Vfend

/ Pfizer

Posology:  Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalcaemia should be monitored and corrected, if necessary, prior to initiation and during voriconazole therapy.
Powder for solution for infusion: It is recommended that this drug is administered at a maximum rate of 3 mg/kg per hour over 1 to 3 hours. This formulation is available as 50 mg film-coated tablets, 200 mg film-coated tablets, 200 mg powder for solution for infusion and 40 mg/ml powder for oral suspension.
Treatment
Adults: Therapy must be initiated with the specified intravenous loading dose regimen of Voriconazole  to achieve adequate plasma concentrations on Day 1. Intravenous treatment should be continued for at least 7 days before switching to oral treatment. Once the patient is clinically improved and can tolerate medication given by mouth, the oral tablet form or oral suspension form of voriconazole may be utilized. On the basis of the high oral bioavailability , switching between intravenous and oral administration is appropriate when clinically indicated.
See prescribing information for full details.
Intravenous: Loading dose regimen (first 24 hours).
Patients 40 kg and above*
Maintenance dose (after first 24 hours), Prophylaxis of invasive fungal infections.
IV:  3-4 mg/kg every 12 hours.
Oral^a: 200 mg (5 ml) every 12 hours.
Patients less than 40 kg*
Oral^a: 100 mg (2.5ml) every 12 hours.
Invasive Aspergillosis/  Scedosporium and Fusarium infections/ Other serious mould infections ^b:
IV: 4 mg/kg every 12 hours.
Oral^a: 200 mg (5 ml) every 12 hours.
Patients less than 40 kg*
Oral^a: 100 mg (2.5ml) every 12 hours.
Candidemia in non-neutropenic patients:
IV: 3-4 mg/kg every 12 hours^c.
Oral^a: 200 mg (5 ml) every 12 hours.
Patients less than 40 kg*
Oral^a: 100 mg (2.5ml) every 12 hours.
a- In healthy volunteer studies, the 200 mg oral every 12 hours dose provided an exposure (AUCτ) similar to a 3 mg/kg IV every 12 hours dose, the 300 mg oral every 12 hours dose provided an exposure (AUCτ) similar to a 4 mg/kg IV every 12 hours dose.
b– In the pivotal clinical study of invasive aspergillosis, the median duration of IV voriconazole therapy was 10 days (range 2-85 days). The median duration of oral voriconazole therapy was 76 days (range 2-232 days).
c- In clinical trials, patients with candidemia received 3 mg/kg every 12 hours as primary therapy, while Patients with other deep tissue Candida infections received 4 mg/kg as salvage therapy. Appropriate dose should be based on severity and nature of the infection.
* This also applies to patients aged 15 years and older.
Duration of treatment: Treatment duration should be as short as possible depending on the patient’s clinical and mycological response. Long term exposure to voriconazole greater than 180 days (6 months) requires careful assessment of the benefit-risk balance.
Dose adjustment (Adults)
Powder for solution for infusion: If patient response at 3 mg/kg every 12 hours is inadequate, the intravenous maintenance dose may be increased to 4 mg/kg every 12 hours. If patients are unable to tolerate 4 mg/kg every 12 hours, reduce the intravenous maintenance dose to a minimum of 3 mg/kg every 12 hours. Phenytoin may be coadministered with voriconazole if the maintenance dose of voriconazole is increased to 5 mg/kg intravenously twice daily. Efavirenz may be coadministered with voriconazole if the maintenance dose of voriconazole is increased to 400 mg every 12 hours and the efavirenz dose is reduced by 50%, i.e. to 300 mg once daily. When treatment with voriconazole is stopped, the initial dosage of efavirenz should be restored.
Tablets and powder for oral suspension: If patient response is inadequate, the maintenance dose may be increased from 200 mg every 12 hours (similar to 3 mg/kg IV every 12 hours) to 300 mg every 12 hours (similar to 4 mg/kg IV every 12 hours) for oral administration. For patients less than 40 kg the oral dose may be increased from 100 mg to 150 mg every 12 hours. If patients are unable to tolerate treatment at these higher doses (i.e. 300 mg oral every 12 hours), reduce the oral maintenance dose by 50 mg steps to a minimum of 200 mg every 12 hours (or 100 mg every 12 hours for patients less than 40 kg). Phenytoin may be coadministered with voriconazole if the maintenance dose of voriconazole is increased from 200 mg to 400 mg orally, twice daily (100 mg to 200 mg orally, twice daily in patients less than 40 kg). Efavirenz may be coadministered with voriconazole if the maintenance dose of voriconazole is increased to 400 mg every 12 hours and the efavirenz dose is reduced by 50%, i.e. to 300 mg once daily. When treatment with voriconazole is stopped, the initial dosage of efavirenz should be restored.
Use in paediatrics
Children (2 to <12 years) and young adolescents with low body weight (12 to 14 years and <50 kg): Voriconazole should be dosed as children as these young adolescents may metabolize voriconazole more similarly to children than to adults. The recommended dosing regimen is as follows:
Loading Dose Regimen (first 24 hours)
IV: 9 mg/kg every 12 hours.
Oral:  Not recommended
Maintenance Dose (after first 24 hours)
IV:  8 mg/kg twice daily.
Oral:  9 mg/kg twice daily (a maximum dose of 350 mg twice daily).
Note: Based on a population pharmacokinetic analysis in 112 immunocompromised paediatric patients aged 2 to <12 years and 26 immunocompromised adolescents aged 12 to <17 years. It is recommended to initiate the therapy with intravenous regimen, and oral regimen should be considered only after there is a significant clinical improvement. It should be noted that an 8 mg/kg intravenous dose will provide voriconazole exposure approximately 2-fold higher than a 9 mg/kg oral dose. These oral dose recommendations for children are based on studies in which VFEND was administered as the powder for oral suspension. Bioequivalence between the powder for oral  suspension and tablets has not been investigated in a paediatric population. Considering the assumed limited gastro-enteric transit time in paediatric patients, the absorption of tablets may be different in paediatric compared to adult patients. It is therefore recommended to use the oral suspension formulation in children aged 2to<12. Safety and effectiveness in pediatric patients below the age of 2 years has not been established. Therefore, voriconazole is not recommended for children less than 2 years of age.
See prescribing information for full details.

Treatment of invasive aspergillosis.
Treatment of candidemia in non-neutropenic patients.
Treatment of fluconazole resistant serious invasive Candida infections (including C. krusei).
Treatment of serious fungal infections caused by Scedosporium spp. and Fusarium spp.
This drug should be administered primarily to immunocompromised patients with progressive, possibly life-threatening infections.
Prophylaxis of invasive fungal infections in high risk allogeneic hematopoietic stem cell transplant (HSCT) recipients.

Hypersensitivity to the active substance or to any of the excipients
Coadministration of voriconazole is contraindicated with medicinal products that are highly dependent on CYP3A4 for metabolism, and for which elevated plasma concentrations are associated with serious and/or life-threatening reactions
• Terfenadine, Astemizole
• Cisapride
• Pimozide, Lurasidone
• Quinidine
• Ivabradine
• Ergot alkaloids (e.g., ergotamine, dihydroergotamine)
• Sirolimus
• Naloxegol
• Tolvaptan
• Finerenone
• Venetoclax: Coadministration contraindicated at initiation and during venetoclax dose titration phase.
Coadministration of voriconazole is contraindicated with medicinal products that induce CYP3A4 and significantly reduce voriconazole plasma concentrations:
• Coadministration with rifabutin, rifampicin, carbamazepine, long-acting barbiturates e.g., phenobarbital and St John’s Wort is contraindicated.
• Efavirenz:
Coadministration of standard doses of voriconazole with efavirenz doses of 400 mg once daily or higher is contraindicated. For information on coadministration of voriconazole and lower doses of efavirenz see section 4.4.
• Ritonavir:
Coadministration with high- dose ritonavir (400 mg and above twice daily) is contraindicated. For information on coadministration with lower doses of ritonavir

Hypersensitivity: Caution should be used in prescribing Voriconazole to patients with hypersensitivity to other azoles.
Duration of IV treatment: The duration of treatment with the intravenous formulation should be no longer than 6 months.
Cardiovascular: Voriconazole has been associated with QTc interval prolongation. There have been rare cases of torsades de pointes in patients taking voriconazole who had risk factors, such as history of cardiotoxic chemotherapy, cardiomyopathy, hypokalaemia and concomitant medicinal products that may have been contributory. Voriconazole should be administered with caution to patients with potentially proarrhythmic conditions, such as: Congenital or acquired QTc-prolongation, Cardiomyopathy, in particular when heart failure is present, Sinus bradycardia, Existing symptomatic arrhythmias. Concomitant medicinal product that is known to prolong QTc interval. Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalcaemia should be monitored and corrected, if necessary, prior to initiation and during voriconazole therapy. A study has been conducted in healthy volunteers which examined the effect on QTc 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.
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.
Hepatic toxicity: In clinical trials, there have been cases of serious hepatic reactions during treatment with voriconazole (including clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities). Instances of hepatic reactions were noted to occur primarily in patients with serious underlying medical conditions (predominantly haematological malignancy).Transient hepatic reactions, including hepatitis and jaundice, have occurred among patients with no other identifiable risk factors. Liver dysfunction has usually been reversible on discontinuation of therapy.
Monitoring of hepatic function: Patients receiving Voriconazole must be carefully monitored for hepatic toxicity. Clinical management should include laboratory evaluation of hepatic function (specifically AST and ALT) at the initiation of treatment with Voriconazole and at least weekly for the first month of treatment. Treatment duration should be as short as possible, however, if based on the benefit-risk assessment, the treatment is continued, monitoring frequency can be reduced to monthly if there are no changes in the liver function tests. If the liver function tests become markedly elevated, Voriconazole should be discontinued, unless the medical judgment of the risk- benefit of the treatment for the patient justifies continued use. Monitoring of hepatic function should be carried out in both children and adults.
Serious dermatological adverse reactions
Phototoxicity: In addition, the drug has been associated with phototoxicity including reactions such as ephelides, lentigo, actinic keratosis and pseudoporphyria. There is a potential increased risk of skin reactions/toxicity with concomitant use of photosensitising agents (e.g., methotrexate, etc). It is recommended that all patients, including children, avoid exposure to direct sunlight during voriconazole treatment and use measures such as protective clothing and sunscreen with high sun protection factor (SPF).
Squamous cell carcinoma of the skin (SCC): Squamous cell carcinoma of the skin has been reported in patients, some of whom have reported prior phototoxic reactions. If phototoxic reactions occur multidisciplinary advice should be sought, Voriconazole discontinuation and use of alternative antifungal agents should be considered and the patient should be referred to a dermatologist. If Voriconazole is continued, however, dermatologic evaluation should be performed on a systematic and regular basis, to allow early detection and management of premalignant lesions. Voriconazole should be discontinued if premalignant skin lesions or squamous cell carcinoma are identified.
Exfoliative cutaneous reactions: Severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic  symptoms (DRESS), which can be life-threatening or fatal, have been reported with the use of voriconazole. If a patient develops a rash he should be monitored closely and VFEND discontinued if lesions progress.
Long-term treatment: Long term exposure (treatment or prophylaxis) greater than 180 days (6 months) requires careful assessment of the benefit-risk balance and physicians should therefore consider the need to limit the exposure to Voriconazole. Squamous cell carcinoma of the skin (SCC) has been reported in relation with long-term voriconazole treatment. Non-infectious periostitis with elevated fluoride and alkaline phosphatase levels has been reported in transplant patients. If a patient develops skeletal pain and radiologic findings compatible with periostitis Voriconazole discontinuation should be considered after multidisciplinary advice.
Adrenal events
Reversible cases of adrenal insufficiency have been reported in patients receiving azoles including voriconazole. Adrenal insufficiency has been reported in patients receiving azoles with or without concomitant corticosteroids. In patients receiving azoles without corticosteroids, adrenal insufficiency is related to direct inhibition of steroidogenesis by azoles. In patients taking corticosteroids, voriconazole associated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess and adrenal suppression. Cushing’s syndrome with and without subsequent adrenal insufficiency has also been reported in patients receiving voriconazole concomitantly with corticosteroids.
Patients on long-term treatment with voriconazole and corticosteroids (including inhaled corticosteroids e.g., budesonide and intranasal corticosteroids) should be carefully monitored for adrenal cortex dysfunction both during treatment and when voriconazole is discontinued. Patients should be instructed to seek immediate medical care if they develop signs and symptoms of Cushing’s syndrome or adrenal insufficiency.
Cyclodextrins
The powder for solution for infusion contains cyclodextrins (3,200 mg cyclodextrins in each vial which is equivalent to 160mg/ml when reconstituted in 20ml, see section 2 and 6.1) which can influence the properties (such as toxicity) of the active substance and other medicines. Safety aspects of cyclodextrins
have been considered during the development and safety assessment of the drug product. As cyclodextrins are renally excreted, in patients with moderate to severe renal dysfunction
accumulation of cyclodextrin may occur.
Sodium content
Each vial contains 221 mg of sodium per vial, equivalent to 11% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
Sodium in tablets:
This medicinal product contains less than 1 mmol sodium (23 mg) per tablet. Patients on low sodium
diets should be informed that this medicinal product is essentially ‘sodium-free’.
Sucrose
This medicinal product contains 0.54 g sucrose per ml. This should be taken into account in patients with diabetes mellitus.
See prescribing information for full details.

The most commonly reported adverse reactions were visual impairments, pyrexia, rash, vomiting, nausea, diarrhoea, headache, peripheral oedema, liver function test abnormal, respiratory distress and abdominal pain.
See prescribing information for full details.

Voriconazole is metabolised by, and inhibits the activity of, cytochrome P450 isoenzymes, CYP2C19, CYP2C9, and CYP3A4. Inhibitors or inducers of these isoenzymes may increase or decrease voriconazole plasma concentrations, respectively, and there is potential for voriconazole to increase the plasma concentrations of substances metabolised by these CYP450 isoenzymes. In particular for substances metabolised by CYP3A4 since voriconazole is a strong CYP3A4 inhibitor though the
increase in AUC is substrate dependent. Unless otherwise specified, drug interaction studies have been performed in healthy adult male subjects using multiple dosing to steady state with oral voriconazole at 200 mg twice daily (BID). These results are relevant to other populations and routes of administration. Voriconazole should be administered with caution in patients with concomitant medication that is known to prolong QTc interval. When there is also a potential for voriconazole to increase the plasma concentrations of substances metabolised by CYP3A4 isoenzymes (certain antihistamines, quinidine, cisapride, pimozide), coadministration is contraindicated.
See prescribing information for full details. 

Pregnancy: There are no adequate data on the use of this drug  in pregnant women available. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. The drug must not be used during pregnancy unless the benefit to the mother clearly outweighs the potential risk to the fetus. 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 this drug.            

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.

Powder for solution for infusion: The unreconstituted vial should be stored below 30ºC. For storage conditions after reconstitution of the medicinal product, see prescribing information.
Film-coated tablets: Store below 30°C.
Powder for oral suspension: Store at 2°C- 8°C (in a refrigerator) before constitution. For storage conditions after constitution, see prescribing information. Keep the container tightly closed.