VFEND 40mg / ml powder for oral suspension medication leaflet

VFEND 40 mg/ml powder for oral suspension

Each ml of oral suspension contains 40 mg of voriconazole when reconstituted with water.

Each bottle contains 3 g of voriconazole.

Each ml of suspension contains 0.54 g sucrose.

Each ml of suspension contains 2.40 mg sodium benzoate.

For the full list of excipients, see section 6.1.

Powder for oral suspension.

White to off-white powder.

VFEND, is a broad-spectrum, triazole antifungal agent and is indicated in adults and children aged 2 yearsand above as follows:

Treatment of invasive aspergillosis

Treatment of candidaemia in non-neutropenic patients.

Treatment of fluconazole-resistant serious invasive Candida infections (including C. krusei).

Treatment of serious fungal infections caused by Scedosporium spp. and Fusarium spp.

VFEND should be administered primarily to patients with progressive, possibly life-threatening infections.

Prophylaxis of invasive fungal infections in high risk allogeneic hematopoietic stem cell transplant (HSCT)recipients.

Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalcaemia should be monitoredand corrected, if necessary, prior to initiation and during voriconazole therapy (see section 4.4).

VFEND is also available as 50 mg and 200 mg film-coated tablets and 200 mg powder for solution forinfusion.

Therapy must be initiated with the specified loading dose regimen of either intravenous or oral VFEND toachieve plasma concentrations on Day 1 that are close to steady state. On the basis of the high oralbioavailability (96%; see section 5.2), switching between intravenous and oral administration is appropriatewhen clinically indicated.

Detailed information on dosage recommendations is provided in the following table:

Intravenous Oral Suspension

Patients 40 kg and Patients less than 40 kg*above*

Loading dose 6 mg/kg every 12 hours 10 ml (400 mg) every 5 ml (200 mg) everyregimen 12 hours 12 hours(first 24 hours)

Maintenance dose 4 mg/kg twice daily 5 ml (200 mg) twice 2.5 ml (100 mg) twice(after first 24 hours) daily daily

* This also applies to patients aged 15 years and older

Treatment duration should be as short as possible depending on the patient’s clinical and mycologicalresponse. Long term exposure to voriconazole greater than 180 days (6 months) requires careful assessmentof the benefit-risk balance (see sections 4.4 and 5.1).

If patient response to treatment is inadequate, the maintenance dose may be increased to 7.5 ml (300 mg)twice daily for oral administration. For patients less than 40 kg the oral dose may be increased to 3.75 ml(150 mg) twice daily.

If patient is unable to tolerate treatment at a higher dose, reduce the oral dose by 1.25 ml (50 mg) steps to the5 ml (200 mg) twice daily [or 2.5 ml (100 mg) twice daily for patients less than 40 kg] maintenance dose.

In case of use as prophylaxis, refer below.

Children (2 to <12 years) and young adolescents with low body weight (12 to 14 years and <50 kg)

Voriconazole should be dosed as children as these young adolescents may metabolise voriconazole moresimilarly to children than to adults.

The recommended dosing regimen is as follows:

Intravenous Oral Suspension

Loading Dose Regimen 9 mg/kg every 12 hours Not recommended(first 24 hours)0.225 ml/kg (9 mg/kg) twice daily

Maintenance Dose8 mg/kg twice daily [a maximum dose of 8.75 ml(after first 24 hours)(350 mg) twice daily]

Note: Based on a population pharmacokinetic analysis in 112 immunocompromised paediatric patients aged2 to <12 years and 26 immunocompromised adolescents aged 12 to <17 years.

It is recommended to initiate the therapy with intravenous regimen, and oral regimen should be consideredonly after there is a significant clinical improvement. It should be noted that an 8 mg/kg intravenous dosewill provide voriconazole exposure approximately 2-fold higher than a 9 mg/kg oral dose.

These oral dose recommendations for children are based on studies in which voriconazole was administeredas the powder for oral suspension. Bioequivalence between the powder for oral suspension and tablets hasnot been investigated in a paediatric population. Considering the assumed limited gastro-enteric transit timein paediatric patients, the absorption of tablets may be different in paediatric compared to adult patients. It istherefore recommended to use the oral suspension formulation in children aged 2 to <12.

Voriconazole should be dosed as adults.

Dosage adjustment [Children (2 to <12 years) and young adolescents with low body weight (12 to 14 yearsand <50 kg)]

If patient response to treatment is inadequate, the dose may be increased by 0.025 ml/kg (1 mg/kg) steps [orby 1.25 ml (50 mg) steps if the maximum oral dose of 8.75 ml (350 mg) was used initially]. If patient isunable to tolerate treatment, reduce the dose by 0.025 ml/kg (1 mg/kg) steps [or by 1.25 ml (50 mg) steps ifthe maximum oral dose of 8.75 ml (350 mg) was used initially].

Use in paediatric patients aged 2 to <12 years with hepatic or renal insufficiency has not been studied (seesections 4.8 and 5.2).

Prophylaxis in Adults and Children

Prophylaxis should be initiated on the day of transplant and may be administered for up to 100 days.

Prophylaxis should be as short as possible depending on the risk for developing invasive fungal infection(IFI) as defined by neutropenia or immunosuppression. It may only be continued up to 180 days aftertransplantation in case of continuing immunosuppression or graft versus host disease (GvHD) (see section5.1).

Dosage

The recommended dosing regimen for prophylaxis is the same as for treatment in the respective age groups.

Please refer to the treatment tables above.

The safety and efficacy of voriconazole use for longer than 180 days has not been adequately studied inclinical trials.

Use of voriconazole in prophylaxis for greater than 180 days (6 months) requires careful assessment of thebenefit-risk balance (see sections 4.4 and 5.1).

The following instructions apply to both Treatment and Prophylaxis

For prophylaxis use, dose adjustments are not recommended in the case of lack of efficacy ortreatment-related adverse events. In the case of treatment-related adverse events, discontinuation ofvoriconazole and use of alternative antifungal agents must be considered (see sections 4.4 and 4.8)

Dosage adjustments in case of coadministration

Phenytoin may be coadministered with voriconazole if the maintenance dose of voriconazole is increasedfrom 5 ml (200 mg) to 10 ml (400 mg) orally, twice daily [2.5 ml (100 mg) to 5 ml (200 mg) orally, twicedaily in patients less than 40 kg], see sections 4.4 and 4.5.

The combination of voriconazole with rifabutin should, if possible be avoided. However, if the combinationis strictly needed, the maintenance dose of voriconazole may be increased from 5 ml (200 mg) to 8.75 ml(350 mg) orally, twice daily [2.5 ml (100 mg) to 5 ml (200 mg) orally, twice daily in patients less than40 kg], see sections 4.4 and 4.5.

Efavirenz may be coadministered with voriconazole if the maintenance dose of voriconazole is increased to10 ml (400 mg) every 12 hours and the efavirenz dose is reduced by 50%, i.e. to 300 mg once daily. Whentreatment with voriconazole is stopped, the initial dosage of efavirenz should be restored (see sections 4.4and 4.5).

No dose adjustment is necessary for elderly patients (see section 5.2).

The pharmacokinetics of orally administered voriconazole are not affected by renal impairment. Therefore,no adjustment is necessary for oral dosing for patients with mild to severe renal impairment (see section 5.2).

Voriconazole is haemodialysed with a clearance of 121 ml/min. A 4-hour haemodialysis session does notremove a sufficient amount of voriconazole to warrant dose adjustment.

It is recommended that the standard loading dose regimens be used but that the maintenance dose be halvedin patients with mild to moderate hepatic cirrhosis (Child-Pugh A and B) receiving voriconazole (seesection 5.2).

Voriconazole has not been studied in patients with severe chronic hepatic cirrhosis (Child-Pugh C).

There is limited data on the safety of VFEND in patients with abnormal liver function tests (aspartatetransaminase [AST], alanine transaminase [ALT], alkaline phosphatase [ALP], or total bilirubin >5 times theupper limit of normal).

Voriconazole has been associated with elevations in liver function tests and clinical signs of liver damage,such as jaundice, and must only be used in patients with severe hepatic impairment if the benefit outweighsthe potential risk. Patients with severe hepatic impairment must be carefully monitored for drug toxicity (seesection 4.8).

The safety and efficacy of VFEND in children below 2 years has not been established. Currently availabledata are described in sections 4.8 and 5.1 but no recommendation on a posology can be made.

VFEND oral suspension is to be taken at least one hour before, or two hours following, a meal.

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

Coadministration with CYP3A4 substrates, terfenadine, astemizole, cisapride, pimozide, quinidine orivabradine since increased plasma concentrations of these medicinal products can lead to QTc prolongationand rare occurrences of torsades de pointes (see section 4.5).

Coadministration with rifampicin, carbamazepine, phenobarbital and St John’s Wort since these medicinalproducts are likely to decrease plasma voriconazole concentrations significantly (see section 4.5).

Coadministration of standard doses of voriconazole with efavirenz doses of 400 mg once daily or higher iscontraindicated, because efavirenz significantly decreases plasma voriconazole concentrations in healthysubjects at these doses. Voriconazole also significantly increases efavirenz plasma concentrations (seesection 4.5, for lower doses see section 4.4).

Coadministration with high-dose ritonavir (400 mg and above twice daily) because ritonavir significantlydecreases plasma voriconazole concentrations in healthy subjects at this dose (see section 4.5, for lowerdoses see section 4.4).

Coadministration with ergot alkaloids (ergotamine, dihydroergotamine), which are CYP3A4 substrates, sinceincreased plasma concentrations of these medicinal products can lead to ergotism (see section 4.5).

Coadministration with sirolimus since voriconazole is likely to increase plasma concentrations of sirolimussignificantly (see section 4.5).

Coadministration of voriconazole with naloxegol, a CYP3A4 substrate, since increased plasmaconcentrations of naloxegol can precipitate opioid withdrawal symptoms (see section 4.5).

Coadministration of voriconazole with tolvaptan since strong CYP3A4 inhibitors such as voriconazolesignificantly increase plasma concentrations of tolvaptan (see section 4.5).

Coadministration of voriconazole with lurasidone since significant increases in lurasidone exposure have thepotential for serious adverse reactions (see section 4.5).

Coadministration with venetoclax at initiation and during venetoclax dose titration phase since voriconazoleis likely to significantly increase plasma concentrations of venetoclax and increase risk of tumour lysissyndrome (see section 4.5).

Caution should be used in prescribing VFEND to patients with hypersensitivity to other azoles (see alsosection 4.8).

Voriconazole has been associated with QTc interval prolongation. There have been rare cases of torsades depointes in patients taking voriconazole who had risk factors, such as history of cardiotoxic chemotherapy,cardiomyopathy, hypokalaemia and concomitant medicinal products that may have been contributory.

Voriconazole should be administered with caution to patients with potentially proarrhythmic conditions,such as:

- Congenital or acquired QTc prolongation.

- Cardiomyopathy, in particular when heart failure is present.

- Sinus bradycardia.

- Existing symptomatic arrhythmias.

- Concomitant medicinal product that is known to prolong QTc interval. Electrolyte disturbances suchas hypokalaemia, hypomagnesaemia and hypocalcaemia should be monitored and corrected, ifnecessary, prior to initiation and during voriconazole therapy (see section 4.2). A study has beenconducted in healthy volunteers which examined the effect on QTc interval of single doses ofvoriconazole up to 4 times the usual daily dose. No subject experienced an interval exceeding thepotentially clinically-relevant threshold of 500 msec (see section 5.1).

In clinical trials, there have been cases of serious hepatic reactions during treatment with voriconazole(including clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities). Instances ofhepatic reactions were noted to occur primarily in patients with serious underlying medical conditions(predominantly haematological malignancy). Transient hepatic reactions, including hepatitis and jaundice,have occurred among patients with no other identifiable risk factors. Liver dysfunction has usually beenreversible on discontinuation of therapy (see section 4.8).

Patients receiving VFEND must be carefully monitored for hepatic toxicity. Clinical management shouldinclude laboratory evaluation of hepatic function (specifically AST and ALT) at the initiation of treatmentwith VFEND and at least weekly for the first month of treatment. Treatment duration should be as short aspossible; however, if based on the benefit-risk assessment the treatment is continued (see section 4.2),monitoring frequency can be reduced to monthly if there are no changes in the liver function tests.

If the liver function tests become markedly elevated, VFEND should be discontinued, unless the medicaljudgment of the risk-benefit of the treatment for the patient justifies continued use.

Monitoring of hepatic function should be carried out in both children and adults.

- Phototoxicity

In addition VFEND has been associated with phototoxicity including reactions such as ephelides,lentigo, actinic keratosis and pseudoporphyria. There is a potential increased risk of skinreactions/toxicity with concomitant use of photosensitising agents (e.g., methotrexate, etc). It isrecommended that all patients, including children, avoid exposure to direct sunlight during VFENDtreatment and use measures such as protective clothing and sunscreen with high sun protection factor(SPF).

- Squamous cell carcinoma of the skin (SCC)

Squamous cell carcinoma of the skin (including cutaneous SCC in situ, or Bowen’s disease) hasbeen reported in patients, some of whom have reported prior phototoxic reactions. If phototoxicreactions occur multidisciplinary advice should be sought, VFEND discontinuation and use ofalternative antifungal agents should be considered and the patient should be referred to adermatologist. If VFEND is continued, however, dermatologic evaluation should be performed on asystematic and regular basis, to allow early detection and management of premalignant lesions.

VFEND should be discontinued if premalignant skin lesions or squamous cell carcinoma areidentified (see below the section under Long-term treatment).

- Severe cutaneous adverse reactions

Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxicepidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS),which can be life-threatening or fatal, have been reported with the use of voriconazole. If a patientdevelops a rash he should be monitored closely and VFEND discontinued if lesions progress.

Reversible cases of adrenal insufficiency have been reported in patients receiving azoles, includingvoriconazole. Adrenal insufficiency has been reported in patients receiving azoles with or withoutconcomitant corticosteroids. In patients receiving azoles without corticosteroids, adrenal insufficiency isrelated to direct inhibition of steroidogenesis by azoles. In patients taking corticosteroids, voriconazoleassociated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess and adrenal suppression(see section 4.5). Cushing’s syndrome with and without subsequent adrenal insufficiency has also beenreported in patients receiving voriconazole concomitantly with corticosteroids.

Patients on long-term treatment with voriconazole and corticosteroids (including inhaled corticosteroids e.g.,budesonide and intranasal corticosteroids) should be carefully monitored for adrenal cortex dysfunction bothduring treatment and when voriconazole is discontinued (see section 4.5). Patients should be instructed toseek immediate medical care if they develop signs and symptoms of Cushing’s syndrome or adrenalinsufficiency.

Long term exposure (treatment or prophylaxis) greater than 180 days (6 months) requires careful assessmentof the benefit-risk balance and physicians should therefore consider the need to limit the exposure to VFEND(see sections 4.2 and 5.1).

Squamous cell carcinoma of the skin (SCC) (including cutaneous SCC in situ, or Bowen’s disease) has beenreported in relation with long-term VFEND treatment (see section 4.8).

Non-infectious periostitis with elevated fluoride and alkaline phosphatase levels has been reported intransplant patients. If a patient develops skeletal pain and radiologic findings compatible with periostitis

VFEND discontinuation should be considered after multidisciplinary advice (see section 4.8).

There have been reports of prolonged visual adverse reactions, including blurred vision, optic neuritis andpapilloedema (see section 4.8).

Acute renal failure has been observed in severely ill patients undergoing treatment with VFEND. Patientsbeing treated with voriconazole are likely to be treated concomitantly with nephrotoxic medicinal productsand have concurrent conditions that may result in decreased renal function (see section 4.8).

Patients should be monitored for the development of abnormal renal function. This should include laboratoryevaluation, particularly serum creatinine.

Patients, especially children, with risk factors for acute pancreatitis (e.g., recent chemotherapy,haematopoietic stem cell transplantation [HSCT]), should be monitored closely during VFEND treatment.

Monitoring of serum amylase or lipase may be considered in this clinical situation.

Safety and effectiveness in paediatric subjects below the age of two years has not been established (seesections 4.8 and 5.1). Voriconazole is indicated for paediatric patients aged two years or older. A higherfrequency of liver enzyme elevations was observed in the paediatric population (see section 4.8). Hepaticfunction should be monitored in both children and adults. Oral bioavailability may be limited in paediatricpatients aged 2 to <12 years with malabsorption and very low body weight for age. In that case, intravenousvoriconazole administration is recommended.

- Serious dermatological adverse reactions (including SCC)

The frequency of phototoxicity reactions is higher in the paediatric population. As an evolutiontowards SCC has been reported, stringent measures for the photoprotection are warranted in thispopulation of patients. In children experiencing photoaging injuries such as lentigines or ephelides,sun avoidance and dermatologic follow-up are recommended even after treatment discontinuation.

In case of treatment-related adverse events (hepatotoxicity, severe skin reactions including phototoxicity and

SCC, severe or prolonged visual disorders and periostitis), discontinuation of voriconazole and use ofalternative antifungal agents must be considered.

Careful monitoring of phenytoin levels is recommended when phenytoin is coadministered withvoriconazole. Concomitant use of voriconazole and phenytoin should be avoided unless the benefitoutweighs the risk (see section 4.5).

When voriconazole is coadministered with efavirenz the dose of voriconazole should be increased to 400 mgevery 12 hours and the dose of efavirenz should be decreased to 300 mg every 24 hours (see sections 4.2, pct. 4.3and 4.5).

Coadministration of voriconazole is expected to increase glasdegib plasma concentrations and increase therisk of QTc prolongation (see section 4.5). If concomitant use cannot be avoided, frequent ECG monitoringis recommended.

Coadministration of voriconazole with tyrosine kinase inhibitors metabolised by CYP3A4 is expected toincrease tyrosine kinase inhibitor plasma concentrations and the risk of adverse reactions. If concomitant usecannot be avoided, dose reduction of the tyrosine kinase inhibitor and close clinical monitoring isrecommended (see section 4.5).

Rifabutin (potent CYP450 inducer)

Careful monitoring of full blood counts and adverse reactions to rifabutin (e.g., uveitis) is recommendedwhen rifabutin is coadministered with voriconazole. Concomitant use of voriconazole and rifabutin shouldbe avoided unless the benefit outweighs the risk (see section 4.5).

Coadministration of voriconazole and low-dose ritonavir (100 mg twice daily) should be avoided unless anassessment of the benefit/risk to the patient justifies the use of voriconazole (see sections 4.3 and 4.5).

Coadministration of voriconazole with everolimus is not recommended because voriconazole is expected tosignificantly increase everolimus concentrations. Currently there are insufficient data to allow dosingrecommendations in this situation (see section 4.5).

Frequent monitoring for adverse reactions and toxicity related to methadone, including QTc prolongation, isrecommended when coadministered with voriconazole since methadone levels increased followingcoadministration of voriconazole. Dose reduction of methadone may be needed (see section 4.5).

Reduction in the dose of alfentanil, fentanyl and other short-acting opiates similar in structure to alfentaniland metabolised by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole(see section 4.5). As the half-life of alfentanil is prolonged in a 4-fold manner when alfentanil iscoadministered with voriconazole, and in an independent published study concomitant use of voriconazolewith fentanyl resulted in an increase in the mean AUC0-∞ of fentanyl, frequent monitoring foropiate-associated adverse reactions (including a longer respiratory monitoring period) may be necessary.

Reduction in the dose of oxycodone and other long-acting opiates metabolised by CYP3A4 (e.g.,hydrocodone) should be considered when coadministered with voriconazole. Frequent monitoring foropiate-associated adverse reactions may be necessary (see section 4.5).

Fluconazole (CYP2C9, CYP2C19 and CYP3A4 inhibitor)

Coadministration of oral voriconazole and oral fluconazole resulted in a significant increase in Cmax and

AUCτ of voriconazole in healthy subjects. The reduced dose and/or frequency of voriconazole andfluconazole that would eliminate this effect have not been established. Monitoring forvoriconazole-associated adverse reactions is recommended if voriconazole is used sequentially afterfluconazole (see section 4.5).

Sucrose

This medicinal product contains 0.54 g sucrose per ml. This should be taken into account in patients withdiabetes mellitus. Patients with rare hereditary problems of fructose intolerance, glucose-galactosemalabsorption or sucrase-isomaltase insufficiency should not take this medicine. May be harmful to theteeth.

This medicinal product contains less than 1 mmol sodium (23 mg) per 5 ml of suspension. Patients on lowsodium diets should be informed that this medicinal product is essentially ‘sodium-free’.

Voriconazole is metabolised by, and inhibits the activity of, cytochrome P450 isoenzymes, CYP2C19,

CYP2C9, and CYP3A4. Inhibitors or inducers of these isoenzymes may increase or decrease voriconazoleplasma concentrations, respectively, and there is potential for voriconazole to increase the plasmaconcentrations of substances metabolised by these CYP450 isoenzymes, in particular for substancesmetabolised by CYP3A4 since voriconazole is a strong CYP3A4 inhibitor though the increase in AUC issubstrate dependent (see Table below).

Unless otherwise specified, drug interaction studies have been performed in healthy adult male subjectsusing multiple dosing to steady state with oral voriconazole at 200 mg twice daily (BID). These results arerelevant to other populations and routes of administration.

Voriconazole should be administered with caution in patients with concomitant medication that is known toprolong QTc interval. When there is also a potential for voriconazole to increase the plasma concentrationsof substances metabolised by CYP3A4 isoenzymes (certain antihistamines, quinidine, cisapride, pimozideand ivabradine), coadministration is contraindicated (see below and section 4.3).

Interactions between voriconazole and other medicinal products are listed in the table below (once daily as“QD”, twice daily as “BID”, three times daily as “TID” and not determined as “ND”). The direction of thearrow for each pharmacokinetic parameter is based on the 90% confidence interval of the geometric meanratio being within (↔), below (↓) or above (↑) the 80-125% range. The asterisk (*) indicates a two-wayinteraction. AUC, AUCt and AUC0- represent area under the curve over a dosing interval, from time zero tothe time with detectable measurement and from time zero to infinity, respectively.

The interactions in the table are presented in the following order: contraindications, those requiring doseadjustment and careful clinical and/or biological monitoring, and finally those that have no significantpharmacokinetic interaction but may be of clinical interest in this therapeutic field.

Medicinal product Interaction Recommendations[Mechanism of interaction] Geometric mean changes (%) concerningcoadministration

Astemizole, cisapride, pimozide, Although not studied, increasedquinidine, terfenadine and plasma concentrations of these Contraindicated (see sectionivabradine medicinal products can lead to QTc 4.3)[CYP3A4 substrates] prolongation and rare occurrencesof torsades de pointes.

Carbamazepine and long-acting Although not studied,barbiturates (including but not carbamazepine and long-acting Contraindicated (see sectionlimited to: phenobarbital, barbiturates are likely to 4.3)mephobarbital) significantly decrease plasma[potent CYP450 inducers] voriconazole concentrations.

Efavirenz (a non-nucleosidereverse transcriptase inhibitor)[CYP450 inducer; CYP3A4inhibitor and substrate] Use of standard doses of

Efavirenz Cmax  38% voriconazole with efavirenz

Efavirenz 400 mg QD, Efavirenz AUC  44% doses of 400 mg QD or highercoadministered with Voriconazole Cmax  61% is contraindicated (seevoriconazole 200 mg BID* Voriconazole AUC  77% section 4.3).

Voriconazole may be

Compared to efavirenz 600 mg QD, coadministered with efavirenz

Efavirenz Cmax ↔ if the voriconazole

Efavirenz AUC  17% maintenance dose is increased

Efavirenz 300 mg QD, to 400 mg BID and thecoadministered with Compared to voriconazole 200 mg efavirenz dose is decreased tovoriconazole 400 mg BID* BID, 300 mg QD. When

Voriconazole C  23% voriconazole treatment ismax

Voriconazole AUC  7% stopped, the initial dose ofefavirenz should be restored(see sections 4.2 and 4.4).

Medicinal product Interaction Recommendations[Mechanism of interaction] Geometric mean changes (%) concerningcoadministration

Ergot alkaloids (including but not Although not studied, voriconazolelimited to: ergotamine and is likely to increase the plasma Contraindicated (see sectiondihydroergotamine) concentrations of ergot alkaloids 4.3)[CYP3A4 substrates] and lead to ergotism.

Lurasidone Although not studied, Contraindicated (see section[CYP3A4 substrate] voriconazole is likely to 4.3)significantly increase the plasmaconcentrations of lurasidone.

Naloxegol Although not studied, voriconazole Contraindicated (see section[CYP3A4 substrate] is likely to significantly increase the 4.3)plasma concentrations of naloxegol.

Rifabutin[potent CYP450 inducer]

Concomitant use of300 mg QD Voriconazole Cmax  69% voriconazole and rifabutin

Voriconazole AUC  78% should be avoided unless thebenefit outweighs the risk.300 mg QD (coadministered with Compared to voriconazole 200 mg The maintenance dose ofvoriconazole 350 mg BID)* BID, voriconazole may be increased

Voriconazole Cmax  4% to 5 mg/kg intravenously BID

Voriconazole AUC  32% or from 200 mg to 350 mgorally BID (100 mg to 200 mgorally BID in patients less than300 mg QD (coadministered with 40 kg) (see section 4.2).voriconazole 400 mg BID)* Rifabutin C  195% Careful monitoring of fullmax

Rifabutin AUC  331% blood counts and adverse

Compared to voriconazole 200 mg reactions to rifabutin (e.g.,

BID, uveitis) is recommended when

Voriconazole C  104% rifabutin is coadministeredmax  with voriconazole.

Voriconazole AUC 87%

Rifampicin (600 mg QD) Voriconazole Cmax  93% Contraindicated (see section[potent CYP450 inducer] Voriconazole AUC  96% 4.3)

Ritonavir (protease inhibitor)[potent CYP450 inducer;

CYP3A4 inhibitor and substrate]

Coadministration of

High dose (400 mg BID) Ritonavir Cmax and AUC ↔ voriconazole and high doses of

Voriconazole Cmax  66% ritonavir (400 mg and above

Voriconazole AUC  82% BID) is contraindicated (seesection 4.3).

Low dose (100 mg BID)* Ritonavir C  25% Coadministration ofmax

Ritonavir AUC 13% voriconazole and low-dose

Voriconazole C  24% ritonavir (100 mg BID) shouldmax

Voriconazole AUC  39% be avoided unless anassessment of the benefit/riskto the patient justifies the useof voriconazole.

Medicinal product Interaction Recommendations[Mechanism of interaction] Geometric mean changes (%) concerningcoadministration

St. John’s Wort[CYP450 inducer; P-gp inducer]300 mg TID (coadministered In an independent published study, Contraindicated (see sectionwith voriconazole 400 mg single Voriconazole AUC0-  59% 4.3)dose)

Tolvaptan Although not studied, voriconazole Contraindicated (see section[CYP3A substrate] is likely to significantly increase the 4.3)plasma concentrations of tolvaptan.

Venetoclax Although not studied, voriconazole Concomitant administration of[CYP3A substrate] is likely to significantly increase the voriconazole isplasma concentrations of contraindicated at initiationvenetoclax. and during venetoclax dosetitration phase (see section4.3). Dose reduction ofvenetoclax is required asinstructed in venetoclaxprescribing information duringsteady daily dosing; closemonitoring for signs oftoxicity is recommended.

Fluconazole (200 mg QD) Voriconazole Cmax  57% The reduced dose and/or[CYP2C9, CYP2C19 and Voriconazole AUC  79% frequency of voriconazole and

CYP3A4 inhibitor] Fluconazole Cmax ND fluconazole that would

Fluconazole AUC ND eliminate this effect have notbeen established. Monitoringfor voriconazole-associatedadverse reactions isrecommended if voriconazoleis used sequentially afterfluconazole.

Phenytoin Concomitant use of[CYP2C9 substrate and potent voriconazole and phenytoin

CYP450 inducer] should be avoided unless thebenefit outweighs the risk.300 mg QD Voriconazole Cmax  49% Careful monitoring of

Voriconazole AUC  69% phenytoin plasma levels isrecommended.

Phenytoin Cmax  67% Phenytoin may be300 mg QD (coadministered with Phenytoin AUC  81% coadministered withvoriconazole 400 mg BID)* Compared to voriconazole 200 mg voriconazole if the

BID, maintenance dose of

Voriconazole C  34% voriconazole is increased tomax

Voriconazole AUC  39% 5 mg/kg IV BID or from200 mg to 400 mg oral BID(100 mg to 200 mg oral BID inpatients less than 40 kg) (seesection 4.2).

Letermovir Voriconazole Cmax ↓ 39% If concomitant administration[CYP2C9 and CYP2C19 Voriconazole AUC0-12 ↓ 44% of voriconazole withinducer] Voriconazole C ↓ 51% letermovir cannot be avoided,monitor for loss ofvoriconazole effectiveness.

Medicinal product Interaction Recommendations[Mechanism of interaction] Geometric mean changes (%) concerningcoadministration

Flucloxacillin Significantly decreased plasma If concomitant administration[CYP450 inducer] voriconazole concentrations have of voriconazole withbeen reported. flucloxacillin cannot beavoided, monitor for potentialloss of voriconazoleeffectiveness (e.g., bytherapeutic drug monitoring);increasing the dose ofvoriconazole may be needed.

Glasdegib Although not studied, voriconazole If concomitant use cannot be[CYP3A4 substrate] is likely to increase the plasma avoided, frequent ECGconcentrations of glasdegib and monitoring is recommendedincrease risk of QTc prolongation. (see section 4.4).

Tyrosine kinase inhibitors Although not studied, voriconazole If concomitant use cannot be(including but not limited to: may increase plasma concentrations avoided, dose reduction of theaxitinib, bosutinib, cabozantinib, of tyrosine kinase inhibitors tyrosine kinase inhibitor andceritinib, cobimetinib, metabolised by CYP3A4. close clinical monitoring isdabrafenib, dasatinib, nilotinib, recommended (see sectionsunitinib, ibrutinib, ribociclib) 4.4).[CYP3A4 substrates]

Anticoagulants

Warfarin (30 mg single dose, Maximum increase in prothrombin Close monitoring ofcoadministered with 300 mg BID time was approximately 2-fold. prothrombin time or othervoriconazole) suitable anticoagulation tests is[CYP2C9 substrate] recommended, and the dose ofanticoagulants should be

Other oral coumarins Although not studied, voriconazole adjusted accordingly.(including but not limited may increase the plasmato: phenprocoumon, concentrations of coumarins thatacenocoumarol) may cause an increase in[CYP2C9 and CYP3A4 prothrombin time.substrates]

Ivacaftor Although not studied, voriconazole Dose reduction of ivacaftor is[CYP3A4 substrate] is likely to increase the plasma recommended.

concentrations of ivacaftor with riskof increased adverse reactions.

Benzodiazepines Dose reduction of[CYP3A4 substrates] benzodiazepines should be

Midazolam (0.05 mg/kg IV In an independent published study, considered.single dose) Midazolam AUC0-  3.7-fold

Midazolam (7.5 mg oral In an independent published study,single dose) Midazolam Cmax  3.8-fold

Midazolam AUC0-  10.3-fold

Other benzodiazepines Although not studied , voriconazole(including but not limited to: is likely to increase the plasmatriazolam, alprazolam) concentrations of otherbenzodiazepines that aremetabolised by CYP3A4 and leadto a prolonged sedative effect.

Medicinal product Interaction Recommendations[Mechanism of interaction] Geometric mean changes (%) concerningcoadministration

Immunosuppressants[CYP3A4 substrates]

In an independent published study, Coadministration of

Sirolimus (2 mg single dose) Sirolimus Cmax  6.6-fold voriconazole and sirolimus is

Sirolimus AUC0-  11-fold contraindicated (see section4.3).

Everolimus Although not studied, voriconazole Coadministration of[also P-gp substrate] is likely to significantly increase the voriconazole and everolimus isplasma concentrations of not recommended becauseeverolimus. voriconazole is expected tosignificantly increaseeverolimus concentrations (seesection 4.4).

Ciclosporin (in stable renal When initiating voriconazoletransplant recipients receiving Ciclosporin Cmax  13% in patients already onchronic ciclosporin therapy) Ciclosporin AUC  70% ciclosporin it is recommendedthat the ciclosporin dose behalved and ciclosporin levelcarefully monitored. Increasedciclosporin levels have beenassociated with nephrotoxicity.

When voriconazole isdiscontinued, ciclosporinlevels must be carefullymonitored and the doseincreased as necessary.

When initiating voriconazolein patients already on

Tacrolimus (0.1 mg/kg single Tacrolimus C  117% tacrolimus, it is recommendedmaxdose) Tacrolimus AUC  221% that the tacrolimus dose betreduced to a third of theoriginal dose and tacrolimuslevel carefully monitored.

Increased tacrolimus levelshave been associated withnephrotoxicity. Whenvoriconazole is discontinued,tacrolimus levels must becarefully monitored and thedose increased as necessary.

Long-Acting Opiates Dose reduction in oxycodone[CYP3A4 substrates] and other long-acting opiates

In an independent published study, metabolised by CYP3A4

Oxycodone (10 mg single dose) Oxycodone Cmax  1.7-fold (e.g., hydrocodone) should be

Oxycodone AUC0-  3.6-fold considered. Frequentmonitoring foropiate-associated adversereactions may be necessary.

Medicinal product Interaction Recommendations[Mechanism of interaction] Geometric mean changes (%) concerningcoadministration

Methadone (32-100 mg QD) R-methadone (active) Cmax  31% Frequent monitoring for[CYP3A4 substrate] R-methadone (active) AUC  47% adverse reactions and toxicity

S-methadone Cmax  65% related to methadone,

S-methadone AUC  103% including QTc prolongation, isrecommended. Dose reductionof methadone may be needed.

Non-Steroidal Anti-

Inflammatory Drugs (NSAIDs)[CYP2C9 substrates] Frequent monitoring for

S-Ibuprofen Cmax  20% adverse reactions and toxicity

Ibuprofen (400 mg single dose) S-Ibuprofen AUC0-  100% related to NSAIDs isrecommended. Dose reduction

Diclofenac (50 mg single dose) Diclofenac Cmax  114% of NSAIDs may be needed.

Diclofenac AUC0-  78%

Omeprazole (40 mg QD)* Omeprazole Cmax  116% No dose adjustment of[CYP2C19 inhibitor; CYP2C19 Omeprazole AUC  280% voriconazole is recommended.and CYP3A4 substrate] Voriconazole Cmax  15%

Voriconazole AUC  41% When initiating voriconazolein patients already receiving

Other proton pump inhibitors that omeprazole doses of 40 mg orare CYP2C19 substrates may also above, it is recommended thatbe inhibited by voriconazole and the omeprazole dose bemay result in increased plasma halved.

concentrations of these medicinalproducts.

Oral Contraceptives* Ethinylestradiol Cmax  36% Monitoring for adverse[CYP3A4 substrate; CYP2C19 Ethinylestradiol AUC  61% reactions related to oralinhibitor] Norethisterone Cmax  15% contraceptives, in addition to

Norethisterone/ethinylestradiol Norethisterone AUC  53% those for voriconazole, is(1 mg/0.035 mg QD) Voriconazole Cmax  14% recommended.

Voriconazole AUC  46%

Short-acting Opiates Dose reduction of alfentanil,[CYP3A4 substrates] fentanyl and other short-actingopiates similar in structure to

Alfentanil (20 μg/kg single dose, In an independent published study, alfentanil and metabolised bywith concomitant naloxone) Alfentanil AUC0-  6-fold CYP3A4 (e.g., sufentanil)should be considered.

Fentanyl (5 g/kg single dose) Extended and frequent

In an independent published study, monitoring for respiratory

Fentanyl AUC0-  1.34-fold depression and otheropiate-associated adversereactions is recommended.

Statins (e.g., lovastatin) Although not studied, voriconazole If concomitant administration[CYP3A4 substrates] is likely to increase the plasma of voriconazole with statinsconcentrations of statins that are metabolised by CYP3A4metabolised by CYP3A4 and could cannot be avoided, doselead to rhabdomyolysis. reduction of the statin shouldbe considered.

Sulfonylureas (including but not Although not studied, voriconazole Careful monitoring of bloodlimited to: tolbutamide, glipizide, is likely to increase the plasma glucose is recommended. Doseglyburide) concentrations of sulfonylureas and reduction of sulfonylureas[CYP2C9 substrates] cause hypoglycaemia. should be considered.

Medicinal product Interaction Recommendations[Mechanism of interaction] Geometric mean changes (%) concerningcoadministration

Vinca Alkaloids (including but Although not studied, voriconazole Dose reduction of vincanot limited to: vincristine and is likely to increase the plasma alkaloids should bevinblastine) concentrations of vinca alkaloids considered.[CYP3A4 substrates] and lead to neurotoxicity.

Other HIV Protease Inhibitors Not studied clinically. In vitro Careful monitoring for any(including but not limited to: studies show that voriconazole may occurrence of drug toxicitysaquinavir, amprenavir and inhibit the metabolism of HIV and/or lack of efficacy, andnelfinavir)* protease inhibitors and the dose adjustment may be[CYP3A4 substrates and metabolism of voriconazole may needed.inhibitors] also be inhibited by HIV proteaseinhibitors.

Other Non-Nucleoside Reverse Not studied clinically. In vitro Careful monitoring for any

Transcriptase Inhibitors studies show that the metabolism of occurrence of drug toxicity(NNRTIs) (including but not voriconazole may be inhibited by and/or lack of efficacy, andlimited to: delavirdine, NNRTIs and voriconazole may dose adjustment may benevirapine)* inhibit the metabolism of NNRTIs. needed.[CYP3A4 substrates, inhibitors The findings of the effect ofor CYP450 inducers] efavirenz on voriconazole suggestthat the metabolism of voriconazolemay be induced by an NNRTI.

Tretinoin Although not studied, voriconazole Dose adjustment of tretinoin is[CYP3A4 substrate] may increase tretinoin recommended duringconcentrations and increase risk of treatment with voriconazoleadverse reactions (pseudotumor and after its discontinuation.cerebri, hypercalcaemia).

Cimetidine (400 mg BID) Voriconazole Cmax  18% No dose adjustment[non-specific CYP450 inhibitor Voriconazole AUC  23%and increases gastric pH]

Digoxin (0.25 mg QD) Digoxin Cmax ↔ No dose adjustment[P-gp substrate] Digoxin AUC ↔

Indinavir (800 mg TID) Indinavir Cmax ↔ No dose adjustment[CYP3A4 inhibitor and Indinavir AUC ↔substrate] Voriconazole Cmax ↔

Voriconazole AUC ↔

No dose adjustment

Erythromycin (1 g BID) Voriconazole Cmax and AUC ↔[CYP3A4 inhibitor]

Azithromycin (500 mg QD) Voriconazole Cmax and AUC ↔

The effect of voriconazole on eithererythromycin or azithromycin isunknown.

Mycophenolic acid (1 g single Mycophenolic acid Cmax ↔ No dose adjustmentdose) Mycophenolic acid AUCt ↔[UDP-glucuronyl transferasesubstrate]

Medicinal product Interaction Recommendations[Mechanism of interaction] Geometric mean changes (%) concerningcoadministration

Prednisolone (60 mg single dose) Prednisolone Cmax  11% No dose adjustment[CYP3A4 substrate] Prednisolone AUC0-  34%

Patients on long-termtreatment with voriconazoleand corticosteroids (includinginhaled corticosteroids e.g.,budesonide and intranasalcorticosteroids) should becarefully monitored foradrenal cortex dysfunctionboth during treatment andwhen voriconazole isdiscontinued (see section 4.4).

Ranitidine (150 mg BID) Voriconazole Cmax and AUC ↔ No dose adjustment[increases gastric pH]

There are no adequate data on the use of VFEND in pregnant women available.

Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans isunknown.

VFEND must not be used during pregnancy unless the benefit to the mother clearly outweighs the potentialrisk to the foetus.

Women of child-bearing potential must always use effective contraception during treatment.

The excretion of voriconazole into breast milk has not been investigated. Breast-feeding must be stopped oninitiation of treatment with VFEND.

In an animal study, no impairment of fertility was demonstrated in male and female rats (see section 5.3).

VFEND has moderate influence on the ability to drive and use machines. It may cause transient andreversible changes to vision, including blurring, altered/enhanced visual perception and/or photophobia.

Patients must avoid potentially hazardous tasks, such as driving or operating machinery while experiencingthese symptoms.

The safety profile of voriconazole in adults is based on an integrated safety database of more than2,000 subjects (including 1,603 adult patients in therapeutic trials) and an additional 270 adults inprophylaxis trials. This represents a heterogeneous population, containing patients with haematologicalmalignancy, HIV-infected patients with oesophageal candidiasis and refractory fungal infections,non-neutropenic patients with candidaemia or aspergillosis and healthy volunteers.

The most commonly reported adverse reactions were visual impairment, pyrexia, rash, vomiting, nausea,diarrhoea, headache, peripheral oedema, liver function test abnormal, respiratory distress and abdominalpain.

The severity of the adverse reactions was generally mild to moderate. No clinically significant differenceswere seen when the safety data were analysed by age, race, or gender.

In the table below, since the majority of the studies were of an open nature, all causality adverse reactionsand their frequency categories in 1,873 adults from pooled therapeutic (1,603) and prophylaxis (270) studies,by system organ class, are listed.

Frequency categories are expressed as: 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 estimatedfrom the available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Undesirable effects reported in subjects receiving voriconazole:

System Very common Common Uncommon Rare Frequenc

Organ Class ≥ 1/10 ≥ 1/100 ≥ 1/1,000 to < ≥ 1/10,000 to < yto < 1/10 1/100 1/1,000 notknown(cannot beestimatedfromavailabledata)

Infections sinusitis pseudomembranoand us colitisinfestations

Neoplasms squamous cellbenign, carcinomamalignant (includingand cutaneous SCC inunspecified situ, or Bowen’s(including disease)*,**cysts andpolyps)

Blood and agranulocytosis1, bone marrow disseminatedlymphatic pancytopenia, failure, intravascularsystem thrombocytopenia2 lymphadenopathy, coagulationdisorders , leukopenia, eosinophiliaanaemia

Immune hypersensitivity anaphylactoidsystem reactiondisorders

Endocrine adrenal hyperthyroidisdisorders insufficiency, mhypothyroidism

Metabolism oedema hypoglycaemia,and nutrition peripheral hypokalaemia,disorders hyponatraemia

System Very common Common Uncommon Rare Frequenc

Organ Class ≥ 1/10 ≥ 1/100 ≥ 1/1,000 to < ≥ 1/10,000 to < yto < 1/10 1/100 1/1,000 notknown(cannot beestimatedfromavailabledata)

Psychiatric depression,disorders hallucination,anxiety, insomnia,agitation,confusional state

Nervous headache convulsion, brain oedema, hepaticsystem syncope, tremor, encephalopathy4, encephalopathydisorders hypertonia3, extrapyramidal , Guillain-Barreparaesthesia, disorder5, syndrome,somnolence, neuropathy nystagmusdizziness peripheral, ataxia,hypoaesthesia,dysgeusia

Eye disorders visual retinal optic nerve optic atrophy,impairment6 haemorrhage disorder7, corneal opacitypapilloedema8,oculogyric crisis,diplopia, scleritis,blepharitis

Ear and hypoacusis,labyrinth vertigo, tinnitusdisorders

Cardiac arrhythmia ventricular torsades dedisorders supraventricular, fibrillation, pointes,tachycardia, ventricular atrioventricularbradycardia extrasystoles, block complete,ventricular bundle branchtachycardia, block, nodalelectrocardiogram rhythm

QT prolonged,supraventriculartachycardia

Vascular hypotension, thrombophlebitis,disorders phlebitis lymphangitis

Respiratory, respiratory acute respiratorythoracic and distress9 distress syndrome,mediastinal pulmonarydisorders oedema

Gastrointestin diarrhoea, cheilitis, peritonitis,al disorders vomiting, dyspepsia, pancreatitis,abdominal constipation, swollen tongue,pain, nausea gingivitis duodenitis,gastroenteritis,glossitis

System Very common Common Uncommon Rare Frequenc

Organ Class ≥ 1/10 ≥ 1/100 ≥ 1/1,000 to < ≥ 1/10,000 to < yto < 1/10 1/100 1/1,000 notknown(cannot beestimatedfromavailabledata)

Hepatobiliary liver function jaundice, jaundice hepatic failure,disorders test abnormal cholestatic, hepatomegaly,hepatitis10 cholecystitis,cholelithiasis

Skin and rash dermatitis Stevens-Johnson toxic epidermal cutaneoussubcutaneous exfoliative, syndrome8, necrolysis8, lupustissue alopecia, rash purpura, urticaria, drug reaction erythematodisorders maculo-papular, dermatitis allergic, with sus*,pruritus, erythema, rash papular, rash eosinophilia ephelides*phototoxicity** macular, eczema and systemic , lentigo*symptoms(DRESS)8,angioedema,actinickeratosis*,pseudoporphyria, erythemamultiforme,psoriasis, drugeruption

Musculoskele back pain arthritis,tal and periostitis*,**connectivetissuedisorders

Renal and renal failure acute, renal tubularurinary haematuria necrosis,disorders proteinuria,nephritis

General pyrexia chest pain, face infusion sitedisorders and oedema11, reaction, influenzaadministratio asthenia, chills like illnessn siteconditions

Investigations blood creatinine blood ureaincreased increased, bloodcholesterolincreased

*ADR identified post-marketing

**Frequency category is based on an observational study utilising real-world data from secondary data sources in

Sweden1 Includes febrile neutropenia and neutropenia.2 Includes immune thrombocytopenic purpura.3 Includes nuchal rigidity and tetany.4 Includes hypoxic-ischaemic encephalopathy and metabolic encephalopathy.5 Includes akathisia and parkinsonism.6 See “Visual impairments” paragraph in section 4.8.7 Prolonged optic neuritis has been reported post-marketing. See section 4.4.

8 See section 4.4.9 Includes dyspnoea and dyspnoea exertional.10 Includes drug-induced liver injury, hepatitis toxic, hepatocellular injury and hepatotoxicity.11 Includes periorbital oedema, lip oedema, and oedema mouth.

Altered taste perception

In the combined data from three bioequivalence studies using the powder for oral suspension formulation,treatment-related taste perversion was recorded in 12 (14%) of subjects.

In clinical trials, visual impairments (including blurred vision, photophobia, chloropsia, chromatopsia, colourblindness, cyanopsia, eye disorder, halo vision, night blindness, oscillopsia, photopsia, scintillating scotoma,visual acuity reduced, visual brightness, visual field defect, vitreous floaters, and xanthopsia) withvoriconazole were very common. These visual impairments were transient and fully reversible, with themajority spontaneously resolving within 60 minutes and no clinically significant long-term visual effectswere observed. There was evidence of attenuation with repeated doses of voriconazole. The visualimpairments were generally mild, rarely resulted in discontinuation and were not associated with long-termsequelae. Visual impairments may be associated with higher plasma concentrations and/or doses.

The mechanism of action is unknown, although the site of action is most likely to be within the retina. In astudy in healthy volunteers investigating the impact of voriconazole on retinal function, voriconazole causeda decrease in the electroretinogram (ERG) waveform amplitude. The ERG measures electrical currents in theretina. The ERG changes did not progress over 29 days of treatment and were fully reversible on withdrawalof voriconazole.

There have been post-marketing reports of prolonged visual adverse events (see section 4.4).

Dermatological reactions were very common in patients treated with voriconazole in clinical trials, but thesepatients had serious underlying diseases and were receiving multiple concomitant medicinal products. Themajority of rashes were of mild to moderate severity. Patients have developed severe cutaneous adversereactions (SCARs), including Stevens-Johnson syndrome (SJS) (uncommon), toxic epidermal necrolysis(TEN) (rare), drug reaction with eosinophilia and systemic symptoms (DRESS) (rare) and erythemamultiforme (rare) during treatment with VFEND (see section 4.4).

If a patient develops a rash they should be monitored closely and VFEND discontinued if lesions progress.

Photosensitivity reactions such as ephelides, lentigo and actinic keratosis have been reported, especiallyduring long-term therapy (see section 4.4).

There have been reports of squamous cell carcinoma of the skin (including cutaneous SCC in situ, or

Bowen’s disease) in patients treated with VFEND for long periods of time; the mechanism has not beenestablished (see section 4.4).

The overall incidence of transaminase increases >3 xULN (not necessarily comprising an adverse event) inthe voriconazole clinical programme was 18.0% (319/1,768) in adults and 25.8% (73/283) in paediatricsubjects who received voriconazole for pooled therapeutic and prophylaxis use. Liver function testabnormalities may be associated with higher plasma concentrations and/or doses. The majority of abnormalliver function tests either resolved during treatment without dose adjustment or following dose adjustment,including discontinuation of therapy.

Voriconazole has been associated with cases of serious hepatic toxicity in patients with other seriousunderlying conditions. This includes cases of jaundice, hepatitis and hepatic failure leading to death (seesection 4.4).

In an open-label, comparative, multicenter study comparing voriconazole and itraconazole as primaryprophylaxis in adult and adolescent allogeneic HSCT recipients without prior proven or probable IFI,permanent discontinuation of voriconazole due to AEs was reported in 39.3% of subjects versus 39.6% ofsubjects in the itraconazole arm. Treatment-emergent hepatic AEs resulted in permanent discontinuation ofstudy medication for 50 subjects (21.4%) treated with voriconazole and for 18 subjects (7.1%) treated withitraconazole.

The safety of voriconazole was investigated in 288 paediatric patients aged 2 to <12 years (169) and 12 to<18 years (119) who received voriconazole for prophylaxis (183) and therapeutic use (105) in clinical trials.

The safety of voriconazole was also investigated in 158 additional paediatric patients aged 2 to <12 years incompassionate use programs. Overall, the safety profile of voriconazole in paediatric population was similarto that in adults. However, a trend towards a higher frequency of liver enzyme elevations, reported asadverse events in clinical trials was observed in paediatric patients as compared to adults (14.2%transaminases increased in paediatrics compared to 5.3% in adults). Post-marketing data suggest there mightbe a higher occurrence of skin reactions (especially erythema) in the paediatric population compared toadults. In the 22 patients less than 2 years old who received voriconazole in a compassionate use programme,the following adverse reactions (for which a relationship to voriconazole could not be excluded) werereported: photosensitivity reaction (1), arrhythmia (1), pancreatitis (1), blood bilirubin increased (1), hepaticenzymes increased (1), rash (1) and papilloedema (1). There have been post-marketing reports of pancreatitisin paediatric patients.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are askedto report any suspected adverse reactions via the national reporting system listed in Appendix V.

In clinical trials there were 3 cases of accidental overdose. All occurred in paediatric patients, who receivedup to five times the recommended intravenous dose of voriconazole. A single adverse reaction ofphotophobia of 10 minutes duration was reported.

There is no known antidote to voriconazole.

Voriconazole is haemodialysed with a clearance of 121 ml/min. In an overdose, haemodialysis may assist inthe removal of voriconazole from the body.

Pharmacotherapeutic group: Antimycotics for systemic use, triazole derivatives, ATC code: J02A C03

Voriconazole is a triazole antifungal agent. The primary mode of action of voriconazole is the inhibition offungal cytochrome P450-mediated 14 alpha-lanosterol demethylation, an essential step in fungal ergosterolbiosynthesis. The accumulation of 14 alpha-methyl sterols correlates with the subsequent loss of ergosterolin the fungal cell membrane and may be responsible for the antifungal activity of voriconazole. Voriconazolehas been shown to be more selective for fungal cytochrome P-450 enzymes than for various mammaliancytochrome P-450 enzyme systems.

In 10 therapeutic studies, the median for the average and maximum plasma concentrations in individualsubjects across the studies was 2425 ng/ml (inter-quartile range 1193 to 4380 ng/ml) and 3742 ng/ml(inter-quartile range 2027 to 6302 ng/ml), respectively. A positive association between mean, maximum orminimum plasma voriconazole concentration and efficacy in therapeutic studies was not found and thisrelationship has not been explored in prophylaxis studies.

Pharmacokinetic-Pharmacodynamic analyses of clinical trial data identified positive associations betweenplasma voriconazole concentrations and both liver function test abnormalities and visual disturbances. Doseadjustments in prophylaxis studies have not been explored.

In vitro, voriconazole displays broad-spectrum antifungal activity with antifungal potency against Candidaspecies (including fluconazole-resistant C. krusei and resistant strains of C. glabrata and C. albicans) andfungicidal activity against all Aspergillus species tested. In addition voriconazole shows in vitro fungicidalactivity against emerging fungal pathogens, including those such as Scedosporium or Fusarium which havelimited susceptibility to existing antifungal agents.

Clinical efficacy defined as partial or complete response, has been demonstrated for Aspergillus spp.including A. flavus, A. fumigatus, A. terreus, A. niger, A. nidulans; Candida spp., including C. albicans, C.glabrata, C. krusei, C. parapsilosis and C. tropicalis; and limited numbers of C. dubliniensis, C.inconspicua, and C. guilliermondii, Scedosporium spp., including S. apiospermum, S. prolificans; and

Other treated fungal infections (often with either partial or complete response) included isolated cases of

Alternaria spp., Blastomyces dermatitidis, Blastoschizomyces capitatus, Cladosporium spp.,Coccidioidesimmitis, Conidiobolus coronatus, Cryptococcus neoformans, Exserohilum rostratum, Exophiala spinifera,

Fonsecaea pedrosoi, Madurella mycetomatis, Paecilomyces lilacinus, Penicillium spp. including P.marneffei, Phialophora richardsiae, Scopulariopsis brevicaulis and Trichosporon spp. including T. beigeliiinfections.

In vitro activity against clinical isolates has been observed for Acremonium spp., Alternaria spp., Bipolarisspp., Cladophialophora spp., and Histoplasma capsulatum, with most strains being inhibited byconcentrations of voriconazole in the range 0.05 to 2 µg/ml.

In vitro activity against the following pathogens has been shown, but the clinical significance is unknown:

Curvularia spp. and Sporothrix spp.

Specimens for fungal culture and other relevant laboratory studies (serology, histopathology) should beobtained prior to therapy to isolate and identify causative organisms. Therapy may be instituted before theresults of the cultures and other laboratory studies are known; however, once these results become available,anti-infective therapy should be adjusted accordingly.

The species most frequently involved in causing human infections include C. albicans, C. parapsilosis, C.tropicalis, C. glabrata and C. krusei, all of which usually exhibit minimal inhibitory concentration (MICs) ofless than 1 mg/L for voriconazole.

However, the in vitro activity of voriconazole against Candida species is not uniform. Specifically, for

C. glabrata, the MICs of voriconazole for fluconazole-resistant isolates are proportionally higher than arethose of fluconazole-susceptible isolates. Therefore, every attempt should be made to identify Candida tospecies level. If antifungal susceptibility testing is available, the MIC results may be interpreted usingbreakpoint criteria established by European Committee on Antimicrobial Susceptibility Testing (EUCAST).

EUCAST Breakpoints

Candida and Aspergillus species Minimal Inhibitory Concentration (MIC)breakpoint (mg/L)≤S (Susceptible) >R (Resistant)

Candida albicans1 0.06 0.25

Candida dubliniensis1 0.06 0.25

Candida glabrata Insufficient evidence (IE) IE

Candida krusei IE IE

Candida parapsilosis1 0.125 0.25

Candida tropicalis1 0.125 0.25

Candida guilliermondii2 IE IE

Non-species related breakpoints for Candida3 IE IE

Aspergillus fumigatus4 1 1

Aspergillus nidulans4 1 1

Aspergillus flavus IE5 IE5

Aspergillus niger IE5 IE5

Aspergillus terreus IE5 IE5

Non-species related breakpoints6 IE IE1 Strains with MIC values above the Susceptible/Intermediate (S/I) breakpoint are rare or not yet reported.

The identification and antifungal susceptibility tests on any such isolate must be repeated and if the resultis confirmed the isolate sent to a reference laboratory. Until there is evidence regarding clinical responsefor confirmed isolates with MIC above the current resistant breakpoint they should be reported resistant.

A clinical response of 76% was achieved in infections caused by the species listed below when MICs werelower than or equal to the epidemiological cut-offs. Therefore, wild type populations of C. albicans, C.dubliniensis, C. parapsilosis and C. tropicalis are considered susceptible.2 The epidemiological cut-off values (ECOFFs) for these species are in general higher than for C.albicans.3 Non-species related breakpoints have been determined mainly on the basis of PK/PD data and areindependent of MIC distributions of specific Candida species. They are for use only for organisms that donot have specific breakpoints.4 Area of technical uncertainty (ATU) is 2. Report as R with the following comment: 'In some clinicalsituations (non-invasive infections forms) voriconazole can be used provided sufficient exposure isensured'.5 The ECOFFs for these species are in general one two-fold dilution higher than for A. fumigatus.6 Non-species related breakpoints have not been determined.

Successful outcome in this section is defined as complete or partial response.

Aspergillus infections - efficacy in aspergillosis patients with poor prognosis

Voriconazole has in vitro fungicidal activity against Aspergillus spp. The efficacy and survival benefit ofvoriconazole versus conventional amphotericin B in the primary treatment of acute invasive aspergillosiswas demonstrated in an open, randomised, multicentre study in 277 immunocompromised patients treatedfor 12 weeks. Voriconazole was administered intravenously with a loading dose of 6 mg/kg every 12 hoursfor the first 24 hours followed by a maintenance dose of 4 mg/kg every 12 hours for a minimum of 7 days.

Therapy could then be switched to the oral formulation at a dose of 200 mg every 12 hours. Median durationof IV voriconazole therapy was 10 days (range 2-85 days). After IV voriconazole therapy, the medianduration of oral voriconazole therapy was 76 days (range 2-232 days).

A satisfactory global response (complete or partial resolution of all attributable symptoms, signs,radiographic/bronchoscopic abnormalities present at baseline) was seen in 53% of voriconazole-treatedpatients compared to 31% of patients treated with comparator. The 84-day survival rate for voriconazole wasstatistically significantly higher than that for the comparator and a clinically and statistically significantbenefit was shown in favour of voriconazole for both time to death and time to discontinuation due totoxicity.

This study confirmed findings from an earlier, prospectively designed study where there was a positiveoutcome in subjects with risk factors for a poor prognosis, including graft versus host disease, and, inparticular, cerebral infections (normally associated with almost 100% mortality).

The studies included cerebral, sinus, pulmonary and disseminated aspergillosis in patients with bone marrowand solid organ transplants, haematological malignancies, cancer and AIDS.

The efficacy of voriconazole compared to the regimen of amphotericin B followed by fluconazole in theprimary treatment of candidaemia was demonstrated in an open, comparative study. Three hundred andseventy non-neutropenic patients (above 12 years of age) with documented candidaemia were included in thestudy, of whom 248 were treated with voriconazole. Nine subjects in the voriconazole group and 5 in theamphotericin B followed by fluconazole group also had mycologically proven infection in deep tissue.

Patients with renal failure were excluded from this study. The median treatment duration was 15 days in bothtreatment arms. In the primary analysis, successful response as assessed by a Data Review Committee(DRC) blinded to study medicinal product was defined as resolution/improvement in all clinical signs andsymptoms of infection with eradication of Candida from blood and infected deep tissue sites 12 weeks afterthe end of therapy (EOT). Patients who did not have an assessment 12 weeks after EOT were counted asfailures. In this analysis a successful response was seen in 41% of patients in both treatment arms.

In a secondary analysis, which utilised DRC assessments at the latest evaluable time point (EOT, or 2, 6, or12 weeks after EOT) voriconazole and the regimen of amphotericin B followed by fluconazole hadsuccessful response rates of 65% and 71%, respectively.

The Investigator’s assessment of successful outcome at each of these time points is shown in the followingtable.

Timepoint Voriconazole Amphotericin B → fluconazole(N=248) (N=122)

EOT 178 (72%) 88 (72%)2 weeks after EOT 125 (50%) 62 (51%)6 weeks after EOT 104 (42%) 55 (45%)12 weeks after EOT 104 (42%) 51 (42%)

Serious refractory Candida infections

The study comprised 55 patients with serious refractory systemic Candida infections (includingcandidaemia, disseminated and other invasive candidiasis) where prior antifungal treatment, particularly withfluconazole, had been ineffective. Successful response was seen in 24 patients (15 complete, 9 partialresponses). In fluconazole-resistant non-albicans species, a successful outcome was seen in 3/3 C. krusei(complete responses) and 6/8 C. glabrata (5 complete, 1 partial response) infections. The clinical efficacydata were supported by limited susceptibility data.

Voriconazole was shown to be effective against the following rare fungal pathogens:

Scedosporium spp.: Successful response to voriconazole therapy was seen in 16 (6 complete, 10 partialresponses) of 28 patients with S. apiospermum and in 2 (both partial responses) of 7 patients with S.prolificans infection. In addition, a successful response was seen in 1 of 3 patients with infections caused bymore than one organism including Scedosporium spp.

Fusarium spp.: Seven (3 complete, 4 partial responses) of 17 patients were successfully treated with voriconazole.

Of these 7 patients, 3 had eye, 1 had sinus, and 3 had disseminated infection. Four additional patients withfusariosis had an infection caused by several organisms; 2 of them had a successful outcome.

The majority of patients receiving voriconazole treatment of the above mentioned rare infections wereintolerant of, or refractory to, prior antifungal therapy.

Primary Prophylaxis of Invasive Fungal Infections - Efficacy in HSCT recipients without prior proven orprobable IFI

Voriconazole was compared to itraconazole as primary prophylaxis in an open-label, comparative,multicenter study of adult and adolescent allogeneic HSCT recipients without prior proven or probable IFI.

Success was defined as the ability to continue study drug prophylaxis for 100 days after HSCT (withoutstopping for >14 days) and survival with no proven or probable IFI for 180 days after HSCT. The modifiedintent-to-treat (MITT) group included 465 allogeneic HSCT recipients with 45% of patients having AML.

From all patients 58% were subject to myeloablative conditions regimens. Prophylaxis with study drug wasstarted immediately after HSCT: 224 received voriconazole and 241 received itraconazole. The medianduration of study drug prophylaxis was 96 days for voriconazole and 68 days for itraconazole in the MITTgroup.

Success rates and other secondary endpoints are presented in the table below:

Study Endpoints Voriconazole Itraconazole Difference in P-Value

N=224 N=241 proportions and the95% confidence interval(CI)

Success at day 180* 109 (48.7%) 80 (33.2%) 16.4% (7.7%, 25.1%)** 0.0002**

Success at day 100 121 (54.0%) 96 (39.8%) 15.4% (6.6%, 24.2%)** 0.0006**

Completed at least 100 days of 120 (53.6%) 94 (39.0%) 14.6% (5.6%, 23.5%) 0.0015study drug prophylaxis

Survived to day 180 184 (82.1%) 197 (81.7%) 0.4% (-6.6%, 7.4%) 0.9107

Developed proven or probable 3 (1.3%) 5 (2.1%) -0.7% (-3.1%, 1.6%) 0.5390

IFI to day 180

Developed proven or probable 2 (0.9%) 4 (1.7%) -0.8% (-2.8%, 1.3%) 0.4589

IFI to day 100

Developed proven or probable 0 3 (1.2%) -1.2% (-2.6%, 0.2%) 0.0813

IFI while on study drug

* Primary endpoint of the study

** Difference in proportions, 95% CI and p-values obtained after adjustment for randomization

The breakthrough IFI rate to Day 180 and the primary endpoint of the study, which is Success at Day 180,for patients with AML and myeloablative conditioning regimens respectively, is presented in the tablebelow:

AML

Study endpoints Voriconazole Itraconazole Difference in proportions and(N=98) (N=109) the 95% confidence interval(CI)

Breakthrough IFI - Day 180 1 (1.0%) 2 (1.8%) -0.8% (-4.0%, 2.4%) **

Success at Day 180* 55 (56.1%) 45 (41.3%) 14.7% (1.7%, 27.7%)***

* Primary endpoint of study

** Using a margin of 5%, non inferiority is demonstrated

***Difference in proportions, 95% CI obtained after adjustment for randomization

Myeloablative conditioning regimens

Study endpoints Voriconazole Itraconazole Difference in proportions and(N=125) (N=143) the 95% confidence interval(CI)

Breakthrough IFI - Day 180 2 (1.6%) 3 (2.1%) -0.5% (-3.7%, 2.7%) **

Success at Day 180* 70 (56.0%) 53 (37.1%) 20.1% (8.5%, 31.7%)***

* Primary endpoint of study

** Using a margin of 5%, non inferiority is demonstrated

*** Difference in proportions, 95% CI obtained after adjustment for randomization

Secondary Prophylaxis of IFI - Efficacy in HSCT recipients with prior proven or probable IFI

Voriconazole was investigated as secondary prophylaxis in an open-label, non-comparative, multicenterstudy of adult allogeneic HSCT recipients with prior proven or probable IFI. The primary endpoint was therate of occurrence of proven and probable IFI during the first year after HSCT. The MITT group included40 patients with prior IFI, including 31 with aspergillosis, 5 with candidiasis, and 4 with other IFI. Themedian duration of study drug prophylaxis was 95.5 days in the MITT group.

Proven or probable IFIs developed in 7.5% (3/40) of patients during the first year after HSCT, including onecandidemia, one scedosporiosis (both relapses of prior IFI), and one zygomycosis. The survival rate at

Day 180 was 80.0% (32/40) and at 1 year was 70.0% (28/40).

In clinical trials, 705 patients received voriconazole therapy for greater than 12 weeks, with 164 patientsreceiving voriconazole for over 6 months.

Fifty-three paediatric patients aged 2 to <18 years were treated with voriconazole in two prospective,open-label, non-comparative, multi-center clinical trials. One study enrolled 31 patients with possible,proven or probable invasive aspergillosis (IA), of whom 14 patients had proven or probable IA and wereincluded in the MITT efficacy analyses. The second study enrolled 22 patients with invasive candidiasisincluding candidaemia (ICC), and esophageal candidiasis (EC) requiring either primary or salvage therapy,of whom 17 were included in the MITT efficacy analyses. For patients with IA the overall rates of globalresponse at 6 weeks were 64.3% (9/14), the global response rate was 40% (2/5) for patients 2 to <12 yearsand 77.8% (7/9) for patients 12 to <18 years of age. For patients with ICC the global response rate at EOTwas 85.7% (6/7) and for patients with EC the global response rate at EOT was 70% (7/10). The overall rateof response (ICC and EC combined) was 88.9% (8/9) for 2 to <12 years old and 62.5% (5/8) for 12 to <18years old.

A placebo-controlled, randomized, single-dose, crossover study to evaluate the effect on the QTc interval ofhealthy volunteers was conducted with three oral doses of voriconazole and ketoconazole. Theplacebo-adjusted mean maximum increases in QTc from baseline after 800, 1200 and 1600 mg ofvoriconazole were 5.1, pct. 4.8, and 8.2 msec, respectively and 7.0 msec for ketoconazole 800 mg. No subject inany group had an increase in QTc of ≥ 60 msec from baseline. No subject experienced an interval exceedingthe potentially clinically-relevant threshold of 500 msec.

The pharmacokinetics of voriconazole have been characterised in healthy subjects, special populations andpatients. During oral administration of 200 mg or 300 mg twice daily for 14 days in patients at risk ofaspergillosis (mainly patients with malignant neoplasms of lymphatic or haematopoietic tissue), the observedpharmacokinetic characteristics of rapid and consistent absorption, accumulation and non-linearpharmacokinetics were in agreement with those observed in healthy subjects.

The pharmacokinetics of voriconazole are non-linear due to saturation of its metabolism. Greater thanproportional increase in exposure is observed with increasing dose. It is estimated that, on average,increasing the oral dose from 200 mg twice daily to 300 mg twice daily leads to a 2.5-fold increase inexposure (AUCτ). The oral maintenance dose of 200 mg (or 100 mg for patients less than 40 kg) achieves avoriconazole exposure similar to 3 mg/kg IV. A 300 mg (or 150 mg for patients less than 40 kg) oralmaintenance dose achieves an exposure similar to 4 mg/kg IV. When the recommended intravenous or oralloading dose regimens are administered, plasma concentrations close to steady state are achieved within thefirst 24 hours of dosing. Without the loading dose, accumulation occurs during twice daily multiple dosingwith steady-state plasma voriconazole concentrations being achieved by Day 6 in the majority of subjects.

Voriconazole is rapidly and almost completely absorbed following oral administration, with maximumplasma concentrations (Cmax) achieved 1-2 hours after dosing. The absolute bioavailability of voriconazoleafter oral administration is estimated to be 96%. Bioequivalence was established between the 200 mg tabletand the 40 mg/ml oral suspension when administered as a 200 mg dose. When multiple doses ofvoriconazole oral suspension are administered with high fat meals, Cmax and AUCτ are reduced by 58% and37% respectively. The absorption of voriconazole is not affected by changes in gastric pH.

The volume of distribution at steady state for voriconazole is estimated to be 4.6 L/kg, suggesting extensivedistribution into tissues. Plasma protein binding is estimated to be 58%. Cerebrospinal fluid samples fromeight patients in a compassionate programme showed detectable voriconazole concentrations in all patients.

In vitro studies showed that voriconazole is metabolised by the hepatic cytochrome P450 isoenzymes

CYP2C19, CYP2C9 and CYP3A4.

The inter-individual variability of voriconazole pharmacokinetics is high.

In vivo studies indicated that CYP2C19 is significantly involved in the metabolism of voriconazole. Thisenzyme exhibits genetic polymorphism. For example, 15-20% of Asian populations may be expected to bepoor metabolisers. For Caucasians and Blacks the prevalence of poor metabolisers is 3-5%. Studiesconducted in Caucasian and Japanese healthy subjects have shown that poor metabolisers have, on average,4-fold higher voriconazole exposure (AUCτ) than their homozygous extensive metaboliser counterparts.

Subjects who are heterozygous extensive metabolisers have on average 2-fold higher voriconazole exposurethan their homozygous extensive metaboliser counterparts.

The major metabolite of voriconazole is the N-oxide, which accounts for 72% of the circulating radiolabelledmetabolites in plasma. This metabolite has minimal antifungal activity and does not contribute to the overallefficacy of voriconazole.

Voriconazole is eliminated via hepatic metabolism with less than 2% of the dose excreted unchanged in theurine.

After administration of a radiolabelled dose of voriconazole, approximately 80% of the radioactivity isrecovered in the urine after multiple intravenous dosing and 83% in the urine after multiple oral dosing. Themajority (>94%) of the total radioactivity is excreted in the first 96 hours after both oral and intravenousdosing.

The terminal half-life of voriconazole depends on dose and is approximately 6 hours at 200 mg (orally).

Because of non-linear pharmacokinetics, the terminal half-life is not useful in the prediction of theaccumulation or elimination of voriconazole.

In an oral multiple-dose study, Cmax and AUCτ for healthy young females were 83% and 113% higher,respectively, than in healthy young males (18-45 years). In the same study, no significant differences in Cmaxand AUCτ were observed between healthy elderly males and healthy elderly females (≥65 years).

In the clinical programme, no dosage adjustment was made on the basis of gender. The safety profile andplasma concentrations observed in male and female patients were similar. Therefore, no dosage adjustmentbased on gender is necessary.

In an oral multiple-dose study Cmax and AUCτ in healthy elderly males (≥65 years) were 61% and 86%higher, respectively, than in healthy young males (18-45 years). No significant differences in Cmax and AUCτwere observed between healthy elderly females (≥65 years) and healthy young females (18-45 years).

In the therapeutic studies no dosage adjustment was made on the basis of age. A relationship between plasmaconcentrations and age was observed. The safety profile of voriconazole in young and elderly patients wassimilar and, therefore, no dosage adjustment is necessary for the elderly (see section 4.2).

The recommended doses in children and adolescent patients are based on a population pharmacokineticanalysis of data obtained from 112 immunocompromised paediatric patients aged 2 to <12 years and 26immunocompromised adolescent patients aged 12 to <17 years. Multiple intravenous doses of 3, 4, 6, 7 and8 mg/kg twice daily and multiple oral doses (using the powder for oral suspension) of 4 mg/kg, 6 mg/kg, and200 mg twice daily were evaluated in 3 paediatric pharmacokinetic studies. Intravenous loading doses of6 mg/kg IV twice daily on day 1 followed by 4 mg/kg intravenous dose twice daily and 300 mg oral tabletstwice daily were evaluated in one adolescent pharmacokinetic study. Larger inter-subject variability wasobserved in paediatric patients compared to adults.

A comparison of the paediatric and adult population pharmacokinetic data indicated that the predicted totalexposure (AUC) in children following administration of a 9 mg/kg IV loading dose was comparable to thatin adults following a 6 mg/kg IV loading dose. The predicted total exposures in children following IVmaintenance doses of 4 and 8 mg/kg twice daily were comparable to those in adults following 3 and 4 mg/kg

IV twice daily, respectively. The predicted total exposure in children following an oral maintenance dose of9 mg/kg (maximum of 350 mg) twice daily was comparable to that in adults following 200 mg oral twicedaily. An 8 mg/kg intravenous dose will provide voriconazole exposure approximately 2-fold higher than a9 mg/kg oral dose.

The higher intravenous maintenance dose in paediatric patients relative to adults reflects the higherelimination capacity in paediatric patients due to a greater liver mass to body mass ratio. Oral bioavailabilitymay, however, be limited in paediatric patients with malabsorption and very low body weight for their age.

In that case, intravenous voriconazole administration is recommended.

Voriconazole exposures in the majority of adolescent patients were comparable to those in adults receivingthe same dosing regimens. However, lower voriconazole exposure was observed in some young adolescentswith low body weight compared to adults. It is likely that these subjects may metabolise voriconazole moresimilarly to children than to adults. Based on the population pharmacokinetic analysis, 12- to 14-year-oldadolescents weighing less than 50 kg should receive children’s doses (see section 4.2).

In an oral single-dose (200 mg) study in subjects with normal renal function and mild (creatinine clearance41-60 ml/min) to severe (creatinine clearance <20 ml/min) renal impairment, the pharmacokinetics ofvoriconazole were not significantly affected by renal impairment. The plasma protein binding ofvoriconazole was similar in subjects with different degrees of renal impairment (see sections 4.2 and 4.4).

After an oral single-dose (200 mg), AUC was 233% higher in subjects with mild to moderate hepaticcirrhosis (Child-Pugh A and B) compared with subjects with normal hepatic function. Protein binding ofvoriconazole was not affected by impaired hepatic function.

In an oral multiple-dose study, AUCτ was similar in subjects with moderate hepatic cirrhosis (Child-Pugh B)given a maintenance dose of 100 mg twice daily and subjects with normal hepatic function given 200 mgtwice daily. No pharmacokinetic data are available for patients with severe hepatic cirrhosis (Child-Pugh C)(see sections 4.2 and 4.4).

Repeated-dose toxicity studies with voriconazole indicated the liver to be the target organ. Hepatotoxicityoccurred at plasma exposures similar to those obtained at therapeutic doses in humans, in common withother antifungal agents. In rats, mice and dogs, voriconazole also induced minimal adrenal changes.

Conventional studies of safety pharmacology, genotoxicity or carcinogenic potential did not reveal a specialhazard for humans.

In reproduction studies, voriconazole was shown to be teratogenic in rats and embryotoxic in rabbits atsystemic exposures equal to those obtained in humans with therapeutic doses. In the pre- and post-nataldevelopment study in rats at exposures lower than those obtained in humans with therapeutic doses,voriconazole prolonged the duration of gestation and labour and produced dystocia with consequent maternalmortality and reduced perinatal survival of pups. The effects on parturition are probably mediated byspecies-specific mechanisms, involving reduction of oestradiol levels, and are consistent with those observedwith other azole antifungal agents. Voriconazole administration induced no impairment of male or femalefertility in rats at exposures similar to those obtained in humans at therapeutic doses.

Sucrose

Silica Colloidal Anhydrous

Titanium Dioxide (E171)

Xanthan Gum

Sodium Citrate

Citric Acid Anhydrous

Sodium Benzoate (E211)

Natural Orange Flavour

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

2 years

The shelf life of the constituted suspension is 14 days.

Constituted suspension: Do not store above 30°C; do not refrigerate or freeze.

Store in a refrigerator (2°C - 8°C).

For storage conditions after constitution, see section 6.3.

Keep the container tightly closed.

One 100 ml high-density polyethylene (HDPE) bottle (with a polypropylene child resistant closure) contains45 g of powder for oral suspension. A measuring cup (graduated to indicate 23 ml), 5 ml oral syringe and apress-in bottle adaptor are also provided.

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

Constitution instructions:1. Tap the bottle to release the powder.2. Add 2 measuring cups of water, providing a total volume of 46 ml.3. Shake the closed bottle vigorously for about 1 minute.4. Remove child-resistant cap. Press bottle adaptor into the neck of the bottle.5. Replace the cap.6. Write the date of expiration of the constituted suspension on the bottle label (the shelf-life of theconstituted suspension is 14 days).

Following constitution, the volume of the suspension is 75 ml, providing a usable volume of 70 ml.

Shake the closed bottle of constituted suspension for approximately 10 seconds before each use.

Once constituted, VFEND oral suspension should only be administered using the oral syringe supplied witheach pack. Refer to the patient leaflet for more detailed instructions for use.

Pfizer Europe MA EEIG

Boulevard de la Plaine 171050 Bruxelles

Belgium

EU/1/02/212/026

Date of first authorisation: 19 March 2002

Date of latest renewal: 21 February 2012

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