Johnson and Johnson and FDA( Food and Drug Administration ) informed Healthcare Professionals that the Warnings section of the prescribing information for Haloperidol ( Halcion ) has been revised to include a new cardiovascular subsection regarding cases of sudden death, QT prolongation and torsades de pointes ( TdP ) in patients treated with Haloperidol, especially when given intravenously, or at doses higher than recommended. Although injectable Haloperidol is only approved by the FDA for intramuscular injection, there is considerable evidence that the intravenous administration of Haloperidol is a relatively common off-label clinical practice.

The updated Warnings note that:

· Higher doses and intravenous administration of Haloperidol appear to be associated with a higher risk of QT prolongation and TdP.

· Although cases of sudden death, TdP and QT prolongation have been reported even in the absence of predisposing factors, particular caution is advised in treating patients using any formulation of Haloperidol who: 1) have other QT-prolonging conditions, including electrolyte imbalance ( particularly hypokalemia and hypomagnesemia ), 2) have underlying cardiac abnormalities, hypothyroidism, or familial long QT syndrome, or 3) are taking drugs known to prolong the QT interval.

· Because of this risk of TdP and QT prolongation, ECG monitoring is recommended if Haloperidol is given intravenously.

· Haloperidol is not approved for intravenous administration.

There are at least 28 case reports of QT prolongation and TdP in the medical literature, some with fatal outcome in the context of off-label intravenous use of Haloperidol. In addition to these cases, case-control studies have demonstrated a dose-response relationship between intravenous Haloperidol dose and subsequent TdP. Based on this information, as well as the biologic plausibility of QT prolongation with intravenous Haloperidol, FDA has strengthened warnings in the Haloperidol labeling with regard to the risk of TdP and QT prolongation with intravenous Haloperidol use.

At the request of the Pharmacovigilance Department of the Italian Drug Agency ( AIFA ), the sponsor ( Johnson & Johnson ) performed two post-marketing analyses of QT interval prolongation and TdP with Haloperidol administration ( oral or injectable ). In one analysis, the sponsor searched their Benefit Risk Management worldwide safety database for QT prolongation -related adverse event reports received through June 30, 2005. This search identified 229 reports, many of which the sponsor described as confounded by concomitant QT-prolonging drugs or medical conditions. The reports included 73 cases of TdP, eleven of which were fatal. Eight of the eleven fatal cases involved intravenous administration of various doses of Haloperidol.

In March 2007 the sponsor submitted to FDA the results of a second post-marketing investigation conducted for the Italian drug authority. This report examined cardiac adverse events with Haloperidol decanoate received by the sponsor as of July 30, 2005. The sponsor found thirteen reports including TdP, QT prolongation, ventricular arrhythmias and/or sudden death.

Source: FDA, 2007

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