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Hypersensitivity: Caution should be used in prescribing voriconazole to patients with hypersensitivity to other azoles.
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 Adverse Reactions).
Cardiac adverse events: Some azoles, including voriconazole, have been associated with prolongation of the QT interval on the electrocardiogram. During clinical development and post-marketing surveillance, there have been rare cases of torsade de pointes in patients taking voriconazole. These cases involved seriously ill patients with multiple confounding risk factors, such as history of cardiotoxic chemotherapy, cardiomyopathy, hypokalemia 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 medicinal product that is known to prolong QT interval (see Interactions).
Electrolyte disturbances such as hypokalemia, hypomagnesemia and hypocalcemia should be monitored and corrected, if necessary, prior to initiation of and during voriconazole therapy (see Dosage & Administration).
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 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 (see Pharmacology: Pharmacodynamics under Actions).
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 hematological 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. If 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 (see Dosage & Administration).
Visual adverse events: There have been post-marketing reports of prolonged visual adverse events, including optic neuritis and papilledema. These events occurred primarily in severely ill patients who had underlying conditions and/or concomitant medications which may have caused or contributed to these events (see Adverse Reactions).
Renal adverse events: Acute renal failure has been observed in severely ill patients undergoing treatment with voriconazole. 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.
Monitoring of renal function: Patients should be monitored for the development of abnormal renal function. This should include laboratory evaluation, particularly serum creatinine (see Dosage & Administration).
Monitoring of pancreatic function: Adults and children with risk factors for acute pancreatitis (e.g., recent chemotherapy, hematopoietic stem cell transplantation [HSCT]), should be monitored for development of pancreatitis during voriconazole treatment.
Dermatological adverse events: During treatment with voriconazole, patients have developed 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 (see Adverse Reactions). If a patient develops severe cutaneous adverse reaction voriconazole should be discontinued.
In addition, voriconazole has been associated with photosensitivity skin reaction. It is recommended that 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).
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 (see Interactions). 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) should be carefully monitored for adrenal cortex dysfunction both during treatment and when voriconazole is discontinued (see Interactions). Patients should be instructed to seek immediate medical care if they develop signs and symptoms of Cushing's syndrome or adrenal insufficiency.
Long-term treatment: The following severe adverse events have been reported in relation with long-term voriconazole treatment: Squamous cell carcinoma of the skin (SCC): In patients with photosensitivity skin reactions and additional risk factors, squamous cell carcinoma of the skin (including cutaneous SCC in situ, or Bowen's disease) and melanoma have been reported during long-term therapy. If phototoxic reactions occur, multidisciplinary advice should be sought and the patient should be referred to a dermatologist. Voriconazole discontinuation should be considered. Dermatologic evaluation should be performed on a systematic and regular basis, whenever voriconazole is continued despite the occurrence of phototoxicity-related lesions, to allow early detection and management of premalignant lesions.
If a patient develops a skin lesion consistent with premalignant skin lesions, squamous cell carcinoma or melanoma, voriconazole discontinuation should be considered.
Non-infectious periostitis: Periostitis has been reported in transplant patients during long-term voriconazole therapy. If a patient develops skeletal pain and radiologic findings compatible with periostitis, voriconazole should be discontinued.
Everolimus (CYP3A4 substrate, P-gp substrate): Co-administration of voriconazole with everolimus is not recommended because voriconazole is expected to significantly increase everolimus concentrations. Currently there are insufficient data to allow dosing recommendations in this situation (see Interactions).
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 inhibitor): Co-administration of oral voriconazole and oral fluconazole resulted in a significant increase in Cmax and AUCτ 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 events is recommended if voriconazole is used sequentially after fluconazole (see Interactions).
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 Dosage & Administration, Contraindications and Interactions).
Glasdegib (CYP3A4 substrate): Coadministration of voriconazole is expected to increase glasdegib plasma concentrations and increase the risk of QTc prolongation (see Interactions). If concomitant use cannot be avoided, frequent ECG monitoring is recommended.
Tyrosine kinase inhibitors (CYP3A4 substrate): 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 (see Interactions).
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 Interactions).
Ritonavir (potent CYP450 inducer, CYP3A4 inhibitor and substrate): Co-administration of voriconazole and low dose ritonavir (100 mg twice daily) should be avoided unless an assessment of the benefit/risk justifies the use of voriconazole (see Interactions, for higher doses see Contraindications).
Methadone (CYP3A4 substrate): Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during co-administration. Dose reduction of methadone may be needed (see Interactions).
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 Interactions). As the half-life of alfentanil is prolonged in a 4-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 AUC0-∞ of fentanyl by 1.4-fold, 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 metabolised by CYP3A4 (e.g., hydrocodone) should be considered when co-administered with voriconazole. Frequent monitoring for opiate-associated adverse events may be necessary (see Interactions).
Effects on ability to drive and use machines: Voriconazole 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. Patients should not drive at night while taking voriconazole.
Use in Children: Safety and effectiveness in pediatric subjects below the age of two years has not been established (see Pharmacology: Pharmacodynamics under Actions). Voriconazole is indicated for pediatric patients aged two years or older. A higher frequency of liver enzyme elevations was observed in the pediatric population (see Adverse Reactions). Hepatic function should be monitored in both children and adults. Oral bioavailability may be limited in pediatric patients 2 to 12 years with malabsorption and very low body weight for age. In that case, intravenous voriconazole administration is recommended.
The frequency of phototoxicity reactions is higher in the pediatric population. As an evolution towards SCC has been reported, stringent measures for the photoprotection are warranted in this population of patients. In children experiencing photoaging injuries such as lentigines or ephelides, sun avoidance and dermatologic follow-up are recommended even after treatment discontinuation.
