NOXAFIL 300mg perfusive solution concentrate medication leaflet

Noxafil 300 mg concentrate for solution for infusion

Each vial contains 300 mg of posaconazole.

Each mL contains 18 mg of posaconazole.

Each vial contains 462 mg (20 mmol) of sodium.

Each vial contains 6,680 mg of cyclodextrin (as Betadex Sulfobutyl Ether Sodium (SBECD)).

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate).

Clear, colourless to yellow liquid.

Noxafil concentrate for solution for infusion is indicated for use in the treatment of the followingfungal infections in adults (see sections 4.2 and 5.1):

- Invasive aspergillosis

Noxafil concentrate for solution for infusion is indicated for use in the treatment of the followingfungal infections in adult and paediatric patients from 2 years of age (see sections 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.

Noxafil concentrate for solution for infusion is also indicated for prophylaxis of invasive fungalinfections in the following adult and paediatric patients from 2 years of age (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 (GVHD) and who are at high-risk ofdeveloping invasive fungal infections.

Please refer to the Summary of Product Characteristics of Noxafil oral suspension for use inoropharyngeal 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.

Noxafil is also available for oral administration (Noxafil 100 mg gastro-resistant tablets, 40 mg/mLoral suspension, and 300 mg gastro-resistant powder and solvent for oral suspension). A switch to oraladministration is recommended as soon as the patients’ condition allows (see section 4.4).

Recommended dose is shown in Table 1.

Table 1. Recommended dose according to indication

Indication Dose and duration of therapy(See section 5.2)

Treatment of invasive Loading dose of 300 mg Noxafil (300 mg concentrate for solutionaspergillosis (only for adults) for infusion or three 100 mg tablets) twice a day on the first day,then 300 mg (300 mg concentrate for solution for infusion or three100 mg tablets) 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 Adults:infections (IFI)/patients with IFI Loading dose of 300 mg Noxafil twice a day on the first day, thenintolerant to 1st line therapy 300 mg once a day thereafter. Duration of therapy should be basedon the severity of the underlying disease, recovery fromimmunosuppression, and clinical response.

Paediatric patients aged 2 to less than 18 years:

Loading dose of 6 mg/kg (to a maximum of 300 mg) twice a dayon the first day, then 6 mg/kg (to a maximum of 300 mg) once aday thereafter. Duration of therapy should be based on the severityof the underlying disease, recovery from immunosuppression, andclinical response.

Prophylaxis of invasive fungal Adults:infections Loading dose of 300 mg Noxafil twice a day on the first day, then300 mg once a day thereafter. Duration of therapy is based onrecovery from neutropenia or immunosuppression. For patientswith AML or MDS, prophylaxis with Noxafil should start severaldays before the anticipated onset of neutropenia and continue for7 days after the neutrophil count rises above 500 cells per mm3.

Paediatric patients aged 2 to less than 18 years:

Loading dose of 6 mg/kg (to a maximum of 300 mg) twice a dayon the first day, then 6 mg/kg (to a maximum of 300 mg) once aday thereafter. Duration of therapy is based on recovery fromneutropenia or immunosuppression. For patients with acutemyelogenous leukaemia or myelodysplastic syndromes,prophylaxis with Noxafil should start several days before theanticipated onset of neutropenia and continue for 7 days after theneutrophil count rises above 500 cells per mm3.

Noxafil should be administered via a central venous line, including a central venous catheter orperipherally inserted central catheter (PICC) by slow intravenous infusion over approximately90 minutes. Noxafil concentrate for solution for infusion should not be given by bolus administration.

If a central venous catheter is not available, a single infusion may be administered through a peripheralvenous catheter. When administered through a peripheral venous catheter, the infusion should beadministered over approximately 30 minutes (see sections 4.8 and 6.6).

In patients with moderate or severe renal impairment (creatinine clearance <50 mL/min),accumulation of the intravenous vehicle, Betadex Sulfobutyl Ether Sodium (SBECD), is expected tooccur. Oral formulations of Noxafil should be used in these patients unless an assessment of thebenefit/risk to the patient justifies the use of Noxafil concentrate for solution for infusion. Serumcreatinine levels should be closely monitored in these patients (see section 4.4).

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.

No clinical data are available.

Noxafil concentrate for solution for infusion should not be used in children aged below 2 yearsbecause of pre-clinical safety concerns (see section 5.3).

Noxafil concentrate for solution for infusion requires dilution (see section 6.6) prior to administration.

Noxafil should be administered via a central venous line, including a central venous catheter orperipherally inserted central catheter (PICC) by slow intravenous (IV) infusion over approximately90 minutes (see sections 4.2, pct. 4.4, and 4.8).

Noxafil concentrate for solution for infusion should not be given by bolus administration.

If a central venous catheter is not available, a single infusion may be administered through a peripheralvenous catheter. When administered through a peripheral venous catheter, the infusion should beadministered over approximately 30 minutes to reduce the likelihood of infusion site reactions (seesection 4.8).

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. elevations in ALT, AST, alkaline phosphatase, total bilirubin and/or clinicalhepatitis) have been reported during treatment with posaconazole. Elevated liver function tests weregenerally reversible on discontinuation of therapy and in some instances these tests normalisedwithout interruption of therapy. Rarely, more severe hepatic reactions with fatal outcomes have beenreported.

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).

Monitoring of patients with severe renal impairment

Due to the variability in exposure, patients with severe renal impairment should be monitored closelyfor breakthrough fungal infections (see sections 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.

In patients, mean maximum plasma concentrations (Cmax) after posaconazole concentrate for solutionfor infusion are 4-fold increased compared to administration of oral suspension. An increased effect onthe QTc interval cannot be ruled out. Particular caution is advised in such cases where posaconazole isadministered peripherally, as the recommended infusion time of 30 minutes may further increase Cmax.

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), 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).

Plasma exposure

Plasma concentrations following administration of posaconazole intravenous concentrate for solutionfor infusion are generally higher than those obtained with posaconazole oral suspension. Posaconazoleplasma concentrations following administration of posaconazole may increase over time in somepatients (see section 5.2).

Thromboembolic events have been identified as a potential risk for posaconazole intravenousconcentrate for solution for infusion but were not observed in the clinical studies. Thrombophlebitiswas observed in clinical studies. Caution is warranted on any sign or symptom of thromboembolicevents (see sections 4.8 and 5.3).

This medicinal product contains 462 mg (20 mmol) sodium per vial, equivalent to 23 % of the WHOrecommended maximum daily intake of sodium.

The maximum daily dose of this product is equivalent to 46% of the WHO recommended maximumdaily intake for sodium.

Noxafil 300 mg concentrate for solution for infusion is considered high in sodium. This should beparticularly taken into account for those on a low salt diet.

Cyclodextrin

This medicinal product contains 6,680 mg of cyclodextrin per vial.

The following information was derived from data with posaconazole oral suspension or early tabletformulation. All drug interactions with posaconazole oral suspension, except for those that affect theabsorption of posaconazole (via gastric pH and motility) are considered relevant to posaconazoleconcentrate for solution for infusion as well.

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.

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.

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.

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.

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

Repeat dose administration of oral 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 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 to 8-10 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 (2.8 times the exposureachieved from a 300 mg intravenous dose in human) or female rats at a dose up to 45 mg/kg (3.4 timesthe exposure from a 300 mg intravenous dose in patients). There is no clinical experience assessing theimpact 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 concentrate for solution for infusion

The safety of posaconazole concentrate for solution for infusion has been assessed in 72 healthyvolunteers and 268 patients enrolled 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.

Posaconazole concentrate for solution for infusion was investigated in AML and MDS patients andthose after HSCT with or at risk for GVHD only. Maximum duration of exposure to the concentratefor solution for infusion was shorter than with the oral suspension. Plasma exposure resulting from thesolution for infusion was higher than observed with the oral suspension.

In initial studies of healthy volunteers, administration of a single dose of posaconazole infused over30 minutes via a peripheral venous catheter was associated with a 12 % incidence of infusion sitereactions (4 % incidence of thrombophlebitis). Multiple doses of posaconazole administered via aperipheral venous catheter were associated with thrombophlebitis (60 % incidence). Therefore, insubsequent studies posaconazole was administered via central venous catheter. If a central venouscatheter was not readily available, patients could receive a single infusion over 30 minutes via aperipheral venous catheter. Peripheral infusion time longer than 30 minutes, leads to a higherincidence of infusion site reactions and thrombophlebitis.

The safety of posaconazole concentrate for solution for infusion has been assessed in 268 patients inclinical studies. Patients were enrolled in a non-comparative pharmacokinetic and safety study ofposaconazole concentrate for solution for infusion when given as antifungal prophylaxis (Study 5520).

Eleven patients received a single dose of 200 mg posaconazole concentrate for solution for infusion,21 patients received 200 mg daily dose for a median of 14 days, and 237 patients received 300 mgdaily dose for a median of 9 days. No safety data are available for administration > 28 days. Safetydata in the elderly are limited.

The most frequently reported adverse reaction (>25 %) with an onset during the posaconazoleintravenous phase of dosing with 300 mg once daily was diarrhoea (32 %).

The most common adverse reaction (>1 %) leading to discontinuation of posaconazole concentrate forsolution for infusion 300 mg once daily was AML (1 %).

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.

Posaconazole gastro-resistant powder and solvent for oral suspension and concentrate for solution forinfusion safety

The safety of posaconazole gastro-resistant powder and solvent for oral suspension and concentrate forsolution for infusion has been assessed in 115 paediatric patients aged 2 to less than 18 years forprophylaxis use. Immunocompromised paediatric patients with known or expected neutropenia wereexposed to posaconazole at 3.5 mg/kg, 4.5 mg/kg or 6 mg/kg.

Reported adverse reactions were generally consistent with those expected in a paediatric oncologypopulation undergoing treatment for malignancy or with the safety profile of posaconazole in adults.

The most frequently reported adverse reactions (>2 %) during treatment were alanine aminotransferaseincreased (2.6 %), aspartate aminotransferase increased (3.5 %) and rash (2.6 %).

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*

Blood and lymphatic systemdisorders

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, myocardial infarction

Common: hypertension

Uncommon: hypotension, thrombophlebitis, vasculitis

Rare: pulmonary embolism, deep vein thrombosis

Respiratory, thoracic andmediastinal disorders

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, livertenderness, asterixis

Skin and subcutaneous tissuedisorders

Common: rash, pruritis

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

Rare: Stevens Johnson syndrome, vesicular rash

Musculoskeletal and connectivetissue disorders

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

Reproductive system and breastdisorders

Uncommon: menstrual disorder

Rare: breast pain

General disorders andadministration site conditions

Common: pyrexia (fever), asthenia, fatigue

Uncommon: oedema, pain, chills, malaise, chest discomfort, drugintolerance, feeling jittery, infusion site pain, infusion sitephlebitis, infusion site thrombosis, 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 suspension.§ See section 4.4.

During post-marketing surveillance severe hepatic injury with fatal outcome has been reported (seesection 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 concentrate for solution for infusion.

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 derivatives, ATC code:

J02A C04.

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.

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

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

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

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

* Candida dubliniensis: S ≤0.06 mg/L, R > 0.06 mg/L

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

Combination with other antifungal agents

The use of combination antifungal therapies should not decrease the efficacy of either posaconazole 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 bridging study

Study 5520 was a non-comparative multi-center study performed to evaluate the pharmacokineticproperties, safety, and tolerability of posaconazole concentrate for solution for infusion.

Study 5520 enrolled a total of 279 subjects, including 268 receiving at least one dose of posaconazoleconcentrate for solution for infusion. Cohort 0 was designed to evaluate the tolerability of a singledose of posaconazole concentrate for solution for infusion when administered via a central line.

The subject population for Cohorts 1 and 2 included subjects with AML or MDS who had recentlyreceived chemotherapy and had developed or were anticipated to develop significant neutropenia. Twodifferent dosing groups were evaluated in Cohorts 1 and 2: 200 mg twice daily on Day 1, followed by200 mg once daily thereafter (Cohort 1) and 300 mg twice daily on Day 1, followed by 300 mg oncedaily thereafter (Cohort 2).

The subject population in Cohort 3 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. These types of patients had been previously studied in a pivotal controlled studyof posaconazole oral suspension. Based on the pharmacokinetics and safety results of Cohorts 1 and 2,all subjects in Cohort 3 received 300 mg twice daily on Day 1, followed by 300 mg once dailythereafter.

The total subject population had a mean age of 51 years (range = 18-82 years), 95 % were White, themajor ethnicity was not Hispanic or Latino (92 %), and 55 % were male. The study treated 155 (65 %)subjects with AML or MDS, and 82 (35 %) subjects with HSCT, as the primary diseases at studyentry.

Serial pharmacokinetic samples were collected on Day 1 and at steady-state on Day 14 for all Cohort 1and 2 subjects and on Day 10 for a subset of Cohort 3 subjects. This serial pharmacokinetic analysisdemonstrated that 94 % of the subjects treated with the 300 mg once daily dose attained steady state

Cav between 500-2,500 ng/mL [Cav was the average concentration of posaconazole at steady state,calculated as AUC/dosing interval (24 hours)]. This exposure was selected based onpharmacokinetic/pharmacodynamic considerations with posaconazole oral suspension. Subjects whoreceived 300 mg once daily achieved a mean Cav at steady state of 1,500 ng/mL.

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 of voriconazole (intravenous), ororally at a dose of 300 mg BID Day 1 followed by 200 mg BID. Median treatment duration was67 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

Population N n (%) N n (%) Difference* (95 % 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 for mortality/pooroutcome), 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 for mortality/pooroutcome), using Cochran-Mantel-Haenszel weighting scheme.

Summary of gastro-resistant powder and solvent for oral suspension and concentrate for solution forinfusion bridging study

The pharmacokinetics and safety of posaconazole concentrate for solution for infusion and gastro-resistant powder and solvent for oral suspension have been assessed in 115 paediatric subjects aged 2to less than 18 years in a non-randomised, multi-centre, open-label, sequential dose-escalation study(Study 097). Immunocompromised paediatric subjects with known or expected neutropenia wereexposed to posaconazole at 3.5 mg/kg, 4.5 mg/kg or 6.0 mg/kg daily (BID on Day 1). All 115 subjectsinitially received posaconazole concentrate for solution for infusion for at least 7 days, and 63 subjectswere transitioned to gastro-resistant powder and solvent for oral suspension. The mean overalltreatment duration (posaconazole concentrate for solution for infusion and gastro-resistant powder andsolvent for oral suspension) of all treated subjects was 20.6 days (see section 5.2).

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. Clinical outcomes were compared with those in an external controlgroup derived from a retrospective review of medical records. The external control group included86 patients treated with available therapy (as above) mostly at the same time and at the same sites asthe patients treated with posaconazole. Most of the cases of aspergillosis were considered to berefractory to prior therapy in both the posaconazole group (88 %) and in the external control group(79 %).

As shown in Table 5 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, randomised controlled study and so all comparisons with the external controlgroup should be viewed with caution.

Table 5. Overall efficacy of posaconazole oral suspension at the end of treatment for invasiveaspergillosis in comparison to an external control group

Posaconazole oral External control groupsuspension

Overall Response 45/107 (42 %) 22/86 (26 %)

Success by Species

All mycologically confirmed

Aspergillus spp.3 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 %)

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

Study 316 was a randomised, 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-randomisation 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 and77 days for fluconazole.

Study 1899 was a randomised, 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-randomisation. New diagnosis of acute myelogenous leukaemia was the most3 Includes other less common species or species unknowncommon 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 6and 7 for results from both studies. There were fewer breakthrough Aspergillus infections in patientsreceiving posaconazole prophylaxis when compared to control patients.

Table 6. 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 randomisation to last dose of study medicinal product plus 7 days; in 316 it was theperiod from first dose to last dose of study medicinal product plus 7 days.c: In 1899, this was the period from randomisation to 100 days post-randomisation; in 316 it was the period from thebaseline day to 111 days post-baseline.d: All randomisede: All treated

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

Study Posaconazole oral suspension Controla

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 randomisation to last dose of study medicinal product plus 7 days; in 316 it was theperiod from first dose to last dose of study medicinal product plus 7 days.c: In 1899, this was the period from randomisation to 100 days post-randomisation; in 316 it was the period from thebaseline day to 111 days post-baseline.d: All randomisede: 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 randomisation, 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 FLUgroup (12/299; P= 0.0413).

There is limited paediatric experience for posaconazole concentrate for solution for infusion.

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 (Noxafil gastro-resistant powder and solvent for oralsuspension; Noxafil 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 of Noxafil in paediatric patients below the age of 2 years have not beenestablished.

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).

Following administration of 300 mg posaconazole concentrate for solution for infusion over90 minutes, mean peak plasma concentration at the end of infusion was 3,280 ng/mL (74 % CV).

Posaconazole exhibits dose proportional pharmacokinetics after single and multiple dosing in thetherapeutic dose range (200-300 mg). Posaconazole has a distribution volume of 261 L, indicatingextravascular distribution.

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

Posaconazole does not have any major circulating metabolites. Of the circulating metabolites, themajority are glucuronide conjugates of posaconazole with only minor amounts of oxidative (CYP450mediated) metabolites observed. The excreted metabolites in urine and faeces account forapproximately 17 % of the administered radiolabelled dose of posaconazole oral suspension.

Posaconazole, after administration of 300 mg of posaconazole concentrate for solution for infusion, isslowly eliminated with a mean half-life (t½) of 27 hours and a mean clearance of 7.3 L/hr. Afteradministration of 14C-posaconazole as oral suspension, radioactivity was predominantly recovered inthe faeces (77 % of the radiolabelled dose) with the major component being parent compound (66 %of the radiolabelled dose). Renal clearance is a minor elimination pathway, with 14 % of theradiolabelled dose excreted in urine (< 0.2 % of the radiolabelled dose is parent compound). Steady-state plasma concentrations are attained by Day 6 at the 300 mg dose (once daily after twice dailyloading dose at Day 1).

Posaconazole plasma concentrations following administration of posaconazole concentrate forsolution for infusion single dose increased in a greater than dose proportional manner over the range of50-200 mg; by comparison, dose-dependent increases were observed over a range of 200-300 mg.

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

Table 8. 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-

Treatment of(Fasted)

Invasive 1,780 1,490

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

Prophylaxis 1,890 1,500

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

Infusion 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 concentrate for solution for infusion inthe study of treatment of invasive aspergillosis (see sections 4.2 and 5.3).

The mean pharmacokinetic parameters after multiple dose administration of posaconazole concentratefor solution for infusion and posaconazole gastro-resistant powder and solvent for oral suspension inneutropenic paediatric patients 2 to less than 18 years of age are shown in Table 9. Patients wereenrolled into 2 age groups and received posaconazole concentrate for solution for infusion andposaconazole gastro-resistant powder and solvent for oral suspension doses at 6 mg/kg (maximum300 mg) once daily (twice daily on Day 1) (see section 5.1).

Table 9. Summary of Steady-State Geometric Mean Pharmacokinetic Parameters (% Geometric CV)

After Multiple Dosing with Posaconazole Concentrate for Solution for Infusion and Posaconazole

Gastro-Resistant Powder and Solvent for Oral Suspension 6 mg/kg in Paediatric Patients with

Neutropenia or Expected Neutropenia

Age Group Dose N AUC † ‡0- Cav* Cmax Cmin Tm ax CL/F

Type 24 hours (ng/mL) (ng/mL) (ng/mL) (hr) (L/hr)(ng·hr/mL)2 to IV 17 31,100 1,300 3,060 626 1.75 3.27<7 years (48.9) (48.9) (54.1) (104.8) (1.57- (49.3)1.83)

PFS 7 23,000 960 1,510 542 4.00 4.60(47.3) (47.3) (43.4) (68.8) (2.17- (35.2)7.92)7 to IV 24 44,200 1,840 3,340 1,160 1.77 4.76(1.33-

Age Group Dose N AUC C * C C T †0- av max min max CL/F ‡

Type 24 hours (ng/mL) (ng/mL) (ng/mL) (hr) (L/hr)(ng·hr/mL)17 years (41.5) (41.5) (39.4) (60.4) 6.00) (55.7)

PFS 12 25,000 1,040 1,370 713 2.78 8.39(184.3) (184.3) (178.5) (300.6) (0.00- (190.3)4.00)

IV= posaconazole concentrate for solution for infusion; PFS=posaconazole gastro-resistant powderand solvent for oral suspension; AUC0-24 hours = Area under the plasma concentration-time curvefrom time zero to 24 hr; Cmax = maximum observed concentration; Cmin = minimum observed plasmaconcentration; Tmax = time of maximum observed concentration; CL /F = apparent total bodyclearance

* Cav = time-averaged concentrations (i.e., AUC0-24 hours/24hr)† Median (minimum-maximum)‡ Clearance (CL for IV and CL/F for PFS)

Based on a population pharmacokinetic model evaluating posaconazole pharmacokinetics andpredicting exposures in paediatric patients, the exposure target of steady-state posaconazole averageconcentration (Cav) of approximately 1,200 ng/mL and Cav ≥ 500 ng/mL in approximately 90 % ofpatients is attained with the recommended dose of posaconazole concentrate for solution for infusionand gastro-resistant powder and solvent for oral suspension. Simulations, using the populationpharmacokinetic model, predict a Cav ≥ 500 ng/mL in 90% of paediatric patients weighing at least40 kg following administration of the adult dose of posaconazole gastro-resistant tablets (300 mgtwice daily on Day 1 and 300 mg once daily starting on Day 2).

The population pharmacokinetic analysis of posaconazole in paediatric patients suggests that age, sex,renal impairment and ethnicity have no clinically meaningful effect on the pharmacokinetics ofposaconazole.

The pharmacokinetics of posaconazole concentration for solution for infusion are comparable in menand 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 concentrate for solution for infusion are comparable in youngand elderly subjects ( 65 years of age).

Pharmacokinetic differences based upon age are not to be considered clinically relevant; therefore, nodose adjustment is required.

There is insufficient data among different races with posaconazole concentrate for solution forinfusion.

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 to closely monitor for breakthrough fungal infections in patients weighingmore 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< 20 mL/min/1.73 m2), 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.

Due to the variability in exposure, patients with severe renal impairment should be monitored closelyfor breakthrough fungal infections (see section 4.2).

Similar recommendations apply to posaconazole concentrate for solution for infusion; however, aspecific study has not been conducted with posaconazole concentrate for solution for infusion.

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 concentrate for solution for infusion; however, aspecific study has not been conducted with posaconazole concentrate for solution for infusion.

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 8.9-fold greater than theconcentrations obtained at therapeutic doses in humans with 300 mg intravenous infusionadministration. Echocardiography revealed no indication of cardiac decompensation in a repeat dosesafety pharmacology study in rats at a systemic exposure 2.2-fold greater than that achievedtherapeutically. Increased systolic and arterial blood pressures (up to 29 mm-Hg) were seen in rats andmonkeys at systemic exposures 2.2-fold and 8.9-fold greater, respectively, than those achieved withthe human therapeutic doses.

A non-dose related incidence of thrombus/emboli in the lung was seen in the 1 month repeated dosestudy in the monkey. The clinical significance of this finding is unknown.

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 posaconazole administrationto juvenile dogs (10 weeks to 23 weeks of age). The clinical significance of this finding is unknown.

Betadex Sulfobutyl Ether Sodium (SBECD)

Disodium edetate

Hydrochloric acid [for pH adjustment]

Sodium hydroxide [for pH adjustment]

Water for injections

Noxafil must not be diluted with:

Lactated Ringer’s solution5 % glucose with Lactated Ringer’s solution4.2 % sodium bicarbonate

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

3 years

From a microbiological point of view, once admixed, the product should be used immediately. If notused immediately, the solution can be stored up to 24 hours refrigerated 2°C-8°C. This medicinalproduct is for single use only.

Store in a refrigerator (2°C-8°C).

For storage conditions after dilution of the medicinal product, see section 6.3.

Type I glass vial closed with bromobutyl rubber stopper and aluminium seal containing 16.7 mL ofsolution.

Pack size: 1 vial

Administration instructions for Noxafil concentrate for solution for infusion

* Equilibrate the refrigerated vial of Noxafil to room temperature.

* Aseptically transfer 16.7 mL of posaconazole to an intravenous bag (or bottle) containing acompatible admixture diluent (see below for list of diluents) using the volume ranging from150 mL to 283 mL depending on the final concentration to be achieved (not less than 1 mg/mLand not greater than 2 mg/mL).

* Administer via a central venous line, including a central venous catheter or peripherally insertedcentral catheter (PICC) by slow intravenous infusion over approximately 90 minutes. Noxafilconcentrate for solution for infusion should not be given by bolus administration.

* If a central venous catheter is not available, a single infusion may be administered through aperipheral venous catheter with a volume to achieve a dilution of approximately 2 mg/mL.

When administered through a peripheral venous catheter, the infusion should be administeredover approximately 30 minutes.

Note: In clinical studies, multiple peripheral infusions given through the same veinresulted in infusion site reactions (see section 4.8).

* Noxafil is for single use.

The following medicinal products can be infused at the same time through the same intravenous line(or cannula) as Noxafil concentrate for solution for infusion:

Amikacin sulfate

Caspofungin

Daptomycin

Dobutamine hydrochloride

Famotidine

Filgrastim

Gentamicin sulfate

Hydromorphone hydrochloride

Levofloxacin

Lorazepam

Meropenem

Micafungin

Morphine sulphate

Norepinephrine bitartrate

Potassium chloride

Vancomycin hydrochloride

Any products not listed in the table above should not be coadministered with Noxafil through the sameintravenous line (or cannula).

Noxafil concentrate for solution for infusion should be inspected visually for particulate matter prior toadministration. The solution of Noxafil ranges from colourless to pale yellow. Variations of colourwithin this range do not affect the quality of the product.

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

This medicinal product must not be mixed with other medicinal products except those mentionedbelow:

5 % glucose in water0.9 % sodium chloride0.45 % sodium chloride5 % glucose and 0.45 % sodium chloride5 % glucose and 0.9 % sodium chloride5 % glucose and 20 mEq KCl

Merck Sharp & Dohme B.V.

Waarderweg 392031 BN Haarlem

The Netherlands

EU/1/05/320/004 1 vial

Date of first authorisation: 25 October 2005

Date of latest renewal: 25 October 2010

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Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.