Voriconazole

QT interval prolongation has been associated with voriconazole use; rare cases of arrhythmia (including torsade de pointes), cardiac arrest, and sudden death have been reported, usually in seriously ill patients with comorbidities and/or risk factors (eg, prior cardiotoxic chemotherapy, cardiomyopathy [especially with concomitant heart failure], electrolyte imbalance, or concomitant QTc-prolonging drugs). Also use with caution in patients with potentially proarrhythmic conditions (eg, congenital or acquired QT syndrome, sinus bradycardia, or preexisting symptomatic arrhythmias); correct electrolyte abnormalities (eg, hypokalemia, hypomagnesemia, hypocalcemia) prior to initiating and during therapy.

Rare cases of malignancy (melanoma, squamous cell carcinoma [SCC]) have been reported in patients with prior onset of severe photosensitivity reactions or exposure to standard dose long-term voriconazole therapy (in lung transplant recipients, SCC increased by ~6% per 60 days with a 28% absolute risk increase at 5 years [Singer 2012]). Other serious exfoliative cutaneous reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme, have also been reported. Patients, including children, should avoid exposure to direct sunlight and should use protective clothing and high SPF sunscreen; may cause photosensitivity, especially with long-term use. Discontinue use in patients who develop an exfoliative cutaneous reaction or a skin lesion consistent with squamous cell carcinoma or melanoma. Periodic total body skin examinations should be performed, particularly with prolonged use. If phototoxic reactions occur, referral to a dermatologist and voriconazole discontinuation should be considered. If therapy is continued, dermatologic evaluation should be performed on a systematic and regular basis to allow early detection and management of premalignant lesions. Pediatric patients are at particular risk for phototoxicity (see Special Populations).

Serious (and rarely fatal) hepatic reactions (eg, hepatitis, cholestasis, fulminant failure) have been observed with voriconazole. In lung transplant recipients, median time to hepatic toxicity was 14 days with the majority occurring within 30 days of therapy initiation (Luong 2012). Use with caution in patients with serious underlying medical conditions (eg, hematologic malignancy); hepatic reactions have occurred in patients with no identifiable underlying risk factors. Liver dysfunction is usually reversible upon therapy discontinuation. Monitor serum transaminase and bilirubin at baseline and at least weekly for the first month of treatment. Monitoring frequency can then be reduced to monthly during continued use if no abnormalities are noted. If marked elevations occur compared to baseline, discontinue unless benefit/risk of treatment justifies continued use.

Anaphylactoid-type reactions including tachycardia, dyspnea, chest tightness, faintness, nausea, rash, pruritus, fever, sweating and flushing have been observed; symptoms have appeared immediately upon initiating the infusion. Stop infusion for severe reactions or as clinical presentation indicates.

Visual changes, including blurred vision, changes in visual acuity, color perception, and photophobia, are commonly associated with treatment; postmarketing cases of optic neuritis and papilledema (lasting >1 month) have also been reported. Patients should be warned to avoid tasks which depend on vision, including operating machinery or driving. Changes are reversible on discontinuation following brief exposure/treatment regimens (≤28 days); reversibility following long-term administration has not been evaluated. If treatment continues >28 days, visual function (eg, acuity, visual field, color perception) should be monitored.

Acute renal failure has been observed in severely ill patients; use with caution in patients receiving concomitant nephrotoxic medications. Evaluate renal function (particularly serum creatinine) at baseline and periodically during therapy.

Fluorosis and/or periostitis may occur during long-term therapy. If patient develops skeletal pain and radiologic findings of fluorosis or periostitis, discontinue therapy.

Voriconazole demonstrates nonlinear pharmacokinetics. Dose modifications may result in unpredictable changes in serum concentrations and contribute to toxicity. For toxicity, the strongest correlations have been made between voriconazole trough concentrations and neurological and dermatological adverse events (Dolton 2012; Hamada 2012; Mitsani 2012; Park 2012; Soler-Palacin 2012). In these studies, increased toxicity was noted when trough concentrations exceeded threshold values. There are much less data supporting the existence between a cutoff threshold and hepatotoxicity. It is important to note that cutoff trough threshold values ranged widely among studies; however, an upper limit of Exserohilum rostratum in Reference Range section) (CDC 2012). Disease-related concerns:

Correct electrolyte abnormalities (eg, hypokalemia, hypomagnesemia, hypocalcemia) prior to initiating and during therapy.

Use with caution; elevated liver function tests and clinical signs of liver damage, such as jaundice, have been associated with voriconazole. Adjustments to maintenance dosing is required in mild to moderate hepatic cirrhosis (Child-Pugh class A and B). In patients with severe hepatic insufficiency use only if the benefit outweighs the potential risk. Evaluate hepatic function (particularly liver function tests and bilirubin) at baseline and periodically during therapy.

Monitor pancreatic function in patients (children and adults) at risk for acute pancreatitis (eg, recent chemotherapy or hematopoietic stem cell transplantation). Pancreatitis has occurred in pediatric patients.

Avoid the use of IV voriconazole in patients with renal impairment. See "Dosage forms specific issues: Injection: formulation." Evaluate renal function (particularly serum creatinine) at baseline and periodically during therapy. Concurrent drug therapy issues:

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Special populations:

In pediatric patients, voriconazole pharmacokinetics are complex. In patients >14 years of age or 12 to 14 years and weighing >50 kg, data suggest that pharmacokinetics are similar to adults (Friberg 2012). In patients • Pediatric dermatologic reactions: Frequency of phototoxic reactions is higher in pediatric patients. Stringent photoprotective measures are necessary in children due to the risk of squamous cell carcinoma. In children experiencing photoaging injuries (eg, lentigines or ephelides), avoidance of sun and dermatologic follow-up are warranted even after treatment is discontinued. Dosage form specific issues:

Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer’s labeling.

Avoid/limit use of IV formulation in patients with moderate to severe renal impairment (CrCl • Oral: - Lactose: Tablets contain lactose; avoid administration in hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption. - Sucrose: Suspension contains sucrose; use caution with fructose intolerance, sucrase-isomaltase deficiency, or glucose-galactose malabsorption. Other warnings/precautions:

Evaluate renal function (particularly serum creatinine) and hepatic function (particularly liver function tests and bilirubin) at baseline and periodically during therapy.