warnings and cautions
5 WARNINGS AND PRECAUTIONS • Hepatic Toxicity : Serious hepatic reactions reported. Evaluate liver function tests at start of and during VFEND therapy ( 5.1 ) • Arrhythmias and QT Prolongation : Correct potassium, magnesium and calcium prior to use; caution patients with proarrhythmic conditions ( 5.2 ) • Infusion Related Reactions (including anaphylaxis) : Stop the infusion ( 5.3 ) • Visual Disturbances (including optic neuritis and papilledema): Monitor visual function if treatment continues beyond 28 days ( 5.4 ) • Severe Cutaneous Adverse Reactions : Discontinue for exfoliative cutaneous reactions ( 5.5 ) • Photosensitivity : Avoid sunlight due to risk of photosensitivity ( 5.6 ) • Adrenal Dysfunction : Carefully monitor patients receiving VFEND and corticosteroids (via all routes of administration) for adrenal dysfunction both during and after VFEND treatment. Instruct patients to seek immediate medical care if they develop signs and symptoms of Cushing's syndrome or adrenal insufficiency ( 5.8 ) • 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 VFEND ( 5.9 , 8.1 , 8.3 ) • Skeletal Adverse Reactions : Fluorosis and periostitis with long-term voriconazole therapy. Discontinue if these adverse reactions occur ( 5.12 ) • Clinically Significant Drug Interactions : Review patient's concomitant medications ( 5.13 , 7 ) • Patients with Hereditary Galactose Intolerance, Lapp Lactase Deficiency or Glucose-Galactose Malabsorption: VFEND tablets should not be given to these patients because it contains lactose ( 5.14 ) 5.1 Hepatic Toxicity In clinical trials, there have been uncommon cases of serious hepatic reactions during treatment with VFEND (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 (6.1) ] . A higher frequency of liver enzyme elevations was observed in the pediatric population [see Adverse Reactions (6.1) ] . Hepatic function should be monitored in both adult and pediatric patients. Measure serum transaminase levels and bilirubin at the initiation of VFEND 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, VFEND should be discontinued unless the medical judgment of the benefit/risk of the treatment for the patient justifies continued use [see Dosage and Administration (2.5) and Adverse Reactions (6.1) ] . 5.2 Arrhythmias and QT Prolongation Some azoles, including VFEND, 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. VFEND 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 (4) , Drug Interactions (7) , and Clinical Pharmacology (12.3) ] Rigorous attempts to correct potassium, magnesium and calcium should be made before starting and during voriconazole therapy [see Clinical Pharmacology (12.3) ] . 5.3 Infusion Related Reactions During infusion of the intravenous formulation of VFEND 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 VFEND 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 (6.2) ] . 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 VFEND. If a patient develops a severe cutaneous adverse reaction, VFEND should be discontinued [see Adverse Reactions (6.1 , 6.2) ] . 5.6 Photosensitivity VFEND has been associated with photosensitivity skin reaction. Patients, including pediatric patients, should avoid exposure to direct sunlight during VFEND treatment and should use measures such as protective clothing and sunscreen with high sun protection factor (SPF). If phototoxic reactions occur, the patient should be referred to a dermatologist and VFEND discontinuation should be considered. If VFEND is continued despite the occurrence of phototoxicity-related lesions, dermatologic evaluation should be performed on a systematic and regular basis to allow early detection and management of premalignant lesions. Squamous cell carcinoma of the skin (including cutaneous SCC in situ , or Bowen's disease) and melanoma have been reported during long-term VFEND therapy in patients with photosensitivity skin reactions. If a patient develops a skin lesion consistent with premalignant skin lesions, squamous cell carcinoma or melanoma, VFEND should be discontinued. In addition, VFEND has been associated with photosensitivity related skin reactions such as pseudoporphyria, cheilitis, and cutaneous lupus erythematosus, as well as increased risk of skin toxicity with concomitant use of methotrexate, a drug associated with ultraviolet (UV) reactivation. There is the potential for this risk to be observed with other drugs associated with UV reactivation. Patients should avoid strong, direct sunlight during VFEND therapy. The frequency of phototoxicity reactions is higher in the pediatric population. Because squamous cell carcinoma has been reported in patients who experience photosensitivity reactions, stringent measures for photoprotection are warranted in children. In children experiencing photoaging injuries such as lentigines or ephelides, sun avoidance and dermatologic follow-up are recommended even after treatment discontinuation. 5.7 Renal Toxicity Acute renal failure has been observed in patients undergoing treatment with VFEND. Patients being treated with voriconazole are likely to be treated concomitantly with nephrotoxic medications and may have concurrent conditions that may result in decreased renal function. Patients should be monitored for the development of abnormal renal function. This should include laboratory evaluation of serum creatinine [see Clinical Pharmacology (12.3) and Dosage and Administration (2.6) ] . 5.8 Adrenal Dysfunction Reversible cases of azole-induced adrenal insufficiency have been reported in patients receiving azoles, including VFEND. 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 Drug Interactions (7) and Clinical Pharmacology (12.3) ] . Cushing's syndrome with and without subsequent adrenal insufficiency has also been reported in patients receiving VFEND concomitantly with corticosteroids. Patients receiving VFEND and corticosteroids (via all routes of administration) should be carefully monitored for adrenal dysfunction both during and after VFEND treatment. Patients should be instructed to seek immediate medical care if they develop signs and symptoms of Cushing's syndrome or adrenal insufficiency. 5.9 Embryo-Fetal Toxicity Voriconazole can cause fetal harm when administered to a pregnant woman. In animals, voriconazole administration was associated with fetal malformations, embryotoxicity, increased gestational length, dystocia and embryomortality [see Use in Specific Populations (8.1) ] . If VFEND is used during pregnancy, or if the patient becomes pregnant while taking VFEND, inform the patient of the potential hazard to the fetus. Advise females of reproductive potential to use effective contraception during treatment with VFEND [see Use in Specific Populations (8.3) ] . 5.10 Laboratory Tests Electrolyte disturbances such as hypokalemia, hypomagnesemia and hypocalcemia should be corrected prior to initiation of and during VFEND therapy. Patient management should include laboratory evaluation of renal (particularly serum creatinine) and hepatic function (particularly liver function tests and bilirubin). 5.11 Pancreatitis Pancreatitis has been observed in patients undergoing treatment with VFEND [see Adverse Reactions (6.1 , 6.2) ] Patients with risk factors for acute pancreatitis (e.g., recent chemotherapy, hematopoietic stem cell transplantation [HSCT]) should be monitored for the development of pancreatitis during VFEND treatment. 5.12 Skeletal Adverse Reactions Fluorosis and periostitis have been reported during long-term VFEND therapy. If a patient develops skeletal pain and radiologic findings compatible with fluorosis or periostitis, VFEND should be discontinued [see Adverse Reactions (6.2) ] . 5.13 Clinically Significant Drug Interactions See Table 10 for a listing of drugs that may significantly alter voriconazole concentrations. Also, see Table 11 for a listing of drugs that may interact with voriconazole resulting in altered pharmacokinetics or pharmacodynamics of the other drug [see Contraindications (4) and Drug Interactions (7) ] . 5.14 Galactose Intolerance VFEND tablets contain lactose and should not be given to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.