ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
VFEND 50 mg film-coated tablets
Each tablet contains 50 mg voriconazole. Excipient: lactose monohydrate 63.42 mg.
For a full list of excipients, see section 6.1.
White to off-white, round tablet, debossed “Pfizer” on one side and “VOR50”on the reverse.
Voriconazole, is a broad spectrum, triazole antifungal agent and is indicated as follows:
Treatment of invasive aspergillosis.
Treatment of candidemia in non-neutropenic patients.
Treatment of fluconazole-resistant serious invasive
Candida
infections (including
C. krusei
).
Treatment of serious fungal infections caused by
Scedosporium
spp. and
Fusarium
spp.
VFEND should be administered primarily to patients with progressive, possibly life-threatening
infections.
VFEND film-coated tablets are to be taken at least one hour before, or one hour following, a
meal.
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 200 mg film-coated tablets, 200 mg powder for solution for infusion and
40 mg/ml powder for oral suspension.
Use in 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.
2
Detailed information on dosage recommendations is provided in the following table:
Intravenous
Oral
Patients 40 kg and Patients less than 40
kg
above
Loading Dose
6 mg/kg every 12
hours
400 mg every 12
hours
200 mg every 12
hours
Regimen
(for the first 24
hours)
(for the first 24
hours)
(for the first 24
hours)
(first 24 hours)
Maintenance Dose
(after first 24
hours)
4 mg/kg twice daily 200 mg twice daily 100 mg twice daily
Dosage adjustment
If patient response 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 patients are unable to tolerate treatment at these higher doses 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.
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.
Rifabutin may be coadministered with voriconazole if the maintenance dose of voriconazole is
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).
Treatment should be as short as possible depending on the patients’clinical and mycological response.
For long term treatment greater than 6 months, a careful assessment of the benefit-risk balance should
events) and section 5.1 Pharmacodynamic properties (Duration of treatment).
Use in the elderly
No dose adjustment is necessary for elderly patients (see section 5.2).
Use in patients with 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 four hour haemodialysis session
does not remove a sufficient amount of voriconazole to warrant dose adjustment.
3
Use in patients with hepatic impairment
No dose adjustment is necessary in patients with acute hepatic injury, manifested by elevated liver
function tests (ALAT, ASAT) (but continued monitoring of liver function tests for further elevations is
recommended).
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 VFEND
(see section 5.2).
VFEND has not been studied in patients with severe chronic hepatic cirrhosis (Child-Pugh C).
VFEND has been associated with elevations in liver function tests and clinical signs of liver damage,
such as jaundice, and must only be used in patients with severe hepatic impairment if the benefit
outweighs the potential risk. Patients with hepatic impairment must be carefully monitored for drug
toxicity (see also section 4.8).
Use in children
VFEND is not recommended for use in children below 2 years due to insufficient data on safety and
efficacy (see also sections 4.8 and 5.1).
The recommended maintenance dosing regimen in paediatric patients 2 to <12 years is as follows:
Intravenous*
Oral**
Loading Dose Regimen
No oral or intravenous loading dose is recommended
Maintenance Dose
7 mg/kg twice daily
200 mg twice daily
*Based on a population pharmacokinetic analysis in 82 immunocompromised patients aged 2 to <12
years **Based on a population pharmacokinetic analysis in 47 immunocompromised patients aged 2
to <12 years
Use in paediatric patients aged 2 to <12 years with hepatic or renal insufficiency has not been studied
(see section 4.8 and section 5.2).
These paediatric dose recommendations are based on studies in which VFEND was administered as
the powder for oral suspension. Bioequivalence between the powder for oral suspension and tablets
has not been investigated in a paediatric population. Considering the assumed limited gastro-enteric
transit time in paediatrics, 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-<12.
Adolescents (12 to 16 years of age): should be dosed as adults.
Hypersensitivity to the active substance or to any of the excipients
Coadministration of the CYP3A4 substrates, terfenadine, astemizole, cisapride, pimozide or quinidine
with VFEND is contraindicated 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 of VFEND with rifampicin, carbamazepine and phenobarbital is contraindicated
since these medicinal products are likely to decrease plasma voriconazole concentrations significantly
(see section 4.5).
4
Coadministration of VFEND with high dose ritonavir (400 mg and above twice daily) is
contraindicated 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 of ergot alkaloids (ergotamine, dihydroergotamine), which are CYP3A4 substrates,
is contraindicated since increased plasma concentrations of these medicinal products can lead to
ergotism (see section 4.5).
Coadministration of voriconazole and sirolimus is contraindicated, since voriconazole is likely to
increase plasma concentrations of sirolimus significantly (see section 4.5).
The concomitant use of voriconazole with St John’s Wort is contraindicated (see section 4.5).
Hypersensitivity: Caution should be used in prescribing VFEND to patients with hypersensitivity to
other azoles (see also section 4.8).
Cardiovascular:
Some azoles, including voriconazole have been associated with QT 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 medications
that may have been contributory. Voriconazole should be administered with caution to patients with
potentially proarrhythmic conditions, such as
•
Congenital or acquired QT-prolongation
•
Cardiomyopathy, in particular when heart failure is present
•
Sinus bradycardia
•
Existing symptomatic arrhythmias
•
Concomitant medication that is known to prolong QT 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 QT interval of single doses of
voriconazole up to 4 times the usual daily dose. No subject experienced an interval exceeding
the potentially clinically relevant threshold of 500 msec (see section 5.1).
Hepatic toxicity
: In clinical trials, there have been uncommon cases of serious hepatic reactions
during treatment with VFEND (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 at the beginning of therapy with voriconazole and patients
who develop abnormal liver function tests during VFEND therapy must be routinely monitored for the
development of more severe hepatic injury. Patient management should include laboratory evaluation
of hepatic function (particularly liver function tests and bilirubin). Discontinuation of VFEND should
be considered if clinical signs and symptoms are consistent with liver disease development.
Monitoring of hepatic function should be carried out in both children and adults.
Visual adverse events
: There have been reports of prolonged visual adverse events, including blurred
vision, optic neuritis and papilloedema (see Section 4.8).
Renal adverse events
: Acute renal failure has been observed in severely ill patients undergoing
5
treatment with VFEND. Patients being treated with voriconazole are likely to be treated
concomitantly with nephrotoxic medications 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, hematopoietic stem cell transplantation (HSCT)), should be
monitored closely during Vfend treatment. Monitoring of serum amylase or lipase may be considered
in this clinical situation.
Dermatological adverse events:
Patients have rarely developed exfoliative cutaneous reactions, such
as Stevens-Johnson syndrome, during treatment with VFEND. If patients develop a rash they should
be monitored closely and VFEND discontinued if lesions progress.
In addition VFEND has been associated with phototoxicity and pseudoporphyria. It is recommended
that patients avoid intense or prolonged exposure to direct sunlight during VFEND treatment and use
measures such as protective clothing and sunscreen when appropriate. In patients with phototoxicity
and additional risk factors, including immunosuppression, squamous cell carcinoma of the skin has
been reported during long-term therapy. Physicians should therefore consider the need to limit the
Pharmacodynamic properties (Duration of treatment). If a patient develops a skin lesion consistent
with squamous cell carcinoma,VFEND discontinuation should be considered.
Paediatric use
: Safety and effectiveness in paediatric subjects below the age of two years has not been
established (see also sections 4.8 and 5.1). Voriconazole is indicated for paediatric patients aged two
years or older. Hepatic function should be monitored in both children and adults. Oral bioavailability
may be limited in paediatric patients aged 2-<12 years with malabsorption and very low body weight
for age. In that case, intravenous voriconazole administration is recommended.
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).
Rifabutin
(CYP450 inducer): Careful monitoring of full blood counts and adverse events 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).
Methadone
(CYP3A4 substrate): Frequent monitoring for adverse events and toxicity related to
methadone, including QTc prolongation, is recommended when coadministered with voriconazole
since methadone levels increased following co-administration of voriconazole. Dose reduction of
methadone may be needed (see section 4.5).
Short Acting Opiates (CYP3A4 substrate
): Reduction in the dose of alfentanil, fentanyl and other short
acting opiates similar in structure to alfentanil and metabolised by CYP3A4 (e.g sufentanil) should be
considered when co-administered with voriconazole (see section 4.5). As the half-life of alfentanil is
prolonged in a four-fold manner when alfentanil is coadministered with voriconazoleand in an
independent published study, concomitant use of voriconazole with fentanyl resulted in an increase in
the mean AUC 0-∞ of fentanyl, frequent monitoring for opiate-associated adverse events (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 events may be necessary (see Section
4.5).
6
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 events is
recommended if voriconazole is used sequentially after fluconazole (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 justifies the use of voriconazole (see section 4.5, for higher doses see section 4.3).
Efavirenz
(CYP450 inducer; CYP3A4 inhibitor and substrate): When voriconazole is coadministered
with efavirenz the dose of voriconazole should be increased to 400 mg every 12 hours and that of
efavirenz should be decreased to 300 mg every 24 hours (see sections 4.2 and 4.5.).
VFEND tablets contain lactose and should not be given to patients with rare hereditary problems of
galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.
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. These
results are relevant to other populations and routes of administration.
This section addresses the effects of other medicinal products on voriconazole, the effects of
voriconazole on other medicinal products and two-way interactions. The interactions for the first two
sections are presented in the following order: contraindications, those requiring dosage 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.
Effects of other medicinal products on voriconazole
Voriconazole is metabolised by cytochrome P450 isoenzymes, CYP2C19, CYP2C9 and CYP3A4.
Inhibitors or inducers of these isoenzymes may increase or decrease voriconazole plasma
concentrations respectively.
Rifampicin
(CYP450 inducer): Rifampicin (600 mg once daily) decreased the Cmax (maximum
plasma concentration) and AUCτ (area under the plasma concentration time curve within a dose
interval) of voriconazole by 93 % and 96 %, respectively. Coadministration of voriconazole and
rifampicin is contraindicated (see section 4.3)
.
Ritonavir
(potent CYP450 inducer; CYP3A4 inhibitor and substrate): The effect of the
coadministration of oral voriconazole (200 mg twice daily) and high dose (400 mg) and low dose (100
mg) oral ritonavir was investigated in two separate studies in healthy volunteers. High doses of
ritonavir (400 mg twice daily) decreased the steady state Cmax and AUCτ of oral voriconazole by an
average of 66 % and 82 %, whereas low doses of ritonavir (100 mg twice daily) decreased the Cmax
and AUCτ of voriconazole by an average of 24 % and 39 % respectively. Administration of
voriconazole did not have a significant effect on mean Cmax and AUCτ of ritonavir in the high dose
study, although a minor decrease in steady state Cmax and AUCτ of ritonavir with an average of 25 %
and 13 % respectively was observed in the low dose ritonavir interaction study. One outlier subject
with raised voriconazole levels was identified in each of the ritonavir interaction studies.
Coadministration of voriconazole and high doses of ritonavir (400 mg and above twice daily) is
contraindicated. 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
section 4.3 and 4.4).
Carbamazepine and phenobarbital
(potent CYP450 inducers): Although not studied, carbamazepine or
phenobarbital are likely to significantly decrease plasma voriconazole concentrations.
7
Coadministration of voriconazole with carbamazepine and phenobarbital is contraindicated (see
section 4.3).
Cimetidine
(non-specific CYP450 inhibitor and increases gastric pH): Cimetidine (400 mg twice
daily) increased voriconazole Cmax and AUCτ by 18 % and 23 %, respectively. No dosage
adjustment of voriconazole is recommended.
Ranitidine
(increases gastric pH): Ranitidine (150 mg twice daily) had no significant effect on
voriconazole Cmax and AUCτ.
Macrolide antibiotics
: Erythromycin (CYP3A4 inhibitor; 1 g twice daily) and azithromycin (500 mg
once daily) had no significant effect on voriconazole Cmax and AUCτ.
St John’s Wort
(CYP450 inducer; P-gp inducer): In a clinical study in healthy volunteers, St John’s
Wort exhibited a short initial inhibitory effect followed by induction of voriconazole metabolism.
After 15 days of treatment with St John’s Wort (300 mg three times daily), plasma exposure
following a single 400 mg dose of voriconazole decreased by 40-60%. Therefore, concomitant use of
voriconazole with St John’s Wort is contraindicated (see section 4.3).
Effects of voriconazole on other medicinal products
Voriconazole inhibits the activity of cytochrome P450 isoenzymes, CYP2C19, CYP2C9 and
CYP3A4. Therefore there is potential for voriconazole to increase the plasma levels of substances
metabolised by these CYP450 isoenzymes.
Voriconazole should be administered with caution in patients with concomitant medication that is
known to prolong QT interval. When there is also a potential for voriconazole to increase the plasma
levels of substances metabolised by CYP3A4 isoenzymes (certain antihistamines, quinidine,
cisapride, pimozide) co-administration is contraindicated (see below and section 4.3).
Terfenadine, astemizole, cisapride, pimozide and quinidine
(CYP3A4 substrates): Although not
studied, coadministration of voriconazole with terfenadine, astemizole, cisapride, pimozide, or
quinidine is contraindicated, since increased plasma concentrations of these medicinal products can
lead to QTc prolongation and rare occurrences of torsades de pointes (see section 4.3).
Sirolimus
(CYP3A4 substrate): Voriconazole increased sirolimus (2 mg single dose) Cmax and
AUCτ by 556 % and 1014 %, respectively. Coadministration of voriconazole and sirolimus is
contraindicated (see section 4.3).
Ergot alkaloids
(CYP3A4 substrates): Although not studied, voriconazole may increase the plasma
concentrations of ergot alkaloids (ergotamine and dihydroergotamine) and lead to ergotism.
Coadministration of voriconazole with ergot alkaloids is contraindicated (see section 4.3).
Ciclosporin
(CYP3A4 substrate): In stable, renal transplant recipients, voriconazole increased
ciclosporin Cmax and AUCτ by at least 13 % and 70 % respectively. When initiating voriconazole
in patients already receiving 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.
Methadone
(CYP3A4 substrate): In subjects receiving a methadone maintenance dose (32-100 mg
once daily) coadministration of oral voriconazole (400 mg twice daily for 1 day, then 200 mg twice
daily for four days) increased the Cmax and AUC of pharmacologically active R-methadone by 31 %
and 47 %, respectively, whereas the Cmax and AUC of the S-enantiomer increased by approximately
65 % and 103 %, respectively. Voriconazole plasma concentrations during coadministration of
methadone were comparable to voriconazole levels (historical data) in healthy subjects without any
comedication. Frequent monitoring for adverse events and toxicity related to increased plasma
8
concentrations of methadone, including QT prolongation, is recommended during coadministration.
Dose reduction of methadone may be needed.
Short Acting Opiates
(CYP3A4 substrate): Steady-state administration of oral voriconazole increased
the AUCτ of a single dose of alfentanil by 6-fold. Reduction in the dose of alfentanil and other short
acting opiates similar in structure to alfentanil and metabolised by CYP3A4
(e.g. fentanyl and
sufentanil), should be considered when coadministered with voriconazole (see section 4.4).
Fentanyl (CYP3A4 substrate): In an independent published study, concomitant use of
voriconazole
(400 mg every 12 hours on Day 1, then 200 mg every 12 hours on Day 2) with a single intravenous
dose of fentanyl (5 µg/kg) resulted in an increase in the mean AUC 0-∞ of fentanyl by 1.34-fold
(range 1.12-1.60-fold). When voriconazole is co-administered with fentanyl, extended and frequent
monitoring of patients for respiratory depression and other fentanyl-associated adverse events is
recommended, and fentanyl dosage should be reduced if warranted.
Long Acting Opiates (CYP3A4 substrate)
:
In an independent published study, coadministration of
multiple doses of oral voriconazole (400 mg every 12 hours, on Day 1 followed by five doses of 200
mg every 12 hours on Days 2 to 4) with a single 10 mg oral dose of oxycodone on Day 3 resulted in an
increase in the mean Cmax and AUC0–∞ of oxycodone by 1.7-fold (range 1.4- to 2.2-fold) and 3.6-
fold (range 2.7- to 5.6-fold), respectively. The mean elimination half-life of oxycodone was also
increased by 2.0-fold (range 1.4- to 2.5-fold). A reduction in oxycodone dosage and other long-acting
opiates metabolized by CYP3A4 (e.g. hydrocodone) may be needed during voriconazole treatment to
avoid opioid related adverse effects. Extended and frequent monitoring for adverse effects associated
with oxycodone and other long-acting opiates metabolized by CYP3A4 is recommended.
Tacrolimus
(CYP3A4 substrate): Voriconazole increased tacrolimus (0.1 mg/kg single dose) Cmax
and AUCt (area under the plasma concentration time curve to the last quantifiable measurement) by
117 % and 221 %, respectively
.
When initiating voriconazole in patients already receiving 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.
Oral anticoagulants:
Warfarin
(CYP2C9 substrate): Coadministration of voriconazole (300 mg twice daily) with warfarin
(30 mg single dose) increased maximum prothrombin time by 93 %. Close monitoring of prothrombin
time is recommended if warfarin and voriconazole are coadministered.
Other oral anticoagulants e.g. phenprocoumon, acenocoumarol
(CYP2C9, CYP3A4 substrates):
Although not studied, voriconazole may increase the plasma concentrations of coumarins and
therefore may cause an increase in prothrombin time. If patients receiving coumarin
preparations are treated simultaneously with voriconazole, the prothrombin time should be
monitored at close intervals and the dosage of anticoagulants adjusted accordingly.
Sulphonylureas
(CYP2C9 substrates): Although not studied, voriconazole may increase the plasma
levels of sulphonylureas (e.g. tolbutamide, glipizide, and glyburide) and therefore cause
hypoglycaemia. Careful monitoring of blood glucose is recommended during coadministration.
Statins
(CYP3A4 substrates): Although not studied clinically, voriconazole has been shown to inhibit
lovastatin metabolism
in vitro
(human liver microsomes). Therefore, voriconazole is likely to increase
plasma levels of statins that are metabolised by CYP3A4. It is recommended that dose adjustment of
the statin be considered during coadministration. Increased statin levels have been associated with
rhabdomyolysis.
Benzodiazepines
(CYP3A4 substrates): Although not studied clinically, voriconazole has been shown
to inhibit midazolam metabolism
in vitro
(human liver microsomes). Therefore, voriconazole is likely
9
to increase the plasma levels of benzodiazepines that are metabolised by CYP3A4 (midazolam and
triazolam) and lead to a prolonged sedative effect. It is recommended that dose adjustment of the
benzodiazepine be considered during coadministration.
Vinca Alkaloids
(CYP3A4 substrates): Although not studied, voriconazole may increase the plasma
levels of the vinca alkaloids (e.g. vincristine and vinblastine) and lead to neurotoxicity.
Prednisolone
(CYP3A4 substrate): Voriconazole increased Cmax and AUCτ of prednisolone (60
mg single dose) by 11 % and 34 %, respectively. No dosage adjustment is recommended.
Digoxin
(P-glycoprotein mediated transport): Voriconazole had no significant effect on Cmax
and AUCτ of digoxin (0.25 mg once daily).
Mycophenolic acid
(UDP-glucuronyl transferase substrate): Voriconazole had no effect on the
Cmax and AUCt of mycophenolic acid (1 g single dose).
Non-Steroidal Anti-Inflammatory Drugs
(CYP2C9 substrates): Voriconazole increased Cmax and
AUC of ibuprofen (400 mg single dose) by 20% and 100%, respectively. Voriconazole increased
Cmax and AUC of diclofenac (50 mg single dose) by 114% and 78%, respectively. Frequent
monitoring for adverse events and toxicity related to NSAIDs is recommended. Adjustment of dosage
of NSAIDs may be needed.
Two-way interactions
Phenytoin
(CYP2C9 substrate and potent CYP450 inducer): Concomitant use of voriconazole and
phenytoin should be avoided unless the benefit outweighs the risk. Phenytoin (300 mg once daily)
decreased the Cmax and AUCτ of voriconazole by 49 % and 69 %, respectively. Voriconazole (400
mg twice daily, see section 4.2) increased Cmax and AUCτ of phenytoin (300 mg once daily) by 67 %
and 81 %, respectively. Careful monitoring of phenytoin plasma levels is recommended when
phenytoin is coadministered with voriconazole.
Phenytoin may be coadministered with voriconazole if the maintenance dose of voriconazole is
increased to 5 mg/kg intravenously twice daily or from 200 mg to 400 mg orally, twice daily (100 mg
to 200 mg orally, twice daily in patients less than 40 kg), see section 4.2.
Rifabutin
(CYP450 inducer): Concomitant use of voriconazole and rifabutin should be avoided unless
the benefit outweighs the risk. Rifabutin (300 mg once daily) decreased the Cmax and AUCτ of
voriconazole at 200 mg twice daily by 69 % and 78 %, respectively. During coadministration with
rifabutin, the Cmax and AUCτ of voriconazole at 350 mg twice daily were 96 % and 68 % of the
levels when administered alone at 200 mg twice daily. At a voriconazole dose of 400 mg twice daily
Cmax and AUCτ were 104 % and 87 % higher, respectively, compared with voriconazole alone at 200
mg twice daily. Voriconazole at 400 mg twice daily increased Cmax and AUCτ of rifabutin by 195 %
and 331 %, respectively.
If rifabutin coadministration with voriconazole is justified then the maintenance dose of voriconazole
may be increased to 5 mg/kg intravenously twice daily or from 200 mg to 350 mg orally, twice daily
(100 mg to 200 mg orally, twice daily in patients less than 40 kg) (see section 4.2). Careful monitoring
of full blood counts and adverse events to rifabutin (e.g. uveitis) is recommended when rifabutin is
coadministered with voriconazole.
Omeprazole
(CYP2C19 inhibitor; CYP2C19 and CYP3A4 substrate): Omeprazole (40 mg once daily)
increased voriconazole Cmax and AUCτ by 15 % and 41 %, respectively. No dosage adjustment of
voriconazole is recommended. Voriconazole increased omeprazole Cmax and AUCτ by 116 % and
280 %, respectively. When initiating voriconazole in patients already receiving omeprazole, it is
recommended that the omeprazole dose be halved. The metabolism of other proton pump inhibitors
which are CYP2C19 substrates may also be inhibited by voriconazole.
10
Oral Contraceptives
: Coadministration of voriconazole and an oral contraceptive (1 mg norethisterone
and 0.035 mg ethinylestradiol; once daily) in healthy female subjects resulted in increases in the Cmax
and AUCτ of ethinylestradiol (36 % and 61 % respectively) and norethisterone (15 % and 53 %
respectively). Voriconazole Cmax and AUCτ increased by 14 % and 46 % respectively. It is expected
that the voriconazole levels will return to standard levels during the pill-free week. As the ratio
between norethisterone and ethinylestradiol remained similar during interaction with voriconazole,
their contraceptive activity would probably not be affected. Although no increase in the incidence of
hormonal related adverse events was observed in the clinical interaction study, higher estrogen and
progestagen levels may cause notably nausea and menstrual disorders. Oral contraceptives containing
doses other than 1 mg norethisterone and 0.035 mg ethinylestradiol have not been studied.
Fluconazole
(CYP2C9, CYP2C19 and CYP3A4 inhibitor)
:
Coadministration of oral voriconazole
(400 mg every12 hours for 1 day, then 200 mg every 12 hours for 2.5 days) and oral fluconazole (400
mg on day 1, then 200 mg every 24 hours for 4 days) to 8 healthy male subjects resulted in an increase
in Cmax and AUCτ of voriconazole by an average of 57% (90% CI: 20%, 107%) and 79% (90% CI:
40%, 128%), respectively. The reduced dose and/or frequency of voriconazole and fluconazole that
would eliminate this effect have not been established. Monitoring for voriconazole associated adverse
events is recommended if voriconazole is used sequentially after fluconazole.
Antiretroviral Agents:
Indinavir
(CYP3A4 inhibitor and substrate): Indinavir (800 mg three times daily) had no significant
effect on voriconazole Cmax, Cmin and AUCτ. Voriconazole did not have a significant effect on
Cmax and AUCτ of indinavir (800 mg three times daily).
Other HIV protease inhibitors
(CYP3A4 inhibitors): In vitro studies suggest that voriconazole may
inhibit the metabolism of HIV protease inhibitors (e.g. saquinavir, amprenavir and nelfinavir). In vitro
studies also show that the metabolism of voriconazole may be inhibited by HIV protease inhibitors.
However results of the combination of voriconazole with other HIV protease inhibitors cannot be
predicted in humans only from
in vitro
studies. Patients should be carefully monitored for any
occurrence of drug toxicity and/or loss of efficacy during the co-administration of voriconazole and
HIV protease inhibitors.
Efavirenz
(a non-nucleoside reverse transcriptase inhibitor) (CYP450 inducer; CYP3A4 inhibitor and
substrate): Standard doses of voriconazole and standard doses of efavirenz must not be coadministered
Steady-state efavirenz (400 mg orally once daily) decreased the steady state Cmax and AUCτ of
voriconazole by an average of 61 % and 77 %, respectively, in healthy subjects. In the same study
voriconazole at steady state increased the steady state Cmax and AUCτ of efavirenz by an average of
38 % and 44 % respectively, in healthy subjects
.
In a separate study in healthy subjects, voriconazole dose of
300mg BID in combination with low dose
efavirenz (300 mg once daily) did not lead to sufficient voriconazole exposure.
Following coadministration of voriconazole 400 mg twice daily with efavirenz 300 mg orally once
daily, in healthy subjects, the AUCτ of voriconazole was decreased by 7 % and Cmax was increased
by 23 %, compared to voriconazole 200 mg twice daily alone. (The AUCτ of efavirenz was
increased by 17 % and Cmax was equivalent compared to efavirenz 600 mg once daily alone). These
differences were not considered to be clinically significant.
When voriconazole is coadministered with efavirenz, voriconazole maintenance dose should be
increased to 400 mg twice daily and the efavirenz dose should be reduced by 50 %, i.e. to 300 mg
once daily (see section 4.2).
When treatment with voriconazole is stopped, the initial dosage of efavirenz should be restored.
11
Non-nucleoside reverse transcriptase inhibitors (NNRTI)
(CYP3A4 substrates, inhibitors or CYP450
inducers):
In vitro
studies show that the metabolism of voriconazole may be inhibited by delavirdine.
Although not studied, the metabolism of voriconazole may be induced by nevirapine. An in-vivo
study showed that voriconazole inhibited the metabolism of efavirenz. Voriconazole may also inhibit
the metabolism of NNRTIs besides efavirenz. Patients should be carefully monitored for any
occurrence of drug toxicity and/or lack of efficacy during the coadministration of voriconazole and
NNRTIs.
Dose adjustments are required when voriconazole is co-administered with efavirenz (see sections 4.2
and 4.4).
Pregnancy
There are no adequate data from the use of VFEND in pregnant women.
Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is
unknown.
VFEND must not be used during pregnancy unless the benefit to the mother clearly outweighs the
potential risk to the foetus.
Women of child-bearing potential
Women of child-bearing potential must always use effective contraception during treatment.
Lactation
The excretion of voriconazole into breast milk has not been investigated. Breast-feeding must be
stopped on initiation of treatment with VFEND.
VFEND may have a 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.
The safety profile of voriconazole is based on an integrated safety database of more than 2000 subjects
(1655 patients in therapeutic 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.
Five hundred and sixty one patients had a duration of voriconazole therapy of greater than 12 weeks,
with 136 patients receiving voriconazole for over 6 months.
In the table below, since the majority of the studies were of an open nature all causality adverse
events, by system organ class and frequency (very common ≥1/10, common ≥1/100 and <1/10,
uncommon ≥1/1000 and <1/100, rare, ≥1/10 000 and <1/1000 and very rare, <1/10 000 if possibly
causally related are listed.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
The most commonly reported adverse events were visual disturbances, pyrexia, rash, vomiting,
nausea, diarrhoea, headache, peripheral oedema and abdominal pain.
The severity of the adverse events was generally mild to moderate. No clinically significant
differences were seen when the safety data were analysed by age, race, or gender.
12
System Organ Class
Adverse drug reactions
Infections and infestation
Common
Gastroenteritis, influenza-like illness
Rare
Pseudomembranous colitis
Blood and Lymphatic system disorders
Common
Pancytopenia, bone marrow depression,
leukopenia, thrombocytopenia, anaemia, purpura,
Uncommon
Disseminated intravascular coagulation,
agranulocytosis, lymphadenopathy, eosinophilia
Immune system disorders
Common
Sinusitis
Uncommon
Anaphylactoid reaction, hypersensitivity
Endocrine disorders
Uncommon
Adrenal insufficiency
Rare
Hyperthyroidism, hypothyroidism
Metabolism and nutrition system disorders
Common
Hypoglycaemia, hypokalaemia
Psychiatric disorders
Common
Depression, hallucination, anxiety
Rare
Insomnia
Nervous system disorders
Very common
Headache
Dizziness, confusional state, tremor, agitation,
paraesthesia
Common
Brain oedema, ataxia, diplopia, vertigo,
hypoaesthesia
Uncommon
Rare
Convulsion, encephalopathy, Guillain-Barre
syndrome, extrapyramidal symptoms, peripheral
neuropathy
Eye disorders
Very common
Visual disturbances (including blurred vision (see
Section 4.4), chromatopsia and photophobia)
Uncommon
Papilloedema (see Section 4.4), optic nerve
disorder (including optic neuritis, see Section 4.4),
nystagmus, scleritis, blepharitis
Rare
Optic atrophy, retinal haemorrhage, oculogyration,
corneal opacity
Ear and labyrinth disorders
Rare
Hypoacusis, tinnitus
Cardiac disorders
Very common
Oedema peripheral
13
Uncommon
Ventricular fibrillation, ventricular arrhythmia,
syncope, supraventricular arrhythmia,
supraventricular tachycardia, tachycardia,
bradycardia
Rare
Torsades de pointes, ventricular tachycardia,
atrioventricular complete block, bundle branch
block, nodal rhythm
Vascular disorders
Common
Thrombophlebitis, hypotension, phlebitis
Rare
Lymphangitis
Respiratory, thoracic and mediastinal disorders
Common
Acute respiratory distress syndrome, pulmonary
oedema, respiratory distress, chest pain
Gastrointestinal disorders
Very common
Abdominal pain, nausea, vomiting, diarrhoea
Uncommon
Pancreatitis, peritonitis, duodenitis, gingivitis,
glossitis, swollen tongue, dyspepsia, constipation
Rare
Dysgeusia
Hepato-biliary disorders
Common
Jaundice, cholestatic jaundice
Uncommon
Hepatic failure, hepatitis, hepatomegaly,
cholecystitis, cholelithiasis
Rare
Hepatic coma
Skin and subcutaneous tissue disorders
Very common
Rash
Common
Exfoliative dermatitis, face oedema,
photosensitivity reaction, maculo-papular rash,
macular rash, papular rash, cheilitis, pruritus,
alopecia, erythema
Uncommon
Stevens-Johnson syndrome, angioneurotic oedema,
allergic dermatitis, urticaria, drug hypersensitivity,
psoriasis
Rare
Toxic epidermal necrolysis, erythema multiforme,
discoid lupus erythematosis, pseudoporphyria
Musculoskeletal and connective tissue disorders
Common
Back pain
Uncommon
Arthritis
Rare
Hypertonia
Renal and urinary disorders
Common
Renal failure acute, haematuria
Uncommon
Proteinuria, nephritis
Rare
Renal tubular necrosis
General disorders and administrative site conditions
Very common
Pyrexia
Common
Injection site reaction / inflammation, chills,
asthenia
14
Investigations
Common
Elevated liver function tests (including ASAT,
ALAT, alkaline phosphatase, GGT, LDH,
bilirubin), blood creatinine increased
Uncommon
Electrocardiogram QT corrected interval
prolonged, blood urea increased, blood cholesterol
increased
Visual disturbances
In clinical trials, voriconazole treatment-related visual disturbances were very common. In these
studies, short-term as well as long-term treatment, approximately 30 % of subjects experienced
altered/enhanced visual perception, blurred vision, colour vision change or photophobia. These visual
disturbances were transient and fully reversible, with the majority spontaneously resolving within 60
minutes and no clinically significant long-term visual effects were observed. There was evidence of
attenuation with repeated doses of voriconazole. The visual disturbances were generally mild, rarely
resulted in discontinuation and were not associated with long-term sequelae. Visual disturbances may
be associated with higher plasma concentrations and/or doses.
The mechanism of action is unknown, although the site of action is most likely to be within the retina.
In a study in healthy volunteers investigating the impact of voriconazole on retinal function,
voriconazole caused a decrease in the electroretinogram (ERG) waveform amplitude. The ERG
measures electrical currents in the retina. The ERG changes did not progress over 29 days of treatment
and were fully reversible on withdrawal of voriconazole.
Dermatological reactions
Dermatological reactions were common in patients treated with voriconazole in clinical trials, but
these patients had serious underlying diseases and were receiving multiple concomitant medications.
The majority of rashes were of mild to moderate severity. Patients have rarely developed serious
cutaneous reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema
multiforme during treatment with VFEND.
If patients develop a rash they should be monitored closely and VFEND discontinued if lesions
progress. Photosensitivity reactions have been reported, especially during long-term therapy (see also
section 4.4).
Liver Function Tests
The overall incidence of clinically significant transaminase abnormalities in the voriconazole clinical
programme was 13.4 % (200/1493) of subjects treated with voriconazole. Liver function test
abnormalities may be associated with higher plasma concentrations and/or doses. The majority of
abnormal liver function tests either resolved during treatment without dose adjustment or following
dose adjustment, including discontinuation of therapy.
Voriconazole has been infrequently associated with cases of serious hepatic toxicity in patients with
other serious underlying conditions. This includes cases of jaundice, and rare cases of hepatitis and
hepatic failure leading to death (see section 4.4).
Paediatric Use
The safety of voriconazole was investigated in 245 paediatric patients aged 2 to <12 years who were
treated with voriconazole in pharmacokinetic studies (87 paediatric patients) and in compassionate use
programs (158 paediatric patients). The adverse event profile of these 245 paediatric patients was
similar to that in adults, although post-marketing data suggest there might be a higher occurrence of
skin reactions (esp. 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
events (for which a relationship to voriconazole could not be excluded) were reported: photosensitivity
15
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.
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 event
of photophobia of 10 minutes duration was reported.
There is no known antidote to voriconazole.
Voriconazole is haemodialysed with a clearance of 121 ml/min. In an overdose, haemodialysis may
assist in the removal of voriconazole from the body.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: ATC code: J02A C03 Antimycotics for Systemic Use – Triazole
derivatives
Mechanism of action
I
n vitro
, voriconazole displays broad-spectrum antifungal activity with antifungal potency against
Candida
species (including fluconazole resistant
C. krusei
and resistant strains of
C. glabrata
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. Its mode of
action is inhibition of fungal cytochrome P450-mediated 14α-sterol demethylation, an essential step in
ergosterol biosynthesis.
Microbiology
Clinical efficacy (with partial or complete response, see below under Clinical Experience) 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 (with often 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.
, Histoplasma capsulatum,
with most strains being inhibited by
concentrations of voriconazole in the range 0.05 to 2µg/ml.
In vitro
activity against the following pathogens has been shown, but the clinical significance is
unknown:
Curvularia
spp. and
Sporothrix
spp.
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
16
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 MICs of less than 1
mg/L for voriconazole.
However, the
in vitro
activity of voriconazole against
Candida
species is not uniform. Specifically,
for
C. glabrata,
the MICs of voriconazole for fluconazole-resistant isolates are proportionally higher
than are those of fluconazole-susceptible isolates. Therefore, every attempt should be made to identify
Candida
to species level. If antifungal susceptibility testing is available, the MIC results may be
interpreted using breakpoint criteria established by European Committee on Antimicrobial
Susceptibility Testing (EUCAST).
EUCAST Breakpoints
Candida Species
MIC breakpoint (mg/L)
≤S (Susceptible)
>R (Resistant)
Candida albicans
1
0.125
0.125
Candida tropicalis
1
0.125
0.125
Candida parapsilosis
1
0.125
0.125
Candida glabrata
2
Insufficient evidence
Candida krusei
3
Insufficient evidence
Other Candida spp.
4
Insufficient evidence
1
Strains with MIC values above the Susceptible (S) breakpoint are rare, or
not yet reported. The identification and antimicrobial susceptibility tests
on any such isolate must be repeated and if the result is confirmed the
isolate sent to a reference laboratory.
2
In clinical studies, response to voriconazole in patients with
C glabrata
infections was 21% lower compared to
C. albicans, C. parapsilosis and C.
tropicalis.
However, this reduced response was not correlated with
elevated MICs.
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. 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).
17
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 five 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 medication was defined as
resolution/improvement in all clinical signs and symptoms of infection with eradication of
Candida
from blood and infected deep tissue sites at 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
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; two of them had a
18
successful outcome.
The majority of patients receiving voriconazole treatment of the above mentioned rare infections were
intolerant of, or refractory to, prior antifungal therapy.
Duration of treatment
In clinical trials, 561 patients received voriconazole therapy for greater than 12 weeks, with 136
patients receiving voriconazole for over 6 months.
Experience in paediatric patients
Sixty one paediatric patients aged 9 months up to 15 years who had definite or probable invasive
fungal infections, were treated with voriconazole. This population included 34 patients 2 to < 12 years
old and 20 patients 12-15 years of age.
The majority (57/61) had failed previous antifungal therapies. Therapeutic studies included 5 patients
aged 12-15 years, the remaining patients received voriconazole in the compassionate use programmes.
Underlying diseases in these patients included haematological malignancies and aplastic anaemia (27
patients) and chronic granulomatous disease (14 patients). The most commonly treated fungal
infection was aspergillosis (43/61; 70 %).
Clinical Studies Examining QT Interval
A placebo-controlled, randomized, single-dose, crossover study to evaluate the effect on the QT
interval of healthy volunteers was conducted with three oral doses of voriconazole and ketoconazole.
The placebo-adjusted mean maximum increases in QTc from baseline after 800, 1200 and 1600 mg of
voriconazole were 5.1, 4.8, and 8.2 msec, respectively and 7.0 msec for ketoconazole 800 mg. No
subject in any group had an increase in QTc of ≥60 msec from baseline. No subject experienced an
interval exceeding the potentially clinically relevant threshold of 500 msec.
5.2 Pharmacokinetic properties
General pharmacokinetic characteristics
The pharmacokinetics of voriconazole have been characterised in healthy subjects, special populations
and patients. During oral administration of 200 mg or 300 mg twice daily for 14 days in patients at risk
of aspergillosis (mainly patients with malignant neoplasms of lymphatic or haematopoietic tissue), the
observed pharmacokinetic characteristics of rapid and consistent absorption, accumulation and non-
linear pharmacokinetics were in agreement with those observed in healthy subjects.
The pharmacokinetics of voriconazole are non-linear due to saturation of its metabolism. Greater than
proportional increase in exposure is observed with increasing dose. It is estimated that, on average,
increasing the oral dose from 200 mg twice daily to 300 mg twice daily leads to a 2.5-fold increase in
exposure (AUCτ). 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
19
concentrations in all patients.
Metabolism
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 35
%. 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.
Excretion
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.
Pharmacokinetic-Pharmacodynamic relationships
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.
Pharmacokinetic-Pharmacodynamic analyses of clinical trial data identified positive associations
between plasma voriconazole concentrations and both liver function test abnormalities and visual
disturbances.
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.
20
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
The recommended oral dose in paediatrics is based on a population pharmacokinetic analysis of data
obtained from 47 immunocompromised paediatric patients aged 2 to <12 years old who were
evaluated in a pharmacokinetic study examining multiple oral suspension doses of 4 and 6 mg/kg
twice daily. A comparison of the paediatric and adult population pharmacokinetic data indicated that
in order to obtain comparable exposures to those obtained in adults following a maintenance dose of
200 mg twice daily, 200 mg of oral suspension twice daily is required in paediatric patients,
independent of body weight. In paediatric patients there is a general trend towards low bioavailability
at lower body weights and high bioavailability at higher body weights (approaching the extent
demonstrated in adults). Based on the population pharmacokinetic analysis, no dosage adjustment
according to age or weight is warranted in patients aged 2 to <12 years old at the 200 mg b.i.d. oral
suspension dosing regimen. A loading dose is not indicated in paediatric patients. 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.
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
dosing and monitoring recommendations under 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 (Child-Pugh C). See dosing and monitoring recommendations under 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 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
21
with those observed with other azole antifungal agents.
6.1 List of excipients
Tablet core:
Lactose Monohydrate
Pregelatinised Starch
Croscarmellose Sodium
Povidone
Magnesium Stearate
Film-coat:
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
No special precautions for storage.
6.5 Nature and contents of container
HDPE tablet containers of 2, 30 and 100.
Not all bottle sizes may be marketed.
PVC / Aluminium blister in cartons of 2, 10, 14, 20, 28, 30, 50, 56 and 100.
Not all pack sizes may be marketed.
6.6 Special precautions for
disposal
No special requirements.
Pfizer Limited, Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom
EU/1/02/212/001-012
22
Date of first authorisation: 21 March 2002
Date of last renewal: 21 March 2007
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMA) http://www.ema.europa.eu
23
VFEND 200 mg film-coated tablets
Each tablet contains 200 mg voriconazole.
Excipient: lactose monohydrate 253.675 mg
For a full list of excipients, see section 6.1.
White to off-white, capsule-shaped tablet, debossed “Pfizer” on one side and “VOR200”on the
reverse.
Voriconazole, is a broad spectrum, triazole antifungal agent and is indicated as follows:
Treatment of invasive aspergillosis.
Treatment of candidemia in non-neutropenic patients.
Treatment of fluconazole-resistant serious invasive
Candida
infections (including
C. krusei
).
Treatment of serious fungal infections caused by
Scedosporium
spp. and
Fusarium
spp.
VFEND should be administered primarily to patients with progressive, possibly life-threatening
infections.
VFEND film-coated tablets are to be taken at least one hour before, or one hour following, a meal.
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 film-coated tablets, 200 mg powder for solution for infusion and 40
mg/ml powder for oral suspension.
Use in 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.
24
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
6 mg/kg every 12
hours
400 mg every 12 hours 200 mg every 12 hours
Regimen
(for the first 24
hours)
(for the first 24 hours) (for the first 24 hours)
(first 24 hours)
Maintenance Dose
(after first 24
hours)
4 mg/kg twice daily 200 mg twice daily
100 mg twice daily
Dosage adjustment
If patient response 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 patients are unable to tolerate treatment at these higher doses 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.
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.
Rifabutin
may be coadministered with voriconazole if the maintenance dose of voriconazole
is 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).
Treatment should be as short as possible depending on the patients’clinical and mycological response.
For long term treatment greater than 6 months, a careful assessment of the benefit-risk balance should
events) and section 5.1 Pharmacodynamic properties (Duration of treatment).
Use in the elderly
No dose adjustment is necessary for elderly patients (see section 5.2).
Use in patients with 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 four hour haemodialysis session
does not remove sufficient amount of voriconazole to warrant dose adjustment.
25
Use in patients with hepatic impairment
No dose adjustment is necessary in patients with acute hepatic injury, manifested by elevated liver
function tests (ALAT, ASAT) (but continued monitoring of liver function tests for further elevations is
recommended).
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 VFEND
(see section 5.2).
VFEND has not been studied in patients with severe chronic hepatic cirrhosis (Child-Pugh C).
VFEND has been associated with elevations in liver function tests and clinical signs of liver damage,
such as jaundice, and must only be used in patients with severe hepatic impairment if the benefit
outweighs the potential risk. Patients with hepatic impairment must be carefully monitored for drug
toxicity (see also section 4.8).
Use in children
VFEND is not recommended for use in children below 2 years due to insufficient data on safety and
efficacy (see also sections 4.8 and 5.1).
The recommended maintenance dosing regimen in paediatric patients 2 to <12 years is as follows:
Intravenous*
Oral**
Loading Dose Regimen
No oral or intravenous loading dose is recommended
Maintenance Dose
7 mg/kg twice daily
200 mg twice daily
*Based on a population pharmacokinetic analysis in 82 immunocompromised patients aged 2 to <12
years **Based on a population pharmacokinetic analysis in 47 immunocompromised patients aged 2
to <12 years
Use in paediatric patients aged 2 to <12 years with hepatic or renal insufficiency has not been studied
(see section 4.8 and section 5.2).
These paediatric dose recommendations are based on studies in which VFEND was administered as
the powder for oral suspension. Bioequivalence between the powder for oral suspension and tablets
has not been investigated in a paediatric population. Considering the assumed limited gastro-enteric
transit time in paediatrics, 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-<12.
Adolescents (12 to 16 years of age): should be dosed as adults.
Hypersensitivity to the active substance or to any of the excipients.
Coadministration of the CYP3A4 substrates, terfenadine, astemizole, cisapride, pimozide or quinidine
with VFEND is contraindicated 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 of VFEND with rifampicin, carbamazepine and phenobarbital is contraindicated
since these medicinal products are likely to decrease plasma voriconazole concentrations significantly
(see section 4.5).
26
Coadministration of VFEND with high dose ritonavir (400 mg and above twice daily) is
contraindicated 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 of ergot alkaloids (ergotamine, dihydroergotamine), which are CYP3A4 substrates,
is contraindicated since increased plasma concentrations of these medicinal products can lead to
ergotism (see section 4.5).
Coadministration of voriconazole and sirolimus is contraindicated, since voriconazole is likely to
increase plasma concentrations of sirolimus significantly (see section 4.5).
The concomitant use of voriconazole with St John’s Wort is contraindicated (see section 4.5).
Hypersensitivity
: Caution should be used in prescribing VFEND to patients with hypersensitivity to
other azoles (see also section 4.8).
Cardiovascular:
Some azoles, including voriconazole have been associated with QT 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 medications that may have been contributory. Voriconazole should be administered with
caution to patients with potentially proarrhythmic conditions, such as
•
Congenital or acquired QT-prolongation
•
Cardiomyopathy, in particular when heart failure is present
•
Sinus bradycardia
•
Existing symptomatic arrhythmias
•
Concomitant medication that is known to prolong QT 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 QT interval of single doses of
voriconazole up to 4 times the usual daily dose. No subject experienced an interval exceeding
the potentially clinically relevant threshold of 500 msec (see section 5.1).
Hepatic toxicity
: In clinical trials, there have been uncommon cases of serious hepatic reactions
during treatment with VFEND (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 at the beginning of therapy with voriconazole and patients
who develop abnormal liver function tests during VFEND therapy must be routinely monitored for the
development of more severe hepatic injury. Patient management should include laboratory evaluation
of hepatic function (particularly liver function tests and bilirubin). Discontinuation of VFEND should
be considered if clinical signs and symptoms are consistent with liver disease development.
Monitoring of hepatic function should be carried out in both children and adults.
Visual adverse events
: There have been reports of prolonged visual adverse events, including blurred
vision, optic neuritis and papilloedema (see Section 4.8).
Renal adverse events
: Acute renal failure has been observed in severely ill patients undergoing
treatment with VFEND. Patients being treated with voriconazole are likely to be treated
27
concomitantly with nephrotoxic medications 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, hematopoietic stem cell transplantation (HSCT)), should be
monitored closely during Vfend treatment. Monitoring of serum amylase or lipase may be
considered in this clinical situation.
Dermatological adverse events:
Patients have rarely developed exfoliative cutaneous reactions, such
as Stevens-Johnson syndrome, during treatment with VFEND. If patients develop a rash they should
be monitored closely and VFEND discontinued if lesions progress.
In addition VFEND has been associated with phototoxicity and pseudoporphyria.
It is
recommended
that patients avoid intense or prolonged exposure to direct sunlight during VFEND
treatment and use measures such as protective clothing and sunscreen when appropriate. In patients
with phototoxicity and additional risk factors, including immunosuppression, squamous cell
carcinoma of the skin has been reported during long-term therapy. Physicians should therefore
consider the need to limit the exposure to VFEND (see Section 4.2 (Posology and method of
administration) and Section 5.1 Pharmacodynamic properties (Duration of treatment). If a patient
develops a skin lesion consistent with squamous cell carcinoma, VFEND discontinuation should be
considered.
Paediatric use
: Safety and effectiveness in paediatric subjects below the age of two years has not been
established (see also sections 4.8 and 5.1). Voriconazole is indicated for paediatric patients aged two
years or older. Hepatic function should be monitored in both children and adults. Oral bioavailability
may be limited in paediatric patients aged 2-<12 years with malabsorption and very low body weight
for age. In that case, intravenous voriconazole administration is recommended.
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).
Rifabutin
(CYP450 inducer): Careful monitoring of full blood counts and adverse events 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).
Methadone
(CYP3A4 substrate): Frequent monitoring for adverse events and toxicity related to
methadone, including QTc prolongation, is recommended when coadministered with voriconazole
since methadone levels increased following co-administration of voriconazole. Dose reduction of
methadone may be needed (see section 4.5).
Short Acting Opiates
(CYP3A4 substrate): Reduction in the dose of alfentanil, fentanyl and other
short acting opiates similar in structure to alfentanil and metabolised by CYP3A4 (e.g sufentanil)
should be considered when co-administered with voriconazole (see section 4.5). As the half-life of
alfentanil is prolonged in a four-fold manner in combination with voriconazoleand in an independent
published study, concomitant use of voriconazole with fentanyl resulted in an increase in the mean
AUC 0-∞ of fentanyl,
frequent monitoring for opiate-associated adverse events (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 events may be necessary (see Section
4.5).
28
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 events is
recommended if voriconazole is used sequentially after fluconazole (see Section 4.5).
Ritonavir
(potent CYP450 inducer; CYP3A4 inhibitor and substrate): Coadministration of
voriconazole and low dose ritonavir (100mg twice daily) should be avoided unless an assessment of
the benefit/risk justifies the use of voriconazole (see section 4.5, for higher doses see section 4.3).
Efavirenz
(CYP450 inducer; CYP3A4 inhibitor and substrate): When voriconazole is coadministered
with efavirenz the dose of voriconazole should be increased to 400 mg every 12 hours and that of
efavirenz should be decreased to 300 mg every 24 hours (see sections 4.2 and 4.5).
VFEND tablets contain lactose and should not be given to patients with rare hereditary problems of
galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.
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. These
results are relevant to other populations and routes of administration.
This section addresses the effects of other medicinal products on voriconazole, the effects of
voriconazole on other medicinal products and two-way interactions. The interactions for the first two
sections are presented in the following order: contraindications, those requiring dosage 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.
Effects of other medicinal products on voriconazole
Voriconazole is metabolised by cytochrome P450 isoenzymes, CYP2C19, CYP2C9 and CYP3A4.
Inhibitors or inducers of these isoenzymes may increase or decrease voriconazole plasma
concentrations respectively.
Rifampicin
(CYP450 inducer): Rifampicin (600 mg once daily) decreased the Cmax (maximum
plasma concentration) and AUCτ (area under the plasma concentration time curve within a dose
interval) of voriconazole by 93 % and 96 %, respectively. Coadministration of voriconazole and
rifampicin is contraindicated (see section 4.3)
.
Ritonavir
(potent CYP450 inducer; CYP3A4 inhibitor and substrate): The effect of the
coadministration of voriconazole (200 mg twice daily) and high dose (400 mg) and low dose (100 mg)
oral ritonavir was investigated in two separate studies in healthy volunteers. High doses of ritonavir
(400 mg twice daily) decreased the steady state Cmax and AUCτ of oral voriconazole by an average of
66 % and 82 %, whereas low doses of ritonavir (100 mg twice daily) decreased the Cmax and AUCτ
of voriconazole by an average of 24 % and 39 % respectively. Administration of voriconazole did not
have a significant effect on mean Cmax and AUCτ of ritonavir in the high dose study although a minor
decrease in steady state Cmax and AUCτ of ritonavir with an average of 25 % and 13 % respectively
was observed in the low dose ritonavir interaction study. One outlier subject with raised voriconazole
levels was identified in each of the ritonavir interaction studies. Coadministration of voriconazole and
high doses of ritonavir (400 mg and above twice daily) is contraindicated. 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 section 4.3 and 4.4).
Carbamazepine and phenobarbital
(potent CYP450 inducers): Although not studied, carbamazepine or
phenobarbital are likely to significantly decrease plasma voriconazole concentrations.
29
Coadministration of voriconazole with carbamazepine and phenobarbital is contraindicated (see
section 4.3).
Cimetidine
(non-specific CYP450 inhibitor and increases gastric pH): Cimetidine (400 mg twice
daily) increased voriconazole Cmax and AUCτ by 18 % and 23 %, respectively. No dosage
adjustment of voriconazole is recommended.
Ranitidine (
increases gastric pH): Ranitidine (150 mg twice daily) had no significant effect on
voriconazole Cmax and AUCτ.
Macrolide antibiotics
: Erythromycin (CYP3A4 inhibitor; 1 g twice daily) and azithromycin (500 mg
once daily) had no significant effect on voriconazole Cmax and AUCτ.
St John’s Wort
(CYP450 inducer; P-gp inducer): In a clinical study in healthy volunteers, St John’s
Wort exhibited a short initial inhibitory effect followed by induction of voriconazole metabolism.
After 15 days of treatment with St John’s Wort (300 mg three times daily), plasma exposure
following a single 400 mg dose of voriconazole decreased by 40-60%. Therefore, concomitant use of
voriconazole with St John’s Wort is contraindicated (see section 4.3).
Effects of voriconazole on other medicinal products
Voriconazole inhibits the activity of cytochrome P450 isoenzymes, CYP2C19, CYP2C9 and
CYP3A4. Therefore there is potential for voriconazole to increase the plasma levels of substances
metabolised by these CYP450 isoenzymes.
Voriconazole should be administered with caution in patients with concomitant medication that is
known to prolong QT interval. When there is also a potential for voriconazole to increase the plasma
levels of substances metabolised by CYP3A4 isoenzymes (certain antihistamines, quinidine,
cisapride, pimozide) co-administration is contraindicated (see section 4.3).
Terfenadine, astemizole, cisapride, pimozide and quinidine
(CYP3A4 substrates): Although not
studied, coadministration of voriconazole with terfenadine, astemizole, cisapride, pimozide, or
quinidine is contraindicated, since increased plasma concentrations of these medicinal products can
lead to QTc prolongation and rare occurrences of torsades de pointes (see section 4.3).
Sirolimus
(CYP3A4 substrate): Voriconazole increased sirolimus (2 mg single dose) Cmax and
AUCτ by 556 % and 1014 %, respectively. Coadministration of voriconazole and sirolimus is
contraindicated (see section 4.3).
Ergot alkaloids
(CYP3A4 substrates): Although not studied, voriconazole may increase the plasma
concentrations of ergot alkaloids (ergotamine and dihydroergotamine) and lead to ergotism.
Coadministration of voriconazole with ergot alkaloids is contraindicated (see section 4.3).
Ciclosporin
(CYP3A4 substrate): In stable, renal transplant recipients, voriconazole increased
ciclosporin Cmax and AUCτ by at least 13 % and 70 % respectively. When initiating voriconazole
in patients already receiving 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.
Methadone
(CYP3A4 substrate): In subjects receiving a methadone maintenance dose (32-100 mg
once daily) coadministration of oral voriconazole (400 mg twice daily for 1 day, then 200 mg twice
daily for four days) increased the Cmax and AUC of pharmacologically active R-methadone by 31
% and 47 %, respectively, whereas the Cmax and AUC of the S-enantiomer increased by
approximately 65 % and 103 %, respectively. Voriconazole plasma concentrations during
coadministration of methadone were comparable to voriconazole levels (historical data) in healthy
subjects without any comedication. Frequent monitoring for adverse events and toxicity related to
30
increased plasma concentrations of methadone, including QT prolongation, is recommended during
coadministration. Dose reduction of methadone may be needed.
Short Acting Opiates
(CYP3A4 substrate): steady-state administration of oral voriconazole increased
the AUCτ of a single dose of alfentanil by 6-fold. Reduction in the dose of alfentanil and other short
acting opiates similar in structure to alfentanil and metabolised by CYP3A4, (e.g. fentanyl and
sufentanil
)
should be considered when coadministered with voriconazole (see section 4.4).
Fentanyl (CYP3A4 substrate):
In an independent published study, concomitant use of voriconazole
(400 mg every 12 hours on Day 1, then 200 mg every 12 hours on Day 2) with a single intravenous
dose of fentanyl (5 µg/kg) resulted in an increase in the mean AUC 0-∞ of fentanyl by 1.34-fold
(range 1.12-1.60-fold). When voriconazole is co-administered with fentanyl, extended and frequent
monitoring of patients for respiratory depression and other fentanyl-associated adverse events is
recommended, and fentanyl dosage should be reduced if warranted.
Long Acting Opiates
(CYP3A4 substrate):
In an independent published study, coadministration of
multiple doses of oral voriconazole (400 mg every 12 hours, on Day 1 followed by five doses of 200
mg every 12 hours on Days 2 to 4) with a single 10 mg oral dose of oxycodone on Day 3 resulted in an
increase in the mean Cmax and AUC0–∞ of oxycodone by 1.7-fold (range 1.4- to 2.2-fold) and 3.6-
fold (range 2.7- to 5.6-fold), respectively. The mean elimination half-life of oxycodone was also
increased by 2.0-fold (range 1.4- to 2.5-fold). A reduction in oxycodone dosage
and other long-acting
opiates metabolized by CYP3A4 (e.g., hydrocodone)
may be needed during voriconazole treatment to
avoid opioid related adverse effects. Extended and frequent monitoring for adverse effects associated
with oxycodone and other long-acting opiates metabolized by CYP3A4 is recommended.
Tacrolimus
(CYP3A4 substrate): Voriconazole increased tacrolimus (0.1 mg/kg single dose) Cmax
and AUCt (area under the plasma concentration time curve to the last quantifiable measurement) by
117 % and 221 %, respectively
.
When initiating voriconazole in patients already receiving 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.
Oral anticoagulants:
Warfarin
(CYP2C9 substrate): Coadministration of voriconazole (300 mg twice daily) with warfarin
(30 mg single dose) increased maximum prothrombin time by 93 %. Close monitoring of prothrombin
time is recommended if warfarin and voriconazole are coadministered.
Other oral anticoagulants e.g. phenprocoumon, acenocoumarol
(CYP2C9, CYP3A4 substrates):
Although not studied, voriconazole may increase the plasma concentrations of coumarins and
therefore may cause an increase in prothrombin time. If patients receiving coumarin preparations are
treated simultaneously with voriconazole, the prothrombin time should be monitored at close intervals
and the dosage of anticoagulants adjusted accordingly.
Sulphonylureas
(CYP2C9 substrates): Although not studied, voriconazole may increase the plasma
levels of sulphonylureas (e.g. tolbutamide, glipizide, and glyburide) and therefore cause
hypoglycaemia. Careful monitoring of blood glucose is recommended during coadministration.
Statins
(CYP3A4 substrates): Although not studied clinically, voriconazole has been shown to inhibit
lovastatin metabolism
in vitro
(human liver microsomes). Therefore, voriconazole is likely to increase
plasma levels of statins that are metabolised by CYP3A4. It is recommended that dose adjustment of
the statin be considered during coadministration. Increased statin levels have been associated with
rhabdomyolysis.
Benzodiazepines
(CYP3A4 substrates): Although not studied clinically, voriconazole has been shown
to inhibit midazolam metabolism
in vitro
(human liver microsomes). Therefore, voriconazole is likely
31
to increase the plasma levels of benzodiazepines that are metabolised by CYP3A4 (midazolam and
triazolam) and lead to a prolonged sedative effect. It is recommended that dose adjustment of the
benzodiazepine be considered during coadministration.
Vinca Alkaloids
(CYP3A4 substrates): Although not studied, voriconazole may increase the plasma
levels of the vinca alkaloids (e.g. vincristine and vinblastine) and lead to neurotoxicity.
Prednisolone
(CYP3A4 substrate): Voriconazole increased Cmax and AUCτ of prednisolone (60
mg single dose) by 11 % and 34 %, respectively. No dosage adjustment is recommended.
Digoxin
(P-glycoprotein mediated transport): Voriconazole had no significant effect on Cmax
and AUCτ of digoxin (0.25 mg once daily).
Mycophenolic acid
(UDP-glucuronyl transferase substrate): Voriconazole had no effect on the
Cmax and AUCt of mycophenolic acid (1 g single dose).
Non-Steroidal Anti-Inflammatory Drugs
(CYP2C9 substrates): Voriconazole increased Cmax and
AUC of ibuprofen (400 mg single dose) by 20% and 100%, respectively. Voriconazole increased
Cmax and AUC of diclofenac (50 mg single dose) by 114% and 78%, respectively. Frequent
monitoring for adverse events and toxicity related to NSAIDs is recommended. Adjustment of dosage
of NSAIDs may be needed.
Two-way interactions
Phenytoin
(CYP2C9 substrate and potent CYP450 inducer): Concomitant use of voriconazole and
phenytoin should be avoided unless the benefit outweighs the risk. Phenytoin (300 mg once daily)
decreased the Cmax and AUCτ of voriconazole by 49 % and 69 %, respectively. Voriconazole (400
mg twice daily, see section 4.2) increased Cmax and AUCτ of phenytoin (300 mg once daily) by 67 %
and 81 %, respectively. Careful monitoring of phenytoin plasma levels is recommended when
phenytoin is coadministered with voriconazole.
Phenytoin may be coadministered with voriconazole if the maintenance dose of voriconazole is
increased to 5 mg /kg intravenously twice daily or from 200 mg to 400 mg orally, twice daily (100 mg
to 200 mg orally, twice daily in patients less than 40 kg), see section 4.2.
Rifabutin
(CYP450 inducer): Concomitant use of voriconazole and rifabutin should be avoided unless
the benefit outweighs the risk. Rifabutin (300 mg once daily) decreased the Cmax and AUCτ of
voriconazole at 200 mg twice daily by 69 % and 78 %, respectively. During coadministration with
rifabutin, the Cmax and AUCτ of voriconazole at 350 mg twice daily were 96 % and 68 % of the
levels when administered alone at 200 mg twice daily. At a voriconazole dose of 400 mg twice daily
Cmax and AUCτ were 104 % and 87 % higher, respectively, compared with voriconazole alone at 200
mg twice daily. Voriconazole at 400 mg twice daily increased Cmax and AUCτ of rifabutin by 195 %
and 331 %, respectively.
If rifabutin coadministration with voriconazole is justified then the maintenance dose of voriconazole
may be increased to 5 mg/kg intravenously twice daily or from 200 mg to 350 mg orally, twice daily
(100 mg to 200 mg orally, twice daily in patients less than 40 kg) (see section 4.2). Careful
monitoring of full blood counts and adverse events to rifabutin (e.g. uveitis) is recommended when
rifabutin is coadministered with voriconazole.
Omeprazole
(CYP2C19 inhibitor; CYP2C19 and CYP3A4 substrate): Omeprazole (40 mg once daily)
increased voriconazole Cmax and AUCτ by 15 % and 41 %, respectively. No dosage adjustment of
voriconazole is recommended. Voriconazole increased omeprazole Cmax and AUCτ by 116 % and
280 %, respectively. When initiating voriconazole in patients already receiving omeprazole, it is
recommended that the omeprazole dose be halved. The metabolism of other proton pump inhibitors
which are CYP2C19 substrates may also be inhibited by voriconazole.
32
Oral Contraceptives
: Coadministration of voriconazole and an oral contraceptive (1 mg norethisterone
and 0.035 mg ethinylestradiol; once daily) in healthy female subjects resulted in increases in the Cmax
and AUC of ethinylestradiol (36 % and 61 % respectively) and norethisterone (15 % and 53 %
respectively). Voriconazole Cmax and AUCτ increased by 14 % and 46 % respectively. It is expected
that the voriconazole levels will return to standard levels during the pill-free week. As the ratio
between norethisterone and ethinylestradiol remained similar during interaction with voriconazole,
their contraceptive activity would probably not be affected. Although no increase in the incidence of
hormonal related adverse events was observed in the clinical interaction study, higher estrogen and
progestagen levels may cause notably nausea and menstrual disorders. Oral contraceptives containing
doses other than 1 mg norethisterone and 0.035 mg ethinylestradiol have not been studied.
Fluconazole
(CYP2C9, CYP2C19
and CYP3A4 inhibitor):
Coadministration of oral voriconazole
(400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 2.5 days) and oral fluconazole (400
mg on day 1, then 200 mg every 24 hours for 4 days) to 8 healthy male subjects resulted in an increase
in Cmax and AUCτ of voriconazole by an average of 57% (90% CI: 20%, 107%) and 79% (90% CI:
40%, 128%), respectively. The reduced dose and/or frequency of voriconazole and fluconazole that
would eliminate this effect have not been established. Monitoring for voriconazole associated adverse
events is recommended if voriconazole is used sequentially after fluconazole.
Antiretroviral Agents:
Indinavir
(CYP3A4 inhibitor and substrate): Indinavir (800 mg three times daily) had no significant
effect on voriconazole Cmax, Cmin and AUCτ. Voriconazole did not have a significant effect on
Cmax and AUCτ of indinavir (800 mg three times daily).
Other HIV protease inhibitors
(CYP3A4 inhibitors): In vitro studies suggest that voriconazole may
inhibit the metabolism of HIV protease inhibitors (e.g. saquinavir, amprenavir and nelfinavir). In vitro
studies also show that the metabolism of voriconazole may be inhibited by HIV protease inhibitors.
However results of the combination of voriconazole with other HIV protease inhibitors cannot be
predicted in humans only from in vitro studies. Patients should be carefully monitored for any
occurrence of drug toxicity and/or loss of efficacy during the co-administration of voriconazole and
HIV protease inhibitors.
Efavirenz
(a non-nucleoside reverse transcriptase inhibitor) (CYP450 inducer; CYP3A4 inhibitor and
substrate): Standard doses of voriconazole and standard doses of efavirenz must not be
coadministered.
Steady-state efavirenz (400 mg orally once daily) decreased the steady state Cmax
and AUCτ of voriconazole by an average of 61 % and 77 %, respectively, in healthy subjects. In the
same study voriconazole at steady state increased the steady state Cmax and AUCτ of efavirenz by an
average of 38 % and 44 % respectively, in healthy subjects.
In a separate study in healthy subjects, voriconazole dose of 300 mg BID in combination with low
dose efavirenz (300 mg once daily) did not lead to sufficient voriconazole exposure.
Following coadministration of voriconazole 400 mg twice daily with efavirenz 300 mg orally once
daily, in healthy subjects, the AUCτ of voriconazole was decreased by 7 % and Cmax was increased
by 23 %, compared to voriconazole 200 mg twice daily alone. (The AUCτ of efavirenz was increased
by 17 % and Cmax was equivalent compared to efavirenz 600 mg once daily alone). These
differences were not considered to be clinically significant.
When voriconazole is coadministered with efavirenz, voriconazole maintenance dose should be
increased to 400 mg twice daily and the efavirenz dose should be reduced by 50 %, i.e. to 300 mg
once daily (see section 4.2).
When treatment with voriconazole is stopped, the initial dosage of efavirenz should be restored.
Non-nucleoside reverse transcriptase inhibitors (NNRTI)
(CYP3A4 substrates, inhibitors or CYP450
33
inducers):
In vitro
studies show that the metabolism of voriconazole may be inhibited by delavirdine.
Although not studied, the metabolism of voriconazole may be induced by nevirapine. An in-vivo study
showed that voriconazole inhibited the metabolism of efavirenz. Voriconazole may also inhibit the
metabolism of NNRTIs besides efavirenz. Patients should be carefully monitored for any occurrence
of drug toxicity and/or lack of efficacy during the coadministration of voriconazole and NNRTIs.
Dose adjustments are required when voriconazole is co-administered with efavirenz (see sections 4.2
and 4.4).
Pregnancy
No adequate information on the use of VFEND in pregnant women is available.
Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is
unknown.
VFEND must not be used during pregnancy unless the benefit to the mother clearly outweighs the
potential risk to the foetus.
Women of child-bearing potential
Women of child-bearing potential must always use effective contraception during treatment.
Lactation
The excretion of voriconazole into breast milk has not been investigated. Breast-feeding must be
stopped on initiation of treatment with VFEND.
VFEND may have a 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.
The safety profile of voriconazole is based on an integrated safety database of more than 2000 subjects
(1655 patients in therapeutic 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.
Five hundred and sixty one patients had a duration of voriconazole therapy of greater than 12 weeks,
with 136 patients receiving voriconazole for over 6 months.
In the table below, since the majority of the studies were of an open nature all causality adverse
events, by system organ class and frequency (very common ≥1/10, common ≥1/100 and <1/10,
uncommon ≥1/1000 and <1/100, rare, ≥1/10 000 and <1/1000 and very rare, <1/10 000 if possibly
causally related are listed.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
The most commonly reported adverse events were visual disturbances, pyrexia, rash, vomiting,
nausea, diarrhoea, headache, peripheral oedema and abdominal pain. The severity of the adverse
events was generally mild to moderate. No clinically significant differences were seen when the
safety data were analysed by age, race, or gender.
34
System Organ Class
Adverse drug reactions
Infections and infestation
Common
Gastroenteritis, influenza-like illness
Rare
Pseudomembranous colitis
Blood and Lymphatic system disorders
Common
Pancytopenia, bone marrow depression, leukopenia,
thrombocytopenia, anaemia, purpura
Uncommon
Disseminated intravascular coagulation, agranulocytosis,
lymphadenopathy, eosinophilia
Immune system disorders
Common
Sinusitis
Uncommon
Anaphylactoid reaction, hypersensitivity
Endocrine disorders
Uncommon
Adrenal insufficiency
Rare
Hyperthyroidism, hypothyroidism
Metabolism and nutrition system disorders
Common
Hypoglycaemia, hypokalaemia
Psychiatric disorders
Common
Depression, hallucination, anxiety
Rare
Insomnia
Nervous system disorders
Very common
Headache
Common
Dizziness, confusional state, tremor, agitation, paraesthesia
Uncommon
Brain oedema, ataxia, diplopia, vertigo, hypoaesthesia
Rare
Convulsion, encephalopathy, Guillain-Barre syndrome,
extrapyramidal symptoms, peripheral neuropathy
Eye disorders
Very common
Visual disturbances (including blurred vision (see Section
4.4), chromotopsia and photophobia)
Uncommon
Papilloedema (see Section 4.4), optic nerve disorder
(including optic neuritis, see Section 4.4), nystagmus,
scleritis, blepharitis
Rare
Optic atrophy, Retinal haemorrhage, , oculogyration, corneal
opacity
Ear and labyrinth disor
ders
Rare
Hypoacusis, tinnitus
Cardiac disorders
Very common
Oedema peripheral
Uncommon
Ventricular fibrillation, ventricular arrhythmia, syncope,
supraventricular arrhythmia, supraventricular tachycardia,
tachycardia, bradycardia
Rare
Torsades de pointes, ventricular tachycardia, atrioventricular
complete block, bundle branch block, nodal rhythm
35
Vascular disorders
Common
Thrombophlebitis, Hypotension, phlebitis
Rare
Lymphangitis
Respiratory, thoracic and mediastinal disorders
Common
Acute respiratory distress syndrome, pulmonary oedema,
respiratory distress, chest pain
Gastrointestinal disorders
Very common
Abdominal pain, nausea, vomiting, diarrhoea
Uncommon
Pancreatitis, peritonitis, duodenitis, gingivitis, glossitis,
swollen tongue, dyspepsia, constipation
Rare
Dysgeusia
Hepato-biliary disorders
Common
Jaundice, cholestatic jaundice
Uncommon
Hepatic failure, hepatitis, hepatomegaly, cholecystitis,
cholelithiasis
Rare
Hepatic coma
Skin and subcutaneous tissue disorders
Very common
Rash
Common
Exfoliative dermatitis, face oedema, photosensitivity reaction,
maculo-papular rash, macular rash, papular rash, cheilitis,
pruritus, alopecia, erythema
Uncommon
Stevens-Johnson syndrome, angioneurotic oedema, allergic
dermatitis, urticaria, drug hypersensitivity, psoriasis
Rare
Toxic epidermal necrolysis, erythema multiforme, discoid
lupus erythematosis, pseudoporphyria
Musculoskeletal and con
nective tissue disorders
Common
Back pain
Uncommon
Arthritis
Rare
Hypertonia
Renal and urinary disorders
Common
Renal failure acute, haematuria
Uncommon
Proteinuria, nephritis
Rare
Renal tubular necrosis
General disorders and a
dministrative site conditions
Very common
Pyrexia
Common
Injection site reaction / inflammation, chills, asthenia
Investigations
Common
Elevated liver function tests (including ASAT, ALAT,
alkaline phosphatase, GGT, LDH, bilirubin), blood creatinine
increased
Uncommon
Electrocardiogram QT corrected interval prolonged, blood
urea increased, blood cholesterol increased
Visual disturbances
In clinical trials, voriconazole treatment-related visual disturbances were very common. In these
studies, short-term as well as long-term treatment, approximately 30 % of subjects experienced
altered/enhanced visual perception, blurred vision, colour vision change or photophobia. These visual
36
disturbances were transient and fully reversible, with the majority spontaneously resolving within 60
minutes and no clinically significant long-term visual effects were observed. There was evidence of
attenuation with repeated doses of voriconazole. The visual disturbances were generally mild, rarely
resulted in discontinuation and were not associated with long-term sequelae. Visual disturbances may
be associated with higher plasma concentrations and/or doses.
The mechanism of action is unknown, although the site of action is most likely to be within the retina.
In a study in healthy volunteers investigating the impact of voriconazole on retinal function,
voriconazole caused a decrease in the electroretinogram (ERG) waveform amplitude. The ERG
measures electrical currents in the retina. The ERG changes did not progress over 29 days of treatment
and were fully reversible on withdrawal of voriconazole.
Dermatological reactions
Dermatological reactions were common in patients treated with voriconazole in clinical trials, but
these patients had serious underlying diseases and were receiving multiple concomitant medications.
The majority of rashes were of mild to moderate severity. Patients have rarely developed serious
cutaneous reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema
multiforme during treatment with VFEND.
If patients develop a rash they should be monitored closely and VFEND discontinued if lesions
progress. Photosensitivity reactions have been reported, especially during long-term therapy (see also
section 4.4).
Liver Function Tests
The overall incidence of clinically significant transaminase abnormalities in the voriconazole clinical
programme was 13.4 % (200/1493) of subjects treated with voriconazole. Liver function test
abnormalities may be associated with higher plasma concentrations and/or doses.
The majority of abnormal liver function tests either resolved during treatment without dose adjustment
or following dose adjustment, including discontinuation of therapy.
Voriconazole has been infrequently associated with cases of serious hepatic toxicity in patients with
other serious underlying conditions. This includes cases of jaundice, and rare cases of hepatitis and
hepatic failure leading to death (see section 4.4).
Paediatric Use
The safety of voriconazole was investigated in 245 paediatric patients aged 2 to <12 years who were
treated with voriconazole in pharmacokinetic studies (87 paediatric patients) and in compassionate use
programs (158 paediatric patients). The adverse event profile of these 245 paediatric patients was
similar to that in adults, although post-marketing data suggest there might be a higher occurrence of
skin reactions (esp. 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
events (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.
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 event
of photophobia of 10 minutes duration was reported.
There is no known antidote to voriconazole.
Voriconazole is haemodialysed with a clearance of 121 ml/min. In an overdose, haemodialysis may
assist in the removal of voriconazole from the body.
37
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: ATC code: J02A C03 Antimycotics for Systemic Use – Triazole
derivatives
Mechanism of action
I
n vitro
, voriconazole displays broad-spectrum antifungal activity with antifungal potency against
Candida
species (including fluconazole resistant
C. krusei
and resistant strains of
C. glabrata
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. Its
mode of action is inhibition of fungal cytochrome P450-mediated 14α-sterol demethylation, an
essential step in ergosterol biosynthesis.
Microbiology
Clinical efficacy (with partial or complete response, see below under Clinical Experience) 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 (with often 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.
, Histoplasma capsulatum,
with most strains being inhibited by
concentrations of voriconazole in the range 0.05 to 2µg/ml.
In vitro
activity against the following pathogens has been shown, but the clinical significance is
unknown:
Curvularia
spp. and
Sporothrix
spp.
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 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).
38
EUCAST Breakpoints
Candida Species
MIC breakpoint (mg/L)
≤S (Susceptible)
>R (Resistant)
Candida albicans
1
0.125
0.125
Candida tropicalis
1
0.125
0.125
Candida parapsilosis
1
0.125
0.125
Candida glabrata
2
Insufficient evidence
Candida krusei
3
Insufficient evidence
Other Candida spp.
4
Insufficient evidence
1
Strains with MIC values above the Susceptible (S) breakpoint are rare, or
not yet reported. The identification and antimicrobial susceptibility tests
on any such isolate must be repeated and if the result is confirmed the
isolate sent to a reference laboratory.
2
In clinical studies, response to voriconazole in patients with
C glabrata
infections was 21% lower compared to
C. albicans, C. parapsilosis and C.
tropicalis.
However, this reduced response was not correlated with
elevated MICs.
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. 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 five 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
39
assessed by a Data Review Committee (DRC) blinded to study medication was defined as
resolution/improvement in all clinical signs and symptoms of infection with eradication of
Candida
from blood and infected deep tissue sites at 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
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; two 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.
Duration of treatment
In clinical trials, 561 patients received voriconazole therapy for greater than 12 weeks, with 136
patients receiving voriconazole for over 6 months.
Experience in paediatric patients
Sixty one paediatric patients aged 9 months up to 15 years who had definite or probable invasive
fungal infections, were treated with voriconazole. This population included 34 patients 2 to < 12 years
old and 20 patients 12-15 years of age.
40
The majority (57/61) had failed previous antifungal therapies. Therapeutic studies included 5 patients
aged 12-15 years, the remaining patients received voriconazole in the compassionate use programmes.
Underlying diseases in these patients included haematological malignancies and aplastic anaemia (27
patients) and chronic granulomatous disease (14 patients). The most commonly treated fungal
infection was aspergillosis (43/61; 70 %).
Clinical Studies Examining QT Interval
A placebo-controlled, randomized, single-dose, crossover study to evaluate the effect on the QT
interval of healthy volunteers was conducted with three oral doses of voriconazole and ketoconazole.
The placebo-adjusted mean maximum increases in QTc from baseline after 800, 1200 and 1600 mg of
voriconazole were 5.1, 4.8, and 8.2 msec, respectively and 7.0 msec for ketoconazole 800 mg. No
subject in any group had an increase in QTc of ≥60 msec from baseline. No subject experienced an
interval exceeding the potentially clinically relevant threshold of 500 msec.
5.2 Pharmacokinetic properties
General pharmacokinetic characteristics
The pharmacokinetics of voriconazole have been characterised in healthy subjects, special populations
and patients. During oral administration of 200 mg or 300 mg twice daily for 14 days in patients at risk
of aspergillosis (mainly patients with malignant neoplasms of lymphatic or haematopoietic tissue), the
observed pharmacokinetic characteristics of rapid and consistent absorption, accumulation and non-
linear pharmacokinetics were in agreement with those observed in healthy subjects.
The pharmacokinetics of voriconazole are non-linear due to saturation of its metabolism. Greater than
proportional increase in exposure is observed with increasing dose. It is estimated that, on average,
increasing the oral dose from 200 mg twice daily to 300 mg twice daily leads to a 2.5-fold increase in
exposure (AUCτ). 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.
Metabolism
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 35
%. Studies conducted in Caucasian and Japanese healthy subjects have shown that poor metabolisers
41
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.
Excretion
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.
Pharmacokinetic-Pharmacodynamic relationships
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.
Pharmacokinetic-Pharmacodynamic analyses of clinical trial data identified positive associations
between plasma voriconazole concentrations and both liver function test abnormalities and visual
disturbances.
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
The recommended oral dose in paediatrics is based on a population pharmacokinetic analysis of data
42
obtained from 47 immunocompromised paediatric patients aged 2 to <12 years old who were
evaluated in a pharmacokinetic study examining multiple oral suspension doses of 4 and 6 mg/kg
twice daily. A comparison of the paediatric and adult population pharmacokinetic data indicated that
in order to obtain comparable exposures to those obtained in adults following a maintenance dose of
200 mg twice daily, 200 mg of oral suspension twice daily is required in paediatric patients,
independent of body weight. In paediatric patients there is a general trend towards low bioavailability
at lower body weights and high bioavailability at higher body weights (approaching the extent
demonstrated in adults). Based on the population pharmacokinetic analysis, no dosage adjustment
according to age or weight is warranted in patients aged 2 to <12 years old at the 200 mg b.i.d. oral
suspension dosing regimen. A loading dose is not indicated in paediatric patients.
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.
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
dosing and monitoring recommendations under 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 (Child-Pugh C). See dosing and monitoring recommendations under 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 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.
6.1 List of excipients
Tablet core:
Lactose Monohydrate
Pregelatinised Starch
Croscarmellose Sodium
43
Povidone
Magnesium Stearate
Film-coat:
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
No special precautions for storage.
6.5 Nature and contents of container
HDPE tablet containers of 2, 30 and 100. Not all bottle sizes may be marketed.
PVC / Aluminium blister in cartons of 2, 10, 14, 20, 28, 30, 50, 56 and 100.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
Pfizer Limited, Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom
EU/1/02/212/013-024
Date of first authorisation: 21 March 2002
Date of last renewal: 21 March 2007
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMA) http://www.ema.europa.eu
44
VFEND 200 mg powder for solution for infusion
Each ml contains 10 mg of voriconazole after reconstitution (see section 6.6) - once reconstituted
further dilution is required before administration.
Each vial contains 200 mg of voriconazole.
Excipient: each vial contains 217.6 mg sodium
For a full list of excipients, see section 6.1.
White lyophilised powder
Voriconazole, is a broad spectrum, triazole antifungal agent and is indicated as follows:
Treatment of invasive aspergillosis.
Treatment of candidemia in non-neutropenic patients
Treatment of fluconazole-resistant serious invasive
Candida
infections (including
C. krusei
)
Treatment of serious fungal infections caused by
Scedosporium
spp. and
Fusarium
spp.
VFEND should be administered primarily to patients with progressive, possibly life-threatening
infections.
VFEND requires reconstitution and dilution (see section 6.6) prior to administration as an intravenous
infusion. Not for bolus injection.
It is recommended that VFEND is administered at a maximum rate of 3 mg/kg per hour over 1 to 2
hours.
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 must not be infused into the same line or cannula concomitantly with other intravenous
products. VFEND must not be administered simultaneously with any blood product or any short-term
infusion of concentrated solutions of electrolytes, even if the two infusions are running in separate
lines. Total parenteral nutrition (TPN) need
not
be discontinued when prescribed with VFEND, but
does need to be infused through a separate line (see section 6.2).
45
VFEND is also available as 50 mg and 200 mg film-coated tablets and 40 mg/ml powder for oral
suspension.
Use in 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
6 mg/kg every 12
hours
400 mg every 12
hours
200 mg every 12
hours
Regimen
(for the first 24
hours)
(for the first 24
hours)
(for the first 24
hours)
(first 24 hours)
Maintenance Dose
(after first 24
hours)
4 mg/kg twice daily 200 mg twice daily 100 mg twice daily
Dosage adjustment
If patients are unable to tolerate treatment at 4 mg/kg twice daily, reduce the intravenous dose to 3
mg/kg twice daily.
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).
Treatment should be as short as possible depending on the patients’clinical andmycological
response.
The duration of treatment with the intravenous formulation should be no longer than 6 months.
See section 5.3 (preclinical safety data). For voriconazole in general, long term treatment greater
than 6 months requires careful assessment of the benefit-risk balance
.
See section 4.4 Special
warnings and precautions for use (Dermatological adverse events), section 5.1
Pharmacodynamic properties (Duration of treatment).
Use in the elderly
No dose adjustment is necessary for elderly patients (see section 5.2).
Use in patients with 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 four hour haemodialysis session
46
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.
Use in patients with hepatic impairment
No dose adjustment is necessary in patients with acute hepatic injury, manifested by elevated liver
function tests (ALAT, ASAT) (but continued monitoring of liver function tests for further elevations is
recommended).
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 VFEND
(see section 5.2).
VFEND has not been studied in patients with severe chronic hepatic cirrhosis (Child-Pugh C).
VFEND 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 also section 4.8).
Use in children
VFEND is not recommended for use in children below 2 years due to insufficient data on safety and
efficacy (see also sections 4.8 and 5.1).
The recommended maintenance dosing regimen in paediatric patients 2 to <12 years is as follows:
Intravenous*
Oral**
No oral or intravenous loading dose is recommended
Maintenance Dose
7 mg/kg twice daily
200 mg twice daily
*Based on a population pharmacokinetic analysis in 82 immunocompromised patients aged 2 to <12
years **Based on a population pharmacokinetic analysis in 47 immunocompromised patients aged 2
to <12 years
Use in paediatric patients aged 2 to <12 years with hepatic or renal insufficiency has not been studied
(see section 4.8 and section 5.2).
If paediatric patients are unable to tolerate an intravenous dose of 7 mg/kg twice daily, a dose
reduction from 7 mg/kg to 4 mg/kg twice daily may be considered based on the population
pharmacokinetic analysis and previous clinical experience. This provides equivalent exposure to 3
mg/kg twice daily in adults (see section 4.2 use in adults).
Adolescents (12 to 16 years of age): should be dosed as adults.
Hypersensitivity to the active substance or to any of the excipients
Coadministration of the CYP3A4 substrates, terfenadine, astemizole, cisapride, pimozide or quinidine
with VFEND is contraindicated 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 of VFEND with rifampicin, carbamazepine and phenobarbital is contraindicated
47
since these medicinal products are likely to decrease plasma voriconazole concentrations significantly
(see section 4.5).
Coadministration of VFEND with high dose ritonavir (400 mg and above twice daily) is
contraindicated 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 of ergot alkaloids (ergotamine, dihydroergotamine), which are CYP3A4 substrates,
is contraindicated since increased plasma concentrations of these medicinal products can lead to
ergotism (see section 4.5).
Coadministration of voriconazole and sirolimus is contraindicated, since voriconazole is likely to
increase plasma concentrations of sirolimus significantly (see section 4.5).
The concomitant use of voriconazole with St John’s Wort is contraindicated (see section 4.5).
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 (Preclinical safety data).
Cardiovascular
: Some azoles, including voriconazole have been associated with QT 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 medications that may have been contributory. Voriconazole should be administered with
caution to patients with potentially proarrhythmic conditions, such as
•
Congenital or acquired QT-prolongation
•
Cardiomyopathy, in particular when heart failure is present
•
Sinus bradycardia
•
Existing symptomatic arrhythmias
•
Concomitant medication that is known to prolong QT 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 QT interval of single doses of
voriconazole up to four 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 uncommon cases of serious hepatic reactions
during treatment with VFEND (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 at the beginning of therapy with voriconazole and patients
who develop abnormal liver function tests during VFEND therapy must be routinely monitored for the
development of more severe hepatic injury. Patient management should include laboratory evaluation
48
of hepatic function (particularly liver function tests and bilirubin). Discontinuation of VFEND should
be considered if clinical signs and symptoms are consistent with liver disease development.
Monitoring of hepatic function should be carried out in both children and adults.
Visual adverse events
: There have been reports of prolonged visual adverse events, including blurred
vision, optic neuritis and papilloedema (see Section 4.8).
Renal adverse events
: Acute renal failure has been observed in severely ill patients undergoing
treatment with VFEND. Patient being treated with voriconazole are likely to be treated concomitantly
with nephrotoxic medications 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, hematopoietic stem cell translplantation (HSCT)), should be
monitored closely during Vfend treatment. Monitoring of serum amylase or lipase may be considered
in this clinical situation.
Dermatological adverse events:
Patients have rarely developed exfoliative cutaneous reactions, such
as Stevens-Johnson syndrome, during treatment with VFEND. If patients develop a rash they should
be monitored closely and VFEND discontinued if lesions progress.
In addition VFEND has been associated with phototoxicity and pseudoporphyria.
It is
recommended
that patients avoid intense or prolonged exposure to direct sunlight during VFEND
treatment and use measures such as protective clothing and sunscreen when appropriate. In patients
with phototoxicity and additional risk factors, including immunosuppression, squamous cell
carcinoma of the skin has been reported during long-term therapy. Physicians should therefore
consider the need to limit the exposure to VFEND (see Section 4.2 Posology and method of
administration and section 5.1 Pharmacodynamic properties (Duration of treatment). If a patient
develops a skin lesion consistent with squamous cell carcinoma, VFEND discontinuation should be
considered.
Paediatric use
: Safety and effectiveness in paediatric subjects below the age of two years has not been
established (see also sections 4.8 and 5.1). Voriconazole is indicated for paediatric patients aged two
years or older. Hepatic function should be monitored in both children and adults. Oral bioavailability
may be limited in paediatric patients aged 2-<12 years with malabsorption and very low body weight
for age. In that case, intravenous voriconazole administration is recommended.
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).
Rifabutin
(CYP450 inducer): Careful monitoring of full blood counts and adverse events 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).
Methadone
(CYP3A4 substrate): Frequent monitoring for adverse events and toxicity related to
methadone, including QTc prolongation, is recommended when coadministered with voriconazole
since methadone levels increased following co-administration of voriconazole. Dose reduction of
methadone may be needed (see section 4.5).
Short Acting Opiates
(CYP3A4 substrate): Reduction in the dose of alfentanil, fentanyl and other
short acting opiates similar in structure to alfentanil and metabolised by CYP3A4 (e.g. sufentanil)
49
should be considered when co-administered with voriconazole (see section 4.5). As the half-life of
alfentanil is prolonged in a four-fold manner when alfentanyl is coadministered with voriconazole
,
and in an independent published study, concomitant use of voriconazole with fentanyl resulted in an
increase in the mean AUC 0-∞ of fentanyl
frequent monitoring for opiate-associated adverse events
(including
a longer respiratory
monitoring period) may be necessary
.
Long Acting Opitates
(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 events 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 events is
recommended if voriconazole is used sequentially after fluconazole (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 justifies the use of voriconazole (see section 4.5, for higher doses see section 4.3).
Efavirenz
(CYP450 inducer; CYP3A4 inhibitor and substrate): When voriconazole is coadministered
with efavirenz the dose of voriconazole should be increased to 400 mg every 12 hours and that of
efavirenz should be decreased to 300 mg every 24 hours (see sections 4.2 and 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.
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. These
results are relevant to other populations and routes of administration.
This section addresses the effects of other medicinal products on voriconazole, the effects of
voriconazole on other medicinal products and two-way interactions. The interactions for the first two
sections are presented in the following order: contraindications, those requiring dosage 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.
Effects of other medicinal products on voriconazole
Voriconazole is metabolised by cytochrome P450 isoenzymes, CYP2C19, CYP2C9 and CYP3A4.
Inhibitors or inducers of these isoenzymes may increase or decrease voriconazole plasma
concentrations respectively.
Rifampicin
(CYP450 inducer): Rifampicin (600 mg once daily) decreased the Cmax (maximum
plasma concentration) and AUCτ (area under the plasma concentration time curve within a dose
interval) of voriconazole by 93 % and 96 %, respectively. Coadministration of voriconazole and
rifampicin is contraindicated (see section 4.3)
.
Ritonavir
(potent CYP450 inducer; CYP3A4 inhibitor and substrate): The effect of the
coadministration of oral voriconazole (200 mg twice daily) and high dose (400 mg) and low dose (100
mg) oral ritonavir (400 mg and 100 mg) was investigated in two separate studies in healthy volunteers.
High doses of ritonavir (400 mg twice daily) decreased the steady state Cmax and AUCτ of oral
voriconazole by an average of 66 % and 82 %, whereas low doses of ritonavir (100 mg twice daily)
50
decreased the Cmax and AUCτ of oral voriconazole by an average of 24 % and 39 % respectively.
Administration of voriconazole did not have a significant effect on mean Cmax and AUCτ in the high
dose study although a minor decrease in steady state Cmax and AUCτ of ritonavir with an average of
25 % and 13 % respectively was observed in the low dose ritonavir interaction study. One outlier
subject with raised voriconazole levels was identified in each of the ritonavir interaction studies.
Coadministration of voriconazole and high doses of ritonavir (400 mg and above twice daily) is
contraindicated). Coadministration of voriconazole and low dose ritonavir (100 mg twice daily) should
be avoided unless an assessment of the benefit/risk justifies the use of voriconazole (see section 4.3
and 4.4).
Carbamazepine and phenobarbital
(potent CYP450 inducers): Although not studied, carbamazepine or
phenobarbital is likely to significantly decrease plasma voriconazole concentrations. Coadministration
of voriconazole with carbamazepine and phenobarbital is contraindicated (see section 4.3).
Cimetidine
(non-specific CYP450 inhibitor and increases gastric pH): Cimetidine (400 mg twice
daily) increased voriconazole Cmax and AUCτ by 18 % and 23 %, respectively. No dosage
adjustment of voriconazole is recommended.
Ranitidine
(increases gastric pH): Ranitidine (150 mg twice daily) had no significant effect on
voriconazole Cmax and AUCτ.
Macrolide antibiotics
: Erythromycin (CYP3A4 inhibitor; 1 g twice daily) and azithromycin (500 mg
once daily) had no significant effect on voriconazole Cmax and AUCτ.
St John’s Wort
(CYP450 inducer; P-gp inducer): In a clinical study in healthy volunteers, St John’s
Wort exhibited a short initial inhibitory effect followed by induction of voriconazole metabolism.
After 15 days of treatment with St John’s Wort (300 mg three times daily), plasma exposure
following a single 400 mg dose of voriconazole decreased by 40-60%. Therefore, concomitant use of
voriconazole with St John’s Wort is contraindicated (see section 4.3).
Effects of voriconazole on other medicinal products
Voriconazole inhibits the activity of cytochrome P450 isoenzymes, CYP2C19, CYP2C9 and
CYP3A4. Therefore there is potential for voriconazole to increase the plasma levels of substances
metabolised by these CYP450 isoenzymes.
Voriconazole should be administered with caution in patients with concomitant medication that is
known to prolong QT interval. When there is also a potential for voriconazole to increase the plasma
levels of substances metabolised by CYP3A4 isoenzymes (certain antihistamines, quinidine,
cisapride, pimozide) co-administration is contraindicated (see section 4.3).
Terfenadine, astemizole, cisapride, pimozide and quinidine
(CYP3A4 substrates): Although not
studied, coadministration of voriconazole with terfenadine, astemizole, cisapride, pimozide, or
quinidine is contraindicated, since increased plasma concentrations of these medicinal products can
lead to QTc prolongation and rare occurrences of torsades de pointes (see section 4.3).
Sirolimus
(CYP3A4 substrate): Voriconazole increased sirolimus (2 mg single dose) Cmax and
AUCτ by 556 % and 1014 %, respectively. Coadministration of voriconazole and sirolimus is
contraindicated (see section 4.3).
Ergot alkaloids
(CYP3A4 substrates): Although not studied, voriconazole may increase the plasma
concentrations of ergot alkaloids (ergotamine and dihydroergotamine) and lead to ergotism.
Coadministration of voriconazole with ergot alkaloids is contraindicated (see section 4.3).
Ciclosporin
(CYP3A4 substrate): In stable, renal transplant recipients, voriconazole increased
ciclosporin Cmax and AUCτ by at least 13 % and 70 % , respectively. When initiating voriconazole
51
in patients already receiving 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.
Methadone
(CYP3A4 substrate): In subjects receiving a methadone maintenance dose (32-100 mg
once daily) coadministration of oral voriconazole (400 mg twice daily for 1 day, then 200 mg twice
daily for four days) increased the Cmax and AUC of pharmacologically active R-methadone by 31
% and 47 %, respectively, whereas the Cmax and AUC of the S-enantiomer increased by
approximately 65 % and 103 %, respectively. Voriconazole plasma concentrations during
coadministration of methadone were comparable to voriconazole levels (historical data) in healthy
subjects without any comedication. Frequent monitoring for adverse events and toxicity related to
increased plasma concentrations of methadone, including QT prolongation, is recommended during
coadministration. Dose reduction of methadone may be needed.
Short Acting Opiates
(CYP3A4 substrate): Steady-state administration of oral voriconazole increased
the AUC∞ of a single dose of alfentanil by 6-fold. Reduction in the dose of alfentanil and other short
acting opiates similar in structure to alfentanil and metabolised by CYP3A4 (e.g fentanyl and
sufentanil), should be considered when coadministered with voriconazole (see section 4.4).
Fentanyl (CYP3A4 substrate):
In an independent published study, concomitant use of voriconazole
(400 mg every 12 hours on Day 1, then 200 mg every 12 hours on Day 2) with a single intravenous
dose of fentanyl (5 µg/kg) resulted in an increase in the mean AUC 0-∞ of fentanyl by 1.34-fold
(range 1.12-1.60-fold). When voriconazole is co-administered with fentanyl, extended and frequent
monitoring of patients for respiratory depression and other fentanyl-associated adverse events is
recommended, and fentanyl dosage should be reduced if warranted.
Long Acting Opiates
(CYP3A4 substrate):
In an independent published study, coadministration of
multiple doses of oral voriconazole (400 mg every 12 hours, on Day 1 followed by five doses of 200
mg every 12 hours on Days 2 to 4) with a single 10 mg oral dose of oxycodone on Day 3 resulted in an
increase in the mean Cmax and AUC0–∞ of oxycodone by 1.7-fold (range 1.4- to 2.2-fold) and 3.6-
fold (range 2.7- to 5.6-fold), respectively. The mean elimination half-life of oxycodone was also
increased by 2.0-fold (range 1.4- to 2.5-fold). A reduction in oxycodone dosage
and other long-acting
opiates metabolized by CYP3A4 (e.g., hydrocodone)
may be needed during voriconazole treatment to
avoid opioid related adverse effects. Extended and frequent monitoring for adverse effects associated
with oxycodone and other long-acting opiates metabolized by CYP3A4 is recommended.
Tacrolimus
(CYP3A4 substrate): Voriconazole increased tacrolimus (0.1 mg/kg single dose) Cmax
and AUCt (area under the plasma concentration time curve to the last quantifiable measurement) by
117 % and 221 %, respectively
.
When initiating voriconazole in patients already receiving 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.
Oral anticoagulants:
Warfarin (CYP2C9 substrate): Coadministration of voriconazole (300 mg twice
daily) with warfarin (30 mg single dose) increased maximum prothrombin time by 93 %. Close
monitoring of prothrombin time is recommended if warfarin and voriconazole are coadministered.
Other oral anticoagulants e.g. phenprocoumon, acenocoumarol
(CYP2C9, CYP3A4 substrates):
Although not studied, voriconazole may increase the plasma concentrations of coumarins and
therefore may cause an increase in prothrombin time. If patients receiving coumarin preparations are
treated simultaneously with voriconazole, the prothrombin time should be monitored at close intervals
and the dosage of anticoagulants adjusted accordingly.
Sulphonylureas
(CYP2C9 substrates): Although not studied, voriconazole may increase the plasma
52
levels of sulphonylureas (e.g. tolbutamide, glipizide, and glyburide) and therefore cause
hypoglycaemia. Careful monitoring of blood glucose is recommended during coadministration.
Statins
(CYP3A4 substrates): Although not studied clinically, voriconazole has been shown to inhibit
lovastatin metabolism
in vitro
(human liver microsomes). Therefore, voriconazole is likely to increase
plasma levels of statins that are metabolised by CYP3A4. It is recommended that dose adjustment of
the statin be considered during coadministration. Increased statin levels have been associated with
rhabdomyolysis.
Benzodiazepines
(CYP3A4 substrates): Although not studied clinically, voriconazole has been shown
to inhibit midazolam metabolism
in vitro
(human liver microsomes). Therefore, voriconazole is likely
to increase the plasma levels of benzodiazepines that are metabolised by CYP3A4 (e.g. midazolam
and triazolam) and lead to a prolonged sedative effect. It is recommended that dose adjustment of the
benzodiazepine be considered during coadministration.
Vinca Alkaloids
(CYP3A4 substrates): Although not studied, voriconazole may increase the plasma
levels of the vinca alkaloids (e.g. vincristine and vinblastine) and lead to neurotoxicity.
Prednisolone
(CYP3A4 substrate): Voriconazole increased Cmax and AUCτ of prednisolone (60
mg single dose) by 11 % and 34 %, respectively. No dosage adjustment is recommended.
Digoxin
(P-glycoprotein mediated transport): Voriconazole had no significant effect on Cmax
and AUCτ of digoxin (0.25 mg once daily).
Mycophenolic acid
(UDP-glucuronyl transferase substrate): Voriconazole had no effect on the
Cmax and AUCt of mycophenolic acid (1 g single dose).
Non-Steroidal Anti-Inflammatory Drugs
(CYP2C9 substrates): Voriconazole increased Cmax and
AUC of ibuprofen (400 mg single dose) by 20% and 100%, respectively. Voriconazole increased
Cmax and AUC of diclofenac (50 mg single dose) by 114% and 78%, respectively. Frequent
monitoring for adverse events and toxicity related to NSAIDs is recommended. Adjustment of dosage
of NSAIDs may be needed.
Two-way interactions
Phenytoin
(CYP2C9 substrate and potent CYP450 inducer): Concomitant use of voriconazole and
phenytoin should be avoided unless the benefit outweighs the risk. Phenytoin (300 mg once daily)
decreased the Cmax and AUCτ of voriconazole by 49 % and 69 %, respectively. Voriconazole (400
mg twice daily, see section 4.2) increased Cmax and AUCτ of phenytoin (300 mg once daily) by 67 %
and 81 %, respectively. Careful monitoring of phenytoin plasma levels is recommended when
phenytoin is coadministered with voriconazole.
Phenytoin may be coadministered with voriconazole if the maintenance dose of voriconazole is
increased to 5 mg /kg intravenously twice daily or from 200 mg to 400 mg orally, twice daily (100 mg
to 200 mg orally, twice daily in patients less than 40 kg), see section 4.2.
Rifabutin
(CYP450 inducer): Concomitant use of voriconazole and rifabutin should be avoided unless
the benefit outweighs the risk. Rifabutin (300 mg once daily) decreased the Cmax and AUCτ of
voriconazole at 200 mg twice daily by 69 % and 78 %, respectively. During coadministration with
rifabutin, the Cmax and AUCτ of voriconazole at 350 mg twice daily were 96 % and 68 % of the
levels when administered alone at 200 mg twice daily. At a voriconazole dose of 400 mg twice daily C
max and AUCτ were 104 % and 87 % higher, respectively, compared with voriconazole alone at 200
mg twice daily. Voriconazole at 400 mg twice daily increased Cmax and AUCτ of rifabutin by 195 %
and 331 %, respectively.
If rifabutin coadministration with voriconazole is justified then the maintenance dose of voriconazole
53
may be increased to 5 mg/kg intravenously twice daily or from 200 mg to 350 mg orally, twice daily
(100 mg to 200 mg orally, twice daily in patients less than 40kg) (see section 4.2). Careful monitoring
of full blood counts and adverse events to rifabutin (e.g. uveitis) is recommended when rifabutin is
coadministered with voriconazole.
Omeprazole
(CYP2C19 inhibitor; CYP2C19 and CYP3A4 substrate): Omeprazole (40 mg once daily)
increased voriconazole Cmax and AUCτ by 15 % and 41 %, respectively. No dosage adjustment of
voriconazole is recommended. Voriconazole increased omeprazole Cmax and AUCτ by 116 % and
280 %, respectively. When initiating voriconazole in patients already receiving omeprazole, it is
recommended that the omeprazole dose be halved. The metabolism of other proton pump inhibitors
which are CYP2C19 substrates may also be inhibited by voriconazole.
Oral Contraceptives
: Coadministration of voriconazole and an oral contraceptive (1 mg norethisterone
and 0.035 mg ethinylestradiol; once daily) in healthy female subjects resulted in increases in the Cmax
and AUCτ of ethinylestradiol (36 % and 61 % respectively) and norethisterone (15 % and 53 %
respectively).
Voriconazole Cmax and AUCτ increased by 14 % and 46 % respectively. It is expected that the
voriconazole levels will return to standard levels during the pill-free week. As the ratio between
norethisterone and ethinylestradiol remained similar during interaction with voriconazole, their
contraceptive activity would probably not be affected. Although no increase in the incidence of
hormonal related adverse events was observed in the clinical interaction study, higher estrogen and
progestagen levels may cause notably nausea and menstrual disorders. Oral contraceptives containing
doses other than 1 mg norethisterone and 0.035 mg ethinylestradiol have not been studied.
Fluconazole
(CYP2C9, CYP2C19
and CYP3A4 inhibitor)
:
Coadministration of oral voriconazole
(400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 2.5 days) and oral fluconazole (400
mg on day 1, then 200 mg every 24 hours for 4 days) to 8 healthy male subjects resulted in an increase
in Cmax and AUCτ of voriconazole by an average of 57% (90% CI: 20%, 107%) and 79% (90% CI:
40%, 128%), respectively. The reduced dose and/or frequency of voriconazole and fluconazole that
would eliminate this effect have not been established.
Monitoring for voriconazole associated adverse
events is recommended if voriconazole is used sequentially after fluconazole
Antiretroviral Agents:
Indinavir
(CYP3A4 inhibitor and substrate): Indinavir (800 mg three times daily) had no significant
effect on voriconazole Cmax , Cmin and AUCτ. Voriconazole did not have a significant effect on
Cmax and AUCτ of indinavir (800 mg three times daily).
Other HIV protease inhibitors
(CYP3A4 inhibitors):
In vitro
studies suggest that voriconazole may
inhibit the metabolism of HIV protease inhibitors (e.g. saquinavir, amprenavir and nelfinavir).
In vitro
studies also show that the metabolism of voriconazole may be inhibited by HIV protease inhibitors.
However results of the combination of voriconazole with other HIV protease inhibitors cannot be
predicted in humans only from
in vitro
studies. Patients should be carefully monitored for any
occurrence of drug toxicity and/or loss of efficacy during the co-administration of voriconazole and
HIV protease inhibitors.
Efavirenz
(a non-nucleoside reverse transcriptase inhibitor) (CYP450 inducer; CYP3A4 inhibitor and
substrate): Standard doses of voriconazole and standard doses of efavirenz must not be
coadministered.
Steady-state efavirenz (400 mg orally once daily) decreased the steady state Cmax
and AUCτ of voriconazole by an average of 61 % and 77 %, respectively, in healthy subjects. In the
same study voriconazole at steady state increased the steady state Cmax and AUCτ of efavirenz by an
average of 38 % and 44 % respectively, in healthy subjects.
In a separate study in healthy subjects voriconazole dose of 300 mg BID in combination with low dose
efavirenz (300 mg once daily) did not lead to sufficient voriconazole exposure.
54
Following coadministration of voriconazole 400 mg twice daily with efavirenz 300 mg orally once
daily, in healthy subjects, the AUCτ of voriconazole was decreased by 7 % and Cmax was increased
by 23 %, compared to voriconazole 200 mg twice daily alone. (The AUCτ of efavirenz was increased
by 17 % and Cmax was equivalent compared to efavirenz 600 mg once daily alone). These
differences were not considered to be clinically significant.
When voriconazole is coadministered with efavirenz, voriconazole maintenance dose should be
increased to 400 mg twice daily and the efavirenz dose should be reduced by 50 %, i.e. to 300 mg
once daily (see section 4.2). When treatment with voriconazole is stopped, the initial dosage of
efavirenz should be restored.
Non-nucleoside reverse transcriptase inhibitors (NNRTI)
(CYP3A4 substrates, inhibitors or CYP450
inducers):
In vitro
studies show that the metabolism of voriconazole may be inhibited by delavirdine.
Although not studied, the metabolism of voriconazole may be induced by nevirapine. An in-vivo study
showed that voriconazole inhibited the metabolism of efavirenz. Voriconazole may also inhibit the
metabolism of NNRTIs besides efavirenz. Patients should be carefully monitored for any occurrence
of drug toxicity and/or lack of efficacy during the coadministration of voriconazole and NNRTIs.
Dose adjustments are required when voriconazole is co-administered with efavirenz (see sections 4.2
and 4.4).
Pregnancy
No adequate information on the use of VFEND in pregnant women is available.
Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is
unknown.
VFEND must not be used during pregnancy unless the benefit to the mother clearly outweighs the
potential risk to the foetus.
Women of child-bearing potential
Women of child-bearing potential must always use effective contraception during treatment.
Lactation
The excretion of voriconazole into breast milk has not been investigated. Breast-feeding must be
stopped on initiation of treatment with VFEND.
VFEND may have a 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.
The safety profile of voriconazole is based on an integrated safety database of more than 2000
subjects (1655 patients in therapeutic 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. Five hundred and sixty one patients had a duration of voriconazole therapy of greater than
12 weeks, with 136 patients receiving voriconazole for over 6 months.
55
In the table below, since the majority of the studies were of an open nature all causality adverse
events, by system organ class and frequency (very common ≥1/10, common ≥1/100 and <1/10,
uncommon ≥1/1000 and <1/100, rare, ≥1/10 000 and <1/1000 and very rare, <1/10 000 if possibly
causally related are listed.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
The most commonly reported adverse events were visual disturbances, pyrexia, rash, vomiting,
nausea, diarrhoea, headache, peripheral oedema and abdominal pain. The severity of the adverse
events was generally mild to moderate. No clinically significant differences were seen when the safety
data were analysed by age, race, or gender.
System Organ Class
Adverse drug reactions
Infections and infestatio
n
Common
Gastroenteritis, influenza-like illness
Rare
Pseudomembranous colitis
Blood and Lymphatic system disorders
Common
Pancytopenia, bone marrow depression, leukopenia,
thrombocytopenia, anaemia, purpura
Uncommon
Disseminated intravascular coagulation, agranulocytosis,
lymphadenopathy, eosinophilia
Immune system disorders
Common
Sinusitis
Uncommon
Anaphylactoid reaction, hypersensitivity
Endocrine disorders
Uncommon
Adrenal insufficiency
Rare
Hyperthyroidism, hypothyroidism
Metabolism and nutrition system disorders
Common
Hypoglycaemia, hypokalaemia
Psychiatric disorders
Common
Depression, hallucination, anxiety
Rare
Insomnia
Nervous system disorders
Very common
Headache
Common
Dizziness, confusional state, tremor, agitation, paraesthesia
Uncommon
Brain oedema, ataxia, diplopia, vertigo, hypoaesthesia
Rare
Convulsion, encephalopathy, Guillain-Barre syndrome,
extrapyramidal symptoms, somnolence during infusion,
peripheral neuropathy
Eye disorders
Very common
Visual disturbances (including blurred vision (see Section
4.4), chromotopsia and photophobia)
Uncommon
Papilloedema (se Section 4.4), optic nerve disorder (including
optic neuritis, see Section 4.4), nystagmus, scleritis,
blepharitis
56
Rare
Optic atrophy, Retinal haemorrhage, oculogyration, corneal
opacity
Ear and labyrinth disorders
Rare
Hypoacusis, tinnitus
Cardiac disorders
Very common
Oedema peripheral
Uncommon
Ventricular fibrillation, ventricular arrhythmia, syncope,
supraventricular arrhythmia, supraventricular tachycardia,
tachycardia, bradycardia
Rare
Torsades de pointes, ventricular tachycardia, atrioventricular
complete block, bundle branch block, nodal rhythm
Vascular disorders
Common
Thrombophlebitis, Hypotension, phlebitis
Rare
Lymphangitis
Respiratory, thoracic and mediastinal disorders
Common
Acute respiratory distress syndrome, pulmonary oedema,
respiratory distress, chest pain
Gastrointestinal disorders
Very common
Abdominal pain, nausea, vomiting, diarrhoea
Uncommon
Pancreatitis, peritonitis, duodenitis, gingivitis, glossitis,
swollen tongue, dyspepsia, constipation
Rare
Dysgeusia
Hepato-biliary disorders
Common
Jaundice, cholestatic jaundice
Uncommon
Hepatic failure, hepatitis, hepatomegaly, cholecystitis,
cholelithiasis
Rare
Hepatic coma
Skin and subcutaneous tissue disorders
Very common
Rash
Common
Exfoliative dermatitis, face oedema, photosensitivity reaction,
maculo-papular rash, macular rash, papular rash, cheilitis,
pruritus, alopecia, erythema
Uncommon
Stevens-Johnson syndrome, angioneurotic oedema, allergic
dermatitis, urticaria, drug hypersensitivity, psoriasis
Rare
Toxic epidermal necrolysis, erythema multiforme, discoid
lupus erythematosis, pseudoporphyria
Musculoskeletal and connective tissue disorders
Common
Back pain
Uncommon
Arthritis
Rare
Hypertonia
Renal and urinary disorders
Common
Renal failure acute, haematuria
Uncommon
Proteinuria, nephritis
Rare
Renal tubular necrosis
57
General disorders and administrative site conditions
Very common
Pyrexia
Common
Injection site reaction / inflammation, chills, asthenia,
Investigations
Common
Elevated liver function tests (including ASAT, ALAT,
alkaline phosphatase, GGT, LDH, bilirubin), blood creatinine
increased
Uncommon
Electrocardiogram QT corrected interval prolonged, blood
urea increased, blood cholesterol increased
Visual disturbances
In clinical trials, voriconazole treatment-related visual disturbances were very common. In these
studies, short-term as well as long-term treatment, approximately 30 % of subjects experienced
altered/enhanced visual perception, blurred vision, colour vision change or photophobia. These visual
disturbances were transient and fully reversible, with the majority spontaneously resolving within 60
minutes and no clinically significant long-term visual effects were observed. There was evidence of
attenuation with repeated doses of voriconazole. The visual disturbances were generally mild, rarely
resulted in discontinuation and were not associated with long-term sequelae. Visual disturbances may
be associated with higher plasma concentrations and/or doses.
The mechanism of action is unknown, although the site of action is most likely to be within the retina.
In a study in healthy volunteers investigating the impact of voriconazole on retinal function,
voriconazole caused a decrease in the electroretinogram (ERG) waveform amplitude. The ERG
measures electrical currents in the retina. The ERG changes did not progress over 29 days of treatment
and were fully reversible on withdrawal of voriconazole.
Dermatological reactions
Dermatological reactions were common in patients treated with voriconazole in clinical trials, but
these patients had serious underlying diseases and were receiving multiple concomitant medications.
The majority of rashes were of mild to moderate severity. Patients have rarely developed serious
cutaneous reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema
multiforme during treatment with VFEND.
If patients develop a rash they should be monitored closely and VFEND discontinued if lesions
progress. Photosensitivity reactions have been reported, especially during long-term therapy (see also
section 4.4).
Liver Function Tests
The overall incidence of clinically significant transaminase abnormalities in the voriconazole clinical
programme was 13.4 % (200/1493) of subjects treated with voriconazole. Liver function test
abnormalities may be associated with higher plasma concentrations and/or doses. The majority of
abnormal liver function tests either resolved during treatment without dose adjustment or following
dose adjustment, including discontinuation of therapy. Voriconazole has been infrequently associated
with cases of serious hepatic toxicity in patients with other serious underlying conditions. This
includes cases of jaundice, and rare cases of hepatitis and hepatic failure leading to death (see section
4.4).
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 also section 4.4).
Paediatric Use
The safety of voriconazole was investigated in 245 paediatric patients aged 2 to <12 years who were
58
treated with voriconazole in pharmacokinetic studies (87 paediatric patients) and in compassionate use
programs (158 paediatric patients). The adverse event profile of these 245 paediatric patients was
similar to that in adults, although post-marketing data suggest there might be a higher occurrence of
skin reactions (esp. 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
events (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.
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 event
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.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: ATC code: J02A C03 Antimycotics for Systemic Use – Triazole
derivatives
Mechanism of action
I
n vitro
, voriconazole displays broad-spectrum antifungal activity with antifungal potency against
Candida
species (including fluconazole resistant
C. krusei
and resistant strains of
C. glabrata
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. Its
mode of action is inhibition of fungal cytochrome P450-mediated 14α-sterol demethylation, an
essential step in ergosterol biosynthesis.
Microbiology
Clinical efficacy (with partial or complete response, see below under Clinical Experience) 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 (with often partial or complete response, see below under Clinical
Experience) 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.
, Histoplasma capsulatum,
with most strains being inhibited by
59
concentrations of voriconazole in the range 0.05 to 2µg/ml.
In vitro
activity against the following pathogens has been shown, but the clinical significance is
unknown:
Curvularia
spp. and
Sporothrix
spp.
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 MICs of less than 1
mg/L for voriconazole.
However, the
in vitro
activity of voriconazole against
Candida
species is not uniform. Specifically,
for
C. glabrata,
the MICs of voriconazole for fluconazole-resistant isolates are proportionally higher
than are those of fluconazole-susceptible isolates. Therefore, every attempt should be made to identify
Candida
to species level. If antifungal susceptibility testing is available, the MIC results may be
interpreted using breakpoint criteria established by European Committee on Antimicrobial
Susceptibility Testing (EUCAST).
EUCAST Breakpoints
Candida Species
MIC breakpoint (mg/L)
≤S (Susceptible) >R (Resistant)
Candida albicans
1
0.125
0.125
Candida tropicalis
1
0.125
0.125
Candida parapsilosis
1
0.125
0.125
Candida glabrata
2
Insufficient evidence
Candida krusei
3
Insufficient evidence
Other Candida spp.
4
Insufficient evidence
1
Strains with MIC values above the Susceptible (S) breakpoint are rare, or
not yet reported. The identification and antimicrobial susceptibility tests
on any such isolate must be repeated and if the result is confirmed the
isolate sent to a reference laboratory.
2
In clinical studies, response to voriconazole in patients with
C glabrata
infections was 21% lower compared to
C. albicans, C. parapsilosis and C.
tropicalis.
However, this reduced response was not correlated with
elevated MICs.
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. A satisfactory global response (complete or partial resolution of all attributable
symptoms signs, radiographic/bronchoscopic abnormalities present at baseline) was seen in 53 % of
60
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 five 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 medication was defined as resolution/improvement in all clinical signs and symptoms of
infection with eradication of
Candida
from blood and infected deep tissue sites at 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 response) of 7 patients
with
S. prolificans
infection. In addition, a successful response was seen in 1 of 3 patients with
61
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; two 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.
Duration of treatment
In clinical trials, 561 patients received voriconazole therapy for greater than 12 weeks, with 136
patients receiving voriconazole for over 6 months.
Experience in paediatric patients
Sixty one paediatric patients aged 9 months up to 15 years who had definite or probable invasive
fungal infections, were treated with voriconazole. This population included 34 patients 2 to < 12 years
old and 20 patients 12-15 years of age.
The majority (57/61) had failed previous antifungal therapies. Therapeutic studies included 5 patients
aged 12-15 years, the remaining patients received voriconazole in the compassionate use programmes.
Underlying diseases in these patients included haematological malignancies and aplastic anaemia (27
patients) and chronic granulomatous disease (14 patients). The most commonly treated fungal
infection was aspergillosis (43/61; 70 %).
Clinical Studies Examining QT Interval
A placebo-controlled, randomized, single-dose, crossover study to evaluate the effect on the QT
interval of healthy volunteers was conducted with three oral doses of voriconazole and ketoconazole.
The placebo-adjusted mean maximum increases in QTc from baseline after 800, 1200 and 1600 mg of
voriconazole were 5.1, 4.8, and 8.2 msec, respectively and 7.0 msec for ketoconazole 800 mg. No
subject in any group had an increase in QTc of ≥ 60 msec from baseline. No subject experienced an
interval exceeding the potentially clinically relevant threshold of 500 msec.
5.2 Pharmacokinetic properties
General pharmacokinetic characteristics
The pharmacokinetics of voriconazole have been characterised in healthy subjects, special populations
and patients. During oral administration of 200 mg or 300 mg twice daily for 14 days in patients at risk
of aspergillosis (mainly patients with malignant neoplasms of lymphatic or haematopoietic tissue), the
observed pharmacokinetic characteristics of rapid and consistent absorption, accumulation and non-
linear pharmacokinetics were in agreement with those observed in healthy subjects.
The pharmacokinetics of voriconazole are non-linear due to saturation of its metabolism. Greater than
proportional increase in exposure is observed with increasing dose. It is estimated that, on average,
increasing the oral dose from 200 mg twice daily to 300 mg twice daily leads to a 2.5-fold increase in
exposure (AUCτ). 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.
62
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.
Metabolism
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 35
%. 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
Excretion
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.
Pharmacokinetic-Pharmacodynamic relationships
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.
Pharmacokinetic-Pharmacodynamic analyses of clinical trial data identified positive associations
between plasma voriconazole concentrations and both liver function test abnormalities and visual
disturbances.
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
63
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).
Paediatrics
The recommended intravenous dose in paediatric patients is based on a population pharmacokinetic
analysis of data pooled from 82 immunocompromised paediatric patients aged 2 to <12 years old who
were evaluated in three pharmacokinetic studies (examining single intravenous doses of 3 and 4 mg/kg
twice daily, multiple intravenous doses of 3, 4, 6 and 8 mg/kg twice daily and multiple oral suspension
doses of 4 and 6 mg/kg twice daily). The majority of patients received more than one dose level with a
maximum duration of dosing of 30 days.
A comparison of the paediatric and adult population pharmacokinetic data indicated that in order to
obtain comparable exposures to those obtained in adults following intravenous maintenance doses of
4 mg/kg twice daily, intravenous maintenance doses of 7 mg/kg twice daily are required in paediatric
patients. 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. In
order to obtain comparable exposures to those obtained in adults following intravenous maintenance
doses of 3 mg/kg twice daily, intravenous maintenance doses of 4 mg/kg twice daily are required in
paediatric patients.
Based on the population pharmacokinetic analysis, no loading dose or dosage adjustment according to
age is warranted in patients aged 2 to <12 years old.
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 dosing and monitoring
recommendations under 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 (Child-Pugh C). See dosing and monitoring recommendations under 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,
64
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.
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 the light of these data the duration
of treatment of the intravenous formulation should be no longer than 6 months.
6.1 List of excipients
Sulphobutylether beta cyclodextrin sodium (SBECD)
6.2 Incompatibilities
VFEND must not be infused into the same line or cannula concomitantly with other intravenous
products. 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 hypokalemia, hypomagnesemia and hypocalcemia should be corrected prior to
initiation of voriconazole therapy (see section 4.2 and section 4.4). VFEND must not be administered
simultaneously with any blood product or any short-term infusion of concentrated solutions of
electrolytes, even if the two infusions are running in separate lines.
Total parenteral nutrition:
Total parenteral nutrition (TPN) need
not
be discontinued when prescribed
with VFEND, but does need to be infused through a separate line. If infused through a multiple-lumen
catheter, TPN needs to be administered using a different port from the one used for VFEND. VFEND
must not be diluted with 4.2 % Sodium Bicarbonate Infusion. Compatibility with other concentrations
is unknown.
This medicinal product must not be mixed with other medicinal products except those mentioned in
section 6.6.
6.3 Shelf life
VFEND powder for solution for infusion: 3 years.
VFEND is a single dose unpreserved sterile lyophile. Therefore, from a microbiological point of view,
65
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, 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.
6.4 Special precautions for storage
Reconstituted concentrate: Store at 2°C-8°C for up to 24 hours (in a refrigerator).
For storage conditions of the reconstituted medicinal product, see section 6.3.
6.5 Nature and contents of container
Packs of 1 single use 30 ml clear Type I glass vials with rubber stoppers and aluminium caps with
plastic seals
.
6.6 Special precautions for disposal and other handling
Any unused product or waste material should be disposed of in accordance with local requirements.
The powder is reconstituted with 19 ml of Water for Injections 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 is dispensed. This medicinal
product is for single use only and any unused solution should be discarded and 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 below) to obtain a final voriconazole solution containing 0.5-5
mg/ml.
Required Volumes of 10 mg/ml VFEND Concentrate
Volume of VFEND Concentrate (10 mg/ml) required for:
Body
Weight
(kg)
3 mg/kg dose
(number of
vials)
4 mg/kg dose
(number of
vials)
6 mg/kg dose
(number of
vials)
7 mg/kg dose
(number of
vials)
10
-
4.0 ml (1)
-
7.0 ml (1)
15
-
6.0 ml (1)
-
10.5 ml (1)
20
-
8.0 ml (1)
-
14.0 ml (1)
25
-
10.0 ml (1)
-
17.5 ml (1)
30
9.0 ml (1)
12.0 ml (1)
18.0 ml (1)
21.0 ml (2)
35
10.5 ml (1)
14.0 ml (1)
21.0 ml (2)
24.5 ml (2)
40
12.0 ml (1)
16.0 ml (1)
24.0 ml (2)
28.0 ml (2)
45
13.5 ml (1)
18.0 ml (1)
27.0 ml (2)
31.5 ml (2)
50
15.0 ml (1)
20.0 ml (1)
30.0 ml (2)
35.0 ml (2)
55
16.5 ml (1)
22.0 ml (2)
33.0 ml (2)
-
60
18.0 ml (1)
24.0 ml (2)
36.0 ml (2)
-
65
19.5 ml (1)
26.0 ml (2)
39.0 ml (2)
-
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)
-
66
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)
-
Voriconazole 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.
The reconstituted solution can be diluted with:
9 mg/ml (0.9 %) Sodium Chloride for Infusion
Lactated Ringer’s 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.
Pfizer Limited, Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom
EU/1/02/212/025
Date of first authorisation: 21 March 2002
Date of last renewal: 21 March 2007
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMA) http://www.ema.europa.eu
67
6. FURTHER 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.
The information in this leaflet is about VFEND 40 mg/ml powder for oral suspension only. For
further information on VFEND 50 mg and 200 mg film-coated tablets or VFEND 200 mg powder for
solution for infusion, please see the User Package Leaflets for these products.
Marketing Authorisation Holder
Pfizer Limited, Ramsgate Rd, Sandwich, Kent, CT13 9NJ, United Kingdom.
Manufacturer
Pfizer PGM, 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
Luxembourg/Luxemburg
Pfizer S.A.
Tél: +32 (0)2 554 62 11
България
Пфайзер Люксембург САРЛ, Клон България
Тел.: +359 2 970 4333
Magyarország
Pfizer Kft.
Tel. + 36 1 488 37 00
Česká republika
Pfizer s.r.o.
Tel: +420-283-004-111
Malta
V.J. Salomone Pharma Ltd.
Tel : +356 21 22 01 74
Danmark
Pfizer ApS Tlf:
+45 44 20 11 00
Nederland
Pfizer bv
Tel: +31 (0)10 406 43 01
Deutschland
Pfizer Pharma GmbH
Tel: +49 (0)30 550055 51000
Norge
Pfizer AS
Tlf: +47 67 52 61 00
Eesti
Pfizer Luxembourg SARL Eesti filiaal
Tel: +372 6 405 328
Österreich
Pfizer Corporation Austria Ges.m.b.H.
Tel: +43 (0)1 521 15-0
138
Ελλάδα
Pfizer Hellas A.E.
Τηλ: +30 210 6785 800
Polska
Pfizer Polska Sp. z o.o.,
Tel.: +48 22 335 61 00
España
Pfizer S.A.
Tel: +34 91 490 99 00
Portugal
Laboratórios Pfizer, Lda.
Tel: + 351 214 235 500
France
Pfizer
Tél: +33 (0)1 58 07 34 40
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
Icepharam hf.,
Sími: + 354 540 8000
Slovenská republika
Pfizer Luxembourg SARL, organizačná zložka
Tel: +421-2-3355 5500
Italia
Pfizer Italia S.r.l.
Tel: +39 06 33 18 21
Suomi/Finland
Pfizer Oy
Puh/Tel: +358(0)9 43 00 40
Κύπρος
GEO. PAVLIDES & ARAOUZOS LTD,
Τηλ: +35722818087
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
Lietuva
Pfizer Luxembourg SARL
Filialas Lietuvoje
Tel. +3705 2514000
This leaflet was last approved in
{MM/YYYY}.
Detailed information on this medicine is available on the European Medicines Agency (EMA) web
site: http://www.ema.europa.eu
139
Source: European Medicines Agency
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