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: lactose monohydrate 63.42 mg or 253.675 mg

For a full list of excipients, see section 6.1.

Powder for solution for infusion:

Each ml contains 10 mg of voriconazole after reconstitution (see section 6.6) - once reconstituted further dilution is required before administration. Each vial contains 200 mg of voriconazole.

Excipient: each vial contains 217.6 mg sodium

For a full list of excipients, see section 6.1.

Powder for oral suspension:

Each ml of oral suspension contains 40 mg of voriconazole when reconstituted with water (see section 6.6). Each bottle contains 3 g of voriconazole.

Excipient: Each ml of suspension contains 0.54 g of sucrose

For a full list of excipients, see section 6.1.

Film-coated tablets:

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

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 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.

Film-coated tablets (50mg and 200mg):

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

Powder for oral suspension:

VFEND oral suspension (40mg/mL) is to be taken at least one hour before, or two hours following, a meal.

Powder for solution for infusion:

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

It is recommended that VFEND is administered at a maximum rate of 3 mg/kg per hour over 1 to 2 hours.

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

VFEND must not be infused into the same line or cannula concomitantly with other intravenous products. VFEND must not be administered simultaneously with any blood product or any short-term infusion of concentrated solutions of electrolytes, even if the two infusions are running in separate lines. Total parenteral nutrition (TPN) need not be discontinued when prescribed with VFEND, but does need to be infused through a separate line (see section 6.2).

Use in adults and adolescents (12 to 16 years of age)

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.

Rifabutin may be co-administered with voriconazole if the maintenance dose of voriconazole is increased from 200 mg to 350 mg orally, twice daily (100 mg to 200 mg orally, twice daily in patients less than 40 kg), see sections 4.4 and 4.5.

Efavirenz may be 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).

Treatment duration depends upon patients' clinical and mycological response.

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).

Treatment duration depends upon patients' clinical and mycological response. The duration of treatment with the intravenous formulation should be no longer than 6 months (see section 5.3).

Use in the elderly

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

Use in patients with 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.

Use in patients with hepatic impairment

No dose adjustment is necessary in patients with acute hepatic injury, manifested by elevated liver function tests (ALAT, ASAT) (but continued monitoring of liver function tests for further elevations is recommended).

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

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

VFEND has been associated with elevations in liver function tests and clinical signs of liver damage, such as jaundice, and must only be used in patients with severe hepatic impairment if the benefit outweighs the potential risk. Patients with hepatic impairment must be carefully monitored for drug toxicity (see also section 4.8).

Use in children

VFEND is not recommended for use in children below 2 years due to insufficient data on safety and efficacy (see also sections 4.8 and 5.1).

Film-coated tablets, Powder for oral suspension & Powder for solution for infusion:

The recommended maintenance dosing regimen in paediatric patients aged 2 to <12 years is as follows:

*Based on a population pharmacokinetic analysis in 82 immunocompromised patients aged 2 to <12 years

**Based on a population pharmacokinetic analysis in 47 immunocompromised patients aged 2 to <12 years

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

Adolescents (12 to 16 years of age): should be dosed as adults.

Film-coated tablets and Powder for oral suspension:

These paediatric dose recommendations are based on studies in which VFEND was administered as the powder for oral suspension. Bioequivalence between the powder for oral suspension and tablets has not been investigated in a paediatric population. Considering the assumed limited gastro-enteric transit time in paediatrics, the absorption of the tablets may be different in paediatric compared to adult patients. It is therefore recommended to use the oral suspension formulation in children aged 2 to <12 years.

Powder for solution for infusion:

If paediatric patients are unable to tolerate an intravenous dose of 7mg/kg twice daily, a dose reduction from 7mg/kg to 4mg/kg twice daily may be considered based on the population pharmacokinetic analysis and previous clinical experience. This provides equivalent exposure to 3mg/kg twice daily in adults (see section 4.2 use in adults).

Hypersensitivity to the active substance or to any of the excipients.

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

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

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

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

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

The concomitant use of voriconazole with St John's Wort is contraindicated (see section 4.5).

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

Cardiovascular:

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

• Congenital or acquired QT-prolongation

• Cardiomyopathy, in particular when heart failure is present

• Sinus bradycardia

• Existing symptomatic arrhythmias

• Concomitant medication that is known to prolong QT interval.

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

Infusion-related reactions: Infusion-related reactions, predominantly flushing and nausea, have been observed during administration of the intravenous formulation of voriconazole. Depending on the severity of symptoms, consideration should be given to stopping treatment (see section 4.8).

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

Monitoring of hepatic function: 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 events: There have been rare reports of prolonged visual adverse events, including blurred vision, optic neuritis and papilloedema (see section 4.8).

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

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

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

Dermatological 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 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 (see also sections 4.8 and 5.1). Voriconazole is indicated for paediatric patients aged two years or older. Hepatic function should be monitored in both children and adults. Oral bioavailability may be limited in paediatric patients aged 2 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).

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).

Methadone (CYP3A4 substrate). Frequent monitoring for adverse events 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 and other short acting opiates similar in structure to alfentanil and metabolised by CYP3A4 (e.g. fentanyl and 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, a longer respiratory monitoring period may be necessary.

Ritonavir (potent CYP450 inducer; CYP3A4 inhibitor and substrate): Co-administration of voriconazole and low dose ritonavir (100mg twice daily) should be avoided unless an assessment of the benefit/risk justifies the use of voriconazole. (see section 4.5, for higher doses see section 4.3).

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

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

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 infusion contains 217.6 mg of sodium. This should be taken into consideration for patients on a controlled sodium diet.

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

This section addresses the effects of other medicinal products on voriconazole, the effects of voriconazole on other medicinal products and two-way interactions. The interactions for the first two sections are presented in the following order: contraindications, those requiring dosage adjustment and careful clinical and/or biological monitoring and finally those that have no significant pharmacokinetic interaction but may be of clinical interest in this therapeutic field.

Effects of other medicinal products on voriconazole

Voriconazole is metabolised by cytochrome P450 isoenzymes, CYP2C19, CYP2C9 and CYP3A4. Inhibitors or inducers of these isoenzymes may increase or decrease voriconazole plasma concentrations respectively.

Rifampicin (CYP450 inducer): Rifampicin (600 mg once daily) decreased the C_max (maximum plasma concentration) and AUC (area under the plasma concentration time curve within a dose interval) of voriconazole by 93 % and 96 %, respectively. Co-administration of voriconazole and rifampicin is contraindicated (see section 4.3).

Ritonavir (potent CYP450 inducer; CYP3A4 inhibitor and substrate): The effect of the co-administration of oral voriconazole (200 mg twice daily) and high dose (400 mg) and low dose (100 mg) oral ritonavir was investigated in two separate studies in healthy volunteers. High doses of ritonavir (400 mg twice daily) decreased the steady state C_max and AUC of oral voriconazole by an average of 66 % and 82 %, , whereas low doses of ritonavir (100mg twice daily) decreased the C_max and AUC of voriconazole by an average of 24 % and 39 % respectively. Administration of voriconazole did not have a significant effect on mean C_max and AUC of ritonavir in the high dose study, although a minor decrease in steady state C_max and AUC of ritonavir with an average of 25 % and 13 % respectively was observed in the low dose ritonavir interaction study. One outlier subject with raised voriconazole levels was identified in each of the ritonavir interaction studies. Co-administration of voriconazole and high doses of ritonavir (400 mg and above twice daily) is contraindicated. Co-administration of voriconazole and low dose ritonavir (100 mg twice daily) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole (see section 4.3 and 4.4).

Carbamazepine and phenobarbital (potent CYP450 inducers): Although not studied, carbamazepine or phenobarbital are likely to significantly decrease plasma voriconazole concentrations. Co-administration of voriconazole with carbamazepine and phenobarbital is contraindicated (see section 4.3).

Cimetidine (non-specific CYP450 inhibitor and increases gastric pH): Cimetidine (400 mg twice daily) increased voriconazole C_max and AUC 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 C_max and AUC.

Macrolide antibiotics: Erythromycin (CYP3A4 inhibitor; 1 g twice daily) and azithromycin (500 mg once daily) had no significant effect on voriconazole C_max and AUC.

St John's Wort (CYP450 inducer; P-gp inducer): In a clinical study in healthy volunteers, St John's Wort exhibited a short initial inhibitory effect followed by induction of voriconazole metabolism. After 15 days of treatment with St John's Wort (300 mg three times daily), plasma exposure following a single 400 mg dose of voriconazole decreased by 40-60%. Therefore, concomitant use of voriconazole with St John's Wort is contraindicated (see section 4.3).

Effects of voriconazole on other medicinal products

Voriconazole inhibits the activity of cytochrome P450 isoenzymes, CYP2C19, CYP2C9 and CYP3A4. Therefore there is potential for voriconazole to increase the plasma levels of substances metabolised by these CYP450 isoenzymes.

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

Terfenadine, astemizole, cisapride, pimozide and quinidine (CYP3A4 substrates): Although not studied, co-administration of voriconazole with terfenadine, astemizole, cisapride, pimozide, or quinidine is contraindicated, since increased plasma concentrations of these medicinal products can lead to QTc prolongation and rare occurrences of torsades de pointes (see section 4.3).

Sirolimus (CYP3A4 substrate): Voriconazole increased sirolimus (2 mg single dose) C_max and AUC by 556 % and 1014 %, respectively. Co-administration of voriconazole and sirolimus is contraindicated (see section 4.3).

Ergot alkaloids (CYP3A4 substrates): Although not studied, voriconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) and lead to ergotism. Co-administration of voriconazole with ergot alkaloids is contraindicated (see section 4.3).

Cyclosporin (CYP3A4 substrate): In stable, renal transplant recipients, voriconazole increased cyclosporin C_max and AUC 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.

Methadone (CYP3A4 substrate): In subjects receiving a methadone maintenance dose (32-100 mg once daily) co-administration of oral voriconazole (400 mg twice daily for 1 day, then 200 mg twice daily for four days) increased the C_max and AUC of pharmacologically active R-methadone by 31 % and 47 %, respectively, whereas the C_max and AUC of the S-enantiomer increased by approximately 65 % and 103 %, respectively. Voriconazole plasma concentrations during co-administration of methadone were comparable to voriconazole levels (historical data) in healthy subjects without any comedication. Frequent monitoring for adverse events and toxicity related to increased plasma concentrations of methadone, including QT prolongation, is recommended during co-administration. Dose reduction of methadone may be needed.

Short Acting Opiates (CYP3A4 substrate): Steady-state administration of oral voriconazole increased the AUC of a single dose of alfentanil by 6-fold. Reduction in the dose of alfentanil and other short acting opiates similar in structure to alfentanil and metabolised by CYP3A4 (e.g. fentanyl and sufentanil), should be considered when co-administered with voriconazole (see section 4.4).

Tacrolimus (CYP3A4 substrate): Voriconazole increased tacrolimus (0.1 mg/kg single dose) C_max and AUC_t (area under the plasma concentration time curve to the last quantifiable measurement) by 117 % and 221 %, respectively. When initiating voriconazole in patients already receiving tacrolimus, it is recommended that the tacrolimus dose be reduced to a third of the original dose and tacrolimus level carefully monitored. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus levels must be carefully monitored and the dose increased as necessary.

Oral anticoagulants:

Warfarin (CYP2C9 substrate): Co-administration 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 co-administered.

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 co-administration.

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 co-administration. Increased statin levels have been associated with rhabdomyolysis.

Benzodiazepines (CYP3A4 substrates): Although not studied clinically, voriconazole has been shown to inhibit midazolam metabolism in vitro (human liver microsomes). Therefore, voriconazole is likely to increase the plasma levels of benzodiazepines that are metabolised by CYP3A4 (e.g. midazolam and triazolam) and lead to a prolonged sedative effect. It is recommended that dose adjustment of the benzodiazepine be considered during co-administration.

Vinca Alkaloids (CYP3A4 substrates): Although not studied, voriconazole may increase the plasma levels of the vinca alkaloids (e.g. vincristine and vinblastine) and lead to neurotoxicity.

Prednisolone (CYP3A4 substrate): Voriconazole increased C_max and AUC 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 C_max and AUC of digoxin (0.25 mg once daily).

Mycophenolic acid (UDP-glucuronyl transferase substrate): Voriconazole had no effect on the C_max and AUC_t of mycophenolic acid (1 g single dose).

Non-Steroidal Anti-Inflammatory Drugs (CYP2C9 substrates): Voriconazole increased Cmax and AUC of ibuprofen (400 mg single dose) by 20% and 100%, respectively. Voriconazole increased Cmax and AUC of diclofenac (50 mg single dose) by 114% and 78%, respectively. Frequent monitoring for adverse events and toxicity related to NSAIDs is recommended. Adjustment of dosage of NSAIDs may be needed.

Two-way interactions

Phenytoin (CYP2C9 substrate and potent CYP450 inducer): Concomitant use of voriconazole and phenytoin should be avoided unless the benefit outweighs the risk.

Phenytoin (300 mg once daily) decreased the C_max and AUC of voriconazole by 49 % and 69 %, respectively. Voriconazole (400 mg twice daily, see section 4.2) increased C_max and AUC of phenytoin (300 mg once daily) by 67 % and 81 %, respectively. Careful monitoring of phenytoin plasma levels is recommended when phenytoin is co-administered with voriconazole.

Phenytoin may be co-administered with voriconazole if the maintenance dose of voriconazole is increased to 5 mg /kg intravenously twice daily or from 200 mg to 400 mg orally, twice daily (100 mg to 200 mg orally, twice daily in patients less than 40 kg), see section 4.2.

Rifabutin (CYP450 inducer): Concomitant use of voriconazole and rifabutin should be avoided unless the benefit outweighs the risk.

Rifabutin (300 mg once daily) decreased the C_max and AUC of voriconazole at 200 mg twice daily by 69 % and 78 %, respectively. During co-administration with rifabutin, the C_max and AUC of voriconazole at 350 mg twice daily were 96 % and 68 % of the levels when administered alone at 200 mg twice daily. At a voriconazole dose of 400 mg twice daily C_max and AUC were 104 % and 87 % higher, respectively, compared with voriconazole alone at 200 mg twice daily. Voriconazole at 400 mg twice daily increased C_max and AUC of rifabutin by 195 % and 331 %, respectively.

If rifabutin co-administration with voriconazole is justified then the maintenance dose of voriconazole may be increased to 5 mg/kg intravenously twice daily or from 200 mg to 350 mg orally, twice daily (100 mg to 200 mg orally, twice daily in patients less than 40 kg) (see section 4.2). Careful monitoring of full blood counts and adverse reactions to rifabutin (e.g. uveitis) is recommended when rifabutin is co-administered with voriconazole.

Omeprazole (CYP2C19 inhibitor; CYP2C19 and CYP3A4 substrate): Omeprazole (40 mg once daily) increased voriconazole C_max and AUC by 15 % and 41 %, respectively. No dosage adjustment of voriconazole is recommended. Voriconazole increased omeprazole C_max and AUC by 116 % and 280 %, respectively. When initiating voriconazole in patients already receiving omeprazole, it is recommended that the omeprazole dose be halved. The metabolism of other proton pump inhibitors which are CYP2C19 substrates may also be inhibited by voriconazole.

Oral Contraceptives Co-administration of voriconazole and an oral contraceptive (1 mg norethisterone and 0.035mg ethinylestradiol; once daily) in healthy female subjects resulted in increases in the Cmax and AUC of ethinylestradiol (36 % and 61 % respectively) and norethisterone (15 % and 53 % respectively). Voriconazole Cmax and AUC increased by 14 % and 46 % respectively. It is expected that the voriconazole levels will return to standard levels during the pill-free week. As the ratio between norethisterone and ethinylestradiol remained similar during interaction with voriconazole, their contraceptive activity would probably not be affected. Although no increase in the incidence of hormonal-related adverse events was observed in the clinical interaction study, higher estrogen and progestagen levels may cause notably nausea and menstrual disorders. Oral contraceptives containing doses other than 1mg norethisterone and 0.035 mg ethinylestradiol have not been studied.

Antiretroviral agents:

Indinavir (CYP3A4 inhibitor and substrate): Indinavir (800 mg three times daily) had no significant effect on voriconazole C_max, C_min and AUC. Voriconazole did not have a significant effect on C_max and AUC of indinavir (800 mg three times daily).

Other HIV protease inhibitors (CYP3A4 inhibitors): In vitro studies suggest that voriconazole may inhibit the metabolism of HIV protease inhibitors (e.g. saquinavir, amprenavir and nelfinavir). In vitro studies also show that the metabolism of voriconazole may be inhibited by HIV protease inhibitors. However results of the combination of voriconazole with other HIV protease inhibitors cannot be predicted in humans only from in vitro studies. Patients should be carefully monitored for any occurrence of drug toxicity and/or loss of efficacy during the co- administration of voriconazole and HIV protease inhibitors.

Efavirenz (a non-nucleoside reverse transcriptase inhibitor) (CYP450 inducer; CYP3A4 inhibitor and substrate)): Standard doses of voriconazole and standard doses of efavirenz must not be co-administered. Steady-state efavirenz (400 mg orally once daily) decreased the steady state C_max and AUC of voriconazole by an average of 61 % and 77 %, respectively, in healthy subjects. In the same study voriconazole at steady state increased the steady state C_max and AUC of efavirenz by an average of 38 % and 44 % respectively, in healthy subjects.

In a separate study in healthy subjects, voriconazole dose of 300mg BID in combination with low dose efavirenz (300 mg once daily) did not lead to sufficient voriconazole exposure.

Following co-administration of voriconazole 400 mg twice daily with efavirenz 300 mg orally once daily, in healthy subjects, the AUC of voriconazole was decreased by 7 % and Cmax was increased by 23 %, compared to voriconazole 200 mg twice daily alone. (The AUC of efavirenz was increased by 17 % and Cmax was equivalent compared to efavirenz 600 mg once daily alone). These differerences were not considered to be clinically significant.

When voriconazole is co-administered with efavirenz, voriconazole maintenance dose should be increased to 400 mg twice daily and the efavirenz dose should be reduced by 50 %, i.e. to 300 mg once daily (see section 4.2). When treatment with voriconazole is stopped, the initial dosage of efavirenz should be restored.

Non-nucleoside reverse transcriptase inhibitors (NNRTI)(CYP3A4 substrates, inhibitors or CYP450 inducers): In vitro studies show that the metabolism of voriconazole may be inhibited by delavirdine. Although not studied, the metabolism of voriconazole may be induced by nevirapine. An in-vivo study showed that voriconazole inhibited the metabolism of efavirenz. Voriconazole may also inhibit the metabolism of NNRTIs besides efavirenz. Patients should be carefully monitored for any occurrence of drug toxicity and/or lack of efficacy during the co-administration of voriconazole and NNRTIs. Dose adjustments are required when voriconazole is co-administered with efavirenz (see sections 4.2 and 4.4).

Pregnancy

No adequate information on the use of VFEND in pregnant women is available.

Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk forhumans is unknown.

VFEND must not be used during pregnancy unless the benefit to the mother clearly outweighs the potential risk to the foetus.

Women of child-bearing potential

Women of child-bearing potential must always use effective contraception during treatment.

Lactation

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

VFEND may have a moderate influence on the ability to drive and use machines. It may cause transient and reversible changes to vision, including blurring, altered/enhanced visual perception and/or photophobia. Patients must avoid potentially hazardous tasks, such as driving or operating machinery while experiencing these symptoms.

The safety profile of voriconazole is based on an integrated safety database of more than 2000 subjects (1655 patients in therapeutic trials). This represents a heterogeneous population, containing patients with haematological malignancy, HIV infected patients with oesophageal candidiasis and refractory fungal infections, non-neutropenic patients with candidaemia or aspergillosis and healthy volunteers. Five hundred and sixty one patients had a duration of voriconazole therapy of greater than 12 weeks, with 136 patients receiving voriconazole for over 6 months.

In the table below, since the majority of the studies were of an open nature all causality adverse events, by system organ class and frequency (very common 1/10, common 1/100 and <1/10, uncommon 1/1000 and <1/100, rare, 1/10 000 and <1/1000 and very rare, <1/10 000) if possibly causally related are listed. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. The most commonly reported adverse events were visual disturbances, pyrexia, rash, vomiting, nausea, diarrhoea, headache, peripheral oedema and abdominal pain. The severity of the adverse events was generally mild to moderate. No clinically significant differences were seen when the safety data were analysed by age, race, or gender.

Undesirable effects reported in subjects receiving voriconazole

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 medications. The majority of rashes were of mild to moderate severity. Patients have rarely developed serious cutaneous reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme during treatment with VFEND.

If patients develop a rash they should be monitored closely and VFEND discontinued if lesions progress.

Photosensitivity reactions have been reported, especially during long-term therapy (see also section 4.4).

Liver function tests

The overall incidence of clinically significant transaminase abnormalities in the voriconazole clinical programme was 13.4 % (200/1493) of subjects treated with voriconazole. Liver function test abnormalities may be associated with higher plasma concentrations and/or doses. The majority of abnormal liver function tests either resolved during treatment without dose adjustment or following dose adjustment, including discontinuation of therapy.

Voriconazole has been infrequently associated with cases of serious hepatic toxicity in patients with other serious underlying conditions. This includes cases of jaundice, and rare cases of hepatitis and hepatic failure leading to death (see section 4.4).

Infusion-related reactions

During infusion of the intravenous formulation of voriconazole in healthy subjects, anaphylactoid-type reactions, including flushing, fever, sweating, tachycardia, chest tightness, dyspnoea, faintness, nausea, pruritus and rash have occurred. Symptoms appeared immediately upon initiating the infusion (see also section 4.4).

Paediatric Use

The safety of voriconazole was investigated in 245 paediatric patients aged 2 to <12 years who were treated with voriconazole in pharmacokinetic studies (87 paediatric patients) and in compassionate use programs (158 paediatric patients). The adverse event profile of these 245 paediatric patients was similar to that in adults, although post-marketing data suggest there might be a higher occurrence of skin reactions (esp. erythema) in the paediatric population compared to adults. In the 22 patients less than 2 years old who received voriconazole in a compassionate use programme, the following adverse events (for which a relationship to voriconazole could not be excluded) were reported: photosensitivity reaction (1), arrhythmia (1), pancreatitis (1), blood bilirubin increased (1), hepatic enzymes increased (1), rash (1) and papilloedema (1).

There have been post-marketing reports of pancreatitis in paediatric patients.

In clinical trials there were 3 cases of accidental overdose. All occurred in paediatric patients, who received up to five times the recommended intravenous dose of voriconazole. A single adverse 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: ATC code: J02A C03

Antimycotics for Systemic Use – Triazole derivatives

Mechanism of action

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. Its mode of action is inhibition of fungal cytochrome P450-mediated 14α-sterol demethylation, an essential step in ergosterol biosynthesis.

In animal studies there is a correlation between minimum inhibitory concentration values and efficacy against experimental mycoses. By contrast, in clinical studies, there appears to be no correlation between minimum inhibitory concentration values and clinical outcome. Furthermore, there does not appear to be a correlation between plasma levels and clinical outcome. This is typical of azole antimycotics.

Microbiology

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

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

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

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. However, elevated minimum inhibitory concentrations did not always correlate with clinical failure and clinical success has been observed in patients infected with organisms resistant to other azoles. Correlation of in vitro activity with clinical outcome is difficult owing to the complexity of the patients studied in clinical trials; breakpoints for voriconazole remain to be established.

Clinical Experience

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

Aspergillus infections – efficacy in aspergillosis patients with poor prognosis

Voriconazole has in vitro fungicidal activity against Aspergillus spp. The efficacy and survival benefit of voriconazole versus conventional amphotericin B in the primary treatment of acute invasive aspergillosis was demonstrated in an open, randomised, multicentre study in 277 immunocompromised patients treated for 12 weeks. A satisfactory global response (complete or partial resolution of all attributable symptoms signs, radiographic/bronchoscopic abnormalities present at baseline) was seen in 53 % of voriconazole-treated patients compared to 31 % of patients treated with comparator. The 84-day survival rate for voriconazole was statistically significantly higher than that for the comparator and a clinically and statistically significant benefit was shown in favour of voriconazole for both time to death and time to discontinuation due to toxicity.

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

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

Candidaemia in non-neutropenic patients

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

In a secondary analysis, which utilised DRC assessments at the latest evaluable time point (EOT, or 2, 6, or 12 weeks after EOT) voriconazole and the regimen of amphotericin B followed by fluconazole had successful response rates of 65 % and 71 %, respectively. The Investigator's assessment of successful outcome at each of these time points is shown in the following table.

Serious refractory Candida infections

The study comprised 55 patients with serious refractory systemic Candida infections (including candidaemia, disseminated and other invasive candidiasis) where prior antifungal treatment, particularly with fluconazole, had been ineffective. Successful response was seen in 24 patients (15 complete, 9 partial responses). In fluconazole-resistant non albicans species, a successful outcome was seen in 3/3 C. krusei (complete responses) and 6/8 C. glabrata (5 complete, 1 partial response) infections. The clinical efficacy data were supported by limited susceptibility data.

Scedosporium and Fusarium infections

Voriconazole was shown to be effective against the following rare fungal pathogens:

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

Fusarium spp.: Seven (3 complete, 4 partial responses) of 17 patients were successfully treated with voriconazole. Of these 7 patients, 3 had eye, 1 had sinus, and 3 had disseminated infection. Four additional patients with fusariosis had an infection caused by several organisms; two of them had a successful outcome.

The majority of patients receiving voriconazole treatment of the above mentioned rare infections were intolerant of, or refractory to, prior antifungal therapy.

Duration of treatment

In clinical trials, 561 patients received voriconazole therapy for greater than 12 weeks, with 136 patients receiving voriconazole for over 6 months.

Experience in paediatric patients

Sixty one paediatric patients aged 9 months up to 15 years who had definite or probable invasive fungal infections, were treated with voriconazole. This population included 34 patients 2 to < 12 years old and 20 patients 12 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). 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.

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 (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.

Excretion

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

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

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

Pharmacokinetic-Pharmacodynamic relationships

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

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

Pharmacokinetics in special patient groups

Gender

In an oral multiple dose study, 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).

Paediatrics

Film-coated tablets & Powder for oral suspension:

The recommended oral dose in paediatrics is based on a population pharmacokinetic analysis of data obtained from 47 immunocompromised paediatric patients aged 2 to <12 years old who were evaluated in a pharmacokinetic study examining multiple oral suspension doses of 4 and 6 mg/kg twice daily. A comparison of the paediatric and adult population pharmacokinetic data indicated that in order to obtain comparable exposures to those obtained in adults following a maintenance dose of 200 mg twice daily, 200 mg of oral suspension twice daily is required in paediatric patients, independent of body weight. In paediatric patients there is a general trend towards low bioavailability at lower body weights and high bioavailability at higher body weights (approaching the extent demonstrated in adults). Based on the population pharmacokinetic analysis, no dosage adjustment according to age or weight is warranted in patients aged 2 to <12 years old at the 200 mg b.i.d. oral solution dosing regimen. A loading dose is not indicated in paediatric patients. Oral bioavailability may, however, be limited in paediatric patients with malabsorption and very low body weight for their age. In that case, intravenous voriconazole administration is recommended.

Powder for Solution for Infusion:

The recommended intravenous dose in paediatric patients is based on a population pharmacokinetic analysis of data pooled from 82 immunocompromised paediatric patients aged 2 to <12 years old who were evaluated in three pharmacokinetic studies (examining single intravenous doses of 3 and 4 mg/kg twice daily, multiple intravenous doses of 3, 4, 6 and 8mg/kg twice daily and multiple oral suspension doses of 4 and 6 mg/kg twice daily). The majority of patients received more than one dose level with a maximum duration of dosing of 30 days.

A comparison of the paediatric and adult population pharmacokinetic data indicated that in order to obtain comparable exposures to those obtained in adults following intravenous maintenance doses of 4 mg/kg twice daily, intravenous maintenance doses of 7 mg/kg twice daily are required in paediatric patients. The higher intravenous maintenance dose in paediatric patients relative to adults reflects the higher elimination capacity in paediatric patients due to a greater liver mass to body mass ratio. In order to obtain comparable exposures to those obtained in adults following intravenous maintenance doses of 3mg/kg twice daily, intravenous maintenance doses of 4 mg/kg twice daily are required in paediatric patients.

Based on the population pharmacokinetic analysis, no loading dose or dosage adjustment according to age is warranted in patients aged 2 to <12 years old.

Renal impairment

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 dosing and monitoring recommendations under 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-coat:

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

Titanium Dioxide (E171)

Xanthan Gum

Sodium Citrate

Sodium Benzoate (E211)

Citric Acid

Natural Orange Flavour (containing orange oil, maltodextrin and tocopherol)

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 section 4.2 and section 4.4). VFEND must not be administered simultaneously with any blood product or any short-term infusion of concentrated solutions of electrolytes, even if the two infusions are running in separate lines.

Total parenteral nutrition:

Total parenteral nutrition (TPN) need not be discontinued when prescribed with VFEND, but does need to be infused through a separate line. If infused through a multiple-lumen catheter, TPN needs to be administered using a different port from the one used for VFEND.

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

Compatibility with other concentrations is unknown.

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

Powder for oral suspension:

This medicinal product must not be mixed with other medicinal products except those mentioned in 6.6. It is not intended that the suspension be further diluted with water or other vehicles.

VFEND film-coated tablets: 3 years.

VFEND powder for solution for infusion: 3 years.

VFEND is a single dose unpreserved sterile lyophile. Therefore, 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, 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:

The shelf-life of the powder for oral suspension is 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:

No special precautions for storage.

Powder for solution for infusion:

Reconstituted concentrate: Store at 2°C-8°C for up to 24 hours (in a refrigerator).

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

Powder for oral suspension:

Powder for oral suspension: Store at 2°C - 8°C (in a refrigerator) before constitution.

For storage conditions of the constituted suspension 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 of 2, 30 and 100. Not all bottle sizes may be marketed.

PVC / Aluminium blister in cartons of 2, 10, 14, 20, 28, 30, 50, 56 and 100.

Not all pack sizes may be marketed.

Powder for solution for infusion:

Packs of 1 single use 30 ml clear Type I glass vials with rubber stoppers and aluminium caps with plastic seals.

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

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

Pack size: 1 bottle.

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 19 ml of Water for Injections to obtain an extractable volume of 20 ml of clear concentrate containing 10 mg/ml of voriconazole. Discard the VFEND vial if vacuum does not pull the diluent into the vial. It is recommended that a standard 20 ml (non-automated) syringe be used to ensure that the exact amount (19.0 ml) of Water for Injections is dispensed. This medicinal product is for single use only and any unused solution should be discarded and only clear solutions without particles should be used.

For administration, the required volume of the reconstituted concentrate is added to a recommended compatible infusion solution (detailed below) to obtain a final voriconazole solution containing 0.5-5 mg/ml.

Required Volumes of 10 mg/ml VFEND Concentrate

Voriconazole is a single dose unpreserved sterile lyophile. Therefore, from a microbiological point of view, the reconstituted solution must be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution has taken place in controlled and validated aseptic conditions.

The reconstituted solution can be diluted with:

9 mg/ml (0.9 %) Sodium Chloride for Infusion

Lactated Ringer's Intravenous Infusion

5 % Glucose and Lactated Ringer's Intravenous Infusion

5 % Glucose and 0.45 % Sodium Chloride Intravenous Infusion

5 % Glucose Intravenous Infusion

5 % Glucose in 20 mEq Potassium Chloride Intravenous Infusion

0.45 % Sodium Chloride Intravenous Infusion

5% Glucose and 0.9 % Sodium Chloride Intravenous Infusion

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

Powder for oral suspension:

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

Any remaining suspension should be discarded 14 days after constitution.

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).

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 last renewal: 21 March 2007

1 September 2009

POM

Ref: VF 20_0

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