Voriconazole - Warnings and Precautions

5 WARNINGS AND PRECAUTIONS Hepatic Toxicity : Serious hepatic reactions reported.

Evaluate liver function tests at start of and during voriconazole therapy Arrhythmias and QT Prolongation : Correct potassium, magnesium, and calcium prior to use; caution patients with proarrhythmic conditions Infusion Related Reactions (including anaphylaxis) : Stop the infusion Visual Disturbances (including optic neuritis and papilledema): Monitor visual function if treatment continues beyond 28 days Severe Cutaneous Adverse Reactions : Discontinue for exfoliative cutaneous reactions Photosensitivity : Avoid sunlight due to risk of photosensitivity Adrenal Dysfunction : Carefully monitor patients receiving voriconazole and corticosteroids (via all routes of administration) for adrenal dysfunction both during and after voriconazole treatment.

Instruct patients to seek immediate medical care if they develop signs and symptoms of Cushing's syndrome or adrenal insufficiency Embryo-Fetal Toxicity : Voriconazole can cause fetal harm when administered to a pregnant woman.

Inform pregnant patients of the potential hazard to the fetus.

Advise females of reproductive potential to use effective contraception during treatment with voriconazole ( 5.9 , 8.1 , 8.3 ) Skeletal Adverse Reactions : Fluorosis and periostitis with long-term voriconazole therapy.

Discontinue if these adverse reactions occur Clinically Significant Drug Interactions : Review patient's concomitant medications ( 5.13 , 7 ) 5.1 Hepatic Toxicity In clinical trials, 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 hematological malignancy).

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 ] .

A higher frequency of liver enzyme elevations was observed in the pediatric population [see Adverse Reactions ] .

Hepatic function should be monitored in both adult and pediatric patients.

Measure serum transaminase levels and bilirubin at the initiation of voriconazole therapy and monitor at least weekly for the first month of treatment.

Monitoring frequency can be reduced to monthly during continued use if no clinically significant changes are noted.

If liver function tests become markedly elevated compared to baseline, voriconazole should be discontinued unless the medical judgment of the benefit/risk of the treatment for the patient justifies continued use [see Dosage and Administration , and Adverse Reactions ] .

5.2 Arrhythmias and QT Prolongation Some azoles, including voriconazole, have been associated with prolongation of the QT interval on the electrocardiogram.

During clinical development and postmarketing surveillance, there have been rare cases of arrhythmias, (including ventricular arrhythmias such as torsade de pointes ), cardiac arrests and sudden deaths in patients taking voriconazole.

These cases usually 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 Contraindications , Drug Interactions , and Clinical Pharmacology ] Rigorous attempts to correct potassium, magnesium and calcium should be made before starting and during voriconazole therapy [see Clinical Pharmacology ] .

5.3 Infusion Related Reactions During infusion of the intravenous formulation of voriconazole in healthy subjects, anaphylactoid-type reactions, including flushing, fever, sweating, tachycardia, chest tightness, dyspnea, faintness, nausea, pruritus and rash, have occurred uncommonly.

Symptoms appeared immediately upon initiating the infusion.

Consideration should be given to stopping the infusion should these reactions occur.

5.4 Visual Disturbances The effect of voriconazole on visual function is not known if treatment continues beyond 28 days.

There have been postmarketing reports of prolonged visual adverse reactions, including optic neuritis and papilledema.

If treatment continues beyond 28 days, visual function including visual acuity, visual field, and color perception should be monitored [see Adverse Reactions ] .

5.5 Severe Cutaneous Adverse 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 during treatment with voriconazole.