SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Voriconazole Apotex 200 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Voriconazole Apotex 200 mg film-coated tablets:

Each tablet contains 200 mg voriconazole

Excipient(s) with known effect: each tablet contains 364.00 mg lactose monohydrate. For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablets. White coloured, modified oval-shaped, bi-convex film-coated tablet (size: 15.50 x 7.90 mm), engraved “APO” on one side and “VOR 200” on the other side.

4    CLINICAL PARTICULARS

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 candidemia 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 tablets 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).

Voriconazole tablets are available as 200 mg film-coated tablets.

Adults

Therapy must be initiated with the specified loading dose regimen of either intravenous or oral Voriconazole tablets 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.

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 (Adult)

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)

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 comparedto 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 treatmentrelated 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 coadministered 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 coadministered 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 tablets has not been studied in patients with severe chronic hepatic cirrhosis (Child-Pugh C).

There is limited data on the safety of Voriconazole tablets in patients with abnormal liver function tests (aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (AP), 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 hepatic impairment must be carefully monitored for drug toxicity (see section 4.8).

Paediatric population

The safety and efficacy of Voriconazole tablets 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 tablets are to be taken at least one hour before, or one hour following a meal.

Contraindications

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

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

Coadministration with rifampicin, carbamazepine and phenobarbital since these medicinal products are likely to decrease plasma voriconazole concentrations significantly (see section 4.5).

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

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

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

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

Coadministration with St John’s Wort (see section 4.5).

4.4 Special warnings and precautions for use

Hypersensitivity

Caution should be used in prescribing Voriconazole tablet 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 uncommon 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 tablets 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 tablets and at least weekly for the first month of treatment. Treatment 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 tablets 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.

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

Dermatological adverse reactions

Patients have rarely developed exfoliative cutaneous reactions, such as Stevens-Johnson syndrome, during treatment with Voriconazole tablets. If patients develop a rash they should be monitored closely and Voriconazole tablets discontinued if lesions progress.

In addition Voriconazole tablets have been associated with phototoxicity and pseudoporphyria. It is recommended that all patients, including children, avoid intense or prolonged exposure to direct sunlight during Voriconazole tablets treatment and use measures such as protective clothing and sunscreen with high sun protection factor (SPF).

Long-term treatment

The following severe adverse events have been reported in relation with long-term Voriconazole tablets treatment; physicians should therefore consider the need to limit the exposure to Voriconazole tablets (see sections 4.2 and 5.1):

Squamous cell carcinoma of the skin has been reported in patients, some of whom have reported prior phototoxic reactions. If phototoxic reactions occur, multidisciplinary advice should be sought and the patient should be referred to a dermatologist. Voriconazole tablets discontinuation should be considered. Dermatologic evaluation should be performed on a systematic and regular basis, whenever Voriconazole tablets are continued despite the occurrence of phototoxicity-related lesions, to allow early detection and management of premalignant lesions. Voriconazole tablets should be discontinued if premalignant skin lesions or squamous cell carcinoma are identified.

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 tablets discontinuation should be considered after multidisciplinary advice.

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. 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.

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 dermatologicfollow-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 that of efavirenz should be decreased to 300 mg every 24 hours (see sections 4.2, 4.3 and 4.5).

Rifabutin (CYP450 inducer)

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

Coadministration 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 4.5 and 4.3).

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 coadministered 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 coadministered with voriconazole and in an independent published study, concomitant use of voriconazole with fentanyl resulted in an increase in the mean AUC0-oo 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 coadministered with voriconazole. Frequent monitoring for opiate-associated adverse reactions may be necessary (see section 4.5).

Fluconazole (CYP2C9, CYP2C19 and CYP3A4 inhibitor)

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

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

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.

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) coadministration 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”). The direction of the arrow for each pharmacokinetic parameter is based on the 90% confidence interval of the geometric mean ratio being within («■), below Q.) or above (|) the 80-125% range. The asterisk (*) indicates a two-way interaction. AUCr, AUCt and AUC0-co 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.

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

Medicinal product [Mechanism of Interaction]	Interaction Geometric mean changes (%)	Recommendations concerning co-administration
Astemizole, cisapride, pimozide, quinidine and terfenadine [CYP3A4 substrates]	Although not studied, increased plasma concentrations of these medicinal products can lead to QTc prolongation and rare occurrences of torsades de pointes.	Contraindicated (see section 4.3)
Carbamazepine and long-acting barbiturates (e.g., 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)

Medicinal product

[Mechanism of Interaction]

Interaction

Geometric mean changes (%)

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

Efavirenz (a non-nucleoside reverse transcriptase inhibitor) [CYP450 inducer; CYP3A4 inhibitor and substrate]

Efavirenz 400 mg QD,

coadministered    with

*

voriconazole 200 mg BID

Efavirenz 300 mg QD, administered

voriconazole 400 mg BID

Voriconazole may be co administered with efavirenz if th voriconazole maintenance dose i increased to 400 mg BID and th efavirenz dose is decreased to 30 mg QD. When voriconazol treatment is stopped, the initia dose of efavirenz should b restored (see section 4.2 and 4.4).

Medicinal product [Mechanism of Interaction]	Interaction Geometric mean changes (%)	Recommendations concerning co-administration
Ergot alkaloids (e.g., 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)

St John’s Wort [CYP450 inducer; P- gp inducer] 300 mg TID (coadministered with voriconazole 400 mg single dose)	In an independent published study, Voriconazole AUC0-ot | 59%	Contraindicated (see section 4.3)
Everolimus [CYP3A4 substrate, PgP substrate]	Although not studied, voriconazole is likely to significantly increase the plasma concentrations of everolimus.	Co-administration of voriconazole with everolimus is not recommended because voriconazole is expected to significantly increase everolimus concentrations (see section 4.4).

Medicinal product [Mechanism of Interaction]	Interaction Geometric mean changes (%)	Recommendations concerning co-administration
Fluconazole (200 mg QD) [CYP2C9, CYP2C19 and CYP3A4 inhibitor]	Voriconazole Cmax t 57% Voriconazole AUCt t 79% Fluconazole Cmax ND Fluconazole AUCt ND	The reduced dose and/or frequency of voriconazole and fluconazole that would eliminate this effect have not been established. Monitoring for vori conazole-associ ated adverse reactions is recommended if voriconazole is used sequentially after fluconazole.
Phenytoin [CYP2C9 substrate and potent CYP450 inducer] 300 mg QD 300 mg QD (coadministered with voriconazole 400 mg * BID)	Voriconazole Cmax i 49% Voriconazole AUCt i 69% Phenytoin Cmax t 67% Phenytoin AUCt t 81% Compared to voriconazole 200 mg BID, Voriconazole Cmax t 34% Voriconazole AUCt t 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).

Methadone (32-100 mg QD) [CYP3A4 substrate]	R-methadone (active) Cmax t 31% R-methadone (active) AUCt t 47% S-methadone Cmax t 65% S-methadone AUCt t 103%	Frequent monitoring for adverse reactions and toxicity related to methadone, including QTc prolongation, is recommended. Dose reduction of methadone may be needed.
Non-Steroidal AntiInflammatory Drugs (NSAIDs) [CYP2C9 substrates] Ibuprofen (400 mg single dose) Diclofenac (50 mg single dose)	S-Ibuprofen Cmax t 20% S-Ibuprofen AUC0-ot t 100% Diclofenac Cmax t 114% Diclofenac AUC0-ot t 78%	Frequent monitoring for adverse reactions and toxicity related to NSAIDs is recommended. Dose reduction of NSAIDs may be needed.

Medicinal product [Mechanism of Interaction]	Interaction Geometric mean changes (%)	Recommendations concerning co-administration
Omeprazole (40 mg QD)* [CYP2C19 inhibitor; CYP2C19 and CYP3A4 substrate]	Omeprazole Cmax t 116% Omeprazole AUCt t 280% Voriconazole Cmax t 15% Voriconazole AUCt t 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.
* Oral Contraceptives [CYP3A4 substrate; CYP2C19 inhibitor] N orethi sterone/ ethi nyl es tradiol (1 mg/0.035 mg QD)	Ethinylestradiol Cmax t 36% Ethinylestradiol AUCt t 61% Nor ethi sterone Cmax t 15% Norethisterone AUCt t 53% Voriconazole Cmax t 14% Voriconazole AUCt t 46%	Monitoring for adverse reactions related to oral contraceptives, in addition to those for voriconazole, is recommended.

Mycophenolic acid (1 g single dose) [UDP-glucuronyl transferase substrate]	Mycophenolic acid Cmax ^ Mycophenolic acid AUCt ^	No dose adjustment
Prednisolone (60 mg single dose) [CYP3A4 substrate]	Prednisolone Cmax T 11% Prednisolone AUC0-ot T 34%	No dose adjustment
Ranitidine (150 mg BID) [increases gastric pH]	Voriconazole Cmax and AUCt ^	No dose adjustment

4.6 Fertility, pregnancy and lactation

Pregnancy

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

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

Voriconazole tablets 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.

Breastfeeding

The excretion of voriconazole into breast milk has not been investigated. Breastfeeding must be stopped on initiation of treatment with Voriconazole tablets.

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 tablets have 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 is based on an integrated safety database of more than 2,000 subjects (1,655 patients in therapeutic trials). This represents a heterogeneous population, containing patients with haematological malignancy, HIV infected patients with oesophageal candidiasis and refractory fungal infections, nonneutropenic patients with candidaemia or aspergillosis and healthy volunteers. Seven hundred and five (705) patients had a duration of voriconazole therapy of greater than 12 weeks, with 164 patients receiving voriconazole for over 6 months.

The most commonly reported adverse reactions were visual disturbances, 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, by system organ class and frequency 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	Adverse drug reactions
Infections and infestation
Common	Gastroenteritis, influenza-like illness
Rare	Pseudomembranous colitis
Neoplasms Benign, Malignant and Unspecified (including cysts and polyps)

Not known	Squamous cell carcinoma*
Blood and lymphatic system disorders
Common	Agranulocytosis, Pancytopenia, thrombocytopenia, anaemia leukopenia, , purpura
Uncommon	Disseminated intravascular coagulation, bone marrow failure, leukopenia, lymphadenopathy, eosinophilia
Immune system disorders
Common	Hypersensitivity
Uncommon	Anaphylactoid reaction
Endocrine disorders
Uncommon	Adrenal insufficiency, hypothyroidism
Rare	Hyperthyroidism
Metabolism and nutrition disorders
Very common	Oedema peripheral
Common	Hypoglycaemia, hypokalaemia, hyponatremia
Psychiatric disorders
Common	Depression, hallucination, anxiety, insomnia, agitation, confusional state
Nervous system disorders
Very common	Headache
Common	Convulsion, tremor, paraesthesia, hypertonia, somnolence, syncope, dizziness
Uncommon	Brain oedema, encephalopathy, extrapyramidal disorder, neuropathy peripheral, ataxia, hypoaesthesia, dysgeusia, nystagmus
Rare	Hepatic encephalopathy, Guillain-Barre syndrome

Eye disorders
Very common	Visual disturbances (including blurred vision (see section 4.4), chromatopsia and photophobia)
Uncommon	Oculogyric crisis, Optic nerve disorder (including opticneuritis, see section 4.4), Papilloedema (see section 4.4), scleritis, blepharitis, diplopia
Rare	Optic atrophy, corneal opacity
Ear and labyrinth disorders
Uncommon	Hypoacusis, vertigo, tinnitus

Cardiac disorders

Very common	Oedema peripheral
Uncommon	Ventricular fibrillation, ventricular extrasystoles, supraventricular tachycardia, ventricular tachycardia
Rare	Torsades de pointes, atrioventricular block complete, bundle branch block, nodal rhythm
Vascular disorders
Common	Hypotension, phlebitis
Uncommon	Thrombophlebitis
Respiratory, thoracic and mediastinal disorders
Very common	Respiratory distress
Common	Acute respiratory distress syndrome, pulmonary
Gastrointestinal disorders
Very common	Abdominal pain, nausea, vomiting, diarrhoea
Uncommon	Dyspepsia, constipation, cheilitis
Hepatobiliary disorders
Very common	Liver function test abnormal (including AST, ALT, alkaline phosphatase, gamma-glutamyl transpeptidase [GGT], lactate dehydrogenase [LDH], bilirubin)
Common	Jaundice, jaundice cholestatic, hepatitis
Uncommon	Hepatic failure, hepatitis, hepatomegaly, cholecystitis, cholelithiasis

Skin and subcutaneous tissue disorders
Very common	Rash
Common	Dermatitis exfoliative, rash maculo-papular, pruritus, alopecia, erythema
Uncommon	Fixed drug eruption, Stevens-Johnson syndrome, angioneurotic oedema, psoriasis, urticaria, dermatitis allergic, phototoxicity, rash macular, rash papular, purpura, eczema
Rare	Pseudoporphyria, fixed drug eruption
Not known	Cutaneous lupus erythematosis*
Musculoskeletal and connective tissue disorders
Common	Back pain
Uncommon	Arthritis
Not known	Periostitis
Renal and urinary disorders
Common	Renal failure acute, haematuria
Uncommon	Renal tubular necrosis, proteinuria, nephritis

General disorders and administ	rative site conditions
Very common	Pyrexia
Common	Chest pain, face oedema, asthenia, influenza like illness, chills
Uncommon	Injection site reaction
Investigations
Common	Blood creatinine increased
Uncommon	Electrocardiogram QTc prolonged, blood urea increased, blood cholesterol increased

*Undesirable events identified during post-approval use

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

Description of selected adverse reactions

Visual disturbances

In clinical trials, visual disturbances with voriconazole were very common. In these studies, short-term as well as long-term treatment, approximately 21 % of subjects experienced altered/enhanced visual perception, blurred vision, colour vision change or photophobia. These visual disturbances 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 disturbances were generally mild, rarely resulted in discontinuation and were not associated with long-term sequelae. Visual disturbances 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 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 rarely developed serious cutaneous reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme during treatment with Voriconazole tablet.

If patients develop a rash they should be monitored closely and Voriconazole tablets discontinued if lesions progress. Photosensitivity reactions have been reported, especially during long-term therapy (see section 4.4).

There have been reports of squamous cell carcinoma of the skin in patients treated with Voriconazole tablet for long periods of time; the mechanism has not been established (see section 4.4).

Liver function tests

The overall incidence of clinically significant transaminase abnormalities in the voriconazole clinical programme was 13.5 % (258/1918) of subjects treated with voriconazole. 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 infrequently associated with cases of serious hepatic toxicity in patients with other serious underlying conditions. This includes cases of jaundice, and rare cases of 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 285 paediatric patients aged 2 to <12 years who were treated with voriconazole in pharmacokinetic studies (127 paediatric patients) and in compassionate use programmes (158 paediatric patients). The adverse reaction profile of these 285 paediatric patients was similar to that in adults. Postmarketing 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.

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.

5 PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

Pharmacotherapetic group: Antimycotics for systemic use, triazole derivatives, ATC: J02AC03

Mode of Action

Voriconazole is a triazole antifungal agent. The primary mode of action of voriconazole is the inhibition of fungal cytochrome P-450-mediated 14 alpha-lanosterol demethylation, an essential step in fungal ergosterol biosynthesis. The accumulation of 14 alpha-methyl sterols correlates with the subsequent loss of ergosterol in the fungal cell membrane and may be responsible for the antifungal activity 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.

Pharmacokinetic/Pharmacodynamic Relationship

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

Pharmacokinetic-Pharmacodynamic analyses of clinical trial data identified positive associations between plasma voriconazole concentrations and both liver function test abnormalities and visual disturbances.

Clinical efficacy and safety

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 shows in vitro fungicidal activity against emerging fungal pathogens, including those such as Scedosporium or 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 cases of 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. including T. 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 inhibited by concentrations of voriconazole in the range 0.05 to 2 pg/ml.

In vitro activity against the following pathogens has been shown, but the clinical significance is unknown: Curvularia spp. and Sporothrix spp.

Breakpoints

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

The species most frequently involved in causing human infections include C. albicans, C. parapsilosis, C. tropicalis, C. glabrata and C. krusei, all of which usually exhibit 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 than are 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 be interpreted using breakpoint criteria established by European Committee on Antimicrobial Susceptibility Testing (EUCAST).

EUCAST Breakpoints

Candida Species	MIC breakpoint (mg/L)
	<S (Susceptible)	>R (Resistant)
1 Candida albicans	0.125	0.125
1 Candida tropicalis	0.125	0.125
1 Candida parapsilosis	0.125	0.125
2 Candida glabrata	Insufficient evidence
3 Candida krusei	Insufficient evidence

Clinical Experience

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

Aspergillus infections - efficacy in aspergillosis patients with poor prognosis Voriconazole has in vitro fungicidal activity against Aspergillus spp. The efficacy and survival benefit of voriconazole versus conventional amphotericin B in the primary treatment of acute invasive aspergillosis was demonstrated in an open, randomised, multicentre study in 277 immunocompromised patients treated for 12 weeks. Voriconazole was administered intravenously with a loading dose of 6 mg/kg every 12 hours for the first 24 hours followed by a maintenance dose of 4 mg/kg every 12 hours for a minimum of 7 days. Therapy could then be switched to the oral formulation at a dose of 200 mg every 12 hours. Median 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 for voriconazole was statistically significantly higher than that for the comparator and a clinically and statistically significant

benefit was shown in favour of voriconazole for both time to death and time to discontinuation due to toxicity.

This study confirmed findings from an earlier, prospectively designed study where there was a positive 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 bone marrow and solid organ transplants, haematological malignancies, cancer and AIDS.

Candidaemia in non-neutropenic patients

The efficacy of voriconazole compared to the regimen of amphotericin B followed by fluconazole in the primary treatment of candidaemia was demonstrated in an open, comparative study. Three hundred and seventy non-neutropenic patients (above 12 years of age) with documented candidaemia were included in the study, of whom 248 were treated with voriconazole. Nine subjects in the voriconazole group and 5 in the amphotericin B followed by fluconazole group also had mycologically proven infection in deep tissue. Patients with renal failure were excluded from this study. The median treatment duration was 15 days in both treatment arms. In the primary analysis, successful response as assessed by a Data Review Committee (DRC) blinded to study medicinal product was defined as resolution/improvement in all clinical signs and symptoms of infection with eradication of Candida from blood and infected deep tissue sites 12 weeks after the end of therapy (EOT). Patients who did not have an assessment 12 weeks after EOT were counted as failures. In this analysis a successful response was seen in 41% of patients in both treatment arms.

In a secondary analysis, which utilised DRC assessments at the latest evaluable time point (EOT, or 2, 6, or 12 weeks after EOT) voriconazole and the regimen of amphotericin B followed by fluconazole had successful response rates of 65% and 71%, respectively.

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

Timepoint	Voriconazole (N=248)	Amphotericin B ^ 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 in:		ections

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

Scedosporium and Fusarium infections

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

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

Fusarium spp. : Seven (3 complete, 4 partial responses) of 17 patients were successfully treated with voriconazole. Of these 7 patients, 3 had eye, 1 had sinus, and 3 had disseminated infection. Four additional patients with fusariosis 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 were intolerant of, or refractory to, prior antifungal therapy.

Primary Prophylaxis of Invasive Fungal Infections - Efficacy in HSCT recipients without prior proven or 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% of patients 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 241 received itraconazole. The median duration of study drug prophylaxis was 96 days for voriconazole and 68 days for itraconazole in the MITT

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

Study Endpoints	Voriconazole N=224	Itraconazole N=241	Difference in proportions and the 95% confidence interval (CI)		P-Value
Success at day 180*	109 (48.7%)	80 (33.2%)	16.4% 25.1%)**	(7.7%,	0.0002**
Success at day 100	121 (54.0%)	96 (39.8%)	15.4% 24.2%)**	(6.6%,	0.0006**
Completed at least 100 days of study drug prophylaxis	120 (53.6%)	94 (39.0%)	14.6% 23.5%)	(5.6%,	0.0015
Survived to day 180	184 (82.1%)	197 (81.7%)	0.4% 7.4%)	(-6.6%,	0.9107
Developed proven or probable IFI to day 180	3 (1.3%)	5 (2.1%)	-0.7% 1.6%)	(-3.1%,	0.5390
Developed proven or probable IFI to day	2 (0.9%)	4 (1.7%)	-0.8% 1.3%)	(-2.8%,	0.4589

100
Developed proven or probable IFI while on study drug	0	3 (1.2%)	-1.2% (-2.6%, 0.2%)	0.0813

* Primary endpoint of the study

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

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

AML

Study Endpoints	Voriconazole (N=98)	Itraconazole (N=109)	Difference in proportions and the 95% confidence interval (CI)
Breakthrough IFI - Day 180	1 (1.0%)	2 (1.8%)	-0.8% (-4.0%, 2.4%) 1
Success at Day 180*	55 (56.1%)	45 (41.3%)	14.7% (1.7%, 27.7%)2

* Primary endpoint of study

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

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

Myeloablative conditioning regimens

Study Endpoints	Voriconazole (N=125)	Itraconazole (N=143)	Difference in proportions and the 95% confidence interval (CI)
Breakthrough IFI - Day 180	2 (1.6%)	3 (2.1%)	-0.5% (-3.7%, 2.7%) 1
Success at Day 180*	70 (56.0%)	53 (37.1%)	20.1% (8.5%, 31.7%)2

* Primary endpoint of study

Voriconazole was investigated as secondary prophylaxis in an open-label, noncomparative, multicenter study of adult allogeneic HSCT recipients with prior proven or probable IFI. The primary endpoint 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 MITT group.

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

Duration of treatment

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

Paediatric population

Sixty-one paediatric patients aged 9 months up to 15 years who had definite or probable invasive fungal infections were treated with voriconazole. This population included 34 patients 2 to <12 years old and 20 patients 12-15 years of age.

The majority (57/61) had failed previous antifungal therapies. Therapeutic studies included 5 patients aged 12-15 years, the remaining patients received voriconazole in the compassionate use programmes. Underlying diseases in these patients included haematological malignancies (27 patients) and chronic granulomatous disease (14 patients). The most commonly treated fungal infection was aspergillosis (43/61; 70%).

Clinical studies examining QTc interval

A placebo-controlled, randomized, single-dose, crossover study to evaluate the effect on the QTc interval 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 of voriconazole were 5.1, 4.8, and

8.2 msec, respectively and 7.0 msec for ketoconazole 800 mg. No subject in any group had an

increase in QTc of >60 msec from baseline. No subject experienced an interval exceeding the potentially clinically-relevant threshold of 500 msec.

5.2 Pharmacokinetic properties

General pharmacokinetic characteristics

The pharmacokinetics of voriconazole have been characterised in healthy subjects, special populations and patients. During oral administration of 200 mg or 300 mg twice daily for 14 days in patients at risk of aspergillosis (mainly patients with malignant neoplasms of lymphatic or haematopoietic tissue), the observed 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 is non-linear due to saturation of its metabolism. Greater than proportional 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 in exposure (AUCr). 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 than 40 kg) oral maintenance dose achieves an exposure similar to 4 mg/kg IV. When the recommended intravenous or oral

loading dose regimens are administered, plasma concentrations close to steady state are achieved within the first 24 hours of dosing. Without the loading dose, accumulation occurs during twice daily multiple dosing with steady-state plasma voriconazole concentrations being achieved by Day 6 in the majority of subjects.

Absorption

Voriconazole is rapidly and almost completely absorbed following oral administration, with maximum plasma concentrations (C_max) achieved 1-2 hours after dosing. The absolute bioavailability of voriconazole after oral administration is estimated to be 96%. When multiple doses of voriconazole are administered with high fat meals, C_max and AUC are reduced by 34% and 24%, respectively. The absorption of voriconazole is

not affected by changes in gastric pH.

Distribution

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

Biotransformation

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 be expected to be poor metabolisers. For Caucasians and Blacks the prevalence of poor metabolisers is 3-5%. Studies conducted in Caucasian and Japanese healthy subjects have shown that poor metabolisers have, on average, 4fold higher voriconazole exposure (AUCr) than their homozygous extensive metabolizer counterparts. Subjects who are heterozygous extensive metabolisers have on average 2-fold higher voriconazole exposure than their homozygous extensive metaboliser counterparts.

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

Elimination

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

After administration of a radiolabelled dose of voriconazole, approximately 80% of the radioactivity is recovered in the urine after multiple intravenous dosing and 83% in the urine after multiple oral dosing. The majority (>94%) of the total radioactivity is excreted in the first 96 hours after both oral and 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 of the accumulation or elimination of voriconazole.

Pharmacokinetics in special patient groups Gender

In an oral multiple -dose study, C_max and AUCr 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 AUC were observed between healthy elderly males and healthy elderly females (>65 years).

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

Elderly

In an oral multiple-dose study C_max and AUCr in healthy elderly males (>65 years) were 61% and 86% higher, respectively, than in healthy young males (18-45 years). No significant differences in C_max and AUCr 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 between plasma concentrations and age was observed. The safety profile of voriconazole in young and elderly patients was similar and, therefore, no dosage adjustment is necessary for the elderly (see section 4.2).

Paediatric population The recommended doses in children and adolescent patients are based on a population pharmacokinetic 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 intravenous doses of 3, 4, 6, 7 and 8 mg/kg twice daily and multiple oral doses (using the powder for oral suspension) of 4 mg/kg, 6 mg/kg, and 200 mg twice daily were evaluated in 3 paediatric pharmacokinetic studies. Intravenous loading doses of

6 mg/kg IV twice daily on day 1 followed by 4 mg/kg intravenous dose twice daily and 300 mg oral tablets twice daily were evaluated in one adolescent pharmacokinetic study. Larger inter-subject variability was observed in paediatric patients compared to adults.

A comparison of the paediatric and adult population pharmacokinetic data indicated that the predicted total exposure (AUCr) in children following administration of a 9 mg/kg IV loading dose was comparable to that in adults following a 6 mg/kg IV loading dose. The predicted total exposures in children following IV maintenance doses of 4 and 8 mg/kg twice daily were comparable to those in adults following 3 and 4 mg/kg IV twice daily, respectively. The predicted total exposure in children following an oral maintenance dose of 9 mg/kg (maximum of 350 mg) twice daily was comparable to that in adults following 200 mg oral twice daily. An 8 mg/kg intravenous dose will provide voriconazole 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 higher elimination capacity in paediatric patients due to a greater liver mass to body mass ratio. Oral bioavailability may, however, be limited in paediatric patients with malabsorption and very low body weight for their age. In that case, intravenous voriconazole administration is recommended.

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

Renal impairment

In an oral single-dose (200 mg) study in subjects with normal renal function and mild (creatinine clearance 41-60 ml/min) to severe (creatinine clearance < 20 ml/min) renal impairment, the pharmacokinetics of voriconazole were not significantly affected by renal impairment. The plasma protein binding of voriconazole was similar in subjects with different degrees of renal impairment (see sections 4.2 and 4.4).

Hepatic impairment

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

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

5.3 Preclinical safety data

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 minimal adrenal changes. Conventional studies of safety pharmacology, genotoxicity or carcinogenic potential did not reveal a special hazard for humans.

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

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Core:

Lactose monohydrate Croscarmellose sodium Magnesium stearate

Coating:

Polyvinyl alcohol Macrogol 8000 Talc

Titanium dioxide (E 171)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Alu-PVC/PE/PVDC blisters.

Voriconazole Apotex 200 mg film-coated tablets: blister packs containing 14, 20, 28, 30, 56 and 100 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements

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

7 MARKETING AUTHORISATION HOLDER

Apotex Europe B.V.

Darwinweg 20 2333 CR Leiden The Netherlands

8    MARKETING AUTHORISATION NUMBER(S)

PL 27583/0228

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

08/10/2015

10    DATE OF REVISION OF THE TEXT

08/10/2015

1

Using a margin of 5%, non inferiority is demonstrated

2

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

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