VFEND 200 MG POWDER FOR SOLUTION FOR INFUSION

VFEND IV, POS & Film-Coated Tablets LPD CC 16 September 2020

2020-0058153

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

VFEND

200 mg Powder for Solution for Infusion

VFEND

50 mg Film-Coated Tablets

VFEND

200 mg Film-Coated Tablets

VFEND

40 MG/ML Powder for Oral Suspension

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Powder for solution for infusion:

Each vial contains 200 mg of voriconazole.

After reconstitution, each ml contains 10 mg of voriconazole. Once reconstituted further

dilution is required before administration.

For the full list of excipients, see section 6.1.

Film-coated tablets:

Each film coated tablet contains 50 mg or 200 mg voriconazole.

Excipient with known effect

Each 50 or 200 mg tablet contains 62.5 or 250.0 mg lactose monohydrate respectively.

For the full list of excipients, see section 6.1.

Powder for oral suspension:

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

bottle contains 3 g of voriconazole.

Excipient with known effect:

Each ml of suspension contains 0.54 g sucrose.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder for solution for infusion:

VFEND powder for solution for infusion is a white lyophilised powder containing nominally

200 mg voriconazole presented in a 30 ml clear glass vial.

Film-coated tablets:

VFEND 50 mg film coated tablets are white to off-white, round film coated tablets, debossed

“Pfizer” on one side and “VOR50” on the reverse.

VFEND 200 mg film coated tablets are white to off-white, capsule-shaped film coated tablets,

debossed “Pfizer” on one side and “VOR200” on the reverse.

Powder for oral suspension:

VFEND 40mg/ml powder for oral suspension is a white to off-white powder providing a white

to off-white opaque fluid containing undissolved solids when constituted.

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4. CLINICAL PARTICULARS

4.1

Therapeutic indications

VFEND, voriconazole, is a broad spectrum, triazole antifungal agent and is indicated 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.

VFEND should be administered primarily to immunocompromised 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).

Powder for solution for infusion:

It is recommended that VFEND is administered at a maximum rate of 3 mg/kg per hour over

1 to 3 hours.

VFEND is available as 50 mg film-coated tablets, 200 mg film-coated tablets, 200 mg powder

for solution for infusion and 40 mg/ml powder for oral suspension.

Treatment

Adults

Therapy must be initiated with the specified intravenous loading dose regimen of VFEND to

achieve adequate plasma concentrations on Day 1. Intravenous treatment should be continued

for at least 7 days before switching to oral treatment (see section 5.1). Once the patient is

clinically improved and can tolerate medication given by mouth, the oral tablet form or oral

suspension form of voriconazole may be utilized. 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:

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Intravenous

Oral

a

Patients 40 kg and

above*

Patients less than

40 kg*

Loading dose

regimen

(first 24 hours)

6 mg/kg every 12

hours

----

-----

Maintenance dose

(after first 24 hours)

Prophylaxis of invasive

fungal infections

3-4 mg/kg every

12 hours

200 mg (5 ml) every

12 hours

100 mg (2.5ml)

every 12 hours

Invasive Aspergillosis/

Scedosporium and

Fusarium infections/

Other serious mould

infections

4 mg/kg every 12

hours

200 mg (5 ml) every

12 hours

100 mg (2.5ml)

every 12 hours

Candidemia in non-

neutropenic patients

3-4 mg/kg every

12 hours

200 mg (5 ml) every

12 hours

100 mg (2.5ml)

every 12 hours

a In healthy volunteer studies, the 200 mg oral every 12 hours dose provided an exposure

(AUCτ) similar to a 3 mg/kg IV every 12 hours dose, the 300 mg oral every 12 hours dose

provided an exposure (AUCτ) similar to a 4 mg/kg IV every 12 hours dose (see section 5.2).

b In the pivotal clinical study of invasive aspergillosis, the median duration of IV voriconazole

therapy was 10 days (range 2-85 days). The median duration of oral voriconazole therapy was

76 days (range 2-232 days) (see Section 5.1).

c In clinical trials, patients with candidemia received 3 mg/kg every 12 hours as primary

therapy, while patients with other deep tissue

Candida

infections received 4 mg/kg as

salvage therapy. Appropriate dose should be based on severity and nature of the infection.

* 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).

Dose adjustment

(Adults)

VFEND powder for solution for infusion

If patient response at 3 mg/kg every 12 hours is inadequate, the intravenous maintenance dose

may be increased to 4 mg/kg every 12 hours.

If patients are unable to tolerate 4 mg/kg every 12 hours, reduce the intravenous maintenance

dose to a minimum of 3 mg/kg every 12 hours.

Phenytoin may be coadministered with voriconazole if the maintenance dose of

voriconazole is increased to 5 mg/kg intravenously twice daily (see sections 4.4 and

4.5).

Efavirenz may be coadministered with voriconazole if the maintenance dose of voriconazole is

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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).

VFEND tablets and VFEND powder for oral suspension

If patient response is inadequate, the maintenance dose may be increased from 200 mg every 12

hours (similar to 3 mg/kg IV every 12 hours) to 300 mg every 12 hours (similar to 4 mg/kg IV

every 12 hours) for oral administration. For patients less than 40 kg the oral dose may be

increased from 100 mg to 150 mg every 12 hours.

If patients are unable to tolerate treatment at these higher doses (i.e. 300 mg oral every 12

hours), reduce the oral maintenance dose by 50 mg steps to a minimum of 200 mg every 12

hours (or 100 mg every 12 hours for patients less than 40 kg).

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.

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).

In case of use as prophylaxis, refer below.

Use in paediatrics

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 VFEND 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 gastro-enteric 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

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oral suspension formulation in children aged 2to<12.

Safety and effectiveness in pediatric patients below the age of 2 years has not been established

(see Section 5.1). Therefore, voriconazole is not recommended for children less than 2 years of

age.

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 a 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).

Adults

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

VFEND 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

Children

The recommended dosing regimen for prophylaxis in children is the same as mentioned in the

table located under the header:

Use in paediatrics

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

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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).

Elderly

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

Renal impairment

Powder for solution for infusion:

In patients with moderate to severe renal dysfunction (creatinine clearance < 50 ml/min),

accumulation of the intravenous vehicle, SBECD, occurs. Oral voriconazole should be

administered to these patients, unless an assessment of the risk benefit to the patient justifies the

use of intravenous voriconazole. Serum creatinine levels should be closely monitored in these

patients and, if increases occur, consideration should be given to changing to oral voriconazole

therapy (see section 5.2).

The intravenous vehicle, SBECD, is haemodialysed with a clearance of 55 ml/min.

Film-coated tablets or Powder for oral suspension:

The pharmacokinetics of orally administered voriconazole arenot 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

There is limited data on the safety of VFEND 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 hepatic impairment must be

carefully monitored for drug toxicity (see section 4.8).

Method of administration

VFEND film-coated tablets are to be taken at least one hour before, or one hour following, a

meal.

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

VFEND powder for solution for infusion requires reconstitution and dilution (see section 6.6)

prior to administration as an intravenous infusion. Not for bolus injection.

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4.3 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 rifabutin, rifampicin, carbamazepine and phenobarbital is contraindicated

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 VFEND to patients with hypersensitivity to other

azoles (see also section 4.8).

Duration of IV treatment

The duration of treatment with the intravenous formulation should be no longer than 6 months

(see section 5.3).

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

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(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).

Infusion-related reactions

Infusion-related reactions, predominantly flushing and nausea, have been observed during

administration of the intravenous formulation of voriconazole. Depending on the severity of

symptoms, consideration should be given to stopping treatment (see section 4.8).

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 VFEND 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 VFEND 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, VFEND 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, VFEND has been associated with phototoxicity including reactions such as

ephelides, lentigo, actinic keratosis and pseudoporphyria. It is recommended that all

patients, including children, avoid exposure to direct sunlight during VFEND 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 has been reported in patients, some of whom have

reported prior phototoxic reactions. If phototoxic reactions occur multidisciplinary

advice should be sought, VFEND discontinuation and use of alternative antifungal

agents should be considered and the patient should be referred to a dermatologist. If

VFEND is continued, however, dermatologic evaluation should be performed on a

systematic and regular basis, to allow early detection and management of premalignant

lesions. VFEND should be discontinued if premalignant skin lesions or squamous cell

carcinoma are identified (see below the section under Long-term treatment).

Exfoliative cutaneous reactions

Severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS),

toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic

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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

VFEND discontinued if lesions progress.

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 VFEND (see sections 4.2 and 5.1).

Squamous cell carcinoma of the skin (SCC) has been reported in relation with long-term

VFEND treatment.

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 VFEND discontinuation should be considered after multidisciplinary

advice.

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

VFEND. 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 VFEND

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

lentigines

ephelides,

avoidance

dermatologic

follow-up

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

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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).

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 4.3 and 4.5).

Everolimus

(CYP3A4 substrate, P-gp substrate)

Coadministration 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 coadministration 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

coadministered 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 AUC

0-∞

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 C

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).

VFEND tablets contain lactose and should not be given to patients with rare hereditary

problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose

malabsorption.

VFEND oral suspension contains sucrose and should not be given to patients with rare

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hereditary problems of fructose intolerance, sucrase-isomaltase deficiency or glucose-

galactose malabsorption.

Sodium content: Each vial of VFEND contains 217.6 mg of sodium. This should be taken into

consideration for patients on a controlled sodium diet.

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 (↓) or above (↑) the

80-125% range. The asterisk (*) indicates a two-way interaction. AUC

, AUC

and AUC

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

coadministration

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)

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Medicinal product

[Mechanism of interaction]

Interaction

Geometric mean changes (%)

Recommendations

concerning

coadministration

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,

coadministered with

voriconazole 400 mg BID*

Efavirenz Cmax

Efavirenz AUC

Voriconazole Cmax

Voriconazole AUC

Compared to efavirenz

600 mg QD,

Efavirenz Cmax ↔

Efavirenz AUC

Compared to voriconazole

200 mg BID,

Voriconazole Cmax

Voriconazole AUC

Use of standard doses of

voriconazole with efavirenz

doses of 400 mg QD or

higher is

contraindicated

(see section 4.3).

Voriconazole may be

coadministered 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).

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)

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

Voriconazole AUC

Compared to voriconazole

200 mg BID,

Voriconazole Cmax

Voriconazole AUC

Rifabutin Cmax

195%

Rifabutin AUC

331%

Compared to voriconazole

200 mg BID,

Voriconazole Cmax

104%

Voriconazole AUC

Contraindicated

(see

Section 4.3)

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Medicinal product

[Mechanism of interaction]

Interaction

Geometric mean changes (%)

Recommendations

concerning

coadministration

Rifampicin (600 mg QD)

[potent CYP450 inducer]

Voriconazole Cmax

Voriconazole AUC

Contraindicated

(see

section 4.3)

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

Voriconazole AUC

Ritonavir Cmax

Ritonavir AUC

Voriconazole Cmax

Voriconazole AUC

Coadministration of

voriconazole and high doses

of ritonavir (400 mg and

above BID) is

contraindicated

(see sec

tion

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.

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 AUC

0−∞↓

Contraindicated

(see

section 4.3)

Everolimus

[CYP3A4 substrate, P-gp

substrate]

Although not studied,

voriconazole is likely to

significantly increase the plasma

concentrations of everolimus.

Coadministration of

voriconazole with

everolimus is not

recommended because

voriconazole is expected to

significantly increase

everolimus concentrations

(see section 4.4).

Fluconazole (200 mg QD)

[CYP2C9, CYP2C19 and

CYP3A4 inhibitor]

Voriconazole Cmax

Voriconazole AUC

Fluconazole Cmax ND

Fluconazole AUC

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.

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Medicinal product

[Mechanism of interaction]

Interaction

Geometric mean changes (%)

Recommendations

concerning

coadministration

Phenytoin

[CYP2C9 substrate and potent

CYP450 inducer]

300 mg QD

300 mg QD (coadministered

with voriconazole 400 mg

BID)*

Voriconazole Cmax

Voriconazole AUC

Phenytoin Cmax

Phenytoin AUC

Compared to voriconazole

200 mg BID,

Voriconazole Cmax

Voriconazole AUC

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

coadministered 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).

Letermovir

[CYP2C9 and CYP2C19

inducer]

Voriconazole C

↓ 39%

Voriconazole AUC

0-12

↓ 44%

Voriconazole C

↓ 51%

If concomitant

administration of

voriconazole with letermovir

cannot be avoided, monitor

for loss of voriconazole

effectiveness.

Anticoagulants

Warfarin (30 mg single dose,

co- administered with 300 mg

BID voriconazole)

[CYP2C9 substrate]

Other oral coumarins

(e.g.,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.

Benzodiazepines (e.g.,

midazolam, triazolam,

alprazolam)

[CYP3A4 substrates]

Although not studied clinically,

voriconazole is likely to increase

the plasma concentrations of

benzodiazepines that are

metabolised by CYP3A4 and

lead to a prolonged sedative

effect.

Dose reduction of

benzodiazepines should be

considered.

Tolvaptan

[CYP3A substrate]

Although not studied clinically,

voriconazole is likely to

significantly increase the plasma

concentrations of tolvaptan.

If concomitant

administration of

voriconazole with tolvaptan

cannot be avoided, dose

reduction of tolvaptan is

recommended.

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Medicinal product

[Mechanism of interaction]

Interaction

Geometric mean changes (%)

Recommendations

concerning

coadministration

Immunosuppressants

[CYP3A4 substrates]

Sirolimus (2 mg single dose)

Ciclosporin (in stable renal

transplant recipients receiving

chronic ciclosporin therapy)

Tacrolimus (0.1 mg/kg single

dose)

In an independent published

study, Sirolimus Cmax

6.6-

fold

Sirolimus AUC

0−∞

11-fold

Ciclosporin Cmax

Ciclosporin AUC

Tacrolimus Cmax

117%

Tacrolimus AUCt

221%

Coadministration of

voriconazole and sirolimus

contraindicated

(see

section 4.3).

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.

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.

Long- Acting Opiates

[CYP3A4 substrates]

Oxycodone (10 mg single dose)

In an independent published

study,

Oxycodone Cmax

1.7-fold

Oxycodone AUC

0−∞

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.

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Medicinal product

[Mechanism of interaction]

Interaction

Geometric mean changes (%)

Recommendations

concerning

coadministration

Methadone (32-100 mg QD)

[CYP3A4 substrate]

R-methadone (active) Cmax

R-methadone (active) AUC

S-methadone Cmax

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.

Non-Steroidal Anti-

Inflammatory Drugs (NSAIDs)

[CYP2C9 substrates]

Ibuprofen (400 mg single dose)

Diclofenac (50 mg single dose)

S-Ibuprofen Cmax

S-Ibuprofen AUC

0−∞

100%

Diclofenac Cmax

114%

Diclofenac AUC

0−∞

Frequent monitoring for

adverse reactions and

toxicity related to NSAIDs is

recommended. Dose

reduction of NSAIDs may be

needed.

Omeprazole (40 mg QD)*

[CYP2C19 inhibitor; CYP2C19

and CYP3A4 substrate]

Omeprazole Cmax

116%

Omeprazole AUC

280%

Voriconazole Cmax

Voriconazole AUC

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]

Norethisterone/ethinylestradiol

(1 mg/0.035 mg QD)

Ethinylestradiol Cmax

Ethinylestradiol AUC

Norethisterone Cmax

Norethisterone AUC

Voriconazole Cmax

Voriconazole AUC

Monitoring for adverse

reactions related to oral

contraceptives, in addition to

those for voriconazole, is

recommended.

Short-acting Opiates

[CYP3A4 substrates]

Alfentanil (20 μg/kg single

dose, with concomitant

naloxone)

Fentanyl (5

g/kg single dose)

In an independent published

study,

Alfentanil AUC

0−∞

6-fold

In an independent published

study,

Fentanyl AUC

0−∞

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.

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Medicinal product

[Mechanism of interaction]

Interaction

Geometric mean changes (%)

Recommendations

concerning

coadministration

Statins (e.g., lovastatin)

[CYP3A4 substrates]

Although not studied clinically,

voriconazole is likely to increase

the plasma concentrations of

statins that are metabolised by

CYP3A4 and could lead to

rhabdomyolysis.

Dose reduction of statins

should be considered.

Sulfonylureas (e.g.,

tolbutamide, glipizide,

glyburide)

[CYP2C9 substrates]

Although not studied,

voriconazole is likely to increase

the plasma concentrations of

sulfonylureas and cause

hypoglycaemia.

Careful monitoring of blood

glucose is recommended.

Dose reduction of

sulfonylureas should be

considered.

Vinca Alkaloids (e.g.,

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.

Other HIV Protease Inhibitors

(e.g., 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.

Other Non-Nucleoside Reverse

Transcriptase Inhibitors

(NNRTIs) (e.g., 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.

Cimetidine (400 mg BID)

[non-specific CYP450 inhibitor

and increases gastric pH]

Voriconazole Cmax

Voriconazole AUC

No dose adjustment

Digoxin (0.25 mg QD)

[P-gp substrate]

Digoxin Cmax ↔

Digoxin AUC

No dose adjustment

Indinavir (800 mg TID)

[CYP3A4 inhibitor and

substrate]

Indinavir Cmax ↔

Indinavir AUC

Voriconazole Cmax ↔

Voriconazole AUC

No dose adjustment

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Medicinal product

[Mechanism of interaction]

Interaction

Geometric mean changes (%)

Recommendations

concerning

coadministration

Macrolide antibiotics

Erythromycin (1 g BID)

[CYP3A4 inhibitor]

Azithromycin (500 mg QD)

Voriconazole Cmax and AUC

Voriconazole Cmax and AUC

The effect of voriconazole on

either erythromycin or

azithromycin is unknown.

No dose adjustment

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

Prednisolone AUC

0−∞

No dose adjustment

Ranitidine (150 mg BID)

[increases gastric pH]

Voriconazole Cmax and AUC

No dose adjustment

4.6 Fertility, pregnancy and lactation

Pregnancy

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

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

humans is unknown.

VFEND 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 VFEND.

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

VFEND 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.

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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

infestations

sinusitis

pseudomembranous

colitis

Neoplasms

benign,

malignant and

unspecified

(including

cysts and

polyps)

squamous

cell

carcinoma*

Blood and

lymphatic

system

disorders

agranulocytosis

pancytopenia,

thrombocytopenia

leukopenia,

anaemia

bone marrow

failure,

lymphadenopathy,

eosinophilia

disseminated

intravascular

coagulation

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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)

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,

hypertonia

paraesthesia,

somnolence,

dizziness

brain oedema,

encephalopathy

extrapyramidal

disorder

neuropathy

peripheral, ataxia,

hypoaesthesia,

dysgeusia

hepatic

encephalopathy,

Guillain-Barre

syndrome,

nystagmus

Eye disorders

visual

impairment

retinal

haemorrhage

optic nerve

disorder

papilloedema

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

torsades de

pointes,

atrioventricular

block complete,

bundle branch

block, nodal

rhythm

Vascular

disorders

hypotension,

phlebitis

thrombophlebitis,

lymphangitis

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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)

Respiratory,

thoracic and

mediastinal

disorders

respiratory

distress

acute respiratory

distress syndrome,

pulmonary oedema

Gastrointestina

l 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,

hepatitis

hepatic failure,

hepatomegaly,

cholecystitis,

cholelithiasis

Skin and

subcutaneous

tissue

disorders

rash

dermatitis

exfoliative,

alopecia, rash

maculo-papular,

pruritus, erythema

Stevens-Johnson

syndrome

phototoxicity,

purpura, urticaria,

dermatitis allergic,

rash papular, rash

macular, eczema

toxic epidermal

necrolysis

, drug

reaction with

eosinophilia and

systemic

symptoms

(DRESS)

angioedema,

actinic

keratosis*,

pseudoporphyria

, erythema

multiforme,

psoriasis, drug

eruption

cutaneous

lupus

erythemato

sus*,

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

oedema

, asthenia,

chills

infusion site

reaction, influenza

like illness

Investigations

blood creatinine

increased

blood urea

increased, blood

cholesterol

increased

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*ADR identified post-marketing

Includes febrile neutropenia and neutropenia.

Includes immune thrombocytopenic purpura.

Includes nuchal rigidity and tetany.

Includes hypoxic-ischaemic encephalopathy and metabolic encephalopathy.

Includes akathisia and parkinsonism.

See “Visual impairments” paragraph in section 4.8.

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

See section 4.4.

Includes dyspnoea and dyspnoea exertional.

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

Includes periorbital oedema, lip oedema, and oedema mouth.

Description of selected adverse reactions

Altered taste perception

In the combined data from three bioequivalence studies using the powder for oral suspension

formulation, treatment related taste perversion was recorded in 12 (14%) of subjects.

Visual impairments

In clinical trials, visual impairments (including blurred vision, photophobia, chloropsia,

chromatopsia, colour blindness, cyanopsia, eye disorder, halo vision, night blindness,

oscillopsia, photopsia, scintillating scotoma, visual acuity reduced, visual brightness, visual

field defect, vitreous floaters, 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 VFEND (see section 4.4).

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

lesions progress. Photosensitivity reactions such as ephelides, lentigo and actinic keratosis have

been reported, especially during long-term therapy (see section 4.4).

There have been reports of squamous cell carcinoma of the skin in patients treated with VFEND

for long periods of time; the mechanism has not been established (see section 4.4).

Liver function tests

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The overall incidence of transaminase increases >3 xULN (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).

Infusion-related reactions

During infusion of the intravenous formulation of voriconazole in healthy subjects,

anaphylactoid-type reactions, including flushing, fever, sweating, tachycardia, chest tightness,

dyspnoea, faintness, nausea, pruritus and rash have occurred. Symptoms appeared immediately

upon initiating the infusion (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 programs. 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. Any

suspected adverse event should be reported to the Ministry of Health according to the National

Regulation by using an online form https://sideeffects.health.gov.il/

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.

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There is no known antidote to voriconazole.

Voriconazole is haemodialysed with a clearance of 121 ml/min. The intravenous vehicle,

SBECD, is haemodialysed with a clearance of 55 ml/min. In an overdose, haemodialysis may

assist in the removal of voriconazole and SBECD from the body.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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

J02 AC03

Mode of action

Voriconazole is a triazole antifungal agent. The primary mode of action of voriconazole is the

inhibition of fungal cytochrome P450-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. Dose adjustments in prophylaxis studies have not

been explored.

Clinical efficacy and safety

n vitro

, voriconazole displays broad-spectrum antifungal activity with antifungal potency

against

Candida

species (including fluconazole-resistant

C. krusei

and resistant strains of

C. glabrata

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

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

limited numbers of

C. dubliniensis, C. inconspicua,

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

., Coccidioides immitis, Conidiobolus coronatus, Cryptococcus neoformans, Exserohilum

rostratum, Exophiala spinifera, Fonsecaea pedrosoi, Madurella mycetomatis, Paecilomyces

lilacinus, Penicillium spp. including P. marneffei, Phialophora richardsiae, Scopulariopsis

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brevicaulis and Trichosporon

spp. including

T. beigelii

infections.

In vitro

activity against clinical isolates has been observed for

Acremonium

spp.,

Alternaria

spp.,

Bipolaris

., Cladophialophora

spp., and

Histoplasma capsulatum,

with most strains

being inhibited by concentrations of voriconazole in the range 0.05 to 2 µg/ml.

In vitro

activity against the following pathogens has been shown, but the clinical

significance 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, anti-infective therapy should be adjusted

accordingly.

The species most frequently involved in causing human infections include

C. albicans, C.

parapsilosis, C. tropicalis, C. glabrata

C. krusei

, all of which usually exhibit minimal

inhibitory concentration (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)

Candida albicans

1

0.125

0.125

Candida tropicalis

1

0.125

0.125

Candida parapsilosis

1

0.125

0.125

Candida glabrata

2

Insufficient evidence

Candida krusei

3

Insufficient evidence

Other Candida spp.

4

Insufficient evidence

1

Strains with MIC values above the Susceptible (S) breakpoint are rare, or not yet

reported. The identification and antimicrobial susceptibility tests on any such isolate

must be repeated and if the result is confirmed the isolate sent to a reference

laboratory.

2

In clinical studies, response to voriconazole in patients with

C. glabrata

infections

was 21% lower compared to

C. albicans, C. parapsilosis and C. tropicalis

In vitro

data showed a slight increase of resistance of

C. glabrata

to voriconazole.

3

In clinical studies, response to voriconazole in

C. krusei

infections was similar to

C.

albicans, C. parapsilosis and C. tropicalis.

However, as there were only 9 cases

available for EUCAST analysis, there is currently insufficient evidence to set clinical

breakpoints for

C. krusei

4

EUCAST has not determined non-species related breakpoints for voriconazole.

Clinical experience

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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)

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178 (72%)

88 (72%)

2 weeks after

125 (50%)

62 (51%)

6 weeks after

104 (42%)

55 (45%)

12 weeks after

104 (42%)

51 (42%)

Serious refractory

Candida

infections

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

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% (7.7%, 25.1%)**

0.0002**

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Success at day 100

121 (54.0%)

96 (39.8%)

15.4% (6.6%, 24.2%)**

0.0006**

Completed at least 100 days of

study drug prophylaxis

120 (53.6%)

94 (39.0%)

14.6% (5.6%, 23.5%)

0.0015

Survived to day 180

184 (82.1%)

197 (81.7%)

0.4% (-6.6%, 7.4%)

0.9107

Developed proven or probable

IFI to day 180

3 (1.3%)

5 (2.1%)

-0.7% (-3.1%, 1.6%)

0.5390

Developed proven or probable

IFI to day 100

2 (0.9%)

4 (1.7%)

-0.8% (-2.8%, 1.3%)

0.4589

Developed proven or probable

IFI while on study drug

3 (1.2%)

-1.2% (-2.6%, 0.2%)

0.0813

* Primary endpoint of the study

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

The breakthrough IFI rate to Day 180 and the primary endpoint of the study, which is Success at

Day 180, for patients with AML and myeloablative conditioning regimens respectively, is

presented in the 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%) **

Success at Day 180*

55 (56.1%)

45 (41.3%)

14.7% (1.7%, 27.7%)***

* Primary endpoint of study

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

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

Myeloablative conditioning regimens

Study endpoints

Voriconazole

(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%) **

Success at Day 180*

70 (56.0%)

53 (37.1%)

20.1% (8.5%, 31.7%)***

* Primary endpoint of study

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

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

Secondary Prophylaxis of IFI – Efficacy in HSCT recipients

with prior proven or probable IFI

Voriconazole was investigated as secondary prophylaxis in an open-label, non-comparative,

multicenter study of adult allogeneic HSCT recipients with prior proven or probable IFI. The

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).

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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

Fifty-three paediatric patients aged 2 to <18 years were treated with voriconazole in two

prospective, open-label, non-comparative, multi-center clinical trials. One study enrolled 31

patients with possible, proven or probable invasive aspergillosis (IA), of whom 14 patients had

proven or probable IA and were included in the MITT efficacy analyses. The second study

enrolled 22 patients with invasive candidiasis including candidaemia (ICC), and esophageal

candidiasis (EC) requiring either primary or salvage therapy, of whom 17 were included in the

MITT efficacy analyses. For patients with IA the overall rates of global response at 6 weeks

were 64.3% (9/14), the global response rate was 40% (2/5) for patients 2 to <12 years and

77.8% (7/9) for patients 12 to <18 years of age. For patients with ICC the global response rate at

EOT was 85.7% (6/7) and for patients with EC the global response rate at EOT was 70% (7/10).

The overall rate of response (ICC and EC combined) was 88.9% (8/9) for 2 to <12 years old and

62.5% (5/8) for 12 to <18 years old.

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 are 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 (AUC

). 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

) 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

and AUC

are reduced by 34 %

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and 24 %, respectively. The absorption of voriconazole is not affected by changes in gastric pH.

Powder for oral suspension

Voriconazole is rapidly and almost completely absorbed following oral administration, with

maximum plasma concentrations (C

) achieved 1-2 hours after dosing. The absolute

bioavailability of voriconazole after oral administration is estimated to be 96%.

Bioequivalence was established between the 200 mg tablet and the 40mg/ml oral suspension

when administered as a 200 mg dose. When multiple doses of voriconazole are administered

with high fat meals, C

and AUC are reduced by 58% and 37%, 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, 4-fold higher voriconazole exposure

(AUC

) than their homozygous extensive metaboliser 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

and AUCτ for healthy young females were 83 % and 113

% higher, respectively, than in healthy young males (18-45 years)

.

In the same study, no

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significant differences in C

and AUCτ were observed between healthy elderly males and

healthy elderly females (≥65 years).

In the clinical programme, no dosage adjustment was made on the basis of gender. The safety

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

and AUCτ in healthy elderly males (≥65 years) were 61 %

and 86 % higher, respectively, than in healthy young males (18-45 years). No significant

differences in C

and AUCτ were observed between healthy elderly females (≥ 65 years) and

healthy young females (18- 45 years).

In the therapeutic studies no dosage adjustment was made on the basis of age. A relationship

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 (AUC

) 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

Film-coated tablets:

In an oral single dose (200 mg) study in subjects with normal renal function and mild (creatinine

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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).

Powder for solution for infusion:

In patients with moderate to severe renal dysfunction (serum creatinine levels > 2.5 mg/dl),

accumulation of the intravenous vehicle, SBECD, occurs (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, AUC

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.

Powder for solution for infusion:

Preclinical data on the intravenous vehicle, SBECD indicated

that the main effects were vacuolation of urinary tract epithelium and activation of

macrophages in the liver and lungs in the repeated-dose toxicity studies. As GPMT (guinea pig

maximisation test) result was positive, prescribers should be aware of the hypersensitivity

potential of the intravenous formulation. Standard genotoxicity and reproduction studies with

the excipient SBECD reveal no special hazard for humans. Carcinogenicity studies were not

performed with SBECD. An impurity, present in SBECD, has been shown to be an alkylating

mutagenic agent with evidence for carcinogenicity in rodents. This impurity should be

considered a substance with carcinogenic potential in humans. In light of these data, the

duration of treatment with the intravenous formulation should be no longer than 6 months.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

VFEND powder for solution for infusion:

Sulphobutylether Beta Cyclodextrin Sodium (SBECD)

VFEND IV, POS & Film-Coated Tablets LPD CC 16 September 2020

2020-0058153

Water for Injections

VFEND film coated tablets:

Tablet Core:

Lactose Monohydrate

Pregelatinised Starch

Croscarmellose Sodium

Povidone

Magnesium Stearate

Film Coat:

Hypromellose

Titanium Dioxide

Lactose Monohydrate

Glycerol Triacetate

VFEND powder for oral suspension:

Sucrose

Citric Acid Anhydrous

Natural Orange Flavour

Sodium Citrate Dihydrate

Sodium Benzoate

Xanthan Gum

Silica Colloidal anhydrous

Titanium Dioxide

6.2 Incompatibilities

VFEND powder for solution for infusion:

VFEND must not be infused into the same line or cannula concomitantly with other intravenous

products. The bag should be checked to ensure that the infusion is complete. When the VFEND

infusion is complete, the line may be used for administration of other intravenous products

.

Blood products and short-term infusion of concentrated solutions of electrolytes:

Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalcaemia should be

corrected prior to initiation of voriconazole therapy (see sections 4.2 and 4.4).

VFEND

must not

be administered simultaneously with any blood product or any short-term infusion of

concentrated solutions of electrolytes, even if the two infusions are running in separate lines.

Total parenteral nutrition

: Total parenteral nutrition (TPN) need

not

be discontinued when

prescribed with

VFEND

but does need to be infused through a separate line. If infused through

a multiple-lumen catheter, TPN needs to be administered using a different port from the one

used for

VFEND

VFEND

must not be diluted with 4.2% Sodium Bicarbonate Infusion.

Compatibility with other concentrations is unknown.

This medicinal product must not be mixed with other medicinal products except those

mentioned in section 6.6.

VFEND film-coated tablets:

Not applicable

VFEND Powder for oral suspension:

This medicinal product must not be mixed with other medicinal products except those

mentioned in section 6.6.

VFEND IV, POS & Film-Coated Tablets LPD CC 16 September 2020

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6.3 Shelf life

VFEND powder for solution for infusion:

The expiry date of the product is indicated on the packaging materials.

From

microbiological

point

view,

once

reconstituted,

product

must

used

immediately. If not used immediately, in-use storage times and conditions prior to use are the

responsibility of the user and would normally not be longer than 24 hours at 2

C to 8

C (in a

refrigerator), unless reconstitution has taken place in controlled and validated aseptic conditions.

Chemical and physical in-use stability has been demonstrated for 24 hours at 2

C to 8

VFEND film-coated tablets:

The expiry date of the product is indicated on the packaging materials.

VFEND powder for oral suspension:

The expiry date of the product is indicated on the packaging materials.

The shelf life of the constituted oral suspension is 14 days at a temperature below 30°C, do not

refrigerate or freeze.

6.4 Special precautions for storage

VFEND powder for solution for infusion:

The unreconstituted vial should be stored below 30ºC.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

VFEND film-coated tablets:

In a cool place.

VFEND powder for oral suspension:

Store at 2

C- 8

C (in a refrigerator) before constitution.

For storage conditions after constitution, see section 6.3.

Keep the container tightly closed.

6.5 Nature and contents of container

VFEND powder for solution for infusion:

Sterile lyophilised powder in single use 30 mL clear Type I glass vial.

Film-coated tablets:

PVC / Aluminium blister in cartons of 2, 10, 14, 20, 28, 30, 50, 56 and 100.

Not all pack sizes may be marketed.

VFEND powder for oral suspension:

One 100ml high-density polyethylene (HDPE) bottle (with polypropylene child resistant

closure) containing 45g of powder for oral suspension. A measuring cup (graduated to indicate

23ml), 5ml oral syringe and a press-in bottle adaptor are also provided.

6.6

Special precautions for disposal and other handling

VFEND powder for solution for infusion:

The powder is reconstituted with either 19 ml of water for injections or 19 ml of 9 mg/ml

(0.9%) Sodium Chloride for Infusion to obtain an extractable volume of 20 ml of clear

concentrate containing 10 mg/ml of voriconazole. Discard the VFEND vial if vacuum does not

pull the diluent into the vial. It is recommended that a standard 20 ml (non-automated) syringe

VFEND IV, POS & Film-Coated Tablets LPD CC 16 September 2020

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be used to ensure that the exact amount (19.0 ml) of water for injections or (9 mg/ml [0.9%])

Sodium Chloride for Infusion is dispensed. This medicinal product is for single use only and

any unused solution should be discarded. Only clear solutions without particles should be used.

For administration, the required volume of the reconstituted concentrate is added to a

recommended compatible infusion solution (detailed in the table below) to obtain a final

voriconazole solution containing 0.5-5 mg/mL.

Required Volumes of 10 mg/mL VFEND Concentrate

Body Weight

(kg)

Volume of VFEND Concentrate (10 mg/mL) required for:

3 mg/kg dose

(number of

vials)

4 mg/kg dose

(number of

vials)

6 mg/kg dose

(number of

vials)

8mg/kg

dose

(number

of vials)

9 mg/kg

dose

(number

of vials)

4.0mL (1)

8.0 mL

9.0 mL

6.0mL (1)

12.0 mL

13.5 mL

8.0mL (1)

16.0 mL

18.0 mL

10.0mL (1)

20.0 mL

22.5 mL

9.0 mL (1)

12 mL (1)

18 mL (1)

24.0 mL

27.0 mL

10.5 mL (1)

14 mL (1)

21 mL (2)

28.0 mL

31.5 mL

12.0 mL (1)

16 mL (1)

24 mL (2)

32.0 mL

36.0 mL

13.5 mL (1)

18 mL (1)

27 mL (2)

36.0 mL

40.5 mL

15.0 mL (1)

20 mL (1)

30 mL (2)

40.0 mL

45.0 mL

16.5 mL (1)

22 mL (2)

33 mL (2)

44.0 mL

49.5 mL

18.0 mL (1)

24 mL (2)

36 mL (2)

48.0 mL

54.0 mL

19.5 mL (1)

26 mL (2)

39 mL (2)

52.0 mL

58.5 mL

21.0 mL (2)

28 mL (2)

42 mL (3)

22.5 mL (2)

30 mL (2)

45 mL (3)

24.0 mL (2)

32 mL (2)

48 mL (3)

25.5 mL (2)

34 mL (2)

51 mL (3)

27.0 mL (2)

36 mL (2)

54 mL (3)

28.5 mL (2)

38 mL (2)

57 mL (3)

30.0 mL (2)

40 mL (2)

60 mL (3)

The reconstituted solution can be diluted with:

Sodium Chloride 9 mg/ml (0.9 %) Solution for Injection

Compound Sodium Lactate Intravenous Infusion

5% Glucose and Lactated Ringer’s Intravenous Infusion

5 % Glucose and 0.45 % Sodium Chloride Intravenous Infusion

5 % Glucose Intravenous Infusion

VFEND IV, POS & Film-Coated Tablets LPD CC 16 September 2020

2020-0058153

5 % Glucose in 20 mEq Potassium Chloride Intravenous Infusion

0.45 % Sodium Chloride Intravenous Infusion

5 % Glucose and 0.9 % Sodium Chloride Intravenous Infusion

The compatibility of voriconazole with diluents other than described above or in section 6.2 is

unknown.

VFEND film-coated tablets:

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

requirements.

VFEND powder for oral suspension:

Constitution instructions:

Tap the bottle to release the powder.

Add 2 measuring cups of water, providing a total volume of 46 ml.

Shake the closed bottle vigorously for about 1 minute.

Remove child-resistant cap. Press bottle adaptor into the neck of the bottle.

Replace the cap.

Write the date of expiration of the constituted suspension on the bottle label

(the shelf life of the constituted oral suspension is 14 days).

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

70ml.

Instructions for use:

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

Once constituted, VFEND oral suspension should only be administered using the oral syringe

supplied with each pack. Refer to the patient leaflet for more detailed instructions for use.

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

requirements.

7. MANUFACTURERS

VFEND powder for solution for infusion:

Fareva Amboise, Poce-Sur-Cisse, France

VFEND film-coated tablets:

R-Pharm Germany GmbH, Illertissen, Germany or Pfizer Italia S.r.l., Ascoli Piceno, Italy.

VFEND powder for oral suspension:

Fareva Amboise, Poce-Sur-Cisse, France

8. LICENSE HOLDER

Pfizer PFE Pharmaceuticals Israel Ltd., 9 Shenkar St., Herzliya Pituach 46725

9. LICENSE NUMBER

VFEND

®

Powder for Solution for Infusion

126-71-30598

VFEND IV, POS & Film-Coated Tablets LPD CC 16 September 2020

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Film-coated tablets

VFEND

®

50 mg Film-Coated Tablets

126-69-30596

VFEND

®

200 mg Film-Coated Tablets

126-70-30597

VFEND

®

Powder for Oral Suspension

134-48-31157

Revised in 09/2020.