Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Merck Sharp & Dohme B.V., Waarderweg 39, 2031 BN Haarlem, The Netherlands
Pharmacotherapeutic group: Antimycotics for systemic use, triazole derivatives
ATC code: J02AC04
Posaconazole inhibits the enzyme lanosterol 14α-demethylase (CYP51), which catalyses an essential step in ergosterol biosynthesis.
Posaconazole has been shown in vitro to be active against the following microorganisms: Aspergillus species (Aspergillus fumigatus, A. flavus, A. terreus, A. nidulans, A. niger, A. ustus), Candida species (Candida albicans, C. glabrata, C. krusei, C. parapsilosis, C. tropicalis, C. dubliniensis, C. famata, C. inconspicua, C. lipolytica, C. norvegensis, C. pseudotropicalis), Coccidioides immitis, Fonsecaea pedrosoi, and species of Fusarium, Rhizomucor, Mucor, and Rhizopus. The microbiological data suggest that posaconazole is active against Rhizomucor, Mucor, and Rhizopus; however the clinical data are currently too limited to assess the efficacy of posaconazole against these causative agents.
Clinical isolates with decreased susceptibility to posaconazole have been identified. The principle mechanism of resistance is the acquisition of substitutions in the target protein, CYP51.
The ECOFF values for posaconazole, which distinguish the wild type population from isolates with acquired resistance, have been determined by EUCAST methodology. EUCAST ECOFF values:
There are currently insufficient data to set clinical breakpoints for Aspergillus spp. ECOFF values do not equate to clinical breakpoints.
EUCAST MIC breakpoints for posaconazole [susceptible (S); resistant (R)]:
There are currently insufficient data to set clinical breakpoints for other Candida species.
The use of combination antifungal therapies should not decrease the efficacy of either posaconazole or the other therapies; however, there is currently no clinical evidence that combination therapy will provide an added benefit.
A correlation between total medicinal product exposure divided by MIC (AUC/MIC) and clinical outcome was observed. The critical ratio for subjects with Aspergillus infections was ~200. It is particularly important to try to ensure that maximal plasma levels are achieved in patients infected with Aspergillus (see sections 4.2 and 5.2 on recommended dose regimens and the effects of food on absorption).
Oral posaconazole suspension 800 mg/day in divided doses was evaluated for the treatment of invasive aspergillosis in patients with disease refractory to amphotericin B (including liposomal formulations) or itraconazole or in patients who were intolerant of these medicinal products in a non-comparative salvage therapy trial (Study 0041). Clinical outcomes were compared with those in an external control group derived from a retrospective review of medical records. The external control group included 86 patients treated with available therapy (as above) mostly at the same time and at the same sites as the patients treated with posaconazole. Most of the cases of aspergillosis were considered to be refractory to prior therapy in both the posaconazole group (88%) and in the external control group (79%).
As shown in Table 3, a successful response (complete or partial resolution) at the end of treatment was seen in 42% of posaconazole-treated patients compared to 26% of the external group. However, this was not a prospective, randomised controlled study and so all comparisons with the external control group should be viewed with caution.
Table 3. Overall efficacy of posaconazole oral suspension at the end of treatment for invasive aspergillosis in comparison to an external control group:
| Posaconazole oral suspension | External control group | |
|---|---|---|
| Overall Response | 45/107 (42%) | 22/86 (26%) |
| Success by Species | ||
| All mycologically confirmed Aspergillus spp.1 | 34/76 (45%) | 19/74 (26%) |
| A. fumigatus | 12/29 (41%) | 12/34 (35%) |
| A. flavus | 10/19 (53%) | 3/16 (19%) |
| A. terreus | 4/14 (29%) | 2/13 (15%) |
| A. niger | 3/5 (60%) | 2/7 (29%) |
1 Includes other less common species or species unknown
11 of 24 patients who had proven or probable fusariosis were successfully treated with posaconazole oral suspension 800 mg/day in divided doses for a median of 124 days and up to 212 days. Among eighteen patients who were intolerant or had infections refractory to amphotericin B or itraconazole, seven patients were classed as responders.
9 of 11 patients were successfully treated with posaconazole oral suspension 800 mg/day in divided doses for a median of 268 days and up to 377 days. Five of these patients had chromoblastomycosis due to Fonsecaea pedrosoi and 4 had mycetoma, mostly due to Madurella species.
11 of 16 patients were successfully treated (at the end of treatment complete or partial resolution of signs and symptoms present at baseline) with posaconazole oral suspension 800 mg/day in divided doses for a median of 296 days and up to 460 days.
A randomised, evaluator-blind, controlled study was completed in HIV-infected patients with azole-susceptible oropharyngeal candidiasis (most patients studied had C. albicans isolated at baseline). 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 response rates from the above study are shown in the Table 4 below. Posaconazole was shown to be non-inferior to fluconazole for clinical success rates at Day 14 as well as 4 weeks after the end of treatment.
Table 4. Clinical success rates in Oropharyngeal Candidiasis:
| Endpoint | Posaconazole | Fluconazole |
|---|---|---|
| Clinical success rate at Day 14 | 91.7% (155/169) | 92.5% (148/160) |
| Clinical success rate 4 weeks after end of treatment | 68.5% (98/143) | 61.8% (84/136) |
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.
Two randomised, controlled prophylaxis studies were conducted 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-randomisation 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 leukaemia 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-randomisation. New diagnosis of acute myelogenous leukaemia 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 Table 5 and 6 for results from both studies. There were fewer breakthrough Aspergillus infections in patients receiving posaconazole prophylaxis when compared to control patients.
Table 5. Results from clinical studies in prophylaxis of Invasive Fungal Infections:
| Study | Posaconazole oral suspension | Controla | P-Value |
|---|---|---|---|
| Proportion (%) of patients with proven/probable IFIs | |||
| On-treatment periodb | |||
| 1899d | 7/304 (2) | 25/298 (8) | 0.0009 |
| 316e | 7/291 (2) | 22/288 (8) | 0.0038 |
| Fixed-time periodc | |||
| 1899d | 14/304 (5) | 33/298 (11) | 0.0031 |
| 316d | 16/301 (5) | 27/299 (9) | 0.0740 |
FLU = fluconazole; ITZ = itraconazole; POS = posaconazole.
a FLU/ITZ (1899); FLU (316).
b In 1899 this was the period from randomisation to last dose of study medicinal product plus 7 days; in 316 it was the period from first dose to last dose of study medicinal product plus 7 days.
c In 1899, this was the period from randomisation to 100 days post-randomisation; in 316 it was the period from the baseline day to 111 days post-baseline.
d All randomised
e All treated
Table 6. Results from clinical studies in prophylaxis of Invasive Fungal Infections:
| Study | Posaconazole oral suspension | Controla |
|---|---|---|
| Proportion (%) of patients with proven/probable Aspergillosis | ||
| On-treatment periodb | ||
| 1899d | 2/304 (1) | 20/298 (7) |
| 316e | 3/291 (1) | 17/288 (6) |
| Fixed-time periodc | ||
| 1899d | 4/304 (1) | 26/298 (9) |
| 316d | 7/301 (2) | 21/299 (7) |
FLU = fluconazole; ITZ = itraconazole; POS = posaconazole.
a FLU/ITZ (1899); FLU (316).
b In 1899 this was the period from randomisation to last dose of study medicinal product plus 7 days; in 316 it was the period from first dose to last dose of study medicinal product plus 7 days.
c In 1899, this was the period from randomisation to 100 days post-randomisation; in 316 it was the period from the baseline day to 111 days post-baseline.
d All randomised
e All treated
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 randomisation, 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).
Sixteen patients 8-17 years of age were treated with posaconazole oral suspension 800 mg/day in a study for invasive fungal infections (Study 0041). 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 posaconazole oral suspension 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. In a study (Study 03579) 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 pre-specified target (Day 7 Cav between 500 ng/mL-2,500 ng/mL) (see section 5.2).
Safety and efficacy in paediatric patients below the age of 18 years have not been established.
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.
Posaconazole is absorbed with a median tmax of 3 hours (fed patients). The pharmacokinetics of posaconazole are linear following single and multiple dose administration of up to 800 mg when taken with a high fat meal. No further increases in exposure were observed when doses above 800 mg daily were administered to patients and healthy volunteers. In the fasting state, AUC increased less than in proportion to dose above 200 mg. In healthy volunteers under fasting conditions, dividing the total daily dose (800 mg) into 200 mg four times daily compared to 400 mg twice daily, was shown to increase posaconazole exposure by 2.6-fold.
The absorption of posaconazole was significantly increased when posaconazole 400 mg (once daily) was administered during and immediately after the consumption of a high fat meal (~50 grams fat) compared to administration before a meal, with Cmax and AUC increasing by approximately 330% and 360%, respectively. The AUC of posaconazole is: 4 times greater when administered with a high-fat meal (~50 grams fat) and about 2.6 times greater when administered during a non-fat meal or nutritional supplement (14 grams fat) relative to the fasted state (see sections 4.2 and 4.5).
Posaconazole is slowly absorbed and slowly eliminated with a large apparent volume of distribution (1,774 litres) and is highly protein bound (>98%), predominantly to serum albumin.
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 radiolabelled dose.
Posaconazole is slowly eliminated with a mean half-life (t1⁄2) of 35 hours (range 20 to 66 hours). After administration of 14C-posaconazole, radioactivity was predominantly recovered in the faeces (77% of the radiolabelled dose) with the major component being parent compound (66% of the radiolabelled dose). Renal clearance is a minor elimination pathway, with 14% of the radiolabelled dose excreted in urine (<0.2% of the radiolabelled dose is parent compound). Steady-state is attained following 7 to 10 days of multiple-dose administration.
Following administration of 800 mg per day of posaconazole 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). Similarly, in the prophylaxis studies, the mean steady-state posaconazole average concentration (Cav) was comparable among ten adolescents (13-17 years of age) to Cav 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 pre-specified target (Day 7 Cav between 500 ng/mL-2,500 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).
The pharmacokinetics of posaconazole are comparable in men and women.
An increase in Cmax (26%) and AUC (29%) was observed in elderly subjects (24 subjects ≥65 years of age) relative to younger subjects (24 subjects 18-45 years of age). However, in clinical efficacy trials, the safety profile of posaconazole between the young and elderly patients was similar.
There was a slight decrease (16%) in the AUC and Cmax of posaconazole oral suspension in Black subjects relative to Caucasian subjects. However, the safety profile of posaconazole between the Black and Caucasian subjects was similar.
Pharmacokinetic modelling with an oral tablet formulation 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. Patients with a low body weight (<60 kg) are more likely to experience higher plasma concentrations of posaconazole and should be closely monitored for adverse events.
Following single-dose administration of posaconazole oral suspension, there was no effect of mild and moderate renal impairment (n=18, Clcr ≥20 mL/min/1.73 m²) on posaconazole pharmacokinetics; therefore, no dose adjustment is required. In subjects with severe renal impairment (n=6, Clcr <20 mL/min/1.73 m²), the AUC of posaconazole was highly variable [>96% CV (coefficient of variance)] compared to other renal groups [<40% CV]. However, as posaconazole is not significantly renally eliminated, an effect of severe renal impairment on the pharmacokinetics of posaconazole is not expected and no dose adjustment is recommended. Posaconazole is not removed by haemodialysis.
After a single oral dose of 400 mg posaconazole oral suspension to patients with mild (Child-Pugh Class A), moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment (six per group), the mean AUC was 1.3 to 1.6-fold higher compared to that for matched control subjects with normal hepatic function. Unbound concentrations were not determined and it cannot be excluded that there is a larger increase in unbound posaconazole exposure than the observed 60% increase in total AUC. The elimination half-life (t½) was prolonged from approximately 27 hours up to ~43 hours in respective groups. No dose adjustment is recommended for patients with mild to severe hepatic impairment but caution is advised due to the potential for higher plasma exposure.
As observed with other azole antifungal agents, effects related to inhibition of steroid hormone synthesis were seen in repeated-dose toxicity studies with posaconazole. Adrenal suppressive effects were observed in toxicity studies in rats and dogs at exposures equal to or greater than those obtained at therapeutic doses in humans.
Neuronal phospholipidosis occurred in dogs dosed for ≥3 months at lower systemic exposures than those obtained at therapeutic doses in humans. This finding was not seen in monkeys dosed for one year. In twelve-month neurotoxicity studies in dogs and monkeys, no functional effects were observed on the central or peripheral nervous systems at systemic exposures greater than those achieved therapeutically.
Pulmonary phospholipidosis resulting in dilatation and obstruction of the alveoli was observed in the 2-year study in rats. These findings are not necessarily indicative of a potential for functional changes in humans.
No effects on electrocardiograms, including QT and QTc intervals, were seen in a repeat dose safety pharmacology study in monkeys at systemic exposures 4.6-fold greater than the concentrations obtained at therapeutic doses in humans. Echocardiography revealed no indication of cardiac decompensation in a repeat dose safety pharmacology study in rats at a systemic exposure 1.4-fold greater than that achieved therapeutically. Increased systolic and arterial blood pressures (up to 29 mm-Hg) were seen in rats and monkeys at systemic exposures 1.4-fold and 4.6-fold greater, respectively, than those achieved with the human therapeutic doses.
Reproduction, peri- and postnatal development studies were conducted in rats. At exposures lower than those obtained at therapeutic doses in humans, posaconazole caused skeletal variations and malformations, dystocia, increased length of gestation, reduced mean litter size and postnatal viability. In rabbits, posaconazole was embryotoxic at exposures greater than those obtained at therapeutic doses. As observed with other azole antifungal agents, these effects on reproduction were considered to be due to a treatment-related effect on steroidogenesis.
Posaconazole was not genotoxic in in vitro and in vivo studies. Carcinogenicity studies did not reveal special hazards for humans.
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