4.1. Therapeutic indications

Noxafil concentrate for solution for infusion is indicated for use in the treatment of the following fungal 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 following fungal 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 or itraconazole or in patients who are intolerant of these medicinal products;

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

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

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

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

Noxafil concentrate for solution for infusion is also indicated for prophylaxis of invasive fungal infections 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 are at high-risk of developing invasive fungal infections;

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

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

4.2. Posology and method of administration

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

Posology

Noxafil is also available for oral administration (Noxafil 100 mg gastro‑resistant tablets, 40 mg/mL oral suspension, and 300 mg gastro‑resistant powder and solvent for oral suspension). A switch to oral administration 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 aspergillosis (only for adults)

Loading dose of 300 mg Noxafil (300 mg concentrate for solution 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 three 100 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 is appropriate when clinically indicated.

Refractory invasive fungal infections (IFI)/patients with IFI intolerant to 1st line therapy

Adults:

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

Prophylaxis of invasive fungal infections

Adults:

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

Noxafil should be administered via a central venous line, including a central venous catheter or peripherally inserted central catheter (PICC) by slow intravenous infusion over approximately 90 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 peripheral venous catheter. When administered through a peripheral venous catheter, the infusion should be administered over approximately 30 minutes (see sections 4.8 and 6.6).

Special populations

Renal impairment

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 to occur. Oral formulations of Noxafil should be used in these patients unless an assessment of the benefit/risk to the patient justifies the use of Noxafil concentrate for solution for infusion. Serum creatinine levels should be closely monitored in these patients (see section 4.4).

Hepatic impairment

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

Paediatric population

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

No clinical data are available.

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

Method of administration

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 or peripherally inserted central catheter (PICC) by slow intravenous (IV) infusion over approximately 90 minutes (see sections 4.2, 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 peripheral venous catheter. When administered through a peripheral venous catheter, the infusion should be administered over approximately 30 minutes to reduce the likelihood of infusion site reactions (see section 4.8).

4.3. Contraindications

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

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

Co-administration with the CYP3A4 substrates terfenadine, astemizole, cisapride, pimozide, halofantrine or quinidine since this may result in increased plasma concentrations of these medicinal products, leading to QTc prolongation and rare occurrences of torsades de pointes (see sections 4.4 and 4.5).

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

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

4.4. Special warnings and precautions for use

Hypersensitivity

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

Hepatic toxicity

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

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

Monitoring of patients with severe renal impairment

Due to the variability in exposure, patients with severe renal impairment should be monitored closely for breakthrough fungal infections (see sections 4.2 and 5.2).

Monitoring of hepatic function

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

QTc prolongation

Some azoles have been associated with prolongation of the QTc interval. Posaconazole must not be administered with medicinal products that are substrates for CYP3A4 and are known to prolong the QTc interval (see sections 4.3 and 4.5). Posaconazole should be administered with caution to patients with pro-arrhythmic conditions such as:

• Congenital or acquired QTc prolongation

• Cardiomyopathy, especially in the presence of cardiac failure

• Sinus bradycardia

• Existing symptomatic arrhythmias

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

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

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

Drug interactions

Posaconazole is an inhibitor of CYP3A4 and should only be used under specific circumstances during treatment with other medicinal products that are metabolised by CYP3A4 (see section 4.5).

Midazolam and other benzodiazepines

Due to the risk of prolonged sedation and possible respiratory depression co‑administration of posaconazole with any benzodiazepines metabolised by CYP3A4 (e.g. midazolam, triazolam, alprazolam) should only be considered if clearly necessary. Dose adjustment of benzodiazepines metabolised by CYP3A4 should be considered (see section 4.5).

Vincristine toxicity

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

Venetoclax toxicity

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

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

Posaconazole concentrations may be significantly lowered in combination; therefore, concomitant use with posaconazole should be avoided unless the benefit to the patient outweighs the risk (see section 4.5).

Plasma exposure

Plasma concentrations following administration of posaconazole intravenous concentrate for solution for infusion are generally higher than those obtained with posaconazole oral suspension. Posaconazole plasma concentrations following administration of posaconazole may increase over time in some patients (see section 5.2).

Thromboembolic events

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

Photosensitivity reaction

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

Sodium

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

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

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

Cyclodextrin

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

4.5. Interaction with other medicinal products and other forms of interaction

The following information was derived from data with posaconazole oral suspension or early tablet formulation. All drug interactions with posaconazole oral suspension, except for those that affect the absorption of posaconazole (via gastric pH and motility) are considered relevant to posaconazole concentrate 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 for p-glycoprotein (P-gp) efflux in vitro. Therefore, inhibitors (e.g. verapamil, ciclosporin, quinidine, clarithromycin, erythromycin, etc.) or inducers (e.g. rifampicin, rifabutin, certain anticonvulsants, etc.) of these clearance pathways may increase or decrease posaconazole plasma concentrations, respectively.

Rifabutin

Rifabutin (300 mg once a day) decreased the Cmax (maximum plasma concentration) and AUC (area under the plasma concentration time curve) of posaconazole to 57 % and 51 %, respectively. Concomitant use of posaconazole and rifabutin and similar inducers (e.g. rifampicin) should be avoided unless the benefit to the patient outweighs the risk. See also below regarding the effect of posaconazole on rifabutin plasma levels.

Flucloxacillin

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

Efavirenz

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

Fosamprenavir

Combining fosamprenavir with posaconazole may lead to decreased posaconazole plasma concentrations. If concomitant administration is required, close monitoring for breakthrough fungal infections is recommended. Repeat dose administration of fosamprenavir (700 mg twice daily x 10 days) decreased the Cmax and AUC of posaconazole oral suspension (200 mg once daily on the 1st 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 with ritonavir is unknown.

Phenytoin

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 patient outweighs the risk.

Effects of posaconazole on other medicinal products

Posaconazole is a potent inhibitor of CYP3A4. Co-administration of posaconazole with CYP3A4 substrates may result in large increases in exposure to CYP3A4 substrates as exemplified by the effects on tacrolimus, sirolimus, atazanavir and midazolam below. Caution is advised during co-administration of posaconazole with CYP3A4 substrates administered intravenously and the dose of the CYP3A4 substrate may need to be reduced. If posaconazole is used concomitantly with CYP3A4 substrates that are administered orally, and for which an increase in plasma concentrations may be associated with unacceptable adverse reactions, plasma concentrations of the CYP3A4 substrate and/or adverse reactions should be closely monitored and the dose adjusted as needed.

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

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

Ergot alkaloids

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

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

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

Vinca alkaloids

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

Rifabutin

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 to the patient outweighs the risk (see also above regarding the effect of rifabutin on plasma levels of posaconazole). If these medicinal products are co-administered, careful monitoring of full blood counts and adverse reactions related to increased rifabutin levels (e.g. uveitis) is recommended.

Sirolimus

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

Ciclosporin

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

Tacrolimus

Posaconazole increased 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/or posaconazole discontinuation were reported in clinical efficacy studies. When initiating posaconazole treatment in patients already receiving tacrolimus, the dose of tacrolimus should be reduced (e.g. to about one third of the current dose). Thereafter blood levels of tacrolimus should be monitored carefully during co-administration, and upon discontinuation of posaconazole, and the dose of tacrolimus should be adjusted as necessary.

HIV Protease inhibitors

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

Midazolam and other benzodiazepines metabolised by CYP3A4

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

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

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

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

Digoxin

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

Sulfonylureas

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

All-trans retinoic acid (ATRA) or tretinoin

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

Venetoclax

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

Refer to the venetoclax SmPC.

Paediatric population

Interaction studies have only been performed in adults.

4.6. Fertility, pregnancy and lactation

Pregnancy

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

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

Breast-feeding

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

Fertility

Posaconazole had no effect on fertility of male rats at doses up to 180 mg/kg (2.8 times the exposure achieved from a 300 mg intravenous dose in human) or female rats at a dose up to 45 mg/kg (3.4 times the exposure from a 300 mg intravenous dose in patients). There is no clinical experience assessing the impact of posaconazole on fertility in humans.

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

Safety data mainly derive from studies with the oral suspension.

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

Posaconazole concentrate for solution for infusion

The safety of posaconazole concentrate for solution for infusion has been assessed in 72 healthy volunteers and 268 patients enrolled in a clinical study of antifungal prophylaxis.

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

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

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

The safety of posaconazole concentrate for solution for infusion has been assessed in 268 patients in clinical studies. Patients were enrolled in a non-comparative pharmacokinetic and safety study of posaconazole 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 mg daily dose for a median of 9 days. No safety data are available for administration > 28 days. Safety data in the elderly are limited.

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

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

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

Posaconazole gastro‑resistant powder and solvent for oral suspension and concentrate for solution for infusion safety

The safety of posaconazole gastro-resistant powder and solvent for oral suspension and concentrate for solution for infusion has been assessed in 115 paediatric patients aged 2 to less than 18 years for prophylaxis use. Immunocompromised paediatric patients with known or expected neutropenia were exposed 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 oncology population undergoing treatment for malignancy or with the safety profile of posaconazole in adults.

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

Tabulated list of adverse reactions

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

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

Blood and lymphatic system disorders

Common:

neutropenia

Uncommon:

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

Rare:

haemolytic uraemic syndrome, thrombotic thrombocytopenic purpura, pancytopenia, coagulopathy, haemorrhage

Immune system disorders

Uncommon:

allergic reaction

Rare:

hypersensitivity reaction

Endocrine disorders

Rare:

adrenal insufficiency, blood gonadotropin decreased, pseudoaldosteronism

Metabolism and nutrition disorders

Common:

electrolyte imbalance, anorexia, decreased appetite, hypokalaemia, hypomagnesaemia

Uncommon:

hyperglycaemia, hypoglycaemia

Psychiatric disorders

Uncommon:

abnormal dreams, confusional state, sleep disorder

Rare:

psychotic disorder, depression

Nervous system disorders

Common:

paraesthesia, dizziness, somnolence, headache, dysgeusia

Uncommon:

convulsions, neuropathy, hypoaesthesia, tremor, aphasia, insomnia

Rare:

cerebrovascular accident, encephalopathy, peripheral neuropathy, syncope

Eye disorders

Uncommon:

blurred vision, photophobia, visual acuity reduced

Rare:

diplopia, scotoma

Ear and labyrinth disorder

Rare:

hearing impairment

Cardiac disorders

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

Vascular disorders

Common:

hypertension

Uncommon:

hypotension, thrombophlebitis, vasculitis

Rare:

pulmonary embolism, deep vein thrombosis

Respiratory, thoracic and mediastinal disorders

Uncommon:

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

Rare:

pulmonary hypertension, interstitial pneumonia, pneumonitis

Gastrointestinal disorders

Very Common

nausea

Common:

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

Uncommon:

pancreatitis, abdominal distension, enteritis, epigastric discomfort, eructation, gastroesophageal reflux disease, oedema mouth

Rare:

gastrointestinal haemorrhage, ileus

Hepatobiliary disorders

Common:

liver function tests raised (ALT increased, AST increased, bilirubin increased, alkaline phosphatase increased, GGT increased)

Uncommon:

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

Rare:

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

Skin and subcutaneous tissue disorders

Common:

rash, pruritis

Uncommon:

mouth ulceration, alopecia, dermatitis, erythema, petechiae

Rare:

Stevens Johnson syndrome, vesicular rash

Not known:

photosensitivity reaction§

Musculoskeletal and connective tissue disorders

Uncommon:

back pain, neck pain, musculoskeletal pain, pain in extremity

Renal and urinary disorders

Uncommon:

acute renal failure, renal failure, blood creatinine increased

Rare:

renal tubular acidosis, interstitial nephritis

Reproductive system and breast disorders

Uncommon:

menstrual disorder

Rare:

breast pain

General disorders and administration site conditions

Common:

pyrexia (fever), asthenia, fatigue

Uncommon:

oedema, pain, chills, malaise, chest discomfort, drug intolerance, feeling jittery, infusion site pain, infusion site phlebitis, infusion site thrombosis, mucosal inflammation

Rare:

tongue oedema, face oedema

Investigations

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.

Description of selected adverse reactions

Hepatobiliary disorders

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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

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