The FDA extended warning for intravenous haloperidol and torsades de pointes: How should institutions respond?

Haloperidol is Food and Drug Administration (FDA)‐approved in the United States for the management of acute and chronic psychotic disorders and widely used in the management of delirium‐associated agitation in hospitalized patients.1 Delirium in the hospital is an acute confusional state that frequently arises from multiple complex factors and may affect up to 30% of hospitalized patients.2 Although the first step in the management of delirium involves identification and treatment of underlying causes and offering supportive behavioral care; medications may be needed to control severe agitation.2 Low dose intravenous (IV) haloperidol (ie, 0.250.5 mg every 4 hours) is a commonly used medication in this setting as recommended by expert‐groups including the Cochrane Collaboration and the American Psychiatric Association.2, 3

Although injectable haloperidol, a butyrophenone‐derived antipsychotic agent pharmacologically related to the piperazine phenothiazines,4 is approved for IV use in many countries (Table 1), parenteral use is approved only for intramuscular (IM) administration in the US. Thus, IV administration of the drug in the US is considered an off‐label use.5

Haloperidol is often preferred over other antipsychotics as a result of its effectiveness, low rate of anticholinergic side effects, familiarity with dosing and usage, and minimal respiratory or sedative properties.6 Use of the IV route in patients with acute delirium has several advantages over the IM or oral route,7 including rapid onset, immediate bioavailability, and ease and safety of administration.

Prior to September 2007, the package insert for haloperidol alerted healthcare professionals to the risk of cardiovascular side effects. Based on case reports of potentially fatal cardiac events, the FDA revised the label, warning that the QT prolongation (QTP) and risk of torsades de pointes (TdP) were increased with IV administration of haloperidol or administration of the drug at greater than recommended doses. Unfortunately, neither the typical dosing range nor the minimum dose associated with these cardiac side effects were specified in this recommendation.5

It is well‐established that haloperidol may prolong the QT interval by blocking the repolarizing potassium I_Kr current.8 Although drugs that block the I_Kr channel can produce arrhythmia in healthy individuals, additional risk factors, such as underlying heart conditions, electrolyte imbalances (ie, hypokalemia and hypomagnesemia), concomitant proarrhythmic drug use, and mechanical ventilation may increase this risk.9 Prolongation of the QT interval has been associated with subsequent malignant cardiac arrhythmias including ventricular fibrillation and TdP.10 Prolongation of the QT interval is considered the strongest risk factor for TdP, particularly with a baseline QTc > 450 msec.9

Based on the increased risk for QTP and TdP and the case reports of cardiac events, the FDA advisory recommended continuous electrocardiogram (ECG) monitoring in patients receiving IV haloperidol.5 However, such monitoring may be impractical and costly in hospitalized patients who require low doses of IV haloperidol to manage acute delirium and who are not in telemetry or intensive care units.

The aim of this review was to evaluate the case reports leading to the recent FDA warning for IV haloperidol, specifically focusing on the presence of risk factors for arrhythmias. Based upon the evidence, an additional aim was to provide an institutional response to this warning toward the optimal use of this agent.

Method

Two search pathways were used to evaluate reports of haloperidol‐associated TdP and/or QT prolongation:

Results

A total of 70 reported cases of IV haloperidol associated TdP and/or QTP were identified. Of these 70, 41 were identified through the PubMed/EMBASE/Scopus review, while an additional 29 cases were identified through the FDA database search.

Of the 29 cases in the FDA database, 21 were reported by health care professionals and 8 by manufacturers.

A total of 35 publications described cases originating from the US. Three cases took place in Japan and 1 case each in Canada, Germany and Spain. Several cases in the MedWatch database were reported outside the US: 1 case each originated from Austria, Canada, France, Japan, Spain, Switzerland and the United Kingdom. A summary of the published case reports is displayed in Table 2 and the FDA cases are summarized in Table 3.

Of the 70 cases, 54 cases of TdP were reported. The remaining 16 of 70 cases involved cases of QTP, 9 of which did not progress to TdP and 7 of which the progression to TdP was unclear. Of note, 42 of 54 of the cases of TdP were reported as preceded by documented QTP. Presence of QTP was unknown in the other 12 original reports. Three out of 70 patients experienced sudden cardiac arrest, 1 of which was fatal. One arrest was preceded by TdP and 2 by QTP (Figure 1).

Figure 1

The patient ages ranged from 18 years to 86 years. Of note, 17 patients experiencing TdP and/or QTP were <40 years old, and 2 of those patients were <30 years old.

Haloperidol‐associated QTP and/or TdP were observed in 27 female and 42 male patients; the gender was not stated in one report. Of the 54 patients experiencing TdP (with or without report of previous QTP), 22 were female and 31 were male (1 gender unknown).

A total of 68 of 70 patients were determined to have associated risk factors15 for QTP/TdP (see Table 4). The circumstances of the remaining 2 patients were not described in sufficient detail to identify associated risk factors.

Overall, 32 patients had underlying heart conditions. Electrolyte imbalances, including hypokalemia, hypomagnesemia, and hypocalcemia, were present in 17 patients. At least 39 patients were receiving potentially proarrhythmic agents (1‐8 proarrhythmic drugs per patient) in addition to IV haloperidol. At least 23 patients were receiving additional drugs with a potential for other cardiac adverse events than QTP and TdP.

A wide range of other disease states previously reported to be associated with QTP15 were identified in these patients: asthma (5 patients), diabetes (5 patients), obesity (3 patients), impaired renal and/or liver function (3 patients each), human immunodeficiency virus (HIV) (2 patients); chronic obstructive pulmonary disease (COPD), pancreatitis and hypothyroidism (1 patient each). A total of 22 patients had a history of substance abuse (alcohol and/or drugs), and 4 patients were smokers.

The administered doses of IV haloperidol varied widely. Considering that information regarding the maximal daily dose was missing in 22 reports and ambiguous in another 20 cases, the results have been presented using cumulative IV haloperidol doses. Patients experiencing TdP without preceding QTP received a cumulative dose (= total dose at event) ranging from 5 mg to 645 mg. Patients with both confirmed QTP and TdP were administered a cumulative dose of 2 mg to 1700 mg. Patients who experienced QTP without TdP received a cumulative dose of 2 mg to 1540 mg of IV haloperidol.

Sudden cardiac arrest following administration of IV haloperidol was observed in cumulative doses ranging from 6 mg to 35 mg. The cardiac arrest leading to a fatal outcome was preceded by an administration of at least 6 mg of IV haloperidol. Overall, 14 out of 70 patients received cumulative doses of 10 mg IV haloperidol.

The time from administration to documentation of QTP and/or TdP ranged from immediately post administration to 8 hours after administration of the last dose of IV haloperidol.

Baseline QTc was known in 44 patients. Baseline QTc was >450 msec in 18 of these 44 patients.

The change from baseline QTc varied widely from 20 msec to 286 msec; 36 patients demonstrated a prolongation of >50 msec.

In those patients with reported haloperidol‐associated QTP, 25 patients demonstrated a QTc >600 msec and 38 patients >520 msec.9 Of the cases with known specific QTc values, the QTc was prolonged >450 msec in 48 out of 50 cases. The lowest reported QTc leading to TdP was 413 msec.

A total of 20 patients were reported as having a normalization of QTc (as defined by the original reports) within several hours to 8 days; minimal QTP was reported as persisting in 2 patients. The specifics of the other patients were unknown, although 25 patients were categorized as recovered, 13 were stated as having an uneventful remainder of hospitalization, and 5 patients were discharged to a rehabilitation facility or a nursing home.

Discussion

The current review was performed in response to the FDA warning recommending the use of continuous ECG monitoring associated with the administration of intravenous haloperiodol.5 This warning has resulted in substantial dilemmas for health care organizations, additional resource allocation, and increased scrutiny from regulatory agencies. The results of our review reveal that intravenous haloperidol‐associated QTP and TdP almost uniformly take place in patients with concomitant risk factors and with cumulative doses 2 mg. In light of these findings, it is possible that hospitals may be able to administer intravenous haloperidol in patients without risk factors without continuous ECG monitoring. In reviewing these published reports, it is important to note that the FDA identified 28 published cases of haloperidol‐associated QTP and TdP, while our review yielded a total of 41 published case reports.

The FDA database included 73 cases of haloperidol‐associated TdP in their database. However, these cases included both oral as well as IV administration; using our methodology, we identified 29 additional case reports associated with intravenous haloperidol from this database. Consequently, our review included 41 published case reports and 29 FDA database cases, resulting in the total of 70 patients.

Our review revealed a number of practical findings. First, our summary demonstrated that neither QTP nor TdP has been documented with a cumulative dose of IV haloperidol of <2 mg. The majority of patients (80%) received cumulative IV doses 10 mg. The lowest dose associated with sudden cardiac arrest was 6 mg and this took place in a 69‐year‐old male patient. Second, the majority (97%) of our patients had additional risk factors for QTP and/or TdP. Pre‐existing heart disease,1619 electrolyte imbalance,17, 1921 concomitant proarrhythmic drugs16, 17, 1922 and mechanical ventilation17, 23 were identified as the most commonly observed risk factors (Table 4). Lastly, in those cases in which the data were reported, baseline QTc was >450 msec in 41% of the patients, and 96% had a QTc at the time of the event >450 msec. Therefore, we conclude that patients: (1) receiving low cumulative doses (<2 mg) with (2) no risk factors for prolonged QTc or TdP, and (3) with a normal QTc on baseline EKG can safely be given IV haloperidol in the hospital setting.

This dosage range is consistent with the labelling for IV haloperidol dosing in Canada24 and Germany25 (Table 1), where single doses of 0.25 mg to 1.5 mg are recommended for the treatment of delirium or acute agitation in the geriatric population.24, 25

In a recent Cochrane review, low‐dose IV haloperidol (<3 mg per day) was concluded to be as safe and effective as atypical antipsychotics in the treatment of acute delirium with respect to extrapyramidal adverse effects.2

The American Psychiatric Association recommends an initial IV dose of 12 mg every 24 hours as needed (0.250.50 mg every 4 hours as needed for elderly patients), with titration to higher doses for patients who continue to be agitated for the treatment of patients with delirium (issued 1999, updated 2004).3

While several expert‐groups and investigators currently consider IV haloperidol as an important therapeutic option for treating acute delirium and agitation in the dose range presented above, less consensus exists regarding monitoring requirements.2, 3, 26, 27

The American Psychiatric Association recommends IV haloperidol only after a baseline ECG is obtained. These guidelines have not been updated since the release of the FDA extended warning.3 In their recent review, Morandi et al.28 support the dosage recommendation of the 1999 American Psychiatric Association's practice guidelines for treatment of delirium,3 ie, administration of IV haloperidol in single doses of 0.5 mg to 2 mg in elderly patients, however, only after a baseline ECG is obtained.28 While the package insert of IV haloperidol in France29 recommends a baseline ECG, Germany,25 Italy30 and Switzerland's31 package information states the need for regular ECG monitoring. Guidelines for the treatment of delirium in the intensive care unit published by the American College of Critical Care Medicine and the Society of Critical Care Medicine in collaboration with the American Society of Health‐System Pharmacists consider IV haloperidol as the preferred agent for the treatment of delirium in critically ill patients (grade of recommendation = C). These expert groups recommend that patients should be monitored for electrocardiographic changes (QT interval prolongation and arrhythmias) when receiving haloperidol (Grade of recommendation = B).32

Nevertheless, continuous ECG monitoring (ie, telemetry) is expensive, labor‐intensive and, potentially overutilized.33, 34 Requiring clinicians to place all patients receiving intravenous haloperidol on telemetry is impractical and potentially costly. Mandating telemetry could also lead to unintended harm, ie, use of a less effective or less safe drug to avoid compliance with the telemetry mandate.

Based on our findings and the current recommendations in the literature, inpatient providers should be thoughtful and deliberate in the use of haloperidol to treat acute delirium with agitation. Patients requiring pharmacologic management of their delirium should be screened for risk factors for QTP and TdP (Table 4) and a baseline ECG should be obtained prior to haloperidol administration. If significant risk factors exist or the baseline ECG reveals a prolonged QTc, then the patient should receive continuous ECG monitoring. Similarly, if cumulative doses of 2 mg are needed, the patient should be placed on telemetry.

There are some limitations to our study design. Our findings are based upon previously published case reports or data submitted to the FDA MedWatch. While the content of the FDA's MedWatch database is accessible to the public via the Freedom of Information Act (FOIA), the events are neither categorized nor peer‐reviewed upon entry into the database. Consequently, information may be incomplete or inaccurate. In addition, the denominator representing the overall use of IV haloperidol is unknown, thus a rate of event cannot be assigned and the true scope of the problem cannot be determined. Despite these limitations, this summary represents the most comprehensive review of the literature to date, expanding on the analysis performed by the FDA. Of note, in our review of the FDA database, we noted several cases of haloperidol‐associated QTP or TdP associated with other routes of administration. Thus, it is unknown whether this complication is any greater with IV vs. the IM or per os (PO) routes of administration.

Conclusion

Although the proarrhythmic potential of haloperidol and other antipsychotics has been well established in the literature, IV haloperidol has been considered relatively safe with respect to this complication from the time of its approval in 1967.5, 1722, 35, 36 In reviewing all reported cases of cardiac complications associated with IV haloperidol, as well as the current literature, an association with QTP and TdP is likely. However, the case reports reveal that QTP and TdP generally occur in the setting of concomitant risk factors, and no cases have been reported utilizing a cumulative IV dose of <2 mg. It may therefore be safe to administer a cumulative dose of IV haloperidol of <2 mg without ECG monitoring in patients without risk factors for QTP. However, ECG monitoring should take place with IV haloperidol doses 2 mg and/or in those patients with additional risk factors of developing QTP and/or TdP.

Based on the findings of this review complemented by the guidelines of various expert‐groups and the official labelling information of different countries, the Pharmacy & Therapeutics Committee of the UCSF Medical Center revised the IV haloperidol policy: administration of a total dose of <2 mg IV haloperidol without concurrent telemetry is allowed in a noncritical care setting in patients without risk factors for QTP and TdP.