POSACONAZOLE ACCORD 100mg gastro-resistant tablets medication leaflet

Posaconazole Accord 100 mg gastro-resistant tablets

Each gastro-resistant tablet contains 100 mg of posaconazole.

For the full list of excipients, see section 6.1.

Gastro-resistant tablet

Yellow coated, capsule shaped tablet of approximate 17.5 mm length and 6.7 mm width, debossedwith “100P” on one side and plain on the other side.

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

- Invasive aspergillosis

Posaconazole Accord gastro-resistant tablets are indicated for use in the treatment of the followingfungal infections in paediatric patients from 2 years of age weighing more than 40 kg and adults (seesections 4.2 and 5.1):

- Invasive aspergillosis in patients with disease that is refractory to amphotericin B oritraconazole 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 areintolerant of amphotericin B;

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

- Coccidioidomycosis in patients with disease that is refractory to amphotericin B, itraconazole orfluconazole 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 daysof prior therapeutic doses of effective antifungal therapy.

Posaconazole Accord is also indicated for prophylaxis of invasive fungal infections in the followingpaediatric 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 leukaemia (AML)or myelodysplastic syndromes (MDS) expected to result in prolonged neutropenia and who areat high -risk of developing invasive fungal infections;

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

Please refer to the Summary of Product Characteristics of Posaconazole AHCL oral suspension for usein oropharyngeal candidiasis.

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

Non-interchangeability between Posaconazole Accord tablets and posaconazole oral suspension

The tablet is not to be used interchangeably with the oral suspension due to the differences betweenthese two formulations in frequency of dosing, administration with food and plasma drugconcentration achieved. Therefore, follow the specific dose recommendations for each formulation.

Posaconazole is also available as 40 mg/mL oral suspension and 300 mg concentrate for solution forinfusion. Posaconazole tablets generally provide higher plasma drug exposures than posaconazole oralsuspension under both fed and fasted conditions. Therefore, the tablets are preferred formulation tooptimise plasma concentrations.

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

Table 1. Recommended dose in paediatric patients from 2 years of age weighing more than 40 kg andin adults according to indication

Indication Dose and duration of therapy(See section 5.2)

Treatment of invasive aspergillosis Loading dose of 300 mg (three 100 mg tablets or 300 mg(only for adults) concentrate for solution for infusion) twice a day on the firstday, then 300 mg (three 100 mg tablets or 300 mgconcentrate for solution for infusion) once a day thereafter.

Each tablet dose may be taken without regard to food intake.

Recommended total duration of therapy is 6-12 weeks.

Switching between intravenous and oral administration isappropriate when clinically indicated.

Refractory invasive fungal infections Loading dose of 300 mg (three 100 mg tablets) twice a day(IFI)/patients with IFI intolerant to 1st on the first day, then 300 mg (three 100 mg tablets) once aline therapy day thereafter. Each dose may be taken without regard tofood intake. Duration of therapy should be based on theseverity of the underlying disease, recovery fromimmunosuppression, and clinical response.

Prophylaxis of invasive fungal Loading dose of 300 mg (three 100 mg tablets) twice a dayinfections on the first day, then 300 mg (three 100 mg tablets) once aday thereafter. Each dose may be taken without regard tofood intake. Duration of therapy is based on recovery fromneutropenia or immunosuppression. For patients with acutemyelogenous leukaemia or myelodysplastic syndromes,prophylaxis with Posaconazole Accord should start severaldays before the anticipated onset of neutropenia and continuefor 7 days after the neutrophil count rises above 500 cells permm3.

An effect of renal impairment on the pharmacokinetics of posaconazole is not expected and no doseadjustment is recommended (see section 5.2).

Limited data on the effect of hepatic impairment (including Child-Pugh C classification of chronicliver disease) on the pharmacokinetics of posaconazole demonstrate an increase in plasma exposurecompared to subjects with normal hepatic function, but do not suggest that dose adjustment isnecessary (see sections 4.4 and 5.2). It is recommended to exercise caution due to the potential forhigher plasma exposure.

The safety and efficacy of posaconazole in children aged below 2 years have not been established. Noclinical data are available.

For oral use.

Posaconazole Accord may be taken with or without food (see section 5.2). The tablets should beswallowed 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 medicinalproducts, leading to QTc prolongation and rare occurrences of torsades de pointes (see sections 4.4and 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).

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

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

Posaconazole should be used with caution in patients with hepatic impairment due to limited clinicalexperience and the possibility that posaconazole plasma levels may be higher in these patients (seesections 4.2 and 5.2).

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 routinelymonitored for the development of more severe hepatic injury. Patient management should includelaboratory evaluation of hepatic function (particularly liver function tests and bilirubin).

Discontinuation of posaconazole should be considered if clinical signs and symptoms are consistentwith development of liver disease.

QTc prolongation

Some azoles have been associated with prolongation of the QTc interval. Posaconazole must not beadministered 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 patientswith 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 thosementioned in section 4.3).

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

Posaconazole is an inhibitor of CYP3A4 and should only be used under specific circumstances duringtreatment 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 ofposaconazole with any benzodiazepines metabolised by CYP3A4 (e.g. midazolam, triazolam,alprazolam) should only be considered if clearly necessary. Dose adjustment of benzodiazepinesmetabolised by CYP3A4 should be considered (see section 4.5).

Vincristine toxicity

Concomitant administration of azole antifungals, including posaconazole, with vincristine has beenassociated with neurotoxicity and other serious adverse reactions, including seizures, peripheralneuropathy, syndrome of inappropriate antidiuretic hormone secretion, and paralytic ileus. Reserveazole antifungals, including posaconazole, for patients receiving a vinca alkaloid, includingvincristine, who have no alternative antifungal treatment options (see section 4.5).

Venetoclax toxicity

Concomitant administration of strong CYP3A inhibitors, including posaconazole, with the CYP3A4substrate 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 usewith posaconazole should be avoided unless the benefit to the patient outweighs the risk (seesection 4.5).

Photosensitivity reaction

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

Plasma exposure

Posaconazole plasma concentrations following administration of posaconazole tablets are generallyhigher than those obtained with posaconazole oral suspension. Posaconazole plasma concentrationsfollowing administration of posaconazole tablets may increase over time in some patients (seesection 5.2).

Gastrointestinal dysfunction

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

This medicinal product contains less than 1 mmol sodium (23 mg) per 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 forp-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.

Flucloxacillin

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

Rifabutin (300 mg once a day) decreased the Cmax (maximum plasma concentration) and AUC (areaunder 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 beavoided unless the benefit to the patient outweighs the risk. See also below regarding the effect ofposaconazole on rifabutin plasma levels.

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

Combining fosamprenavir with posaconazole may lead to decreased posaconazole plasmaconcentrations. If concomitant administration is required, close monitoring for breakthrough fungalinfections is recommended. Repeat dose administration of fosamprenavir (700 mg twice daily x10 days) decreased the Cmax and AUC of posaconazole oral suspension (200 mg once daily on the1st day, 200 mg twice daily on the 2nd 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 withritonavir is unknown.

Phenytoin (200 mg once a day) decreased the Cmax 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 patientoutweighs the risk.

H2 receptor antagonists and proton pump inhibitors

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

Effects of posaconazole on other medicinal products

Posaconazole is a potent inhibitor of CYP3A4. Co-administration of posaconazole with CYP3A4substrates may result in large increases in exposure to CYP3A4 substrates as exemplified by theeffects on tacrolimus, sirolimus, atazanavir and midazolam below. Caution is advised during co-administration of posaconazole with CYP3A4 substrates administered intravenously and the dose ofthe CYP3A4 substrate may need to be reduced. If posaconazole is used concomitantly with CYP3A4substrates that are administered orally, and for which an increase in plasma concentrations may beassociated with unacceptable adverse reactions, plasma concentrations of the CYP3A4 substrateand/or adverse reactions should be closely monitored and the dose adjusted as needed. Several of theinteraction studies were conducted in healthy volunteers in whom a higher exposure to posaconazoleoccurs compared to patients administered the same dose. The effect of posaconazole on CYP3A4substrates in patients might be somewhat lower than that observed in healthy volunteers, and isexpected to be variable between patients due to the variable posaconazole exposure in patients. Theeffect of co-administration with posaconazole on plasma levels of CYP3A4 substrates may also bevariable within a patient.

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

Co-administration of posaconazole and terfenadine, astemizole, cisapride, pimozide, halofantrine orquinidine is contraindicated. Co-administration may result in increased plasma concentrations of thesemedicinal products, leading to QTc prolongation and rare occurrences of torsades de pointes (seesection 4.3).

Ergot alkaloids

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

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

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

Vinca alkaloids

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

Posaconazole increased the Cmax and AUC of rifabutin by 31 % and 72 %, respectively. Concomitantuse of posaconazole and rifabutin should be avoided unless the benefit to the patient outweighs therisk (see also above regarding the effect of rifabutin on plasma levels of posaconazole). If thesemedicinal products are co-administered, careful monitoring of full blood counts and adverse reactionsrelated to increased rifabutin levels (e.g. uveitis) is recommended.

Repeat dose administration of posaconazole oral suspension (400 mg twice daily for 16 days)increased the Cmax and AUC of sirolimus (2 mg single dose) an average of 6.7-fold and 8.9-fold (range3.1 to 17.5-fold), respectively, in healthy subjects. The effect of posaconazole on sirolimus in patientsis 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 avoidedwhenever possible. If it is considered that co-administration is unavoidable, then it is recommendedthat the dose of sirolimus should be greatly reduced at the time of initiation of posaconazole therapyand that there should be very frequent monitoring of trough concentrations of sirolimus in wholeblood. Sirolimus concentrations should be measured upon initiation, during co-administration, and atdiscontinuation of posaconazole treatment, with sirolimus doses adjusted accordingly. It should benoted that the relationship between sirolimus trough concentration and AUC is changed duringco-administration with posaconazole. As a result, sirolimus trough concentrations that fall within theusual therapeutic range may result in sub-therapeutic levels. Therefore, trough concentrations that fallin the upper part of the usual therapeutic range should be targeted and careful attention should be paidto clinical signs and symptoms, laboratory parameters and tissue biopsies.

In heart transplant patients on stable doses of ciclosporin, posaconazole oral suspension 200 mg oncedaily increased ciclosporin concentrations requiring dose reductions. Cases of elevated ciclosporinlevels resulting in serious adverse reactions, including nephrotoxicity and one fatal case ofleukoencephalopathy, were reported in clinical efficacy studies. When initiating treatment withposaconazole 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 monitoredcarefully during co-administration, and upon discontinuation of posaconazole treatment, and the doseof ciclosporin should be adjusted as necessary.

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

As HIV protease inhibitors are CYP3A4 substrates, it is expected that posaconazole will increaseplasma levels of these antiretroviral agents. Following co-administration of posaconazole oralsuspension (400 mg twice daily) with atazanavir (300 mg once daily) for 7 days in healthy subjects

Cmax 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) withatazanavir and ritonavir (300/100 mg once daily) for 7 days in healthy subjects Cmax and AUC ofatazanavir increased by an average of 1.5-fold and 2.5-fold (range 0.9 to 4.1-fold), respectively. Theaddition of posaconazole to therapy with atazanavir or with atazanavir plus ritonavir was associatedwith increases in plasma bilirubin levels. Frequent monitoring for adverse reactions and toxicityrelated 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 inhealthy volunteers, repeat dose administration of posaconazole oral suspension (200 mg twice dailyfor 7 days) increased the Cmax and AUC of intravenous midazolam (0.4 mg single dose) by an averageof 1.3- and 4.6-fold (range 1.7 to 6.4-fold), respectively; Posaconazole oral suspension 400 mg twicedaily for 7 days increased the intravenous midazolam Cmax and AUC by 1.6 and 6.2-fold (range 1.6 to7.6-fold), respectively. Both doses of posaconazole increased Cmax and AUC of oral midazolam (2 mgsingle oral dose) by 2.2 and 4.5-fold, respectively. In addition, posaconazole oral suspension (200 mgor 400 mg) prolonged the mean terminal half-life of midazolam from approximately 3-4 hours to8-10 hours during co-administration.

Due to the risk of prolonged sedation it is recommended that dose adjustments should be consideredwhen 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 isrecommended during co-administration with posaconazole. Dose adjustment of calcium channelblockers may be required.

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 monitoredwhen initiating or discontinuing posaconazole treatment.

Sulfonylureas

Glucose concentrations decreased in some healthy volunteers when glipizide was co-administeredwith 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, concomitantadministration with posaconazole, which is a strong inhibitor of CYP3A4, may lead to increasedexposure to tretinoin resulting in an increased toxicity (especially hypercalcaemia). Serum calciumlevels should be monitored and, if needed, appropriate dose adjustments of tretinoin shouldbeconsidered 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, astrong CYP3A inhibitor, with venetoclax 50 mg and 100 mg for 7 days in 12 patients, increasedvenetoclax Cmax to 1.6-fold and 1.9-fold, and AUC to 1.9-fold and 2.4-fold, respectively (see sections4.3 and 4.4).

Refer to the venetoclax SmPC.

Interaction studies have only been performed in adults.

There is insufficient information on the use of posaconazole in pregnant women. Studies in animalshave 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. Posaconazolemust not be used during pregnancy unless the benefit to the mother clearly outweighs the potential riskto the foetus.

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

Posaconazole had no effect on fertility of male rats at doses up to 180 mg/kg (3.4 times the 300 mgtablet 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 noclinical experience assessing the impact of posaconazole on fertility in humans.

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

Safety data mainly derive from studies with the oral suspension.

The safety of posaconazole oral suspension has been assessed in > 2,400 patients and healthyvolunteers enrolled in clinical studies and from post-marketing experience. The most frequentlyreported serious related adverse reactions included nausea, vomiting, diarrhoea, pyrexia, and increasedbilirubin.

Posaconazole tablets

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

The safety of posaconazole concentrate for solution for infusion and posaconazole tablet has beenassessed in 288 patients enrolled in a clinical study of aspergillosis of whom 161 patients received theconcentrate 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 atrisk for Graft versus Host Disease (GVHD) only. Maximum duration of exposure to the tabletformulation was shorter than with the oral suspension. Plasma exposure resulting from the tabletformulation was higher than observed with the oral suspension.

The safety of posaconazole tablets has been assessed in 230 patients enrolled in the pivotal clinicalstudy. Patients were enrolled in a non-comparative pharmacokinetic and safety study of posaconazoletablets when given as antifungal prophylaxis. Patients were immunocompromised with underlyingconditions including haematological malignancy, neutropenia post-chemotherapy, GVHD, and post

HSCT. Posaconazole therapy was given for a median duration of 28 days. Twenty patients received200 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 acontrolled study of treatment of invasive aspergillosis. The maximum duration of invasiveaspergillosis treatment was similar to that studied with the oral suspension for salvage treatment andwas longer than that with the tablets or concentrate for solution for infusion in prophylaxis.

Within the organ system classes, adverse reactions are listed under headings of frequency using thefollowing 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 fromthe available data).

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

Common: neutropenia

Uncommon: thrombocytopenia, leukopenia, anaemia, eosinophilia,lymphadenopathy, splenic infarction

Rare: haemolytic uraemic syndrome, thrombotic thrombocytopenicpurpura, pancytopenia, coagulopathy, haemorrhage

Uncommon: allergic reaction

Rare: hypersensitivity reaction

Rare: adrenal insufficiency, blood gonadotropin decreased,pseudoaldosteronism

Common: electrolyte imbalance, anorexia, decreased appetite,hypokalaemia, hypomagnesaemia

Uncommon: hyperglycaemia, hypoglycaemia

Uncommon: abnormal dreams, confusional state, sleep disorder

Rare: psychotic disorder, depression

Common: paraesthesia, dizziness, somnolence, headache, dysgeusia

Uncommon: convulsions, neuropathy, hypoaesthesia, tremor, aphasia,insomnia

Rare: cerebrovascular accident, encephalopathy, peripheralneuropathy, syncope

Uncommon: blurred vision, photophobia, visual acuity reduced

Rare: diplopia, scotoma

Ear and labyrinth disorder

Rare: hearing impairment

Uncommon: long QT syndrome§, electrocardiogram abnormal§,palpitations, bradycardia, supraventricular extrasystoles,tachycardia

Rare: torsade de pointes, sudden death, ventricular tachycardia,cardio-respiratory arrest, cardiac failure, myocardialinfarction

Common: hypertension

Uncommon: hypotension, vasculitis

Rare: pulmonary embolism, deep vein thrombosis

Uncommon: cough, epistaxis, hiccups, nasal congestion, pleuritic pain,tachypnoea

Rare: pulmonary hypertension, interstitial pneumonia, pneumonitis

Very Common: nausea

Common: vomiting, abdominal pain, diarrhoea, dyspepsia, dry mouth,flatulence, constipation, anorectal discomfort

Uncommon: pancreatitis, abdominal distension, enteritis, epigastricdiscomfort, eructation, gastroesophageal reflux disease,oedema mouth

Rare: gastrointestinal haemorrhage, ileus

Common: liver function tests raised (ALT increased, AST increased,bilirubin increased, alkaline phosphatase increased, GGTincreased)

Uncommon: hepatocellular damage, hepatitis, jaundice, hepatomegaly,cholestasis, hepatic toxicity, hepatic function abnormal

Rare: hepatic failure, hepatitis cholestatic, hepatosplenomegaly,liver tenderness, asterixis

Common: rash, pruritis

Uncommon: mouth ulceration, alopecia, dermatitis, erythema, petechiae

Rare: Stevens Johnson syndrome, vesicular rash

Not Known: Photosensitivity reaction§

Uncommon: back pain, neck pain, musculoskeletal pain, pain in extremity

Uncommon: acute renal failure, renal failure, blood creatinine increased

Rare: renal tubular acidosis, interstitial nephritis

Uncommon: menstrual disorder

Rare: breast pain

Common: pyrexia (fever), asthenia, fatigue

Uncommon: oedema, pain, chills, malaise, chest discomfort, drugintolerance, feeling jittery, mucosal inflammation

Rare: tongue oedema, face oedema

Uncommon: altered medicine levels, blood phosphorus decreased, chestx-ray abnormal

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

§ See section 4.4.

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is no experience with overdose of posaconazole tablets.

During clinical studies, patients who received posaconazole oral suspension doses up to 1,600 mg/dayexperienced 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 twicea 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 ofoverdose with posaconazole. Supportive care may be considered.

Pharmacotherapeutic group: Antimycotics for systemic use, Triazole and tetrazole derivatives, ATCcode: J02AC04

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

Posaconazole has been shown in vitro to be active against the following microorganisms: Aspergillusspecies (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, Fonsecaeapedrosoi, and species of Fusarium, Rhizomucor, Mucor, and Rhizopus. The microbiological datasuggest that posaconazole is active against Rhizomucor, Mucor, and Rhizopus; however, the clinicaldata 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 surveillancestudy of > 3,000 clinical mold isolates from 2010-2018, 90 % of non-Aspergillus fungi exhibited thefollowing 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.

Clinical isolates with decreased susceptibility to posaconazole have been identified. The principlemechanism 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 withacquired 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 donot equate to clinical breakpoints.

Susceptibility testing breakpoints

MIC (minimum inhibitory concentration) interpretive criteria for susceptibility testing have beenestablished by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for

Posaconazole and are listed here: <https://www.ema.europa.eu/documents/other/minimum-inhibitory-concentration-mic-breakpoints_en.xlsx>

Combination with other antifungal agents

The use of combination antifungal therapies should not decrease the efficacy of either posaconazole orthe other therapies; however, there is currently no clinical evidence that combination therapy willprovide an added benefit.

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 wasevaluated in a double-blind controlled study (study-69) in 575 patients with proven, probable, orpossible invasive fungal infections per EORTC/MSG criteria.

Patients were treated with posaconazole (n=288) concentrate for solution for infusion or tablet given ata 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), 288patients received posaconazole and 287 patients received voriconazole. The full analysis setpopulation (FAS) is the subset of all subjects within the ITT population who were classified byindependent adjudication as having proven or probable invasive aspergillosis: 163 subjects forposaconazole and 171 subjects for voriconazole. The all-cause mortality and global clinical responsein 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

Posaconazole Voriconazole

Difference* (95 %

Population N n (%) N n (%)

CI)

Mortality in ITT at288 44 (15.3) 287 59 (20.6) -5.3 % (-11.6, 1.0)

Day 42

Mortality in ITT at288 81 (28.1) 287 88 (30.7) -2.5 % (-9.9, 4.9)

Day 84

Mortality in FAS at163 31 (19.0) 171 32 (18.7) 0.3% (-8.2, 8.8)

Day 42

Mortality in FAS at163 56 (34.4) 171 53 (31.0) 3.1% (-6.9, 13.1)

Day 84

* Adjusted treatment difference based on Miettinen and Nurminen’s method stratified by randomisation factor (risk formortality/poor outcome), using Cochran-Mantel-Haenszel weighting scheme.

Table 4. Posaconazole invasive aspergillosis treatment study 1: global clinical response at Week 6 and

Week 12 in the FAS population

Posaconazole Voriconazole

Population N Success (%) N Success (%) Difference* (95 %

CI)

Global clinicalresponse in the FAS 163 73 (44.8) 171 78 (45.6) -0.6 % (-11.2, 10.1)at 6 weeks

Global clinicalresponse in the FAS 163 69 (42.3) 171 79 (46.2) -3.4 % (-13.9, 7.1)at 12 weeks

* Successful Global Clinical Response was defined as survival with a partial or complete response

Adjusted treatment difference based on Miettinen and Nurminen’s method stratified by randomisation factor (risk formortality/poor outcome), using Cochran-Mantel-Haenszel weighting scheme.

Summary of posaconazole tablet bridging study

Study 5615 was a non-comparative multi-centre study performed to evaluate the pharmacokineticproperties, safety, and tolerability of posaconazole tablet. Study 5615 was conducted in a similarpatient population to that previously studied in the pivotal posaconazole oral suspension clinicalprogram. 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 receivedchemotherapy and had developed or were anticipated to develop significant neutropenia, or 2) patientswho had undergone a HSCT and were receiving immunosuppressive therapy for prevention ortreatment 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 by300 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 asubset of Part 2 subjects. Moreover, sparse PK samples were collected at several days during steadystate before the next dose (Cmin) for a larger subject population. Based on average Cmin concentrations,a predicted average concentration (Cav) could be calculated for 186 subjects dosed with 300 mg. PKanalysis in patients of Cav found that 81 % of the subjects treated with the 300 mg once daily doseattained 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. Subjectsachieved 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 andposaconazole oral suspension at therapeutic doses in patients depicted as quartile analysis. Exposuresafter tablet administration are generally higher than, but overlapping with, exposures afteradministration of posaconazole oral suspension.

Table 5. Cav quartile analyses of pivotal patient studies with posaconazole tablet and oral suspension

Posaconazole Posaconazole oral suspensiontablet

Prophylaxis in Prophylaxis Prophylaxis in Treatment -

AML and HSCT in Neutropenia Invasive

Study 5615 GVHD Study 1899 Aspergillosis

Study 316 Study 0041300 mg once 200 mg three 200 mg three 200 mg four timesdaily (Day 1 300 times daily times daily dailymg twice daily)* (hospitalized) then400 mg twice daily

Quartile pCav Range Cav Range Cav Range Cav Range(ng/mL) (ng/mL) (ng/mL) (ng/mL)

Q1 442 - 1,223 22 - 557 90 - 322 55 - 277

Q2 1,240 - 1,710 557 - 915 322 - 490 290 - 544

Q3 1,719 - 2,291 915 - 1563 490 - 734 550 - 861

Q4 2,304 - 9,523 1,563 - 3,650 734 - 2200 877 - 2010pCav: predicted Cav

Cav = the average concentration when measured at steady state

*20 patients received 200 mg once daily (Day 1 200 mg twice daily)

Summary of posaconazole oral suspension studies

Invasive aspergillosis

Oral posaconazole suspension 800 mg/day in divided doses was evaluated for the treatment ofinvasive aspergillosis in patients with disease refractory to amphotericin B (including liposomalformulations) or itraconazole or in patients who were intolerant of these medicinal products in a non-comparative salvage therapy study (Study 0041). Clinical outcomes were compared with those in anexternal control group derived from a retrospective review of medical records. The external controlgroup included 86 patients treated with available therapy (as above) mostly at the same time and at thesame sites as the patients treated with posaconazole. Most of the cases of aspergillosis were consideredto be refractory to prior therapy in both the posaconazole group (88 %) and in the external controlgroup (79 %).

As shown in Table 6, a successful response (complete or partial resolution) at the end of treatment wasseen in 42 % of posaconazole-treated patients compared to 26 % of the external group. However, thiswas not a prospective, randomized controlled study and so all comparisons with the external controlgroup should be viewed with caution.

Table 6. Overall efficacy of posaconazole oral suspension at the end of treatment for invasiveaspergillosis 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.2 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 %)2 Includes other less common species or species unknown

11 of 24 patients who had proven or probable fusariosis were successfully treated with posaconazoleoral suspension 800 mg/day in divided doses for a median of 124 days and up to 212 days. Amongeighteen patients who were intolerant or had infections refractory to amphotericin B or itraconazole,seven patients were classed as responders.

Chromoblastomycosis/Mycetoma9 of 11 patients were successfully treated with posaconazole oral suspension 800 mg/day in divideddoses for a median of 268 days and up to 377 days. Five of these patients had chromoblastomycosisdue to Fonsecaea pedrosoi and 4 had mycetoma, mostly due to Madurella species.

Coccidioidomycosis11 of 16 patients were successfully treated (at the end of treatment complete or partial resolution ofsigns and symptoms present at baseline) with posaconazole oral suspension 800 mg/day in divideddoses for a median of 296 days and up to 460 days.

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

Two randomized, controlled prophylaxis studies were conducted among patients at high-risk fordeveloping invasive fungal infections.

Study 316 was a randomized, double-blind study of posaconazole oral suspension (200 mg three timesa day) versus fluconazole capsules (400 mg once daily) in allogeneic hematopoietic stem celltransplant recipients with graft-versus-host disease (GVHD). The primary efficacy endpoint was theincidence 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 IFIsduring the on-treatment period (first dose to last dose of study medicinal product + 7 days). Themajority (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 77days for fluconazole.

Study 1899 was a randomized, evaluator-blinded study of posaconazole oral suspension (200 mg threetimes a day) versus fluconazole suspension (400 mg once daily) or itraconazole oral solution (200 mgtwice a day) in neutropenic patients who were receiving cytotoxic chemotherapy for acutemyelogenous leukaemia or myelodysplastic syndromes. The primary efficacy endpoint was theincidence of proven/probable IFIs as determined by an independent, blinded external expert panelduring the on-treatment period. A key secondary endpoint was the incidence of proven/probable IFIsat 100 days post-randomization. New diagnosis of acute myelogenous leukaemia was the mostcommon underlying condition (435/602, [72 %]). The mean duration of therapy was 29 days forposaconazole and 25 days for fluconazole/itraconazole.

In both prophylaxis studies, aspergillosis was the most common breakthrough infection. See Table 7and 8 for results from both studies. There were fewer breakthrough Aspergillus infections in patientsreceiving posaconazole prophylaxis when compared to control patients.

Table 7. Results from clinical studies in prophylaxis of Invasive Fungal Infections

Study Posaconazole oral Controla P-Valuesuspension

Proportion (%) of patients with proven/probable IFIs

On-treatment periodb1899d 7/304 (2) 25/298 (8) 0.0009316e 7/291 (2) 22/288 (8) 0.0038

Fixed-time periodc1899d 14/304 (5) 33/298 (11) 0.0031316 d 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 randomization to last dose of study medicinal product plus 7 days; in 316it 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 periodfrom the baseline day to 111 days post-baseline.

d: All randomizede: All treated

Table 8. Results from clinical studies in prophylaxis of Invasive Fungal Infections

Study Posaconazole oral Controlasuspension

Proportion (%) of patients with proven/probable Aspergillosis

On-treatment periodb1899d 2/304 (1) 20/298 (7)316e 3/291 (1) 17/288 (6)

Fixed-time periodc1899d 4/304 (1) 26/298 (9)316 d 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 randomization to last dose of study medicinal product plus 7 days; in 316it 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 periodfrom the baseline day to 111 days post-baseline.

d: All randomizede: 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, theprobability of survival up to day 100 after randomization, was significantly higher for posaconazolerecipients; 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).

There is limited paediatric experience for posaconazole tablets.

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

The safety and efficacy of posaconazole (Posaconazole gastro-resistant powder and solvent for oralsuspension; Posaconazole concentrate for solution for infusion) have been established in paediatricpatients 2 to less than 18 years of age. Use of posaconazole in these age groups is supported byevidence from adequate and well-controlled studies of posaconazole in adults and pharmacokineticand safety data from paediatric studies (see section 5.2). No new safety signals associated with the useof 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 duringadministration of posaconazole oral suspension (400 mg twice daily with high fat meals) from173 healthy male and female volunteers aged 18 to 85 years. No clinically relevant changes in themean QTc (Fridericia) interval from baseline were observed.

Pharmacokinetic/Pharmacodynamic relationships

A correlation between total medicinal product exposure divided by MIC (AUC/MIC) and clinicaloutcome was observed. The critical ratio for subjects with Aspergillus infections was ~200. It isparticularly important to try to ensure that maximal plasma levels are achieved in patients infectedwith Aspergillus (see sections 4.2 and 5.2 on recommended dose regimens).

Posaconazole tablets are absorbed with a median Tmax of 4 to 5 hours and exhibits dose proportionalpharmacokinetics 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 healthyvolunteers, the AUC0-72 hours and Cmax were higher compared to administration under fasted condition(51 % and 16 % for AUC0-72 hours and Cmax respectively). Based on a population pharmacokineticmodel, posaconazole Cav is increased 20 % when given with a meal compared to a fasted state.

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

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.

Posaconazole does not have any major circulating metabolites and its concentrations are unlikely to bealtered by inhibitors of CYP450 enzymes. Of the circulating metabolites, the majority are glucuronideconjugates of posaconazole with only minor amounts of oxidative (CYP450 mediated) metabolitesobserved. The excreted metabolites in urine and faeces account for approximately 17 % of theadministered radiolabelled dose.

Posaconazole after administration of the tablets, is slowly eliminated with a mean half-life (t½) of29 hours (range 26 to 31 hours) and a mean apparent clearance ranging from 7.5 to 11 L/hr. Afteradministration of 14C-posaconazole, radioactivity was predominantly recovered in the faeces (77% ofthe radiolabelled dose) with the major component being parent compound (66 % of the radiolabelleddose). Renal clearance is a minor elimination pathway, with 14 % of the radiolabelled dose excreted inurine (< 0.2 % of the radiolabelled dose is parent compound). Steady-state plasma concentrations areattained by Day 6 at the 300 mg dose (once daily after twice daily loading dose at Day 1).

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

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

Regimen Population Cav (ng/mL) Cmin (ng/mL)

Prophylaxis 1,550 1,330(874; 2,690) (667; 2,400)

Tablet-(Fasted)

Treatment of Invasive 1,780 1,490

Aspergillosis (879; 3,540) (663; 3,230)

Prophylaxis 1,890 1,500

Concentrate for Solution (1,100; 3,150) (745; 2,660)for Infusion Treatment of Invasive 2,240 1,780

Aspergillosis (1,230; 4,160) (874; 3,620)

The population pharmacokinetic analysis of posaconazole in patients suggests that race, sex, renalimpairment and disease (prophylaxis or treatment) have no clinically meaningful effect on thepharmacokinetics 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 fortreatment of invasive fungal infections, mean trough plasma concentrations from 12 patients8 -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 ofage).

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

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 andtablets indicates that posaconazole clearance is related to age. Posaconazole Cav is generallycomparable between young and elderly patients (≥ 65 years of age); however, the Cav is increased by11 % 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, nodose adjustment is required.

There is insufficient data among different races with posaconazole tablets.

There was a slight decrease (16 %) in the AUC and Cmax of posaconazole oral suspension in Blacksubjects relative to Caucasian subjects. However, the safety profile of posaconazole between the Blackand Caucasian subjects was similar.

Weight

The population pharmacokinetic model of posaconazole concentrate for solution for infusion andtablets indicates that posaconazole clearance is related to weight. In patients > 120 kg, the Cav isdecreased by 25 % and in patients <50 kg, the Cav is increased by 19 %. It is, therefore, suggested toclosely monitor for breakthrough fungal infections in patients weighing more than 120 kg.

Following single-dose administration of posaconazole oral suspension, there was no effect of mild andmoderate 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 2cr< 20 mL/min/1.73 m ), the AUC of posaconazole was highly variable [> 96 % CV (coefficient ofvariance)] compared to other renal groups [< 40 % CV]. However, as posaconazole is not significantlyrenally eliminated, an effect of severe renal impairment on the pharmacokinetics of posaconazole isnot 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 beenconducted with the posaconazole tablets.

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 pergroup), the mean AUC was 1.3 to 1.6-fold higher compared to that for matched control subjects withnormal hepatic function. Unbound concentrations were not determined and it cannot be excluded thatthere 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 inrespective groups. No dose adjustment is recommended for patients with mild to severe hepaticimpairment but caution is advised due to the potential for higher plasma exposure.

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

As observed with other azole antifungal agents, effects related to inhibition of steroid hormonesynthesis were seen in repeated-dose toxicity studies with posaconazole. Adrenal suppressive effectswere observed in toxicity studies in rats and dogs at exposures equal to or greater than those obtainedat therapeutic doses in humans.

Neuronal phospholipidosis occurred in dogs dosed for ≥ 3 months at lower systemic exposures thanthose obtained at therapeutic doses in humans. This finding was not seen in monkeys dosed for oneyear. In twelve-month neurotoxicity studies in dogs and monkeys, no functional effects were observedon the central or peripheral nervous systems at systemic exposures greater than those achievedtherapeutically.

Pulmonary phospholipidosis resulting in dilatation and obstruction of the alveoli was observed in the2-year study in rats. These findings are not necessarily indicative of a potential for functional changesin humans.

No effects on electrocardiograms, including QT and QTc intervals, were seen in a repeat dose safetypharmacology study in monkeys at maximal plasma concentrations 8.5-fold greater than theconcentrations obtained at therapeutic doses in humans. Echocardiography revealed no indication ofcardiac decompensation in a repeat dose safety pharmacology study in rats at a systemic exposure2.1-fold greater than that achieved therapeutically. Increased systolic and arterial blood pressures (upto 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 lowerthan those obtained at therapeutic doses in humans, posaconazole caused skeletal variations andmalformations, dystocia, increased length of gestation, reduced mean litter size and postnatal viability.

In rabbits, posaconazole was embryotoxic at exposures greater than those obtained at therapeuticdoses. As observed with other azole antifungal agents, these effects on reproduction were consideredto be due to a treatment-related effect on steroidogenesis.

Posaconazole was not genotoxic in in vitro and in vivo studies. Carcinogenicity studies did not revealspecial hazards for humans.

In a nonclinical study using intravenous administration of posaconazole in very young dogs (dosedfrom 2-8 weeks of age) an increase in the incidence of brain ventricle enlargement was observed intreated animals as compared with concurrent control animals. No difference in the incidence of brainventricle enlargement between control and treated animals was observed following the subsequent5 month treatment-free period. There were no neurologic, behavioural or developmental abnormalitiesin the dogs with this finding, and a similar brain finding was not seen with either oral posaconazoleadministration to juvenile dogs (4 days to 9 months of age) or intravenous posaconazoleadministration to juvenile dogs (10 weeks to 23 weeks of age). The clinical significance of this findingis unknown.

Methacrylic acid-Ethyl acrylate copolymer (1:1)

Triethyl citrate (E1505)

Xylitol (E967)

Hydroxypropyl cellulose (E463)

Propyl gallate (E310)

Cellulose, microcrystalline (E460)

Silica, colloidal anhydrous

Croscarmellose sodium

Sodium stearyl fumarate

Polyvinyl alcohol-part hydrolyzed

Titanium dioxide (E171)

Macrogol

Talc (E553b)

Iron oxide yellow (E172)

Not applicable.

3 years

This medicinal product does not require any special storage conditions.

Triplex (PVC/PE/PVdC) white opaque-aluminium blister or perforated unit dose blister in cartons of24 or 96 tablets.

Not all pack sizes may be marketed.

No special requirements.

Accord Healthcare S.L.U.

World Trade Center, Moll de Barcelona s/n,

Edifici Est, 6a planta, Barcelona,08039 Barcelona, Spain

EU/1/19/1379/001-004

Date of first authorisation: 25th July 2019

Date of latest renewal: 09th April 2024

Detailed information on this product is available on the website of the European Medicines Agencyhttp://www.ema.europa.eu