Droperidol and the Black Box Warning

In December 2001, the Food and Drug Administration placed a black box warning on droperidol (Inapsine) because of concerns over QT prolongation and torsades de pointes.

This action took the medical and pharmacy communities by surprise and created tremendous controversy. Although the labeling information always had contained warnings of serious and even life-threatening arrhythmias, droperidol had a 30-year history of safe and effective use in a range of patients.

Since its release in 1970, droperidol had been one of the preferred antiemetics for the prevention and treatment of postoperative nausea and vomiting (PONV) and the treatment of hyperemesis gravidarum (HG). But the agency's action resulted in a marked decrease in its use for both indications.

In the early 1990s, manufacturing problems curtailed the availability of parenteral prochlorperazine, the other preferred antiemetic for these indications. With no other viable alternatives, there was an increase in the use of ondansetron (Zofran), which was expensive, but is now available as a generic.

What remains unresolved is the use of droperidol in clinical situations, in which it is the preferred agent for PONV, including after cesarean section, and for HG.

Several small studies that compared droperidol and ondansetron for PONV found no differences between the two in terms of efficacy and toxicity. However, a large study with more than 2,000 subjects concluded that droperidol (1.25 mg IV) was superior to ondansetron (4 mg IV) for both vomiting and nausea (Anesth. Analg. 1998;86:731–8).

A review of 76 trials of 5,351 patients receiving 24 different droperidol regimens found no serious adverse events (Can. J. Anaesth. 2000;47:537–51). Other studies from California and Montreal reported that droperidol infusions were highly effective in the treatment of HG (Am. J. Obstet. Gynecol. 1996;174:1801–6; J. Soc. Obstet. Gynaecol. Can 2001; 23:133–9). None of these studies found evidence that droperidol was related to torsades de pointes.

A 2005 study of droperidol (0.625–1.25 mg) for antiemetic prophylaxis during general anesthesia in outpatient surgery observed no significant increase in the corrected QT (QTc) interval, compared with saline (Anesthesiology 2005;102:1101–5). A 2007 Mayo Clinic study reported no documented cases of torsades de pointes in the 16,791 patients exposed to droperidol over the 3-year period preceding the black box warning, and the authors concluded the FDA warning for low-dose droperidol was excessive and unnecessary (Anesthesiology 2007;107:531–6).

An editorial voiced the same opinion (N. Engl. J. Med. 2004;350:2511–2). In a small study, 49 women with hyperemesis gravidarum received droperidol 1 mg/hr for 37 hours. The pretreatment QTc interval was 404 milliseconds, compared with 412 milliseconds at 37 hours, a clinically insignificant increase. A 2007 report analyzed data received under the Freedom of Information Act used by the FDA to support their black box warning. After excluding duplicate reports, there were 65 cases of cardiac toxicity possibly caused by droperidol.

Some of these reports appeared to have occurred more than 30 years ago, not merely over the past 4 years as suggested by the FDA. Only two of the cases involved doses commonly used in the United States, one of which was a patient with preexisting cardiovascular disease. In addition, the FDA used European data that involved doses 50–100 times higher than those used in the United States. The authors concluded that it did not appear that drugs such as ondansetron were safer than droperidol with regard to QT interval prolongation (Am. J. Health-Syst. Pharm. 2007;64:1174–86).

For 23 years, my colleagues and I have successfully used droperidol infusions for HG. Before receiving droperidol, patients must have normal concentrations of potassium and magnesium; they are excluded if they have a history of QT prolongation (slow heart rate), congestive heart failure, cardiac arrhythmias, or are taking other drugs known to increase the QT interval.

Because there is a genetic component for QT prolongation, women also are excluded if there is a history of an immediate blood relative (mother, father, or sibling) with QT prolongation or sudden cardiac death secondary to cardiac arrhythmia. Not a single patient has had to be excluded because of personal or family histories, or because of the use of other medications. Nor have we observed any serious adverse effects in the six to seven patients with hyperemesis gravidarum we treat each month.

Considering the strong evidence of safety and efficacy, it is time for the FDA to remove the antiemetic doses of droperidol from the black box warning.

In December 2001, the Food and Drug Administration placed a black box warning on droperidol (Inapsine) because of concerns over QT prolongation and torsades de pointes.

This action took the medical and pharmacy communities by surprise and created tremendous controversy. Although the labeling information always had contained warnings of serious and even life-threatening arrhythmias, droperidol had a 30-year history of safe and effective use in a range of patients.

Since its release in 1970, droperidol had been one of the preferred antiemetics for the prevention and treatment of postoperative nausea and vomiting (PONV) and the treatment of hyperemesis gravidarum (HG). But the agency's action resulted in a marked decrease in its use for both indications.

In the early 1990s, manufacturing problems curtailed the availability of parenteral prochlorperazine, the other preferred antiemetic for these indications. With no other viable alternatives, there was an increase in the use of ondansetron (Zofran), which was expensive, but is now available as a generic.

What remains unresolved is the use of droperidol in clinical situations, in which it is the preferred agent for PONV, including after cesarean section, and for HG.

Several small studies that compared droperidol and ondansetron for PONV found no differences between the two in terms of efficacy and toxicity. However, a large study with more than 2,000 subjects concluded that droperidol (1.25 mg IV) was superior to ondansetron (4 mg IV) for both vomiting and nausea (Anesth. Analg. 1998;86:731–8).

A review of 76 trials of 5,351 patients receiving 24 different droperidol regimens found no serious adverse events (Can. J. Anaesth. 2000;47:537–51). Other studies from California and Montreal reported that droperidol infusions were highly effective in the treatment of HG (Am. J. Obstet. Gynecol. 1996;174:1801–6; J. Soc. Obstet. Gynaecol. Can 2001; 23:133–9). None of these studies found evidence that droperidol was related to torsades de pointes.

A 2005 study of droperidol (0.625–1.25 mg) for antiemetic prophylaxis during general anesthesia in outpatient surgery observed no significant increase in the corrected QT (QTc) interval, compared with saline (Anesthesiology 2005;102:1101–5). A 2007 Mayo Clinic study reported no documented cases of torsades de pointes in the 16,791 patients exposed to droperidol over the 3-year period preceding the black box warning, and the authors concluded the FDA warning for low-dose droperidol was excessive and unnecessary (Anesthesiology 2007;107:531–6).

An editorial voiced the same opinion (N. Engl. J. Med. 2004;350:2511–2). In a small study, 49 women with hyperemesis gravidarum received droperidol 1 mg/hr for 37 hours. The pretreatment QTc interval was 404 milliseconds, compared with 412 milliseconds at 37 hours, a clinically insignificant increase. A 2007 report analyzed data received under the Freedom of Information Act used by the FDA to support their black box warning. After excluding duplicate reports, there were 65 cases of cardiac toxicity possibly caused by droperidol.

Some of these reports appeared to have occurred more than 30 years ago, not merely over the past 4 years as suggested by the FDA. Only two of the cases involved doses commonly used in the United States, one of which was a patient with preexisting cardiovascular disease. In addition, the FDA used European data that involved doses 50–100 times higher than those used in the United States. The authors concluded that it did not appear that drugs such as ondansetron were safer than droperidol with regard to QT interval prolongation (Am. J. Health-Syst. Pharm. 2007;64:1174–86).

For 23 years, my colleagues and I have successfully used droperidol infusions for HG. Before receiving droperidol, patients must have normal concentrations of potassium and magnesium; they are excluded if they have a history of QT prolongation (slow heart rate), congestive heart failure, cardiac arrhythmias, or are taking other drugs known to increase the QT interval.

Because there is a genetic component for QT prolongation, women also are excluded if there is a history of an immediate blood relative (mother, father, or sibling) with QT prolongation or sudden cardiac death secondary to cardiac arrhythmia. Not a single patient has had to be excluded because of personal or family histories, or because of the use of other medications. Nor have we observed any serious adverse effects in the six to seven patients with hyperemesis gravidarum we treat each month.

Considering the strong evidence of safety and efficacy, it is time for the FDA to remove the antiemetic doses of droperidol from the black box warning.

In December 2001, the Food and Drug Administration placed a black box warning on droperidol (Inapsine) because of concerns over QT prolongation and torsades de pointes.

This action took the medical and pharmacy communities by surprise and created tremendous controversy. Although the labeling information always had contained warnings of serious and even life-threatening arrhythmias, droperidol had a 30-year history of safe and effective use in a range of patients.

Since its release in 1970, droperidol had been one of the preferred antiemetics for the prevention and treatment of postoperative nausea and vomiting (PONV) and the treatment of hyperemesis gravidarum (HG). But the agency's action resulted in a marked decrease in its use for both indications.

In the early 1990s, manufacturing problems curtailed the availability of parenteral prochlorperazine, the other preferred antiemetic for these indications. With no other viable alternatives, there was an increase in the use of ondansetron (Zofran), which was expensive, but is now available as a generic.

What remains unresolved is the use of droperidol in clinical situations, in which it is the preferred agent for PONV, including after cesarean section, and for HG.

Several small studies that compared droperidol and ondansetron for PONV found no differences between the two in terms of efficacy and toxicity. However, a large study with more than 2,000 subjects concluded that droperidol (1.25 mg IV) was superior to ondansetron (4 mg IV) for both vomiting and nausea (Anesth. Analg. 1998;86:731–8).

A review of 76 trials of 5,351 patients receiving 24 different droperidol regimens found no serious adverse events (Can. J. Anaesth. 2000;47:537–51). Other studies from California and Montreal reported that droperidol infusions were highly effective in the treatment of HG (Am. J. Obstet. Gynecol. 1996;174:1801–6; J. Soc. Obstet. Gynaecol. Can 2001; 23:133–9). None of these studies found evidence that droperidol was related to torsades de pointes.

A 2005 study of droperidol (0.625–1.25 mg) for antiemetic prophylaxis during general anesthesia in outpatient surgery observed no significant increase in the corrected QT (QTc) interval, compared with saline (Anesthesiology 2005;102:1101–5). A 2007 Mayo Clinic study reported no documented cases of torsades de pointes in the 16,791 patients exposed to droperidol over the 3-year period preceding the black box warning, and the authors concluded the FDA warning for low-dose droperidol was excessive and unnecessary (Anesthesiology 2007;107:531–6).

An editorial voiced the same opinion (N. Engl. J. Med. 2004;350:2511–2). In a small study, 49 women with hyperemesis gravidarum received droperidol 1 mg/hr for 37 hours. The pretreatment QTc interval was 404 milliseconds, compared with 412 milliseconds at 37 hours, a clinically insignificant increase. A 2007 report analyzed data received under the Freedom of Information Act used by the FDA to support their black box warning. After excluding duplicate reports, there were 65 cases of cardiac toxicity possibly caused by droperidol.

Some of these reports appeared to have occurred more than 30 years ago, not merely over the past 4 years as suggested by the FDA. Only two of the cases involved doses commonly used in the United States, one of which was a patient with preexisting cardiovascular disease. In addition, the FDA used European data that involved doses 50–100 times higher than those used in the United States. The authors concluded that it did not appear that drugs such as ondansetron were safer than droperidol with regard to QT interval prolongation (Am. J. Health-Syst. Pharm. 2007;64:1174–86).

For 23 years, my colleagues and I have successfully used droperidol infusions for HG. Before receiving droperidol, patients must have normal concentrations of potassium and magnesium; they are excluded if they have a history of QT prolongation (slow heart rate), congestive heart failure, cardiac arrhythmias, or are taking other drugs known to increase the QT interval.

Because there is a genetic component for QT prolongation, women also are excluded if there is a history of an immediate blood relative (mother, father, or sibling) with QT prolongation or sudden cardiac death secondary to cardiac arrhythmia. Not a single patient has had to be excluded because of personal or family histories, or because of the use of other medications. Nor have we observed any serious adverse effects in the six to seven patients with hyperemesis gravidarum we treat each month.

Considering the strong evidence of safety and efficacy, it is time for the FDA to remove the antiemetic doses of droperidol from the black box warning.