1. Name Of The Medicinal Product
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.
2. Qualitative And Quantitative Composition
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.
3. Pharmaceutical Form
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
4. Clinical Particulars
4.1 Therapeutic Indications
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.
4.2 Posology And Method Of Administration
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:
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Intravenous
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Oral (Tablets and Suspension)
|
|
|
|
Patients 40 kg and above
|
Patients less than 40 kg
|
Loading Dose Regimen
(first 24 hours)
|
6 mg/kg every 12 hours (for the first 24 hours)
|
400 mg (10 ml) every 12 hours (for the first 24 hours)
|
200 mg (5 ml) every 12 hours (for the first 24 hours)
|
Maintenance Dose
(after first 24 hours)
|
4 mg/kg twice daily
|
200 mg (5 ml) twice daily
|
100 mg (2.5 ml) twice daily
|
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 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 section 4.4 Special warnings and precautions for use (Dermatological adverse events) and section 5.1 Pharmacodynamic properties (Duration of treatment).
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 should be as short as possible depending on the patients' clinical and mycological response.
The duration of treatment with the intravenous formulation should be no longer than 6 months. See section 5.3 (preclinical safety data). For voriconazole in general, long term treatment greater than 6 months requires careful assessment of the benefit-risk balance. See section 4.4 Special warnings and precautions for use (Dermatological adverse events), section 5.1 Pharmacodynamic properties (Duration of treatment).
Use in the elderly
No dose adjustment is necessary for elderly patients (see section 5.2).
Use in patients with renal impairment
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:
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Intravenous*
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Oral (Tablets and suspension) **
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Loading Dose Regimen
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No oral or intravenous loading dose is recommended
|
|
Maintenance Dose
|
7 mg/kg twice daily
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200 mg (5 ml) twice daily
|
*Based on a population pharmacokinetic analysis in 82 immunocompromised patients aged 2 to <12 years
**Based on a population pharmacokinetic analysis in 47 immunocompromised patients aged 2 to <12 years
Use in paediatric patients aged 2 to <12 years with hepatic or renal insufficiency has not been studied (see section 4.8 and section 5.2).
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).
4.3 Contraindications
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).
4.4 Special Warnings And Precautions For Use
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 (Preclinical safety data).
Cardiovascular:
Some azoles, including voriconazole have been associated with QT interval prolongation. There have been rare cases of torsades de pointes in patients taking voriconazole who had risk factors, such as history of cardiotoxic chemotherapy, cardiomyopathy, hypokalaemia and concomitant medications that may have been contributory. Voriconazole should be administered with caution to patients with potentially proarrhythmic conditions, such as
• Congenital or acquired QT-prolongation
• Cardiomyopathy, in particular when heart failure is present
• Sinus bradycardia
• Existing symptomatic arrhythmias
• Concomitant medication that is known to prolong QT interval.
Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalcaemia should be monitored and corrected, if necessary, prior to initiation and during voriconazole therapy (see section 4.2). A study has been conducted in healthy volunteers which examined the effect on QT interval of single doses of voriconazole up to 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 adverse events: Patients have rarely developed exfoliative cutaneous reactions, such as Stevens-Johnson syndrome, during treatment with VFEND. If patients develop a rash they should be monitored closely and VFEND discontinued if lesions progress.
In addition VFEND has been associated with phototoxicity and pseudoporphyria. It is recommended that patients avoid intense or prolonged exposure to direct sunlight during VFEND treatment and use measures such as protective clothing and sunscreen when appropriate. In patients with phototoxicity and additional risk factors, including immunosuppression, squamous cell carcinoma of the skin has been reported during long-term therapy. Physicians should therefore consider the need to limit the exposure to VFEND (see Section 4.2 (Posology and method of administration) and Section 5.1 Pharmacodynamic properties (Duration of treatment). If a patient develops a skin lesion consistent with squamous cell carcinoma, VFEND discontinuation should be considered.
Paediatric use: Safety and effectiveness in paediatric subjects below the age of two years has not been established (see also sections 4.8 and 5.1). Voriconazole is indicated for paediatric patients aged two years or older. Hepatic function should be monitored in both children and adults. Oral bioavailability may be limited in paediatric patients aged 2 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, 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-frequent monitoring for opiate-associated adverse events (including a longer respiratory monitoring period) may be necessary.
Long Acting Opiates (CYP3A4 substrate): Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 (e.g., hydrocodone) should be considered when coadministered with voriconazole. Frequent monitoring for opiate-associated adverse events may be necessary (see Section 4.5).
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 inhibitor): Coadministration of oral voriconazole and oral fluconazole resulted in a significant increase in Cmax and AUC
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.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Unless otherwise specified, drug interaction studies have been performed in healthy adult male subjects using multiple dosing to steady state with oral voriconazole at 200 mg twice daily. These results are relevant to other populations and routes of administration.
This section addresses the effects of other medicinal products on voriconazole, the effects of voriconazole on other medicinal products and two-way interactions. The interactions for the first two sections are presented in the following order: contraindications, those requiring dosage adjustment and careful clinical and/or biological monitoring and finally those that have no significant pharmacokinetic interaction but may be of clinical interest in this therapeutic field.
Effects of other medicinal products on voriconazole
Voriconazole is metabolised by cytochrome P450 isoenzymes, CYP2C19, CYP2C9 and CYP3A4. Inhibitors or inducers of these isoenzymes may increase or decrease voriconazole plasma concentrations respectively.
Rifampicin (CYP450 inducer): Rifampicin (600 mg once daily) decreased the Cmax (maximum plasma concentration) and 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 Cmax and AUC of oral voriconazole by an average of 66 % and 82 %, , whereas low doses of ritonavir (100mg twice daily) decreased the Cmax and AUC of voriconazole by an average of 24 % and 39 % respectively. Administration of voriconazole did not have a significant effect on mean Cmax and AUC of ritonavir in the high dose study, although a minor decrease in steady state Cmax 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 Cmax 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 Cmax and AUC.
Macrolide antibiotics: Erythromycin (CYP3A4 inhibitor; 1 g twice daily) and azithromycin (500 mg once daily) had no significant effect on voriconazole Cmax 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) Cmax 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 Cmax 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 Cmax and AUC of pharmacologically active R-methadone by 31 % and 47 %, respectively, whereas the Cmax and AUC of the S-enantiomer increased by approximately 65 % and 103 %, respectively. Voriconazole plasma concentrations during 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
Fentanyl (CYP3A4 substrate): In an independent published study, concomitant use of voriconazole (400 mg every 12 hours on Day 1, then 200 mg every 12 hours on Day 2) with a single intravenous dose of fentanyl (5 µg/kg) resulted in an increase in the mean AUC 0-
Long Acting Opiates (CYP3A4 substrate): In an independent published study, coadministration of multiple doses of oral voriconazole (400 mg every 12 hours, on Day 1 followed by five doses of 200 mg every 12 hours on Days 2 to 4) with a single 10 mg oral dose of oxycodone on Day 3 resulted in an increase in the mean Cmax and AUC0–
Tacrolimus (CYP3A4 substrate): Voriconazole increased tacrolimus (0.1 mg/kg single dose) Cmax and AUCt (area under the plasma concentration time curve to the last quantifiable measurement) by 117 % and 221 %, respectively. When initiating voriconazole in patients already receiving tacrolimus, it is recommended that the tacrolimus dose be reduced to a third of the original dose and tacrolimus level carefully monitored. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus levels must be carefully monitored and the dose increased as necessary.
Oral anticoagulants:
Warfarin (CYP2C9 substrate): 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 Cmax 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 Cmax and AUC of digoxin (0.25 mg once daily).
Mycophenolic acid (UDP-glucuronyl transferase substrate): Voriconazole had no effect on the Cmax and AUCt of mycophenolic acid (1 g single dose).
Non-Steroidal Anti-Inflammatory Drugs (CYP2C9 substrates): Voriconazole increased Cmax and AUC of ibuprofen (400 mg single dose) by 20% and 100%, respectively. Voriconazole increased Cmax and AUC of diclofenac (50 mg single dose) by 114% and 78%, respectively. Frequent monitoring for adverse events and toxicity related to NSAIDs is recommended. Adjustment of dosage of NSAIDs may be needed.
Two-way interactions
Phenytoin (CYP2C9 substrate and potent CYP450 inducer): Concomitant use of voriconazole and phenytoin should be avoided unless the benefit outweighs the risk.
Phenytoin (300 mg once daily) decreased the Cmax and AUC of voriconazole by 49 % and 69 %, respectively. Voriconazole (400 mg twice daily, see section 4.2) increased Cmax and AUCof 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 Cmax and AUCof voriconazole at 200 mg twice daily by 69 % and 78 %, respectively. During co-administration with rifabutin, the Cmax 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 Cmax and AUCwere 104 % and 87 % higher, respectively, compared with voriconazole alone at 200 mg twice daily. Voriconazole at 400 mg twice daily increased Cmax and AUCof 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 Cmax and AUCby 15 % and 41 %, respectively. No dosage adjustment of voriconazole is recommended. Voriconazole increased omeprazole Cmax and AUCby 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.
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 inhibitor): Coadministration of oral voriconazole (400 mg every12 hours for 1 day, then 200 mg every 12 hours for 2.5 days) and oral fluconazole (400 mg on day 1, then 200 mg every 24 hours for 4 days) to 8 healthy male subjects resulted in an increase in Cmax and AUC
Antiretroviral agents:
Indinavir (CYP3A4 inhibitor and substrate): Indinavir (800 mg three times daily) had no significant effect on voriconazole Cmax, Cmin and AUC. Voriconazole did not have a significant effect on Cmax 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 Cmax 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 Cmax 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).
4.6 Pregnancy And Lactation
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.
4.7 Effects On Ability To Drive And Use Machines
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.
4.8 Undesirable Effects
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 c
