Posaconazole AHCL - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Posaconazole AHCL 40 mg/mL oral suspension

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each mL of oral suspension contains 40 mg of posaconazole.

Excipient(s) with known effect

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

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Oral suspension

White to off-white free flowing suspension.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

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

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

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

Posaconazole AHCL oral suspension is also indicated for prophylaxis of invasive fungal infections in the following patients:

• – Patients receiving remission-induction chemotherapy for acute myelogenous leukemia (AML)

or myelodysplastic syndromes (MDS) expected to result in prolonged neutropenia and who are at high risk of developing invasive fungal infections;

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

4.2 Posology and method of administration

Non-Interchangeability between posaconazole tablets and Posaconazole AHCL Oral Suspension

The tablet and oral suspension are not to be used interchangeably due to the differences between these two formulations in frequency of dosing, administration with food and plasma drug concentration achieved. Therefore, follow the specific dosage recommendations for each formulation.

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

Posology

Posaconazole is also available as 100 mg gastro-resistant tablet and 300 mg concentrate for solution for infusion. Posaconazole tablets are the preferred formulation to optimize plasma concentrations and generally provide higher plasma drug exposures than posaconazole oral suspension.

Recommended dose is shown in Table 1.

Table 1. Recommended dose according to indication.

Indication	Dose and duration of therapy (See section 5.2)
Refractory invasive fungal infections (IFI)/patients with IFI intolerant to 1st line therapy	200 mg (5 mL) four times a day. Alternatively, patients who can tolerate food or a nutritional supplement may take 400 mg (10 mL) twice a day during or immediately following a meal or nutritional supplement. Duration of therapy should be based on the severity of the underlying disease, recovery from immunosuppression, and clinical response.
Oropharyngeal candidiasis	Loading dose of 200 mg (5 mL) once a day on the first day, then 100 mg (2.5 mL) once a day for 13 days. Each dose of Posaconazole AHCL should be administered during or immediately after a meal, or a nutritional supplement in patients who cannot tolerate food to enhance the oral absorption and to ensure adequate exposure
Prophylaxis of invasive fungal infections	200 mg (5 mL) three times a day. Each dose of Posaconazole AHCL should be administered during or immediately after a meal, or a nutritional supplement in patients who cannot tolerate food to enhance the oral absorption and to ensure adequate exposure. The duration of therapy is based on recovery from neutropenia or immunosuppression. For patients with acute myelogenous leukemia or myelodysplastic syndromes, prophylaxis with Posaconazole AHCL 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.

Special populations

Renal impairment

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

Hepatic impairment

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

Paediatric population

The safety and efficacy of posaconazole in children aged below 18 years have not been established. Currently available data are described in sections 5.1 and 5.2, but no recommendation on a posology can be made.

Method of administration

For oral use.

The oral suspension must be shaken well before use. Bottles showing any visible settling should be vigorously shaken for a minimum of 10 seconds.

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).

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 AHCL to patients with hypersensitivity to other azoles.

Hepatic toxicity

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

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

Monitoring of hepatic function

Liver function tests should be evaluated at the start of and during the course of posaconazole therapy. Patients who develop abnormal liver function tests during Posaconazole AHCLtherapy 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 AHCL 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 AHCL 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 AHCL should be administered with caution to patients with pro-arrhythmic conditions such as:

• – Congenital or acquired QTc prolongation

• – Cardiomyopathy, especially in the presence of cardiac failure

• – Sinus bradycardia

• – Existing symptomatic arrhythmias

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

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

Drug interactions

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

Midazolam and other benzodiazepines

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

Vincristine toxicity

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

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

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).

Gastrointestinal dysfunction

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

Excipients

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

This medicine contains less than 1 mmol sodium (23 mg) per 5 mL of suspension, that is to say essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

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.

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.

H 2 receptor antagonists and proton pump inhibitors

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

Food

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

Effects of posaconazole on other medicinal products

Posaconazole is a potent inhibitor of CYP3A4. Co-administration of posaconazole with 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 coadministration of posaconazole with CYP3A4 substrates administered intravenously and the dose of the CYP3A4 substrate may need to be reduced. If posaconazole is used concomitantly with CYP3A4 substrates that are administered orally, and for which an increase in plasma concentrations may be associated with unacceptable adverse reactions, plasma concentrations of the CYP3A4 substrate and/or adverse reactions should be closely monitored and the dose adjusted as needed. Several of the interaction studies were conducted in healthy volunteers in whom a higher exposure to posaconazole occurs compared to patients administered the same dose. The effect of posaconazole on CYP3A4 substrates in patients might be somewhat lower than that observed in healthy volunteers, and is expected to be variable between patients due to the variable posaconazole exposure in patients. The effect of co-administration with posaconazole on plasma levels of CYP3A4 substrates may also be variable within a patient, unless posaconazole is administered in a strictly standardised way with food, given the large food effect on posaconazole exposure (see section 5.2).

Terfenadine, astemizole, cisapride, pimozide, halofantrine and quinidine (CYP3A4 substrates) Co-administration of posaconazole and terfenadine, astemizole, cisapride, pimozide, halofantrine or quinidine is contraindicated. Co-administration may result in increased plasma concentrations of these medicinal products, leading to QTc prolongation and rare occurrences of torsades de pointes (see section 4.3).

Ergot alkaloids

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

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

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

Vinca alkaloids

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

Rifabutin

Posaconazole increased the 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 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. Coadministration 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 beconsidered during the treatment with posaconazole, and during the following days after treatment.

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 (1.7 times the 400 mg twice daily regimen based on steady-state plasma concentrations in healthy volunteers) or female rats at a dose up to 45 mg/kg (2.2 times the 400-mg twice daily regimen). 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

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

The safety of posaconazole tablet has been assessed in 336 patients and healthy volunteers enrolled in clinical trials. The safety profile of tablets was similar to that of the oral suspension.

Tabulated list of adverse reactions

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

Table 2. Adverse reactions by body system and frequency reported in clinical trials and/or postmarketing 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
Not known:	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:	paresthesia, 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, 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, gastrooesophageal 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
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, 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, and

concentrate for solution for infusion.

§ See section 4.4.

Description of selected adverse reactions

Hepatobiliary disorders

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in

4.9 Overdose

During clinical trials, patients who received posaconazole oral suspension doses up to 1,600 mg/day experienced no different adverse reactions from those reported with patients at the lower doses. Accidental overdose was noted in one patient who took posaconazole oral suspension 1,200 mg twice a day for 3 days. No adverse reactions were noted by the investigator.

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

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antimycotics for systemic use, triazole derivatives, ATC code: J02AC04.

Mechanism of action

Posaconazole inhibits the enzyme lanosterol 14a-demethylase (CYP51), which catalyses an essential step in ergosterol biosynthesis.

Microbiology

Posaconazole has been shown in vitro to be active against the following microorganisms: Aspergillus species (Aspergillus fumigatus, A. flavus, A. terreus, A. nidulans, A. niger, A. ustus), Candida species (Candida albicans, C. glabrata, C. krusei, C. parapsilosis, C. tropicalis, C. dubliniensis, C. famata, C. inconspicua, C. lipolytica, C. norvegensis, C. pseudotropicalis), Coccidioides immitis, Fonsecaea pedrosoi, and species of Fusarium, Rhizomucor, Mucor, and Rhizopus. The microbiological data suggest that posaconazole is active against Rhizomucor, Mucor, and Rhizopus; however the clinical data are currently too limited to assess the efficacy of posaconazole against these causative agents.

Resistance

Clinical isolates with decreased susceptibility to posaconazole have been identified. The principle mechanism of resistance is the acquisition of substitutions in the target protein, CYP51.

Epidemiological Cut-off (ECOFF) Values for Aspergillus spp .

The ECOFF values for posaconazole, which distinguish the wild type population from isolates with acquired resistance, have been determined by EUCAST methodology.

EUCAST ECOFF values:

• - Aspergillus flavus: 0.5 mg/L

• - Aspergillus fumigatus: 0.25 mg/L

• - Aspergillus nidulans: 0.5 mg/L

• - Aspergillus niger: 0.5 mg/L

• - Aspergillus terreus: 0.25 mg/L

There are currently insufficient data to set clinical breakpoints for Aspergillus spp. ECOFF values do not equate to clinical breakpoints.

Breakpoints

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

• - Candida albicans: S <0.06 mg/L, R >0.06 mg/L

• - Candida tropicalis: S <0.06 mg/L, R >0.06 mg/L

• - Candidaparapsi­losis: S <0.06 mg/L, R >0.06 mg/L

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

Combination with other antifungal agents

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

Pharmacokinetic / Pharmacodynamic relationships

A correlation between total medicinal product exposure divided by MIC (AUC/MIC) and clinical outcome was observed. The critical ratio for subjects with Aspergillus infections was ~200. It is particularly important to try to ensure that maximal plasma levels are achieved in patients infected with Aspergillus (see sections 4.2 and 5.2 on recommended dose regimens and the effects of food on absorption).

Clinical experience

Summary of posaconazole oral suspension studies

Invasive aspergillosis

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

As shown in Table 3, a successful response (complete or partial resolution) at the end of treatment was seen in 42 % of posaconazole-treated patients compared to 26 % of the external group. However, this was not a prospective, randomized controlled study and so all comparisons with the external control group should be viewed with caution.

Table 3. Overall efficacy of posaconazole oral suspension at the end of treatment for invasive aspergillosis in comparison to an external control group

	Posaconazole oral suspension		External control group
Overall Response	45/107 (42 %)		22/86 (26 %)
Success by Species All mycologically confirmed Aspergillus spp.1	34/76	(45 %)	19/74	(26%)
A. fumigatus	12/29	(41 %)	12/34	(35%)
A. flavus	10/19	(53 %)	3/16	(19%)
A. terreus	4/14	(29 %)	2/13	(15%)
A. niger	3/5	(60 %)	2/7	(29%)

1 Includes other less common species or species unknown

Fusarium spp.

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

Chromoblastomy­cosis/Mycetoma

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

Coccidioidomy­cosis

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

Treatment of azole-susceptible Oropharyngeal Candidiasis (OPC)

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

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

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

Table 4. Clinical success rates in Oropharyngeal Candidiasis

Endpoint	Posaconazole	Fluconazole
Clinical success rate at Day 14	91.7 % (155/169)	92.5 % (148/160)
Clinical success rate 4 weeks after end of treatment	68.5 % (98/143)	61.8 % (84/136)

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

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

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

Study 316 was a randomized, double-blind trial of posaconazole oral suspension (200 mg three times a day) versus fluconazole capsules (400 mg once daily) in allogeneic hematopoietic stem cell transplant recipients with graft-versus-host disease (GVHD). The primary efficacy endpoint was the incidence of proven/probable IFIs at 16 weeks post-randomization as determined by an independent, blinded external expert panel. A key secondary endpoint was the incidence of proven/probable IFIs during the on-treatment period (first dose to last dose of study medicinal product + 7 days). The majority (377/600, [63 %]) of patients included had Acute Grade 2 or 3 or chronic extensive (195/600, [32.5%]) GVHD at study start. The mean duration of therapy was 80 days for posaconazole and 77 days for fluconazole.

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

In both prophylaxis studies, aspergillosis was the most common breakthrough infection. See Table 5 and 6 for results from both studies. There were fewer breakthrough Aspergillus infections in patients receiving posaconazole prophylaxis when compared to control patients.

Table 5 . Results from clinical studies in prophylaxis of Invasive Fungal Infections

Study	Posaconazole oral suspension	Controla	P-Value
Proportion (%) of patients with proven/probable IFIs
On-treatment periodb
1899d	7/304 (2)	25/298 (8)	0.0009
316e	7/291 (2)	22/288 (8)	0.0038
Fixed-time period0
1899d	14/304 (5)	33/298 (11)	0.0031
316 d	16/301 (5)	27/299 (9)	0.0740

FLU = fluconazole; ITZ = itraconazole; POS = posaconazole.

a:   FLU/ITZ (1899); FLU (316).

b: In 1899 this was the period from randomization to last dose of study medicinal product plus 7 days; in 316

it was the period from first dose to last dose of study medicinal product plus 7 days.

c: In 1899, this was the period from randomization to 100 days post-randomization; in 316 it was the period from the baseline day to 111 days post-baseline.

d:   All randomized

e:    All treated

Table 6. Results from clinical studies in prophylaxis of Invasive Fungal Infections

Study	Posaconazole oral suspension	Controla
Proportion (%) of patients with proven/probable Aspergillosis
On-treatment periodb
1899d	2/304 (1)	25/298 (7)
316e	3/291 (1)	17/288 (6)
Fixed-time period0
1899d	4/304(1)	26/298 (9)
316 d	7/301 (2)	21/299 (9)

FLU = fluconazole; ITZ = itraconazole; POS = posaconazole.

a: FLU/ITZ (1899); FLU (316).

b: In 1899 this was the period from randomization to last dose of study medicinal product plus 7 days; in 316

it was the period from first dose to last dose of study medicinal product plus 7 days.

• c: In 1899, this was the period from randomization to 100 days post-randomization; in 316 it was the period from the baseline day to 111 days post-baseline.

• d: All randomized

• e: All treated

5.2 Pharmacokinetic properties

Absorption

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

Effect of food on oral absorption in healthy volunteers

The absorption of posaconazole was significantly increased when posaconazole 400 mg (once daily) was administered during and immediately after the consumption of a high fat meal (~ 50 grams fat) compared to administration before a meal, with Cmax and AUC increasing by approximately 330 % and 360 %, respectively. The AUC of posaconazole is: 4 times greater when administered with a high fat meal (~ 50 grams fat) and about 2.6 times greater when administered during a non-fat meal or nutritional supplement (14 grams fat) relative to the fasted state (see sections 4.2 and 4.5).

Distribution

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

Biotransformation

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

Elimination

Posaconazole is slowly eliminated with a mean half-life (t'/z) of 35 hours (range 20 to 66 hours). After administration of 14C-posaconazole, radioactivity was predominantly recovered in the faeces (77 % of the radiolabelled dose) with the major component being parent compound (66 % of the radiolabelled dose). Renal clearance is a minor elimination pathway, with 14 % of the radiolabelled dose excreted in urine (< 0.2 % of the radiolabelled dose is parent compound). Steady-state is attained following 7 to 10 days of multiple-dose administration.

Pharmacokinetics in special populations

Children (< 18 years)

Following administration of 800 mg per day of posaconazole as a divided dose for treatment of invasive fungal infections, mean trough plasma concentrations from 12 patients 8 – 17 years of age (776 ng/mL) were similar to concentrations from 194 patients 18 – 64 years of age (817 ng/mL). Similarly, in the prophylaxis studies, the mean steady-state posaconazole average concentration (Cav) was comparable among ten adolescents (13–17 years of age) to Cav achieved in adults (> 18 years of age). In a study of 136 neutropenic paediatric patients 11 months – 17 years treated with posaconazole oral suspension at doses up to 18 mg/kg/day divided TID, approximately 50% met the pre-specified target (Day 7 Cav between 500 ng/mL-2,500 ng/mL). In general, exposures tended to be higher in the older patients (7 to <18 years) than in younger patients (2 to <7 years).

Gender

The pharmacokinetics of posaconazole are comparable in men and women.

Elderly (> 65 years)

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

Race

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

Weight

Pharmacokinetic modelling with an oral tablet formulation suggests that patients weighing greater than 120 kg may have lower posaconazole exposure. It is, therefore, suggested to closely monitor for breakthrough fungal infections in patients weighing more than 120 kg. Patients with a low body weight (< 60 kg) are more likely to experience higher plasma concentrations of posaconazole and should be closely monitored for adverse events.

Renal impairment

Following single-dose administration of posaconazole oral suspension, there was no effect of mild and moderate renal impairment (n=18, Cl cr > 20 mL/min/1.73 m2) on posaconazole pharmacokinetics; therefore, no dose adjustment is required. In subjects with severe renal impairment (n=6, Cl cr< 20 mL/min/1.73 m2), the AUC of posaconazole was highly variable [> 96 % CV (coefficient of variance)] compared to other renal groups [< 40 % CV]. However, as posaconazole is not significantly renally eliminated, an effect of severe renal impairment on the pharmacokinetics of posaconazole is not expected and no dose adjustment is recommended. Posaconazole is not removed by haemodialysis.

Hepatic impairment

After a single oral dose of 400 mg posaconazole oral suspension to patients with mild (Child-Pugh Class A), moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment (six per group), the mean AUC was 1.3 to 1.6-fold higher compared to that for matched control subjects with normal hepatic function. Unbound concentrations were not determined and it cannot be excluded that there is a larger increase in unbound posaconazole exposure than the observed 60 % increase in total AUC. The elimination half-life (t1/2) was prolonged from approximately 27 hours up to ~43 hours in respective groups. No dose adjustment is recommended for patients with mild to severe hepatic impairment but caution is advised due to the potential for higher plasma exposure.

5.3 Preclinical safety data

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

Neuronal phospholipidosis occurred in dogs dosed for > 3 months at lower systemic exposures than those obtained at therapeutic doses in humans. This finding was not seen in monkeys dosed for one year. In twelve-month neurotoxicity studies in dogs and monkeys, no functional effects were observed on the central or peripheral nervous systems at systemic exposures greater than those achieved therapeutically.

Pulmonary phospholipidosis resulting in dilatation and obstruction of the alveoli was observed in the 2-year study in rats. These findings are not necessarily indicative of a potential for functional changes in humans.

No effects on electrocardiograms, including QT and QTc intervals, were seen in a repeat dose safety pharmacology study in monkeys at systemic exposures 4.6-fold greater than the concentrations obtained at therapeutic doses in humans. Echocardiography revealed no indication of cardiac decompensation in a repeat dose safety pharmacology study in rats at a systemic exposure 1.4-fold greater than that achieved therapeutically. Increased systolic and arterial blood pressures (up to 29 mm-Hg) were seen in rats and monkeys at systemic exposures 1.4-fold and 4.6-fold greater, respectively, than those achieved with the human therapeutic doses.

Reproduction, peri- and postnatal development studies were conducted in rats. At exposures lower than those obtained at therapeutic doses in humans, posaconazole caused skeletal variations and malformations, dystocia, increased length of gestation, reduced mean litter size and postnatal viability. In rabbits, posaconazole was embryotoxic at exposures greater than those obtained at therapeutic doses. As observed with other azole antifungal agents, these effects on reproduction were considered to be due to a treatment-related effect on steroidogenesis.

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

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Macrogolglycerol hydroxystearate

Sodium citrate dihydrate

Citric acid monohydrate

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

Xanthan gum (E415)

Sodium benzoate (E211)

Liquid glucose

Glycerol (E422)

Titanium dioxide (E171)

Strawberry flavour (containing propylene glycol) Purified water

6.2 Incompatibilities

Not applicable.

6.3 Shelf life 30 months

After first opening the container: 30 days

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

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

6.6 Special precautions for disposal

No special requirements

7. MARKETING AUTHORISATION HOLDER

Accord Healthcare S.L.U.

World Trade Center, Moll de Barcelona s/n,

Edifici Est, 6a planta, Barcelona,

08039 Barcelona, Spain

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/19/1380/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 25th July 2019