4.1. Therapeutic indications

Voriconazole is a broad-spectrum, triazole antifungal agent and is indicated in adults and children 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 Aristo 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.

4.2. Posology and method of administration

Posology

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

Treatment

Adults

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

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

Intravenous**

Oral

Patients 40 kg and above*

Patients less than 40 kg*

Loading dose regimen (first 24 hours)

6 mg/kg every 12 hours

400 mg every 12 hours

200 mg every 12 hours

Maintenance dose (after first 24 hours)

4 mg/kg twice daily

200 mg twice daily

100 mg twice daily

* This also applies to patients aged 15 years and older

** Voriconazole Aristo is not available for intravenous use. For this method of administration, other products should be used.

Duration of treatment

Treatment duration should be as short as possible depending on the patient's clinical and mycological 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).

Dosage adjustment (Adults)

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

If patient is unable to tolerate treatment at a higher dose, reduce the oral dose by 50 mg steps to the 200 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 voriconazole more similarly to children than to adults.

The recommended dosing regimen is as follows:

Intravenous*

Oral

Loading dose regimen (first 24 hours)

9 mg/kg every 12 hours

Not recommended

Maintenance dose (after first 24 hours)

8 mg/kg twice daily

9 mg/kg twice daily

(a maximum dose of 350 mg twice daily)

* Voriconazole Aristo is not available for intravenous use. For this method of administration, other products should be used.

Note: Based on a population pharmacokinetic analysis in 112 immunocompromised paediatric patients 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 be considered only after there is a significant clinical improvement. It should be noted that an 8 mg/kg intravenous dose will 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 administered as the powder for oral suspension. Bioequivalence between the powder for oral suspension and tablets has not been investigated in a paediatric population. Considering the assumed limited gastroenteric transit time in paediatric patients, the absorption of tablets may be different in paediatric compared to adult patients. It is therefore recommended to use the oral suspension formulation in children aged 2 to <12.

All other adolescents (12 to 14 years and ≥50 kg; 15 to 17 years regardless of body weight)

Voriconazole should be dosed as adults.

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

If patient response to treatment is inadequate, the dose may be increased by 1 mg/kg steps (or by 50 mg steps if the maximum oral dose of 350 mg was used initially). If patient is unable to tolerate treatment, reduce the dose by 1 mg/kg steps (or by 50 mg steps if the maximum oral dose of 350 mg was 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 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 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 age groups. Please refer to the treatment tables above.

Duration of prophylaxis

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

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

The following instructions apply to both Treatment and Prophylaxis

Dosage adjustment

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

Dosage adjustments in case of co-administration

Phenytoin may be co-administered with voriconazole if the maintenance dose of voriconazole is increased from 200 mg to 400 mg orally, twice daily (100 mg to 200 mg orally, twice daily 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 combination is strictly needed, the maintenance dose of voriconazole may be increased from 200 mg to 350 mg orally, twice daily (100 mg to 200 mg orally, twice daily in patients less than 40 kg), see sections 4.4 and 4.5.

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

Elderly

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

Renal impairment

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 not remove a sufficient amount of voriconazole to warrant dose adjustment.

Hepatic impairment

It is recommended that the standard loading dose regimens be used but that the maintenance dose be halved in patients with mild to moderate hepatic cirrhosis (Child-Pugh A and B) receiving voriconazole (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 total bilirubin >5 times the upper 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 outweighs the potential risk. Patients with severe hepatic impairment must be carefully monitored for drug toxicity (see section 4.8).

Paediatric population

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

Method of administration

Voriconazole Aristo is to be taken at least one hour before, or one hour following, a meal.

4.3. Contraindications

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

Co-administration of voriconazole is contraindicated with medicinal products that are highly dependent on CYP3A4 for metabolism, and for which elevated plasma concentrations are associated with serious and/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: Co-administration contraindicated at initiation and during venetoclax dose titration phase.

Co-administration of voriconazole is contraindicated with medicinal products that induce CYP3A4 and significantly reduce voriconazole plasma concentrations:

• Co-administration with rifampicin, carbamazepine, long-acting barbiturates e.g. phenobarbital, and St. John´s Wort (see section 4.5).

• Efavirenz: Co-administration of standard doses of voriconazole with efavirenz doses of 400 mg once daily or higher is contraindicated (see section 4.5). For information on co-administration of voriconazole and lower doses of efavirenz see section 4.4.

• Ritonavir: Co-administration with high-dose ritonavir (400 mg and above twice daily) is contraindicated (see section 4.5). For information on co-administation with lower doses of ritonavir see section 4.4.

4.4. Special warnings and precautions for use

Hypersensitivity

Caution should be used in prescribing Voriconazole Aristo to patients with hypersensitivity to other azoles (see also section 4.8).

Cardiovascular

Voriconazole has been associated with QTc interval prolongation. There have been rare cases of torsades de pointes 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 such as hypokalaemia, hypomagnesaemia and hypocalcaemia should be monitored and corrected, if necessary, prior to initiation and during voriconazole therapy (see section 4.2). A study has been conducted in healthy volunteers which examined the effect on QTc interval of single doses of voriconazole up to 4 times the usual daily dose. No subject experienced an interval exceeding the potentially clinically-relevant threshold of 500 msec (see section 5.1).

Hepatic toxicity

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 of hepatic 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 been reversible on discontinuation of therapy (see section 4.8).

Monitoring of hepatic function

Patients receiving Voriconazole Aristo must be carefully monitored for hepatic toxicity. Clinical management should include laboratory evaluation of hepatic function (specifically AST and ALT) at the initiation of treatment with Voriconazole Aristo and at least weekly for the first month of treatment. Treatment duration should be as short as possible; 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, Voriconazole Aristo 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.

Serious dermatological adverse reactions

• Phototoxicity

In addition voriconazole has been associated with phototoxicity including reactions such as ephelides, lentigo, actinic keratosis and pseudoporphyria. There is a potential increased risk of skin reaction/toxicity with concomitant use of photosensitising agents (e.g., methotrexate, etc). It is recommended that all patients, including children, avoid exposure to direct sunlight during voriconazole treatment 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) has been reported in patients, some of whom have reported prior phototoxic reactions. If phototoxic reactions occur multidisciplinary advice should be sought, voriconazole discontinuation and use of alternative antifungal agents should be considered and the patient should be referred to a dermatologist. If voriconazole is continued, however, dermatologic evaluation should be performed on a systematic and regular basis, to allow early detection and management of premalignant lesions. Voriconazole should be discontinued if premalignant skin lesions or squamous cell carcinoma 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 systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported with the use of voriconazole. If a patient develops a rash he should be monitored closely and voriconazole discontinued if lesions progress.

Adrenal events

Reversible cases of adrenal insufficiency have been reported in patients receiving azoles including voriconazole. Adrenal insufficiency has been reported in patients receiving azoles with or without concomitant corticosteroids. In patients receiving azoles without corticosteroids, adrenal insufficiency is related to direct inhibition of steroidogenesis by azoles. In patients taking corticosteroids, voriconazole associated 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 been reported 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 both during treatment and when voriconazole is discontinued (see section 4.5). Patients should be instructed to seek immediate medical care if they develop signs and symptoms of Cushing´s syndrome or adrenal insufficiency.

Long-term treatment

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

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

Non-infectious periostitis with elevated fluoride and alkaline phosphatase levels has been reported in transplant patients. If a patient develops skeletal pain and radiologic findings compatible with periostitis, voriconazole discontinuation should be considered after multidisciplinary advice (see section 4.8).

Visual adverse reactions

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

Renal adverse reactions

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 nephrotoxic medicinal products and have concurrent conditions that may result in decreased renal function (see section 4.8).

Monitoring of renal function

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

Monitoring of pancreatic function

Patients, especially children, with risk factors for acute pancreatitis (e.g., recent chemotherapy, haematopoietic stem cell transplantation [HSCT]), should be monitored closely during Voriconazole Aristo treatment. Monitoring of serum amylase or lipase may be considered in this clinical situation.

Paediatric population

Safety and effectiveness in paediatric subjects below the age of two years has not been established (see sections 4.8 and 5.1). Voriconazole is indicated for paediatric patients aged two years or older. A higher frequency of liver enzyme elevations was observed in the paediatric population (see section 4.8). Hepatic function should be monitored in both children and adults. Oral bioavailability may be limited in paediatric patients aged 2 to <12 years with malabsorption and very low body weight 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 evolution towards SCC has been reported, stringent measures for the photoprotection are warranted in this population of patients. In children experiencing photoaging injuries such as lentigines or ephelides, sun avoidance and dermatologic follow-up are recommended even after treatment discontinuation.

Prophylaxis

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 of alternative antifungal agents must be considered.

Phenytoin (CYP2C9 substrate and potent CYP450 inducer)

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

Efavirenz (CYP450 inducer; CYP3A4 inhibitor and substrate)

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

Glasdegib (CYP3A4 substrate)

Co-administration of voriconazole is expected to increase glasdegib plasma concentrations and increase the risk of QTc prolongation (see section 4.5). If concomitant use cannot be avoided, frequent ECG monitoring is recommended.

Tyrosine kinase inhibitors (CYP3A4 substrate)

Co-administration of voriconazole with tyrosine kinase inhibitors metabolised by CYP3A4 is expected to increase tyrosine kinase inhibitor plasma concentrations and the risk of adverse reactions. If concomitant use cannot be avoided, dose reduction of the tyrosine kinase inhibitor and close clinical monitoring is recommended (see section 4.5).

Rifabutin (Potent CYP450 inducer)

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

Ritonavir (potent CYP450 inducer; CYP3A4 inhibitor and substrate)

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

Everolimus (CYP3A4 substrate, P-gp substrate)

Co-administration of voriconazole with everolimus is not recommended because voriconazole is expected to significantly increase everolimus concentrations. Currently there are insufficient data to allow dosing recommendations in this situation (see section 4.5).

Methadone (CYP3A4 substrate)

Frequent monitoring for adverse reactions and toxicity related to methadone, including QTc prolongation, is recommended when co-administered with voriconazole since methadone levels increased following co-administration of voriconazole. Dose reduction of methadone may be needed (see section 4.5).

Short-acting opiates (CYP3A4 substrate)

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

Long-acting opiates (CYP3A4 substrate)

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

Fluconazole (CYP2C9, CYP2C19 and CYP3A4 inhibitor)

Co-administration of oral voriconazole and oral fluconazole resulted in a significant increase in Cmax and AUC of voriconazole in healthy subjects. The reduced dose and/or frequency of voriconazole and fluconazole that would eliminate this effect have not been established. Monitoring for voriconazole-associated adverse reactions is recommended if voriconazole is used sequentially after fluconazole (see section 4.5).

Excipients

Lactose

Voriconazole Aristo contains lactose and should not be given to patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet. Patients on low sodium diets should be informed that this medicinal product is essentially `sodium-free´.

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

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 voriconazole plasma concentrations, respectively, and there is potential for voriconazole to increase the plasma concentrations of substances metabolised by these CYP450 isoenzymes, in particular for substances metabolised by CYP3A4 since voriconazole is a strong CYP3A4 inhibitor though the increase in AUC is substrate dependent (see Table below).

Unless otherwise specified, drug interaction studies have been performed in healthy adult male subjects 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 is known to prolong QTc interval. When there is also a potential for voriconazole to increase the plasma concentrations of substances metabolised by CYP3A4 isoenzymes (certain antihistamines, quinidine, cisapride, pimozide and ivabradine), co-administration is contraindicated (see below and section 4.3).

Interaction table

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”) ordered by therapeutic class. The direction of the arrow for each pharmacokinetic parameter is based on the 90% confidence interval of the geometric mean ratio being within (↔), below (↓) or above (↑) the 80-125% range. The asterisk (*) indicates a two-way interaction. AUC, AUCt and AUC0-∞ represent area under the curve over a dosing interval, from time zero to the time with detectable measurement and from time zero to infinity, respectively.

Medicinal product

Interaction

Geometric mean changes (%)

Recommendations concerning co-administration

Antacids

Cimetidine (400 mg BID)

[non-specific CYP450 inhibitor and increases gastric pH]

Voriconazole Cmax ↑ 18%

Voriconazole AUC ↑ 23%

No dose adjustment

Omeprazole (40 mg QD)*

[CYP2C19 inhibitor; CYP2C19 and CYP3A4 substrate]

Omeprazole Cmax ↑ 116%

Omeprazole AUC ↑ 280%

Voriconazole Cmax ↑ 15%

Voriconazole AUC ↑ 41%

Other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of these medicinal products.

No dose adjustment of voriconazole is recommended.

When initiating voriconazole in patients already receiving omeprazole doses of 40 mg or above, it is recommended that the omeprazole dose be halved.

Ranitidine (150 mg BID)

[increases gastric pH]

Voriconazole Cmax and AUC ↔

No dose adjustment

Antiarrhythmics

Digoxin (0.25 mg QD)

[P-gp substrate]

Digoxin Cmax ↔

Digoxin AUC ↔

No dose adjustment

Quinidine

[CYP3A4 substrates]

Although not studied, increased plasma concentrations of quinidine can lead to QTc prolongation and rare occurrences of torsades de pointes.

Contraindicated (see section 4.3)

Antibacterials

Flucloxacillin

[CYP450 inducer]

Significantly decreased plasma voriconazole concentrations have been reported.

If concomitant administration of voriconazole with flucloxacillin cannot be avoided, monitor for potential loss of voriconazole effectiveness (e.g. by therapeutic drug monitoring); increasing the dose of voriconazole may be needed.

Macrolide antibiotics

Azithromycin (500 mg QD)

Erythromycin (1 g BID)

[CYP3A4 inhibitor]

Voriconazole Cmax and AUC ↔

Voriconazole Cmax and AUC ↔

The effect of voriconazole on either erythromycin or azithromycin is unknown.

No dose adjustment

Rifabutin

[potent CYP450 inducer]

300 mg QD

300 mg QD (coadministered with voriconazole 350 mg BID)*

300 mg QD (coadministered with voriconazole 400 mg BID)*

Voriconazole Cmax ↓ 69%

Voriconazole AUC ↓ 78%

Compared to voriconazole 200 mg BID,

Voriconazole Cmax ↓ 4%

Voriconazole AUC ↓ 32%

Rifabutin Cmax ↑ 195%

Rifabutin AUC ↑ 331%

Compared to voriconazole 200 mg BID,

Voriconazole Cmax ↑ 104%

Voriconazole AUC ↑ 87%

Concomitant use of voriconazole and rifabutin should be avoided unless the benefit outweighs the risk.

The maintenance dose of voriconazole may be increased to 5 mg/kg intravenously BID or from 200 mg to 350 mg orally BID (100 mg to 200 mg orally BID in patients less than 40 kg) (see section 4.2).

Careful monitoring of full blood counts and adverse reactions to rifabutin (e.g., uveitis) is recommended when rifabutin is coadministered with voriconazole.

Rifampicin (600 mg QD)

[potent CYP450 inducer]

Voriconazole Cmax ↓ 93%

Voriconazole AUC ↓96%

Contraindicated (see section 4.3)

Anti-cancer agents

Glasdegib

[CYP3A4 substrate]

Although not studied, voriconazol is likely to increase the plasma concentrations of glasdegib and increase risk of QTc prolongation.

If concomitant use cannot be avoided, frequent ECG monitoring is recommended (see section 4.4).

Tretinoin

[CYP3A4 substrate]

Although not studied, voriconazole may increase tretinoin concentrations and increase risk of adverse reactions (pseudotumor cerebri, hypercalcaemia).

Dose adjustment of tretinoin is recommended during treatment with voriconazole and after its discontinuation.

Tyrosine kinase inhibitors (including but not limited to: axitinib, bosutinib, cabozantinib, ceritinib, cobimetinib, dabrafenib, dasatinib, nilotinib, sunitinib, ibrutinib, ribociclib)

[CYP3A4 substrates]

Although not studied, voriconazole may increase plasma concentrations of tyrosine kinase inhibitors metabolised by CYP3A4.

If concomitant use cannot be avoided, dose reduction of the tyrosine kinase inhibitor and close clinical monitoring is recommended (see section 4.4).

Venetoclax

[CYP3A4 substrate]

Although not studied, voriconazole is likely to significantly increase the plasma concentrations of venetoclax

Concomitant administration of voriconazole is contraindicated at initiation and during venetoclax dose titration phase (see section 4.3). Dose reduction of venetoclax is required as instructed in venetoclax prescribing information during steady daily dosing; close monitoring for signs of toxicity is recommended.

Vinca Alkaloids (including but not limited to: vincristine and vinblastine)

[CYP3A4 substrates]

Although not studied, voriconazole is likely to increase the plasma concentrations of vinca alkaloids and lead to neurotoxicity.

Dose reduction of vinca alkaloids should be considered.

Anticoagulants

Warfarin (30 mg single dose, coadministered with 300 mg BID voriconazole)

[CYP2C9 substrate]

Other oral coumarins (including but not limited to: phenprocoumon, acenocoumarol)

[CYP2C9 and CYP3A4 substrates]

Maximum increase in prothrombin time was approximately 2-fold.

Although not studied, voriconazole may increase the plasma concentrations of coumarins that may cause an increase in prothrombin time.

Close monitoring of prothrombin time or other suitable anticoagulation tests is recommended, and the dose of anticoagulants should be adjusted accordingly.

Anticonvulsants

Carbamazepine and long-acting barbiturates (including but not limited to phenobarbital, mephobarbital)

[potent CYP450 inducers]

Although not studied, carbamazepine and long-acting barbiturates are likely to significantly decrease plasma voriconazole concentrations.

Contraindicated (see section 4.3)

Phenytoin

[CYP2C9 substrate and potent CYP450 inducer]

300 mg QD

300 mg QD (co-administered with voriconazole 400 mg BID)*

Voriconazole Cmax ↓ 49%

Voriconazole AUC ↓ 69%

Phenytoin Cmax ↑ 67%

Phenytoin AUC ↑ 81%

Compared to voriconazole 200 mg BID,

Voriconazole Cmax ↑ 34%

Voriconazole AUC ↑ 39%

Concomitant use of voriconazole and phenytoin should be avoided unless the benefit outweighs the risk. Careful monitoring of phenytoin plasma levels is recommended.

Phenytoin may be co-administered with voriconazole if the maintenance dose of voriconazole is increased to 5 mg/kg IV BID or from 200 mg to 400 mg oral BID (100 mg to 200 mg oral BID in patients less than 40 kg) (see section 4.2).

Antidiabetics

Sulphonylureas (including but not limited to: tolbutamide, glipizide, glyburide)

[CYP2C9 substrates]

Although not studied, voriconazole is likely to increase the plasma concentrations of sulphonylureas and cause hypoglycaemia.

Careful monitoring of blood glucose is recommended. Dose reduction of sulfonylureas should be considered.

Anti-fungals

Fluconazole (200 mg QD)

[CYP2C9, CYP2C19 and CYP3A4 inhibitor]

Voriconazole Cmax ↑ 57%

Voriconazole AUC ↑ 79%

Fluconazole Cmax ND

Fluconazole AUC ND

The reduced dose and/or frequency of voriconazole and fluconazole that would eliminate this effect have not been established. Monitoring for voriconazole-associated adverse reactions is recommended if voriconazole is used sequentially after fluconazole.

Antihistamines

Astemizole

[CYP3A4 substrate]

Although not studied, increased plasma concentrations of astemizole can lead to QTc prolongation and rare ocurrences of torsades de pointes.

Contraindicated (see section 4.3)

Terfenadine

[CYP3A4 substrate]

Although not studied, increased plasma concentrations of terfenadine can lead to QTc prolongation and rare ocurrences of torsades de pointes.

Contraindicated (see section 4.3)

Anti HIV agents

Indinavir (800 mg TID)

[CYP3A4 inhibitor and substrate]

Indinavir Cmax ↔

Indinavir AUC ↔

Voriconazole Cmax ↔

Voriconazole AUC ↔

No dose adjustment

Ritonavir (protease inhibitor)

[potent CYP450 inducer; CYP3A4 inhibitor and substrate]

High dose (400 mg BID)

Low dose (100 mg BID)*

Ritonavir Cmax and AUC ↔

Voriconazole Cmax ↓ 66%

Voriconazole AUC ↓ 82%

Ritonavir Cmax ↓ 25%

Ritonavir AUC ↓13%

Voriconazole Cmax ↓ 24%

Voriconazole AUC ↓ 39%

Coadministration of voriconazole and high doses of ritonavir (400 mg and above BID) is contraindicated (see section 4.3).

Coadministration of voriconazole and low-dose ritonavir (100 mg BID) should be avoided unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.

Other HIV Protease Inhibitors (including but not limited to: saquinavir, amprenavir and nelfinavir)*

[CYP3A4 substrates and inhibitors]

Not studied clinically. In vitro studies show that voriconazole may inhibit the metabolism of HIV protease inhibitors and the metabolism of voriconazole may also be inhibited by HIV protease inhibitors.

Careful monitoring for any occurrence of drug toxicity and/or lack of efficacy, and dose adjustment may be needed.

Efavirenz (a non-nucleoside reverse transcriptase inhibitor)(NNRTI)

[CYP450 inducer; CYP3A4 inhibitor and substrate]

Efavirenz 400 mg QD, co-administered with voriconazole 200 mg BID*

Efavirenz 300 mg QD, co-administered with voriconazole 400 mg BID*

Efavirenz Cmax ↑ 38%

Efavirenz AUC ↑44%

Voriconazole Cmax↓61%

Voriconazole AUC ↓ 77%

Compared to efavirenz 600 mg QD, Efavirenz Cmax ↔

Efavirenz AUC ↑ 17%

Compared to voriconazole 200 mg BID,

Voriconazole Cmax ↑ 23%

Voriconazole AUC ↓ 7%

Use of standard doses of voriconazole with efavirenz doses of 400 mg QD or higher is contraindicated (see section 4.3).

Voriconazole may be co-administered with efavirenz if the voriconazole maintenance dose is increased to 400 mg BID and the efavirenz dose is decreased to 300 mg QD. When voriconazole treatment is stopped, the initial dose of efavirenz should be restored (see section 4.2 and 4.4).

Other Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) (including but not limited to: delavirdine, nevirapine)*

[CYP3A4 substrates, inhibitors or CYP450 inducers]

Not studied clinically. In vitro studies show that the metabolism of voriconazole may be inhibited by NNRTIs and voriconazole may inhibit the metabolism of NNRTIs. The findings of the effect of efavirenz on voriconazole suggest that the metabolism of voriconazole may be induced by an NNRTI.

Careful monitoring for any occurrence of drug toxicity and/or lack of efficacy, and dose adjustment may be needed.

Antipsychotics

Lurasidone

[CYP3A4 substrate]

Although not studied, voriconazole is likely to significantly increase the plasma concentrations of lurasidone.

Contraindicated (see section 4.3)

Pimozide

[CYP3A4 substrate]

Although not studied, increased plasma concentrations of pimozide can lead to QTc prolongation and rare occurrences of torsades de pointes.

Contraindicated (see section 4.3)

Anti virals

Letermovir

[CYP2C9 and CYP2C19 inducer]

Voriconazole Cmax ↓ 39%

Voriconazole AUC0-12 ↓ 44%

Voriconazole C12 ↓ 51%

If concomitant administration of voriconazole with letermovir cannot be avoided, monitor for loss of voriconazole effectiveness.

Benzodiazepines

[CYP3A4 substrates]

Midazolam (0.05 mg/kg IV single dose)

Midazolam (7.5 mg oral single dose)

Other benzodiazepines (including but not limited to: triazolam, alprazolam)

In an independent published study, Midazolam AUC0-∞ ↑ 3.7-fold.

In an independent published study, Midazolam Cmax ↑ 3.8-fold

Midazolam AUC0-∞ ↑ 10.3-fold

Although not studied, voriconazole is likely to increase the plasma concentrations of other benzodiazepines that are metabolised by CYP3A4 and lead to a prolonged sedative effect.

Dose reduction of benzodiazepines should be considered.

Cardiovascular agents

Ivabradine

[CYP3A4 substrates]

Although not studied, increased plasma concentrations of ivabradine can lead to QTc prolongation and rare occurrences of torsades de pointes.

Contraindicated (see section 4.3)

Cystic fibrosis transmembrane conductance regulator potentiators

Ivacaftor

[CYP3A4 substrate]

Although not studied, voriconazole is likely to increase the plasma concentrations of ivacaftor with risk of increased adverse reactions.

Dose reduction of ivacaftor is recommended.

Ergot derivatives

Ergot alkaloids (including but not limited to ergotamine and dihydroergotamine)

[CYP3A4 substrates]

Although not studied, voriconazole is likely to increase the plasma concentrations of ergot alkaloids and lead to ergotism.

Contraindicated (see section 4.3)

GI motility agents

Cisapride

[CYP3A4 substrate]

Although not studied, increased plasma concentrations of cisapride can lead to QTc prolongation and rare occurrences of torsades de pointes.

Contraindicated (see section 4.3)

Herbal medicines

St. John's Wort

[CYP450 inducer;

P-gp inducer]

300 mg TID (co-administered with voriconazole 400 mg single dose)

In an independent published study, Voriconazole AUC0-∞ ↓ 59%

Contraindicated (see section 4.3)

Inmunosupressants

[CYP3A4 substrates]

Ciclosporin (in stable renal transplant recipients receiving chronic ciclosporin therapy)

Everolimus

[also P-gP substrate]

Sirolimus (2 mg single dose)

Tacrolimus (0.1 mg/kg single dose)

Ciclosporin Cmax ↑ 13%

Ciclosporin AUC ↑ 70%

Although not studied, voriconazole is likely to significantly increase the plasma concentrations of everolimus.

In an independent published study, Sirolimus Cmax ↑ 6.6-fold

Sirolimus AUC0-∞ ↑ 11-fold

Tacrolimus Cmax ↑ 117%

Tacrolimus AUCt ↑ 221%

When initiating voriconazole in patients already on ciclosporin it is recommended that the ciclosporin dose be halved and ciclosporin level carefully monitored. Increased ciclosporin levels have been associated with nephrotoxicity. When voriconazole is discontinued, ciclosporin levels must be carefully monitored and the dose increased as necessary.

Coadministration of voriconazole and everolimus is not recommended because voriconazole is expected to significantly increase everolimus concentrations (see section 4.4).

Coadministration of voriconazole and sirolimus is contraindicated (see section 4.3).

When initiating voriconazole in patients already on tacrolimus, it is recommended that the tacrolimus dose be reduced to a third of the original dose and tacrolimus level carefully monitored. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus levels must be carefully monitored and the dose increased as necessary.

Mycophenolic acid (1 g single dose)

[UDP-glucuronyl transferase substrate]

Mycophenolic acid Cmax ↔

Mycophenolic acid AUCt ↔

No dose adjustment

Lipid lowering agents/HMG-CoA reductase inhibitors

Statins (e.g., lovastatin)

[CYP3A4 substrates]

Although not studied, voriconazole is likely to increase the plasma concentrations of statins that are metabolised by CYP3A4 and could lead to rhabdomyolysis.

If concomitant administration of voriconazole with statins metabolised by CYP3A4 cannot be avoided, dose reduction of the statin should be considered.

Non-steroidal selective mineralocorticoid receptor (MR) antagonist

Finerenone

[CYP3A4 substrate]

Although not studied, voriconazole is likely to significantly increase the plasma concentrations of finerenone.

Contraindicated (see section 4.3)

Non-steroidal anti-inflammatory drugs (NSAIDs)

[CYP2C9 substrates]

Ibuprofen (400 mg single dose)

Diclofenac (50 mg single dose)

S-Ibuprofen Cmax ↑ 20%

S-Ibuprofen AUC0-∞ ↑ 100%

Diclofenac Cmax ↑ 114%

Diclofenac AUC0-∞ ↑ 78%

Frequent monitoring for adverse reactions and toxicity related to NSAIDs is recommended. Dose reduction of NSAIDs may be needed.

Opioids

Long-Acting Opiates

[CYP3A4 substrates]

Oxycodone (10 mg single dose)

In an independent published study,

Oxycodone Cmax ↑ 1.7-fold

Oxycodone AUC0-∞ ↑ 3.6-fold

Dose reduction in oxycodone and other long-acting opiates metabolized by CYP3A4 (e.g., hydrocodone) should be considered. Frequent monitoring for opiate-associated adverse reactions may be necessary.

Methadone (32-100 mg QD)

[CYP3A4 substrate]

R-methadone (active) Cmax ↑ 31%

R-methadone (active) AUC ↑ 47%

S-methadone Cmax ↑ 65%

S-methadone AUC ↑ 103%

Frequent monitoring for adverse reactions and toxicity related to methadone, including QTc prolongation, is recommended. Dose reduction of methadone may be needed.

Short-acting Opiates

[CYP3A4 substrates]

Alfentanil (20 μg/kg single dose, with concomitant naloxone)

Fentanyl (5 µg/kg single dose)

In an independent published study, Alfentanil AUC0-∞ ↑ 6-fold

In an independent published study,

Fentanyl AUC0-∞ ↑ 1.34-fold

Dose reduction of alfentanil, fentanyl and other short-acting opiates similar in structure to alfentanil and metabolised by CYP3A4 (e.g., sufentanil) should be considered. Extended and frequent monitoring for respiratory depression and other opiate-associated adverse reactions is recommended.

Opioid receptor antagonists

Naloxegol

[CYP3A4 substrate]

Although not studied, voriconazole is likely to significantly increase the plasma concentrations of naloxegol.

Contraindicated (see section 4.3)

Oral contraceptives

Oral Contraceptives*

[CYP3A4 substrate; CYP2C19 inhibitor]

Norethisterone/ ethinylestradiol

(1 mg/0.035 mg QD)

Ethinylestradiol Cmax ↑ 36%

Ethinylestradiol AUC ↑ 61%

Norethisterone Cmax ↑ 15%

Norethisterone AUC ↑ 53%

Voriconazole Cmax ↑ 14%

Voriconazole AUC ↑ 46%

Monitoring for adverse reactions related to oral contraceptives, in addition to those for voriconazole, is recommended.

Steroids

Corticosteroids

Prednisolone (60 mg single dose)

[CYP3A4 substrate]

Prednisolone Cmax ↑ 11%

Prednisolone AUC0-∞ ↑ 34%

No dose adjustment

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 both during treatment and when voriconazole is discontinued (see section 4.4).

Vasopressin receptor antagonists

Tolvaptan

[CYP3A4 substrate]

Although not studied, voriconazole is likely to significantly increase the plasma concentrations of tolvaptan.

Contraindicated (see section 4.3)

4.6. Fertility, pregnancy and lactation

Pregnancy

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

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

Voriconazole Aristo must not be used during pregnancy unless the benefit to the mother clearly outweighs the potential risk to the foetus.

Women of child-bearing potential

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

Breast-feeding

The excretion of voriconazole into breast milk has not been investigated. Breast-feeding must be stopped on initiation of treatment with Voriconazole Aristo.

Fertility

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

4.7. Effects on ability to drive and use machines

Voriconazole Aristo has moderate influence on the ability to drive and use machines. It may cause transient and reversible 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 experiencing these symptoms.

4.8. Undesirable effects

Summary of safety profile

The safety profile of voriconazole in adults is based on an integrated safety database of more than 2,000 subjects (including 1,603 adult patients in therapeutic trials) and an additional 270 adults in prophylaxis trials. This represents a heterogeneous population, containing patients with haematological malignancy, 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 abdominal pain.

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

Tabulated list of adverse reactions

In the table below, since the majority of the studies were of an open nature, all causality adverse reactions and 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 estimated 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 Organ Class

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

Frequency not known (cannot be estimated from available data)

Infections and Infestation

sinusitis

pseudomembranous colitis

Neoplasms benign, malignant and unspecified (including cysts and polyps)

squamous cell carcinoma (including cutaneous SCC in situ, or Bowen's disease)*,**

Blood and lymphatic system disorders

agranulocytosis1, pancytopenia, thrombocytopenia2, leukopenia, anaemia,

bone marrow failure, lymphadenopathy, eosinophilia

disseminated intravascular coagulation

Immune system disorders

hypersensitivity

anaphylactoid reaction

Endocrine disorders

adrenal insufficiency, hypothyroidism

hyperthyroidism

Metabolism and nutrition disorders

oedema peripheral

hypoglycaemia, hypokalaemia, hyponatraemia

Psychiatric disorders

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

Nervous system disorders

headache

convulsion, syncope, tremor, hypertonia3, paraesthesia, somnolence, dizziness

brain oedema, encephalopathy4, extrapyramidal disorder5, neuropathy peripheral, ataxia, hypoaesthesia, dysgeusia

hepatic encephalopathy, Guillain-Barre syndrome, nystagmus

Eye disorders

visual impairment6

retinal haemorrhage

optic nerve disorder7, papilloedema8, oculogyric crisis, diplopia, scleritis, blepharitis

optic atrophy, corneal opacity

Ear and labyrinth disorders

hypoacusis, vertigo, tinnitus

Cardiac disorders

arrhythmia supraventricular, tachycardia, bradycardia

ventricular fibrillation, ventricular extrasystoles, ventricular tachycardia, electrocardiogram QT prolonged, supraventricular tachycardia

torsade de pointes, atrioventricular block complete, bundle branch block, nodal rhythm

Vascular disorders

hypotension, phlebitis

thrombophlebitis, lymphangitis

Respiratory, thoracic and mediastinal disorders

respiratory distress9

acute respiratory distress syndrome, pulmonary oedema

Gastrointestinal disorders

diarrhoea, vomiting, abdominal pain, nausea

cheilitis, dyspepsia, constipation, gingivitis

peritonitis, pancreatitis, swollen tongue, duodenitis, gastroenteritis, glossitis

Hepatobiliary disorders

liver function test abnormal

jaundice, jaundice cholestatic, hepatitis10

hepatic failure, hepatomegaly, cholecystitis, cholelithiasis

Skin and subcutaneous tissue disorders

rash

dermatitis exfoliative, alopecia, rash maculo-papular, pruritus, erythema, phototoxicity**

Stevens-Johnson syndrome8, purpura, urticaria, dermatitis allergic, rash papular, rash macular, eczema

toxic epidermal necrolysis8, drug reaction with eosinophilia and systemic symptoms (DRESS)8, angioedema, actinic keratosis*, pseudoporphyria, erythema multiforme, psoriasis, drug eruption

cutaneous lupus erythematosus*, ephelides*, lentigo*

Musculoskeletal and connective tissue disorders

back pain

Arthritis, periostitis*,**

Renal and urinary disorders

renal failure acute, haematuria

renal tubular necrosis, proteinuria, nephritis

General disorders and administration site conditions

pyrexia

chest pain, face oedema11, asthenia, chills

infusion site reaction, influenza like illness

Investigations

blood creatinine increased

blood urea increased, blood cholesterol increased

*ADR identified post-marketing

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

1Includes febrile neutropenia and neutropenia

2Includes immune thrombocytopenic purpura

3Includes nuchal rigidity and tetany

4Includes hypoxic-ischaemic encephalopathy and metabolic encephalopathy

5Includes akathisia and parkinsonism

6See “Visual impairments” paragraph in section 4.8.

7Prolonged optic neuritis has been reported post-marketing. See section 4.4.

8See section 4.4.

9Includes dyspnoea and dyspnoea exertional.

10Includes drug-induced liver injury, hepatitis toxic, hepatocellular injury and hepatotoxicity.

11Includes periorbital oedema, lip oedema and mouth oedema.

Description of selected adverse reactions

Visual impairments

In clinical trials, visual impairment (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 and xanthopsia) with voriconazole were very common. These visual impairments were transient and fully reversible, with the majority spontaneously resolving within 60 minutes and no clinically significant long-term visual effects were observed. There was evidence of attenuation with repeated doses of voriconazole. The visual impairments were generally mild, rarely resulted in discontinuation and were not associated with long-term sequelae. 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 a study in healthy volunteers investigating the impact of voriconazole on retinal function, voriconazole caused a decrease in the electroretinogram (ERG) waveform amplitude. The ERG measures electrical currents in the retina. The ERG changes did not progress over 29 days of treatment and were fully reversible on withdrawal of voriconazole.

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

Dermatological reactions

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

If a patient develops a rash they should be monitored closely and Voriconazole Aristo discontinued if lesions progress. Photosensitivity reactions such as ephelides, lentigo and actinic keratosis have been reported, 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 for long periods of time; the mechanism has not been established (see section 4.4).

Liver function tests

The overall incidence of transaminase increases > 3x ULN (not necessarily comprising an adverse event) in the voriconazole clinical programme was 18.0 % (319/1,768) in adults and 25.8 % (73/283) in paediatric subjects who received voriconazole for pooled therapeutic and prophylaxis use. Liver function test abnormalities may be associated with higher plasma concentrations and/or doses. The majority of abnormal liver 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 serious underlying conditions. This includes cases of jaundice, hepatitis and hepatic failure leading to death (see section 4.4).

Prophylaxis

In an open-label, comparative, multicenter study comparing voriconazole and itraconazole as primary prophylaxis 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% of subjects in the itraconazole arm. Treatment-emergent hepatic AEs resulted in permanent discontinuation of study medication for 50 subjects (21.4%) treated with voriconazole and for 18 subjects (7.1%) treated with itraconazole.

Paediatric population

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 in compassionate use programmes. Overall, the safety profile of voriconazole in paediatric population was similar to that in adults. However, a trend towards a higher frequency of liver enzyme elevations, reported as adverse 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 might be a higher occurrence of skin reactions (especially erythema) in the paediatric population compared to adults. 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) 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 of suspected adverse reactions

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

4.9. Overdose

In clinical trials there were 3 cases of accidental overdose. All occurred in paediatric patients, who received up to five times the recommended intravenous dose of voriconazole. A single adverse reaction 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 may assist in the removal of voriconazole from the body.