in patients and subpopulations of AML/MDS and HSCT patients are displayed in Table 7. (See Table 7.)
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Coadministration of food, or medications known to alter gastric pH (antacid, ranitidine, esomeprazole) or motility (metoclopramide) shows no clinically meaningful effect on the pharmacokinetics of posaconazole when administered as a modified release tablet.
In Table 8 a comparison is shown of exposure (C
avg) in patients after administration of posaconazole modified release tablet and posaconazole oral suspension at therapeutic doses. (See Table 8.)
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Oral Suspension: In addition, the phenomenon of dose-limited absorption of posaconazole at 800 mg/day was observed both in healthy volunteers and patients. The mean pharmacokinetic parameters in patients and healthy volunteers following administration of posaconazole 400 mg twice a day for 7 days are displayed in Table 9. (See Table 9.)
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The exposure to posaconazole following administration of 400 mg twice a day was ~3 times higher in healthy volunteers than in patients, without additional safety findings at the higher concentrations (Table 9).
Pharmacokinetics in Special Populations: Children (<18 years): There is limited paediatric experience for posaconazole tablets.
Following administration of 800 mg per day of posaconazole oral suspension as a divided dose for treatment of invasive fungal infections, mean trough plasma concentrations from 12 patients 8-17 years of age (776 ng/ml) were similar to concentrations from 194 patients 18-64 years of age (817 ng/ml). No pharmacokinetic data are available from paediatric patients less than 8 years of age. Similarly, in the prophylaxis studies, the mean steady-state posaconazole average concentration (C
avg) was comparable among ten adolescents (13-17 years of age) to C
avg achieved in adults (≥18 years of age).
In a study of 136 neutropenic paediatric patients 11 months-17 years treated with posaconazole oral suspension, at doses up to 18 mg/kg/day divided TID, approximately 50% met the prespecified target (Day 7 C
avg between 500 ng/mL-2500 ng/mL).
In general, exposures tended to be higher in the older patients (7 to <18 years) than in younger patients (2 to <7 years).
Gender: The pharmacokinetics of posaconazole are comparable in men and women. No adjustment in the dosage of NOXAFIL is necessary based on gender.
Elderly: MR Tablet: The pharmacokinetics of posaconazole modified release tablets are comparable in young and elderly subjects. No overall differences in safety were observed between the geriatric patients and younger patients; therefore, no dosage adjustment is recommended for geriatric patients.
Oral Suspension: Results from a multiple dose study in healthy volunteers (n=48) indicated that at steady state, there was an increase in C
max (26%) and AUC (29%) observed in elderly subjects (24 subjects ≥65 years of age) relative to younger subjects (24 subjects 18-45 years of age). A similar trend was observed in the clinical program based on a small proportion of elderly subjects ≥65 years of age (n=25 vs.194 patients 18-64 years of age). However, in a population pharmacokinetic analysis (Study 1899), age did not influence the pharmacokinetics of posaconazole. The safety profile of posaconazole between the young and elderly patients was similar. Therefore no dose adjustment is required for age.
Race: MR Tablet: There is insufficient data among different races with posaconazole modified release tablets.
Oral Suspension: Results from a multiple dose study in healthy volunteers (n=56) indicated that there was only a slight decrease (16%) in the AUC and C
max of posaconazole in Black subjects relative to Caucasian subjects, therefore, no dose adjustment for race is required.
Weight: MR Tablet: Pharmacokinetic modeling for posaconazole suggests that patients weighing greater than 120 kg may have lower posaconazole exposure. It is, therefore, suggested to closely monitor for breakthrough fungal infections in patients weighing more than 120 kg.
Renal insufficiency: Following single-dose administration, there was no effect of mild and moderate renal insufficiency (n=18, Cl
cr ≥20 mL/min/1.73 m
2) on posaconazole pharmacokinetics, therefore, no dose adjustment is required. In subjects with severe renal insufficiency (n=6, Cl
cr <20 mL/min/1.73 m
2), the exposure of posaconazole was highly variable (96% CV) compared to the exposure in the other renal groups (40% CV). However, as posaconazole is not significantly renally eliminated, an effect of severe renal insufficiency on the pharmacokinetics of posaconazole is not expected and no dose adjustment is recommended. Posaconazole is not removed by haemodialysis.
MR Tablet: Due to the variability in exposure, patients with severe renal impairment should be monitored closely for breakthrough fungal infections.
Similar recommendations apply to posaconazole modified release tablets; however, a specific study has not been conducted with posaconazole modified release tablets.
Hepatic insufficiency: In a small number of subjects (n=12) studied with hepatic insufficiency (Child-Pugh class A, B or C), C
max values generally decreased with the severity of hepatic dysfunction (545, 414 and 347 ng/mL for the mild, moderate, and severe groups, respectively), even though the C
max values (mean 508 ng/mL) for the normal subjects were consistent with previous trials in healthy volunteers. In addition, an increase in half-life was also associated with a decrease in hepatic function (26.6, 35.3, and 46.1 hours for the mild, moderate, and severe groups, respectively), as all groups had longer half-life values than subjects with normal hepatic function (22.1 hours). Due to the limited pharmacokinetic data in patients with hepatic insufficiency; no recommendation for dose adjustment can be made.
MR Tablet: Similar recommendations apply to posaconazole modified release tablets; however, a specific study has not been conducted with posaconazole modified release tablets.
Electrocardiogram evaluation: Oral Suspension: Multiple, time-matched ECGs collected over a 12 hour period were recorded at baseline and steady-state from 173 healthy male and female volunteers (18 to 85 years of age) administered posaconazole 400 mg BID with a high-fat meal. In this pooled analysis, the mean QT
c (Fridericia) interval change was -5 msec following administration of the recommended clinical dose. A decrease in the QT
c (F) interval (-3 msec) was also observed in a small number of subjects (n=16) administered placebo. No subject administered posaconazole had a QT
c (F) interval of ≥500 msec or an increase ≥60 msec in their QT
c (F) interval from baseline.
Microbiology: Posaconazole has been shown
in vitro and in clinical infections to be active against the following microorganisms: (See Indications/Uses):
Aspergillus species (
Aspergillus fumigatus, A. flavus,
A. terreus,
A. nidulans,
A. niger,
A. ustus,
A. ochraceus),
Candida species (
Candida albicans,
C. glabrata,
C. krusei,
C. parapsilosis),
Cryptococcus neoformans,
Coccidioides immitisFonsecaea pedrosoi,
Histoplasma capsulatum,
Pseudallescheria boydii and species of
Alternaria, Exophiala, Fusarium, Ramichloridium, Rhizomucor, Mucor, and
Rhizopus. While posaconazole has been used in a clinical setting against these micro organisms, sufficient evidence for efficacy has not been collected for all the listed microorganisms (see Clinical Trials as previously mentioned).
Posaconazole also exhibits in vitro activity against the following yeasts and moulds:
Candida dubliniensis, C. famata, C. guilliermondii, C. lusitaniae, C. kefyr, C. rugosa, C. tropicalis, C. zeylanoides, C. inconspicua, C. lipolytica, C. norvegensis, C. pseudotropicalis, Cryptococcus laurentii, Kluyveromyces marxianus, Saccharomyces cerevisiae, Yarrowia lipolytica, species of
Pichia, and
Trichosporon, Aspergillus sydowii, Bjerkandera adusta, Blastomyces dermatitidis, Epidermophyton floccosum, Paracoccidioides brasiliensis, Scedosporium apiospermum, Sporothrix schenckii, Wangiella dermatitidis and species of
Absidia, Apophysomyces, Bipolaris, Curvularia, Microsporum, Paecilomyces, Penicillium, and
Trichophyton. However, the safety and effectiveness of posaconazole in treating clinical infections due to these microorganisms have not been established in clinical trials.
The following
in vitro data are available, but their clinical significance is unknown. In a surveillance study of >3,000 clinical mould isolates from 2010-2018, 90% of non-Aspergillus fungi exhibited the following
in vitro minimum inhibitory concentration (MIC):
Mucorales spp (n=81) of 2 mg/L;
Scedosporium apiospermum/
S. boydii (n=65) of 2 mg/L;
Exophiala dermatiditis (n=15) of 0.5 mg/L, and
Purpureocillium lilacinum (n=21) of 1 mg/L.
NOXAFIL exhibits broad-spectrum antifungal activity against some yeasts and moulds not generally responsive to azoles, or resistant to other azoles: species of
Candida (including
C. albicans isolates resistant to fluconazole, voriconazole and itraconazole,
C. krusei and
C. glabrata which are inherently less susceptible to fluconazole,
C. lusitaniae which is inherently less susceptible to amphotericin B),
Aspergillus (including isolates resistant to fluconazole, voriconazole, itraconazole and amphotericin B), organisms not previously regarded as being susceptible to azoles such as the zygomycetes (e.g. species of
Absidia, Mucor, Rhizopus and
Rhizomucor).
In vitro NOXAFIL exhibited fungicidal activity against species of:
Aspergillus, dimorphic fungi (
Blastomyces dermatitidis, Histoplasma capsulatum, Penicillium marneffei, Coccidioides immitis), some species of
Candida.
In animal infection models NOXAFIL was active against a wide variety of fungal infections caused by moulds or yeasts. However, there was no consistent correlation between minimum inhibitory concentration and efficacy.
Specimens for fungal culture and other relevant laboratory studies (including histopathology) should be obtained prior to therapy to isolate and identify causative organism(s). Therapy may be instituted before the results of the cultures and other laboratory studies are known. However, once these results become available, antifungal therapy should be adjusted accordingly.
Drug Resistance: C. albicans strains resistant to posaconazole could not be generated in the laboratory; spontaneous laboratory
Aspergillus fumigatus mutants exhibiting a decrease in susceptibility to posaconazole arose at a frequency of 1x10
-8 to 1x10
-9. Clinical isolates of
Candida albicans and
Aspergillus fumigatus exhibiting significant decreases in posaconazole susceptibility are rare. In those rare instances where decreased susceptibility was noted, there was no clear correlation between decreased susceptibility and clinical failure. Clinical success has been observed in patients infected with organisms resistant to other azoles; consistent with these observations posaconazole was active
in vitro against many Aspergillus and Candida strains that developed resistance to other azoles and/or amphotericin B. Breakpoints for posaconazole have not been established for any fungi.
Antifungal drug combinations: When combinations of posaconazole with either amphotericin B or caspofungin were tested
in vitro and
in vivo there was little or no antagonism and in some instances there was an additive effect. Clinical studies of posaconazole in combination with antifungal drugs including amphotericin B-based drugs and caspofungin have not been conducted.
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