VORICAN 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.
VORICAN 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.
 

Posology
Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalcaemia should be
monitored and corrected, if necessary, prior to initiation and during voriconazole therapy (see section
4.4).
Powder for solution for infusion:
It is recommended that VORICAN is administered at a maximum rate of 3 mg/kg per hour over 1 to 3
hours.
Treatment
Adults
Therapy must be initiated with the specified loading dose regimen of either intravenous or oral
VORICAN 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:

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.
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:

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.
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.
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).
Elderly
No dose adjustment is necessary for elderly patients (see section 5.2).
Renal impairment
Powder for solution for infusion:
In patients with moderate to severe renal dysfunction (creatinine clearance < 50 ml/min), accumulation
of the intravenous vehicle, SBECD, occurs. Oral voriconazole should be administered to these
patients, unless an assessment of the risk benefit to the patient justifies the use of intravenous
voriconazole. Serum creatinine levels should be closely monitored in these patients and, if increases
occur, consideration should be given to changing to oral voriconazole therapy (see section 5.2).
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 VORICAN 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 VORICAN 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
VORICAN powder for solution for infusion requires reconstitution and dilution (see section 6.6) prior to
administration as an intravenous infusion. Not for bolus injection.
 

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).

Hypersensitivity
Caution should be used in prescribing VORICAN to patients with hypersensitivity to other azoles (see
also section 4.8).
Duration of IV treatment
The duration of treatment with the intravenous formulation should be no longer than 6 months (see
section 5.3).
Cardiovascular
Voriconazole has been associated with QTc interval prolongation. There have been rare cases of
torsades de pointes in patients taking voriconazole who had risk factors, such as history of cardiotoxic
chemotherapy, cardiomyopathy, hypokalaemia and concomitant medicinal products that may have
been contributory. Voriconazole should be administered with caution to patients with potentially
proarrhythmic conditions, such as:
• Congenital or acquired QTc-prolongation.
• Cardiomyopathy, in particular when heart failure is present.
• Sinus bradycardia.
• Existing symptomatic arrhythmias.
• Concomitant medicinal product that is known to prolong QTc interval. Electrolyte disturbances such
as hypokalaemia, hypomagnesaemia and hypocalcaemia should be monitored and corrected, if
necessary, prior to initiation and during voriconazole therapy (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 VORICAN 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 VORICAN 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, VORICAN 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 VORICAN 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 VORICAN 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,
VORICAN discontinuation and use of alternative antifungal agents should be considered and the
patient should be referred to a dermatologist. If VORICAN is continued, however, dermatologic
evaluation should be performed on a systematic and regular basis, to allow early detection and
management of premalignant lesions. VORICAN 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 VORICAN 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 VORICAN (see sections 4.2 and 5.1).
Squamous cell carcinoma of the skin (SCC) has been reported in relation with long-term VORICAN
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
VORICAN 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 VORICAN.
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 VORICAN
treatment. Monitoring of serum amylase or lipase may be considered in this clinical situation.
Paediatric population
Safety and effectiveness in paediatric subjects below the age of two years has not been established
(see sections 4.8 and 5.1). Voriconazole is indicated for paediatric patients aged two years or older. A
higher frequency of liver enzyme elevations was observed in the paediatric population (see section
4.8). Hepatic function should be monitored in both children and adults. Oral bioavailability may be
limited in paediatric patients aged 2 to <12 years with malabsorption and very low body weight for age.
In that case, intravenous voriconazole administration is recommended.
• Serious dermatological adverse reactions (including SCC)
The frequency of phototoxicity reactions is higher in the paediatric population. As an evolution towards
SCC has been reported, stringent measures for the photoprotection are warranted in this population of
patients. In children experiencing photoaging injuries such as lentigines or ephelides, sun avoidance
and dermatologic follow-up are recommended even after treatment discontinuation.
Prophylaxis
In case of treatment-related adverse events (hepatotoxicity, severe skin reactions including
phototoxicity and SCC, severe or prolonged visual disorders and periostitis), discontinuation of
voriconazole and use of alternative antifungal agents must be considered.
Phenytoin (CYP2C9 substrate and potent CYP450 inducer)
Careful monitoring of phenytoin levels is recommended when phenytoin is coadministered with
voriconazole. Concomitant use of voriconazole and phenytoin should be avoided unless the benefit
outweighs the risk (see section 4.5).
Efavirenz (CYP450 inducer; CYP3A4 inhibitor and substrate)
When voriconazole is coadministered with efavirenz the dose of voriconazole should be increased to
400 mg every 12 hours and the dose of efavirenz should be decreased to 300 mg every 24 hours (see
sections 4.2, 4.3 and 4.5).
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
AUC of voriconazole in healthy subjects. The reduced dose and/or frequency of voriconazole and
fluconazole that would eliminate this effect have not been established. Monitoring for voriconazole -
associated adverse reactions is recommended if voriconazole is used sequentially after fluconazole
(see section 4.5).
Sodium content: Each vial of VORICAN powder for solution for infusion contains 217.6 mg of sodium.
This should be taken into consideration for patients on a controlled sodium diet.
 

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.

Pregnancy Category D
Pregnancy
There are no adequate data on the use of VORICAN in pregnant women available.
Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is
unknown.
VORICAN 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 VORICAN.
Fertility
In an animal study, no impairment of fertility was demonstrated in male and female rats (see section
5.3).
 

VORICAN 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.
 

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.
TABULATED LIST OF ADVERSE REACTIONS
Undesirable effects reported in subjects receiving voriconazole:

Description of selected adverse reactions
Altered taste perception
In the combined data from three bioequivalence studies using the powder for oral suspension
formulation, treatment-related taste perversion was recorded in 12 (14%) of subjects.
Visual impairments
In clinical trials, visual impairments (including blurred vision, photophobia, chloropsia, chromatopsia,
colour blindness, cyanopsia, eye disorder, halo vision, night blindness, oscillopsia, photopsia,
scintillating scotoma, visual acuity reduced, visual brightness, visual field defect, vitreous floaters, and
xanthopsia) with voriconazole were very common. These visual impairments were transient and fully
reversible, with the majority spontaneously resolving within 60 minutes and no clinically significant
long-term visual effects were observed. There was evidence of attenuation with repeated doses of
voriconazole. The visual impairments were generally mild, rarely resulted in discontinuation and were
not associated with long-term sequelae. Visual impairments may be associated with higher plasma
concentrations and/or doses.
The mechanism of action is unknown, although the site of action is most likely to be within the retina.
In a study in healthy volunteers investigating the impact of voriconazole on retinal function,
voriconazole caused a decrease in the electroretinogram (ERG) waveform amplitude. The ERG
measures electrical currents in the retina. The ERG changes did not progress over 29 days of
treatment and were fully reversible on withdrawal of voriconazole.
There have been post-marketing reports of prolonged visual adverse events (see section 4.4).
Dermatological reactions
Dermatological reactions were very common in patients treated with voriconazole in clinical trials, but
these patients had serious underlying diseases and were receiving multiple concomitant medicinal
products. The majority of rashes were of mild to moderate severity. Patients have developed severe
cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) (uncommon), toxic
epidermal necrolysis (TEN) (rare), drug reaction with eosinophilia and systemic symptoms (DRESS)
(rare) and erythema multiforme (rare) during treatment with VORICAN (see section 4.4).
If a patient develops a rash they should be monitored closely and VORICAN 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 VORICAN 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 populationwas 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). Postmarketing data suggest there might be a higher occurrence of skin reactions (especially erythema) in
the paediatric population compared to adults. In the 22 patients less than 2 years old who received
voriconazole in a compassionate use programme, the following adverse reactions (for which a
relationship to voriconazole could not be excluded) were reported: photosensitivity reaction (1),
arrhythmia (1), pancreatitis (1), blood bilirubin increased (1), hepatic enzymes increased (1), rash (1)
and papilloedema (1). There have been post-marketing reports of pancreatitis in paediatric patients.
Renal impairment
Powder for solution for infusion:
In patients with moderate to severe renal dysfunction (creatinine clearance < 50 ml/min), accumulation
of the intravenous vehicle, SBECD, occurs. Oral voriconazole should be administered to these
patients, unless an assessment of the risk benefit to the patient justifies the use of intravenous
voriconazole. Serum creatinine levels should be closely monitored in these patients and, if increases
occur, consideration should be given to changing to oral voriconazole therapy (see section 5.2).
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.

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. 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.
 

Pharmacotherapeutic group: Antimycotics for systemic use, triazole derivatives, ATC code: J02 AC03
Mode of action
Voriconazole is a triazole antifungal agent. The primary mode of action of voriconazole is the inhibition
of fungal cytochrome P450-mediated 14 alpha-lanosterol demethylation, an essential step in fungal
ergosterol biosynthesis. The accumulation of 14 alpha-methyl sterols correlates with the subsequent
loss of ergosterol in the fungal cell membrane and may be responsible for the antifungal activity of
voriconazole. Voriconazole has been shown to be more selective for fungal cytochrome P-450
enzymes than for various mammalian cytochrome P-450 enzyme systems.
Pharmacokinetic/pharmacodynamic relationship
In 10 therapeutic studies, the median for the average and maximum plasma concentrations in
individual subjects across the studies was 2425 ng/ml (inter-quartile range 1193 to 4380 ng/ml) and
3742 ng/ml (inter-quartile range 2027 to 6302 ng/ml), respectively. A positive association between
mean, maximum or minimum plasma voriconazole concentration and efficacy in therapeutic studies
was not found and this relationship has not been explored in prophylaxis studies.
Pharmacokinetic-Pharmacodynamic analyses of clinical trial data identified positive associations
between plasma voriconazole concentrations and both liver function test abnormalities and visual
disturbances. Dose adjustments in prophylaxis studies have not been explored.
Clinical efficacy and safety
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 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

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 voriconazoletreated 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.

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
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:

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,
multicentre 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-centre 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 oesophageal 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.
 

General pharmacokinetic characteristics
The pharmacokinetics of voriconazole have been characterised in healthy subjects, special
populations and patients. During oral administration of 200 mg or 300 mg twice daily for 14 days in
patients at risk of aspergillosis (mainly patients with malignant neoplasms of lymphatic or
haematopoietic tissue), the observed pharmacokinetic characteristics of rapid and consistent
absorption, accumulation and non-linear pharmacokinetics were in agreement with those observed in
healthy subjects.
The pharmacokinetics of voriconazole are non-linear due to saturation of its metabolism. Greater than
proportional increase in exposure is observed with increasing dose. It is estimated that, on average,
increasing the oral dose from 200 mg twice daily to 300 mg twice daily leads to a 2.5-fold increase in
exposure (AUC ). The oral maintenance dose of 200 mg (or 100 mg for patients less than 40 kg)
achieves a voriconazole exposure similar to 3 mg/kg IV. A 300 mg (or 150 mg for patients less than 40
kg) oral maintenance dose achieves an exposure similar to 4 mg/kg IV. When the recommended
intravenous or oral loading dose regimens are administered, plasma concentrations close to steady
state are achieved within the first 24 hours of dosing. Without the loading dose, accumulation occurs
during twice daily multiple dosing with steady-state plasma voriconazole concentrations being
achieved by Day 6 in the majority of subjects.
Absorption
Voriconazole is rapidly and almost completely absorbed following oral administration, with maximum
plasma concentrations (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, Cmaxand AUC are reduced by 34% and 24%, respectively. The
absorption of voriconazole is not affected by changes in gastric pH.
Powder for oral suspension
Voriconazole is rapidly and almost completely absorbed following oral administration, with maximum
plasma concentrations (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 40mg/ml oral suspension when
administered as a 200 mg dose. When multiple doses of voriconazole are administered with high fat
meals, Cmaxand AUC are reduced by 58% and 37%, respectively. The absorption of voriconazole is
not affected by changes in gastric pH.
Distribution
The volume of distribution at steady state for voriconazole is estimated to be 4.6 L/kg, suggesting
extensive distribution into tissues. Plasma protein binding is estimated to be 58%. Cerebrospinal fluid
samples from eight patients in a compassionate programme showed detectable voriconazole
concentrations in all patients.
Biotransformation
In vitro studies showed that voriconazole is metabolised by the hepatic cytochrome P450 isoenzymes
CYP2C19, CYP2C9 and CYP3A4.
The inter-individual variability of voriconazole pharmacokinetics is high.
In vivo studies indicated that CYP2C19 is significantly involved in the metabolism of voriconazole. This
enzyme exhibits genetic polymorphism. For example, 15-20% of Asian populations may be expected
to be poor metabolisers. For Caucasians and Blacks the prevalence of poor metabolisers is 3-
5%. Studies conducted in Caucasian and Japanese healthy subjects have shown that poor
metabolisers have, on average, 4-fold higher voriconazole exposure (AUC ) than their homozygous
extensive metaboliser counterparts. Subjects who are heterozygous extensive metabolisers have on
average 2-fold higher voriconazole exposure than their homozygous extensive metaboliser
counterparts.
The major metabolite of voriconazole is the N-oxide, which accounts for 72% of the circulating
radiolabelled metabolites in plasma. This metabolite has minimal antifungal activity and does not
contribute to the overall efficacy of voriconazole.
Elimination
Voriconazole is eliminated via hepatic metabolism with less than 2% of the dose excreted unchanged
in the urine.
After administration of a radiolabelled dose of voriconazole, approximately 80% of the radioactivity is
recovered in the urine after multiple intravenous dosing and 83% in the urine after multiple oral dosing.
The majority (> 94%) of the total radioactivity is excreted in the first 96 hours after both oral and
intravenous dosing.
The terminal half-life of voriconazole depends on dose and is approximately 6 hours at 200 mg (orally).
Because of non-linear pharmacokinetics, the terminal half-life is not useful in the prediction of the
accumulation or elimination of voriconazole.
Pharmacokinetics in special patient groups
Gender
In an oral multiple-dose study, Cmax and AUC for healthy young females were 83% and 113% higher,
respectively, than in healthy young males (18-45 years). In the same study, no significant differences
in Cmax and AUC were observed between healthy elderly males and healthy elderly females (≥ 65
years).
In the clinical programme, no dosage adjustment was made on the basis of gender. The safety profile
and plasma concentrations observed in male and female patients were similar. Therefore, no dosage
adjustment based on gender is necessary.
Elderly
In an oral multiple-dose study Cmax and AUC 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
AUC were observed between healthy elderly females (≥ 65 years) and healthy young females (18-45
years).
In the therapeutic studies no dosage adjustment was made on the basis of age. A relationship
between plasma concentrations and age was observed. The safety profile of voriconazole in young
and elderly patients was similar and, therefore, no dosage adjustment is necessary for the elderly (see
section 4.2).
Paediatric population
The recommended doses in children and adolescent patients are based on a population
pharmacokinetic analysis of data obtained from 112 immunocompromised paediatric patients aged 2
to <12 years and 26 immunocompromised adolescent patients aged 12 to <17 years. Multiple
intravenous doses of 3, 4, 6, 7 and 8 mg/kg twice daily and multiple oral doses (using the powder for
oral suspension) of 4 mg/kg, 6 mg/kg, and 200 mg twice daily were evaluated in 3 paediatric
pharmacokinetic studies. Intravenous loading doses of 6 mg/kg IV twice daily on day 1 followed by 4
mg/kg intravenous dose twice daily and 300 mg oral tablets twice daily were evaluated in one
adolescent pharmacokinetic study. Larger inter-subject variability was observed in paediatric patients
compared to adults.
A comparison of the paediatric and adult population pharmacokinetic data indicated that the predicted
total exposure (AUC ) in children following administration of a 9 mg/kg IV loading dose was
comparable to that in adults following a 6 mg/kg IV loading dose. The predicted total exposures in
children following IV maintenance doses of 4 and 8 mg/kg twice daily were comparable to those in
adults following 3 and 4 mg/kg IV twice daily, respectively. The predicted total exposure in children
following an oral maintenance dose of 9 mg/kg (maximum of 350 mg) twice daily was comparable to
that in adults following 200 mg oral twice daily. An 8 mg/kg intravenous dose will provide voriconazole
exposure approximately 2-fold higher than a 9 mg/kg oral dose.
The higher intravenous maintenance dose in paediatric patients relative to adults reflects the higher
elimination capacity in paediatric patients due to a greater liver mass to body mass ratio. Oral
bioavailability may, however, be limited in paediatric patients with malabsorption and very low body
weight for their age. In that case, intravenous voriconazole administration is recommended.
Voriconazole exposures in the majority of adolescent patients were comparable to those in adults
receiving the same dosing regimens. However, lower voriconazole exposure was observed in some
young adolescents with low body weight compared to adults. It is likely that these subjects may
metabolize voriconazole more similarly to children than to adults. Based on the population
pharmacokinetic analysis, 12- to 14-year-old adolescents weighing less than 50 kg should receive
children's doses (see section 4.2).
Renal impairment
Film-coated tablets:
In an oral single-dose (200 mg) study in subjects with normal renal function and mild (creatinine
clearance 41-60 ml/min) to severe (creatinine clearance < 20 ml/min) renal impairment, the
pharmacokinetics of voriconazole were not significantly affected by renal impairment. The plasma
protein binding of voriconazole was similar in subjects with different degrees of renal impairment. (see
sections 4.2 and 4.4).
Powder for solution for infusion:
In patients with moderate to severe renal dysfunction (serum creatinine levels >2.5 mg /dl),
accumulation of the intravenous vehicle, SBECD, occurs. (see sections 4.2 and 4.4).
Hepatic impairment
After an oral single-dose (200 mg), AUC was 233% higher in subjects with mild to moderate hepatic
cirrhosis (Child-Pugh A and B) compared with subjects with normal hepatic function. Protein binding of
voriconazole was not affected by impaired hepatic function.
In an oral multiple-dose study, AUC was similar in subjects with moderate hepatic cirrhosis (ChildPugh 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).
 

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 postnatal development study in rats at exposures lower than those obtained in humans with therapeutic
doses, voriconazole prolonged the duration of gestation and labour and produced dystocia with
consequent maternal mortality and reduced perinatal survival of pups. The effects on parturition are
probably mediated by species-specific mechanisms, involving reduction of oestradiol levels, and are
consistent with those observed with other azole antifungal agents. Voriconazole administration induced
no impairment of male or female fertility in rats at exposures similar to those obtained in humans at
therapeutic doses.
Powder for solution for infusion:
Preclinical data on the intravenous vehicle SBECD indicated that the main effects were vacuolation of
urinary tract epithelium and activation of macrophages in the liver and lungs in the repeated-dose
toxicity studies. As GPMT (guinea pig maximisation test) result was positive, prescribers should be
aware of the hypersensitivity potential of the intravenous formulation. Standard genotoxicity and
reproduction studies with the excipient SBECD reveal no special hazard for humans. Carcinogenicity
studies were not performed with SBECD. An impurity present in SBECD has been shown to be an
alkylating mutagenic agent with evidence for carcinogenicity in rodents. This impurity should be
considered a substance with carcinogenic potential in humans. In light of these data the duration of
treatment with the intravenous formulation should be no longer than 6 months.
 

Hydroxypropyl ß-cyclodextrin (HPβCD)
 

VORICAN 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 VORICAN
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). VORICAN must not be
administered simultaneously with any blood product or any short-term infusion of concentrated
solutions of electrolytes, even if the two infusions are running in separate lines.
Total parenteral nutrition:
Total parenteral nutrition (TPN) need not be discontinued when prescribed with VORICAN, 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 VORICAN. VORICAN 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.
 

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.

Unopened vials
Do not store above 30 °C
For storage conditions after reconstitution of the medicinal product, see section 6.3.
 

Clear vial with rubber stopper and aluminium seal with red plastic flip off button.
Pack size: packs of 1 vial.
 

Any unused medicinal product or waste material should be disposed of in accordance with local
requirements.
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 VORICAN 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.
Required Volumes of 10 mg/ml VORICAN Concentrate