Posaconazole Sandoz 100 mg gastro-resistant tablets

Posaconazole is indicated for use in the treatment of the following fungal infections in adults (see sections 4.2 and 5.1):

- Invasive aspergillosis Posaconazole is indicated for use in the treatment of the following fungal infections in paediatric patients from 2 years of age weighing more than 40 kg and adults (see sections 4.2 and 5.1):

- 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 is also indicated for prophylaxis of invasive fungal infections in the following paediatric patients from 2 years of age weighing more than 40 kg and adults (see sections 4.2 and 5.1):

- 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 oral suspension products for use in oropharyngeal candidiasis.

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

Non-Interchangeability between posaconazole tablets and posaconazole oral suspension

The tablet is not to be used interchangeably with the oral suspension 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.

Posology

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

Recommended dose in paediatric patients from 2 years of age weighing more than 40 kg and in adults is shown in Table 1.

Table 1. Recommended dose in paediatric patients from 2 years of age weighing more than 40 kg and in adults 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 (see section 5.2).

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 (see sections 4.4 and 5.2). It is recommended to exercise caution due to the potential for higher plasma exposure.

Paediatric population

The safety and efficacy of posaconazole in children aged below 2 years have not been established. No clinical data are available.

Method of administration

For oral use

The gastro-resistant tablets may be taken with or without food (see section 5.2). The tablets should be swallowed whole with water and should not be crushed, chewed or broken.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Co-administration with ergot alkaloids (see section 4.5).

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 (see sections 4.4 and 4.5).

Co-administration with the HMG-CoA reductase inhibitors simvastatin, lovastatin and atorvastatin (see section 4.5).

Co-administration during the initiation and dose-titration phase of venetoclax in Chronic Lymphocytic Leukaemia (CLL) patients (see sections 4.4 and 4.5).

Hypersensitivity

There is no information regarding cross-sensitivity between posaconazole and other azole antifungal agents. Caution should be used when prescribing posaconazole 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 (see sections 4.2 and 5.2).

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 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 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 must not be administered with medicinal products that are substrates for CYP3A4 and are known to prolong the QTc interval (see sections 4.3 and 4.5). Posaconazole 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

• Concomitant use with medicinal products known to prolong the QTc interval (other than those mentioned in section 4.3).

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 (see section 4.5).

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 (see section 4.5).

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 (see section 4.5).

Venetoclax toxicity

Concomitant administration of strong CYP3A inhibitors, including posaconazole, with the CYP3A4 substrate venetoclax, may increase venetoclax toxicities, including the risk of tumour lysis syndrome (TLS) and neutropenia (see sections 4.3 and 4.5). Refer to the venetoclax SmPC for detailed guidance.

Rifamycin antibacterials (rifampicin, rifabutin), flucloxacillin, 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 (see section 4.5).

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 (see section 5.2).

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.

Photosensitivity reaction

Posaconazole may cause increased risk of photosensitivity reaction. Patients should be advised to avoid sun exposure during treatment without adequate protection such as protective clothing and sunscreen with a high sun protection factor (SPF).

Posaconazole contains sodium:

This medicinal product contains less than 1 mmol sodium (23 mg) per gastro-resistant tablet, that is to say essentially 'sodium-free'.

Effects of other medicinal products on posaconazole

Posaconazole is metabolised via UDP glucuronidation (phase 2 enzymes) and is a substrate for p- glycoprotein (P-gp) efflux in vitro. Therefore, inhibitors (e.g. verapamil, ciclosporin, quinidine, clarithromycin, erythromycin, etc.) or inducers (e.g. rifampicin, rifabutin, certain anticonvulsants, etc.) of these clearance pathways may increase or decrease posaconazole plasma concentrations, respectively.

Rifabutin

Rifabutin (300 mg once a day) decreased the C_max (maximum plasma concentration) and AUC (area under the plasma concentration time curve) of posaconazole to 57 % and 51 %, respectively.

Concomitant use of posaconazole and rifabutin and similar inducers (e.g. rifampicin) should be avoided unless the benefit to the patient outweighs the risk. See also below regarding the effect of posaconazole on rifabutin plasma levels.

Flucloxacillin

Flucloxacillin (a CYP450 inducer) may decrease plasma posaconazole concentrations. Concomitant use of posaconazole and flucloxacillin should be avoided unless the benefit to the patient outweighs the risk (see section 4.4).

Efavirenz

Efavirenz (400 mg once a day) decreased the C_max and AUC of posaconazole by 45 % and 50 %, respectively. Concomitant use of posaconazole and efavirenz should be avoided unless the benefit to the patient outweighs the risk.

Fosamprenavir

Combining fosamprenavir with posaconazole may lead to decreased posaconazole plasma concentrations. If concomitant administration is required, close monitoring for breakthrough fungal infections is recommended. Repeat dose administration of fosamprenavir (700 mg twice daily x 10 days) decreased the C_max and AUC of posaconazole oral suspension (200 mg once daily on the 1^st day, 200 mg twice daily on the 2^nd day, then 400 mg twice daily x 8 Days) by 21 % and 23 %, respectively. The effect of posaconazole on fosamprenavir levels when fosamprenavir is given with ritonavir is unknown.

Phenytoin

Phenytoin (200 mg once a day) decreased the C_max and AUC of posaconazole by 41 % and 50 %, respectively. Concomitant use of posaconazole and phenytoin and similar inducers (e.g. carbamazepine, phenobarbital, primidone) should be avoided unless the benefit to the patient outweighs the risk.

H₂ receptor antagonists and proton pump inhibitors

No clinically relevant effects were observed when posaconazole tablets are concomitantly used with antacids, H₂-receptor antagonists and proton pump inhibitors. No dosage adjustment of posaconazole tablets is required when posaconazole tablets are concomitantly used with antacids, H₂-receptor antagonists and proton pump inhibitors.

Effects of posaconazole on other medicinal products

Posaconazole is a potent inhibitor of CYP3A4. Co-administration of posaconazole with CYP3A4 substrates may result in large increases in exposure to CYP3A4 substrates as exemplified by the effects on tacrolimus, sirolimus, atazanavir and midazolam below. Caution is advised during co- administration of posaconazole with CYP3A4 substrates administered intravenously and the dose of the CYP3A4 substrate may need to be reduced. If posaconazole is used concomitantly with CYP3A4 substrates that are administered orally, and for which an increase in plasma concentrations may be associated with unacceptable adverse reactions, plasma concentrations of the CYP3A4 substrate and/or adverse reactions should be closely monitored and the dose adjusted as needed. Several of the interaction studies were conducted in healthy volunteers in whom a higher exposure to posaconazole occurs compared to patients administered the same dose. The effect of posaconazole on CYP3A4 substrates in patients might be somewhat lower than that observed in healthy volunteers, and is expected to be variable between patients due to the variable posaconazole exposure in patients. The effect of co-administration with posaconazole on plasma levels of CYP3A4 substrates may also be variable within a patient.

Terfenadine, astemizole, cisapride, pimozide, halofantrine and quinidine (CYP3A4 substrates)

Co-administration of posaconazole and terfenadine, astemizole, cisapride, pimozide, halofantrine or quinidine is contraindicated. Co-administration may result in increased plasma concentrations of these medicinal products, leading to QTc prolongation and rare occurrences of torsades de pointes (see section 4.3).

Ergot alkaloids

Posaconazole may increase the plasma concentration of ergot alkaloids (ergotamine and dihydroergotamine), which may lead to ergotism. Co-administration of posaconazole and ergot alkaloids is contraindicated (see section 4.3).

HMG-CoA reductase inhibitors metabolised through CYP3A4 (e.g. simvastatin, lovastatin, and atorvastatin)

Posaconazole may substantially increase plasma levels of HMG-CoA reductase inhibitors that are metabolised by CYP3A4. Treatment with these HMG-CoA reductase inhibitors should be discontinued during treatment with posaconazole as increased levels have been associated with rhabdomyolysis (see section 4.3).

Vinca alkaloids

Most of the vinca alkaloids (e.g., vincristine and vinblastine) are substrates of CYP3A4. Concomitant administration of azole antifungals, including posaconazole, with vincristine has been associated with serious adverse reactions (see section 4.4). Posaconazole may increase the plasma concentrations of vinca alkaloids which may lead to neurotoxicity and other serious adverse reactions. Therefore, reserve azole antifungals, including posaconazole, for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options.

Rifabutin

Posaconazole increased the C_max and AUC of rifabutin by 31 % and 72 %, respectively. Concomitant use of posaconazole and rifabutin should be avoided unless the benefit to the patient outweighs the risk (see also above regarding the effect of rifabutin on plasma levels of posaconazole). If these medicinal products are co-administered, careful monitoring of full blood counts and adverse reactions related to increased rifabutin levels (e.g. uveitis) is recommended.

Sirolimus

Repeat dose administration of posaconazole oral suspension (400 mg twice daily for 16 days) increased the C_max and AUC of sirolimus (2 mg single dose) an average of 6.7-fold and 8.9-fold (range 3.1 to 17.5-fold), respectively, in healthy subjects. The effect of posaconazole on sirolimus in patients is unknown, but is expected to be variable due to the variable posaconazole exposure in patients. Co- administration of posaconazole with sirolimus is not recommended and should be avoided whenever possible. If it is considered that co-administration is unavoidable, then it is recommended that the dose of sirolimus should be greatly reduced at the time of initiation of posaconazole therapy and that there should be very frequent monitoring of trough concentrations of sirolimus in whole blood. Sirolimus concentrations should be measured upon initiation, during co-administration, and at discontinuation of posaconazole treatment, with sirolimus doses adjusted accordingly. It should be noted that the relationship between sirolimus trough concentration and AUC is changed during co- administration with posaconazole. As a result, sirolimus trough concentrations that fall within the usual therapeutic range may result in sub-therapeutic levels. Therefore, trough concentrations that fall in the upper part of the usual therapeutic range should be targeted and careful attention should be paid to clinical signs and symptoms, laboratory parameters and tissue biopsies.

Ciclosporin

In heart transplant patients on stable doses of ciclosporin, posaconazole oral suspension 200 mg once daily increased ciclosporin concentrations requiring dose reductions. Cases of elevated ciclosporin levels resulting in serious adverse reactions, including nephrotoxicity and one fatal case of leukoencephalopathy, were reported in clinical efficacy studies. When initiating treatment with posaconazole in patients already receiving ciclosporin, the dose of ciclosporin should be reduced (e.g. to about three quarters of the current dose). Thereafter blood levels of ciclosporin should be monitored carefully during co-administration, and upon discontinuation of posaconazole treatment, and the dose of ciclosporin should be adjusted as necessary.

Tacrolimus

Posaconazole increased C_max and AUC of tacrolimus (0.05 mg/kg body weight single dose) by 121 % and 358 %, respectively. Clinically significant interactions resulting in hospitalisation and/or posaconazole discontinuation were reported in clinical efficacy studies. When initiating posaconazole treatment in patients already receiving tacrolimus, the dose of tacrolimus should be reduced (e.g. to about one third of the current dose). Thereafter blood levels of tacrolimus should be monitored carefully during co-administration, and upon discontinuation of posaconazole, and the dose of tacrolimus should be adjusted as necessary.

HIV Protease inhibitors

As HIV protease inhibitors are CYP3A4 substrates, it is expected that posaconazole will increase plasma levels of these antiretroviral agents. Following co-administration of posaconazole oral suspension (400 mg twice daily) with atazanavir (300 mg once daily) for 7 days in healthy subjects C_max and AUC of atazanavir increased by an average of 2.6-fold and 3.7-fold (range 1.2 to 26-fold), respectively. Following co-administration of posaconazole oral suspension (400 mg twice daily) with atazanavir and ritonavir (300/100 mg once daily) for 7 days in healthy subjects C_max and AUC of atazanavir increased by an average of 1.5-fold and 2.5-fold (range 0.9 to 4.1-fold), respectively. The addition of posaconazole to therapy with atazanavir or with atazanavir plus ritonavir was associated with increases in plasma bilirubin levels. Frequent monitoring for adverse reactions and toxicity related to antiretroviral agents that are substrates of CYP3A4 is recommended during co- administration with posaconazole.

Midazolam and other benzodiazepines metabolised by CYP3A4

In a study in healthy volunteers posaconazole oral suspension (200 mg once daily for 10 days) increased the exposure (AUC) of intravenous midazolam (0.05 mg/kg) by 83 %. In another study in healthy volunteers, repeat dose administration of posaconazole oral suspension (200 mg twice daily for 7 days) increased the C_max and AUC of intravenous midazolam (0.4 mg single dose) by an average of 1.3- and 4.6-fold (range 1.7 to 6.4-fold), respectively; Posaconazole oral suspension 400 mg twice daily for 7 days increased the intravenous midazolam C_max and AUC by 1.6 and 6.2-fold (range 1.6 to 7.6-fold), respectively. Both doses of posaconazole increased C_max and AUC of oral midazolam (2 mg single oral dose) by 2.2 and 4.5-fold, respectively. In addition, posaconazole oral suspension (200 mg or 400 mg) prolonged the mean terminal half-life of midazolam from approximately 3-4 hours to 8-10 hours during co-administration.

Due to the risk of prolonged sedation it is recommended that dose adjustments should be considered when posaconazole is administered concomitantly with any benzodiazepine that is metabolised by CYP3A4 (e.g. midazolam, triazolam, alprazolam) (see section 4.4).

Calcium channel blockers metabolised through CYP3A4 (e.g. diltiazem, verapamil, nifedipine, nisoldipine)

Frequent monitoring for adverse reactions and toxicity related to calcium channel blockers is recommended during co-administration with posaconazole. Dose adjustment of calcium channel blockers may be required.

Digoxin

Administration of other azoles has been associated with increases in digoxin levels. Therefore, posaconazole may increase plasma concentration of digoxin and digoxin levels need to be monitored when initiating or discontinuing posaconazole treatment.

Sulfonylureas

Glucose concentrations decreased in some healthy volunteers when glipizide was co-administered with posaconazole. Monitoring of glucose concentrations is recommended in diabetic patients.

All-trans retinoic acid (ATRA) or tretinoin

As ATRA is metabolised by the hepatic CYP450 enzymes, notably CYP3A4, concomitant administration with posaconazole, which is a strong inhibitor of CYP3A4, may lead to increased exposure to tretinoin resulting in an increased toxicity (especially hypercalcaemia). Serum calcium levels should be monitored and, if needed, appropriate dose adjustments of tretinoin should be considered during the treatment with posaconazole, and during the following days after treatment.

Venetoclax

Compared with venetoclax 400 mg administered alone, co-administration of 300 mg posaconazole, a strong CYP3A inhibitor, with venetoclax 50 mg and 100 mg for 7 days in 12 patients, increased venetoclax C_max to 1.6-fold and 1.9-fold, and AUC to 1.9-fold and 2.4-fold, respectively (see sections 4.3 and 4.4).

Refer to the venetoclax SmPC.

Paediatric population

Interaction studies have only been performed in adults.

Pregnancy

There is insufficient information on the use of posaconazole in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

Women of childbearing potential have to use effective contraception during treatment. Posaconazole must not be used during pregnancy unless the benefit to the mother clearly outweighs the potential risk to the foetus.

Breast-feeding

Posaconazole is excreted into the milk of lactating rats (see section 5.3). The excretion of posaconazole in human breast milk has not been investigated. Breast-feeding must be stopped on initiation of treatment with posaconazole.

Fertility

Posaconazole had no effect on fertility of male rats at doses up to 180 mg/kg (3.4 times the 300-mg tablet based on steady-state plasma concentrations in patients) or female rats at a dose up to 45 mg/kg (2.6 times the 300-mg tablet based on steady-state plasma concentrations in patients). There is no clinical experience assessing the impact of posaconazole on fertility in humans.

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.

Summary of the safety profile

Safety data mainly derive from studies with the oral suspension.

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

Posaconazole tablets

The safety of posaconazole tablet has been assessed in 104 healthy volunteers and 230 patients enrolled in a clinical study of antifungal prophylaxis.

The safety of posaconazole concentrate for solution for infusion and posaconazole tablet has been assessed in 288 patients enrolled in a clinical study of aspergillosis of whom 161 patients received the concentrate for solution for infusion and 127 patients received the tablet formulation.

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.

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).

The safety of posaconazole tablets and concentrate for solution for infusion were also investigated in a controlled study of treatment of invasive aspergillosis. The maximum duration of invasive aspergillosis treatment was similar to that studied with the oral suspension for salvage treatment and was longer than that with the tablets or concentrate for solution for infusion in prophylaxis.

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 (cannot be estimated from the available data).

Table 2. Adverse reactions by body system and frequency reported in clinical trials and/or post marketing use*

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

^§ See section 4.4.

Description of selected adverse reactions

Hepatobiliary disorders

During post-marketing surveillance of posaconazole oral suspension, severe hepatic injury with fatal outcome has been reported (see section 4.4).

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: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in Google play or Apple App store.

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.

The following in vitro data are available, but their clinical significance is unknown. In a surveillance study of > 3,000 clinical mold 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.

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: 0.5 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

• Candida dubliniensis: 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 concentrate for solution for infusion and tablet study invasive aspergillosis The safety and efficacy of posaconazole for the treatment of patients with invasive aspergillosis was evaluated in a double-blind controlled study (study-69) in 575 patients with proven, probable, or possible invasive fungal infections per EORTC/MSG criteria.

Patients were treated with posaconazole (n=288) concentrate for solution for infusion or tablet given at a dose of 300 mg QD (BID on Day 1). Comparator patients were treated with voriconazole (n=287) given IV at a dose of 6 mg/kg BID Day 1 followed by 4 mg/kg BID, or orally at a dose of 300 mg BID Day 1 followed by 200 mg BID. Median treatment duration was 67 days (posaconazole) and 64 days (voriconazole).

In the intent-to-treat (ITT) population (all subjects who received at least one dose of study drug), 288 patients received posaconazole and 287 patients received voriconazole. The full analysis set population (FAS) is the subset of all subjects within the ITT population who were classified by independent adjudication as having proven or probable invasive aspergillosis: 163 subjects for posaconazole and 171 subjects for voriconazole. The all-cause mortality and global clinical response in these two populations are presented in Table 3 and 4, respectively.

Table 3. Posaconazole invasive aspergillosis treatment study 1: all-cause mortality at Day 42 and Day 84, in the ITT and FAS populations

Table 4. Posaconazole invasive aspergillosis treatment study 1: global clinical response at Week 6 and Week 12 in the FAS population

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 5 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 5. 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 6, 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 6. 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 7 and 8 for results from both studies. There were fewer breakthrough Aspergillus infections in patients receiving posaconazole prophylaxis when compared to control patients.

Table 7. 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 8. 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 limited paediatric experience for posaconazole tablets.

Three patients 14-17 years of age were treated with posaconazole concentrate for solution for infusion and tablet 300 mg/day (BID on Day 1 followed by QD thereafter) in the study of treatment of invasive aspergillosis.

The safety and efficacy of posaconazole for oral suspension have been established in paediatric patients 2 to less than 18 years of age. Use of posaconazole in these age groups is supported by evidence from adequate and well-controlled studies of posaconazole in adults and pharmacokinetic and safety data from paediatric studies (see section 5.2). No new safety signals associated with the use of posaconazole in paediatric patients were identified in the paediatric studies (see section 4.8).

Safety and efficacy in paediatric patients below the age of 2 years have not been established. No data are available.

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. 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).

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). Based on a population pharmacokinetic model, posaconazole Cav is increased 20 % when given with a meal compared to a fasted state.

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 (t½) 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

Based on a population pharmacokinetic model evaluating posaconazole pharmacokinetics, steady state posaconazole concentrations were predicted in patients administered posaconazole concentrate for solution for infusion or tablets 300 mg once a day following BID dosing on Day 1 for the treatment of invasive aspergillosis and prophylaxis of invasive fungal infections.

Table 9. Population predicted median (10^th percentile, 90^th percentile) posaconazole steady state plasma concentrations in patients following administration of posaconazole concentrate for solution for infusion or tablets 300 mg QD (BID on Day 1)

The population pharmacokinetic analysis of posaconazole in patients suggests that race, sex, renal impairment and disease (prophylaxis or treatment) have no clinically meaningful effect on the pharmacokinetics of posaconazole.

Children (< 18 years)

There is limited (n=3) 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

No overall differences in safety were observed between the geriatric patients and younger patients. The population pharmacokinetic model of posaconazole concentrate for solution for infusion and tablets indicates that posaconazole clearance is related to age. Posaconazole Cav is generally comparable between young and elderly patients (≥ 65 years of age); however, the Cav is increased by 11 % in the very elderly (≥ 80 years). It is, therefore, suggested to closely monitor very elderly patients (≥ 80 years) for adverse events.

The pharmacokinetics of posaconazole tablets are comparable in young and elderly subjects (≥ 65 years of age).

Pharmacokinetic differences based upon age are not considered to be clinically relevant; therefore, no dose adjustment is required.

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

The population pharmacokinetic model of posaconazole concentrate for solution for infusion and tablets indicates that posaconazole clearance is related to weight. In patients > 120 kg, the Cav is decreased by 25 % and in patients <50 kg, the Cav is increased by 19 %.

It is, therefore, suggested to closely monitor for breakthrough fungal infections in patients weighing more than 120 kg.

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.

In a nonclinical study using intravenous administration of posaconazole in very young dogs (dosed from 2-8 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 5 month treatment-free period. There were no neurologic, behavioural or developmental abnormalities in the dogs with this finding, and a similar brain finding was not seen with either oral posaconazole administration to juvenile dogs (4 days to 9 months of age) or intravenous posaconazole administration to juvenile dogs (10 weeks to 23 weeks of age). The clinical significance of this finding is unknown.

Tablet core

Methacrylic acid-Ethyl acrylate copolymer (1:1) (Type B)

Triethyl citrate

Xylitol

Hydroxypropylcellulose

Propyl gallate

Cellulose, microcrystalline

Silica, colloidal anhydrous

Croscarmellose sodium

Sodium Stearyl Fumarate

Tablet coat

Polyvinyl alcohol

Titanium dioxide (E 171)

Macrogol 3350

Talc

Iron oxide yellow (E 172)

Not applicable.

36 months

This medicinal product does not require any special storage conditions.

The tablets are provided in Alu -Alu blisters - 24 or 96 gastro-resistant tablets in non-perforated blisters and 24 x 1 and 96 x 1 tablets in perforated unit dose blisters.

White opaque PVC/PCTFE-Alu blisters – 24 or 96 gastro-resistant tablets in non-perforated blisters and 24 x 1 and 96 x 1 tablets in perforated unit dose blisters.

White opaque PVC/PE/PVdC-Alu blisters- 24 or 96 gastro-resistant tablets in non-perforated blisters and 24 x 1 and 96 x 1 tablets in perforated unit dose blisters.

HDPE bottles with Polypropylene cap – 60 gastro-resistant tablets

Not all pack sizes may be marketed.

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