Posaconazole SP

Posaconazole SP gastro-resistant tablets are indicated for use in the treatment of the following fungal infections in adults :

- Invasive aspergillosis in patients with disease that is refractory to amphotericin B or itraconazole or in patients who are intolerant of these medicinal products;

- Fusariosis in patients with disease that is refractory to amphotericin B or in patients who are intolerant of amphotericin B;

- Chromoblastomycosis and mycetoma in patients with disease that is refractory to itraconazole or in patients who are intolerant of itraconazole;

- Coccidioidomycosis in patients with disease that is refractory to amphotericin B, itraconazole or fluconazole or in patients who are intolerant of these medicinal products.

Refractoriness is defined as progression of infection or failure to improve after a minimum of 7 days of prior therapeutic doses of effective antifungal therapy.

Posaconazole SP gastro-resistant tablets are also indicated for prophylaxis of invasive fungal infections in the following patients:

- Patients receiving remission-induction chemotherapy for acute myelogenous leukemia (AML) or myelodysplastic syndromes (MDS) expected to result in prolonged neutropenia and who are at high risk of developing invasive fungal infections;

- Hematopoietic stem cell transplant (HSCT) recipients who are undergoing high-dose immunosuppressive therapy for graft versus host disease and who are at high risk of developing invasive fungal infections.

Please refer to the Summary of Product Characteristics of Posaconazole SP oral suspension for use in oropharyngeal candidiasis.

Non-Interchangeability between Posaconazole SP Tablets and Posaconazole SP Oral Suspension

The tablet and oral suspension are not to be used interchangeably due to the differences between these two formulations in frequency of dosing, administration with food and plasma drug concentration achieved. Therefore, follow the specific dosage recommendations for each formulation.

Treatment should be initiated by a physician experienced in the management of fungal infections or in the supportive care in the high risk patients for which posaconazole is indicated as prophylaxis.

Posology

Posaconazole SP is also available as 40 mg/mL oral suspension and 300 mg concentrate for solution for infusion. Posaconazole SP tablets are the preferred formulation to optimize plasma concentrations and generally provide higher plasma drug exposures than Posaconazole SP oral suspension.

Recommended dose is shown in Table 1.

Table 1. Recommended dose according to indication

Special populations

Renal impairment

An effect of renal impairment on the pharmacokinetics of posaconazole is not expected and no dose adjustment is recommended.

Hepatic impairment

Limited data on the effect of hepatic impairment (including Child-Pugh C classification of chronic liver disease) on the pharmacokinetics of posaconazole demonstrate an increase in plasma exposure compared to subjects with normal hepatic function, but do not suggest that dose adjustment is necessary. It is recommended to exercise caution due to the potential for higher plasma exposure.

Paediatric population

The safety and efficacy of Posaconazole SP in children aged below 18 years have not been established.2, but no recommendation on a posology can be made.

No data are available for the tablet formulation.

Method of administration

For oral use

Posaconazole SP gastro-resistant tablets may be taken with or without food. The tablets should be swallowed whole with water and should not be crushed, chewed, or broken.

Co-administration with ergot alkaloids.

Co-administration with the CYP3A4 substrates terfenadine, astemizole, cisapride, pimozide, halofantrine or quinidine since this may result in increased plasma concentrations of these medicinal products, leading to QTc prolongation and rare occurrences of torsades de pointes.

Co-administration with the HMG-CoA reductase inhibitors simvastatin, lovastatin and atorvastatin.

Hypersensitivity

There is no information regarding cross-sensitivity between posaconazole and other azole antifungal agents. Caution should be used when prescribing Posaconazole SP to patients with hypersensitivity to other azoles.

Hepatic toxicity

Hepatic reactions (e.g. mild to moderate elevations in ALT, AST, alkaline phosphatase, total bilirubin and/or clinical hepatitis) have been reported during treatment with posaconazole. Elevated liver function tests were generally reversible on discontinuation of therapy and in some instances these tests normalised without interruption of therapy. Rarely, more severe hepatic reactions with fatal outcomes have been reported.

Posaconazole should be used with caution in patients with hepatic impairment due to limited clinical experience and the possibility that posaconazole plasma levels may be higher in these patients.

Monitoring of hepatic function

Liver function tests should be evaluated at the start of and during the course of posaconazole therapy. Patients who develop abnormal liver function tests during Posaconazole SP therapy must be routinely monitored for the development of more severe hepatic injury. Patient management should include laboratory evaluation of hepatic function (particularly liver function tests and bilirubin). Discontinuation of Posaconazole SP should be considered if clinical signs and symptoms are consistent with development of liver disease.

QTc prolongation

Some azoles have been associated with prolongation of the QTc interval. Posaconazole SP must not be administered with medicinal products that are substrates for CYP3A4 and are known to prolong the QTc interval. Posaconazole SP should be administered with caution to patients with pro-arrhythmic conditions such as:

- Congenital or acquired QTc prolongation

- Cardiomyopathy, especially in the presence of cardiac failure

- Sinus bradycardia

- Existing symptomatic arrhythmias

- ).

Electrolyte disturbances, especially those involving potassium, magnesium or calcium levels, should be monitored and corrected as necessary before and during posaconazole therapy.

Drug Interactions

Posaconazole is an inhibitor of CYP3A4 and should only be used under specific circumstances during treatment with other medicinal products that are metabolised by CYP3A4.

Midazolam and other benzodiazepines

Due to the risk of prolonged sedation and possible respiratory depression co-administration of posaconazole with any benzodiazepines metabolised by CYP3A4 (e.g. midazolam, triazolam, alprazolam) should only be considered if clearly necessary. Dose adjustment of benzodiazepines metabolised by CYP3A4 should be considered.

Vincristine Toxicity

Concomitant administration of azole antifungals, including posaconazole, with vincristine has been associated with neurotoxicity and other serious adverse reactions, including seizures, peripheral neuropathy, syndrome of inappropriate antidiuretic hormone secretion, and paralytic ileus. Reserve azole antifungals, including posaconazole, for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options.

Rifamycin antibacterials (rifampicin, rifabutin), certain anticonvulsants (phenytoin, carbamazepine, phenobarbital, primidone), and efavirenz.

Posaconazole concentrations may be significantly lowered in combination; therefore, concomitant use with posaconazole should be avoided unless the benefit to the patient outweighs the risk.

Plasma exposure

Posaconazole plasma concentrations following administration of posaconazole tablets are generally higher than those obtained with posaconazole oral suspension. Posaconazole plasma concentrations following administration of posaconazole tablets may increase over time in some patients. Safety data at higher exposure levels achieved with posaconazole tablets are at present limited.

Gastrointestinal dysfunction

There are limited pharmacokinetic data in patients with severe gastrointestinal dysfunction (such as severe diarrhoea). Patients who have severe diarrhoea or vomiting should be monitored closely for breakthrough fungal infections.

Since certain adverse reactions (e.g. dizziness, somnolence, etc.) have been reported with posaconazole use, which potentially may affect driving/operating machinery, caution needs to be used.

Safety data mainly derive from studies with the oral suspension.

The tablet formulation was investigated in AML and MDS patients and those after HSCT with or at risk for Graft versus Host Disease (GvHD) only. Maximum duration of exposure to the tablet formulation was shorter than with the oral suspension. Plasma exposure resulting from the tablet formulation was higher than observed with the oral suspension. A higher incidence of adverse reactions cannot be ruled out.

Summary of the safety profile

Posaconazole tablets

The safety of posaconazole tablets has been assessed in 230 patients enrolled in the pivotal clinical study. Patients were enrolled in a non-comparative pharmacokinetic and safety trial of posaconazole tablets when given as antifungal prophylaxis. Patients were immunocompromised with underlying conditions including haematological malignancy, neutropenia post-chemotherapy, GVHD, and post HSCT. Posaconazole therapy was given for a median duration of 28 days. Twenty patients received 200 mg daily dose and 210 patients received 300 mg daily dose (following twice daily dosing on Day 1 in each cohort).

Posaconazole tablet and oral suspension safety

The safety of posaconazole oral suspension has been assessed in > 2,400 patients and healthy volunteers enrolled in clinical trials and from post-marketing experience. The most frequently reported serious related adverse reactions included nausea, vomiting, diarrhoea, pyrexia, and increased bilirubin.

The safety of posaconazole tablet has been assessed in 336 patients and healthy volunteers enrolled in clinical trials. The safety profile of tablets was similar to that of the oral suspension.

Tabulated list of adverse reactions

Within the organ system classes, adverse reactions are listed under headings of frequency using the following categories: very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (> 1/10,000 to <1/1,000); very rare (<1/10,000); not known.

Table 2. Adverse reactions by body system and frequency*

* Based on adverse reactions observed with the oral suspension, gastro-resistant tablets, and concentrate for solution for infusion.

^§

Description of selected adverse reactions

Hepatobiliary disorders

During post-marketing surveillance of posaconazole oral suspension, severe hepatic injury with fatal outcome has been reported.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

There is no experience with overdose of posaconazole tablets.

During clinical trials, patients who received posaconazole oral suspension doses up to 1,600 mg/day experienced no different adverse reactions from those reported with patients at the lower doses. Accidental overdose was noted in one patient who took posaconazole oral suspension 1,200 mg twice a day for 3 days. No adverse reactions were noted by the investigator.

Posaconazole is not removed by haemodialysis. There is no special treatment available in the case of overdose with posaconazole. Supportive care may be considered.

Pharmacotherapeutic group: Antimycotics for systemic use, triazole derivatives, ATC code: J02AC04.

Mechanism of action

Posaconazole inhibits the enzyme lanosterol 14α-demethylase (CYP51), which catalyses an essential step in ergosterol biosynthesis.

Microbiology

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.

Resistance

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.

Epidemiological Cut-off (ECOFF) Values for Aspergillus spp.

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:

- Aspergillus flavus: 0.5 mg/L

- Aspergillus fumigatus: 0.25 mg/L

- Aspergillus nidulans: 0.5 mg/L

- Aspergillus niger: 0.5 mg/L

- Aspergillus terreus: 0.25 mg/L

There are currently insufficient data to set clinical breakpoints for Aspergillus spp. ECOFF values do not equate to clinical breakpoints.

Breakpoints

EUCAST MIC breakpoints for posaconazole [susceptible (S); resistant (R)]:

- Candida albicans: S ≤0.06 mg/L, R >0.06 mg/L

- Candida tropicalis: S ≤0.06 mg/L, R >0.06 mg/L

- Candida parapsilosis: S ≤0.06 mg/L, R >0.06 mg/L

There are currently insufficient data to set clinical breakpoints for other Candida species.

Combination with other antifungal agents

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.

Clinical experience

Summary of posaconazole tablet bridging study

Study 5615 was a non-comparative multi-center study performed to evaluate the pharmacokinetic properties, safety, and tolerability of posaconazole 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.

The subject population included: 1) patients with AML or MDS who had recently received chemotherapy and had developed or were anticipated to develop significant neutropenia, or 2) patients who had undergone a HSCT and were receiving immunosuppressive therapy for prevention or treatment of GVHD. Two different dosing groups were evaluated: 200 mg twice daily on Day 1, followed by 200 mg once daily thereafter (Part IA) and 300 mg twice daily on Day 1, followed by 300 mg once daily thereafter (Part 1B and Part 2).

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. Moreover, sparse PK samples were collected at several days during steady state before the next dose (C_min) for a larger subject population. Based on average C_min concentrations, a predicted average concentration (Cav) could be calculated for 186 subjects dosed with 300 mg. PK analysis in patients of Cav found that 81 % of the subjects treated with the 300 mg once daily dose attained steady state predicted Cav between 500-2,500 ng/mL. One subject (<1 %) had a predicted Cav below 500 ng/mL and 19 % of the subjects had a predicted Cav above 2,500 ng/mL. Subjects achieved a mean predicted Cav at steady state of 1,970 ng/mL.

In Table 3 a comparison is shown of exposure (Cav) after administration of posaconazole tablet and posaconazole oral suspension at therapeutic doses in patients depicted as quartile analysis. Exposures after tablet administration are generally higher than, but overlapping with, exposures after administration of posaconazole oral suspension.

Table 3. Cav quartile analyses of pivotal patient studies with posaconazole tablet and oral suspension

Summary of posaconazole oral suspension studies

Invasive aspergillosis

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 4, 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 4. Overall efficacy of posaconazole oral suspension at the end of treatment for invasive aspergillosis in comparison to an external control group

Fusarium spp.

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.

Chromoblastomycosis/Mycetoma

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.

Coccidioidomycosis

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.

Prophylaxis of Invasive Fungal Infections (IFIs) (Studies 316 and 1899)

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-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 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-randomization. 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

FLU = fluconazole; ITZ = itraconazole; POS = posaconazole.

a: FLU/ITZ (1899); FLU (316).

b: In 1899 this was the period from randomization 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 randomization to 100 days post-randomization; in 316 it was the period from the baseline day to 111 days post-baseline.

d: All randomized

e: All treated

Table 6. Results from clinical studies in prophylaxis of Invasive Fungal Infections

FLU = fluconazole; ITZ = itraconazole; POS = posaconazole.

a: FLU/ITZ (1899); FLU (316).

b: In 1899 this was the period from randomization 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 randomization to 100 days post-randomization; in 316 it was the period from the baseline day to 111 days post-baseline.

d: All randomized

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 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).

Paediatric population

There is no paediatric experience for posaconazole tablets.

Sixteen patients 8-17 years of age were treated with posaconazole oral suspension 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 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.

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.

¹ Includes other less common species or species unknown

Pharmacokinetic / Pharmacodynamic relationships

A correlation between total medicinal product exposure divided by MIC (AUC/MIC) and clinical outcome was observed.2 on recommended dose regimens).

Absorption

Posaconazole tablets are absorbed with a median T_max of 4 to 5 hours and exhibits dose proportional pharmacokinetics after single and multiple dosing up to 300 mg.

Following a single dose administration of 300 mg posaconazole tablets after a high fat meal to healthy volunteers, the AUC_{0-72 hours} and C_max were higher compared to administration under fasted condition (51 % and 16 % for AUC_{0-72 hours} and C_max respectively).

Posaconazole plasma concentrations following administration of posaconazole tablets may increase over time in some patients. The reason for this time-dependency is not completely understood.

Distribution

Posaconazole, after administration of the tablet, has a mean apparent volume of distribution of 394 L (42 %), ranging between 294-583 L among the studies in healthy volunteers.

Posaconazole is highly protein bound (> 98 %), predominantly to serum albumin.

Biotransformation

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.

Elimination

Posaconazole after administration of the tablets, is slowly eliminated with a mean half-life (t_½) of 29 hours (range 26 to 31 hours) and a mean apparent clearance ranging from 7.5 to 11 L/hr. 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 plasma concentrations are attained by Day 6 at the 300 mg dose (once daily after twice daily loading dose at Day 1).

Pharmacokinetics in special populations

Children (< 18 years)

There is no paediatric experience with posaconazole tablets.

The pharmacokinetics of posaconazole oral suspension have been evaluated in paediatric patients. 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 (Cav) was comparable among ten adolescents (13-17 years of age) to Cav achieved in adults (> 18 years of age).

Gender

The pharmacokinetics of posaconazole tablets are comparable in men and women.

Elderly

The pharmacokinetics of posaconazole 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.

Race

There is insufficient data among different races with posaconazole tablets.

There was a slight decrease (16 %) in the AUC and C_max 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.

Weight

Pharmacokinetic modeling 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, in particular those receiving posaconazole after HSCT, who have a low body weight (< 60 kg) are more likely to experience higher plasma concentrations of posaconazole and should be closely monitored for adverse events.

Renal impairment

Following single-dose administration of posaconazole oral suspension, there was no effect of mild and moderate renal impairment (n=18, Cl _cr > 20 mL/min/1.73 m²) on posaconazole pharmacokinetics; therefore, no dose adjustment is required. In subjects with severe renal impairment (n=6, Cl _cr < 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.

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

Hepatic impairment

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 (t^1/2) 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.

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

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 maximal plasma concentrations 8.5-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 2.1-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 2.1-fold and 8.5-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.

Not applicable.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.