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Hypersensitivity: Caution should be used in prescribing Voriconazole Kabi to patients with hypersensitivity to other azoles (see also Adverse Reactions).
Duration of treatment: The duration of treatment with the intravenous formulation should be no longer than 6 months (see Pharmacology: Toxicology: Preclinical safety data under Actions).
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 (see Dosage & Administration). 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 (see Pharmacology: Pharmacodynamics under Actions).
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).
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 (see Adverse Reactions).
Monitoring of hepatic function: Patients receiving Voriconazole Kabi 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 Kabi 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 (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 Kabi 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 Voriconazole Kabi has been associated with phototoxicity including reactions such as ephelides, lentigo, actinic keratosis and pseudoporphyria. It is recommended that all patients, including children, avoid exposure to direct sunlight during Voriconazole Kabi 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 Kabi discontinuation and use of alternative antifungal agents should be considered and the patient should be referred to a dermatologist. If Voriconazole Kabi is continued, however, dermatologic evaluation should be performed on a systematic and regular basis, to allow early detection and management of premalignant lesions. Voriconazole Kabi should be discontinued if premalignant skin lesions or squamous cell carcinoma are identified (see Long-term treatment as follows).
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 Voriconazole Kabi 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 Kabi (see Dosage & Administration and Pharmacology: Pharmacodynamics under Actions).
Squamous cell carcinoma of the skin (SCC) has been reported in relation with long-term Voriconazole Kabi 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 Kabi discontinuation should be considered after multidisciplinary advice.
Visual adverse reactions: There have been reports of prolonged visual adverse reactions, including blurred vision, optic neuritis and papilloedema (see Adverse Reactions).
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 Adverse Reactions).
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, haematopoietic stem cell transplantation [HSCT]), should be monitored closely during Voriconazole Kabi treatment. Monitoring of serum amylase or lipase may be considered in this clinical situation.
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 data 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 AUC0-∞ 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 metabolised 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 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 (see Interactions).
Sodium content: This medicinal product contains up to 69 mg sodium per vial, equivalent to 3.45% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
Cyclodextrins: This medicinal product contains 2660 mg cyclodextrin in each vial.
In patients with moderate to severe renal dysfunction accumulation of cyclodextrins may occur (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Effects on ability to drive and use machines: 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.
Use in Children: Safety and effectiveness in paediatric subjects below the age of two years has not been established (see Adverse Reactions and Pharmacology: Pharmacodynamics under Actions). Voriconazole is indicated for paediatric patients aged two years or older. A higher frequency of liver enzyme elevations was observed in the paediatric population (see Adverse Reactions). 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.
Serious dermatological adverse reactions (including SCC): 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.
