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Hypersensitivity: Caution should be used in prescribing Vortimal to patients with hypersensitivity to other azoles (see also Side Effects).
Duration of 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 a 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 intervals Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalcaemia should be monitored and corrected, if necessary, prior to initiation and during voriconazole therapy (see Dosage & Administration).
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 Side Effects).
Visual adverse reactions: There have been reports of prolonged visual adverse reactions, including blurred vision, optic neuritis and papilloedema (see Side Effects).
Monitoring of pancreatic function: 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.
Dermatological adverse reactions: Patients have rarely developed exfoliative cutaneous reactions, such as Stevens-Johnson syndrome, during treatment with voriconazole. If a patient develops a rash he should be monitored closely and voriconazole discontinued if lesions progress.
In addition, voriconazole has been associated with phototoxicity and pseudoporphyria. 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).
Long-term treatment: Long-term exposure treatment or prophylaxis) grated 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 (see Pharmacology: Pharmacodynamics under Actions and Dosage & Administration). The following severe adverse events have been reported in relation to long-term voriconazole treatment.
Squamous cell carcinoma of the skin (SCC) has been reported in patients, some of whom have reported prior phototoxic reactions. If phototoxic reactions occur, multidisciplinary advice should be sought and the patient should be referred to a dermatologist. Voriconazole discontinuation and use of alternative antifungal agents 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. Voriconazole should be discontinued if premalignant skin lesions or squamous cell carcinoma are identified.
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.
Prophylaxis: In case of treatment-related adverse events (hepatotoxicity, severe skin reactions including phototoxicity and SCC, severe or prolonged visual disorders and periostitis), discontinuation of voriconazole and use of alternative antifungal agents must be considered.
Phenytoin (CYP2C9 substrate and potent CYP450 inducer): 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 (see Interactions).
Efavirenz (CYP450 inducer; CYP3A4 inhibitor and substrate): When voriconazole is coadministered with efavirenz the dose of voriconazole should be increased to 400 mg every 12 hours and the dose of efavirenz should be decreased to 300 mg every 24 hours (see Dosage & Administration, Contraindications and Interactions).
Rifabutin (potent CYP450 inducer): 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 (see Interactions).
Ritonavir (potent CYP450 inducer; CYP3A4 inhibitor and substrate): Coadministration 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 Contraindications and Interactions).
Everolimus (CYP3A4 substrate, P-gp substrate): Coadministration of voriconazole with everolimus is not recommended because voriconazole is expected to significantly increase everolimus concentrations. Currently, there are insufficient sub to allow dosing recommendations in this situation (see Interactions).
Methadone (CYP3A4 substrate): Frequent monitoring for adverse reactions and toxicity related to methadone, including QTc prolongation, is recommended when coadministered with voriconazole since methadone levels increased following coadministration of voriconazole. 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 coadministered with voriconazole (see Interactions). 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.
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 reactions may be necessary (see Interactions).
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 inhibitor): Coadministration of oral voriconazole and oral fluconazole resulted in a significant increase in Cmax and AUCτ of voriconazole. 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 (see Interactions).
Sodium content: Each vial of Vortimal contains 225.6 mg of sodium chloride. This should be taken into consideration for patients on a controlled sodium diet.
Effects on Ability to Drive and Use Machine: Vortimal has 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.
Hepatic toxicity: There have been uncommon 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 (see Side Effects).
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, is based on the benefit-risk assessment the treatment is continued (see Dosage & Administration), 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.
Renal adverse reactions: 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 medicinal products and have concurrent conditions that may result in decreased renal function (see Side Effects).
Monitoring of renal function: Patients should be monitored for the development of abnormal renal function. This should include laboratory evaluation, particularly serum creatinine.
Use in Children: Safety and effectiveness in paediatric subjects below the age of two years have not been established (see Pharmacology: Pharmacodynamics under Actions and Side Effects). 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.
The frequency of phototoxicity reactions is higher in the paediatric 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.
