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 (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)].
The effect of voriconazole tablets 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)].
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 tablets. If a patient develops a severe cutaneous adverse reaction, voriconazole tablets should be discontinued [see Adverse Reaction (6.1, 6.2)].
Voriconazole has been associated with photosensitivity skin reaction. Patients, including pediatric patients, should avoid exposure to direct sunlight during voriconazole 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 voriconazole tablets discontinuation should be considered. If voriconazole tablets are 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 voriconazole tablets therapy in patients with photosensitivity skin reactions. If a patient develops a skin lesion consistent with premalignant skin lesions, squamous cell carcinoma or melanoma, voriconazole tablets should be discontinued. In addition, voriconazole 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 ultraviolet (UV) reactivation. Patients should avoid strong, direct sunlight during voriconazole 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.
Acute renal failure has been observed in patients undergoing treatment with voriconazole tablets. 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)].
Reversible cases of azole-induced adrenal insufficiency have been reported in patients receiving azoles, including voriconazole tablets. 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 voriconazole tablets concomitantly with corticosteroids.
Patients receiving voriconazole tablets and corticosteroids (via all routes of administration) should be carefully monitored for adrenal dysfunction both during and after voriconazole tablets treatment. Patients should be instructed to seek immediate medical care if they develop signs and symptoms of Cushing’s syndrome or adrenal insufficiency.
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 voriconazole tablets are used during pregnancy, or if the patient becomes pregnant while taking voriconazole tablets, inform the patient of the potential hazard to the fetus. Advise females of reproductive potential to use effective contraception during treatment with voriconazole tablets[see Use in Specific Populations (8.3)].
Electrolyte disturbances such as hypokalemia, hypomagnesemia and hypocalcemia should be corrected prior to initiation of and during voriconazole tablets therapy.
Patient management should include laboratory evaluation of renal (particularly serum creatinine) and hepatic function (particularly liver function tests and bilirubin).
Pancreatitis has been observed in patients undergoing treatment with voriconazole tablets [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 voriconazole tablets treatment.
Fluorosis and periostitis have been reported during long-term voriconazole therapy. If a patient develops skeletal pain and radiologic findings compatible with fluorosis or periostitis, voriconazole should be discontinued [see Adverse Reactions (6.2)].
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)].
Voriconazole tablets contain lactose and should not be given to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.
The following serious adverse reactions are described elsewhere in the labeling:
Hepatic Toxicity [see Warnings and Precautions (5.1)]
Arrhythmias and QT Prolongation [see Warnings and Precautions (5.2)]
Visual Disturbances [see Warnings and Precautions (5.4)]
Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.5)]
Photosensitivity [see Warnings and Precautions (5.6)]
Renal Toxicity [see Warnings and Precautions (5.7)]
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