Voriconazole

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.

Frequent monitoring for adverse reactions and toxicity related to NSAIDs is recommended. Dose reduction of NSAIDs may be needed.

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.

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

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

There is limited data on the safety of voriconazole in patients with abnormal liver function tests (aspartate transaminase [AST], alanine transaminase [ALT], alkaline phosphatase [ALP], or total bilirubin >5 times the upper limit of normal).

Voriconazole 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 severe hepatic impairment must be carefully monitored for drug toxicity.

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.

Although not studied, voriconazole is likely to increase the plasma concentrations of sulfonylureas and cause hypoglycaemia.

Careful monitoring of blood glucose is recommended. Dose reduction of sulfonylureas should be considered.

Although not studied, voriconazole is likely to increase the plasma concentrations of statins that are metabolised by CYP3A4 and could lead to rhabdomyolysis.

If concomitant administration of voriconazole with statins metabolised by CYP3A4 cannot be avoided, dose reduction of the statin should be considered.

Monitoring for adverse reactions related to oral contraceptives, in addition to those for voriconazole, is recommended.

Not studied clinically. In vitro studies show that voriconazole may inhibit the metabolism of HIV protease inhibitors and the metabolism of voriconazole may also be inhibited by HIV protease inhibitors.

Careful monitoring for any occurrence of drug toxicity and/or lack of efficacy, and dose adjustment may be needed.

Not studied clinically. In vitro studies show that the metabolism of voriconazole may be inhibited by NNRTIs and voriconazole may inhibit the metabolism of NNRTIs. The findings of the effect of efavirenz on voriconazole suggest that the metabolism of voriconazole may be induced by an NNRTI.

Careful monitoring for any occurrence of drug toxicity and/or lack of efficacy, and dose adjustment may be needed.

Although not studied, voriconazole is likely to increase the plasma concentrations of vinca alkaloids and lead to neurotoxicity.

Dose reduction of vinca alkaloids should be considered.

Coadministration of voriconazole with tyrosine kinase inhibitors metabolised by CYP3A4 is expected to increase tyrosine kinase inhibitor plasma concentrations and the risk of adverse reactions. If concomitant use cannot be avoided, dose reduction of the tyrosine kinase inhibitor and close clinical monitoring is recommended.

Although not studied, voriconazole is likely to increase the plasma concentrations of other benzodiazepines that are metabolised by CYP3A4 and lead to a prolonged sedative effect.

Dose reduction of benzodiazepines should be considered.

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 coadministered with voriconazole. As the half-life of alfentanil is prolonged in a 4-fold manner when alfentanil is coadministered with voriconazole, and in an independent published study concomitant use of voriconazole with fentanyl resulted in an increase in the mean AUC_0-∞ of fentanyl, frequent monitoring for opiate-associated adverse reactions (including a longer respiratory monitoring period) may be necessary.

When initiating voriconazole in patients already on ciclosporin it is recommended that the ciclosporin dose be halved and ciclosporin level carefully monitored. Increased ciclosporin levels have been associated with nephrotoxicity.

When voriconazole is discontinued, ciclosporin levels must be carefully monitored and the dose increased as necessary.

Voriconazole may be coadministered with efavirenz if the voriconazole maintenance dose is increased to 400 mg BID and the efavirenz dose is decreased to 300 mg QD. When voriconazole treatment is stopped, the initial dose of efavirenz should be restored.

Coadministration of voriconazole with everolimus is not recommended because voriconazole is expected to significantly increase everolimus concentrations. Currently there are insufficient data to allow dosing recommendations in this situation.

Significantly decreased plasma voriconazole concentrations have been reported.

If concomitant administration of voriconazole with flucloxacillin cannot be avoided, monitor for potential loss of voriconazole effectiveness (e.g., by therapeutic drug monitoring); increasing the dose of voriconazole may be needed.

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

Coadministration of voriconazole is expected to increase glasdegib plasma concentrations and increase the risk of QTc prolongation. If concomitant use cannot be avoided, frequent ECG monitoring is recommended.

Although not studied, voriconazole is likely to increase the plasma concentrations of ivacaftor with risk of increased adverse reactions.

Dose reduction of ivacaftor is recommended.

If concomitant administration of voriconazole with letermovir cannot be avoided, monitor for loss of voriconazole effectiveness.

Although not studied, voriconazole is likely to increase the plasma concentrations of mavacamten with increased risk of heart failure.

efer to the mavacamten summary of product characteristics (SmPC) for more information.

No dose adjustment of voriconazole is recommended.

When initiating voriconazole in patients already receiving omeprazole doses of 40 mg or above, it is recommended that the omeprazole dose be halved.

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

Frequent monitoring for adverse reactions and toxicity related to NSAIDs is recommended. Dose reduction of NSAIDs may be needed.

Careful monitoring of phenytoin levels is recommended when phenytoin is coadministered with voriconazole. Concomitant use of voriconazole and phenytoin should be avoided unless the benefit outweighs the risk.

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

Coadministration of voriconazole and low-dose ritonavir (100 mg BID) should be avoided unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.

When initiating voriconazole in patients already on 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.

Dose adjustment of tretinoin is recommended during treatment with voriconazole and after its discontinuation.

Close monitoring of prothrombin time or other suitable anticoagulation tests is recommended, and the dose of anticoagulants should be adjusted accordingly.

Warfarin (30 mg single dose, coadministered with 300 mg BID voriconazole) [CYP2C9 substrate]: Maximum increase in prothrombin time was approximately 2-fold.

Other oral coumarins (including but not limited to: phenprocoumon, acenocoumarol) [CYP2C9 and CYP3A4 substrates]: Although not studied, voriconazole may increase the plasma concentrations of coumarins that may cause an increase in prothrombin time.

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

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.

Caution should be used in prescribing voriconazole to patients with hypersensitivity to other azoles.

There are no adequate data on the use of voriconazole in pregnant women available.

Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown.

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

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

Women of child-bearing potential

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

Fertility

In an animal study, no impairment of fertility was demonstrated in male and female rats.

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

Summary of safety profile

The safety profile of voriconazole in adults is based on an integrated safety database of more than 2,000 subjects (including 1,603 adult patients in therapeutic trials) and an additional 270 adults in prophylaxis 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.

The most commonly reported adverse reactions were visual impairment, pyrexia, rash, vomiting, nausea, diarrhoea, headache, peripheral oedema, liver function test abnormal, respiratory distress and abdominal pain.

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

Tabulated list of adverse reactions

In the table below, since the majority of the studies were of an open nature, all causality adverse reactions and their frequency categories in 1,873 adults from pooled therapeutic (1,603) and prophylaxis (270) studies, by system organ class, are listed.

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

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

Undesirable effects reported in subjects receiving voriconazole:

^* ADR identified post-marketing
^** Frequency category is based on an observational study utilising real-world data from secondary data sources in Sweden
¹ Includes febrile neutropenia and neutropenia.
² Includes immune thrombocytopenic purpura.
³ Includes nuchal rigidity and tetany.
⁴ Includes hypoxic-ischaemic encephalopathy and metabolic encephalopathy.
⁵ Includes akathisia and parkinsonism.
⁶ See "Visual impairments" paragraph.
⁷ Prolonged optic neuritis has been reported post-marketing.
⁸ Includes dyspnoea and dyspnoea exertional.
⁹ Includes drug-induced liver injury, hepatitis toxic, hepatocellular injury and hepatotoxicity.
¹⁰ Includes periorbital oedema, lip oedema, and oedema mouth.

Description of selected adverse reactions

Visual impairments

In clinical trials, visual impairments (including blurred vision, photophobia, chloropsia, chromatopsia, colour blindness, cyanopsia, eye disorder, halo vision, night blindness, oscillopsia, photopsia, scintillating scotoma, visual acuity reduced, visual brightness, visual field defect, vitreous floaters, and xanthopsia) with voriconazole were very common. These visual impairments 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 impairments were generally mild, rarely resulted in discontinuation and were not associated with long-term sequelae. Visual impairments 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.

There have been post-marketing reports of prolonged visual adverse events.

Dermatological reactions

Dermatological reactions were very common in patients treated with voriconazole in clinical trials, but these patients had serious underlying diseases and were receiving multiple concomitant medicinal products. The majority of rashes were of mild to moderate severity. Patients have developed severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) (uncommon), toxic epidermal necrolysis (TEN) (rare), drug reaction with eosinophilia and systemic symptoms (DRESS) (rare) and erythema multiforme (rare) during treatment with voriconazole.

If a patient develops a rash they should be monitored closely and voriconazole discontinued if lesions progress. Photosensitivity reactions such as ephelides, lentigo and actinic keratosis have been reported, especially during long-term therapy.

There have been reports of squamous cell carcinoma of the skin (including cutaneous SCC in situ, or Bowen's disease) in patients treated with voriconazole for long periods of time; the mechanism has not been established.

Liver function tests

The overall incidence of transaminase increases >3 xULN (not necessarily comprising an adverse event) in the voriconazole clinical programme was 18.0% (319/1,768) in adults and 25.8% (73/283) in paediatric subjects who received voriconazole for pooled therapeutic and prophylaxis use. 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 associated with cases of serious hepatic toxicity in patients with other serious underlying conditions. This includes cases of jaundice, hepatitis and hepatic failure leading to death.

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.

Prophylaxis

In an open-label, comparative, multicenter study comparing voriconazole and itraconazole as primary prophylaxis in adult and adolescent allogeneic HSCT recipients without prior proven or probable IFI, permanent discontinuation of voriconazole due to AEs was reported in 39.3% of subjects versus 39.6% of subjects in the itraconazole arm. Treatment-emergent hepatic AEs resulted in permanent discontinuation of study medication for 50 subjects (21.4%) treated with voriconazole and for 18 subjects (7.1%) treated with itraconazole.

Paediatric population

The safety of voriconazole was investigated in 288 paediatric patients aged 2 to <12 years (169) and 12 to <18 years (119) who received voriconazole for prophylaxis (183) and therapeutic use (105) in clinical trials. The safety of voriconazole was also investigated in 158 additional paediatric patients aged 2 to <12 years in compassionate use programs. Overall, the safety profile of voriconazole in paediatric population was similar to that in adults. However, a trend towards a higher frequency of liver enzyme elevations, reported as adverse events in clinical trials was observed in paediatric patients as compared to adults (14.2% transaminases increased in paediatrics compared to 5.3% in adults). Post-marketing data suggest there might be a higher occurrence of skin reactions (especially erythema) in the paediatric population compared to adults. In the 22 patients less than 2 years old who received voriconazole in a compassionate use programme, the following adverse reactions (for which a relationship to voriconazole could not be excluded) were reported: photosensitivity reaction (1), arrhythmia (1), pancreatitis (1), blood bilirubin increased (1), hepatic enzymes increased (1), rash (1) and papilloedema (1). There have been post-marketing reports of pancreatitis in paediatric patients.