Leaflet VORICONAZOLE ACCORD 200mg film-coated tablets

Each tablet contains 50 mg voriconazole.

Each tablet contains 63 mg lactose (as monohydrate).

Each tablet contains 200 mg voriconazole.

Each tablet contains 251 mg lactose (as monohydrate).

For the full list of excipients, see section 6.1.

White to off white, round, approximate 7.0 mm in diameter, film-coated tablets, debossed with ‘V50’on one side and plain on the other side.

White to off white, oval, approximately 15.6 mm in length and 7.8 mm in width, film-coated tablets,debossed with ‘V200’ on one side and plain on the other side.

Voriconazole Accord, is a broad spectrum, triazole antifungal agent and is indicated in adults andchildren aged 2 years and 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.

Voriconazole Accord 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 bemonitored and corrected, if necessary, prior to initiation and during voriconazole therapy (seesection 4.4).

Voriconazole is also available as 200mg powder for solution for infusion and 40 mg/ml powder fororal suspension.

Therapy must be initiated with the specified loading dose regimen of either intravenous or oralvoriconazole to achieve plasma concentrations on Day 1 that are close to steady state. On the basis ofthe high oral bioavailability (96 %; see section 5.2), switching between intravenous and oraladministration is appropriate when clinically indicated.

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

Intravenous Oral

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

Loading dose 6 mg/kg every 12 400 mg every 12 hours 200 mg every 12 hoursregimen hours(first 24 hours)

Maintenance dose 4 mg/kg twice 200 mg twice daily 100 mg twice daily(after first 24 dailyhours)

*This also applies to patients aged 15 years and older.

Treatment duration should be as short as possible depending on the patient’s clinical andmycological response. Long term exposure to voriconazole greater than 180 days (6 months)requires careful assessment of 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 300 mg twicedaily for oral administration. For patients less than 40 kg the oral dose may be increased to 150 mgtwice daily.

If patient is unable to tolerate treatment at a higher dose, reduce the oral dose by 50 mg steps to the200 mg twice daily (or 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 metabolize voriconazolemore similarly to children than to adults.

The recommended dosing regimen is as follows:

Intravenous Oral

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

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

Note: Based on a population pharmacokinetic analysis in 112 immunocompromised paediatricpatients aged 2 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 beconsidered only after there is a significant clinical improvement. It should be noted that an 8 mg/kgintravenous dose will provide voriconazole exposure approximately 2-fold higher than a 9 mg/kg oraldose.

These oral dose recommendations for children are based on studies in which voriconazole wasadministered as the powder for oral suspension. Bioequivalence between the powder for oralsuspension and tablets has not been investigated in a paediatric population. Considering the assumedlimited gastro-enteric transit time in paediatric patients, the absorption of tablets may be different inpaediatric compared to adult patients. It is therefore recommended to use the oral suspensionformulation 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 to14 years and <50 kg])

If patient response to treatment is inadequate, the dose may be increased by 1 mg/kg steps (or by50 mg steps if the maximum oral dose of 350 mg was used initially). If patient is unable to toleratetreatment, reduce the dose by 1 mg/kg steps (or by 50 mg steps if the maximum oral dose of 350 mgwas used initially).

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

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 fungalinfection (IFI) as defined by neutropenia or immunosuppression. It may only be continued up to180 days after transplantation in case of continuing immunosuppression or graft versus host disease(GvHD) (see section 5.1).

Dosage

The recommended dosing regimen for prophylaxis is the same as for treatment in the respective agegroups. Please refer to the treatment tables above.

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

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

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)

Phenytoin may be coadministered with voriconazole if the maintenance dose of voriconazole isincreased from 200 mg to 400 mg orally, twice daily (100 mg to 200 mg orally, twice daily in patientsless than 40 kg), see sections 4.4 and 4.5.

The combination of voriconazole with rifabutin should, if possible be avoided. However, if thecombination is strictly needed, the maintenance dose of voriconazole may be increased from 200 mgto 350 mg orally, twice daily (100 mg to 200 mg orally, twice daily in patients less than 40 kg), seesections 4.4 and 4.5.

Efavirenz may be coadministered with voriconazole if the maintenance dose of voriconazole isincreased to 400 mg every 12 hours and the efavirenz dose is reduced by 50 %, i.e. to 300 mg oncedaily. When treatment with voriconazole is stopped, the initial dosage of efavirenz should be restored(see sections 4.4 and 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 doesnot remove 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 behalved in patients with mild to moderate hepatic cirrhosis (Child-Pugh A and B) receivingvoriconazole (see section 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 voriconazole in patients with abnormal liver function tests(aspartate transaminase [AST], alanine transaminase [ALT], alkaline phosphatase [ALP], or totalbilirubin >5 times the upper limit of normal).

Voriconazole has been associated with elevations in liver function tests and clinical signs of liverdamage, such as jaundice, and must only be used in patients with severe hepatic impairment if thebenefit outweighs the potential risk. Patients with severe hepatic impairment must be carefullymonitored for drug toxicity (see section 4.8).

The safety and efficacy of voriconazole in children below 2 years has not been established. Currentlyavailable data are described in sections 4.8 and 5.1 but no recommendation on a posology can bemade.

Voriconazole Accord film-coated tablets are to be taken at least one hour before, or one hourfollowing, a meal.

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

Coadministration of voriconazole is contraindicated with medicinal products that are highly dependenton CYP3A4 for metabolism, and for which elevated plasma concentrations are associated with seriousand/or life-threatening reactions (see section 4.5):

* Terfenadine, Astemizole

* Cisapride

* Pimozide, Lurasidone

* Quinidine

* Ivabradine

* Ergot alkaloids (e.g., ergotamine, dihydroergotamine)

* Sirolimus

* Naloxegol

* Tolvaptan

* Finerenone

* Venetoclax: Coadministration contraindicated at initiation and during venetoclax dose titrationphase.

Coadministration of voriconazole is contraindicated with medicinal products that induce CYP3A4 andsignificantly reduce voriconazole plasma concentrations:

* Coadministration with rifampicin, carbamazepine, long-acting barbiturates e.g., phenobarbitaland St. John’s Wort (see section 4.5).

* Efavirenz:

Coadministration of standard doses of voriconazole with efavirenz doses of 400 mg once dailyor higher is contraindicated, (see section 4.5). For information on coadministration ofvoriconazole and lower doses of efavirenz see section 4.4.

* Ritonavir

Coadministration with high-dose ritonavir (400 mg and above twice daily) is contraindicated(see section 4.5). For information on coadministration with lower doses of ritonavir seesection 4.4.

Caution should be used in prescribing Voriconazole Accord to patients with hypersensitivity to otherazoles (see also section 4.8).

Voriconazole has been associated with QTc interval prolongation. There have been rare cases oftorsades de pointes in patients taking voriconazole who had risk factors, such as history of cardiotoxicchemotherapy, cardiomyopathy, hypokalaemia and concomitant medicinal products that may havebeen contributory. Voriconazole should be administered with caution to patients with potentiallyproarrhythmic 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 disturbancessuch as hypokalaemia, hypomagnesaemia and hypocalcaemia should be monitored andcorrected, if necessary, prior to initiation and during voriconazole therapy (see section 4.2). Astudy has been conducted in healthy volunteers which examined the effect on QTc interval ofsingle doses of voriconazole up to 4 times the usual daily dose. No subject experienced aninterval exceeding the potentially 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 andjaundice, have occurred among patients with no other identifiable risk factors. Liver dysfunction hasusually been reversible on discontinuation of therapy (see section 4.8).

Patients receiving Voriconazole Accord must be carefully monitored for hepatic toxicity. Clinicalmanagement should include laboratory evaluation of hepatic function (specifically AST and ALT) atthe initiation of treatment with Voriconazole Accord and at least weekly for the first month oftreatment. Treatment duration should be as short as possible; however, if based on the benefit-riskassessment the treatment is continued (see section 4.2), monitoring frequency can be reduced tomonthly if there are no changes in the liver function tests.

If the liver function tests become markedly elevated, Voriconazole Accord should be discontinued,unless the medical judgment 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 Voriconazole Accord has been associated with phototoxicity including reactions such asephelides, 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

Voriconazole Accord treatment and use measures such as protective clothing and sunscreen with highsun 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) has beenreported in patients, some of whom have reported prior phototoxic reactions. If phototoxic reactionsoccur multidisciplinary advice should be sought, Voriconazole Accord discontinuation and use ofalternative antifungal agents should be considered and the patient should be referred to adermatologist. If Voriconazole Accord is continued, however, dermatologic evaluation should beperformed on a systematic and regular basis, to allow early detection and management of premalignantlesions. Voriconazole Accord should be discontinued if premalignant skin lesions or squamous cellcarcinoma are identified (see below the section under Long-term treatment).

* Severe cutaneous adverse reactions

Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome(SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemicsymptoms (DRESS), which can be life-threatening or fatal, have been reported with the useof voriconazole. If a patient develops a rash he should be monitored closely and Voriconazole Accorddiscontinued 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 insufficiencyis related to direct inhibition of steroidogenesis by azoles. In patients taking corticosteroids,voriconazole associated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess andadrenal suppression (see section 4.5). Cushing’s syndrome with and without subsequent adrenalinsufficiency has also been reported in patients receiving voriconazole concomitantly withcorticosteroids.

Patients on long-term treatment with voriconazole and corticosteroids (including inhaled corticosteroidse.g., budesonide and intranasal corticosteroids) should be carefully monitored for adrenal cortexdysfunction both during treatment and when voriconazole is discontinued (see section 4.5). Patientsshould be instructed to seek immediate medical care if they develop signs and symptoms of Cushing’ssyndrome or adrenal insufficiency.

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

Squamous cell carcinoma of the skin (SCC) (including cutaneous SCC in situ, or Bowen’s disease) hasbeen reported in relation with long-term Voriconazole Accord 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 withperiostitis Voriconazole Accord discontinuation should be considered after multidisciplinary advice(see section 4.8).

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

Acute renal failure has been observed in severely ill patients undergoing treatment with voriconazole.

Patients being treated with voriconazole are likely to be treated concomitantly with nephrotoxicmedicinal products and have concurrent conditions that may result in decreased renal function (seesection 4.8).

Patients should be monitored for the development of abnormal renal function. This should includelaboratory evaluation, 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 Voriconazole

Accord 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. Ahigher frequency of liver enzyme elevations was observed in the paediatric population (seesection 4.8). Hepatic function should be monitored in both children and adults. Oral bioavailabilitymay be limited in paediatric patients aged 2 to <12 years with malabsorption and very low bodyweight for age. In that case, intravenous voriconazole 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 includingphototoxicity and SCC, severe or prolonged visual disorders and periostitis), discontinuation ofvoriconazole and use of alternative 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 to400 mg every 12 hours and the dose of efavirenz should be decreased to 300 mg every 24 hours (seesections 4.2, pct. 4.3 and 4.5).

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

Coadministration of voriconazole with tyrosine kinase inhibitors metabolised by CYP3A4 is expectedto increase tyrosine kinase inhibitor plasma concentrations and the risk of adverse reactions. Ifconcomitant use cannot be avoided, dose reduction of the tyrosine kinase inhibitor and close clinicalmonitoring is recommended (see section 4.5).

Rifabutin (potent CYP450 inducer)

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

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

Coadministration of voriconazole with everolimus is not recommended because voriconazole isexpected to significantly increase everolimus concentrations. Currently there are insufficient data toallow dosing recommendations in this situation (see section 4.5).

Frequent monitoring for adverse reactions and toxicity related to methadone, including QTcprolongation, is recommended when coadministered with voriconazole since methadone levelsincreased following coadministration 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 toalfentanil and metabolised by CYP3A4 (e.g., sufentanil) should be considered when coadministeredwith voriconazole (see section 4.5). As the half-life of alfentanil is prolonged in a 4-fold manner whenalfentanil is coadministered with voriconazole, and in an independent published study concomitant useof voriconazole with fentanyl resulted in an increase in the mean AUC0-∞ of fentanyl, frequentmonitoring for opiate-associated adverse reactions (including a longer respiratory monitoring period)may be necessary.

Reduction in the dose of oxycodone and other long-acting opiates metabolized 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 Cmaxand 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).

This medicinal product contains lactose and should not be given to patients with rare hereditaryproblems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet. Patients on low sodiumdiets 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 decreasevoriconazole plasma concentrations, respectively, and there is potential for voriconazole to increasethe plasma concentrations of substances metabolised by these CYP450 isoenzymes, in particular forsubstances metabolised by CYP3A4 since voriconazole is a strong CYP3A4 inhibitor though theincrease in AUC is substrate dependent (see Table below).

Unless otherwise specified, drug interaction studies have been performed in healthy adult malesubjects using multiple dosing to steady state with oral voriconazole at 200 mg twice daily (BID).

These results are relevant to other populations and routes of administration.

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

Interactions between voriconazole and other medicinal products are listed in the table below (oncedaily as “QD”, twice daily as “BID”, three times daily as “TID” and not determined as “ND”) orderedby therapeutic class. The direction of the arrow for each pharmacokinetic parameter is based on the90% confidence interval of the geometric mean ratio being within (↔), below (↓) or above (↑) the 80-125% range. The asterisk (*) indicates a two-way interaction. AUCτ, AUCt and AUC0-∞ represent areaunder the curve over a dosing interval, from time zero to the time with detectable measurement andfrom time zero to infinity, respectively.

Medicinal product Interaction geometric Recommendations concerningmean changes (%) coadministration

Antacids

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

Omeprazole (40 mg QD)* Omeprazole Cmax  116% No dose adjustment of[CYP2C19 inhibitor; CYP2C19 Omeprazole AUCτ  280% voriconazole is recommended.

and CYP3A4 substrate] Voriconazole Cmax  15%

Voriconazole AUC  41% When initiating voriconazole inτpatients already receiving

Other proton pump omeprazole doses of 40 mg orinhibitors that are CYP2C19 above, it is recommended that thesubstrates may also be omeprazole dose be halved.

inhibited by voriconazoleand may result in increasedplasma concentrations ofthese medicinal products.

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

Antiarrhythmics

Digoxin (0.25 mg QD) [P-gp Digoxin Cmax ↔ No dose adjustmentsubstrate] Digoxin AUCτ ↔

Quinidine Although not studied, Contraindicated (see section[CYP3A4 substrate] increased plasma 4.3)concentrations of quinidinecan lead to QTcprolongation and rareoccurrences of torsades depointes.

Antibacterials

Flucloxacillin [CYP450 Significantly decreased If concomitant administration ofinducer] plasma voriconazole voriconazole with flucloxacillinconcentrations have been cannot be avoided, monitor forreported. potential loss of voriconazoleeffectiveness (e.g., by therapeuticdrug monitoring); increasing thedose of voriconazole may beneeded.

Macrolide antibiotics No dose adjustment

Azithromycin (500 mg QD) Voriconazole Cmax and

AUCτ ↔

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

AUCτ ↔

The effect of voriconazoleon either erythromycin orazithromycin is unknown.

Rifabutin Concomitant use of voriconazole[potent CYP450 inducer] and rifabutin should be avoided

Voriconazole Cmax ↓ 69% unless the benefit outweighs the300 mg QD Voriconazole AUCτ ↓ 78% risk.

The maintenance dose of300 mg QD (coadministered Compared to voriconazole voriconazole may be increased towith voriconazole 350 mg BID) 200 mg BID, 5 mg/kg intravenously BID or

* Voriconazole Cmax ↓ 4% from 200 mg to 350 mg orally

Voriconazole AUCτ ↓ 32% BID (100 mg to 200 mg orally

BID in patients less than 40 kg)

Rifabutin Cmax  195% (see section 4.2).

300 mg QD (coadministered Rifabutin AUCτ 331% Careful monitoring of full bloodwith voriconazole 400 mg BID) Compared to voriconazole counts and adverse reactions to

* 200 mg BID, rifabutin (e.g., uveitis) is

Voriconazole Cmax  104% recommended when rifabutin is

Voriconazole AUC  87% coadministered withτvoriconazole.

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

Anti-cancer agents

Glasdegib Although not studied, If concomitant use cannot be[CYP3A4 substrate] voriconazole is likely to avoided, frequent ECGincrease the plasma monitoring is recommended (seeconcentrations of glasdegib section 4.4).

and increase risk of QTcprolongation.

Tretinoin Although not studied, Dose adjustment of tretinoin is[CYP3A4 substrate] voriconazole may increase recommended during treatmenttretinoin concentrations and with voriconazole and after itsincrease risk of adverse discontinuation.

reactions (pseudotumorcerebri, hypercalcaemia).

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

sunitinib, ibrutinib, ribociclib)[CYP3A4 substrates]

Venetoclax Although not studied, Concomitant administration of[CYP3A substrate] voriconazole is likely to voriconazole is contraindicatedsignificantly increase the at initiation and duringplasma concentrations of venetoclax dose titration phasevenetoclax. (see section 4.3). Dose reductionof venetoclax is required asinstructed in venetoclaxprescribing information duringsteady daily dosing; closemonitoring for signs of toxicity isrecommended.

Vinca Alkaloids (including but Although not studied, Dose reduction of vinca alkaloidsnot limited to: vincristine and voriconazole is likely to should be considered.

vinblastine) increase the plasma[CYP3A4 substrates] concentrations of vincaalkaloids and lead toneurotoxicity.

Anticoagulants

Warfarin (30 mg single dose, Maximum increase in Close monitoring of prothrombincoadministered with 300 mg prothrombin time was time or other suitable

BID voriconazole) approximately 2-fold. anticoagulation tests is[CYP2C9 substrate] recommended, and the dose ofanticoagulants should be adjusted

Other oral coumarins (including Although not studied, accordingly.

but not limited to: voriconazole may increasephenprocoumon, the plasma concentrations ofacenocoumarol) coumarins that may cause[CYP2C9 and CYP3A4 an increase in prothrombinsubstrates] time.

Anticonvulsants

Carbamazepine and long-acting Although not studied, Contraindicated (see sectionbarbiturates (including but not carbamazepine and long- 4.3)limited to phenobarbital, acting barbiturates are likelymephobarbital) [potent CYP450 to significantly decreaseinducers] plasma voriconazoleconcentrations.

Phenytoin [CYP2C9 substrate Concomitant use of voriconazoleand potent CYP450 inducer] and phenytoin should be avoidedunless the benefit outweighs therisk. Careful monitoring of300 mg QD Voriconazole Cmax ↓ 49% phenytoin plasma levels is

Voriconazole AUCτ ↓ 69% recommended.

300 mg QD (coadministered Phenytoin Cmax  67% Phenytoin may bewith voriconazole 400 mg BID) Phenytoin AUCτ  81% coadministered with

* Compared to voriconazole voriconazole if the maintenance200 mg BID, dose of voriconazole is increased

Voriconazole Cmax  34% to 5 mg/kg IV BID or from 200

Voriconazole AUC  39% mg to 400 mg oral BID (100 mgτto 200 mg oral BID in patientsless than 40 kg) (see section 4.2).

Antidiabetics

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

sulfonylureas and causehypoglycaemia.

Anti-fungals

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

CYP3A4 inhibitor] Fluconazole Cmax ND fluconazole that would eliminatethis effect have not been

Fluconazole AUCτ ND established. Monitoring forvoriconazole-associated adversereactions is recommended ifvoriconazole is used sequentiallyafter fluconazole.

Antihistamines

Astemizole Although not studied, Contraindicated (see section[CYP3A4 substrate] increased plasma 4.3)concentrations of astemizolecan lead to QTcprolongation and rareoccurrences of torsades depointes.

Terfenadine Although not studied, Contraindicated (see section[CYP3A4 substrate] increased plasma 4.3)concentrations ofterfenadine can lead to QTcprolongation and rareoccurrences of torsades depointes.

Anti HIV agents

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

Voriconazole AUCτ ↔

Ritonavir (protease inhibitor)[potent CYP450 inducer;

CYP3A4 inhibitor andsubstrate]

High dose (400 mg BID) Ritonavir Cmax and AUCτ ↔ Coadministration of voriconazole

Voriconazole Cmax ↓ 66% and high doses of ritonavir (400

Voriconazole AUCτ ↓ 82% mg and above BID) iscontraindicated (see section4.3).

Low dose (100 mg BID) * Ritonavir Cmax ↓ 25% Coadministration of voriconazole

Ritonavir AUCτ ↓13% and low-dose ritonavir (100 mg

Voriconazole Cmax ↓ 24% BID) should be avoided unless an

Voriconazole AUCτ ↓ 39% assessment of the benefit/risk tothe patient justifies the use ofvoriconazole.

Other HIV Protease Inhibitors Not studied clinically. In Careful monitoring for any(including but not limited to: vitro studies show that occurrence of drug toxicitysaquinavir, amprenavir and voriconazole may inhibit the and/or lack of efficacy, and dosenelfinavir)* metabolism of HIV protease adjustment may be needed.

[CYP3A4 substrates and inhibitors and theinhibitors] metabolism of voriconazolemay also be inhibited by

HIV protease inhibitors.

Efavirenz (a non-nucleosidereverse transcriptase inhibitor,(NNRTI)) [CYP450 inducer;

CYP3A4 inhibitor andsubstrate]

Efavirenz 400 mg QD, Efavirenz Cmax  38% Use of standard doses ofcoadministered with Efavirenz AUCτ  44% voriconazole with efavirenzvoriconazole 200 mg BID* Voriconazole Cmax ↓ 61% doses of 400 mg QD or higher is

Voriconazole AUCτ ↓ 77% contraindicated (see section4.3).

Efavirenz 300 mg QD, Compared to efavirenz 600 Voriconazole may becoadministered with mg QD, coadministered with efavirenz ifvoriconazole 400 mg BID* Efavirenz Cmax ↔ the voriconazole maintenance

Efavirenz AUC 17% dose is increased to 400 mg BIDτ

Compared to voriconazole and the efavirenz dose is200 mg BID, decreased to 300 mg QD. When

Voriconazole C  23% voriconazole treatment ismax

Voriconazole AUC ↓ 7% stopped, the initial dose ofτefavirenz should be restored (seesections 4.2 and 4.4).

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

Transcriptase Inhibitors vitro studies show that the occurrence of drug toxicity(NNRTIs) (including but not metabolism of voriconazole and/or lack of efficacy, and doselimited to: delavirdine, may be inhibited by adjustment may be needed.

nevirapine)* [CYP3A4 NNRTIs and voriconazolesubstrates, inhibitors or CYP450 may inhibit the metabolisminducers] of NNRTIs.

The findings of the effect ofefavirenz on voriconazolesuggest that the metabolismof voriconazole may beinduced by an NNRTI.

Antipsychotics

Lurasidone Although not studied, Contraindicated (see section[CYP3A4 substrate] voriconazole is likely to 4.3)significantly increase theplasma concentrations oflurasidone.

Pimozide Although not studied, Contraindicated (see section[CYP3A4 substrate] increased plasma 4.3)concentrations of pimozidecan lead to QTcprolongation and rareoccurrences of torsades depointes.

Anti virals

Letermovir Voriconazole Cmax ↓ 39% If concomitant administration of[CYP2C9 and CYP2C19 Voriconazole AUC0-12 ↓ voriconazole with letermovirinducer] 44% cannot be avoided, monitor for

Voriconazole C12 ↓ 51% loss of voriconazoleeffectiveness.

Benzodiazepines[CYP3A4 substrates] Dose reduction of

Midazolam (0.05 mg/kg IV In an independent published benzodiazepines should besingle dose) study, considered.

Midazolam AUC0-∞  3.7-fold

Midazolam (7.5 mg oral singledose) In an independent publishedstudy,

Other benzodiazepines Midazolam Cmax  3.8-fold(including but not limited to: Midazolam AUC0-∞  10.3-triazolam, alprazolam) fold

Although not studied,voriconazole is likely toincrease the plasmaconcentrations of otherbenzodiazepines that aremetabolised by CYP3A4and lead to a prolongedsedative effect.

Cardiovascular agents

Ivabradine Although not studied, Contraindicated (see section[CYP3A4 substrates] increased plasma 4.3)concentrations of ivabradinecan lead to QTcprolongation and rareoccurrences of torsades depointes.

Cystic fibrosis transmembrane conductance regulator potentiators

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

increase the plasmaconcentrations of ivacaftorwith risk of increasedadverse reactions.

Ergot derivatives

Ergot alkaloids (including but Although not studied, Contraindicated (see sectionnot limited to: ergotamine and voriconazole is likely to 4.3)dihydroergotamine) [CYP3A4 increase the plasmasubstrates] concentrations of ergotalkaloids and lead toergotism.

GI motility agents

Cisapride Although not studied, Contraindicated (see section[CYP3A4 substrate] increased plasma 4.3)concentrations of cisapridecan lead to QTcprolongation and rareoccurrences of torsades depointes.

Herbal medicines

St. John’s Wort In an independent published Contraindicated (see section[CYP450 inducer; P-gp study, 4.3)inducer] Voriconazole AUC0-∞ ↓59%300 mg TID (coadministeredwith voriconazole 400 mg singledose)

Immunosuppressants[CYP3A4 substrates]

Ciclosporin (in stable renal Ciclosporin Cmax  13% When initiating voriconazole intransplant recipients receiving Ciclosporin AUCτ 70% patients already on ciclosporin itchronic ciclosporin therapy) is recommended that theciclosporin dose be halved andciclosporin level carefullymonitored. Increased ciclosporinlevels have been associated withnephrotoxicity. Whenvoriconazole is discontinued,ciclosporin levels must becarefully monitored and the doseincreased as necessary.

Everolimus Although not studied, Coadministration of voriconazole[also P-gp substrate] voriconazole is likely to and everolimus is notsignificantly increase the recommended becauseplasma concentrations of voriconazole is expected toeverolimus. significantly increase everolimusconcentrations (see section 4.4).

Sirolimus (2 mg single dose) In an independent published Coadministration of voriconazolestudy, Sirolimus Cmax  6.6- and sirolimus is contraindicatedfold Sirolimus AUC0-∞ 11- (see section 4.3).

fold

Tacrolimus (0.1 mg/kg single Tacrolimus Cmax  117% When initiating voriconazole indose) Tacrolimus AUCt  221% patients already on tacrolimus, itis recommended that thetacrolimus dose be reduced to athird of the original dose andtacrolimus level carefullymonitored. Increased tacrolimuslevels have been associated withnephrotoxicity. Whenvoriconazole is discontinued,tacrolimus levels must becarefully monitored and the doseincreased as necessary.

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

Lipid lowering agents/HMG- CoA reductase inhibitors

Statins (e.g., lovastatin) Although not studied, If concomitant administration of[CYP3A4 substrates] voriconazole is likely to voriconazole with statinsincrease the plasma metabolised by CYP3A4 cannotconcentrations of statins that be avoided, dose reduction of theare metabolised by CYP3A4 statin should be consideredand could lead torhabdomyolysis.

Non-steroidal selective mineralocorticoid receptor (MR) antagonists

Finerenone Although not studied, Contraindicated (see section[CYP3A4 substrate] voriconazole is likely to 4.3)significantly increase theplasma concentrations offinerenone.

Non-steroidal anti-inflammatory drugs (NSAIDs)[CYP2C9 substrates] Frequent monitoring for adversereactions and toxicity related to

Ibuprofen (400 mg single dose) S-Ibuprofen Cmax  20% S- NSAIDs is recommended. Dose

Ibuprofen AUC0-∞ 100% reduction of NSAIDs may beneeded.

Diclofenac (50 mg single dose) Diclofenac Cmax  114%

Diclofenac AUC0-∞  78%

Opioids

Long-Acting Opiates In an independent published Dose reduction in oxycodone and[CYP3A4 substrates] study, other long-acting opiates

Oxycodone Cmax  1.7-fold metabolised by CYP3A4 (e.g.,

Oxycodone (10 mg single dose) Oxycodone AUC0-∞  3.6- hydrocodone) should befold considered. Frequent monitoringfor opiate-associated adversereactions may be necessary.

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

AUCɽ  47% S-methadone methadone, including QTc

Cmax  65% S-methadone prolongation, is recommended.

AUC 103% Dose reduction of methadoneɽmay be needed.

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

Alfentanil (20 μg/kg single In an independent published alfentanil and metabolised bydose, with concomitant study, Alfentanil AUC0-∞  CYP3A4 (e.g., sufentanil) shouldnaloxone) 6-fold be considered. Extended andfrequent monitoring for

Fentanyl (5 µg/kg single dose) In an independent published respiratory depression and otherstudy, Fentanyl AUC0-∞  opiate-associated adverse1.34-fold reactions is recommended.

Opioid receptor antagonists

Naloxegol Although not studied, Contraindicated (see section[CYP3A4 substrate] voriconazole is likely to 4.3)significantly increase theplasma concentrations ofnaloxegol.

Oral Contraceptives* Ethinylestradiol Cmax  36% Monitoring for adverse reactions[CYP3A4 substrate; CYP2C19 Ethinylestradiol AUCτ  related to oral contraceptives, ininhibitor] 61% addition to those for

Norethisterone/ethinylestradiol Norethisterone Cmax  15% voriconazole, is recommended.

(1 mg/0.035 mg QD) Norethisterone AUC  53%τ

Voriconazole Cmax  14%

Voriconazole AUCτ  46%

Steroids

Prednisolone (60 mg single Prednisolone Cmax  11% No dose adjustmentdose) Prednisolone AUC0-∞  34%[CYP3A4 substrate] Patients on long-term treatmentwith voriconazole andcorticosteroids (including inhaledcorticosteroids e.g., budesonideand intranasal corticosteroids)should be carefully monitored foradrenal cortex dysfunction bothduring treatment and whenvoriconazole is discontinued (seesection 4.4).

Vasopressin receptor antagonists

Tolvaptan Although not studied, Contraindicated (see section[CYP3A substrate] voriconazole is likely to 4.3)significantly increase theplasma concentrations oftolvaptan.

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

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

Voriconazole Accord must not be used during pregnancy unless the benefit to the mother clearlyoutweighs the potential risk 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 bestopped on initiation of treatment with Voriconazole Accord.

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

Voriconazole Accord has moderate influence on the ability to drive and use machines. It may causetransient and reversible changes to vision, including blurring, altered/enhanced visual perceptionand/or photophobia. Patients must avoid potentially hazardous tasks, such as driving or operatingmachinery while experiencing these 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 withhaematological malignancy, HIV infected patients with oesophageal candidiasis and refractory fungalinfections, 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 andabdominal pain.

The severity of the adverse reactions was generally mild to moderate. No clinically significantdifferences were 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 beestimated from 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 Frequency

Organ Class ≥ 1/10 ≥ 1/100 ≥ 1/1,000 to < ≥ 1/10,000 to < not knownto < 1/10 1/100 1/1,000 (cannot beestimatedfromavailabledata)

Infections and sinusitis pseudomembranouinfestations s colitis

Neoplasms squamous cellbenign, carcinomamalignant and (includingunspecified cutaneous SCC in(including situ, or Bowen’scysts and disease)*,**polyps)

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

Psychiatric depression,disorders hallucination,anxiety, insomnia,

System Very common Common Uncommon Rare Frequency

Organ Class ≥ 1/10 ≥ 1/100 ≥ 1/1,000 to < ≥ 1/10,000 to < not knownto < 1/10 1/100 1/1,000 (cannot beestimatedfromavailabledata)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

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

System Very common Common Uncommon Rare Frequency

Organ Class ≥ 1/10 ≥ 1/100 ≥ 1/1,000 to < ≥ 1/10,000 to < not knownto < 1/10 1/100 1/1,000 (cannot beestimatedfromavailabledata)

Skin and rash dermatitis Stevens-Johnson toxic epidermal cutaneoussubcutaneous exfoliative, syndrome8, necrolysis8, lupustissue alopecia, rash purpura, urticaria, angioedema, erythematodisorders maculo-papular, dermatitis allergic, actinic sus*,pruritus, erythema, rash papular, rash keratosis*, ephelides*,phototoxicity** macular, eczema pseudoporphyri lentigo*a erythemamultiforme,psoriasis, drugeruption, drugreaction witheosinophiliaand systemicsymptoms(DRESS) 8

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 datasources 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.

In clinical trials, visual impairments (including blurred vision, photophobia, chloropsia, chromatopsia,colour blindness, cyanopsia, eye disorder, halo vision, night blindness, oscillopsia, photopsia,scintillating scotoma, visual acuity reduced, visual brightness, visual field defect, vitreous floaters, andxanthopsia) with voriconazole were very common. These visual impairments were transient and fullyreversible, with the majority spontaneously resolving within 60 minutes and no clinically significantlong-term visual effects were observed. There was evidence of attenuation with repeated doses ofvoriconazole. The visual impairments were generally mild, rarely resulted in discontinuation and werenot associated with long-term sequelae. Visual impairments may be associated with higher plasmaconcentrations and/or doses.

The mechanism of action is unknown, although the site of action is most likely to be within the retina.

In a study in healthy volunteers investigating the impact of voriconazole on retinal function,voriconazole caused a decrease in the electroretinogram (ERG) waveform amplitude. The ERGmeasures electrical currents in the retina. The ERG changes did not progress over 29 days of treatmentand were fully reversible on withdrawal of 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, butthese patients had serious underlying diseases and were receiving multiple concomitant medicinalproducts. The majority of rashes were of mild to moderate severity. Patients have developed severecutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) (uncommon), toxicepidermal necrolysis (TEN) (rare), drug reaction witheosinophilia and systemic symptoms (DRESS) (rare) and erythema multiforme (rare) during treatmentwith voriconazole (see section 4.4).

If a patient develops a rash they should be monitored closely and Voriconazole Accord discontinued iflesions progress. Photosensitivity reactions such as ephelides, lentigo and actinic keratosis have beenreported, especially during 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 Voriconazole Accord for long periods of time; themechanism has not been established (see section 4.4).

The overall incidence of transaminase increases >3 xULN (not necessarily comprising an adverseevent) in the voriconazole clinical programme was 18.0% (319/1,768) in adults and 25.8% (73/283) inpaediatric subjects who received voriconazole for pooled therapeutic and prophylaxis use. Liverfunction test abnormalities may be associated with higher plasma concentrations and/or doses. Themajority of abnormal liver function tests either resolved during treatment without dose adjustment orfollowing 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(see section 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 versus39.6% of subjects in the itraconazole arm. Treatment-emergent hepatic AEs resulted in permanentdiscontinuation of study medication for 50 subjects (21.4%) treated with voriconazole and for 18subjects (7.1%) treated with itraconazole.

The safety of voriconazole was investigated in 288 paediatric patients aged 2 to <12 years (169) and12 to <18 years (119) who received voriconazole for prophylaxis (183) and therapeutic use (105) inclinical trials. The safety of voriconazole was also investigated in 158 additional paediatric patientsaged 2 to <12 years in compassionate use programs. Overall, the safety profile of voriconazole inpaediatric population was similar to that in adults. However, a trend towards a higher frequency ofliver enzyme elevations, reported as adverse events in clinical trials was observed in paediatricpatients as compared to adults (14.2% transaminases increased in paediatrics compared to 5.3% inadults). Post-marketing data suggest there might be a higher occurrence of skin reactions (especiallyerythema) in the paediatric population compared to adults. In the 22 patients less than 2 years old whoreceived voriconazole in a compassionate use programme, the following adverse reactions (for whicha relationship to voriconazole could not be excluded) were reported: photosensitivity reaction (1),arrhythmia (1), pancreatitis (1), blood bilirubin increased (1), hepatic enzymes increased (1), rash (1)and papilloedema (1). There have been post-marketing reports of pancreatitis in paediatric patients.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In clinical trials there were 3 cases of accidental overdose. All occurred in paediatric patients, whoreceived up to five times the recommended intravenous dose of voriconazole. A single adversereaction of photophobia 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 mayassist in the removal of voriconazole from the body.

Pharmacotherapeutic group: Antimycotics for systemic use, Triazole and tetrazole derivatives, ATCcode: J02A C03

Voriconazole is a triazole antifungal agent. The primary mode of action of voriconazole is theinhibition of fungal cytochrome P450-mediated 14 alpha-lanosterol demethylation, an essential step infungal ergosterol biosynthesis. The accumulation of 14 alpha-methyl sterols correlates with thesubsequent loss of ergosterol in the fungal cell membrane and may be responsible for the antifungalactivity of voriconazole. Voriconazole has been shown to be more selective for fungal cytochrome P-450 enzymes than for various mammalian cytochrome P-450 enzyme systems.

In 10 therapeutic studies, the median for the average and maximum plasma concentrations inindividual subjects across the studies was 2425 ng/ml (inter-quartile range 1193 to 4380 ng/ml) and3742 ng/ml (inter-quartile range 2027 to 6302 ng/ml), respectively. A positive association betweenmean, maximum or minimum plasma voriconazole concentration and efficacy in therapeutic studieswas not found and this relationship has not been explored in prophylaxis studies.

Pharmacokinetic-Pharmacodynamic analyses of clinical trial data identified positive associationsbetween plasma voriconazole concentrations and both liver function test abnormalities and visualdisturbances. Dose adjustments in prophylaxis studies have not been explored.

In vitro, voriconazole displays broad-spectrum antifungal activity with antifungal potency against

Candida species (including fluconazole resistant C. krusei and resistant strains of C. glabrata and C.

albicans) and fungicidal activity against all Aspergillus species tested. In addition voriconazole showsin vitro fungicidal activity against emerging fungal pathogens, including those such as Scedosporiumor Fusarium which have limited 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 Fusarium spp.

Other treated fungal infections (often with either partial or complete response) included isolated casesof Alternaria spp., Blastomyces dermatitidis, Blastoschizomyces capitatus, Cladosporium spp.,

Coccidioides immitis, 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. IncludingT. beigelii infections.

In vitro activity against clinical isolates has been observed for Acremonium spp., Alternaria spp.,

Bipolaris spp., Cladophialophora spp., and Histoplasma capsulatum, with most strains being inhibitedby concentrations 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 isunknown: Curvularia spp. and Sporothrix spp.

Specimens for fungal culture and other relevant laboratory studies (serology, histopathology) shouldbe obtained prior to therapy to isolate and identify causative organisms. Therapy may be institutedbefore the results of the cultures and other laboratory studies are known; however, once these resultsbecome 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 andC. krusei, all of which usually exhibit minimal inhibitoryconcentration (MICs) of less 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 thanare those of fluconazole-susceptible isolates. Therefore, every attempt should be made to identify

Candida to species level. If antifungal susceptibility testing is available, the MIC results may beinterpreted using breakpoint criteria established by European Committee on Antimicrobial

Susceptibility Testing (EUCAST).

Susceptibility testing breakpoints

MIC (minimum inhibitory concentration) interpretive criteria for susceptibility testing have beenestablished by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) forvoriconazole and are listed here: <https://www.ema.europa.eu/documents/other/minimum-inhibitory-concentration-mic-breakpoints_en.xlsx>

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 benefitof voriconazole versus conventional amphotericin B in the primary treatment of acute invasiveaspergillosis was demonstrated in an open, randomised, multicentre study in 277immunocompromisedpatients treated for 12 weeks. Voriconazole was administered intravenously with a loading dose of6 mg/kg every 12 hours for the first 24 hours followed by a maintenance dose of 4 mg/kg every 12hours for a minimum of 7 days. Therapy could then be switched to the oral formulation at a dose of200 mg every 12 hours. Median duration of IV voriconazole therapy was 10 days (range 2-85 days).

After IV voriconazole therapy, the median duration 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-treated patients compared to 31% of patients treated with comparator. The 84-day survival rate forvoriconazole was statistically significantly higher than that for the comparator and a clinically andstatistically significant benefit was shown in favour of voriconazole for both time to death and time todiscontinuation due to toxicity.

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

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

The efficacy of voriconazole compared to the regimen of amphotericin B followed by fluconazole inthe primary treatment of candidaemia was demonstrated in an open, comparative study. Three hundredand seventy non-neutropenic patients (above 12 years of age) with documented candidaemia wereincluded in the study, of whom 248 were treated with voriconazole. Nine subjects in the voriconazolegroup and 5 in the amphotericin B followed by fluconazole group also had mycologically proveninfection in deep tissue. Patients with renal failure were excluded from this study. The mediantreatment duration was 15 days in both treatment arms. In the primary analysis, successful response asassessed by a Data Review Committee (DRC) blinded to study medicinal product was defined asresolution/improvement in all clinical signs and symptoms of infection with eradication of Candidafrom blood and infected deep tissue sites 12 weeks after the end of therapy (EOT). Patients who didnot have an assessment 12 weeks after EOT were counted as failures. In this analysis a successfulresponse 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, or 12 weeks after EOT) voriconazole and the regimen of amphotericin B followed by fluconazolehad successful response rates of 65% and 71%, respectively. The Investigator’s assessment ofsuccessful outcome at each of these time points is shown in the following table.

Timepoint Voriconazole Amphotericin B(N=248) → fluconazole(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 with fluconazole, had been ineffective. Successful response was seen in 24 patients (15complete, 9 partial responses). In fluconazole-resistant non albicans species, a successful outcome wasseen in3/3 C.krusei (complete responses) and 6/8 C. glabrata (5 complete, 1 partial response)infections. The clinical efficacy data were supported by limited susceptibility data.

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

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

Seven (3 complete, 4 partial responses) of 17 patients were successfully treated with voriconazole. Ofthese 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 provenor probable 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(without stopping for >14 days) and survival with no proven or probable IFI for 180 days after HSCT.

The modified intent-to-treat (MITT) group included 465 allogeneic HSCT recipients with 45% ofpatients having AML. From all patients 58% were subject to myeloablative conditions regimens.

Prophylaxis with study drug was started immediately after HSCT: 224 received voriconazole and 241received itraconazole. The median duration of study drug prophylaxis was 96 days for voriconazoleand 68 days for itraconazole in the MITT group.

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

Study Endpoints Voriconazo Itraconazo Difference in P-le le proportions and the Value

N=224 N=241 95% confidenceinterval (CI)

Success at day 180* 109 (48.7%) 80 (33.2%) 16.4% (7.7%, 0.000225.1%)** **

Success at day 100 121 (54.0%) 96 (39.8%) 15.4% (6.6%, 0.000624.2%)** **

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 0.4% (-6.6%, 7.4%) 0.9107(81.7%)

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 Day180, for patients with AML and myeloablative conditioning regimens respectively, is presented in thetable below:

AML

Study endpoints Voriconazo Itraconazo Difference in proportionsle le and the 95% confidence(N=98) (N=109) interval (CI)

Breakthrough IFI - Day 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 Voriconazo Itraconazo Difference in proportionsle le and the 95% confidence(N=125) (N=143) interval (CI)

Breakthrough IFI - Day 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,multicenter study of adult allogeneic HSCT recipients with prior proven or probable IFI. The primaryendpoint was the rate of occurrence of proven and probable IFI during the first year after HSCT. The

MITT group included 40 patients with prior IFI, including 31 with aspergillosis, 5 with candidiasis,and 4 with other IFI. The median duration of study drug prophylaxis was 95.5 days in the MITTgroup.

Proven or probable IFIs developed in 7.5% (3/40) of patients during the first year after HSCT,including one candidemia, one scedosporiosis (both relapses of prior IFI), and one zygomycosis. Thesurvival 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 164patients receiving 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 andwere included in the MITT efficacy analyses. The second study enrolled 22 patients with invasivecandidiasis including candidaemia (ICC), and esophageal candidiasis (EC) requiring either primary orsalvage therapy, of whom 17 were included in the MITT efficacy analyses. For patients with IA theoverall rates of global response at 6 weeks were 64.3% (9/14), the global response rate was 40% (2/5)for patients 2 to <12 years and 77.8% (7/9) for patients 12 to <18 years of age. For patients with ICCthe global response rate at EOT was 85.7% (6/7) and for patients with EC the global response rate at

EOT was 70% (7/10). The overall rate of response (ICC and EC combined) was 88.9% (8/9) for 2 to<12 years old and 62.5% (5/8) for 12 to <18 years old.

A placebo-controlled, randomized, single-dose, crossover study to evaluate the effect on the QTcinterval of healthy volunteers was conducted with three oral doses of voriconazole and ketoconazole.

The placebo-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. Nosubject in any group had an increase in QTc of ≥60 msec from baseline. No subject experienced aninterval exceeding the potentially clinically relevant threshold of 500 msec.

The pharmacokinetics of voriconazole have been characterised in healthy subjects, special populationsand patients. During oral administration of 200 mg or 300 mg twice daily for 14 days in patients at riskof aspergillosis (mainly patients with malignant neoplasms of lymphatic or haematopoietic tissue), theobserved pharmacokinetic characteristics of rapid and consistent absorption, accumulation and non-linear pharmacokinetics 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 a voriconazole exposure similar to 3 mg/kg IV. A 300 mg (or 150 mg for patients less than40 kg) oral maintenance dose achieves an exposure similar to 4 mg/kg IV. When the recommendedintravenous or oral loading dose regimens are administered, plasma concentrations close to steady stateare achieved within the first 24 hours of dosing. Without the loading dose, accumulation occurs duringtwice daily multiple dosing with 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 ofvoriconazole after oral administration is estimated to be 96%.When multiple doses of voriconazole areadministered with high fat meals, Cmax and AUCτ are reduced by 34 % and 24 %, respectively. Theabsorption 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, suggestingextensive distribution into tissues. Plasma protein binding is estimated to be 58%. Cerebrospinal fluidsamples from eight patients in a compassionate programme showed detectable voriconazoleconcentrations 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.

This enzyme exhibits genetic polymorphism. For example, 15-20 % of Asian populations may beexpected to be poor metabolisers. For Caucasians and Blacks the prevalence of poor metabolisers is3-5 %. Studies conducted in Caucasian and Japanese healthy subjects have shown that poormetabolisers have, on average, 4-fold higher voriconazole exposure (AUCτ) than their homozygousextensive metaboliser counterparts. Subjects who are heterozygous extensive metabolisers have onaverage 2-fold higher voriconazole exposure than their homozygous extensive metabolisercounterparts.

The major metabolite of voriconazole is the N-oxide, which accounts for 72% of the circulatingradiolabeled metabolites in plasma. This metabolite has minimal antifungal activity and does notcontribute to the overall efficacy of voriconazole.

Voriconazole is eliminated via hepatic metabolism with less than 2% of the dose excreted unchangedin the urine.

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 oraldosing. The majority (>94%) of the total radioactivity is excreted in the first 96 hours after both oraland intravenous dosing.

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 ofthe accumulation 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

Cmax and 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 profileand plasma concentrations observed in male and female patients were similar. Therefore, no dosageadjustment based 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 Cmaxand AUCτ were 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 betweenplasma concentrations and age was observed. The safety profile of voriconazole in young and elderlypatients was similar 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 populationpharmacokinetic analysis of data obtained from 112 immunocompromised paediatric patients aged 2 to<12 years and 26 immunocompromised adolescent patients aged 12 to <17 years. Multiple intravenousdoses of 3, 4, 6, 7 and 8 mg/kg twice daily and multiple oral doses (using the powder for oralsuspension) of 4 mg/kg, 6 mg/kg, and 200 mg twice daily were evaluated in 3 paediatricpharmacokinetic studies. Intravenous loading doses of 6 mg/kg IV twice daily on day 1 followed by 4mg/kg intravenous dose twice daily and 300 mg oral tablets twice daily were evaluated in oneadolescent pharmacokinetic study. Larger inter-subject variability was observed in paediatric patientscompared to adults.

A comparison of the paediatric and adult population pharmacokinetic data indicated that the predictedtotal exposure (AUCτ) in children following administration of a 9 mg/kg IV loading dose wascomparable to that in adults following a 6 mg/kg IV loading dose. The predicted total exposures inchildren following IV maintenance doses of 4 and 8 mg/kg twice daily were comparable to those inadults following 3 and 4 mg/kg IV twice daily, respectively. The predicted total exposure in childrenfollowing an oral maintenance dose of 9 mg/kg (maximum of 350 mg) twice daily was comparable tothat in adults following 200 mg oral twice daily. An 8 mg/kg intravenous dose will providevoriconazole exposure approximately 2-fold higher than a 9 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. Oralbioavailability may, however, be limited in paediatric patients with malabsorption and very low bodyweight for their age. In that case, intravenous voriconazole administration is recommended.

Voriconazole exposures in the majority of adolescent patients were comparable to those in adultsreceiving the same dosing regimens. However, lower voriconazole exposure was observed in someyoung adolescents with low body weight compared to adults. It is likely that these subjects maymetabolize voriconazole more similarly to children than to adults. Based on the populationpharmacokinetic analysis, 12 to 14 year old adolescents weighing less than 50 kg should receivechildren’s doses (see section 4.2).

In an oral single dose (200 mg) study in subjects with normal renal function and mild (creatinineclearance 41-60 ml/min) to severe (creatinine clearance < 20ml/min) renal impairment, thepharmacokinetics of voriconazole were not significantly affected by renal impairment. The plasmaprotein binding of voriconazole was similar in subjects with different degrees of renal impairment. (seesections 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 bindingof voriconazole 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 functiongiven 200 mg twice daily. No pharmacokinetic data are available for patients with severe hepaticcirrhosis (Child-Pugh C) (see sections 4.2 and 4.4).

Repeated-dose toxicity studies with voriconazole indicated the liver to be the target organ.

Hepatotoxicity occurred at plasma exposures similar to those obtained at therapeutic doses in humans,in common with other antifungal agents. In rats, mice and dogs, voriconazole also induced minimaladrenal changes. Conventional studies of safety pharmacology, genotoxicity or carcinogenic potentialdid not reveal a special hazard 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 consequentmaternal mortality and reduced perinatal survival of pups. The effects on parturition are probablymediated by species-specific mechanisms, involving reduction of oestradiol levels, and are consistentwith those observed with other azole antifungal agents. Voriconazole administration induced noimpairment of male or female fertility in rats at exposures similar to those obtained in humans attherapeutic doses.

Lactose monohydrate

Pregelatinized starch

Croscarmellose sodium

Povidone

Magnesium stearate

Hypromellose

Titanium dioxide (E171)

Lactose monohydrate

Triacetin

Not applicable.

4 years

This medicinal product does not require any special storage conditions.

PVC/Aluminium blister in cartons of 2, 10, 14, 20, 28, 30, 50, 56 or 100 film-coated tablets or unitdose PVC/Aluminium blister in pack sizes of 10x1, 14x1, 28x1, 30x1, 56x1 or 100x1 film-coatedtablets.

Not all pack sizes may be marketed.

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

Accord Healthcare S.L.U.

World Trade Center, Moll de Barcelona, s/n,

Edifici Est 6ª planta,08039 Barcelona,

Spain

EU/1/13/835/001-009,

EU/1/13/835/019-024

EU/1/13/835/010-018,

EU/1/13/835/025-030

Date of first authorisation: 16 May 2013

Date of latest renewal: 8th February 2018

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

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