Vfend

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS



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1. NAME OF THE MEDICINAL PRODUCT 

VFEND 50 mg film-coated tablets 

VFEND 200 mg film-coated tablets 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 50 or 200 mg voriconazole. 

Excipient with known effect

VFEND 50 mg film-coated tablets 
Each tablet contains 63.42 mg lactose monohydrate.

VFEND 200 mg film-coated tablets
Each tablet contains 253.675 mg lactose monohydrate.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

VFEND 50 mg film-coated tablets
White to off-white, round tablet, debossed “Pfizer” on one side and “VOR50”on the reverse.

VFEND 200 mg film-coated tablets
White to off-white, capsule-shaped tablet, debossed “Pfizer” on one side and “VOR200”on the reverse. 

4. CLINICAL PARTICULARS 

4.1 Therapeutic indications 

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

Treatment of invasive aspergillosis.

Treatment of candidaemia in non-neutropenic patients. 

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

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

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

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

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).



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VFEND is also available as 200 mg powder for solution for infusion, 200 mg powder and solvent for 
solution for infusion and 40 mg/ml powder for oral suspension.

Treatment
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

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

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

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

In case of use as prophylaxis, refer below.

Children (2 to <12 years) and young adolescents with low body weight (12 to 14 years and <50 kg)
Voriconazole should be dosed as children as these young adolescents may metabolize voriconazole more 
similarly to children than to adults. 

The recommended dosing regimen is as follows:

Intravenous Oral
Loading Dose Regimen 
(first 24 hours)

9 mg/kg every 12 hours Not recommended

Maintenance Dose
(after first 24 hours)

8 mg/kg twice daily 
9 mg/kg twice daily 
(a maximum dose of 350 mg 
twice daily)

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.



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These oral dose recommendations for children are based on studies in which voriconazole was 
administered as the powder for oral suspension. Bioequivalence between the powder for oral suspension 
and tablets has not been investigated in a paediatric population. Considering the assumed limited 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 oral suspension formulation in children aged 
2 to <12. 

All other adolescents (12 to 14 years and ≥50 kg; 15 to 17 years regardless of body weight)
Voriconazole should be dosed as adults.

Dosage adjustment (Children [2 to <12 years] and young adolescents with low body weight [12 to 14 years 
and <50 kg])
If patient response to treatment is inadequate, the dose may be increased by 1 mg/kg steps (or by 50 mg steps 
if the maximum oral dose of 350 mg was used initially). If patient is unable to tolerate treatment, reduce the 
dose by 1 mg/kg steps (or by 50 mg steps if the maximum oral dose of 350 mg was used initially).

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

Prophylaxis in Adults and Children
Prophylaxis should be initiated on the day of transplant and may be administered for up to 100 days. 
Prophylaxis should be as short as possible depending on the risk for developing invasive fungal infection 
(IFI) as defined by neutropenia or immunosuppression. It may only be continued up to 180 days after 
transplantation in case of continuing immunosuppression or graft versus host disease (GvHD) (see section 
5.1). 

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

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

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

The following instructions apply to both Treatment and Prophylaxis

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

Dosage adjustments in case of co-administration
Phenytoin may be coadministered with voriconazole if the maintenance dose of voriconazole is increased 
from 200 mg to 400 mg orally, twice daily (100 mg to 200 mg orally, twice daily in patients less than 40 kg), 
see sections 4.4 and 4.5.

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

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



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

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

Voriconazole is haemodialysed with a clearance of 121 ml/min. A 4-hour haemodialysis session does not 
remove a sufficient amount of voriconazole to warrant dose adjustment. 

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

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

There is limited data on the safety of 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 severe hepatic impairment must be carefully monitored for drug toxicity (see 
section 4.8). 

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

Method of administration
VFEND film-coated tablets are to be taken at least one hour before, or one hour following, a meal.

4.3 Contraindications 

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

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

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

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

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

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

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



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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). 

Cardiovascular 
Voriconazole has been associated with QTc interval prolongation. There have been rare cases of torsades de 
pointes in patients taking voriconazole who had risk factors, such as history of cardiotoxic chemotherapy, 
cardiomyopathy, hypokalaemia and concomitant medicinal products that may have been contributory. 
Voriconazole should be administered with caution to patients with potentially proarrhythmic conditions, 
such as:

 Congenital or acquired QTc-prolongation.
 Cardiomyopathy, in particular when heart failure is present.
 Sinus bradycardia.
 Existing symptomatic arrhythmias.
 Concomitant medicinal product that is known to prolong QTc interval. Electrolyte disturbances such 

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

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

Monitoring of hepatic function
Patients receiving 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).



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 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 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 



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population of patients. In children experiencing photoaging injuries such as lentigines or ephelides, 
sun avoidance and dermatologic follow-up are recommended even after treatment discontinuation.

Prophylaxis
In case of treatment-related adverse events (hepatotoxicity, severe skin reactions including phototoxicity and 
SCC, severe or prolonged visual disorders and periostitis), discontinuation of voriconazole and use of 
alternative antifungal agents must be considered.

Phenytoin (CYP2C9 substrate and potent CYP450 inducer)
Careful monitoring of phenytoin levels is recommended when phenytoin is coadministered with 
voriconazole. Concomitant use of voriconazole and phenytoin should be avoided unless the benefit 
outweighs the risk (see section 4.5). 

Efavirenz (CYP450 inducer; CYP3A4 inhibitor and substrate)
When voriconazole is coadministered with efavirenz the dose of voriconazole should be increased to 
400 mg every 12 hours and the dose of efavirenz should be decreased to 300 mg every 24 hours (see 
sections 4.2, 4.3 and 4.5). 

Rifabutin (Potent CYP450 inducer)
Careful monitoring of full blood counts and adverse reactions to rifabutin (e.g., uveitis) is recommended 
when rifabutin is coadministered with voriconazole. Concomitant use of voriconazole and rifabutin should 
be avoided unless the benefit outweighs the risk (see section 4.5). 

Ritonavir (potent CYP450 inducer; CYP3A4 inhibitor and substrate) 
Coadministration of voriconazole and low-dose ritonavir (100 mg twice daily) should be avoided unless an 
assessment of the benefit/risk to the patient justifies the use of voriconazole (see sections 4.3 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 AUC0-∞ of fentanyl, frequent monitoring for opiate-
associated adverse reactions (including a longer respiratory monitoring period) may be necessary.

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

Fluconazole (CYP2C9, CYP2C19 and CYP3A4 inhibitor)
Coadministration of oral voriconazole and oral fluconazole resulted in a significant increase in Cmax and 
AUCτ 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). 



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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. 

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, AUCt and AUC0- represent area under the curve over a dosing interval, from time 
zero to the time with detectable measurement and from time zero to infinity, respectively.

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  38%
Efavirenz AUC  44%
Voriconazole Cmax  61%
Voriconazole AUC  77%

Compared to efavirenz 600 mg QD,
Efavirenz Cmax ↔
Efavirenz AUC  17%

Compared to voriconazole 200 mg 
BID,
Voriconazole Cmax  23%
Voriconazole AUC  7%

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

Voriconazole may be 
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  69%
Voriconazole AUC  78%

Compared to voriconazole 200 mg 
BID,
Voriconazole Cmax  4%
Voriconazole AUC  32% 

Rifabutin Cmax  195%
Rifabutin AUC  331%
Compared to voriconazole 200 mg 
BID,
Voriconazole Cmax  104%
Voriconazole AUC  87% 

Concomitant use of 
voriconazole and rifabutin 
should be avoided unless the 
benefit outweighs the risk.
The maintenance dose of 
voriconazole may be increased 
to 5 mg/kg intravenously BID 
or from 200 mg to 350 mg 
orally BID (100 mg to 200 mg 
orally BID in patients less than 
40 kg) (see section 4.2). 
Careful monitoring of full 
blood counts and adverse 
reactions to rifabutin (e.g., 
uveitis) is recommended when 
rifabutin is coadministered 
with voriconazole.

Rifampicin (600 mg QD)
[potent CYP450 inducer]

Voriconazole Cmax  93%
Voriconazole AUC  96%

Contraindicated (see section 
4.3)



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Medicinal product
[Mechanism of interaction]

Interaction
Geometric mean changes (%)

Recommendations 
concerning
coadministration

Ritonavir (protease inhibitor) 
[potent CYP450 inducer; 
CYP3A4 inhibitor and 
substrate]

High dose (400 mg BID)

Low dose (100 mg BID)*

Ritonavir Cmax and AUC ↔
Voriconazole Cmax  66%
Voriconazole AUC  82%

Ritonavir Cmax  25%
Ritonavir AUC 13%
Voriconazole Cmax  24%
Voriconazole AUC  39%

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

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

St. John’s Wort 
[CYP450 inducer; P-
gp inducer]

300 mg TID (coadministered
with voriconazole 400 mg 
single dose)

In an independent published study, 
Voriconazole AUC0-  59%

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  57%
Voriconazole AUC  79%
Fluconazole Cmax ND
Fluconazole AUC ND

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



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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  49%
Voriconazole AUC  69%

Phenytoin Cmax  67%
Phenytoin AUC  81%
Compared to voriconazole 200 mg 
BID,
Voriconazole Cmax  34%
Voriconazole AUC  39%

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

Phenytoin may be 
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). 

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. 



13

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 AUC0-  11-fold

Ciclosporin Cmax  13%
Ciclosporin AUC  70%

Tacrolimus Cmax  117%
Tacrolimus AUCt  221%

Coadministration of 
voriconazole and sirolimus is 
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 AUC0-  3.6-fold

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

Methadone (32-100 mg QD)
[CYP3A4 substrate]

R-methadone (active) Cmax  31%
R-methadone (active) AUC  47%
S-methadone Cmax  65%
S-methadone AUC  103%

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



14

Medicinal product
[Mechanism of interaction]

Interaction
Geometric mean changes (%)

Recommendations 
concerning
coadministration

Non-Steroidal Anti-
Inflammatory Drugs (NSAIDs) 
[CYP2C9 substrates]

Ibuprofen (400 mg single 
dose)

Diclofenac (50 mg single 
dose)

S-Ibuprofen Cmax  20%
S-Ibuprofen AUC0-  100%

Diclofenac Cmax  114%
Diclofenac AUC0-  78%

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

Omeprazole (40 mg QD)*

[CYP2C19 inhibitor; CYP2C19 
and CYP3A4 substrate]

Omeprazole Cmax  116%
Omeprazole AUC  280%
Voriconazole Cmax  15%
Voriconazole AUC  41%

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

No dose adjustment of 
voriconazole is recommended.  

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

Oral Contraceptives*

[CYP3A4 substrate; CYP2C19 
inhibitor]

Norethisterone/ethinylestradiol 
(1 mg/0.035 mg QD) 

Ethinylestradiol Cmax  36%
Ethinylestradiol AUC  61%
Norethisterone Cmax  15%
Norethisterone AUC  53%
Voriconazole Cmax  14%
Voriconazole AUC  46%

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

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 AUC0-  6-fold

In an independent published study,
Fentanyl AUC0-  1.34-fold

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

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.



15

Medicinal product
[Mechanism of interaction]

Interaction
Geometric mean changes (%)

Recommendations 
concerning
coadministration

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  18%
Voriconazole AUC  23%

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 

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  11%
Prednisolone AUC0-  34%

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 



16

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. 

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:



17

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

agranulocytosis1, 
pancytopenia, 
thrombocytopenia2, 
leukopenia, 
anaemia

bone marrow 
failure, 
lymphadenopathy, 
eosinophilia

disseminated 
intravascular 
coagulation

Immune 
system 
disorders

hypersensitivity anaphylactoid 
reaction

Endocrine 
disorders

adrenal 
insufficiency, 
hypothyroidism

hyperthyroidism

Metabolism 
and nutrition 
disorders

oedema 
peripheral

hypoglycaemia, 
hypokalaemia, 
hyponatraemia

Psychiatric 
disorders

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

Nervous 
system 
disorders 

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

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

hepatic 
encephalopathy, 
Guillain-Barre 
syndrome, 
nystagmus

Eye disorders visual 
impairment6

retinal 
haemorrhage

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

optic atrophy, 
corneal opacity

Ear and 
labyrinth 
disorders 

hypoacusis, 
vertigo, tinnitus



18

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)

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

Respiratory, 
thoracic and 
mediastinal 
disorders 

respiratory 
distress9

acute respiratory 
distress syndrome, 
pulmonary oedema

Gastrointestin
al disorders 

diarrhoea, 
vomiting, 
abdominal 
pain, nausea

cheilitis, dyspepsia, 
constipation, 
gingivitis

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

Hepatobiliary 
disorders 

liver function 
test abnormal

jaundice, jaundice 
cholestatic, 
hepatitis10

hepatic failure, 
hepatomegaly, 
cholecystitis, 
cholelithiasis

Skin and 
subcutaneous 
tissue 
disorders 

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

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

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

cutaneous 
lupus 
erythemato
sus*, 
ephelides*, 
lentigo*

Musculoskelet
al and 
connective 
tissue 
disorders 

back pain arthritis periostitis*



19

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)

Renal and 
urinary 
disorders 

renal failure acute, 
haematuria

renal tubular 
necrosis, 
proteinuria, 
nephritis

General 
disorders and 
administration 
site conditions 

pyrexia chest pain, face 
oedema11, asthenia, 
chills

infusion site 
reaction, influenza 
like illness

Investigations blood creatinine 
increased

blood urea 
increased, blood 
cholesterol 
increased

*ADR identified post-marketing
1 Includes febrile neutropenia and neutropenia.
2 Includes immune thrombocytopenic purpura.
3 Includes nuchal rigidity and tetany.
4 Includes hypoxic-ischaemic encephalopathy and metabolic encephalopathy.
5 Includes akathisia and parkinsonism.
6 See “Visual impairments” paragraph in section 4.8.
7 Prolonged optic neuritis has been reported post-marketing. See section 4.4.
8 See section 4.4.
9 Includes dyspnoea and dyspnoea exertional.
10 Includes drug-induced liver injury, hepatitis toxic, hepatocellular injury and hepatotoxicity.
11 Includes periorbital oedema, lip oedema, and oedema mouth.

Description of selected adverse reactions

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 



20

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 
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). 

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. Healthcare professionals are asked 
to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose 

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

There is no known antidote to voriconazole. 

Voriconazole is haemodialysed with a clearance of 121 ml/min. In an overdose, haemodialysis may assist 



21

in the removal of voriconazole from the body. 

5. PHARMACOLOGICAL PROPERTIES 

5.1 Pharmacodynamic properties 

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

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

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

Other treated fungal infections (often with either partial or complete response) included isolated cases of 
Alternaria spp., Blastomyces dermatitidis, Blastoschizomyces capitatus, Cladosporium spp., Coccidioides 
immitis, Conidiobolus coronatus, Cryptococcus neoformans, Exserohilum rostratum, Exophiala spinifera, 
Fonsecaea pedrosoi, Madurella mycetomatis, Paecilomyces lilacinus, Penicillium spp. including 
P. marneffei, Phialophora richardsiae, Scopulariopsis brevicaulis and Trichosporon spp. including
T. beigelii infections.

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



22

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 and 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 albicans1 0.125 0.125
Candida tropicalis1 0.125 0.125
Candida parapsilosis1 0.125 0.125
Candida glabrata2 Insufficient evidence
Candida krusei3 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 
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. 



23

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

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

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

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

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

Timepoint Voriconazole 
(N=248)  

Amphotericin B 
→ fluconazole 
(N=122)

EOT 178 (72%) 88 (72%) 
2 weeks after 
EOT 

125 (50%) 62 (51%)

6 weeks after 
EOT 

104 (42%) 55 (45%)

12 weeks after 
EOT 

104 (42%) 51 (42%)

Serious refractory Candida 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 and Fusarium infections 
Voriconazole was shown to be effective against the following rare fungal pathogens: 

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

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



24

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**
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

0 3 (1.2%) -1.2% (-2.6%, 0.2%) 0.0813

* Primary endpoint of the study
** Difference in proportions, 95% CI and p-valuesobtained after adjustment for randomization

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

AML

Study endpoints Voriconazole 
(N=98) 

Itraconazole
(N=109)

Difference in proportions and 
the 95% confidence interval 

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

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



25

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).

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 



26

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 (AUCτ). The oral maintenance dose of 200 mg (or 100 mg for patients less than 40 kg) achieves a 
voriconazole exposure similar to 3 mg/kg IV. A 300 mg (or 150 mg for patients less 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 (Cmax) 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, Cmax and AUCτ are reduced by 34% and 24%, respectively. The absorption of voriconazole is 
not affected by changes in gastric pH. 

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

Biotransformation 
In vitro studies showed that voriconazole is metabolised by the hepatic cytochrome P450 isoenzymes 
CYP2C19, CYP2C9 and CYP3A4. 

The inter-individual variability of voriconazole pharmacokinetics is high. 

In vivo studies indicated that CYP2C19 is significantly involved in the metabolism of voriconazole. This 
enzyme exhibits genetic polymorphism. For example, 15-20% of Asian populations may be expected to be 
poor metabolisers. For Caucasians and Blacks the prevalence of poor metabolisers is 3-5%. Studies 
conducted in Caucasian and Japanese healthy subjects have shown that poor metabolisers have, on average, 
4-fold higher voriconazole exposure (AUCτ) than their homozygous extensive metaboliser counterparts. 
Subjects who are heterozygous extensive metabolisers have on average 2-fold higher voriconazole 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, Cmax and AUCτ for healthy young females were 83% and 113% higher, 
respectively, than in healthy young males (18-45 years). In the same study, no significant differences in Cmax
and AUCτ were observed between healthy elderly males and healthy elderly females (≥65 years). 



27

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 Cmax and AUCτ in healthy elderly males (≥65 years) were 61% and 86% 
higher, respectively, than in healthy young males (18-45 years). No significant differences in Cmax and 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
In an oral single-dose (200 mg) study in subjects with normal renal function and mild (creatinine clearance 
41-60 ml/min) to severe (creatinine clearance < 20 ml/min) renal impairment, the pharmacokinetics of 
voriconazole were not significantly affected by renal impairment. The plasma protein binding of 
voriconazole was similar in subjects with different degrees of renal impairment (see sections 4.2 and 4.4). 

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

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



28

(Child-Pugh C) (see sections 4.2 and 4.4). 

5.3 Preclinical safety data 

Repeated-dose toxicity studies with voriconazole indicated the liver to be the target organ. Hepatotoxicity 
occurred at plasma exposures similar to those obtained at therapeutic doses in humans, in common with 
other antifungal agents. In rats, mice and dogs, voriconazole also induced minimal adrenal changes. 
Conventional studies of safety pharmacology, genotoxicity or carcinogenic potential did not reveal a special 
hazard for humans. 

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

6. PHARMACEUTICAL PARTICULARS 

6.1 List of excipients 

Tablet core
Lactose monohydrate 
Pregelatinised starch
Croscarmellose sodium
Povidone
Magnesium stearate

Film-coating
Hypromellose
Titanium dioxide (E171)
Lactose monohydrate 
Glycerol triacetate

6.2 Incompatibilities 

Not applicable. 

6.3 Shelf life 

3 years

6.4 Special precautions for storage 

This medicinal product does not require any special storage conditions. 

6.5 Nature and contents of container

HDPE tablet containers containing 2, 30 or 100 film-coated tablets.
PVC / Aluminium blister in cartons of 2, 10, 14, 20, 28, 30, 50, 56 or 100 film-coated 
tablets.
PVC / Aluminium/PVC/PVDC blister in cartons of 2, 10, 14, 20, 28, 30, 50, 56 or 100 
film-coated tablets.

Not all pack sizes may be marketed. 



29

6.6 Special precautions for disposal 

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

7. MARKETING AUTHORISATION HOLDER 

Pfizer Europe MA EEIG
Boulevard de la Plaine 17
1050 Bruxelles
Belgium

8. MARKETING AUTHORISATION NUMBER(S) 

VFEND 50 mg film-coated tablets 
EU/1/02/212/001-012
EU/1/02/212/028-036

VFEND 200 mg film-coated tablets
EU/1/02/212/013-024
EU/1/02/212/037-045

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 19 March 2002 
Date of latest renewal: 21 February 2012

10. DATE OF REVISION OF THE TEXT 

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



30

1. NAME OF THE MEDICINAL PRODUCT 

VFEND 200 mg powder for solution for infusion 

VFEND 200 mg powder and solvent for solution for infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

VFEND 200 mg 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.

Excipient with known effect
Each vial contains 217.6 mg sodium. 

VFEND 200 mg powder and solvent for solution for infusion
Each 50 ml polypropylene bag contains sodium chloride 0.9% in Water for Injections.

Excipient with known effect
Each bag contains 177.02 mg sodium.

For the full list of excipients, see section 6.1. 

3. PHARMACEUTICAL FORM 

VFEND 200 mg powder for solution for infusion
Powder for solution for infusion:White lyophilised powder.

VFEND 200 mg powder and solvent for solution for infusion
Powder for solution for infusion: White lyophilised powder.

Solvent for solution for infusion: Clear diluent solution.

4. CLINICAL PARTICULARS 

4.1 Therapeutic indications 

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

Treatment of invasive aspergillosis.

Treatment of candidaemia in non-neutropenic patients.

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

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

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

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



31

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). 

It is recommended that VFEND is administered at a maximum rate of 3 mg/kg per hour over 1 to 3 hours. 

VFEND is also available as 50 mg and 200 mg film-coated tablets and 40 mg/ml powder for oral 
suspension. 

Treatment
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

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

Dosage adjustment (Adults)
If patient is unable to tolerate intravenous treatment at 4 mg/kg twice daily, reduce the dose to 3 mg/kg twice 
daily. 

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

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

In case of use as prophylaxis, refer below.

Children (2 to <12 years) and young adolescents with low body weight (12 to 14 years and <50 kg)
Voriconazole should be dosed as children as these young adolescents may metabolize voriconazole more 
similarly to children than to adults.

The recommended dosing regimen is as follows: 



32

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. 

All other adolescents (12 to 14 years and ≥50 kg; 15 to 17 years regardless of body weight)
Voriconazole should be dosed as adults.

Dosage adjustment (Children [2 to <12 years] and young adolescents with low body weight [12 to 14 years 
and <50 kg])
If patient response to treatment is inadequate, the intravenous dose may be increased by 1 mg/kg steps. If 
patient is unable to tolerate treatment, reduce the intravenous dose by 1 mg/kg steps.

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

Prophylaxis in Adults and Children
Prophylaxis should be initiated on the day of transplant and may be administered for up to 100 days. 
Prophylaxis should be as short as possible depending on the risk for developing invasive fungal 
infection (IFI) as defined by neutropenia or immunosuppression. It may only be continued up to 180 
days after transplantation in case of continuing immunosuppression or graft versus host disease 
(GvHD) (see section 5.1). 

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

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

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

The following instructions apply to both Treatment and Prophylaxis

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

Dosage adjustments in case of co-administration
Rifabutin or 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 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). 



33

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

Renal impairment
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). 

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. 

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

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

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

There is limited data on the safety of 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 severe hepatic impairment must be carefully monitored for drug toxicity (see 
section 4.8). 

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

Method of administration
VFEND requires reconstitution and dilution (see section 6.6) prior to administration as an intravenous 
infusion. Not for bolus injection. 

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

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

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



34

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 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 (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. 



35

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 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. 



36

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

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

Prophylaxis
In case of treatment-related adverse events (hepatotoxicity, severe skin reactions including phototoxicity and 
SCC, severe or prolonged visual disorders and periostitis), discontinuation of voriconazole and use of 
alternative antifungal agents must be considered.

Phenytoin (CYP2C9 substrate and potent CYP450 inducer)
Careful monitoring of phenytoin levels is recommended when phenytoin is coadministered with 
voriconazole. Concomitant use of voriconazole and phenytoin should be avoided unless the benefit 
outweighs the risk (see section 4.5). 

Efavirenz (CYP450 inducer; CYP3A4 inhibitor and substrate)
When voriconazole is coadministered with efavirenz the dose of voriconazole should be increased to 400 mg 
every 12 hours and the dose of efavirenz should be decreased to 300 mg every 24 hours (see sections 4.2, 4.3
and 4.5). 

Rifabutin (Potent CYP450 inducer)
Careful monitoring of full blood counts and adverse reactions to rifabutin (e.g., uveitis) is recommended 
when rifabutin is coadministered with voriconazole. Concomitant use of voriconazole and rifabutin should 
be avoided unless the benefit outweighs the risk (see section 4.5). 

Ritonavir (potent CYP450 inducer; CYP3A4 inhibitor and substrate)
Coadministration of voriconazole and low-dose ritonavir (100 mg twice daily) should be avoided unless an 
assessment of the benefit/risk to the patient justifies the use of voriconazole (see sections 4.3 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 AUC0-∞ of fentanyl, frequent monitoring for opiate-
associated adverse reactions (including a longer respiratory monitoring period) may be necessary.



37

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

Fluconazole (CYP2C9, CYP2C19 and CYP3A4 inhibitor)
Coadministration of oral voriconazole and oral fluconazole resulted in a significant increase in Cmax and 
AUCτ 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). 

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, AUCt and AUC0- represent area under the curve over a dosing interval, from time 
zero to the time with detectable measurement and from time zero to infinity, respectively.

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)



38

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  38%
Efavirenz AUC  44%
Voriconazole Cmax  61%
Voriconazole AUC  77%

Compared to efavirenz 600 mg QD,
Efavirenz Cmax ↔
Efavirenz AUC  17%

Compared to voriconazole 200 mg 
BID,
Voriconazole Cmax  23%
Voriconazole AUC  7%

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

Voriconazole may be 
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  69%
Voriconazole AUC  78%

Compared to voriconazole 200 mg 
BID,
Voriconazole Cmax  4%
Voriconazole AUC  32% 

Rifabutin Cmax  195%
Rifabutin AUC  331%
Compared to voriconazole 200 mg 
BID,
Voriconazole Cmax  104%
Voriconazole AUC  87% 

Concomitant use of 
voriconazole and rifabutin 
should be avoided unless the 
benefit outweighs the risk.
The maintenance dose of 
voriconazole may be increased 
to 5 mg/kg intravenously BID 
or from 200 mg to 350 mg 
orally BID (100 mg to 200 mg 
orally BID in patients less than 
40 kg) (see section 4.2). 
Careful monitoring of full 
blood counts and adverse 
reactions to rifabutin (e.g., 
uveitis) is recommended when 
rifabutin is coadministered 
with voriconazole.

Rifampicin (600 mg QD)
[potent CYP450 inducer]

Voriconazole Cmax  93%
Voriconazole AUC  96%

Contraindicated (see section 
4.3)



39

Medicinal product
[Mechanism of interaction]

Interaction
Geometric mean changes (%)

Recommendations 
concerning
coadministration

Ritonavir (protease inhibitor) 
[potent CYP450 inducer; 
CYP3A4 inhibitor and 
substrate]

High dose (400 mg BID)

Low dose (100 mg BID)*

Ritonavir Cmax and AUC ↔
Voriconazole Cmax  66%
Voriconazole AUC  82%

Ritonavir Cmax  25%
Ritonavir AUC 13%
Voriconazole Cmax  24%
Voriconazole AUC  39%

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

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

St. John’s Wort 
[CYP450 inducer; P-
gp inducer]

300 mg TID (coadministered
with voriconazole 400 mg 
single dose)

In an independent published study, 
Voriconazole AUC0-  59%

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  57%
Voriconazole AUC  79%
Fluconazole Cmax ND
Fluconazole AUC ND

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



40

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  49%
Voriconazole AUC  69%

Phenytoin Cmax  67%
Phenytoin AUC  81%
Compared to voriconazole 200 mg 
BID,
Voriconazole Cmax  34%
Voriconazole AUC  39%

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

Phenytoin may be 
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). 

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. 



41

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 AUC0-  11-fold

Ciclosporin Cmax  13%
Ciclosporin AUC  70%

Tacrolimus Cmax  117%
Tacrolimus AUCt  221%

Coadministration of 
voriconazole and sirolimus is 
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 AUC0-  3.6-fold

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

Methadone (32-100 mg QD)
[CYP3A4 substrate]

R-methadone (active) Cmax  31%
R-methadone (active) AUC  47%
S-methadone Cmax  65%
S-methadone AUC  103%

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



42

Medicinal product
[Mechanism of interaction]

Interaction
Geometric mean changes (%)

Recommendations 
concerning
coadministration

Non-Steroidal Anti-
Inflammatory Drugs (NSAIDs) 
[CYP2C9 substrates]

Ibuprofen (400 mg single 
dose)

Diclofenac (50 mg single 
dose)

S-Ibuprofen Cmax  20%
S-Ibuprofen AUC0-  100%

Diclofenac Cmax  114%
Diclofenac AUC0-  78%

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

Omeprazole (40 mg QD)*

[CYP2C19 inhibitor; CYP2C19 
and CYP3A4 substrate]

Omeprazole Cmax  116%
Omeprazole AUC  280%
Voriconazole Cmax  15%
Voriconazole AUC  41%

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

No dose adjustment of 
voriconazole is recommended.  

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

Oral Contraceptives*

[CYP3A4 substrate; CYP2C19 
inhibitor]

Norethisterone/ethinylestradiol 
(1 mg/0.035 mg QD) 

Ethinylestradiol Cmax  36%
Ethinylestradiol AUC  61%
Norethisterone Cmax  15%
Norethisterone AUC  53%
Voriconazole Cmax  14%
Voriconazole AUC  46%

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

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 AUC0-  6-fold

In an independent published study,
Fentanyl AUC0-  1.34-fold

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

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.



43

Medicinal product
[Mechanism of interaction]

Interaction
Geometric mean changes (%)

Recommendations 
concerning
coadministration

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  18%
Voriconazole AUC  23%

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 

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  11%
Prednisolone AUC0-  34%

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 



44

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.  

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: 



45

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

agranulocytosis1, 
pancytopenia, 
thrombocytopenia2, 
leukopenia, 
anaemia

bone marrow 
failure, 
lymphadenopathy, 
eosinophilia

disseminated 
intravascular 
coagulation

Immune 
system 
disorders

hypersensitivity anaphylactoid 
reaction

Endocrine 
disorders

adrenal 
insufficiency, 
hypothyroidism

hyperthyroidism

Metabolism 
and nutrition 
disorders

oedema 
peripheral

hypoglycaemia, 
hypokalaemia, 
hyponatraemia

Psychiatric 
disorders

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

Nervous 
system 
disorders 

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

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

hepatic 
encephalopathy, 
Guillain-Barre 
syndrome, 
nystagmus

Eye disorders visual 
impairment6

retinal 
haemorrhage

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

optic atrophy, 
corneal opacity

Ear and 
labyrinth 
disorders 

hypoacusis, 
vertigo, tinnitus



46

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)

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

Respiratory, 
thoracic and 
mediastinal 
disorders 

respiratory 
distress9

acute respiratory 
distress syndrome, 
pulmonary oedema

Gastrointestin
al disorders 

diarrhoea, 
vomiting, 
abdominal 
pain, nausea

cheilitis, dyspepsia, 
constipation, 
gingivitis

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

Hepatobiliary 
disorders 

liver function 
test abnormal

jaundice, jaundice 
cholestatic, 
hepatitis10

hepatic failure, 
hepatomegaly, 
cholecystitis, 
cholelithiasis

Skin and 
subcutaneous 
tissue 
disorders 

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

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

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

cutaneous 
lupus 
erythemato
sus*, 
ephelides*, 
lentigo*

Musculoskelet
al and 
connective 
tissue 
disorders 

back pain arthritis periostitis*



47

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)

Renal and 
urinary 
disorders 

renal failure acute, 
haematuria

renal tubular 
necrosis, 
proteinuria, 
nephritis

General 
disorders and 
administration 
site conditions 

pyrexia chest pain, face 
oedema11, asthenia, 
chills

infusion site 
reaction, influenza 
like illness

Investigations blood creatinine 
increased

blood urea 
increased, blood 
cholesterol 
increased

*ADR identified post-marketing
1 Includes febrile neutropenia and neutropenia.
2 Includes immune thrombocytopenic purpura.
3 Includes nuchal rigidity and tetany.
4 Includes hypoxic-ischaemic encephalopathy and metabolic encephalopathy.
5 Includes akathisia and parkinsonism.
6 See “Visual impairments” paragraph in section 4.8.
7 Prolonged optic neuritis has been reported post-marketing. See section 4.4.
8 See section 4.4.
9 Includes dyspnoea and dyspnoea exertional.
10 Includes drug-induced liver injury, hepatitis toxic, hepatocellular injury and hepatotoxicity.
11 Includes periorbital oedema, lip oedema, and oedema mouth.

Description of selected adverse reactions

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 



48

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
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. Healthcare professionals are asked 
to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose 

In clinical trials there were 3 cases of accidental overdose. All occurred in paediatric patients, who received 



49

up to five times the recommended intravenous dose of voriconazole. A single adverse reaction of 
photophobia of 10 minutes duration was reported. 

There is no known antidote to voriconazole. 

Voriconazole is haemodialysed with a clearance of 121 ml/min. 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: J02A 
C03

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

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

Other treated fungal infections (often with either partial or complete response) included isolated cases of 
Alternaria spp., Blastomyces dermatitidis, Blastoschizomyces capitatus, Cladosporium spp., 
Coccidioides immitis, Conidiobolus coronatus, Cryptococcus neoformans, Exserohilum rostratum, 
Exophiala spinifera, Fonsecaea pedrosoi, Madurella mycetomatis, Paecilomyces lilacinus, 
Penicillium spp. including P. marneffei, Phialophora richardsiae, Scopulariopsis brevicaulis and 
Trichosporon spp. including T. beigelii infections. 

In vitro activity against clinical isolates has been observed for Acremonium spp., Alternaria spp., 
Bipolaris spp., Cladophialophora spp., and Histoplasma capsulatum, with most strains being inhibited by 



50

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 and 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 albicans1 0.125 0.125
Candida tropicalis1 0.125 0.125
Candida parapsilosis1 0.125 0.125
Candida glabrata2 Insufficient evidence
Candida krusei3 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 
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 



51

duration of oral voriconazole therapy was 76 days (range 2-232 days).

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

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

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

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

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

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

Timepoint Voriconazole 
(N=248)  

Amphotericin B 
→ fluconazole 
(N=122)

EOT 178 (72%) 88 (72%) 

2 weeks after 
EOT 

125 (50%) 62 (51%)

6 weeks after 
EOT 

104 (42%) 55 (45%)

12 weeks after 
EOT 

104 (42%) 51 (42%)

Serious refractory Candida 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 and Fusarium infections 



52

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**
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

0 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%) **



53

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).

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 



54

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 (AUCτ). The oral maintenance dose of 200 mg (or 100 mg for patients less than 40 kg) achieves a 
voriconazole exposure similar to 3 mg/kg IV. A 300 mg (or 150 mg for patients less 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 (Cmax) 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, Cmax and AUCτ are reduced by 34% and 24%, respectively. The absorption of voriconazole is 
not affected by changes in gastric pH. 

Distribution 
The volume of distribution at steady state for voriconazole is estimated to be 4.6 L/kg, suggesting extensive 
distribution into tissues. Plasma protein binding is estimated to be 58%. 

Cerebrospinal fluid samples from eight patients in a compassionate programme showed detectable 
voriconazole concentrations in all patients. 

Biotransformation
In vitro studies showed that voriconazole is metabolised by the hepatic cytochrome P450 isoenzymes 
CYP2C19, CYP2C9 and CYP3A4.

The inter-individual variability of voriconazole pharmacokinetics is high. 

In vivo studies indicated that CYP2C19 is significantly involved in the metabolism of voriconazole. This 
enzyme exhibits genetic polymorphism. For example, 15-20% of Asian populations may be expected to be 
poor metabolisers. For Caucasians and Blacks the prevalence of poor metabolisers is 3-5%. Studies 
conducted in Caucasian and Japanese healthy subjects have shown that poor metabolisers have, on average, 
4-fold higher voriconazole exposure (AUCτ) than their homozygous extensive metaboliser counterparts. 
Subjects who are heterozygous extensive metabolisers have on average 2-fold higher voriconazole 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 



55

accumulation or elimination of voriconazole. 

Pharmacokinetics in special patient groups 

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

In the clinical programme, no dosage adjustment was made on the basis of gender. The safety 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 Cmax and AUCτ in healthy elderly males (≥65 years) were 61% and 86% 
higher, respectively, than in healthy young males (18-45 years). No significant differences in Cmax and 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 adolescents/adults. Based on the population pharmacokinetic analysis, 12- to 14-
year-old adolescents weighing less than 50 kg should receive children’s doses (see section 4.2).

Renal impairment 
In 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 



56

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, AUCτ was similar in subjects with moderate hepatic cirrhosis (Child-Pugh 
B) given a maintenance dose of 100 mg twice daily and subjects with normal hepatic function given 
200 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.

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 

Powder for solution for infusion:
Sulfobutylether beta cyclodextrin sodium (SBECD)

Solvent for solution for infusion:
Sodium chloride 0.9% in Water for Injections

6.2 Incompatibilities 

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. 



57

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.

6.3 Shelf life 

VFEND 200 mg powder for solution for infusion and VFEND 200 mg powder and solvent for solution for 
infusion:

3 years. 

From a microbiological point of view, once reconstituted, the product must be 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°C. 

Solvent for solution for infusion:

VFEND solvent for solution for infusion is a sterile, single use polypropylene infusion bag. Therefore, from 
a microbiological point of view, once solvent has been removed from the bag to reconstitute the VFEND 
powder for solution for infusion and then reintroduced into the bag, the product must be 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, unless reconstitution has taken place in controlled 
and validated aseptic conditions.

6.4 Special precautions for storage 

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

6.5 Nature and contents of container 

VFEND 200 mg powder for solution for infusion:
30 ml clear Type I glass vial with rubber stopper and aluminium cap with plastic seal. 

VFEND 200 mg powder and solvent for solution for infusion:
VFEND powder and solvent for solution for infusion is available in a box containing:

1 single use 30 ml clear Type I glass vial with rubber stopper and aluminium cap with plastic seal of 
VFEND 200 mg, powder for solution.

1 sterile, single use, foil overwrapped, polypropylene bag containing VFEND solvent for solution for 
infusion in one compartment (50 ml). 

1 sterile, single use vial adapter.

1 sterile, single use syringe.

6.6 Special precautions for disposal and other handling 

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



58

VFEND 200 mg 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 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. 

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 
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 200 mg powder and solvent for solution for infusion:
Use only items provided in the box with VFEND powder and solvent for solution for infusion in the 
preparation of the infusion.

Instructions for reconstitution and use:

 This medicinal product is for single use only and any unused solution should be discarded.
 To prepare the VFEND vial for reconstitution, remove the plastic cap from the vial and wipe the top 

with an antiseptic swab. Hold the vial adapter over the vial and press down firmly, until the vial locks 
into place. The spike in the vial adapter will penetrate the vial seal.

 Remove the bag of VFEND solvent for solution for infusion from the foil overwrap (do not use 
scissors or any other sharp tool). Snap open the blue port of the infusion bag.

 The VFEND powder is reconstituted by using the specially marked syringe provided to remove 19 ml 
of VFEND solvent for solution for infusion (Sodium Chloride (0.9%) from the blue port of the 
infusion bag. 

 The VFEND solvent for solution for infusion is then added to the vial by unscrewing the syringe from 
the bag, connecting it to the vial adapter and then emptying the contents from the syringe into the vial. 

 This will provide an extractable volume of 20 ml of clear concentrate containing 10 mg/ml of 
voriconazole. The connected syringe and vial are then gently swirled to ensure that the VFEND 
powder has completely dissolved and no particulates are visible (do not shake). 

 For dilution, gently invert the vial, vial adapter and syringe assembly and withdraw the required 
volume of the reconstituted concentrate into the syringe (see table below). Only clear solutions 
without particulates should be used. Do not administer to the patient as a bolus injection.

 Once the syringe is reconnected to the blue port of the infusion bag, the contents are then emptied into 
the infusion bag from the syringe to provide a final voriconazole solution containing 0.5-5 mg/ml.

 The syringe may then be removed and the contents of the infusion bag mixed gently by inverting the 
bag several times. The bag should be carefully inspected to ensure that there are no particulates. The 
syringe, vial and vial adapter can then be discarded.

If the required volume of VFEND concentrate as described in the table below requires the use of multiple 



59

vials in order to provide the appropriate dose for a given body weight, then multiple infusion kits should be 
used. The instructions should be followed for reconstitution, dilution and administration of each kit. Each kit 
is for single use only. 

If multiple vials are required, each individual vial used must be administered using a separate sterile sodium 
chloride bag.

For administration, the twist-off port at the bottom of the infusion bag should be opened and the infusion line 
connected and primed. The contents of the infusion bag are now ready for infusion to the patient. 

The infusion bag should be checked to ensure that the entire contents of the bag have been infused, 
especially if the same intravenous line is to be used for sequential infusion of other drugs. Other additives 
should not be introduced into the infusion bag.

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) 

8 mg/kg dose 
(number of 

vials) 

9 mg/kg dose 
(number of 

vials)
10 - 4.0 ml (1) - 8.0 ml (1) 9.0 ml (1) 
15 - 6.0 ml (1) - 12.0 ml (1) 13.5 ml (1) 
20 - 8.0 ml (1) - 16.0 ml (1) 18.0 ml (1) 
25 - 10.0 ml (1) - 20.0 ml (1) 22.5 ml (2) 
30 9.0 ml (1) 12.0 ml (1) 18.0 ml (1) 24.0 ml (2) 27.0 ml (2) 
35 10.5 ml (1) 14.0 ml (1) 21.0 ml (2) 28.0 ml (2) 31.5 ml (2) 
40 12.0 ml (1) 16.0 ml (1) 24.0 ml (2) 32.0 ml (2) 36.0 ml (2) 
45 13.5 ml (1) 18.0 ml (1) 27.0 ml (2) 36.0 ml (2) 40.5 ml (3) 
50 15.0 ml (1) 20.0 ml (1) 30.0 ml (2) 40.0 ml (2) 45.0 ml (3) 
55 16.5 ml (1) 22.0 ml (2) 33.0 ml (2) 44.0 ml (3) 49.5 ml (3) 
60 18.0 ml (1) 24.0 ml (2) 36.0 ml (2) 48.0 ml (3) 54.0 ml (3) 
65 19.5 ml (1) 26.0 ml (2) 39.0 ml (2) 52.0 ml (3) 58.5 ml (3) 
70 21.0 ml (2) 28.0 ml (2) 42.0 ml (3) - -
75 22.5 ml (2) 30.0 ml (2) 45.0 ml (3) - -
80 24.0 ml (2) 32.0 ml (2) 48.0 ml (3) - -
85 25.5 ml (2) 34.0 ml (2) 51.0 ml (3) - -
90 27.0 ml (2) 36.0 ml (2) 54.0 ml (3) - -
95 28.5 ml (2) 38.0 ml (2) 57.0 ml (3) - -

100 30.0 ml (2) 40.0 ml (2) 60.0 ml (3) - -

Further information is provided for medical or healthcare professionals at the end of the Package 
Leaflet.

7. MARKETING AUTHORISATION HOLDER 

Pfizer Europe MA EEIG
Boulevard de la Plaine 17
1050 Bruxelles
Belgium

8. MARKETING AUTHORISATION NUMBER(S) 

VFEND 200 mg powder for solution for infusion
EU/1/02/212/025 



60

VFEND 200 mg powder and solvent for solution for infusion
EU/1/02/212/027

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

Date of first authorisation: 19 March 2002 
Date of latest renewal: 21 February 2012

10. DATE OF REVISION OF THE TEXT 

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



61

1. NAME OF THE MEDICINAL PRODUCT 

VFEND 40 mg/ml powder for oral suspension 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

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 oral suspension
White to off-white powder 

4. CLINICAL PARTICULARS 

4.1 Therapeutic indications 

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

Treatment of invasive aspergillosis

Treatment of candidaemia in non-neutropenic patients.

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

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

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

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

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). 

VFEND is also available as 50 mg and 200 mg film-coated tablets, 200 mg powder for solution for injection
and 200 mg powder and solvent for solution for infusion. 

Treatment
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. 



62

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

Intravenous Oral Suspension 

Patients 40 kg and
above*

Patients less than 
40 kg*

Loading dose 
regimen 
(first 24 hours) 

6 mg/kg every 12 
hours 

400 mg (10 ml) 
every 12 hours 

200 mg (5 ml) every 
12 hours 

Maintenance dose 
(after first 24 
hours) 

4 mg/kg twice daily 200 mg (5 ml) twice
daily

100 mg (2.5 ml) 
twice daily

* This also applies to patients aged 15 years and older

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

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

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

In case of use as prophylaxis, refer below.

Children (2 to <12 years) and young adolescents with low body weight (12 to 14 years and <50 kg)
Voriconazole should be dosed as children as these young adolescents may metabolize voriconazole more 
similarly to children than to adults.

The recommended dosing regimen is as follows:

Intravenous Oral
Loading Dose Regimen
(first 24 hours)

9 mg/kg every 12 hours Not recommended

Maintenance Dose
(after first 24 hours)

8 mg/kg twice daily 
9 mg/kg twice daily 
(a maximum dose of 350 mg 
twice daily)

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

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

These oral dose recommendations for children are based on studies in which voriconazole was 
administered as the powder for oral suspension. Bioequivalence between the powder for oral suspension 
and tablets has not been investigated in a paediatric population. Considering the assumed limited 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 oral suspension formulation in children aged 2 to 
<12. 

All other adolescents (12 to 14 years and ≥50 kg; 15 to 17 years regardless of body weight)
Voriconazole should be dosed as adults.



63

Dosage adjustment (Children [2 to <12 years] and young adolescents with low body weight [12 to 14 years 
and <50 kg])
If patient response to treatment is inadequate, the dose may be increased by 1 mg/kg steps (or by 50 mg steps 
if the maximum oral dose of 350 mg was used initially). If patient is unable to tolerate treatment, reduce the 
dose by 1 mg/kg steps (or by 50 mg steps if the maximum oral dose of 350 mg was used initially).

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

Prophylaxis in Adults and Children
Prophylaxis should be initiated on the day of transplant and may be administered for up to 100 days. 
Prophylaxis should be as short as possible depending on the risk for developing invasive fungal infection 
(IFI) as defined by neutropenia or immunosuppression. It may only be continued up to 180 days after 
transplantation in case of continuing immunosuppression or graft versus host disease (GvHD) (see section 
5.1). 

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

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

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

The following instructions apply to both Treatment and Prophylaxis

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

Dosage adjustments in case of co-administration
Phenytoin may be coadministered with voriconazole if the maintenance dose of voriconazole is increased 
from 200 mg to 400 mg orally, twice daily (100 mg to 200 mg orally, twice daily in patients less than 40 kg), 
see sections 4.4 and 4.5. 

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

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

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

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

Voriconazole is haemodialysed with a clearance of 121 ml/min. A 4-hour haemodialysis session does not 
remove a sufficient amount of voriconazole to warrant dose adjustment.



64

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

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

There is limited data on the safety of 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 severe hepatic impairment must be carefully monitored for drug toxicity (see 
section 4.8). 

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

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

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

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

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

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

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

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

4.4 Special warnings and precautions for use 

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



65

Cardiovascular
Voriconazole has been associated with QTc interval prolongation. There have been rare cases of torsades de 
pointes in patients taking voriconazole who had risk factors, such as history of cardiotoxic chemotherapy, 
cardiomyopathy, hypokalaemia and concomitant medicinal products that may have been contributory. 
Voriconazole should be administered with caution to patients with potentially proarrhythmic conditions, 
such as:

 Congenital or acquired QTc-prolongation.
 Cardiomyopathy, in particular when heart failure is present.
 Sinus bradycardia.
 Existing symptomatic arrhythmias.
 Concomitant medicinal product that is known to prolong QTc interval. Electrolyte disturbances such 

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

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

Monitoring of hepatic function
Patients receiving 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).



66

 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 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 as lentigines or ephelides, 
sun avoidance and dermatologic follow-up are recommended even after treatment discontinuation.

Prophylaxis
In case of treatment-related adverse events (hepatotoxicity, severe skin reactions including phototoxicity and 
SCC, severe or prolonged visual disorders and periostitis), discontinuation of voriconazole and use of 
alternative antifungal agents must be considered.

Phenytoin (CYP2C9 substrate and potent CYP450 inducer)
Careful monitoring of phenytoin levels is recommended when phenytoin is coadministered with 



67

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).

Rifabutin (Potent CYP450 inducer)
Careful monitoring of full blood counts and adverse reactions to rifabutin (e.g., uveitis) is recommended 
when rifabutin is coadministered with voriconazole. Concomitant use of voriconazole and rifabutin should 
be avoided unless the benefit outweighs the risk (see section 4.5). 

Ritonavir (potent CYP450 inducer; CYP3A4 inhibitor and substrate)
Coadministration of voriconazole and low-dose ritonavir (100 mg twice daily) should be avoided unless an 
assessment of the benefit/risk to the patient justifies the use of voriconazole (see sections 4.3 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 AUC0-∞ of fentanyl, frequent monitoring for 
opiate-associated adverse reactions (including a longer respiratory monitoring period) may be necessary. 

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

Fluconazole (CYP2C9, CYP2C19 and CYP3A4 inhibitor)
Coadministration of oral voriconazole and oral fluconazole resulted in a significant increase in Cmax and 
AUCτ 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 oral suspension contains sucrose and should not be given to patients with rare hereditary 
problems of fructose intolerance, sucrase-isomaltase deficiency or glucose-galactose malabsorption. 

4.5 Interaction with other medicinal products and other forms of interaction 

Voriconazole is metabolised by, and inhibits the activity of, cytochrome P450 isoenzymes, CYP2C19, 
CYP2C9, and CYP3A4. Inhibitors or inducers of these isoenzymes may increase or decrease voriconazole 
plasma concentrations, respectively, and there is potential for voriconazole to increase the plasma 
concentrations of substances metabolised by these CYP450 isoenzymes.  
Unless otherwise specified, drug interaction studies have been performed in healthy adult male subjects 



68

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, AUCt and AUC0- represent area under the curve over a dosing interval, from time 
zero to the time with detectable measurement and from time zero to infinity, respectively.

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)

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  38%
Efavirenz AUC  44%
Voriconazole Cmax  61%
Voriconazole AUC  77%

Compared to efavirenz 600 mg QD,
Efavirenz Cmax ↔
Efavirenz AUC  17%

Compared to voriconazole 200 mg 
BID,
Voriconazole Cmax  23%
Voriconazole AUC  7%

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

Voriconazole may be 
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)



69

Medicinal product
[Mechanism of interaction]

Interaction
Geometric mean changes (%)

Recommendations 
concerning
coadministration

Rifabutin 
[potent CYP450 inducer]

300 mg QD 

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

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

Voriconazole Cmax  69%
Voriconazole AUC  78%

Compared to voriconazole 200 mg 
BID,
Voriconazole Cmax  4%
Voriconazole AUC  32% 

Rifabutin Cmax  195%
Rifabutin AUC  331%
Compared to voriconazole 200 mg 
BID,
Voriconazole Cmax  104%
Voriconazole AUC  87% 

Concomitant use of 
voriconazole and rifabutin 
should be avoided unless the 
benefit outweighs the risk.
The maintenance dose of 
voriconazole may be increased 
to 5 mg/kg intravenously BID 
or from 200 mg to 350 mg 
orally BID (100 mg to 200 mg 
orally BID in patients less than 
40 kg) (see section 4.2). 
Careful monitoring of full 
blood counts and adverse 
reactions to rifabutin (e.g., 
uveitis) is recommended when 
rifabutin is coadministered 
with voriconazole.

Rifampicin (600 mg QD)
[potent CYP450 inducer]

Voriconazole Cmax  93%
Voriconazole AUC  96%

Contraindicated (see section 
4.3)

Ritonavir (protease inhibitor) 
[potent CYP450 inducer; 
CYP3A4 inhibitor and 
substrate]

High dose (400 mg BID)

Low dose (100 mg BID)*

Ritonavir Cmax and AUC ↔
Voriconazole Cmax  66%
Voriconazole AUC  82%

Ritonavir Cmax  25%
Ritonavir AUC 13%
Voriconazole Cmax  24%
Voriconazole AUC  39%

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

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

St. John’s Wort 
[CYP450 inducer; P-
gp inducer]

300 mg TID (coadministered
with voriconazole 400 mg 
single dose)

In an independent published study, 
Voriconazole AUC0-  59%

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).



70

Medicinal product
[Mechanism of interaction]

Interaction
Geometric mean changes (%)

Recommendations 
concerning
coadministration

Fluconazole (200 mg QD)
[CYP2C9, CYP2C19 and 
CYP3A4 inhibitor]

Voriconazole Cmax  57%
Voriconazole AUC  79%
Fluconazole Cmax ND
Fluconazole AUC ND

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

Phenytoin 
[CYP2C9 substrate and potent 
CYP450 inducer]

300 mg QD

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

Voriconazole Cmax  49%
Voriconazole AUC  69%

Phenytoin Cmax  67%
Phenytoin AUC  81%
Compared to voriconazole 200 mg 
BID,
Voriconazole Cmax  34%
Voriconazole AUC  39%

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

Phenytoin may be 
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). 

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. 



71

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 AUC0-  11-fold

Ciclosporin Cmax  13%
Ciclosporin AUC  70%

Tacrolimus Cmax  117%
Tacrolimus AUCt  221%

Coadministration of 
voriconazole and sirolimus is 
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 AUC0-  3.6-fold

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

Methadone (32-100 mg QD)
[CYP3A4 substrate]

R-methadone (active) Cmax  31%
R-methadone (active) AUC  47%
S-methadone Cmax  65%
S-methadone AUC  103%

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



72

Medicinal product
[Mechanism of interaction]

Interaction
Geometric mean changes (%)

Recommendations 
concerning
coadministration

Non-Steroidal Anti-
Inflammatory Drugs (NSAIDs) 
[CYP2C9 substrates]

Ibuprofen (400 mg single 
dose)

Diclofenac (50 mg single 
dose)

S-Ibuprofen Cmax  20%
S-Ibuprofen AUC0-  100%

Diclofenac Cmax  114%
Diclofenac AUC0-  78%

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

Omeprazole (40 mg QD)*

[CYP2C19 inhibitor; CYP2C19 
and CYP3A4 substrate]

Omeprazole Cmax  116%
Omeprazole AUC  280%
Voriconazole Cmax  15%
Voriconazole AUC  41%

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

No dose adjustment of 
voriconazole is recommended.  

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

Oral Contraceptives*

[CYP3A4 substrate; CYP2C19 
inhibitor]

Norethisterone/ethinylestradiol 
(1 mg/0.035 mg QD) 

Ethinylestradiol Cmax  36%
Ethinylestradiol AUC  61%
Norethisterone Cmax  15%
Norethisterone AUC  53%
Voriconazole Cmax  14%
Voriconazole AUC  46%

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

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 AUC0-  6-fold

In an independent published study,
Fentanyl AUC0-  1.34-fold

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

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.



73

Medicinal product
[Mechanism of interaction]

Interaction
Geometric mean changes (%)

Recommendations 
concerning
coadministration

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  18%
Voriconazole AUC  23%

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 

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  11%
Prednisolone AUC0-  34%

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. 



74

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. 

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: 



75

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

agranulocytosis1, 
pancytopenia, 
thrombocytopenia2, 
leukopenia, 
anaemia

bone marrow 
failure, 
lymphadenopathy, 
eosinophilia

disseminated 
intravascular 
coagulation

Immune 
system 
disorders

hypersensitivity anaphylactoid 
reaction

Endocrine 
disorders

adrenal 
insufficiency, 
hypothyroidism

hyperthyroidism

Metabolism 
and nutrition 
disorders

oedema 
peripheral

hypoglycaemia, 
hypokalaemia, 
hyponatraemia

Psychiatric 
disorders

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

Nervous 
system 
disorders 

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

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

hepatic 
encephalopathy, 
Guillain-Barre 
syndrome, 
nystagmus

Eye disorders visual 
impairment6

retinal 
haemorrhage

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

optic atrophy, 
corneal opacity

Ear and 
labyrinth 
disorders 

hypoacusis, 
vertigo, tinnitus



76

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)

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

Respiratory, 
thoracic and 
mediastinal 
disorders 

respiratory 
distress9

acute respiratory 
distress syndrome, 
pulmonary oedema

Gastrointestin
al disorders 

diarrhoea, 
vomiting, 
abdominal 
pain, nausea

cheilitis, dyspepsia, 
constipation, 
gingivitis

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

Hepatobiliary 
disorders 

liver function 
test abnormal

jaundice, jaundice 
cholestatic, 
hepatitis10

hepatic failure, 
hepatomegaly, 
cholecystitis, 
cholelithiasis

Skin and 
subcutaneous 
tissue 
disorders 

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

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

toxic epidermal 
necrolysis8, drug 
reaction with 
eosinophilia and 
systemic 
symptoms 
(DRESS)8, 

angioedema, 
actinic 
keratosis*, 
pseudoporphyria
, erythema 
multiforme, 
psoriasis, drug 
eruption

cutaneous 
lupus 
erythemato
sus*, 
ephelides*, 
lentigo*

Musculoskelet
al and 
connective 
tissue 
disorders 

back pain arthritis periostitis*



77

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)

Renal and 
urinary 
disorders 

renal failure acute, 
haematuria

renal tubular 
necrosis, 
proteinuria, 
nephritis

General 
disorders and 
administration 
site conditions 

pyrexia chest pain, face 
oedema11, asthenia, 
chills

infusion site 
reaction, influenza 
like illness

Investigations blood creatinine 
increased

blood urea 
increased, blood 
cholesterol 
increased

*ADR identified post-marketing
1 Includes febrile neutropenia and neutropenia.
2 Includes immune thrombocytopenic purpura.
3 Includes nuchal rigidity and tetany.
4 Includes hypoxic-ischaemic encephalopathy and metabolic encephalopathy.
5 Includes akathisia and parkinsonism.
6 See “Visual impairments” paragraph in section 4.8.
7 Prolonged optic neuritis has been reported post-marketing. See section 4.4.
8 See section 4.4.
9 Includes dyspnoea and dyspnoea exertional.
10 Includes drug-induced liver injury, hepatitis toxic, hepatocellular injury and hepatotoxicity.
11 Includes periorbital oedema, lip oedema, and oedema mouth.

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 



78

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 
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).

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. Healthcare professionals are asked 
to report any suspected adverse reactions via the national reporting system listed in Appendix V.

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. 



79

There is no known antidote to voriconazole.

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

5. PHARMACOLOGICAL PROPERTIES 

5.1 Pharmacodynamic properties 

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

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

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

Other treated fungal infections (often with either partial or complete response) included isolated cases of 
Alternaria spp., Blastomyces dermatitidis, Blastoschizomyces capitatus, Cladosporium spp.,
Coccidioides immitis, Conidiobolus coronatus, Cryptococcus neoformans, Exserohilum rostratum,
Exophiala spinifera, Fonsecaea pedrosoi, Madurella mycetomatis, Paecilomyces lilacinus, Penicillium spp. 
including P. marneffei, Phialophora richardsiae, Scopulariopsis brevicaulis and Trichosporon spp. 
including T. beigelii infections.

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

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



80

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 and 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 albicans1 0.125 0.125
Candida tropicalis1 0.125 0.125
Candida parapsilosis1 0.125 0.125
Candida glabrata2 Insufficient evidence
Candida krusei3 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 
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, 



81

radiographic/bronchoscopic abnormalities present at baseline) was seen in 53% of voriconazole-treated 
patients compared to 31% of patients treated with comparator. The 84-day survival rate for voriconazole was 
statistically significantly higher than that for the comparator and a clinically and statistically significant 
benefit was shown in favour of voriconazole for both time to death and time to discontinuation due to 
toxicity. 

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

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

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

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

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

Timepoint Voriconazole 
(N=248)  

Amphotericin B 
→ fluconazole 
(N=122)

EOT 178 (72%) 88 (72%) 

2 weeks after 
EOT 

125 (50%) 62 (51%)

6 weeks after 
EOT 

104 (42%) 55 (45%)

12 weeks after 
EOT 

104 (42%) 51 (42%)

Serious refractory Candida 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 and Fusarium infections
Voriconazole was shown to be effective against the following rare fungal pathogens:

Scedosporium spp.: Successful response to voriconazole therapy was seen in 16 (6 complete, 10 partial



82

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**
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

0 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%)***



83

*   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).

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 



84

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 (AUCτ). The oral maintenance dose of 200 mg (or 100 mg for patients less than 40 kg) achieves a 
voriconazole exposure similar to 3 mg/kg IV. A 300 mg (or 150 mg for patients less 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 (Cmax) 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 40 mg/ml oral suspension when administered as a 200 mg dose. When multiple doses of 
voriconazole oral suspension are administered with high fat meals, Cmax and AUCτ 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 (AUCτ) 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 



85

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

In the clinical programme, no dosage adjustment was made on the basis of gender. The safety 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 Cmax and AUCτ in healthy elderly males (≥65 years) were 61% and 86% 
higher, respectively, than in healthy young males (18-45 years). No significant differences in Cmax and 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 
In an oral single-dose (200 mg) study in subjects with normal renal function and mild (creatinine clearance 
41-60 ml/min) to severe (creatinine clearance <20 ml/min) renal impairment, the pharmacokinetics of 
voriconazole were not significantly affected by renal impairment. The plasma protein binding of 
voriconazole was similar in subjects with different degrees of renal impairment (see sections 4.2 and 4.4). 

Hepatic impairment 
After an oral single-dose (200 mg), AUC was 233% higher in subjects with mild to moderate hepatic 
cirrhosis (Child-Pugh A and B) compared with subjects with normal hepatic function. Protein binding of 



86

voriconazole was not affected by impaired hepatic function. 

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

5.3 Preclinical safety data 

Repeated-dose toxicity studies with voriconazole indicated the liver to be the target organ. Hepatotoxicity 
occurred at plasma exposures similar to those obtained at therapeutic doses in humans, in common with 
other antifungal agents. In rats, mice and dogs, voriconazole also induced minimal adrenal changes. 
Conventional studies of safety pharmacology, genotoxicity or carcinogenic potential did not reveal a special 
hazard for humans. 

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

6. PHARMACEUTICAL PARTICULARS 

6.1 List of excipients 

Sucrose  
Silica Colloidal Anhydrous
Titanium Dioxide (E171) 
Xanthan Gum 
Sodium Citrate 
Citric Acid Anhydrous
Sodium Benzoate (E211) 
Natural Orange Flavour 

6.2 Incompatibilities 

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

6.3 Shelf life 

2 years
The shelf life of the constituted suspension is 14 days.  
Constituted suspension: Do not store above 30°C; do not refrigerate or freeze.

6.4 Special precautions for storage 

Store in a refrigerator (2°C - 8°C).
For storage conditions after constitution, see section 6.3.
Keep the container tightly closed.

6.5 Nature and contents of container

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



87

45 g of powder for oral suspension. A measuring cup (graduated to indicate 23 ml), 5 ml oral syringe and a 
press-in bottle adaptor are also provided.

6.6 Special precautions for disposal and other handling 

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

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

constituted suspension is 14 days). 

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

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. 

7. MARKETING AUTHORISATION HOLDER 

Pfizer Europe MA EEIG
Boulevard de la Plaine 17
1050 Bruxelles
Belgium

8. MARKETING AUTHORISATION NUMBER(S) 

EU/1/02/212/026

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

Date of first authorisation: 19 March 2002 
Date of latest renewal: 21 February 2012

10. DATE OF REVISION OF THE TEXT 

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



88

ANNEX II

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT



89

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturers responsible for batch release 

Tablets 
R-Pharm Germany GmbH 
Heinrich-Mack-Str. 35, 89257 Illertissen 
Germany 

Pfizer Italia S.r.l.
Località Marino del Tronto
63100 Ascoli Piceno (AP)
Italy

Powder for solution for infusion and powder for oral suspension: 
Fareva Amboise
Zone Industrielle 
29 route des Industries 
37530 Pocé-sur-Cisse 
France 

The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to medical prescription.

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION

 Periodic Safety Update Reports

The requirements for submission of periodic safety update reports for this medicinal product are set out in 
the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC 
and any subsequent updates published on the European medicines web-portal.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE 
USE OF THE MEDICINAL PRODUCT

 Risk Management Plan (RMP)

The MAH shall perform the pharmacovigilance activities and interventions detailed in the agreed 
RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates 
of the RMP.

An updated RMP should be submitted:
 At the request of the European Medicines Agency;
 Whenever the risk management system is modified, especially as the result of new 

information being received that may lead to significant change to the benefit/risk profile or as 
the result of an important (pharmacovigilance or risk minimisation) milestone being reached.



90

 Additional risk minimisation measures

 Health Care Professional (HCP) Question and Answer Brochure for Phototoxicity, SCC and Hepatic 
toxicity; 
- Advises HCPs on the risks of phototoxicity, skin SCC and liver toxicity associated with 

voriconazole use.
- Provides HCPs with the current recommendations to monitor and manage these risks.
- Reminds HCPs of use of the HCP Checklist and the Patient Alert Card and how to obtain 

additional copies.

 Health Care Professional (HCP) Checklist for Phototoxicity, SCC and Hepatic toxicity:
- Reminds HCPs of the risks of phototoxicity, skin SCC and hepatotoxicity reported with 

voriconazole use.
- Provides HCPs with the current recommendations to monitor and manage these risks.
- Reminds HCPs to discuss with the patient/care giver the risks of phototoxicity/skin SCC and 

hepatotoxicity, what to look for, how and when to seek immediate attention.
- Reminds HCPs to provide a Patient Alert Card to the patient.

 Patient Alert Card for Phototoxicity and SCC:
- Reminds patients of the risk of phototoxicity and skin SCC.
- Reminds patients when and how to report relevant signs and symptoms of phototoxicity and skin 

cancer.
- Reminds patients to take steps to minimize the risk of skin reactions and skin SCC (by avoiding 

exposure to direct sunlight, use of a sunscreen and protective clothing) and inform HCPs if they 
experience relevant skin abnormalities.



91

ANNEX III

LABELLING AND PACKAGE LEAFLET 



92

A. LABELLING



93

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

Blister pack for 50 mg film-coated tablets – Pack of 2, 10, 14, 20, 28, 30, 50, 56, 100

1. NAME OF THE MEDICINAL PRODUCT 

VFEND 50 mg film-coated tablets
voriconazole 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

Each tablet contains 50 mg voriconazole. 

3. LIST OF EXCIPIENTS 

Contains lactose monohydrate. See leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS 

2 film-coated tablets 
10 film-coated tablets 
14 film-coated tablets 
20 film-coated tablets 
28 film-coated tablets 
30 film-coated tablets 
50 film-coated tablets 
56 film-coated tablets 
100 film-coated tablets 

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use.

Sealed Pack
Do not use if box has been opened.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE 
SIGHT AND REACH OF CHILDREN 

Keep out of the sight and reach of children. 

7. OTHER SPECIAL WARNING(S), IF NECESSARY



94

8. EXPIRY DATE 

EXP

9. SPECIAL STORAGE CONDITIONS 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

Pfizer Europe MA EEIG
Boulevard de la Plaine 17
1050 Bruxelles
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/02/212/001 2 film-coated tablets
EU/1/02/212/002 10 film-coated tablets
EU/1/02/212/003 14 film-coated tablets
EU/1/02/212/004 20 film-coated tablets
EU/1/02/212/005 28 film-coated tablets
EU/1/02/212/006 30 film-coated tablets
EU/1/02/212/007 50 film-coated tablets
EU/1/02/212/008 56 film-coated tablets
EU/1/02/212/009 100 film-coated tablets
EU/1/02/212/028 2 film-coated tablets
EU/1/02/212/029 10 film-coated tablets
EU/1/02/212/030 14 film-coated tablets
EU/1/02/212/031 20 film-coated tablets
EU/1/02/212/032 28 film-coated tablets
EU/1/02/212/033 30 film-coated tablets
EU/1/02/212/034 50 film-coated tablets
EU/1/02/212/035 56 film-coated tablets
EU/1/02/212/036 100 film-coated tablets

13. BATCH NUMBER 

Batch

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE 



95

16. INFORMATION IN BRAILLE 

VFEND 50 mg 

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER –HUMAN READABLE DATA

PC:
SN: 
NN: 



96

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

Blister foil for 50 mg film-coated tablets (all blister packs)

1. NAME OF THE MEDICINAL PRODUCT 

VFEND 50 mg film-coated tablets 
voriconazole 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

Pfizer Europe MA EEIG (as MA Holder logo) 

3. EXPIRY DATE 

EXP

4. BATCH NUMBER 

Batch

5. OTHER 



97

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING

Bottle outer pack and bottle label for 50 mg film-coated tablets – Pack of 2, 30, 100 

1. NAME OF THE MEDICINAL PRODUCT 

VFEND 50 mg film-coated tablets
voriconazole 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

Each tablet contains 50 mg voriconazole. 

3. LIST OF EXCIPIENTS 

Contains lactose monohydrate. See leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS 

2 film-coated tablets 
30 film-coated tablets
100 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE 
SIGHT AND REACH OF CHILDREN 

Keep out of the sight and reach of children. 

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE 

EXP:

9. SPECIAL STORAGE CONDITIONS 



98

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

Pfizer Europe MA EEIG
Boulevard de la Plaine 17
1050 Bruxelles
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/02/212/010 2 film-coated tablets
EU/1/02/212/011 30 film-coated tablets
EU/1/02/212/012 100 film-coated tablets

13. BATCH NUMBER 

Batch

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE 

16. INFORMATION IN BRAILLE 

VFEND 50 mg 

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC: 
SN: 
NN: 



99

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

Blister pack for 200 mg film-coated tablets – Pack of 2, 10, 14, 20, 28, 30, 50, 56, 100 

1. NAME OF THE MEDICINAL PRODUCT

VFEND 200 mg film-coated tablets 
voriconazole 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

Each tablet contains 200 mg voriconazole. 

3. LIST OF EXCIPIENTS 

Contains lactose monohydrate. See leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS 

2 film-coated tablets 
10 film-coated tablets
14 fim-coated tablets
20 film-coated tablets
28 film-coated tablets
30 film-coated tablets
50 film-coated tablets
56 film-coated tablets
100 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read enclosed leaflet before use.
Oral use

Sealed Pack
Do not use if box has been opened.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE 
SIGHT AND REACH OF CHILDREN 

Keep out of the sight and reach of children. 

7. OTHER SPECIAL WARNING(S), IF NECESSARY



100

8. EXPIRY DATE 

EXP

9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

Pfizer Europe MA EEIG
Boulevard de la Plaine 17
1050 Bruxelles
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/02/212/013 2 film-coated tablets
EU/1/02/212/014 10 film-coated tablets
EU/1/02/212/015 14 film-coated tablets
EU/1/02/212/016 20 film-coated tablets
EU/1/02/212/017 28 film-coated tablets
EU/1/02/212/018 30 film-coated tablets
EU/1/02/212/019 50 film-coated tablets
EU/1/02/212/020 56 film-coated tablets
EU/1/02/212/021 100 film-coated tablets
EU/1/02/212/037 2 film-coated tablets
EU/1/02/212/038 10 film-coated tablets
EU/1/02/212/039 14 film-coated tablets
EU/1/02/212/040 20 film-coated tablets
EU/1/02/212/041 28 film-coated tablets
EU/1/02/212/042 30 film-coated tablets
EU/1/02/212/043 50 film-coated tablets
EU/1/02/212/044 56 film-coated tablets
EU/1/02/212/045 100 film-coated tablets

13. BATCH NUMBER 

Batch

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE 



101

16. INFORMATION IN BRAILLE 

VFEND 200 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC: 
SN: 
NN: 



102

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

Blister foil for 200 mg film-coated tablets (all blister packs) 

1. NAME OF THE MEDICINAL PRODUCT

VFEND 200 mg film-coated tablets 
voriconazole 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

Pfizer Europe MA EEIG (as MA Holder logo) 

3. EXPIRY DATE 

EXP

4. BATCH NUMBER 

Batch

5. OTHER 



103

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING

Bottle outer pack and bottle label for 200 mg film-coated tablets – Pack of 2, 30, 100 

1. NAME OF THE MEDICINAL PRODUCT

VFEND 200 mg film-coated tablets 
voriconazole 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

Each tablet contains 200 mg voriconazole. 

3. LIST OF EXCIPIENTS 

Contains lactose monohydrate. See leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS 

2 tablets 
30 film-coated tablets
100 film-coated tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read enclosed leaflet before use.
Oral use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE 
SIGHT AND REACH OF CHILDREN 

Keep out of the sight and reach of children. 

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE 

EXP

9. SPECIAL STORAGE CONDITIONS 



104

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

Pfizer Europe MA EEIG
Boulevard de la Plaine 17
1050 Bruxelles
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/02/212/022 2 film-coated tablets
EU/1/02/212/023 30 film-coated tablets
EU/1/02/212/024 100 film-coated tablets

13. BATCH NUMBER 

Batch

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE 

VFEND 200 mg 

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC: 
SN: 
NN: 



105

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

Outer carton 

1. NAME OF THE MEDICINAL PRODUCT

VFEND 200 mg powder for solution for infusion 
voriconazole 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

Each vial contains 200 mg of voriconazole.
After reconstitution each ml contains 10 mg of voriconazole.

3. LIST OF EXCIPIENTS 

Excipient: sulfobutylether beta cyclodextrin sodium. See leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS 

Powder for solution for infusion
1 vial

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use
Reconstitute and dilute before use.
Intravenous use only
Not for bolus injection

Single use vial
Infuse at a maximum rate of 3 mg/kg per hour.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE 
SIGHT AND REACH OF CHILDREN 

Keep out of the sight and reach of children. 

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE 

EXP
Shelf life after reconstitution: 24 hours when stored at 2°C - 8°C.



106

9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

Pfizer Europe MA EEIG
Boulevard de la Plaine 17
1050 Bruxelles
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/02/212/025

13. BATCH NUMBER

Batch

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC: 
SN: 
NN: 



107

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

Outer carton 

1. NAME OF THE MEDICINAL PRODUCT

VFEND 200 mg powder and solvent for solution for infusion 
voriconazole 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

Vial contains 200 mg of voriconazole.
After reconstitution each ml contains 10 mg of voriconazole.

3. LIST OF EXCIPIENTS 

50 ml infusion bag containing 0.9% of sodium chloride.

4. PHARMACEUTICAL FORM AND CONTENTS 

Powder and solvent for solution for infusion
Each pack contains:
1 vial of VFEND powder for solution for infusion (single use vial)
1 overwrap
1 vial adaptor
1 syringe

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Please refer to Patient Information Leaflet for detailed instructions.
Reconstitute and dilute before use.
For intravenous use
Not for bolus injection
Not for use with other products

Infuse at a maximum rate of 3 mg/kg per hour.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE 
SIGHT AND REACH OF CHILDREN 

Keep out of the sight and reach of children. 

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE 



108

EXP
Shelf life after reconstitution: 24 hours when stored at 2°C - 8°C.

9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

Pfizer Europe MA EEIG
Boulevard de la Plaine 17
1050 Bruxelles
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/02/212/027

13. BATCH NUMBER

Batch

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

Instructions for Use – please be guided by the pictograms to understand how to use this product.

16. INFORMATION IN BRAILLE

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC: 
SN: 
NN: 



109

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 

Label on the vial 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 

VFEND 200 mg powder for solution for infusion
voriconazole 
Intravenous use

2. METHOD OF ADMINISTRATION 

Reconstitute and dilute before use – see leaflet. 
Infuse at a maximum rate of 3 mg/kg per hour. 

3. EXPIRY DATE 

EXP

4. BATCH NUMBER 

Batch

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

200 mg (10 mg/ml) 

6. OTHER 



110

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 

Label on the overwrap 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 

Solvent for VFEND powder for solution for infusion
Sodium Chloride 0.9% in Water for Injections
Intravenous use

2. METHOD OF ADMINISTRATION 

Not for bolus injection

3. EXPIRY DATE 

EXP

4. BATCH NUMBER 

Batch

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

50 ml 

6. OTHER 

Keep out of the sight and reach of children. 



111

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

Outer carton 

1. NAME OF THE MEDICINAL PRODUCT

VFEND 40 mg/ml powder for oral suspension 
voriconazole 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

1 ml of the constituted suspension contains 40 mg voriconazole. 

3. LIST OF EXCIPIENTS 

Also contains sucrose. See leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS 

Powder for oral suspension 
1 bottle of 45 g
A measuring cup (graduated to indicate 23 ml), 5 ml oral syringe and a press-in bottle adaptor

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

Read the package leaflet before use.
For oral use after constitution
Shake bottle for approximately 10 seconds before use.
Use the oral syringe provided in the pack to measure the correct dose.

Constitution instructions: 
Tap the bottle to release the powder.
Add 46 ml of water and shake vigorously for about 1 minute.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE 
SIGHT AND REACH OF CHILDREN 

Keep out of the sight and reach of children. 

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP
Any remaining suspension should be discarded 14 days after constitution. 



112

9. SPECIAL STORAGE CONDITIONS 

Powder: store at in a refrigerator before constitution.

For the constituted oral suspension:
Do not store above 30°C.
Do not refrigerate or freeze.

Keep the container tightly closed.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

Pfizer Europe MA EEIG
Boulevard de la Plaine 17
1050 Bruxelles
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/02/212/026 

13. BATCH NUMBER 

Batch

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE 

VFEND 40 mg/ml 

17.UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18.UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC: 
SN: 
NN: 



113

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 

Bottle 

1. NAME OF THE MEDICINAL PRODUCT

VFEND 40 mg/ml powder for oral suspension 
voriconazole 

2. STATEMENT OF ACTIVE SUBSTANCE(S)

1 ml of the constituted suspension contains 40 mg voriconazole. 

3. LIST OF EXCIPIENTS 

Also contains sucrose. See leaflet for further information. 

4. PHARMACEUTICAL FORM AND CONTENTS 

Powder for oral suspension
45 g

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

Read the package leafet before use.
For oral use after constitution
Shake bottle for approximately 10 seconds before use.
Use the oral syringe provided in the pack to measure the correct dose.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE 
SIGHT AND REACH OF CHILDREN 

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE 

EXP
Any remaining suspension should be discarded 14 days after constitution. 
Expiry date of the constituted suspension:



114

9. SPECIAL STORAGE CONDITIONS

Powder: store at in a refrigerator before constitution.

For the constituted oral suspension:
Do not store above 30°C. 
Do not refrigerate or freeze.
Keep the container tighly closed.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

Pfizer Europe MA EEIG
Boulevard de la Plaine 17
1050 Bruxelles
Belgium

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/02/212/026 

13. BATCH NUMBER 

Batch

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE 

Justification for not including Braille accepted. 



115

B. PACKAGE LEAFLET



116

Package Leaflet: Information for the user

VFEND 50 mg film-coated tablets 
VFEND 200 mg film-coated tablets 

Voriconazole 

Read all of this leaflet carefully before you start taking this medicine because it contains important 
information for you. 
 Keep this leaflet. You may need to read it again. 
 If you have any further questions, ask your doctor, pharmacist or nurse.
 This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if 

their signs of illness are the same as yours. 
 If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 

effects not listed in this leaflet. See section 4. 

What is in this leaflet
1. What VFEND is and what it is used for 
2. What you need to know before you take VFEND 
3. How to take VFEND 
4. Possible side effects 
5. How to store VFEND 
6. Content of the pack and other information 

1. What VFEND is and what it is used for 

VFEND contains the active substance voriconazole. VFEND is an antifungal medicine. It works by 
killing or stopping the growth of the fungi that cause infections.

It is used for the treatment of patients (adults and children over the age of 2) with:
 invasive aspergillosis (a type of fungal infection due to Aspergillus sp),
 candidaemia (another type of fungal infection due to Candida sp) in non-neutropenic patients 

(patients without abnormally low white blood cells count),
 serious invasive Candida sp. infections when the fungus is resistant to fluconazole (another 

antifungal medicine),
 serious fungal infections caused by Scedosporium sp. or Fusarium sp. (two different species of 

fungi).

VFEND is intended for patients with worsening, possibly life-threatening, fungal infections.

Prevention of fungal infections in high risk bone marrow transplant recipients.

This product should only be taken under the supervision of a doctor. 

2. What you need to know before you take VFEND 

Do not take VFEND:
If you are allergic to voriconazole or any of the other ingredients of this medicine (listed in section 6).

It is very important that you inform your doctor or pharmacist if you are taking or have taken any other 
medicines, even those that are obtained without a prescription, or herbal medicines. 

The medicines in the following list must not be taken during your course of VFEND treatment: 

 Terfenadine (used for allergy) 
 Astemizole (used for allergy) 



117

 Cisapride (used for stomach problems) 
 Pimozide (used for treating mental illness) 
 Quinidine (used for irregular heart beat) 
 Rifampicin (used for treating tuberculosis)
 Efavirenz (used for treating HIV) in doses of 400 mg and above once daily
 Carbamazepine (used to treat seizures) 
 Phenobarbital (used for severe insomnia and seizures) 
 Ergot alkaloids (e.g., ergotamine, dihydroergotamine; used for migraine) 
 Sirolimus (used in transplant patients) 
 Ritonavir (used for treating HIV) in doses of 400mg and more twice daily 
 St. John’s Wort (herbal supplement) 

Warnings and precautions
Talk to your doctor, pharmacist or nurse before taking VFEND if:

 you have had an allergic reaction to other azoles. 
 you are suffering from, or have ever suffered from liver disease. If you have liver disease, your 

doctor may prescribe a lower dose of VFEND. Your doctor should also monitor your liver function 
while you are being treated with VFEND by doing blood tests. 

 you are known to have cardiomyopathy, irregular heart beat, slow heart rate or an abnormality of 
electrocardiogram (ECG) called ‘long QTc syndrome’. 

You should avoid any sunlight and sun exposure while being treated. It is important to cover sun exposed 
areas of skin and use sunscreen with high sun protection factor (SPF), as an increased sensitivity of skin to 
the sun’s UV rays can occur. These precautions are also applicable to children.

While being treated with VFEND: 
 tell your doctor immediately if you develop

o sunburn
o severe skin rash or blisters 
o bone pain

If you develop skin disorders as described above, your doctor may refer you to a dermatologist, who after 
consultation may decide that it is important for you to be seen on a regular basis. There is a small chance that 
skin cancer could develop with long-term use of VFEND.

Your doctor should monitor the function of your liver and kidney by doing blood tests. 

Children and adolescents
VFEND should not be given to children younger than 2 years of age. 

Other medicines and VFEND
Please tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines, including those that are obtained without a prescription. 

Some medicines, when taken at the same time as VFEND, may affect the way VFEND works or VFEND 
may affect the way they work. 

Tell your doctor if you are taking the following medicine, as treatment with VFEND at the same time should 
be avoided if possible: 

 Ritonavir (used for treating HIV) in doses of 100 mg twice daily

Tell your doctor if you are taking either of the following medicines, as treatment with VFEND at the same 
time should be avoided if possible, and a dose adjustment of voriconazole may be required: 

 Rifabutin (used for treating tuberculosis). If you are already being treated with rifabutin your blood 



118

counts and side effects to rifabutin will need to be monitored.
 Phenytoin (used to treat epilepsy). If you are already being treated with phenytoin your blood 

concentration of phenytoin will need to be monitored during your treatment with VFEND and your 
dose may be adjusted.

Tell your doctor if you are taking any of the following medicines, as a dose adjustment or monitoring may be 
required to check that the medicines and/ or VFEND are still having the desired effect: 

 Warfarin and other anticoagulants (e.g., phenprocoumon, acenocoumarol; used to slow down clotting 
of the blood) 

 Ciclosporin (used in transplant patients) 
 Tacrolimus (used in transplant patients) 
 Sulfonylureas (e.g., tolbutamide, glipizide, and glyburide) (used for diabetes) 
 Statins (e.g., atorvastatin, simvastatin) (used for lowering cholesterol) 
 Benzodiazepines (e.g midazolam, triazolam) (used for severe insomnia and stress) 
 Omeprazole (used for treating ulcers) 
 Oral contraceptives (if you take VFEND whilst using oral contraceptives, you may get side effects 

such as nausea and menstrual disorders) 
 Vinca alkaloids (e.g., vincristine and vinblastine) (used in treating cancer) 
 Indinavir and other HIV protease inhibitors (used for treating HIV) 
 Non-nucleoside reverse transcriptase inhibitors (e.g., efavirenz, delavirdine, nevirapine) (used for 

treating HIV) (some doses of efavirenz can NOT be taken at the same time as VFEND)
 Methadone (used to treat heroin addiction) 
 Alfentanil and fentanyl and other short-acting opiates such as sufentanil (painkillers used for surgical 

procedures) 
 Oxycodone and other long-acting opiates such as hydrocodone (used for moderate to severe pain)
 Non-steroidal anti-inflammatory drugs (e.g., ibuprofen, diclofenac) (used for treating pain and 

inflammation)
 Fluconazole (used for fungal infections)
 Everolimus (used for treating advanced kidney cancer and in transplant patients)

Pregnancy and breast-feeding
VFEND must not be taken during pregnancy, unless indicated by your doctor. Effective contraception must 
be used in women of childbearing potential. Contact your doctor immediately if you become pregnant while 
taking VFEND. 

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your 
doctor or pharmacist for advice before taking this medicine.

Driving and using machines
VFEND may cause blurring of vision or uncomfortable sensitivity to light. While affected, do not drive 
or operate any tools or machines. Contact your doctor if you experience this.  

VFEND contains lactose
If you have been told by your doctor that you have an intolerance to some sugars, tell your doctor before 
taking VFEND. 

3. How to take VFEND 

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if 
you are not sure. 

Your doctor will determine your dose depending on your weight and the type of infection you have. 

The recommended dose for adults (including elderly patients) is as follows: 



119

Tablets 
Patients 40 kg and above Patients less than 40 kg 

Dose for the first 24 
hours 

400 mg every 12 hours 
for 

200 mg every 12 hours 
for 

(Loading Dose) the first 24 hours the first 24 hours 

Dose after the first 24 
hours 200 mg twice a day 100 mg twice a day 
(Maintenance Dose) 

Depending on your response to treatment, your doctor may increase the daily dose to 300 mg twice a day.

The doctor may decide to decrease the dose if you have mild to moderate cirrhosis. 

Use in children and adolescents
The recommended dose for children and teenagers is as follows: 

Tablets 
Children aged 2 to less 
than 12 years and 
teenagers aged 12 to 14 
years weighing less than 
50 kg 

Teenagers aged 12 to 14 
years weighing 50 kg or 
more; and all teenagers 
older than 14

Dose for the first 24 
hours 
(Loading Dose) 

Your treatment will be 
started as an infusion

400 mg every 12 hours 
for the first 24 hours

Dose after the first 24 
hours 
(Maintenance Dose)

9 mg/kg twice a day
(a maximum dose of 
350 mg twice daily)

200 mg twice a day

Depending on your response to treatment, your doctor may increase or decrease the daily dose.

 Tablets must only be given if the child is able to swallow tablets. 

Take your tablet at least one hour before, or one hour after a meal. Swallow the tablet whole with some 
water. 

If you or your child are taking VFEND for prevention of fungal infections, your doctor may stop giving 
VFEND if you or your child develop treatment related side effects. 

If you take more VFEND than you should 
If you take more tablets than prescribed (or if someone else takes your tablets) you must seek medical 
advice or go to the nearest hospital casualty department immediately. Take your box of VFEND tablets with 
you. You may experience abnormal intolerance to light as a result of taking more VFEND than you should.

If you forget to take VFEND 
It is important to take your VFEND tablets regularly at the same time each day. If you forget to take one 
dose, take your next dose when it is due. Do not take a double dose to make up for a forgotten dose.

If you stop taking VFEND 
It has been shown that taking all doses at the appropriate times may greatly increase the effectiveness of 
your medicine. Therefore unless your doctor instructs you to stop treatment, it is important to keep taking 
VFEND correctly, as described above. 



120

Continue taking VFEND until your doctor tells you to stop. Do not stop treatment early because your 
infection may not be cured. Patients with a weakened immune system or those with difficult infections may 
require long-term treatment to prevent the infection from returning. 

When VFEND treatment is stopped by your doctor you should not experience any effects. 

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. 

If any side effects occur, most are likely to be minor and temporary. However, some may be serious and 
need medical attention. 

Serious side effects – Stop taking VFEND and see a doctor immediately
- Rash
- Jaundice; Changes in blood tests of liver function
- Pancreatitis

Other side effects

Very common: may affect more than 1 in 10 people 

- Visual impairment (change in vision including blurred vision, visual color alterations, abnormal 
intolerance to visual perception of light, colour blindness, eye disorder, halo vision, night blindness, 
swinging vision, seeing sparks, visual aura, visual acuity reduced, visual brightness, loss of part of 
the usual field of vision, spots before the eyes) 

- Fever 
- Rash 
- Nausea, vomiting, diarrhoea 
- Headache 
- Swelling of the extremities 
- Stomach pains 
- Breathing difficulties
- Elevated liver enzymes

Common: may affect up to 1 in 10 people

- Inflammation of the sinuses, inflammation of the gums, chills, weakness 
- Low numbers of some types, including severe, of red (sometimes immune-related) and/or white 

blood cells (sometimes with fever), low numbers of cells called platelets that help the blood to clot
- Low blood sugar, low blood potassium, low sodium in the blood
- Anxiety, depression, confusion, agitation, inability to sleep, hallucinations 
- Seizures, tremors or uncontrolled muscle movements, tingling or abnormal skin 

sensations, increase in muscle tone, sleepiness, dizziness
- Bleeding in the eye
- Heart rhythm problems including very fast heartbeat, very slow heartbeat, fainting 
- Low blood pressure, inflammation of a vein (which may be associated with the formation of a blood 

clot) 
- Acute breathing difficulty, chest pain, swelling of the face (mouth, lips and around eyes), fluid 

accumulation in the lungs 
- Constipation, indigestion, inflammation of the lips
- Jaundice, inflammation of the liver and liver injury
- Skin rashes which may lead to severe blistering and peeling of the skin characterized by a flat, red

area on the skin that is covered with small confluent bumps, redness of the skin



121

- Itchiness 
- Hair loss 
- Back pain
- Kidney failure, blood in the urine, changes in kidney function tests  

Uncommon: may affect up to 1 in 100 people

- Flu-like symptoms, irritation and inflammation of the gastrointestinal tract, inflammation of the 
gastrointestinal tract causing antibiotic associated diarrhoea, inflammation of the lymphatic vessels

- Inflammation of the thin tissue that lines the inner wall of the abdomen and covers the abdominal 
organ

- Enlarged lymph glands (sometimes painful), failure of blood marrow, increased eosinophil
- Depressed function of the adrenal gland, underactive thyroid gland
- Abnormal brain function, Parkinson-like symptoms, nerve injury resulting in numbness, pain, 

tingling or burning in the hands or feet
- Problems with balance or coordination 
- Swelling of the brain  
- Double vision, serious conditions of the eye including: pain and inflammation of the eyes and

eyelids, abnormal eye movement, damage to the optic nerve resulting in vision impairment, optic 
disc swelling

- Decreased sensitivity to touch 
- Abnormal sense of taste
- Hearing difficulties, ringing in the ears, vertigo
- Inflammation of certain internal organs- pancreas and duodenum, swelling and inflammation of the 

tongue 
- Enlarged liver, liver failure, gallbladder disease, gallstones 
- Joint inflammation, inflammation of the veins under the skin (which may be associated with the

formation of a blood clot) 
- Inflammation of the kidney, proteins in the urine, damage to the kidney  
- Very fast heart rate or skipped heartbeats, sometimes with erratic electrical impulses
- Abnormal electrocardiogram (ECG) 
- Blood cholesterol increased, blood urea increased
- Allergic skin reactions (sometimes severe), including life-threatening skin condition that causes 

painful blisters and sores of the skin and mucous membranes, especially in the mouth, 
inflammation of the skin, hives, sunburn or severe skin reaction following exposure to light or sun, 
skin redness and irritation, red or purple discoloration of the skin which may be caused by low 
platelet count, eczema

- Infusion site reaction
- Allergic reaction or exaggerated immune response

Rare: may affect up to 1 in 1000 people

- Overactive thyroid gland
- Deterioration of brain function that is a serious complication of liver disease
- Loss of most fibers in the optic nerve, clouding of the cornea, involuntary movement of the eye
- Bullous photosensitivity
- A disorder in which the body’s immune system attacks part of the peripheral nervous system
- Heart rhythm or conduction problems (sometimes life threatening)
- Life threatening allergic reaction 
- Disorder of blood clotting system
- Allergic skin reactions (sometimes severe), including rapid swelling (oedema) of the dermis,

subcutaneous tissue, mucosa and submucosal tissues, itchy or sore patches of thick, red skin with
silvery scales of skin, irritation of the skin and mucous membranes, life-threatening skin condition
that causes large portions of the epidermis, the skin's outermost layer, to detach from the layers of
skin below

- Small dry scaly skin patches, sometimes thick with spikes or ‘horns’



122

Side effects with frequency not known:
- Freckles and pigmented spots

Other significant side effects whose frequency is not known, but should be reported to your doctor 
immediately:
- Skin cancer 
- Inflammation of the tissue surrounding the bone 
- Red, scaly patches or ring-shaped skin lesions that may be a symptom of an autoimmune disease 

called cutaneous lupus erythematosus

As VFEND has been known to affect the liver and the kidney, your doctor should monitor the function 
of your liver and kidney by doing blood tests. Please advise your doctor if you have any stomach pains 
or if your stools have a different consistency.

There have been reports of skin cancer in patients treated with VFEND for long periods of time.

Sunburn or severe skin reaction following exposure to light or sun was experienced more frequently in 
children. If you or your child develops skin disorders, your doctor may refer you to a dermatologist, who 
after consultation may decide that it is important for you or your child to be seen on a regular basis. Elevated
liver enzymes were also observed more frequently in children.

If any of these side effects persist or are troublesome, please tell your doctor. 

Reporting of side effects
If you get any side effects, talk to your doctor or, pharmacist or nurse. This includes any possible side effects 

not listed in this leaflet. You can also report side effects directly via the national reporting system listed in 

Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store VFEND 

Keep this medicine out of the sight and reach of children. 

Do not use this medicine after the expiry date which is stated on the label. The expiry date refers to the last 
day of that month.

This medicine does not require any special storage conditions. 

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw 
away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information 

What VFEND contains 
 The active substance is voriconazole. Each tablet contains either 50 mg voriconazole (for VFEND 50 

mg film-coated tablets) or 200 mg voriconazole (for VFEND 200 mg film-coated tablets). 
 The other ingredients are lactose monohydrate, pregelatinised starch, croscarmellose sodium, 

povidone and magnesium stearate which make up the tablet core and hypromellose, titanium dioxide 
(E171), lactose monohydrate and glycerol triacetate which make up the film-coat. 

What VFEND looks like and contents of the pack 
VFEND 50 mg film-coated tablets are supplied as white to off-white round film-coated tablets with Pfizer 
marked on one side and VOR50 on the reverse. 

VFEND 200 mg film-coated tablets are supplied as white to off-white capsule shaped film-coated tablets 
with Pfizer marked on one side and VOR200 on the reverse. 



123

VFEND 50 mg film-coated tablets and 200 mg film-coated tablets are available as packs of 2, 10, 14, 20, 
28, 30, 50, 56 and 100. 

Not all pack sizes may be marketed.

Marketing Authorisation Holder 
Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium. 

Manufacturers
R-Pharm Germany GmbH 
Heinrich-Mack-Str. 35, 89257 Illertissen 
Germany 

Pfizer Italia S.r.l.
Località Marino del Tronto
63100 Ascoli Piceno (AP)
Italy

For any information about this medicine, please contact the local representative of the 
Marketing Authorisation Holder: 

België /Belgique/Belgien 
Pfizer S.A./N.V.  
Tél/Tel: +32 (0)2 554 62 11

Lietuva 
Pfizer Luxembourg SARL 
Filialas Lietuvoje 
Tel. +3705 2514000

България 
Пфайзер Люксембург САРЛ, Клон България 
Тел.: +359 2 970 4333 

Luxembourg/Luxemburg 
Pfizer S.A. 
Tél: +32 (0)2 554 62 11

Česká republika 
Pfizer s.r.o.
Tel: +420-283-004-111

Magyarország 
Pfizer Kft. 
Tel. + 36 1 488 37 00

Danmark 
Pfizer ApS Tlf: 
+45 44 20 11 00 

Malta 
Vivian Corporation Ltd. 
Tel : +356 21344610

Deutschland 
Pfizer Pharma PFE GmbH 
Tel: +49 (0)800 8535555

Nederland 
Pfizer bv 
Tel: +31 (0)10 406 43 01

Eesti 
Pfizer Luxembourg SARL Eesti filiaal 
Tel: +372 666 7500

Norge 
Pfizer AS 
Tlf: +47 67 52 61 00

Ελλάδα

Pfizer ΕΛΛΑΣ A.E.

Τηλ.: +30 210 6785 800

Österreich 
Pfizer Corporation Austria 
Ges.m.b.H. Tel: +43 (0)1 
521 15-0

España 
Pfizer, S.L.
Tel: +34 91 490 99 00

Polska 
Pfizer Polska Sp. z o.o., 
Tel.: +48 22 335 61 00



124

France
Pfizer
Tél: +33 (0)1 58 07 34 40 

Portugal 
Laboratórios Pfizer, Lda. 
Tel: + 351 214 235 500

Hrvatska
Pfizer Croatia d.o.o.
Tel: + 385 1 3908 777

România 
Pfizer România S.R.L 
Tel: +40 (0)21 207 28 00

Ireland 
Pfizer Healthcare Ireland 
Tel: 1800 633 363 (toll free)
+44 (0)1304 616161

Slovenija 
Pfizer Luxembourg SARL 
Pfizer, podružnica za svetovanje s področja 
farmacevtske dejavnosti, Ljubljana 
Tel: + 386 (0)152 11 400 

Ísland 
Icepharma hf., 
Sími: + 354 540 8000 

Slovenská republika
Pfizer Luxembourg SARL, organizačná zložka
Tel: +421-2-3355 5500

Italia 
Pfizer S.r.l. 
Tel: +39 06 33 18 21 

Suomi/Finland
Pfizer Oy 
Puh/Tel: +358(0)9 43 00 40

Kύπρος

Pfizer ΕΛΛΑΣ Α.Ε. (Cyprus Branch) 

Τηλ: +357 22 817690

Sverige  
Pfizer AB 
Tel: +46 (0)8 5505 2000

Latvija
Pfizer Luxembourg SARL 
Filiāle Latvijā 
Tel: +371 670 35 775

United Kingdom 
Pfizer Limited 
Tel: +44 (0)1304 616161

This leaflet was last approved in {MM/YYYY}.

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu



125

Package Leaflet: Information for the user

VFEND 200 mg powder for solution for infusion 
Voriconazole 

Read all of this leaflet carefully before you start taking this medicine because it contains important 
information for you. 
 Keep this leaflet. You may need to read it again. 
 If you have any further questions, ask your doctor, pharmacist or nurse. 
 This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if 

their signs of illness are the same as yours. 
 If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 

effects not listed in this leaflet. See section 4. 

What is in this leaflet
1. What VFEND is and what it is used for 
2. What you need to know before you take VFEND  
3. How to use VFEND 
4. Possible side effects 
5. How to store VFEND 
6. Content of the pack and other information 

1. What VFEND is and what it is used for 

VFEND contains the active substance voriconazole. VFEND is an antifungal medicine. It works by killing 
or stopping the growth of the fungi that cause infections.

It is used for the treatment of patients (adults and children over the age of 2) with:
 invasive aspergillosis (a type of fungal infection due to Aspergillus sp),
 candidaemia (another type of fungal infection due to Candida sp) in non-neutropenic patients 

(patients without abnormally low white blood cells count),
 serious invasive Candida sp. infections when the fungus is resistant to fluconazole (another 

antifungal medicine),
 serious fungal infections caused by Scedosporium sp. or Fusarium sp. (two different species of 

fungi).

VFEND is intended for patients with worsening, possibly life-threatening, fungal infections.

Prevention of fungal infections in high risk bone marrow transplant recipients.

This product should only be used under the supervision of a doctor. 

2. What you need to know before you take VFEND 

Do not take VFEND:
- If you are allergic to the active ingredient voriconazole, or to sulfobutylether beta cyclodextrin sodium

(listed in section 6). 

It is very important that you inform your doctor or pharmacist if you are taking or have taken any other 
medicines, even those that are obtained without a prescription, or herbal medicines. 

The medicines in the following list must not be taken during your course of VFEND treatment: 

 Terfenadine (used for allergy) 
 Astemizole (used for allergy) 



126

 Cisapride (used for stomach problems) 
 Pimozide (used for treating mental illness) 
 Quinidine (used for irregular heart beat) 
 Rifampicin (used for treating tuberculosis) 
 Efavirenz (used for treating HIV) in doses of 400 mg and above once daily
 Carbamazepine (used to treat seizures) 
 Phenobarbital (used for severe insomnia and seizures) 
 Ergot alkaloids (e.g., ergotamine, dihydroergotamine; used for migraine) 
 Sirolimus (used in transplant patients) 
 Ritonavir (used for treating HIV) in doses of 400mg and more twice daily 
 St. John’s Wort (herbal supplement) 

Warnings and precautions
Talk to your doctor, pharmacist or nurse before taking VFEND if:

 you have had an allergic reaction to other azoles. 
 you are suffering from, or have ever suffered from liver disease. If you have liver disease, your 

doctor may prescribe a lower dose of VFEND. Your doctor should also monitor your liver function 
while you are being treated with VFEND by doing blood tests. 

 you are known to have cardiomyopathy, irregular heart beat, slow heart rate or an abnormality of 
electrocardiogram (ECG) called ‘long QTc syndrome’. 

You should avoid any sunlight and sun exposure while being treated. It is important to cover sun exposed 
areas of skin and use sunscreen with high sun protection factor (SPF), as an increased sensitivity of skin to 
the sun’s UV rays can occur. These precautions are also applicable to children.

While being treated with VFEND: 
 tell your doctor immediately if you develop

o sunburn
o severe skin rash or blisters  
o bone pain

If you develop skin disorders as described above, your doctor may refer you to a dermatologist, who after 
consultation may decide that it is important for you to be seen on a regular basis. There is a small chance that 
skin cancer could develop with long-term use of VFEND.

Your doctor should monitor the function of your liver and kidney by doing blood tests. 

Children and adolescents
VFEND should not be given to children younger than 2 years of age. 

Other medicines and VFEND
Please tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines, including those that are obtained without a prescription. 

Some medicines, when taken at the same time as VFEND, may affect the way VFEND works or VFEND 
may affect the way they work.

Tell your doctor if you are taking the following medicine, as treatment with VFEND at the same time should 
be avoided if possible: 

 Ritonavir (used for treating HIV) in doses of 100 mg twice daily 

Tell your doctor if you are taking either of the following medicines, as treatment with VFEND at the same 
time should be avoided if possible, and a dose adjustment of voriconazole may be required: 

 Rifabutin (used for treating tuberculosis). If you are already being treated with rifabutin your blood 



127

counts and side effects to rifabutin will need to be monitored.
 Phenytoin (used to treat epilepsy). If you are already being treated with phenytoin your blood 

concentration of phenytoin will need to be monitored during your treatment with VFEND and your 
dose may be adjusted.

Tell your doctor if you are taking any of the following medicines, as a dose adjustment or monitoring may be 
required to check that the medicines and/ or VFEND are still having the desired effect: 

 Warfarin and other anticoagulants (e.g., phenprocoumon, acenocoumarol; used to slow down clotting 
of the blood) 

 Ciclosporin (used in transplant patients) 
 Tacrolimus (used in transplant patients) 
 Sulfonylureas (e.g., tolbutamide, glipizide, and glyburide) (used for diabetes) 
 Statins (e.g., atorvastatin, simvastatin) (used for lowering cholesterol) 
 Benzodiazepines (e.g midazolam, triazolam) (used for severe insomnia and stress) 
 Omeprazole (used for treating ulcers) 
 Oral contraceptives (if you take VFEND whilst using oral contraceptives, you may get side effects 

such as nausea and menstrual disorders) 
 Vinca alkaloids (e.g., vincristine and vinblastine) (used in treating cancer) 
 Indinavir and other HIV protease inhibitors (used for treating HIV) 
 Non-nucleoside reverse transcriptase inhibitors (e.g., efavirenz, delavirdine, nevirapine) (used for 

treating HIV) (some doses of efavirenz can NOT be taken at the same time as VFEND)
 Methadone (used to treat heroin addiction) 
 Alfentanil and fentanyl and other short-acting opiates such as sufentanil (painkillers used for surgical 

procedures) 
 Oxycodone and other long-acting opiates such as hydrocodone (used for moderate to severe pain)
 Non-steroidal anti-inflammatory drugs (e.g., ibuprofen, diclofenac) (used for treating pain and 

inflammation)
 Fluconazole (used for fungal infections)
 Everolimus (used for treating advanced kidney cancer and in transplant patients)

Pregnancy and breast-feeding
VFEND must not be used during pregnancy, unless indicated by your doctor. Effective contraception must 
be used in women of childbearing potential. Contact your doctor immediately if you become pregnant 
while being treated with VFEND. 

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your 
doctor or pharmacist for advice before taking this medicine.

Driving and using machines
VFEND may cause blurring of vision or uncomfortable sensitivity to light. While affected, do not drive 
or operate any tools or machines. Tell your doctor if you experience this. 

VFEND contains sodium
Each vial of VFEND contains 217.6 mg of sodium per vial. This should be taken into consideration if you 
are on a strictly controlled sodium diet. 

3. How to use VFEND 

Always take this medicine exactly as your doctor has told you. Check with your doctor if you are not sure. 

Your doctor will determine your dose depending on your weight and the type of infection you have. 

Your doctor may change your dose depending on your condition. 



128

The recommended dose for adults (including elderly patients) is as follows: 

Intravenous 

Dose for the first 24 hours 
6 mg/kg every 12 hours for 
the 

(Loading Dose) first 24 hours 

Dose after the first 24 
hours 4 mg/kg twice a day 
(Maintenance Dose) 

Depending on your response to treatment, your doctor may decrease the dose to 3 mg/kg twice daily. 

The doctor may decide to decrease the dose if you have mild to moderate cirrhosis. 

Use in children and adolescents
The recommended dose for children and teenagers is as follows: 

Intravenous 
Children aged 2 to less 
than 12 years and 
teenagers aged 12 to 14 
years weighing less than 
50 kg 

Teenagers aged 12 to 14 
years weighing 50 kg or 
more; and all teenagers 
older than 14

Dose for the first 24 
hours 
(Loading Dose)

9 mg/kg every 12 hours 
for the first 24 hours

6 mg/kg every 12 hours 
for the first 24 hours

Dose after the first 24 
hours 8 mg/kg twice a day 4 mg/kg twice a day 
(Maintenance Dose) 

Depending on your response to treatment, your doctor may increase or decrease the daily dose.

VFEND powder for solution for infusion will be reconstituted and diluted to the correct concentration by 
your hospital pharmacist or nurse. (Please refer to the end of this leaflet for further information)   

This will be given to you by intravenous infusion (into a vein) at a maximum rate of 3 mg/kg per hour over 1 
to 3 hours.

If you or your child are taking VFEND for prevention of fungal infections, your doctor may stop giving 
VFEND if you or your child develop treatment related side effects. 

If a dose of VFEND has been forgotten
As you will be given this medicine under close medical supervision, it is unlikely that a dose would be 
missed. However tell your doctor or pharmacist if you think that a dose has been forgotten. 

If you stop taking VFEND 
VFEND treatment will continue for as long as your doctor advises, however duration of treatment with 
VFEND powder for solution for infusion should be no more than 6 months. 

Patients with a weakened immune system or those with difficult infections may require long-term treatment 
to prevent the infection from returning. You may be switched from the intravenous infusion to tablets once 
your condition improves. 

When VFEND treatment is stopped by your doctor you should not experience any effects. 



129

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 

4. Possible side effects 

Like all medicines, this medicine can cause side effects, although not everybody gets them. 

If any side effects occur, most are likely to be minor and temporary. However, some may be serious and 
need medical attention. 

Serious side effects – Stop taking VFEND and see a doctor immediately
- Rash
- Jaundice; Changes in blood tests of liver function
- Pancreatitis

Other side effects

Very common: may affect more than 1 in 10 people

- Visual impairment (change in vision including blurred vision, visual color alterations, abnormal 
intolerance to visual perception of light, colour blindness, eye disorder, halo vision, night blindness, 
swinging vision, seeing sparks, visual aura, visual acuity reduced, visual brightness, loss of part of 
the usual field of vision, spots before the eyes) 

- Fever 
- Rash 
- Nausea, vomiting, diarrhoea 
- Headache 
- Swelling of the extremities 
- Stomach pains 
- Breathing difficulties
- Elevated liver enzymes

Common: may affect up to 1 in 10 people

- Inflammation of the sinuses, inflammation of the gums, chills, weakness 
- Low numbers of some types, including severe, of red (sometimes immune-related) and/or white 

blood cells (sometimes with fever), low numbers of cells called platelets that help the blood to clot 
- Low blood sugar, low blood potassium, low sodium in the blood 
- Anxiety, depression, confusion, agitation, inability to sleep, hallucinations 
- Seizures, tremors or uncontrolled muscle movements, tingling or abnormal skin 

sensations, increase in muscle tone, sleepiness, dizziness
- Bleeding in the eye
- Heart rhythm problems including very fast heartbeat, very slow heartbeat, fainting 
- Low blood pressure, inflammation of a vein (which may be associated with the formation of a blood 

clot) 
- Acute breathing difficulty, chest pain, swelling of the face (mouth, lips and around eyes), fluid 

accumulation in the lungs 
- Constipation, indigestion, inflammation of the lips
- Jaundice, inflammation of the liver and liver injury
- Skin rashes which may lead to severe blistering and peeling of the skin characterized by a flat, red

area on the skin that is covered with small confluent bumps, redness of the skin
- Itchiness 
- Hair loss 
- Back pain
- Kidney failure, blood in the urine, changes in kidney function tests



130

Uncommon: may affect up to 1 in 100 people

- Flu-like symptoms, irritation and inflammation of the gastrointestinal tract, inflammation of the 
gastrointestinal tract causing antibiotic associated diarrhoea, inflammation of the lymphatic vessels

- Inflammation of the thin tissue that lines the inner wall of the abdomen and covers the abdominal 
organ

- Enlarged lymph glands (sometimes painful), failure of blood marrow, increased eosinophil
- Depressed function of the adrenal gland, underactive thyroid gland
- Abnormal brain function, Parkinson-like symptoms, nerve injury resulting in numbness, pain, 

tingling or burning in the hands or feet
- Problems with balance or coordination 
- Swelling of the brain  
- Double vision, serious conditions of the eye including: pain and inflammation of the eyes and

eyelids, abnormal eye movement, damage to the optic nerve resulting in vision impairment, optic 
disc swelling 

- Decreased sensitivity to touch 
- Abnormal sense of taste
- Hearing difficulties, ringing in the ears, vertigo 
- Inflammation of certain internal organs- pancreas and duodenum, swelling and inflammation of the 

tongue 
- Enlarged liver, liver failure, gallbladder disease, gallstones 
- Joint inflammation, inflammation of the veins under the skin (which may be associated with the 

formation of a blood clot) 
- Inflammation of the kidney, proteins in the urine, damage to the kidney  
- Very fast heart rate or skipped heartbeats, sometimes with erratic electrical impulses
- Abnormal electrocardiogram (ECG) 
- Blood cholesterol increased, blood urea increased
- Allergic skin reactions (sometimes severe), including life-threatening skin condition that causes 

painful blisters and sores of the skin and mucous membranes, especially in the mouth, 
inflammation of the skin, hives, sunburn or severe skin reaction following exposure to light or sun, 
skin redness and irritation, red or purple discoloration of the skin which may be caused by low 
platelet count, eczema

- Infusion site reaction
- Allergic reaction or exaggerated immune response

Rare: may affect up to 1 in 1000 people

- Overactive thyroid gland
- Deterioration of brain function that is a serious complication of liver disease
- Loss of most fibers in the optic nerve, clouding of the cornea, involuntary movement of the eye
- Bullous photosensitivity
- A disorder in which the body’s immune system attacks part of the peripheral nervous system
- Heart rhythm or conduction problems (sometimes life threatening)
- Life threatening allergic reaction 
- Disorder of blood clotting system
- Allergic skin reactions (sometimes severe), including rapid swelling (oedema) of the dermis,

subcutaneous tissue, mucosa and submucosal tissues, itchy or sore patches of thick, red skin with
silvery scales of skin, irritation of the skin and mucous membranes, life-threatening skin condition
that causes large portions of the epidermis, the skin's outermost layer, to detach from the layers of
skin below

- Small dry scaly skin patches, sometimes thick with spikes or ‘horns’

Side effects with frequency not known:
- Freckles and pigmented spots

Other significant side effects whose frequency is not known, but should be reported to your doctor 
immediately:
- Skin cancer 



131

- Inflammation of the tissue surrounding the bone 
- Red, scaly patches or ring-shaped skin lesions that may be a symptom of an autoimmune disease 

called cutaneous lupus erythematosus

Reactions during the infusion have occurred uncommonly with VFEND (including flushing, fever, 
sweating, increased heart rate and shortness of breath). Your doctor may stop the infusion if this occurs. 

As VFEND has been known to affect the liver and the kidney, your doctor should monitor the function 
of your liver and kidney by doing blood tests. Please advise your doctor if you have any stomach pains 
or if your stools have a different consistency. 

There have been reports of skin cancer in patients treated with VFEND for long periods of time. 

Sunburn or severe skin reaction following exposure to light or sun was experienced more frequently in 
children. If you or your child develops skin disorders, your doctor may refer you to a dermatologist, who 
after consultation may decide that it is important for you or your child to be seen on a regular basis. Elevated
liver enzymes were also observed more frequently in children.

If any of these side effects persist or are troublesome, please tell your doctor. 

Reporting of side effects
If you get any side effects, talk to your doctor or, pharmacist or nurse. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system listed in 
Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store VFEND 

Keep this medicine out of the sight and reach of children. 

Do not use this medicine after the expiry date which is stated on the label. The expiry date refers to the last 
day of that month.

Once reconstituted, VFEND should be used immediately, but if necessary may be stored for up to 24 hours 
at 2°C - 8°C (in a refrigerator). Reconstituted VFEND needs to be diluted with a compatible infusion 
solution first before it is infused. (Please refer to the end of this leaflet for further information). 

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw 
away medicines you no longer required. These measures will help protect the environment. 

6. Contents of the pack and other information 

What VFEND contains 
-The active substance is voriconazole.
-The other ingredient is sulfobutylether beta cyclodextrin sodium.
Each vial contains 200 mg voriconazole, equivalent to a 10 mg/ml solution when reconstituted as
directed by your hospital pharmacist or nurse (see the information at the end of this leaflet).

What VFEND looks like and contents of the pack 
VFEND is presented in single use glass vials as a powder for solution for infusion. 

Marketing Authorisation Holder 
Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium. 

Manufacturer 
Fareva Amboise, Zone Industrielle, 29 route des Industries, 37530 Pocé-sur-Cisse, France. 



132

For any information about this medicinal product, please contact the local representative of the 
Marketing Authorisation Holder: 

België /Belgique/Belgien 
Pfizer S.A./N.V.  
Tél/Tel: +32 (0)2 554 62 11

Lietuva 
Pfizer Luxembourg SARL 
Filialas Lietuvoje 
Tel. +3705 2514000

България 
Пфайзер Люксембург САРЛ, Клон България 
Тел.: +359 2 970 4333 

Luxembourg/Luxemburg 
Pfizer S.A. 
Tél: +32 (0)2 554 62 11

Česká republika 
Pfizer s.r.o.
Tel: +420-283-004-111

Magyarország 
Pfizer Kft. 
Tel. + 36 1 488 37 00

Danmark 
Pfizer ApS Tlf: 
+45 44 20 11 00 

Malta 
Vivian Corporation Ltd. 
Tel : +356 21344610

Deutschland 
Pfizer Pharma PFE GmbH 
Tel: +49 (0)800 8535555

Nederland 
Pfizer bv 
Tel: +31 (0)10 406 43 01

Eesti 
Pfizer Luxembourg SARL Eesti filiaal 
Tel: +372 666 7500

Norge 
Pfizer AS 
Tlf: +47 67 52 61 00

Ελλάδα

Pfizer ΕΛΛΑΣ A.E.

Τηλ.: +30 210 6785 800

Österreich 
Pfizer Corporation Austria 
Ges.m.b.H. Tel: +43 (0)1 
521 15-0

España 
Pfizer, S.L.
Tel: +34 91 490 99 00

Polska 
Pfizer Polska Sp. z o.o., 
Tel.: +48 22 335 61 00

France
Pfizer
Tél: +33 (0)1 58 07 34 40 

Portugal 
Laboratórios Pfizer, Lda. 
Tel: + 351 214 235 500

Hrvatska
Pfizer Croatia d.o.o.
Tel: + 385 1 3908 777

România 
Pfizer România S.R.L 
Tel: +40 (0)21 207 28 00

Ireland 
Pfizer Healthcare Ireland 
Tel: 1800 633 363 (toll free)
+44 (0)1304 616161

Slovenija 
Pfizer Luxembourg SARL 
Pfizer, podružnica za svetovanje s področja 
farmacevtske dejavnosti, Ljubljana 
Tel: + 386 (0)152 11 400 

Ísland 
Icepharma hf., 
Sími: + 354 540 8000 

Slovenská republika
Pfizer Luxembourg SARL, organizačná zložka
Tel: +421-2-3355 5500

Italia 
Pfizer S.r.l. 
Tel: +39 06 33 18 21 

Suomi/Finland
Pfizer Oy 
Puh/Tel: +358(0)9 43 00 40



133

Kύπρος

Pfizer ΕΛΛΑΣ Α.Ε. (Cyprus Branch) 

Τηλ: +357 22 817690

Sverige  
Pfizer AB 
Tel: +46 (0)8 5505 2000

Latvija
Pfizer Luxembourg SARL 
Filiāle Latvijā 
Tel: +371 670 35 775

United Kingdom 
Pfizer Limited 
Tel: +44 (0)1304 616161

This leaflet was last approved in {MM/YYYY}. 

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu

<-----------------------------------------------------------------------------------------------------------------
The following information is intended for medical or healthcare professionals only: 

Reconstitution and Dilution information 
 VFEND powder for solution for infusion needs to first be 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 voriconazole. 

 Discard the VFEND vial if the vacuum does not pull the diluent into the vial. 
 It is recommended that a standard 20 ml (non-automated) syringe be used to ensure that the exact 

amount (19.0 ml) of Water for Injections or of 9 mg/ml (0.9%) Sodium Chloride for Infusion is 
dispensed. 

 The required volume of the reconstituted concentrate is then added to a recommended compatible 
infusion solution listed below to obtain a final VFEND solution containing 0.5 to 5 mg/ml of 
voriconazole. 

 This medicinal product is for single use only and any unused solution should be discarded and only 
clear solutions without particles should be used. 

 Not for administration as a bolus injection. 
 For storage information, please refer to Section 5 ‘How to store VFEND’. 

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) 

8 mg/kg dose 
(number of 

vials) 

9 mg/kg dose 
(number of 

vials)
10 - 4.0 ml (1) - 8.0 ml (1) 9.0 ml (1) 
15 - 6.0 ml (1) - 12.0 ml (1) 13.5 ml (1) 
20 - 8.0 ml (1) - 16.0 ml (1) 18.0 ml (1) 
25 - 10.0 ml (1) - 20.0 ml (1) 22.5 ml (2) 
30 9.0 ml (1) 12.0 ml (1) 18.0 ml (1) 24.0 ml (2) 27.0 ml (2) 
35 10.5 ml (1) 14.0 ml (1) 21.0 ml (2) 28.0 ml (2) 31.5 ml (2) 
40 12.0 ml (1) 16.0 ml (1) 24.0 ml (2) 32.0 ml (2) 36.0 ml (2) 
45 13.5 ml (1) 18.0 ml (1) 27.0 ml (2) 36.0 ml (2) 40.5 ml (3) 
50 15.0 ml (1) 20.0 ml (1) 30.0 ml (2) 40.0 ml (2) 45.0 ml (3) 
55 16.5 ml (1) 22.0 ml (2) 33.0 ml (2) 44.0 ml (3) 49.5 ml (3) 
60 18.0 ml (1) 24.0 ml (2) 36.0 ml (2) 48.0 ml (3) 54.0 ml (3) 
65 19.5 ml (1) 26.0 ml (2) 39.0 ml (2) 52.0 ml (3) 58.5 ml (3)
70 21.0 ml (2) 28.0 ml (2) 42.0 ml (3) - -
75 22.5 ml (2) 30.0 ml (2) 45.0 ml (3) - -
80 24.0 ml (2) 32.0 ml (2) 48.0 ml (3) - -
85 25.5 ml (2) 34.0 ml (2) 51.0 ml (3) - -



134

90 27.0 ml (2) 36.0 ml (2) 54.0 ml (3) - -
95 28.5 ml (2) 38.0 ml (2) 57.0 ml (3) - -

100 30.0 ml (2) 40.0 ml (2) 60.0 ml (3) - -

VFEND is a single dose unpreserved sterile lyophile. Therefore, from a microbiological point of view, the 
reconstituted solution must be 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 
to 8°C, unless reconstitution has taken place in controlled and validated aseptic conditions. 

Compatible Infusion Solutions: 
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 
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 VFEND with diluents other than listed above (or listed below under 
‘Incompatibilities’) is unknown.

Incompatibilities: 

VFEND must not be infused into the same line or cannula concomitantly with other drug infusions, 
including parenteral nutrition (e.g., Aminofusin 10% Plus).

Infusions of blood products must not occur simultaneously with VFEND. 

Infusion of total parenteral nutrition can occur simultaneously with VFEND but not in the same line or 
cannula. 

VFEND must not be diluted with 4.2% Sodium Bicarbonate Infusion.  



135

Package Leaflet: Information for the user

VFEND 200 mg powder and solvent for solution for infusion
Voriconazole 

Read all of this leaflet carefully before you start taking this medicine because it contains important 
information for you. 
 Keep this leaflet. You may need to read it again. 
 If you have any further questions, ask your doctor, pharmacist or nurse. 
 This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if 

their signs of illness are the same as yours. 
 If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 

effects not listed in this leaflet. See section 4. 

What is in this leaflet
1. What VFEND is and what it is used for 
2. What you need to know before you take VFEND  
3. How to use VFEND 
4. Possible side effects 
5. How to store VFEND 
6. Content of the pack and other information 

1. What VFEND is and what it is used for 

VFEND contains the active substance voriconazole. VFEND is an antifungal medicine. It works by killing 
or stopping the growth of the fungi that cause infections.

It is used for the treatment of patients (adults and children over the age of 2) with:
 invasive aspergillosis (a type of fungal infection due to Aspergillus sp),
 candidaemia (another type of fungal infection due to Candida sp) in non-neutropenic patients 

(patients without abnormally low white blood cells count),
 serious invasive Candida sp. infections when the fungus is resistant to fluconazole (another

antifungal medicine),
 serious fungal infections caused by Scedosporium sp. or Fusarium sp. (two different species of 

fungi).

VFEND is intended for patients with worsening, possibly life-threatening, fungal infections.

Prevention of fungal infections in high risk bone marrow transplant recipients.

This product should only be used under the supervision of a doctor. 

2. What you need to know before you take VFEND 

Do not take VFEND:
- If you are allergic to the active ingredient voriconazole, or to sulfobutylether beta cyclodextrin sodium 

(listed in section 6). 

It is very important that you inform your doctor or pharmacist if you are taking or have taken any other 
medicines, even those that are obtained without a prescription, or herbal medicines. 

The medicines in the following list must not be taken during your VFEND treatment: 

 Terfenadine (used for allergy) 
 Astemizole (used for allergy) 



136

 Cisapride (used for stomach problems) 
 Pimozide (used for treating mental illness) 
 Quinidine (used for irregular heart beat) 
 Rifampicin (used for treating tuberculosis) 
 Efavirenz (used for treating HIV) in doses of 400 mg and above once daily
 Carbamazepine (used to treat seizures) 
 Phenobarbital (used for severe insomnia and seizures) 
 Ergot alkaloids (e.g., ergotamine, dihydroergotamine; used for migraine) 
 Sirolimus (used in transplant patients) 
 Ritonavir (used for treating HIV) in doses of 400mg and more twice daily 
 St. John’s Wort (herbal supplement) 

Warnings and precautions
Talk to your doctor, pharmacist or nurse before taking VFEND if:

 you have had an allergic reaction to other azoles. 
 you are suffering from, or have ever suffered from liver disease. If you have liver disease, your 

doctor may prescribe a lower dose of VFEND. Your doctor should also monitor your liver function 
while you are being treated with VFEND by doing blood tests. 

 you are known to have cardiomyopathy, irregular heart beat, slow heart rate or an abnormality of 
electrocardiogram (ECG) called ‘long QTc syndrome’. 

You should avoid any sunlight and sun exposure while being treated. It is important to cover sun exposed 
areas of skin and use sunscreen with high sun protection factor (SPF), as an increased sensitivity of skin to 
the sun’s UV rays can occur. These precautions are also applicable to children.

While being treated with VFEND: 
 tell your doctor immediately if you develop

o sunburn
o severe skin rash or blisters 
o bone pain 

If you develop skin disorders as described above, your doctor may refer you to a dermatologist, who after 
consultation may decide that it is important for you to be seen on a regular basis. There is a small chance that 
skin cancer could develop with long-term use of VFEND.

Your doctor should monitor the function of your liver and kidney by doing blood tests. 

Children and adolescents
VFEND should not be given to children younger than 2 years of age. 

Other medicines and VFEND
Please tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines, including those that are obtained without a prescription. 

 Some medicines, when taken at the same time as VFEND, may affect the way VFEND works or 
VFEND may affect the way they work.

Tell your doctor if you are taking the following medicine, as treatment with VFEND at the same time should 
be avoided if possible: 

 Ritonavir (used for treating HIV) in doses of 100 mg twice daily 

Tell your doctor if you are taking either of the following medicines, as treatment with VFEND at the same 
time should be avoided if possible, and a dose adjustment of voriconazole may be required: 

 Rifabutin (used for treating tuberculosis). If you are already being treated with rifabutin your blood 



137

counts and side effects to rifabutin will need to be monitored. 
 Phenytoin (used to treat epilepsy). If you are already being treated with phenytoin your blood 

concentration of phenytoin will need to be monitored during your treatment with VFEND and your 
dose may be adjusted. 

Tell your doctor if you are taking any of the following medicines, as a dose adjustment or monitoring may be 
required to check that the medicines and/ or VFEND are still having the desired effect: 

 Warfarin and other anticoagulants (e.g., phenprocoumon, acenocoumarol; used to slow down clotting 
of the blood) 

 Ciclosporin (used in transplant patients) 
 Tacrolimus (used in transplant patients) 
 Sulfonylureas (e.g., tolbutamide, glipizide, and glyburide) (used for diabetes) 
 Statins (e.g., atorvastatin, simvastatin) (used for lowering cholesterol) 
 Benzodiazepines (e.g midazolam, triazolam) (used for severe insomnia and stress) 
 Omeprazole (used for treating ulcers) 
 Oral contraceptives (if you take VFEND whilst using oral contraceptives, you may get side effects 

such as nausea and menstrual disorders) 
 Vinca alkaloids (e.g., vincristine and vinblastine) (used in treating cancer) 
 Indinavir and other HIV protease inhibitors (used for treating HIV) 
 Non-nucleoside reverse transcriptase inhibitors (e.g., efavirenz, delavirdine, nevirapine) (used for 

treating HIV) (some doses of efavirenz can NOT be taken at the same time as VFEND)
 Methadone (used to treat heroin addiction) 
 Alfentanil and fentanyl and other short-acting opiates such as sufentanil (painkillers used for surgical 

procedures) 
 Oxycodone and other long-acting opiates such as hydrocodone (used for moderate to severe pain)
 Non-steroidal anti-inflammatory drugs (e.g., ibuprofen, diclofenac) (used for treating pain and 

inflammation)
 Fluconazole (used for fungal infections)
 Everolimus (used for treating advanced kidney cancer and in transplant patients)

Pregnancy and breast-feeding
VFEND must not be used during pregnancy, unless indicated by your doctor. Effective contraception must 
be used in women of childbearing potential. Contact your doctor immediately if you become pregnant 
while being treated with VFEND. 

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your 
doctor or pharmacist for advice before taking this medicine.

Driving and using machines
VFEND may cause blurring of vision or uncomfortable sensitivity to light. While affected, do not drive 
or operate any tools or machines. Tell your doctor if you experience this. 

VFEND contains sodium
Each vial of VFEND contains 217.6 mg of sodium per vial. This should be taken into consideration if you 
are on a strictly controlled sodium diet. 

3. How to use VFEND 

Always take this medicine exactly as your doctor has told you. Check with your doctor if you are not sure. 

Your doctor will determine your dose depending on your weight and the type of infection you have. 

Your doctor may change your dose depending on your condition. 



138

The recommended dose for adults (including elderly patients) is as follows: 

Intravenous 

Dose for the first 24 hours 
6 mg/kg every 12 hours for 
the 

(Loading Dose) first 24 hours 

Dose after the first 24 
hours 4 mg/kg twice a day 
(Maintenance Dose) 

Depending on your response to treatment, your doctor may decrease the dose to 3 mg/kg twice daily. 

The doctor may decide to decrease the dose if you have mild to moderate cirrhosis. 

Use in children and adolescents
The recommended dose for children and teenagers is as follows: 

Intravenous 
Children aged 2 to less 
than 12 years and 
teenagers aged 12 to 14 
years weighing less than 
50 kg 

Teenagers aged 12 to 14 
years weighing 50 kg or 
more; and all teenagers 
older than 14

Dose for the first 24 
hours 
(Loading Dose)

9 mg/kg every 12 hours 
for the first 24 hours

6 mg/kg every 12 hours 
for the first 24 hours

Dose after the first 24 
hours 8 mg/kg twice a day 4 mg/kg twice a day 
(Maintenance Dose) 

Depending on your response to treatment, your doctor may increase or decrease the daily dose.

VFEND powder and solvent for solution for infusion will be reconstituted and diluted to the correct 
concentration by your hospital pharmacist or nurse. (Please refer to the end of this leaflet for further 
information)   

This will be given to you by intravenous infusion (into a vein) at a maximum rate of 3 mg/kg per hour over 1 
to 3 hours.

If you or your child are taking VFEND for prevention of fungal infections, your doctor may stop giving 
VFEND if you or your child develop treatment related side effects. 

If a dose of VFEND has been forgotten 
As you will be given this medicine under close medical supervision, it is unlikely that a dose would be 
missed. However tell your doctor or pharmacist if you think that a dose has been forgotten. 

If you stop taking VFEND 
VFEND treatment will continue for as long as your doctor advises, however duration of treatment with 
VFEND powder for solution for infusion should be no more than 6 months. 

Patients with a weakened immune system or those with difficult infections may require long-term treatment 
to prevent the infection from returning. You may be switched from the intravenous infusion to tablets once 
your condition improves. 



139

When VFEND treatment is stopped by your doctor you should not experience any effects. 

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 

4. Possible side effects 

Like all medicines, this medicine can cause side effects, although not everybody gets them. 

If any side effects occur, most are likely to be minor and temporary. However, some may be serious and 
need medical attention. 

Serious side effects – Stop taking VFEND and see a doctor immediately

- Rash
- Jaundice; Changes in blood tests of liver function
- Pancreatitis

Other side effects

Very common: may affect more than 1 in 10 people

- Visual impairment (change in vision including blurred vision, visual color alterations, abnormal 
intolerance to visual perception of light, colour blindness, eye disorder, halo vision, night blindness, 
swinging vision, seeing sparks, visual aura, visual acuity reduced, visual brightness, loss of part of 
the usual field of vision, spots before the eyes) 

- Fever 
- Rash 
- Nausea, vomiting, diarrhoea 
- Headache 
- Swelling of the extremities 
- Stomach pains 
- Breathing difficulties
- Elevated liver enzymes

Common: may affect up to 1 in 10 people

- Inflammation of the sinuses, inflammation of the gums, chills, weakness 
- Low numbers of some types, including severe, of red (sometimes immune-related) and/or white 

blood cells (sometimes with fever), low numbers of cells called platelets that help the blood to clot 
- Low blood sugar, low blood potassium, low sodium in the blood 
- Anxiety, depression, confusion, agitation, inability to sleep, hallucinations 
- Seizures, tremors or uncontrolled muscle movements, tingling or abnormal skin 

sensations, increase in muscle tone, sleepiness, dizziness
- Bleeding in the eye
- Heart rhythm problems including very fast heartbeat, very slow heartbeat, fainting 
- Low blood pressure, inflammation of a vein (which may be associated with the formation of a blood 

clot) 
- Acute breathing difficulty, chest pain, swelling of the face (mouth, lips and around eyes), fluid 

accumulation in the lungs 
- Constipation, indigestion, inflammation of the lips
- Jaundice, inflammation of the liver and liver injury
- Skin rashes which may lead to severe blistering and peeling of the skin characterized by a flat, red

area on the skin that is covered with small confluent bumps, redness of the skin
- Itchiness 
- Hair loss 
- Back pain
- Kidney failure, blood in the urine, changes in kidney function tests  



140

Uncommon: may affect up to 1 in 100 people

- Flu-like symptoms, irritation and inflammation of the gastrointestinal tract, inflammation of the 
gastrointestinal tract causing antibiotic associated diarrhoea, inflammation of the lymphatic vessels

- Inflammation of the thin tissue that lines the inner wall of the abdomen and covers the abdominal 
organ

- Enlarged lymph glands (sometimes painful), failure of blood marrow, increased eosinophil
- Depressed function of the adrenal gland, underactive thyroid gland
- Abnormal brain function, Parkinson-like symptoms, nerve injury resulting in numbness, pain, 

tingling or burning in the hands or feet
- Problems with balance or coordination 
- Swelling of the brain  
- Double vision, serious conditions of the eye including: pain and inflammation of the eyes and

eyelids, abnormal eye movement, damage to the optic nerve resulting in vision impairment, optic 
disc swelling 

- Decreased sensitivity to touch 
- Abnormal sense of taste
- Hearing difficulties, ringing in the ears, vertigo 
- Inflammation of certain internal organs- pancreas and duodenum, swelling and inflammation of the 

tongue 
- Enlarged liver, liver failure, gallbladder disease, gallstones 
- Joint inflammation, inflammation of the veins under the skin (which may be associated with the 

formation of a blood clot) 
- Inflammation of the kidney, proteins in the urine, damage to the kidney
- Very fast heart rate or skipped heartbeats, sometimes with erratic electrical impulses
- Abnormal electrocardiogram (ECG) 
- Blood cholesterol increased, blood urea increased
- Allergic skin reactions (sometimes severe), including life-threatening skin condition that causes 

painful blisters and sores of the skin and mucous membranes, especially in the mouth, 
inflammation of the skin, hives, sunburn or severe skin reaction following exposure to light or sun, 
skin redness and irritation, red or purple discoloration of the skin which may be caused by low 
platelet count, eczema

- Infusion site reaction
- Allergic reaction or exaggerated immune response

Rare: may affect up to 1 in 1000 people

- Overactive thyroid gland
- Deterioration of brain function that is a serious complication of liver disease
- Loss of most fibers in the optic nerve, clouding of the cornea, involuntary movement of the eye
- Bullous photosensitivity
- A disorder in which the body’s immune system attacks part of the peripheral nervous system
- Heart rhythm or conduction problems (sometimes life threatening)
- Life threatening allergic reaction 
- Disorder of blood clotting system
- Allergic skin reactions (sometimes severe), including rapid swelling (oedema) of the dermis,

subcutaneous tissue, mucosa and submucosal tissues, itchy or sore patches of thick, red skin with
silvery scales of skin, irritation of the skin and mucous membranes, life-threatening skin condition
that causes large portions of the epidermis, the skin's outermost layer, to detach from the layers of
skin below

- Small dry scaly skin patches, sometimes thick with spikes or ‘horns’

Side effects with frequency not known:
- Freckles and pigmented spots



141

Other significant side effects whose frequency is not known, but should be reported to your doctor 
immediately:
- Skin cancer 
- Inflammation of the tissue surrounding the bone 
- Red, scaly patches or ring-shaped skin lesions that may be a symptom of an autoimmune disease 

called cutaneous lupus erythematosus

Reactions during the infusion have occurred uncommonly with VFEND (including flushing, fever, 
sweating, increased heart rate and shortness of breath). Your doctor may stop the infusion if this occurs. 

As VFEND has been known to affect the liver and the kidney, your doctor should monitor the function 
of your liver and kidney by doing blood tests. Please advise your doctor if you have any stomach pains 
or if your stools have a different consistency. 

There have been reports of skin cancer in patients treated with VFEND for long periods of time. 

Sunburn or severe skin reaction following exposure to light or sun was experienced more frequently in 
children. If you or your child develops skin disorders, your doctor may refer you to a dermatologist, who 
after consultation may decide that it is important for you or your child to be seen on a regular basis. Elevated
liver enzymes were also observed more frequently in children.

If any of these side effects persist or are troublesome, please tell your doctor. 

Reporting of side effects
If you get any side effects, talk to your doctor or, pharmacist or nurse. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system listed in 
Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store VFEND 

Keep this medicine out of the sight and reach of children. 

Do not use this medicine after the expiry date which is stated on the label. The expiry date refers to the last 
day of that month.

Once the powder in the vial has been reconstituted, VFEND should be used immediately, but if necessary 
may be stored for up to 24 hours at 2°C - 8°C (in a refrigerator) with the infusion bag. Reconstituted VFEND 
concentrate needs to be further diluted with sodium chloride (0.9%) infusion solution within the infusion bag 
before it is infused. The bag containing the reconstituted and diluted VFEND should be used immediately, 
but if necessary may be stored for up to a total of 24 hours at 2°C - 8°C (in a refrigerator) or at room 
temperature. (Please refer to the end of this leaflet for further information). 

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw 
away medicines you no longer required. These measures will help protect the environment. 

6. Contents of the pack and other information 

What VFEND contains 
-The active substance is voriconazole.
-The other ingredient is sulfobutylether beta cyclodextrin sodium.

Each vial contains 200 mg voriconazole, equivalent to a 10 mg/ml solution when reconstituted as
directed by your hospital pharmacist or nurse (see the information at the end of this leaflet).

Each bag contains 50 ml of sodium chloride 0.9% in Water for Injections.



142

What VFEND looks like and contents of the pack 
VFEND powder and solvent for solution for infusion is presented as an administration kit containing:

 VFEND powder for solution for infusion in single use glass vial.
 VFEND solvent for solution for infusion in an overwrapped, sterile, single use, polypropylene 

infusion bag.
 A sterile, single use, syringe. 
 A sterile, single use vial adapter.

Marketing Authorisation Holder 
Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium. 

Manufacturer
Fareva Amboise, Zone Industrielle, 29 route des Industries, 37530 Pocé-sur-Cisse, France. 

For any information about this medicinal product, please contact the local representative of the 
Marketing Authorisation Holder: 

België /Belgique/Belgien 
Pfizer S.A./N.V.  
Tél/Tel: +32 (0)2 554 62 11

Lietuva 
Pfizer Luxembourg SARL 
Filialas Lietuvoje 
Tel. +3705 2514000

България 
Пфайзер Люксембург САРЛ, Клон България 
Тел.: +359 2 970 4333 

Luxembourg/Luxemburg 
Pfizer S.A. 
Tél: +32 (0)2 554 62 11

Česká republika 
Pfizer s.r.o.
Tel: +420-283-004-111

Magyarország 
Pfizer Kft. 
Tel. + 36 1 488 37 00

Danmark 
Pfizer ApS Tlf: 
+45 44 20 11 00 

Malta 
Vivian Corporation Ltd. 
Tel : +356 21344610

Deutschland 
Pfizer Pharma PFE GmbH 
Tel: +49 (0)800 8535555

Nederland 
Pfizer bv
Tel: +31 (0)10 406 43 01

Eesti 
Pfizer Luxembourg SARL Eesti filiaal 
Tel: +372 666 7500

Norge 
Pfizer AS 
Tlf: +47 67 52 61 00

Ελλάδα

Pfizer ΕΛΛΑΣ A.E.

Τηλ.: +30 210 6785 800

Österreich 
Pfizer Corporation Austria 
Ges.m.b.H. Tel: +43 (0)1 
521 15-0

España 
Pfizer, S.L.
Tel: +34 91 490 99 00

Polska 
Pfizer Polska Sp. z o.o., 
Tel.: +48 22 335 61 00

France
Pfizer
Tél: +33 (0)1 58 07 34 40 

Portugal 
Laboratórios Pfizer, Lda. 
Tel: + 351 214 235 500

Hrvatska
Pfizer Croatia d.o.o.
Tel: + 385 1 3908 777

România 
Pfizer România S.R.L 
Tel: +40 (0)21 207 28 00



143

Ireland 
Pfizer Healthcare Ireland 
Tel: 1800 633 363 (toll free)
+44 (0)1304 616161

Slovenija 
Pfizer Luxembourg SARL 
Pfizer, podružnica za svetovanje s področja 
farmacevtske dejavnosti, Ljubljana 
Tel: + 386 (0)152 11 400 

Ísland 
Icepharma hf., 
Sími: + 354 540 8000 

Slovenská republika
Pfizer Luxembourg SARL, organizačná zložka
Tel: +421-2-3355 5500

Italia 
Pfizer S.r.l. 
Tel: +39 06 33 18 21 

Suomi/Finland
Pfizer Oy 
Puh/Tel: +358(0)9 43 00 40

Kύπρος

Pfizer ΕΛΛΑΣ Α.Ε. (Cyprus Branch) 

Τηλ: +357 22 817690

Sverige  
Pfizer AB 
Tel: +46 (0)8 5505 2000

Latvija
Pfizer Luxembourg SARL 
Filiāle Latvijā 
Tel: +371 670 35 775

United Kingdom 
Pfizer Limited 
Tel: +44 (0)1304 616161 

This leaflet was last approved in {MM/YYYY}. 

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu

<-----------------------------------------------------------------------------------------------------------------
The following information is intended for medical or healthcare professionals only: 

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) 

8 mg/kg dose 
(number of 

vials) 

9 mg/kg dose 
(number of 

vials)
10 - 4.0 ml (1) - 8.0 ml (1) 9.0 ml (1) 
15 - 6.0 ml (1) - 12.0 ml (1) 13.5 ml (1) 
20 - 8.0 ml (1) - 16.0 ml (1) 18.0 ml (1) 
25 - 10.0 ml (1) - 20.0 ml (1) 22.5 ml (2) 
30 9.0 ml (1) 12.0 ml (1) 18.0 ml (1) 24.0 ml (2) 27.0 ml (2) 
35 10.5 ml (1) 14.0 ml (1) 21.0 ml (2) 28.0 ml (2) 31.5 ml (2) 
40 12.0 ml (1) 16.0 ml (1) 24.0 ml (2) 32.0 ml (2) 36.0 ml (2) 
45 13.5 ml (1) 18.0 ml (1) 27.0 ml (2) 36.0 ml (2) 40.5 ml (3) 
50 15.0 ml (1) 20.0 ml (1) 30.0 ml (2) 40.0 ml (2) 45.0 ml (3) 
55 16.5 ml (1) 22.0 ml (2) 33.0 ml (2) 44.0 ml (3) 49.5 ml (3) 
60 18.0 ml (1) 24.0 ml (2) 36.0 ml (2) 48.0 ml (3) 54.0 ml (3) 
65 19.5 ml (1) 26.0 ml (2) 39.0 ml (2) 52.0 ml (3) 58.5 ml (3)
70 21.0 ml (2) 28.0 ml (2) 42.0 ml (3) - -
75 22.5 ml (2) 30.0 ml (2) 45.0 ml (3) - -
80 24.0 ml (2) 32.0 ml (2) 48.0 ml (3) - -
85 25.5 ml (2) 34.0 ml (2) 51.0 ml (3) - -
90 27.0 ml (2) 36.0 ml (2) 54.0 ml (3) - -
95 28.5 ml (2) 38.0 ml (2) 57.0 ml (3) - -



144

100 30.0 ml (2) 40.0 ml (2) 60.0 ml (3) - -

VFEND is a single dose unpreserved sterile lyophile. Therefore, from a microbiological point of view, the 
reconstituted solution must be used immediately. 

If not used immediately, in-use storage times and conditions of the reconstituted vial prior to use are the 
responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution 
has taken place in controlled and validated aseptic conditions. 

Incompatibilities: 

VFEND must not be infused into the same line or cannula concomitantly with other drug infusions, 
including parenteral nutrition (e.g., Aminofusin 10% Plus).

Infusions of blood products must not occur simultaneously with VFEND. 

Infusion of total parenteral nutrition can occur simultaneously with VFEND but not in the same line or 
cannula. 

VFEND must not be diluted with 4.2% Sodium Bicarbonate Infusion.  



145

Kit Operating Instructions for Use:
VFEND Powder and Solvent for Solution for Infusion

Critical Instructions for safe and effective use of infusion kit
Aseptic procedures will be followed during kit preparation
Bag must be inverted when the reconstituted Voriconazole is added

Step 1
1a Peel back the seal from the vial adaptor. Do not remove casing.
1b To prepare the IV vial for reconstitution, remove the plastic cap from the vial and wipe the top with 

an antiseptic swab. Place the vial on a flat surface. Ensure the internal spike of the vial adaptor is 
placed at the centre of the vial septum and push the adaptor firmly onto the vial until it snaps into 
place.



146

Step 2
2a Snap open Blue port. Bend the outer tube by 90° each way to ensure it is fully broken.
2b Push the syringe plunger down fully. Push and screw the syringe securely onto Blue port.
2c Withdraw exactly 19 mL of the solution and unscrew the syringe.

Step 3
3a Remove the adaptor casing from the vial adaptor and discard.
3b Screw the syringe onto the vial adapter. Keeping the vial upright, empty contents of the syringe into 

the vial.
3c Swirl the vial gently until all the powder is dissolved. Inspect the vial. If particles are seen, swirl again 

and re-inspect.

Step 4
4 Gently invert the vial. Slowly draw off the required volume of the solution. The potential to block the 

venting action exists if large amounts of air or drug are injected when the vial is inverted. If this 
occurs, turn the vial upright and pull the piston up the syringe barrel. When cleared, proceed as 
directed. Unscrew the syringe and discard the vial adaptor and vial.



147

Step 5
5a Invert the infusion bag and screw the syringe into Blue port.
5b Empty the contents of the syringe into the bag. Remove the syringe. Gently mix the contents of the 

infusion bag. If any particles are seen, discard the infusion bag.

Step 6
6a Invert the infusion bag. Open the Twist-off port.
6b Keeping the infusion bag inverted, connect the infusion line.
6c Prime the IV line according to the manufacturer’s guidelines. Hang the infusion bag.

Step 7
7a Attach the IV line to the patient injection site. Set the infusion rate accurately.
7b Once the infusion delivery to the patient starts, do not manually squeeze the bag compartment as this 

may interfere with the dose delivery to the patient and may cause air ingress into the IV line.



148

Package Leaflet: Information for the user 

VFEND 40 mg/ml powder for oral suspension 
Voriconazole 

Read all of this leaflet carefully before you start taking this medicine because it contains important 
information for you. 
 Keep this leaflet. You may need to read it again. 
 If you have any further questions, ask your doctor, pharmacist or nurse.
 This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if 

their signs of illness are the same as yours. 
 If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 

effects not listed in this leaflet. See section 4. 

What is in this leaflet
1. What VFEND is and what it is used for 
2. What you need to know before you take VFEND 
3. How to take VFEND 
4. Possible side effects 
5. How to store VFEND 
6 Content of the pack and other information 

1. What VFEND is and what it is used for 

VFEND contains the active substance voriconazole. VFEND is an antifungal medicine. It works by 
killing or stopping the growth of the fungi that cause infections.

It is used for the treatment of patients (adults and children over the age of 2) with:
 invasive aspergillosis (a type of fungal infection due to Aspergillus sp),
 candidaemia (another type of fungal infection due to Candida sp) in non-neutropenic patients 

(patients without abnormally low white blood cells count),
 serious invasive Candida sp. infections when the fungus is resistant to fluconazole (another 

antifungal medicine),
 serious fungal infections caused by Scedosporium sp. or Fusarium sp. (two different species of 

fungi).

VFEND is intended for patients with worsening, possibly life-threatening, fungal infections.

Prevention of fungal infections in high risk bone marrow transplant recipients.

This product should only be taken under the supervision of a doctor.

2. What you need to know before you take VFEND 

Do not take VFEND:
If you are allergic to voriconazole or any of the other ingredients of this medicine (listed in section 6).

It is very important that you inform your doctor or pharmacist if you are taking or have taken any other 
medicines, even those that are obtained without a prescription, or herbal medicines. 

The medicines in the following list must not be taken during your course of VFEND treatment: 

 Terfenadine (used for allergy) 
 Astemizole (used for allergy) 
 Cisapride (used for stomach problems) 



149

 Pimozide (used for treating mental illness) 
 Quinidine (used for irregular heart beat) 
 Rifampicin (used for treating tuberculosis) 
 Efavirenz (used for treating HIV) in doses of 400 mg and above once daily
 Carbamazepine (used to treat seizures)  
 Phenobarbital (used for severe insomnia and seizures) 
 Ergot alkaloids (e.g., ergotamine, dihydroergotamine; used for migraine) 
 Sirolimus (used in transplant patients) 
 Ritonavir (used for treating HIV) in doses of 400mg and more twice daily 
 St. John’s Wort (herbal supplement) 

Warnings and precautions
Talk to your doctor, pharmacist or nurse before taking VFEND if:

 you have had an allergic reaction to other azoles. 
 you are suffering from, or have ever suffered from liver disease. If you have liver disease, your 

doctor may prescribe a lower dose of VFEND. Your doctor should also monitor your liver function 
while you are being treated with VFEND by doing blood tests. 

 you are known to have cardiomyopathy, irregular heart beat, slow heart rate or an abnormality of 
electrocardiogram (ECG) called ‘long QTc syndrome’. 

You should avoid any sunlight and sun exposure while being treated. It is important to cover sun exposed 
areas of skin and use sunscreen with high sun protection factor (SPF), as an increased sensitivity of skin to 
the sun’s UV rays can occur. These precautions are also applicable to children.

While being treated with VFEND: 
 tell your doctor immediately if you develop

o sunburn
o severe skin rash or blisters 
o bone pain 

If you develop skin disorders as described above, your doctor may refer you to a dermatologist, who after 
consultation may decide that it is important for you to be seen on a regular basis. There is a small chance that 
skin cancer could develop with long-term use of VFEND.

Your doctor should monitor the function of your liver and kidney by doing blood tests. 

Children and adolescents
VFEND should not be given to children younger than 2 years of age. 

Other medicines and VFEND
Please tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines, including those that are obtained without a prescription. 

Some medicines, when taken at the same time as VFEND, may affect the way VFEND works or VFEND 
may affect the way they work. 

Tell your doctor if you are taking the following medicine, as treatment with VFEND at the same time should 
be avoided if possible: 

 Ritonavir (used for treating HIV) in doses of 100 mg twice daily 

Tell your doctor if you are taking either of the following medicines, as treatment with VFEND at the same 
time should be avoided if possible, and a dose adjustment of voriconazole may be required: 

 Rifabutin (used for treating tuberculosis). If you are already being treated with rifabutin your blood 
counts and side effects to rifabutin will need to be monitored. 



150

 Phenytoin (used to treat epilepsy). If you are already being treated with phenytoin your blood 
concentration of phenytoin will need to be monitored during your treatment with VFEND and your 
dose may be adjusted.

Tell your doctor if you are taking any of the following medicines, as a dose adjustment or monitoring may be 
required to check that the medicines and/ or VFEND are still having the desired effect: 

 Warfarin and other anticoagulants (e.g., phenprocoumon, acenocoumarol; used to slow down clotting 
of the blood) 

 Ciclosporin (used in transplant patients) 
 Tacrolimus (used in transplant patients) 
 Sulfonylureas (e.g., tolbutamide, glipizide, and glyburide) (used for diabetes) 
 Statins (e.g., atorvastatin, simvastatin) (used for lowering cholesterol) 
 Benzodiazepines (e.g midazolam, triazolam) (used for severe insomnia and stress) 
 Omeprazole (used for treating ulcers) 
 Oral contraceptives (if you take VFEND whilst using oral contraceptives, you may get side effects 

such as nausea and menstrual disorders) 
 Vinca alkaloids (e.g., vincristine and vinblastine) (used in treating cancer) 
 Indinavir and other HIV protease inhibitors (used for treating HIV) 
 Non-nucleoside reverse transcriptase inhibitors (e.g., efavirenz, delavirdine, nevirapine) (used for 

treating HIV) (some doses of efavirenz can NOT be taken at the same time as VFEND)
 Methadone (used to treat heroin addiction) 
 Alfentanil and fentanyl and other short-acting opiates such as sufentanil (painkillers used for surgical 

procedures)
 Oxycodone and other long-acting opiates such as hydrocodone (used for moderate to severe pain)
 Non-steroidal anti-inflammatory drugs (e.g., ibuprofen, diclofenac) (used for treating pain and 

inflammation)
 Fluconazole (used for fungal infections)
 Everolimus (used for treating advanced kidney cancer and in transplant patients)

Pregnancy and breast-feeding
VFEND must not be taken during pregnancy, unless indicated by your doctor. Effective contraception 
must be used in women of childbearing potential. Contact your doctor immediately if you become 
pregnant while taking VFEND. 

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your 
doctor or pharmacist for advice before taking this medicine.

Driving and using machines
VFEND may cause blurring of vision or uncomfortable sensitivity to light. While affected, do not drive 
or operate any tools or machines. Contact your doctor if you experience this. 

VFEND contains sucrose
VFEND suspension contains 0.54g sucrose per ml of suspension. If you have been told by your doctor that 
you have an intolerance to some sugars, contact your doctor before taking VFEND. 

3. How to take VFEND 

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if 
you are not sure. 

Your doctor will determine your dose depending on your weight and the type of infection you have. 

The recommended dose for adults (including elderly patients) is as follows: 



151

Oral suspension 
Patients 40 kg and above Patients less than 40 kg 

Dose for the first 24 
hours 400 mg (10 ml) every 12 200 mg (5 ml) every 12 
(Loading Dose) hours for the first 24 

hours 
hours for the first 24 
hours 

Dose after the first 24 
hours (Maintenance Dose) 

200 mg (5 ml) twice a 
day 

100 mg (2.5 ml) twice a 
day 

Depending on your response to treatment, your doctor may increase the daily dose to 300 mg twice a day. 

The doctor may decide to decrease the dose if you have mild to moderate cirrhosis. 

Use in children and adolescents
The recommended dose for children and teenagers is as follows:

Oral suspension 
Children aged 2 to less 
than 12 years and 
teenagers aged 12 to 14 
years weighing less than 
50 kg 

Teenagers aged 12 to 14 
years weighing 50 kg or 
more; and all teenagers 
older than 14

Dose for the first 24 
hours 
(Loading Dose)

Your treatment will be 
started as an infusion

400 mg every 12 hours 
for the first 24 hours

Dose after the first 24 
hours 
(Maintenance Dose)

9 mg/kg twice a day
(a maximum dose of 
350 mg twice daily)

200 mg twice a day

Depending on your response to treatment, your doctor may increase or decrease the daily dose.

Take your suspension at least one hour before, or two hours after a meal.

If you or your child are taking VFEND for prevention of fungal infections, your doctor may stop giving 
VFEND if you or your child develop treatment related side effects. 

VFEND suspension should not be mixed with any other medicine. The suspension should not be further 
diluted with water or any other liquids. 

Instructions to constitute the suspension: 
It is recommended that your pharmacist constitutes VFEND suspension before giving it to you.
VFEND suspension is constituted if it is in a liquid form. If it appears to be a dry powder you should 
constitute the oral suspension by following the instructions below. 

1. Tap the bottle to release the powder. 
2. Remove the cap. 
3. Add 2 measuring cups (measure cup included in the carton) of water (total of 46 ml) to the bottle.

Fill the measuring cup to the top of the marked line then pour the water into the bottle. You should 
always add a total of 46 ml of water irrespective of the dose you are taking.

4. Replace the cap and shake the bottle vigorously for about 1 minute. Following constitution, the total 
volume of the suspension must be 75 ml.

5. Remove the cap. Press the bottle adaptor into the neck of the bottle (as shown on figure below). The 



152

adaptor is provided so that you can fill the oral syringe with medicine from the bottle. Replace the 
cap on the bottle. 

6. Write the date of expiry of the constituted suspension on the bottle label (the shelf-life of the 
constituted suspension is 14 days). Any unused suspension should be discarded after this date.

Instructions for use: 
Your pharmacist should advise you how to measure the medicine using the multi-dosing oral syringe 
provided in the pack. Please see instructions below before using VFEND suspension. 

1. Shake the closed bottle of constituted suspension for approximately 10 seconds before use. Remove 
the cap. 

2. While the bottle is upright, on a flat surface, insert the tip of the oral syringe into the adaptor. 
3. Turn the bottle upside down while holding the oral syringe in place. Slowly pull back the plunger of 

the oral syringe to the graduation mark that marks the dose for you. To measure the dose accurately, 
the top edge of the black ring should be lined up with the graduated mark on the oral syringe. 

4. If large bubbles can be seen, slowly push the plunger back into the syringe. This will force the 
medicine back into the bottle. Repeat step 3 again.  

5. Turn the bottle back upright with the oral syringe still in place. Remove the oral syringe from the 
bottle. 

6. Put the tip of the oral syringe into the mouth. Point the tip of the oral syringe towards the inside of 
the cheek. SLOWLY push down the plunger of the oral syringe. Do not squirt the medicine out 
quickly. If the medicine is to be given to a child, make sure the child is sitting, or is held, upright 
before giving the medicine.

7. Replace the cap on the bottle, leaving the bottle adaptor in place. Wash the oral syringe as instructed
below. 

1    2       3/4               5            6

Cleaning and storing the syringe: 
1. The syringe should be washed after each dose. Pull the plunger out of the syringe and wash both 

parts in warm soapy water. Then rinse with water. 
2. Dry the two parts.  Push the plunger back in to the syringe. Keep it in a clean safe place with the 



153

medicine. 

If you take more VFEND than you should
If you take more suspension than prescribed (or if someone else takes your suspension) you must seek 
medical advice or go to the nearest hospital casualty department immediately. Take your bottle of VFEND 
suspension with you. You may experience abnormal intolerance to light as a result of taking more VFEND 
than you should.

If you forget to take VFEND
It is important to take your VFEND suspension regularly at the same time each day. If you forget to take 
one dose, take your next dose when it is due. Do not take a double dose to make up for the forgotten dose. 

If you stop taking VFEND
It has been shown that taking all doses at the appropriate times may greatly increase the effectiveness of your 
medicine. Therefore unless your doctor instructs you to stop treatment, it is important to keep taking VFEND 
correctly, as described above. 

Continue taking VFEND until your doctor tells you to stop. Do not stop treatment early because your 
infection may not be cured. Patients with a weakened immune system or those with difficult infections may 
require long-term treatment to prevent the infection from returning. 

When VFEND treatment is stopped by your doctor you should not experience any effects. 

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 

4. Possible side effects 

Like all medicines, this medicine can cause side effects, although not everybody gets them. 

If any side effects occur, most are likely to be minor and temporary. However, some may be serious and 
need medical attention. 

Serious side effects – Stop taking VFEND and see a doctor immediately
- Rash
- Jaundice; Changes in blood tests of liver function
- Pancreatitis

Other side effects

Very common: may affect more than 1 in 10 people

- Visual impairment (change in vision including blurred vision, visual color alterations, abnormal 
intolerance to visual perception of light, colour blindness, eye disorder, halo vision, night blindness, 
swinging vision, seeing sparks, visual aura, visual acuity reduced, visual brightness, loss of part of 
the usual field of vision, spots before the eyes) 

- Fever 
- Rash 
- Nausea, vomiting, diarrhoea 
- Headache 
- Swelling of the extremities 
- Stomach pains 
- Breathing difficulties
- Elevated liver enzymes



154

Common: may affect up to 1 in 10 people

- Inflammation of the sinuses, inflammation of the gums, chills, weakness 
- Low numbers of some types, including severe, of red (sometimes immune-related) and/or white 

blood cells (sometimes with fever), low numbers of cells called platelets that help the blood to clot 
- Low blood sugar, low blood potassium, low sodium in the blood 
- Anxiety, depression, confusion, agitation, inability to sleep, hallucinations 
- Seizures, tremors or uncontrolled muscle movements, tingling or abnormal skin 

sensations, increase in muscle tone, sleepiness, dizziness
- Bleeding in the eye
- Heart rhythm problems including very fast heartbeat, very slow heartbeat, fainting 
- Low blood pressure, inflammation of a vein (which may be associated with the formation of a blood 

clot) 
- Acute breathing difficulty, chest pain, swelling of the face (mouth, lips and around eyes), fluid 

accumulation in the lungs 
- Constipation, indigestion, inflammation of the lips
- Jaundice, inflammation of the liver and liver injury
- Skin rashes which may lead to severe blistering and peeling of the skin characterized by a flat, red

area on the skin that is covered with small confluent bumps, redness of the skin
- Itchiness 
- Hair loss 
- Back pain
- Kidney failure, blood in the urine, changes in kidney function tests

Uncommon: may affect up to 1 in 100 people

- Flu-like symptoms, irritation and inflammation of the gastrointestinal tract, inflammation of the 
gastrointestinal tract causing antibiotic associated diarrhoea, inflammation of the lymphatic vessels

- Inflammation of the thin tissue that lines the inner wall of the abdomen and covers the abdominal 
organ

- Enlarged lymph glands (sometimes painful), failure of blood marrow, increased eosinophil
- Depressed function of the adrenal gland, underactive thyroid gland
- Abnormal brain function, Parkinson-like symptoms, nerve injury resulting in numbness, pain, 

tingling or burning in the hands or feet
- Problems with balance or coordination 
- Swelling of the brain  
- Double vision, serious conditions of the eye including: pain and inflammation of the eyes and

eyelids, abnormal eye movement, damage to the optic nerve resulting in vision impairment, optic 
disc swelling 

- Decreased sensitivity to touch 
- Abnormal sense of taste
- Hearing difficulties, ringing in the ears, vertigo 
- Inflammation of certain internal organs- pancreas and duodenum, swelling and inflammation of the 

tongue 
- Enlarged liver, liver failure, gallbladder disease, gallstones 
- Joint inflammation, inflammation of the veins under the skin (which may be associated with the 

formation of a blood clot) 
- Inflammation of the kidney, proteins in the urine, damage to the kidney  
- Very fast heart rate or skipped heartbeats, sometimes with erratic electrical impulses
- Abnormal electrocardiogram (ECG) 
- Blood cholesterol increased, blood urea increased
- Allergic skin reactions (sometimes severe), including life-threatening skin condition that causes 

painful blisters and sores of the skin and mucous membranes, especially in the mouth, 
inflammation of the skin, hives, sunburn or severe skin reaction following exposure to light or sun, 
skin redness and irritation, red or purple discoloration of the skin which may be caused by low 
platelet count, eczema

- Infusion site reaction
- Allergic reaction or exaggerated immune response



155

Rare: may affect up to 1 in 1000 people

- Overactive thyroid gland
- Deterioration of brain function that is a serious complication of liver disease
- Loss of most fibers in the optic nerve, clouding of the cornea, involuntary movement of the eye
- Bullous photosensitivity
- A disorder in which the body’s immune system attacks part of the peripheral nervous system
- Heart rhythm or conduction problems (sometimes life threatening)
- Life threatening allergic reaction 
- Disorder of blood clotting system
- Allergic skin reactions (sometimes severe), including rapid swelling (oedema) of the dermis,

subcutaneous tissue, mucosa and submucosal tissues, itchy or sore patches of thick, red skin with
silvery scales of skin, irritation of the skin and mucous membranes, life-threatening skin condition
that causes large portions of the epidermis, the skin's outermost layer, to detach from the layers of
skin below

- Small dry scaly skin patches, sometimes thick with spikes or ‘horns’

Side effects with frequency not known:
- Freckles and pigmented spots

Other significant side effects whose frequency is not known, but should be reported to your doctor 
immediately:
- Skin cancer 
- Inflammation of the tissue surrounding the bone 
- Red, scaly patches or ring-shaped skin lesions that may be a symptom of an autoimmune disease 

called cutaneous lupus erythematosus

As VFEND has been known to affect the liver and the kidney, your doctor should monitor the function 
of your liver and kidney by doing blood tests. Please advise your doctor if you have any stomach pains 
or if your stools have a different consistency. 

There have been reports of skin cancer in patients treated with VFEND for long periods of time. 

Sunburn or severe skin reaction following exposure to light or sun was experienced more frequently in 
children. If you or your child develops skin disorders, your doctor may refer you to a dermatologist, who 
after consultation may decide that it is important for you or your child to be seen on a regular basis. Elevated
liver enzymes were also observed more frequently in children.

If any of these side effects persist or are troublesome, please tell your doctor. 

Reporting of side effects
If you get any side effects, talk to your doctor or, pharmacist or nurse. This includes any possible side effects 

not listed in this leaflet. You can also report side effects directly via the national reporting system listed in 

Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store VFEND 

Keep this medicine out of the sight and reach of children. 

Do not use this medicine after the expiry date which is stated on the label. The expiry date refers to the last 
day of that month.

Powder for oral suspension: store at 2°C - 8°C (in a refrigerator) before constitution.
For the constituted suspension:
Do not store above 30°C.  



156

Do not refrigerate or freeze.
Store in the original container 
Keep the container tightly closed.
Any remaining suspension should be discarded 14 days after constitution. 

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw 
away medicines you no longer required. These measures will help protect the environment. 

6. Contents of the pack and other information 

What VFEND contains: 
- The active substance is voriconazole. Each bottle contains 45 g of powder providing 70 ml of suspension 

when constituted with water as recommended. One ml of the constituted suspension contains 40 mg 
voriconazole. (See section 3 ‘How to take VFEND’). 

- The other ingredients are sucrose; silica colloidal; titanium dioxide; xanthan gum; sodium citrate; 
sodium benzoate; citric acid; natural orange flavour. 

What VFEND looks like and contents of the pack 
VFEND is supplied as a white to off-white powder for oral suspension providing a white to off-white, orange 
flavoured suspension when constituted with water.

Marketing Authorisation Holder 
Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium. 

Manufacturer 
Fareva Amboise, Zone Industrielle, 29 route des Industries, 37530 Pocé-sur-Cisse, France. 

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 

België /Belgique/Belgien 
Pfizer S.A./N.V.  
Tél/Tel: +32 (0)2 554 62 11

Lietuva 
Pfizer Luxembourg SARL 
Filialas Lietuvoje 
Tel. +3705 2514000

България 
Пфайзер Люксембург САРЛ, Клон България 
Тел.: +359 2 970 4333 

Luxembourg/Luxemburg 
Pfizer S.A. 
Tél: +32 (0)2 554 62 11

Česká republika 
Pfizer s.r.o.
Tel: +420-283-004-111

Magyarország 
Pfizer Kft. 
Tel. + 36 1 488 37 00

Danmark 
Pfizer ApS Tlf: 
+45 44 20 11 00 

Malta 
Vivian Corporation Ltd. 
Tel : +356 21344610

Deutschland 
Pfizer Pharma PFE GmbH 
Tel: +49 (0)800 8535555

Nederland 
Pfizer bv 
Tel: +31 (0)10 406 43 01

Eesti 
Pfizer Luxembourg SARL Eesti filiaal 
Tel: +372 666 7500

Norge 
Pfizer AS 
Tlf: +47 67 52 61 00



157

Ελλάδα

Pfizer ΕΛΛΑΣ A.E.

Τηλ.: +30 210 6785 800

Österreich 
Pfizer Corporation Austria 
Ges.m.b.H. Tel: +43 (0)1 
521 15-0

España 
Pfizer, S.L.
Tel: +34 91 490 99 00

Polska 
Pfizer Polska Sp. z o.o., 
Tel.: +48 22 335 61 00

France
Pfizer
Tél: +33 (0)1 58 07 34 40 

Portugal 
Laboratórios Pfizer, Lda. 
Tel: + 351 214 235 500

Hrvatska
Pfizer Croatia d.o.o.
Tel: + 385 1 3908 777

România 
Pfizer România S.R.L 
Tel: +40 (0)21 207 28 00

Ireland 
Pfizer Healthcare Ireland 
Tel: 1800 633 363 (toll free)
+44 (0)1304 616161

Slovenija 
Pfizer Luxembourg SARL 
Pfizer, podružnica za svetovanje s področja 
farmacevtske dejavnosti, Ljubljana 
Tel: + 386(0)152 11 400 

Ísland 
Icepharm hf., 
Sími: + 354 540 8000 

Slovenská republika
Pfizer Luxembourg SARL, organizačná zložka
Tel: +421-2-3355 5500

Italia 
Pfizer S.r.l. 
Tel: +39 06 33 18 21 

Suomi/Finland
Pfizer Oy 
Puh/Tel: +358(0)9 43 00 40

Kύπρος

Pfizer ΕΛΛΑΣ Α.Ε. (Cyprus Branch) 

Τηλ: +357 22 817690

Sverige  
Pfizer AB 
Tel: +46 (0)8 5505 2000

Latvija
Pfizer Luxembourg SARL 
Filiāle Latvijā 
Tel: +371 670 35 775

United Kingdom 
Pfizer Limited 
Tel: +44 (0)1304 616161

This leaflet was last approved in {MM/YYYY}. 

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETINGAUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVEUSE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET