POSACONAZOLE AHCL 40mg / ml oral suspension medication leaflet

Posaconazole AHCL 40 mg/mL oral suspension

Each mL of oral suspension contains 40 mg of posaconazole.

This medicinal product contains approximately 1.75 g of glucose per 5 mL of suspension.

This medicinal product contains up to 5.2 mg propylene glycol (E1520) per 5ml of suspension.

This medicinal product contains 11.4 mg sodium benzoate (E211) in each 5ml of suspension.

This medicinal product contains up to 0.114 mg benzoic acid (E210) in each 5ml of suspension.

For the full list of excipients, see section 6.1.

Oral suspension

White to off-white free flowing suspension.

Posaconazole AHCL oral suspension is indicated for use in the treatment of the following fungalinfections in adults (see section 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.

- Oropharyngeal candidiasis: as first-line therapy in patients who have severe disease or areimmunocompromised, in whom response to topical therapy is expected to be poor.

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 AHCL oral suspension is also indicated for prophylaxis of invasive fungal infections inthe following patients:

- 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.

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 AHCL oral suspension and posaconazole tabletsor posaconazole gastro-resistant powder and solvent for oral suspension.

Posaconazole oral suspension is indicated for the adult population (≥18 years old) only.

The oral suspension is not to be used interchangeably with either the tablet or gastro-resistant powderand solvent for oral suspension due to the differences in frequency of dosing, administration with foodand plasma drug concentration achieved. Therefore, follow the specific dose recommendations foreach formulation.

Posaconazole is also available as 100 mg gastro-resistant tablet, 300 mg concentrate for solution forinfusion and 300 mg gastro-resistant powder and solvent for oral suspension. Posaconazole tabletsgenerally provide higher plasma drug exposures than posaconazole oral suspension under both fed andfasted conditions. Therefore, the tablets are the preferred formulation over the oral suspension tooptimize plasma concentrations.

Recommended dose is shown in Table 1.

Table 1. Recommended dose in adults according to indication.

Indication Dose and duration of therapy(See section 5.2)

Refractory invasive fungal infections 200 mg (5 mL) four times a day. Alternatively, patients who(IFI)/patients with IFI intolerant to 1st can tolerate food or a nutritional supplement may take 400line therapy mg (10 mL) twice a day during or immediately following ameal or nutritional supplement.

Duration of therapy should be based on the severity of theunderlying disease, recovery from immunosuppression, andclinical response.

Oropharyngeal candidiasis Loading dose of 200 mg (5 mL) once a day on the first day,then 100 mg (2.5 mL) once a day for 13 days.

Each dose of Posaconazole AHCL should be administeredduring or immediately after a meal, or a nutritionalsupplement in patients who cannot tolerate food to enhancethe oral absorption and to ensure adequate exposure

Prophylaxis of invasive fungal 200 mg (5 mL) three times a day. Each dose of Posaconazoleinfections AHCL should be administered during or immediately after ameal, or a nutritional supplement in patients who cannottolerate food to enhance the oral absorption and to ensureadequate exposure. The duration of therapy is based onrecovery from neutropenia or immunosuppression. Forpatients with acute myelogenous leukaemia ormyelodysplastic syndromes, prophylaxis with Posaconazole

AHCL should start several days before the anticipated onsetof neutropenia and continue for 7 days after the neutrophilcount rises above 500 cells per mm3.

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 oral suspension have not been established in children andadolescents aged below 18 years. Currently available data are described in sections 5.1 and 5.2, but norecommendation on a posology can be made. Two other oral formulations, posaconazole gastro-resistant powder and solvent for oral suspension and posaconazole tablets, are available for thepaediatric population.

For oral use.

The oral suspension must be shaken well before use. Bottles showing any visible settling should bevigorously shaken for a minimum of 10 seconds.Other formulations containing posaconazole areavailable in the market for the use in primary treatment of invasive aspergilosis.

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), efavirenz and cimetidine

Posaconazole concentrations may be significantly lowered in combination; therefore, concomitant usewith posaconazole should be avoided unless the benefit to the patient outweighs the risk (see section4.5).

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).

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 up to 5.2 mg propylene glycol (E1520) per 5ml of suspension.

This medicinal product contains 11.4mg sodium benzoate (E211) in each 5ml of suspension.

Benzoic acid

This medicinal product contains up to 0.114mg benzoic acid (E210) in each 5ml of suspension.

Glucose

This medicinal product contains approximately 1.75 g of glucose per 5 mL of suspension. Patientswith rare glucose-galactose malabsorption should not take this medicinal product.

This medicinal product contains less than 1 mmol sodium (23 mg) per 5 mL of suspension, that is tosay 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

Posaconazole plasma concentrations (Cmax and AUC) were reduced by 39 % when posaconazole wasadministered with cimetidine (400 mg twice a day) due to reduced absorption possibly secondary to adecrease in gastric acid production. Co-administration of posaconazole with H2 receptor antagonistsshould be avoided if possible. Similarly, administration of 400 mg posaconazole with esomeprazole(40 mg daily) decreased mean Cmax and AUC by 46 % and 32 %, respectively, compared to dosingwith 400 mg posaconazole alone. Co-administration of posaconazole with proton pump inhibitorsshould be avoided if possible.

The absorption of posaconazole is significantly increased by food (see sections 4.2 and 5.2).

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, unless posaconazole is administered in a strictly standardised way with food,given the large food effect on posaconazole exposure (see section 5.2).

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 avoided wheneverpossible. If it is considered that co-administration is unavoidable, then it is recommended that the doseof sirolimus should be greatly reduced at the time of initiation of posaconazole therapy and that thereshould be very frequent monitoring of trough concentrations of sirolimus in whole blood. Sirolimusconcentrations should be measured upon initiation, during co-administration, and at discontinuation ofposaconazole treatment, with sirolimus doses adjusted accordingly. It should be noted that therelationship between sirolimus trough concentration and AUC is changed during co- administrationwith posaconazole. As a result, sirolimus trough concentrations that fall within the usual therapeuticrange may result in sub-therapeutic levels. Therefore, trough concentrations that fall in the upper partof the usual therapeutic range should be targeted and careful attention should be paid to clinical signsand 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 duringco-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 should beconsidered 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 (1.7 times the 400 mgtwice daily regimen based on steady-state plasma concentrations in healthy volunteers) or female ratsat a dose up to 45 mg/kg (2.2 times the 400-mg twice daily regimen). There is no clinical experienceassessing 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.

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.

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, chest x-ray abnormal

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

§ 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.

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.

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 and the effects of food onabsorption).

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 3, 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 3. 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.1 34/76 (45 %) 19/74 (26 %)

A. fumigatus 12/29 (41 %) 12/34 (35 %)

A. flavus 10/19 (53 %) 3/16 (19 %)

A. terreus 4/14 (29 %) 2/13 (15 %)

A. niger 3/5 (60 %) 2/7 (29 %)1 Includes other less common species or species unknown

11 of 24 patients who had proven or probable fusariosis were successfully treated with 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.

Treatment of azole-susceptible Oropharyngeal Candidiasis (OPC)

A randomized, evaluator-blind, controlled study was completed in HIV-infected patients with azolesusceptible oropharyngeal candidiasis (most patients studied had C. albicans isolated at baseline). Theprimary efficacy variable was the clinical success rate (defined as cure or improvement) after 14 daysof treatment. Patients were treated with posaconazole or fluconazole oral suspension (bothposaconazole and fluconazole were given as follows: 100 mg twice a day for 1 day followed by100 mg once a day for 13 days).

The clinical response rates from the above study are shown in the Table 4 below.

Posaconazole was shown to be non-inferior to fluconazole for clinical success rates at Day 14 as wellas 4 weeks after the end of treatment.

Table 4. Clinical success rates in Oropharyngeal Candidiasis

Endpoint Posaconazole Fluconazole

Clinical success rate at Day 14 91.7 % (155/169) 92.5 % (148/160)

Clinical success rate 4 weeks after end of treatment 68.5 % (98/143) 61.8 % (84/136)

Clinical success rate was defined as the number of cases assessed as having a clinical response (cure or improvement)divided by the total number of cases eligible for analysis

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

Table 5. 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 randomisation 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 6. 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 randomisation 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).

No dose of posaconazole oral suspension could be recommended for paediatric patients. However, thesafety and efficacy of other formulations of posaconazole (posaconazole gastro-resistant powder andsolvent for oral suspension; posaconazole concentrate for solution for infusion) have been establishedin paediatric patients 2 to less than 18 years of age. Refer to their SmPC for additional information.

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) from 173healthy male and female volunteers aged 18 to 85 years. No clinically relevant changes in the mean

QTc (Fridericia) interval from baseline were observed.

Posaconazole is absorbed with a median Tmax of 3 hours (fed patients). The pharmacokinetics ofposaconazole are linear following single and multiple dose administration of up to 800 mg when takenwith a high fat meal. No further increases in exposure were observed when doses above 800 mg dailywere administered to patients and healthy volunteers. In the fasting state, AUC increased less than inproportion to dose above 200 mg. In healthy volunteers under fasting conditions, dividing the totaldaily dose (800 mg) into 200 mg four times daily compared to 400 mg twice daily, was shown toincrease posaconazole exposure by 2.6-fold.

Effect of food on oral absorption in healthy volunteers

The absorption of posaconazole was significantly increased when posaconazole 400 mg (once daily)was administered during and immediately after the consumption of a high fat meal (~ 50 grams fat)compared to administration before a meal, with Cmax and AUC increasing by approximately 330 % and360 %, respectively. The AUC of posaconazole is: 4 times greater when administered with a high fatmeal (~ 50 grams fat) and about 2.6 times greater when administered during a non-fat meal ornutritional supplement (14 grams fat) relative to the fasted state (see sections 4.2 and 4.5).

Posaconazole is slowly absorbed and slowly eliminated with a large apparent volume of distribution(1,774 litres) and is highly protein bound (> 98 %), predominantly to serum albumin.

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

Posaconazole is slowly eliminated with a mean half-life (t½) of 35 hours (range 20 to 66 hours). 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 is attained following7 to 10 days of multiple-dose administration.

Children (< 18 years)

Following administration of 800 mg per day of posaconazole as a divided dose for treatment ofinvasive fungal infections, mean trough plasma concentrations from 12 patients 8 - 17 years of age(776 ng/mL) were similar to concentrations from 194 patients 18 - 64 years of age (817 ng/mL).

Similarly, in the prophylaxis studies, the mean steady-state posaconazole average concentration (Cav)was comparable among ten adolescents (13-17 years of age) to Cav achieved in adults (≥ 18 years ofage). In a study of 136 neutropenic paediatric patients 11 months - 17 years treated with posaconazoleoral suspension at doses up to 18 mg/kg/day divided TID, approximately 50 % met the pre-specifiedtarget (Day 7 Cav between 500 ng/mL-2,500 ng/mL). In general, exposures tended to be higher in theolder patients (7 to <18 years) than in younger patients (2 to <7 years).

The pharmacokinetics of posaconazole are comparable in men and women.

An increase in Cmax (26 %) and AUC (29 %) was observed in elderly subjects (24 subjects ≥ 65 yearsof age) relative to younger subjects (24 subjects 18 - 45 years of age). However, in clinical efficacystudies, the safety profile of posaconazole between the young and elderly patients was similar.

There was a slight decrease (16 %) in the AUC and Cmax of posaconazole oral suspension in 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 cr< 20mL/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 renallyeliminated, an effect of severe renal impairment on the pharmacokinetics of posaconazole is notexpected and no dose adjustment is recommended. Posaconazole is not removed by haemodialysis.

After a single oral dose of 400 mg posaconazole oral suspension to patients with mild (Child-Pugh

Class A), moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment (six 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.

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 systemic exposures 4.6-fold greater than the concentrationsobtained at therapeutic doses in humans. Echocardiography revealed no indication of cardiacdecompensation in a repeat dose safety pharmacology study in rats at a systemic exposure 1.4-foldgreater than that achieved therapeutically. Increased systolic and arterial blood pressures (up to29 mm-Hg) were seen in rats and monkeys at systemic exposures 1.4-fold and 4.6-fold greater,respectively, than those achieved with the human therapeutic doses.

Reproduction, peri- and postnatal development studies were conducted in rats. At exposures 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.

Macrogolglycerol hydroxystearate

Sodium citrate dihydrate

Citric acid monohydrate

Simeticone emulsion (containing polydimethylsiloxane, polyethylene glycol sorbitan tristearate,methylcellulose, silica gel, polyethylene glycol stearate, sorbic acid (E200), benzoic acid (E210) andsulfuric acid (E513))

Xanthan gum (E415)

Sodium benzoate (E211)

Liquid glucose

Glycerol (E422)

Titanium dioxide (E171)

Strawberry flavour (containing propylene glycol)

Purified water

Not applicable.

30 months

After first opening the container: 30 days

This medicinal product does not require any special storage conditions.

The primary packaging is an amber glass bottle (Type III) closed with a child-resistant and tamperevident polypropylene cap. The filled and sealed bottle is packed into a carton along with a graduatedpolystyrene spoon (2.5 mL and 5 mL) for dispensing and administration of the suspension.

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/1/19/1380/001

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