VFEND 50 mg and 200 mg film-coated tablets.

VFEND 200 mg powder for solution for infusion.

VFEND 40 mg/ml powder for oral suspension.

Film-coated tablets:

Each tablet contains 50 mg or 200 mg voriconazole.

Excipient with known effect: each tablet contains 63.42 mg or 253.675 mg lactose monohydrate

For the full list of excipients, see section 6.1.

Powder for solution for infusion

Each vial contains 200 mg of voriconazole.

After reconstitution each ml contains 10 mg of voriconazole. Once reconstituted further dilution is required before administration.

Excipient with known effect: each vial contains 217.6 mg sodium

For the full list of excipients, see section 6.1.

Powder for oral suspension:

Each ml of oral suspension contains 40 mg of voriconazole when reconstituted with water. Each bottle contains 3 g of voriconazole.

Excipient with known effects: each ml of suspension contains 0.54 g sucrose

For the full list of excipients, see section 6.1.

Film-coated tablets:

White to off-white, round tablets, debossed “Pfizer” on one side and “VOR50” on the reverse.

White to off-white, capsule-shaped tablets, debossed “Pfizer” on one side and “VOR200” on the reverse.

Powder for solution for infusion:

White lypophilised powder

Powder for oral suspension:

White to off-white powder

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

• Treatment of invasive aspergillosis.

• Treatment of candidaemia in non-neutropenic patients

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

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

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

Posology

Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalcaemia should be monitored and corrected, if necessary, prior to initiation and during voriconazole therapy (see section 4.4).

Powder for solution for infusion:

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

Adults and adolescents (12 to 14 years and 50 kg; 15 to 17 years regardless of body weight)

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:

Dosage adjustment

Film-coated tablets & Powder for oral suspension:

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 co-administered with voriconazole if the maintenance dose of voriconazole is increased from 200 mg to 400 mg orally, twice daily (100 mg to 200 mg orally, twice daily in patients less than 40 kg), see sections 4.4 and 4.5.

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

Efavirenz may be co-administered 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).

Powder for solution for infusion:

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 co-administered 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 co-administered 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).

Children (2 to <12 years) and young adolescents (12 to 14 years and <50 kg)

The recommended dosing regimen is as follows:

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

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

These oral dose recommendations for children are based on studies in which VFEND was administered as the powder for oral suspension. Bioequivalence between the powder for oral suspension and tablets has not been investigated in a paediatric population. Considering the assumed limited gastro-enteric transit time in 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.

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

Dose adjustment

If patient response is inadequate, the dose may be increased by 1 mg/kg steps (or by 50 mg steps if the maximum oral dose of 350 mg was used initially). If patients are unable to tolerate treatment, reduce the dose by 1 mg/kg steps (or by 50 mg steps if the maximum oral dose of 350 mg was used initially).

Duration of treatment

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 be considered (see sections 4.4 and 5.1).

The duration of treatment with the intravenous formulation should be no longer than 6 months. (see section 5.3). For voriconazole in general, long term treatment greater than 6 months requires careful assessment of the benefit-risk balance. (see sections 4.4 and 5.1).

Elderly

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

Renal impairment

Film-coated tablets & Powder for oral suspension:

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.

Powder for solution for infusion:

In patients with moderate to severe renal dysfunction (creatinine clearance < 50 ml/min), accumulation of the intravenous vehicle, SBECD, occurs. Oral voriconazole should be administered to these patients, unless an assessment of the risk benefit to the patient justifies the use of intravenous voriconazole. Serum creatinine levels should be closely monitored in these patients and, if increases occur, consideration should be given to changing to oral voriconazole therapy (see section 5.2).

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

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

Hepatic impairment

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 voriconazole (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 section 4.8).

Paediatric population

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

Method of administration

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

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

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

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

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

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

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

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

Co-administration with sirolimus, since voriconazole is likely to increase plasma concentrations of sirolimus significantly (see section 4.5).

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

Hypersensitivity

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

Duration of IV treatment

The duration of treatment with the intravenous formulation should be no longer than 6 months (see section 5.3).

Cardiovascular

Voriconazole has been associated with 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 medicinal products 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 medicinal product 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).

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

Monitoring of hepatic function

Monitoring of hepatic function should be carried out in both children and adults. 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 reactions

There have been rare reports of prolonged visual adverse reactions, including blurred vision, optic neuritis and papilloedema (see section 4.8).

Renal adverse reactions

Acute renal failure has been observed in severely ill patients undergoing treatment with VFEND. Patients being treated with voriconazole are likely to be treated concomitantly with nephrotoxic medicinal products and have concurrent conditions that may result in decreased renal function (see section 4.8).

Monitoring of renal function

Patients should be monitored for the development of abnormal renal function. This should include laboratory evaluation, particularly serum creatinine.

Monitoring of pancreatic function

Patients, especially children, with risk factors for acute pancreatitis (e.g. recent chemotherapy, haematopoietic stem cell transplantation (HSCT)), should be monitored closely during VFEND treatment. Monitoring of serum amylase or lipase may be considered in this clinical situation.

Dermatological adverse reactions

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 sections 4.2 and 5.1). If phototoxic reactions occur, VFEND discontinuation should be considered after multidisciplinary advice and the patient should be referred to a dermatologist.

Paediatric population

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

Phenytoin (CYP2C9 substrate and potent CYP450 inducer)

Careful monitoring of phenytoin levels is recommended when phenytoin is co-administered with voriconazole. Concomitant use of voriconazole and phenytoin should be avoided unless the benefit outweighs the risk (see section 4.5).

Efavirenz (CYP450 inducer; CYP3A4 inhibitor and substrate)

When voriconazole is coadministered with efavirenz the dose of voriconazole should be increased to 400 mg every 12 hours and that of efavirenz should be decreased to 300 mg every 24 hours (see sections 4.2 and 4.5).

Rifabutin (CYP450 inducer)

Careful monitoring of full blood counts and adverse reactions to rifabutin (e.g. uveitis) is recommended when rifabutin is co-administered with voriconazole. Concomitant use of voriconazole and rifabutin should be avoided unless the benefit outweighs the risk (see section 4.5).

Ritonavir (potent CYP450 inducer; CYP3A4 inhibitor and substrate)

Coadministration of voriconazole and low dose ritonavir (100 mg twice daily) should be avoided unless an assessment of the benefit/risk justifies the use of voriconazole (see sections 4.5 and 4.3).

Everolimus (CYP3A4 substrate, P-gp substrate)

Co-administration of voriconazole with everolimus is not recommended because voriconazole is expected to significantly increase everolimus concentrations. Currently there are insufficient data to allow dosing recommendations in this situation (see section 4.5).

Methadone (CYP3A4 substrate)

Frequent monitoring for adverse reactions and toxicity related to methadone, including QTc prolongation, is recommended when co-administered 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 co-administered with voriconazole and in an independent published study, concomitant use of voriconazole with fentanyl resulted in an increase in the mean AUC 0- of fentanyl, frequent monitoring for opiate-associated adverse reactions (including a longer respiratory monitoring period) may be necessary.

Long acting opiates (CYP3A4 substrate)

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

Fluconazole (CYP2C9, CYP2C19 and CYP3A4 inhibitor)

Coadministration of oral voriconazole and oral fluconazole resulted in a significant increase in Cmax and AUC of voriconazole in healthy subjects. The reduced dose and/or frequency of voriconazole and fluconazole that would eliminate this effect have not been established. Monitoring for voriconazole associated adverse reactions is recommended if voriconazole is used sequentially after fluconazole (see section 4.5).

VFEND tablets contain lactose and should not be given to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

VFEND oral suspension contains sucrose and should not be given to patients with rare hereditary problems of fructose intolerance, sucrase-isomaltase deficiency or glucose-galactose malabsorption.

Sodium content: Each vial of VFEND powder for solution for infusion contains 217.6 mg of sodium. This should be taken into consideration for patients on a controlled sodium diet.

Voriconazole is metabolised by, and inhibits the activity of, cytochrome P450 isoenzymes, CYP2C19, CYP2C9, and CYP3A4. Inhibitors or inducers of these isoenzymes may increase or decrease voriconazole plasma concentrations, respectively, and there is potential for voriconazole to increase the plasma concentrations of substances metabolised by these CYP450 isoenzymes.

Unless otherwise specified, drug interaction studies have been performed in healthy adult male subjects using multiple dosing to steady state with oral voriconazole at 200 mg twice daily (BID). These results are relevant to other populations and routes of administration.

Voriconazole should be administered with caution in patients with concomitant medication that is known to prolong QT interval. When there is also a potential for voriconazole to increase the plasma concentrations of substances metabolised by CYP3A4 isoenzymes (certain antihistamines, quinidine, cisapride, pimozide) co-administration is contraindicated (see below and section 4.3).

Interaction table

Interactions between voriconazole and other medicinal products are listed in the table below (once daily as “QD”, twice daily as “BID”, three times daily as “TID” and not determined as “ND”). The direction of the arrow for each pharmacokinetic parameter is based on the 90% confidence interval of the geometric mean ratio being within (↔), below () or above (↑) the 80-125% range. The asterisk (*) indicates a two-way interaction. AUC, AUC_t and AUC_0- represent area under the curve over a dosing interval, from time zero to the time with detectable measurement and from time zero to infinity, respectively.

The interactions in the table are presented in the following order: contraindications, those requiring dose adjustment and careful clinical and/or biological monitoring, and finally those that have no significant pharmacokinetic interaction but may be of clinical interest in this therapeutic field.

Pregnancy

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.

Breastfeeding

The excretion of voriconazole into breast milk has not been investigated. Breast-feeding must be stopped on initiation of treatment with VFEND.

VFEND has 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.

Summary of safety profile

The safety profile of voriconazole is based on an integrated safety database of more than 2000 subjects (1,655 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 (561) patients had a duration of voriconazole therapy of greater than 12 weeks, with 136 patients receiving voriconazole for over 6 months.

The most commonly reported adverse reactions were visual disturbances, pyrexia, rash, vomiting, nausea, diarrhoea, headache, peripheral oedema and abdominal pain.

The severity of the adverse reactions was generally mild to moderate. No clinically significant differences were seen when the safety data were analysed by age, race, or gender.

Tabulated list of adverse reactions

In the table below, since the majority of the studies were of an open nature all causality adverse reactions, by system organ class and frequency are listed.

Frequency categories are expressed as: Very common (1/10); Common (1/100 to <1/10); Uncommon (1/1,000 to <1/100); Rare (1/10,000 to <1/1,000); Very rare (<1/10,000); Not known (cannot be estimated from the available data)

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Undesirable effects reported in subjects receiving voriconazole

Description of selected adverse reactions

Altered taste perception

In the combined data from three bioequivalence studies using the powder for oral suspension formulation, treatment related taste perversion was recorded in 12 (14 %) of subjects.

Visual 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 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 medicinal products. 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 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 population

The safety of voriconazole was investigated in 285 paediatric patients aged 2 to <12 years who were treated with voriconazole in pharmacokinetic studies (127 paediatric patients) and in compassionate use programs (158 paediatric patients). The adverse reaction profile of these 285 paediatric patients was similar to that in adults. 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 reactions (for which a relationship to voriconazole could not be excluded) were reported: photosensitivity reaction (1), arrhythmia (1), pancreatitis (1), blood bilirubin increased (1), hepatic enzymes increased (1), rash (1) and papilloedema (1). There have been post-marketing reports of pancreatitis in paediatric patients.

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

There is no known antidote to voriconazole.

Voriconazole is haemodialysed with a clearance of 121 ml/min. The intravenous vehicle, SBECD, is haemodialysed with a clearance of 55 ml/min. In an overdose, haemodialysis may assist in the removal of voriconazole and SBECD from the body.

Pharmacotherapeutic group: Antimycotics for systemic use – triazole derivatives, ATC: J02AC03

Mode of Action

Voriconazole is a triazole antifungal agent. The primary mode of action of voriconazole is the inhibition of fungal cytochrome P-450-mediated 14 alpha-lanosterol demethylation, an essential step in fungal ergosterol biosynthesis. The accumulation of 14 alpha-methyl sterols correlates with the subsequent loss of ergosterol in the fungal cell membrane and may be responsible for the antifungal activity of voriconazole. Voriconazole has been shown to be more selective for fungal cytochrome P-450 enzymes than for various mammalian cytochrome P-450 enzyme systems.

Pharmacokinetic/Pharmacodynamic Relationship

In 10 therapeutic studies, the median for the average and maximum plasma concentrations in individual subjects across the studies was 2425 ng/ml (inter-quartile range 1193 to 4380 ng/ml) and 3742 ng/ml (inter-quartile range 2027 to 6302 ng/ml), respectively. A positive association between mean, maximum or minimum plasma voriconazole concentration and efficacy in therapeutic studies was not found.

Pharmacokinetic-Pharmacodynamic analyses of clinical trial data identified positive associations between plasma voriconazole concentrations and both liver function test abnormalities and visual disturbances.

Clinical efficacy and safety

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

Clinical efficacy (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 concentrations of voriconazole in the range 0.05 to 2 μg/ml.

In vitro activity against the following pathogens has been shown, but the clinical significance is unknown: Curvularia spp. and Sporothrix spp.

Breakpoints

Specimens for fungal culture and other relevant laboratory studies (serology, histopathology) should be obtained prior to therapy to isolate and identify causative organisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, anti-infective therapy should be adjusted accordingly.

The species most frequently involved in causing human infections include C. albicans, C. parapsilosis, C. tropicalis, C. glabrata and C. krusei, all of which usually exhibit MICs of less than 1 mg/L for voriconazole.

However, the in vitro activity of voriconazole against Candida species is not uniform. Specifically, for C. glabrata, the MICs of voriconazole for fluconazole-resistant isolates are proportionally higher than are those of fluconazole-susceptible isolates. Therefore, every attempt should be made to identify Candida to species level. If antifungal susceptibility testing is available, the MIC results may be interpreted using breakpoint criteria established by European Committee on Antimicrobial Susceptibility Testing (EUCAST).

EUCAST Breakpoints

Clinical Experience

Successful outcome in this section is defined as complete or partial response.

Aspergillus infections – efficacy in aspergillosis patients with poor prognosis

Voriconazole has in vitro fungicidal activity against Aspergillus spp. The efficacy and survival benefit of voriconazole versus conventional amphotericin B in the primary treatment of acute invasive aspergillosis was demonstrated in an open, randomised, multicentre study in 277 immunocompromised patients treated for 12 weeks. Voriconazole was administered intravenously with a loading dose of 6 mg/kg every 12 hours for the first 24 hours followed by a maintenance dose of 4 mg/kg every 12 hours for a minimum of seven days. Therapy could then be switched to the oral formulation at a dose of 200 mg every 12 hours. Median duration of IV voriconazole therapy was 10 days (range 2-85 days). After IV voriconazole therapy, the median duration of oral voriconazole therapy was 76 days (range 2-232 days).

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

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

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

Candidaemia in non-neutropenic patients

The efficacy of voriconazole compared to the regimen of amphotericin B followed by fluconazole in the primary treatment of candidaemia was demonstrated in an open, comparative study. Three hundred and seventy non-neutropenic patients (above 12 years of age) with documented candidaemia were included in the study, of whom 248 were treated with voriconazole. Nine subjects in the voriconazole group and 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 medicinal product was defined as resolution/improvement in all clinical signs and symptoms of infection with eradication of Candida from blood and infected deep tissue sites 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.

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.

Paediatric population

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 to 15 years of age.

The majority (57/61) had failed previous antifungal therapies. Therapeutic studies included 5 patients aged 12 to15 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.

General pharmacokinetic characteristics

The pharmacokinetics of voriconazole have been characterised in healthy subjects, special populations and patients. During oral administration of 200 mg or 300 mg twice daily for 14 days in patients at risk of aspergillosis (mainly patients with malignant neoplasms of lymphatic or haematopoietic tissue), the observed pharmacokinetic characteristics of rapid and consistent absorption, accumulation and non-linear pharmacokinetics were in agreement with those observed in healthy subjects.

The pharmacokinetics of voriconazole are non-linear due to saturation of its metabolism. Greater than proportional increase in exposure is observed with increasing dose. It is estimated that, on average, increasing the oral dose from 200 mg twice daily to 300 mg twice daily leads to a 2.5-fold increase in exposure (AUC). The oral maintenance dose of 200 mg (or 100 mg for patients less than 40 kg) achieves a voriconazole exposure similar to 3 mg/kg IV. A 300 mg (or 150 mg for patients less than 40 kg) oral maintenance dose achieves an exposure similar to 4 mg/kg IV. When the recommended intravenous or oral loading dose regimens are administered, plasma concentrations close to steady state are achieved within the first 24 hours of dosing. Without the loading dose, accumulation occurs during twice daily multiple dosing with steady-state plasma voriconazole concentrations being achieved by day 6 in the majority of subjects.

Absorption

Voriconazole is rapidly and almost completely absorbed following oral administration, with maximum plasma concentrations (C_max) achieved 1-2 hours after dosing. The absolute bioavailability of voriconazole after oral administration is estimated to be 96 %. Bioequivalence was established between the 200 mg tablets and the 40mg/ml oral suspension when administered as a 200 mg dose. When multiple doses of voriconazole are administered with high fat meals, C_max and AUC are reduced by 34 % and 24 %, respectively. The absorption of voriconazole is not affected by changes in gastric pH.

Distribution

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

Biotransformation

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

The inter-individual variability of voriconazole pharmacokinetics is high.

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

The major metabolite of voriconazole is the N-oxide, which accounts for 72 % of the circulating radiolabelled metabolites in plasma. This metabolite has minimal antifungal activity and does not contribute to the overall efficacy of voriconazole.

Elimination

Voriconazole is eliminated via hepatic metabolism with less than 2 % of the dose excreted unchanged in the urine.

After administration of a radiolabelled dose of voriconazole, approximately 80 % of the radioactivity is recovered in the urine after multiple intravenous dosing and 83 % in the urine after multiple oral dosing. The majority (> 94 %) of the total radioactivity is excreted in the first 96 hours after both oral and intravenous dosing.

The terminal half-life of voriconazole depends on dose and is approximately 6 hours at 200 mg (orally). Because of non-linear pharmacokinetics, the terminal half-life is not useful in the prediction of the accumulation or elimination of voriconazole.

Pharmacokinetics in special patient groups

Gender

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

In the clinical programme, no dosage adjustment was made on the basis of gender. The safety profile and plasma concentrations observed in male and female patients were similar. Therefore, no dosage adjustment based on gender is necessary.

Elderly

In an oral multiple dose study C_max and AUC in healthy elderly males ( 65 years) were 61 % and 86 % higher, respectively, than in healthy young males (18-45 years). No significant differences in C_max and AUC were observed between healthy elderly females ( 65 years) and healthy young females (18- 45 years).

In the therapeutic studies no dosage adjustment was made on the basis of age. A relationship between plasma concentrations and age was observed. The safety profile of voriconazole in young and elderly patients was similar and, therefore, no dosage adjustment is necessary for the elderly (see section 4.2).

Paediatric

The recommended doses in children and adolescent patients are based on a population pharmacokinetic analysis of data obtained from 112 immunocompromised paediatric patients aged 2 to <12 years and 26 immunocompromised adolescent patients aged 12 to <17 years.. Multiple intravenous doses of 3, 4, 6, 7 and 8 mg/kg twice daily and multiple oral doses (using the powder for oral suspension) of 4 mg/kg, 6 mg/kg, and 200 mg twice daily were evaluated in 3 paediatric pharmacokinetic studies. Intravenous loading doses of 6 mg/kg IV twice daily on day 1 followed by 4 mg/kg intravenous dose twice daily and 300 mg oral tablets twice daily were evaluated in one adolescent pharmacokinetic study. Larger inter-subject variability was observed in paediatric patients compared to adults.

A comparison of the paediatric and adult population pharmacokinetic data indicated that the predicted total exposure (AUC) in children following administration of a 9 mg/kg IV loading dose was comparable to that in adults following a 6 mg/kg IV loading dose. The predicted total exposures in children following IV maintenance doses of 4 and 8 mg/kg twice daily were comparable to those in adults following 3 and 4 mg/kg IV twice daily, respectively. The predicted total exposure in children following an oral maintenance dose of 9 mg/kg (maximum of 350 mg) twice daily was comparable to that in adults following 200 mg oral twice daily. An 8 mg/kg intravenous dose will provide voriconazole exposure approximately 2-fold higher than a 9 mg/kg oral dose.

The higher intravenous maintenance dose in paediatric patients relative to adults reflects the higher elimination capacity in paediatric patients due to a greater liver mass to body mass ratio. Oral bioavailability may, however, be limited in paediatric patients with malabsorption and very low body weight for their age. In that case, intravenous voriconazole administration is recommended.

Voriconazole exposures in the majority of adolescent patients were comparable to those in adults receiving the same dosing regimens. However, lower voriconazole exposure was observed in some young adolescents with low body weight compared to adults. It is likely that these subjects may metabolize voriconazole more similarly to children than to adults. Based on the population pharmacokinetic analysis, 12- to 14-year-old adolescents weighing less than 50 kg should receive children's doses (see section 4.2).

Renal impairment

Film-coated tablets:

In an oral single dose (200 mg) study in subjects with normal renal function and mild (creatinine clearance 41-60 ml/min) to severe (creatinine clearance < 20 ml/min) renal impairment, the pharmacokinetics of voriconazole were not significantly affected by renal impairment. The plasma protein binding of voriconazole was similar in subjects with different degrees of renal impairment. See dosing and monitoring recommendations under sections 4.2 and 4.4.

Powder for solution for infusion:

In patients with moderate to severe renal dysfunction (serum creatinine levels >2.5 mg /dl), accumulation of the intravenous vehicle, SBECD, occurs. See 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, AUC was similar in subjects with moderate hepatic cirrhosis (Child-Pugh B) given a maintenance dose of 100 mg twice daily and subjects with normal hepatic function given 200 mg twice daily. No pharmacokinetic data are available for patients with severe hepatic cirrhosis (Child-Pugh C) (see sections 4.2 and 4.4).

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.

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.

Film-coated tablets:

Tablet core:

Lactose monohydrate

Pregelatinised starch

Croscarmellose sodium

Povidone

Magnesium stearate

Film-coating:

Hypromellose

Titanium dioxide (E171)

Lactose monohydrate

Glycerol triacetate

Powder for solution for infusion:

Sulphobutylether beta cyclodextrin sodium (SBECD)

Powder for oral suspension:

Sucrose

Silica Colloidal Anhydrous

Titanium Dioxide (E171)

Xanthan Gum

Sodium Citrate

Citric Acid Anhydrous

Sodium Benzoate (E211)

Natural Orange Flavour

Film-coated tablets:

Not applicable

Powder for solution for infusion:

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 sections 4.2 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.

Powder for oral suspension:

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

VFEND film-coated tablets:

3 years.

VFEND powder for solution for infusion:

3 years.

From a microbiological point of view, once reconstituted, the product must be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C (in a refrigerator), unless reconstitution has taken place in controlled and validated aseptic conditions.

Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C to 8°C.

Powder for oral suspension:

2 years.

The shelf-life of the constituted suspension is 14 days.

Constituted suspension: Do not store above 30°C, do not refrigerate or freeze.

Film-coated tablets:

This medicinal product does not require any special storage conditions.

Powder for solution for infusion:

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

Powder for oral suspension:

Store in a refridgerator (2°C - 8°C)

For storage conditions after constitution see section 6.3.

Constituted suspension: Do not store above 30°C, do not refrigerate or freeze.

Keep the container tightly closed.

Film-coated tablets:

HDPE tablet containers containing 2, 30 or 100 film-coated tablets.

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

Not all pack sizes may be marketed.

Powder for solution for infusion:

30 ml clear Type I glass vial with rubber stopper and aluminium cap with plastic seal.

Powder for oral suspension:

One 100 ml high-density polyethylene (HDPE) bottle (with a polypropylene child resistant closure) contains 45 g of powder for oral suspension.

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

Film-coated tablets:

No special requirements.

Powder for solution for infusion:

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

The powder is reconstituted with either 19 ml of water for injections or 19 ml of 9 mg/ml (0.9%) Sodium Chloride for Infusion to obtain an extractable volume of 20 ml of clear concentrate containing 10 mg/ml of voriconazole. Discard the VFEND vial if vacuum does not pull the diluent into the vial. It is recommended that a standard 20 ml (non-automated) syringe be used to ensure that the exact amount (19.0 ml) of water for injections or 9 mg/ml (0.9%) Sodium Chloride for Infusion is dispensed. This medicinal product is for single use only and any unused solution should be discarded 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

The reconstituted solution can be diluted with:

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

Compound Sodium Lactate Intravenous Infusion 5 % Glucose and Lactated Ringer's Intravenous Infusion

5 % Glucose and 0.45 % Sodium Chloride Intravenous Infusion

5 % Glucose Intravenous Infusion

5 % Glucose in 20 mEq Potassium Chloride Intravenous Infusion

0.45 % Sodium Chloride Intravenous Infusion

5% Glucose and 0.9 % Sodium Chloride Intravenous Infusion

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

Powder for oral suspension:

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

Constitution instructions:

1. Tap the bottle to release the powder.

2. Measure 23 ml of water by filling the measuring cup to the top of the marked line. Add the water to the bottle. Using the cup measure another 23 ml of water and add this to the bottle.

3. Shake the closed bottle vigorously for about 1 minute.

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

5. Replace the cap.

6. Write the date of expiration of the constituted suspension on the bottle label (the shelf-life of the constituted suspension is 14 days).

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

Instructions for use:

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

Once constituted, VFEND oral suspension should only be administered using the oral syringe supplied with each pack. Refer to the patient leaflet for more detailed instructions for use.

Pfizer Limited, Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom

EU/1/02/212/001 VFEND 50 mg Film-coated tablets; Pack size 2 tablets; Blister

EU/1/02/212/002 VFEND 50 mg Film-coated tablets; Pack size 10 tablets; Blister

EU/1/02/212/003 VFEND 50 mg Film-coated tablets; Pack size 14 tablets; Blister

EU/1/02/212/004 VFEND 50 mg Film-coated tablets; Pack size 20 tablets; Blister

EU/1/02/212/005 VFEND 50 mg Film-coated tablets; Pack size 28 tablets; Blister

EU/1/02/212/006 VFEND 50 mg Film-coated tablets; Pack size 30 tablets; Blister

EU/1/02/212/007 VFEND 50 mg Film-coated tablets; Pack size 50 tablets; Blister

EU/1/02/212/008 VFEND 50 mg Film-coated tablets; Pack size 56 tablets; Blister

EU/1/02/212/009 VFEND 50 mg Film-coated tablets; Pack size 100 tablets; Blister

EU/1/02/212/010 VFEND 50 mg Film-coated tablets; Pack size 2 tablets; Bottle

EU/1/02/212/011 VFEND 50 mg Film-coated tablets; Pack size 30 tablets; Bottle

EU/1/02/212/012 VFEND 50 mg Film-coated tablets; Pack size 100 tablets; Bottle

EU/1/02/212/013 VFEND 200 mg Film-coated tablets; Pack size 2 tablets; Blister

EU/1/02/212/014 VFEND 200 mg Film-coated tablets; Pack size 10 tablets; Blister

EU/1/02/212/015 VFEND 200 mg Film-coated tablets; Pack size 14 tablets; Blister

EU/1/02/212/016 VFEND 200 mg Film-coated tablets; Pack size 20 tablets; Blister

EU/1/02/212/017 VFEND 200 mg Film-coated tablets; Pack size 28 tablets; Blister

EU/1/02/212/018 VFEND 200 mg Film-coated tablets; Pack size 30 tablets; Blister

EU/1/02/212/019 VFEND 200 mg Film-coated tablets; Pack size 50 tablets; Blister

EU/1/02/212/020 VFEND 200 mg Film-coated tablets; Pack size 56 tablets; Blister

EU/1/02/212/021 VFEND 200 mg Film-coated tablets; Pack size 100 tablets; Blister

EU/1/02/212/022 VFEND 200 mg Film-coated tablets; Pack size 2 tablets; Bottle

EU/1/02/212/023 VFEND 200 mg Film-coated tablets; Pack size 30 tablets; Bottle

EU/1/02/212/024 VFEND 200 mg Film-coated tablets; Pack size 100 tablets; Bottle

EU/1/02/212/025 VFEND 200 mg Powder for solution for infusion; Vial

EU/1/02/212/026 VFEND 40 mg/ml Powder for oral suspension; Bottle

Date of first authorisation: 21 March 2002

Date of latest renewal: 21 March 2007

April 2012

POM

Ref: VF 27_0

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