What is the documentation concerning the risk of cardiac arrhythmia during voriconazole treatment i

Fråga: What is the documentation concerning the risk of cardiac arrhythmia during voriconazole treatment in a patient with hypocalcemia?

The question deals with a woman on voriconazole treatment due to a severe Aspergillus infection. Her S-voriconazole is above 3 ug/mL. The patient has hypocalcemia, S-Ca 2.00 mM (reference value 2.15-2.5 mM).

Sammanfattning: Hypocalcemia is associated with an increased risk of QT-prolongation and caridac-arrhythmias in itself, especially in vulnarable individuals. Whether voriconazole treatment further increases this risk cannot be concluded from available data. There are only a few case-reports where QT-prolongation has been associated with voriconazol treatment.

Svar: According to the SPC (Summary of Product Characteristic), voriconazole in combination with hypocalcemia might be associated with an increased risk of QT-prolongation, Torsades de Pointes and cardiac arrest. The SPC also states that patients should not be treated with voriconazole if they have hypokalemia, hypomagnesemia or hypocalcemia, and that voriconazole treatment should not be started until these conditions are normalised (1). (1).

There are case-reports of QT-prolongation after treatment with anti-mycotic drugs of the azole-type, mainly in connection to ketoconazole and itraconazole (2). However, the fact that all azole antifungals also to a varying degree inhibits CYP enzymes and thus give rise to numerous pharmacokinetic drug interactions, makes it difficult to evaluate whether there truly exists a proarrhythmic effect of the drug itself.

We have found two case-reports where voriconazole treatment has been associated with QT-prolongation and Torsades de Pointes (3,4).

In the first case QT-prolongation and Torsades de Pointes were noted 22 days after starting voriconazole treatment. The patient was suffering from hypokalemia, but her S-calcium and S-magnesium levels were normal. The QT-prolongation disappeared when voriconazole treatment was stopped. Voriconazole treatment was restarted after 96h when the serum potassium level was normalised but still QT-prolongation recurred, supporting connection with voriconazole treatment. The S-voriconazole levels were varying between 4.6 and 0.11 ug/ mL at different time points (4).

In the other case, a patient with previously unknown long QT-syndrome had an episode of reversible cardiac arrest 3 weeks after starting on intravenously voriconazole treatment. An ECG revealed QT-prolongation and torsades de pointes. The patient had hypomagnesemia, but normal S-potassium and S-calcium levels. The ECG was normalised when the hypomagnesemia was treated. The S-voriconazole level was high, (7 ug/mL) (3).

We have found no case-reports of voriconazole treatment during hypocalcemia in the literature.

In SWEDIS (The Swedish adverse drug reaction register) there are no reports of QT-prolongation during voriconazole treatment (5). In the WHO adverse drug reaction database there are 13 reports of Torsades de pointes and 20 reports of QT-prolongation for voriconazole. These are not evaluated as to the cause-relationship (6).

According to the recommendation at the Pharmacological Laboratory, Karolinska University Hospital Huddinge, it is usually sufficient with S-voriconazole levels above 0.25 ug/ mL but for the treatment of a few rare groups of Aspargillus species a level above 1 ug/mL might be needed.

We recommend immediate treatment for normalising the hypocalcemia and to check for QT-prolongation with an ECG. Should the ECG findings be of concern, a decrease in voriconazole dose might be considered. SPC Voriconazole 2009 Owens RC, Jr., Nolin TD. Antimicrobial-associated QT interval prolongation: pointes of interest. Clin Infect Dis 2006;43(12):1603-1611 Eiden C, Peyriere H, Tichit R, Cociglio M, Amedro P, Blayac JP et al. Inherited long QT syndrome revealed by antifungals drug-drug interaction. J Clin Pharm Ther 2007;32(3):321-324 Alkan Y, Haefeli WE, Burhenne J, Stein J, Yaniv I, Shalit I. Voriconazole-induced QT interval prolongation and ventricular tachycardia: a non-concentration-dependent adverse effect. Clin Infect Dis 2004;39(6):e49-e52 SWEDIS (cited 2009-04-23) WHO adverse drug reaction database (cited 09-04-28)