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VFEND

SCHEDULING STATUS:
Schedule 4

PROPRIETARY NAME
(and dosage form):

VFEND

VFEND 50 mg film-coated tablets
VFEND 200 mg film-coated tablets
VFEND IV 200 mg powder for solution for infusion

COMPOSITION
Each VFEND 50 mg and 200 mg film-coated tablet contains voriconazole 50 mg and 200 mg respectively.
Each VFEND IV 200 mg vial contains 200 mg voriconazole. When reconstituted as directed, each mL contains 10 mg voriconazole.
VFEND film-coated tablets contain the following inactive ingredients: lactose monohydrate, pregelatinised starch, croscarmellose sodium, povidone, magnesium stearate, hypromellose, titanium dioxide, and glycerol triacetate.
VFEND IV 200 mg powder for solution for infusion contains the following inactive ingredients: sulphobutylether beta cyclodextrin sodium (SBECD) and water for injections.

PHARMACOLOGICAL CLASSIFICATION
A 20.1.7 Antimicrobial (chemotherapeutic) agents: Antifungal antibiotics

PHARMACOLOGICAL ACTION
1. Pharmacodynamic Properties
Mechanism of action:
Voriconazole is a broad spectrum triazole antifungal agent. Its mode of action is inhibition of fungal cytochrome P450-mediated 14alpha-sterol demethylation, an essential step in ergosterol biosynthesis.
Microbiology
In vitro, voriconazole displays broad-spectrum antifungal activity with antifungal potency against Candida species (including fluconazole resistant C. krusei and resistant strains of C. glabrata and C. albicans) and fungicidal activity against all Aspergillus species tested. In addition voriconazole shows in vitro fungicidal activity against emerging fungal pathogens, including those such as Scedosporium or Fusarium.
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.
Clinical isolates with decreased susceptibility to voriconazole have been identified. Correlation of in vitro activity with clinical outcome is difficult owing to the complexity of the patients studied in clinical trials.
2. Pharmacokinetic Properties
General Pharmacokinetic Characteristics
The pharmacokinetics of voriconazole have been characterised in healthy subjects, special populations and patients. During oral administration of 200 mg or 300 mg twice daily for 14 days in patients at risk of aspergillosis (mainly patients with malignant neoplasms of lymphatic or haematopoietic tissue), the observed pharmacokinetic characteristics of rapid and consistent absorption, accumulation and non-linear pharmacokinetics were in agreement with those observed in healthy subjects.
The pharmacokinetics of voriconazole are non-linear due to saturation of its metabolism. Greater than proportional increase in exposure is observed with increasing dose. It is estimated that, on average, increasing the oral dose from 200 mg twice daily to 300 mg twice daily leads to a 2.5-fold increase in exposure (AUC_t). 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 regimens, 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 AUC_t 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%.
Detectable voriconazole concentrations are present in the cerebrospinal fluid of patients treated with voriconazole.
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 3-5%. Studies conducted in Caucasian and Japanese healthy subjects have shown that poor metabolisers have, on average, 4-fold higher voriconazole exposure (AUCt) 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
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 AUC_t for healthy young females were 83% and 113% higher, respectively, than in healthy young males (18-45 years). In the same study, no significant differences in Cmax and AUC_t were observed between healthy elderly males and healthy elderly females (> 65 years).
In the clinical programme, no dosage adjustment was made on the basis of gender. The safety profile and plasma concentrations observed in male and female patients were similar. Therefore, no dosage adjustment based on gender is necessary.
Elderly
In an oral multiple dose study Cmax and AUC_tin healthy elderly males (> 65 years) were 61% and 86% higher, respectively, than in healthy young males (18-45 years). No significant differences in Cmax and AUC_t 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. However, the safety profile of voriconazole in young and elderly patients was similar and, therefore, no dosage adjustment is necessary for the elderly.
Paediatrics
VFEND IV 200 mg powder for solution for infusion
A population pharmacokinetic analysis was conducted on data from 35 immunocompromised subjects aged 2 to < 12 years old who were included in the intravenous single or multiple dose pharmacokinetic studies. Twenty four of these subjects received multiple doses of voriconazole. Average steady state plasma concentrations in children receiving a maintenance dose of 4 mg/kg every 12 hours were similar to those in adults receiving 3 mg/kg every 12 hours, with medians of 1186 ng/mL in children and 1155 ng/mL in adults. Therefore a maintenance dose of 4 mg/kg every 12 hours is recommended for children aged between 2 to < 12 years of age.
Renal Impairment
VFEND 50 mg and 200 mg film-coated tablets
In an oral single dose (200 mg) study in subjects with normal renal function and mild (creatinine clearance 41-60 mL/min) to severe (creatinine clearance < 20 mL/min) renal impairment, the pharmacokinetics of voriconazole were not significantly affected by renal impairment. The plasma protein binding of voriconazole was similar in subjects with different degrees of renal impairment (See ‘Dosage and directions for use’and ‘Warnings’sections).
VFEND IV 200 mg powder for solution for infusion
In patients with moderate to severe renal dysfunction (serum creatinine levels > 2.5 mg/dL), accumulation of the intravenous vehicle, SBECD, occurs. See dosing and monitoring recommendations under ‘Dosage and directions for use’and ‘Warnings’sections.
Hepatic Impairment
After an oral single dose (200 mg), AUC was 233% higher in subjects with mild to moderate hepatic cirrhosis (Child-Pugh A and B) compared with subjects with normal hepatic function. Protein binding of voriconazole was not affected by impaired hepatic function.
In an oral multiple dose study, AUC_t 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 ‘Dosage and directions for use’and ‘Warnings’sections.

INDICATIONS
Treatment of invasive aspergillosis.
Treatment of serious infections caused by Candida spp (including C. krusei) refractory to fluconazole therapy.
Voriconazole has been used in the treatment of serious fungal infections caused by Scedosporium spp and Fusarium spp.
Prevention of breakthrough of fungal infections in febrile high-risk patients (allogeneic bone marrow transplants, relapsed leukaemia patients) where liposomal amphotericin B cannot be used.

CONTRA-INDICATIONS
VFEND is contra-indicated in patients with known hypersensitivity to voriconazole or to any of the excipients.
Coadministration of the CYP3A4 substrates, terfenadine, astemizole, cisapride, pimozide or quinidine with VFEND is contra-indicated since increased plasma concentrations of these medicinal products can lead to QTc prolongation and rare occurrences of torsades de pointes (see ‘Interactions’section).
Coadministration of VFEND with rifampicin, carbamazepine and phenobarbital is contra-indicated since these drugs are likely to decrease plasma voriconazole concentrations significantly (see ‘Interactions’section).
Coadministration of ergot alkaloids (ergotamine, dihydroergotamine), which are CYP3A4 substrates, is contra-indicated since increased plasma concentrations of these drugs can lead to ergotism (see ‘Interactions’section).
Coadministration of voriconazole and sirolimus is contra-indicated, since voriconazole is likely to increase plasma concentrations of sirolimus significantly (see ‘Interactions’section).
Coadministration of voriconazole and rifabutin is contra-indicated since voriconazole is likely to increase plasma concentrations of rifabutin significantly (see ‘Interactions’section).
Pregnancy and lactation.
Severe impairment of hepatic function.

WARNINGS
Pregnancy (see ‘Contra-indications’)
No adequate information on the use of VFEND in pregnant women is available.
Studies in animals have shown reproductive toxicity and teratogenicity. The potential risk to humans is unknown. VFEND must not be used during pregnancy.
Women of child-bearing potential
Women of childbearing 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 (see ‘Contra-indications’).
Hypersensitivity
Caution should be used in prescribing VFEND to patients with hypersensitivity to other azoles (see also ‘Side effects and special precautions’section).

Infusion-related reaction
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. Depending on the severity of the symptoms, consideration should be given to stopping treatment.

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 ‘Side effects and special precautions’ section).
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.
Patients with 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 concomitantly with nephrotoxic medications and have concurrent conditions that may result in decreased renal function (see ‘Side effects and special precautions’section).
Monitoring of renal function: Patients should be monitored for the development of abnormal renal function. This should include laboratory evaluation, particularly serum creatinine.
Dermatological reactions
Patients have 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 photosensitivity skin reaction, especially during long-term therapy. It is recommended that patients should be informed to avoid sunlight during the treatment.
Paediatric use
Safety and effectiveness in paediatric subjects below the age of two years has not been established.
Cyclosporin and tacrolimus (CYP3A4 substrates)
Clinically significant drug interactions with VFEND may occur in patients who are receiving treatment with cyclosporin or tacrolimus (see ‘Interactions’section).
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 ‘Interactions’section).

VFEND 50 mg and 200 mg film-coated tablets
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.

Effects on ability to drive and use machines
Voriconazole 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 whilst experiencing these symptoms.

DOSAGE AND DIRECTIONS FOR USE
VFEND 50 mg and 200 mg film-coated tablets:
VFEND tablets are to be taken at least one hour before, or one hour following, a meal.

VFEND IV 200 mg powder for solution for infusion:
It is recommended that VFEND is administered at a maximum rate of 3 mg/kg per hour over 1 to 2 hours.
VFEND requires reconstitution and dilution prior to administration as an intravenous infusion.
Not for bolus injection.
The vial contents are reconstituted with 19 mL of Water for Injections to obtain a clear solution containing 10 mg/mL of voriconazole and an extractable volume of 20 mL. For administration, the required volume of the reconstituted solution is added to a recommended compatible infusion solution (detailed below) to obtain, where appropriate, a final VFEND solution containing 2-5 mg/mL.
VFEND IV does not contain an antimicrobial preservative. If the reconstituted solution is not used immediately, the reconstituted solution will remain suitable for its intended use for up to 24 hours, stored at 2-8°C, if reconstitution has taken place in controlled and validated aseptic conditions.
The reconstituted solution can be diluted with:
0.9% Sodium Chloride Intravenous Infusion
Compound Sodium Lactate Intravenous Infusion
5% Glucose and Compound Sodium Lactate Intravenous Infusion
5% Glucose and 0.45% Sodium Chloride Intravenous Infusion
5% Glucose Intravenous Infusion
5% Glucose in 20 mEq Potassium Chloride Intravenous Infusion
0.45% Sodium Chloride Intravenous Infusion
5% Glucose and 0.9% Sodium Chloride Intravenous Infusion

The compatibility of VFEND with diluents other than those described above is unknown (see incompatibilities below).
VFEND must not be infused into the same line or cannula concomitantly with other drug infusions, including parenteral nutrition. 4.2% Sodium Bicarbonate Intravenous Infusion is not compatible with VFEND and is not recommended for use as a diluent. Compatibility with other concentrations is unknown.
Infusions of blood products and any electrolyte supplementation must not occur simultaneously with VFEND.

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%), switching between intravenous and oral administration is appropriate when clinically indicated.
Detailed information on dosage recommendations is provided in the following table:

	Intravenous	Oral
		Patients 40 kg and above	Patients less than 40 kg
Loading Dose Regimen (first 24 hours)	6 mg/kg every 12 hours (for the first 24 hours)	400 mg every 12 hours (for the first 24 hours)	200 mg every 12 hours (for the first 24 hours)
Maintenance Dose (after first 24 hours) Prevention of breakthrough infections	3 mg/kg every 12 hours	200 mg twice daily	100 mg twice daily
Invasive aspergillosis, serious Candida infections, Scedosporium/Fusarium infections	4 mg/kg every 12 hours	200 mg twice daily	100 mg twice daily

Dosage adjustment
Powder for solution for infusion:
If patient response is inadequate, the maintenance dose may be increased to 4 mg/kg twice daily for intravenous administration.
Film-coated tablets:
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.
Powder for solution for infusion:
If patients are unable to tolerate treatment at these higher doses, reduce the intravenous dose to the original maintenance dose, 3 mg/kg twice daily.
Film-coated tablets:
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.
Powder for solution for infusion:
Phenytoin may be coadministered with voriconazole if the maintenance dose of voriconazole is increased to 5 mg/kg intravenously twice daily (see ‘Side-effects and special precautions’).
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 ‘Side-effects and special precautions’.
Treatment duration depends upon patients’clinical and mycological response.
Use in the elderly
No dose adjustment is necessary for elderly patients.
Use in patients with renal impairment
Film-coated tablets:
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.
Powder for solution for infusion:
In patients with moderate to severe renal dysfunction (creatinine clearance < 50 mL/min), accumulation of the intravenous vehicle, SBECD, occurs. Oral voriconazole should be administered to these patients, unless an assessment of the risk benefit to the patient justifies the use of intravenous voriconazole. Serum creatinine levels should be closely monitored in these patients and, if increases occur, consideration should be given to changing to oral voriconazole therapy.
Film-coated tablets and Powder for solution for infusion
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.
Powder for solution for infusion
The intravenous vehicle, SBECD, is haemodyalised 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 future elevations is recommended.
It is recommended that half the standard loading dose regimens be used and that the maintenance dose be halved in patients with mild to moderate hepatic cirrhosis (Child-Pugh A and B) receiving VFEND.
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. Patients with hepatic impairment must be carefully monitored for drug toxicity (see also ‘Side effects and special precautions’section).
Use in children
Safety and effectiveness in paediatrics subjects below the age of 2 years has not been established. Therefore, voriconazole is not recommended for children less than 2 years of age.
Limited data are currently available to determine the optimal posology. However, the following regimen has been used in paediatric studies.
Children aged 2 to < 12 years:

	Intravenous	Oral
Loading Dose Regimen (first 24 hours)	6 mg/kg every 12 hours (for the first 24 hours)	6 mg/kg every 12 hours (for the first 24 hours)
Maintenance Dose (after first 24 hours)	4 mg/kg every 12 hours	4 mg/kg every 12 hours

If a child is able to swallow tablets, the dose should be administered to the nearest mg/kg dose possible using whole 50 mg tablets.
The pharmacokinetics and tolerability of higher doses have not been characterised in paediatric populations.
Adolescents (12 to 16 years of age): should be dosed as adults.

Duration of Treatment
Treatment duration depends on the patient’s clinical and mycological response. The duration of oral and intravenous voriconazole treatment in the clinical studies ranged from 12 weeks to more than 6 months.

SIDE EFFECTS AND SPECIAL PRECAUTIONS
The safety profile of voriconazole is based on an integrated safety database of patients who participated in clinical 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. Duration of treatment ranged from 12 weeks to more than 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 and rare, <1/1000) if possibly causally related are listed. The most commonly reported adverse events were visual disturbances, fever, 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.
Side-effects reported in subjects receiving voriconazole

Body System	Adverse Drug Reactions
Body as a whole
Very common	Fever, headache, abdominal pain
Common	Chills, asthenia, back pain, chest pain, injection site reaction/inflammation, face oedema, flu syndrome
Uncommon	Allergic reaction, anaphylactoid reaction, angioedema, peritonitis
Cardiovascular
Common	Hypotension, thrombophlebitis, phlebitis
Uncommon	Atrial arrhythmia, bradycardia,syncope, tachycardia,ventricular arrhythmia, ventricular fibrillation
Rare	Supraventricular tachycardia, AV complete block, bundle branch block, nodal arrhythmia
Digestive
Very common	Nausea, vomiting, diarrhoea
Common	Elevated liver function tests (including ASAT, ALAT, alkaline phosphatase, GGT, LDH, bilirubin), jaundice, cheilitis, cholestatic jaundice, gastroenteritis
Uncommon	Cholecystitis, cholelithiasis, constipation, duodenitis, dyspepsia, enlarged liver, gingivitis, glossitis, hepatitis, hepatic failure, pancreatitis, tongue oedema
Rare	Pseudomembranous colitis, hepatic coma
Endocrine
Uncommon	Adrenal cortex insufficiency
Haemic and lymphatic
Common	Thrombocytopenia, anaemia (including macrocytic, microcytic, normocytic, megaloblastic, aplastic), leukopenia, pancytopenia, purpura
Uncommon	Lymphadenopathy, agranulocytosis, eosinophilia, disseminated intravascular coagulation, marrow depression
Rare	Lymphangitis
Metabolic and nutritional
Very common	Peripheral oedema
Common	Hypokalaemia, creatinine increased, hypoglycaemia
Uncommon	BUN increased, albuminuria, hypercholesterolaemia
Rare	Hyperthyroisim, hypothyroidism
Musculoskeletal
Uncommon	Arthritis
Nervous
Common	Dizziness, hallucinations, confusion, depression, anxiety, tremor, agitation, paraesthesia
Uncommon	Ataxia, brain oedema, diplopia, hypoesthesia, nystagmus, vertigo
Rare	Guillain-Barre syndrome, oculogyric crisis, hypertonia, Extrapyramidal Syndrome
Respiratory
Common	Respiratory distress syndrome, lung oedema, sinusitis
Skin and appendages
Very common	Rash
Common	Pruritus, maculopapular rash, photosensitivity skin reaction, alopecia, exfoliative dermatitis
Uncommon	Fixed drug eruption, eczema, psoriasis, Stevens-Johnson syndrome, urticaria
Rare	Discoid lupus erythematosis, erythema multiforme, toxic epidermal necrolysis
Special senses
Very Common	Visual disturbances (including altered/enhanced visual perception, blurred vision, colour vision change, photophobia)
Uncommon	Blepharitis, optic neuritis, papilloedema, scleritis, altered taste perception
Rare	Retinal haemorrhage, corneal opacity, optic atrophy
Urogenital
Common	Acute kidney failure, haematuria
Uncommon	Nephritis
Rare	Kidney tubular necrosis

Visual disturbances
Voriconazole treatment-related visual disturbances are common. In clinical trials, approximately 30% of subjects experienced altered/enhanced visual perception, blurred vision, colour vision change or photophobia. The visual disturbances are transient and fully reversible, with the majority spontaneously resolving within 60 minutes. There is evidence of attenuation with repeated doses of voriconazole. The visual disturbance is generally mild, rarely results in discontinuation and has not been 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 ‘Warnings’section).
Liver function tests
The overall incidence of clinically significant transaminase abnormalities in the voriconazole clinical programme was 13.4% 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 ‘Warnings’).
Interactions with other medicinal products and other forms of interaction
Unless otherwise specified, drug interaction studies have been performed in healthy 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: contra-indications, those requiring dosage adjustment and careful clinical and/or biological monitoring and finally those that have no significant pharmacokinetic interaction but that 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 AUC_t (area under the plasma concentration time curve within a dose interval) of voriconazole by 93% and 96%, respectively. Coadministration of voriconazole and rifampicin is contra-indicated (See ‘Contra-indications’).
Carbamazepine and phenobarbital (potent CYP450 inducers): Although not studied, carbamazepine or phenobarbital are likely to significantly decrease plasma voriconazole concentrations. Coadministration of voriconazole with carbamazepine and phenobarbital is contra-indicated (see ‘Contra-indications’).
Cimetidine (non-specific CYP450 inhibitor and increases gastric pH): Cimetidine (400 mg twice daily) increased voriconazole Cmax and AUC_t 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 AUC_t.
Macrolide antibiotics: Erythromycin (CYP3A4 inhibitor; 1g twice daily) and azithromycin (500 mg once daily) had no significant effect on voriconazole Cmax and AUC_t.
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.
Terfenadine, astemizole, cisapride, pimozide and quinidine (CYP3A4 substrates): Although not studied, coadministration of voriconazole with terfenadine, astemizole, cisapride, pimozide, or quinidine is contra-indicated, since increased plasma concentrations of these drugs can lead to QTc prolongation and rare occurrences of torsades de pointes (see ‘Contra-indications’).
Sirolimus (CYP3A4 substrate): Voriconazole increased sirolimus (2 mg single dose) Cmax and AUC by 556% and 1014% respectively. Coadministration of voriconazole and sirolimus is contra-indicated (see ‘Contra-indications’).
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 contra-indicated (see ‘Contra-indications’).
Cyclosporin (CYP3A4 substrate): In stable, renal transplant recipients, voriconazole increased cyclosporin Cmax and AUC_t by at least 13% and 70% respectively. When initiating voriconazole in patients already receiving cyclosporin it is recommended that the cyclosporin dose be halved and cyclosporin level carefully monitored. Increased cyclosporin levels have been associated with nephrotoxicity. When voriconazole is discontinued, cyclosporin levels must be carefully monitored and the dose increased as necessary (see ‘Warnings’).
Tacrolimus (CYP3A4 substrate): Voriconazole increased tacrolimus (0.1 mg/kg single dose) Cmaxand 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 (see ‘Warnings’).
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 to increase the plasma levels of benzodiazepines that are metabolised by CYP3A4 (e.g. midazolam, triazolam and alprazolam) 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. It is therefore recommended that dose adjustment of the vinca alkaloid be considered.
Prednisolone (CYP3A4 substrate): Voriconazole increased Cmaxand AUC_t 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 AUC_t 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).
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 AUC_t of voriconazole by 49% and 69%, respectively. Voriconazole (400 mg twice daily, see ‘Dosage and directions for use’) increased Cmax and AUC_tof phenytoin (300 mg once daily) by 67% and 81%, respectively. Careful monitoring of plasma phenytoin levels is recommended when phenytoin is coadministered with voriconazole.
Phenytoin may be coadministered with voriconazole if the maintenance dose of voriconazole is increased from 3 mg/kg to 5mg /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 ‘Dosage and directions for use’.
Rifabutin (CYP450 inducer): Concomitant use of voriconazole and rifabutin is contra-indicated. (see ‘Contra-indications’)
Rifabutin (300 mg once daily) decreased the Cmax and AUC_t of voriconazole at 200 mg twice daily by 69% and 78%, respectively. During coadministration with rifabutin, the Cmax and AUC_t 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, Cmaxand AUC_t were 104% and 87% higher, respectively, compared with voriconazole alone at 200 mg twice daily Voriconazole at 400 mg twice daily increased Cmax and AUC_t of rifabutin by 195% and 331%, respectively.
Omeprazole (CYP2C19 inhibitor; CYP2C19 and CYP3A4 substrate): Omeprazole (40 mg once daily) increased voriconazole Cmax and AUC_Tby15% and 41%, respectively. No dosage adjustment of voriconazole is recommended.
Voriconazole increased omeprazole Cmax and AUC_tby 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.
Indinavir (CYP3A4 inhibitor and substrate): Indinavir (800 mg three times daily) had no significant effect on voriconazole Cmax and AUC_t.
Voriconazole did not havea significant effect on Cmax and AUC_t 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.
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 and efavirenz. Although not studied, the metabolism of voriconazole may be induced by efavirenz and nevirapine. Voriconazolemay also inhibit the metabolism of NNRTIs. Due to the lack of in vivo studies, patients should be carefully monitored for any occurrence of drug toxicity and/or lack of efficacy during the co-administration of voriconazole and NNRTIs.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
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.
VFEND 50 mg and 200 mg film-coated tablets
Voriconazole is haemodialysed with a clearance of 121 mL/min. In an overdose, haemodialysis may assist in the removal of voriconazole from the body.
VFEND IV 200 mg powder for solution for infusion
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.

IDENTIFICATION
VFEND 50 mg film-coated tablets are white to off-white, standard round convex tablets, debossed with “Pfizer”on one side and “VOR50”on the other.
VFEND 200 mg film-coated tablets are white to off-white, capsule-shaped tablets, debossed with “Pfizer”on one side and “VOR200”on the other.
VFEND IV 200 mg powder for solution for infusion is a white lyophilised powder containing nominally 200 mg voriconazole presented in a 30 mL clear glass vial.

PRESENTATION
VFEND film-coated tablets are available in the following containers:
Opaque plastic bottles containing 2, 30 or 100 tablets
Transparent PVC/Aluminium blisters with foil backing composed of hard tempered aluminium with vinylacrylate-based heat coating on the bright side of the foil, and polyester-based lacquer on the matt side. The blisters are contained in cartons of 2, 10, 14, 20, 28, 30, 50, 56 or 100 tablets.
VFEND IV 200 mg powder for solution for infusion is available as a sterile lyophilised powder in individually boxed, single use 30 mL clear Type I glass vials with rubber stoppers and aluminium caps with plastic seals.

STORAGE INSTRUCTIONS
VFEND 50 mg film-coated tablets and VFEND 200 mg film-coated tablets: Store below 25°C.
VFEND IV 200 mg powder for solution for infusion: Store below 25°C.
Reconstituted concentrate: Store at 2°C - 8°C for up to 24 hours (in a refrigerator). (For storage instructions after reconstitution, see ‘Dosage and directions for use’).
Keep out of reach of children.
REGISTRATION NUMBERS
Vfend 50 mg film-coated tablets: 36/20.1.7/0106
Vfend 200 mg film-coated tablets: 36/20.1.7/0107
Vfend IV 200 mg powder for solution for infusion: 36/20.1.7/0108

NAME AND BUSINESS ADDRESS OF APPLICANT
Pfizer Laboratories (Pty) Ltd
102 Rivonia Road
Sandton
2196

DATE OF PUBLICATION OF THIS PACKAGE INSERT
15 September 2003

New addition to this site: January 2005
Source: Pharmaceutical Industry
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