Portal de Periódicos da CAPES

CON: The Black Box Warning on Droperidol Should Not Be Removed (But Should Be Clarified!)

2008; Lippincott Williams & Wilkins; Volume: 106; Issue: 5 Linguagem: Inglês

10.1213/ane.0b013e3181684e6a

1526-7598

Danielle Ludwin, Steven L. Shafer,

Pharmacy and Medical Practices

Anesthesiologists have used droperidol off-label for the last 30 yr for the prevention and treatment of postoperative nausea and vomiting. In 2001, a “black box” warning was added to the droperidol package insert due to concerns of prolonged QT and ventricular arrhythmias, specifically torsades de pointes.* Since the Food and Drug Administration (FDA) added the black box warning, the use of droperidol by anesthesiologists has dramatically diminished.1 In our view, the FDA is justified in placing a warning on a drug that is linked to adverse effects. Nevertheless, the label should be clarified with respect to doses below those approved in the droperidol package insert. In June 1968, McNeil laboratories submitted a new drug application for droperidol to the FDA. The drug was approved on June 11, 1970, for use preoperatively, during induction and maintenance for sedation or tranquilization, for antianxiety activity, and for reduction of the incidence of nausea and vomiting. Droperidol was approved based on the standards of that time, which seem incomplete by contemporary standards. QT prolongation was not appreciated as a risk factor for fatal arrhythmia, and no electrocardiogram studies were performed. Even more amazingly, droperidol was approved without any human pharmacokinetic studies. The droperidol package insert has a starting dose of 2.5 mg. Doses below 2.5 mg are not discussed. The package insert, and thus the FDA, are mute on the efficacy and safety of doses lower than 2.5 mg. The irony is that, even though droperidol is an approved antiemetic, by using doses below those in the package insert anesthesiologists have been using droperidol off-label for 30 yr. During the 1990s, reports emerged describing QT prolongation with droperidol.2–5 In 1999, Drolet et al.6examined the potency of droperidol at inducing QT prolongation in three guinea pig models: isolated hearts, ventricular myocytes, and HERG channels expressed in HEK293 cells. They found a significant effect on the QT interval at concentrations of 4 ng/mL. Scaling the concentrations reported by Lehmann et al.7 in a clinical trial, we can calculate that a droperidol dose of 0.625 mg would give an expected concentration of 10 ng/mL, 2.5 fold higher than concentrations shown in vitro to affect QT interval. This is consistent with the subsequent findings of White et al. who studied patients receiving 0.625 mg (n = 20) and 1.25 mg (n = 20) of droperidol.8 Given that the European Agency for the Evaluation of Medicinal Products says that “changes greater than 60 ms raise clear concerns about the potential risk … including torsades de pointes,”9 it is somewhat alarming that one patient in the study by White et al. had a QT prolongation of 120 ms after 0.625 mg, and another patient had a QT prolongation of 133 ms after a dose of 1.25 mg. Thus, in this small sample, 5% of the patients (2 of 40) had significant QT prolongation. In a retrospective study of drug-induced QT prolongation and torsades de pointes in more than 250,000 general surgical patients, the incidence of QT prolongation was 1.66% before the black box warning, when droperidol was used in about 12% of their patients, and 1.46% after the black box warning was placed and droperidol use decreased to 0.1 Although the authors conclude that the difference of 0.2% was insignificant and the FDA black box warning was not necessary for low concentrations, an accompanying editorial noted that this modest change was highly statistically significant and argued to retain the black box warning.10 Because of the accumulating evidence of QT prolongation and risk for torsades de pointes, Janssen Pharmaceuticals stopped marketing droperidol outside of the United States in March of 2001. After the Janssen announcement, the FDA reviewed the Janssen data and postmarketing spontaneous reports of adverse events and subsequently placed a black box warning on droperidol to advise clinicians of the risks of torsades de pointes induced by droperidol. The cases reviewed by the FDA included 22 instances of QT prolongation or torsades de pointes, including five fatalities. Four of the 22 cases were associated with doses <2.5 mg.† Habib and Gan reviewed some of the cases linked to doses of 1.25 mg or less and concluded that all of the cases reviewed had confounding factors that could account for the adverse reactions.11 At the FDA Advisory Committee meeting in 2003 to discuss droperidol labeling, the FDA medical officer (Dr. Chang) responsible for droperidol labeling observed that the FDA is often forced to make decisions with poor data. “Unfortunately, this is not atypical. We see a lot of cases like this where the information is just simply incomplete.”‡ Complicating the task for the FDA was the difficulty of studying small-dose droperidol in volunteers. A study funded by the FDA was terminated prematurely secondary to adverse neuropsychiatric events in volunteer patients and thus inconclusive. At the 2003 Advisory Committee meeting, an FDA medical officer explained the role of the sponsor in product labeling: “The determination of safety and efficacy is something that’s under the purview of the FDA and that’s based on the information that’s provided to the agency by the sponsor. So we only have information delivered to us by the sponsor with which to address these issues.”§ Before placing the black box warning, the FDA requested that Akorn Pharmaceuticals undertake studies to establish the risk of QT prolongation, or even prepare a literature review to document safety.∥ Akorn refused to do so, citing economic infeasibility. ¶Since the sponsor did not make any effort to assuage the FDA safety concerns, the FDA had no choice but to apply the blunt tool of the black box warning. The anesthesia community has debated whether the black box warning is justified.1,10,11–16 This debate misses the point. According to Title 21 of the Code of Federal Regulations Part 201.57 (e), “Labeling shall be revised to include a warning as soon as there is reasonable evidence of an association of a serious hazard with a drug; a causal relationship need not have been proved … Special problems, particularly those that may lead to death or serious injury, may be required by the FDA to be placed in a prominently displayed box.” Since multiple studies demonstrated a relationship between droperidol and the risk of prolonged QT, and case reports were suggestive (although by nature could not demonstrate causality), the FDA was compelled by law to place a black box warning on droperidol. At the 2003 Advisory Committee meeting, the primary FDA medical office responsible for droperidol labeling stated that “the boxed warning really is not about doses of droperidol <2.5 mg because the use of droperidol at doses <2.5 mg is off-label. We don’t have data submitted to the agency to make a determination of safety and efficacy at <2.5 mg, and we really are not making any statement about the safety or lack of safety of droperidol at those doses.”# The FDA also strongly affirms that they believe in discretionary medical judgment. At the same FDA hearing, the primary medical office responsible for FDA labeling of droperidol stated “the FDA recognizes that clinicians should exercise medical judgments and use drugs according to their own medical judgment, we really don’t regulate off-label use of drugs.”** In an article in Anesthesiology, Dr. Chang et al. from the FDA further clarified the agency’s position on off-label drug administration: “The FDA does not restrict a physician’s discretionary use of an approved drug, which is considered the practice of medicine. In fact, it is recognized that off-label use can be essential to medical care, that it is not always investigational or experimental, and that there is no legal or ethical obligation for physicians to discuss FDA regulatory status issues with their patients.”17 Let’s revisit the black box. The black box warning states “Cases of QT prolongation and/or torsade de pointes have been reported in patients receiving Inapsine at doses at or below (emphasis added) recommended doses … INAPSINE should be reserved for use in the treatment of patients who fail to show an acceptable response to other adequate treatments … ECG monitoring should be performed prior to treatment and continued for 2–3 h after completing treatment to monitor for arrhythmias.”** Don’t the words “or below” refer to doses below 2.5 mg, thus extending the black box warning to all droperidol doses? No. The text “at or below” accurately refers to a historical observation. It does not refer to the black box recommendation. Unfortunately, it has been widely misinterpreted as implying that the FDA black box warning on droperidol applies to all doses. In the years since the black box warning was written, the FDA has clarified that they did not intend to comment on doses <2.5 mg, as the risk of prolonged QT and torsades de pointes is not clear at these lower doses. The fallout from the black box warning has been near cessation of droperidol use in the United States,1,18 which has been accompanied, at least in one trial, by an increase in overall adverse event rate when promethazine was substituted for droperidol.19 This issue of Anesthesia & Analgesia includes several studies exploring whether haloperidol, another butyrophenone, could replace droperidol as an antiemesis drug.20–22 The only advantage haloperidol offers over droperidol is that there is no black box warning. There has also been unwelcome regulatory fallout. For example, blithely ignoring the FDA’s clearly stated position that they do not regulate medical practice, and the statements by the agency at the advisory panel meeting that the black box warning does not apply to doses below 2.5 mg, the California Health and Human Services Agency has begun citing hospitals for any use of droperidol that does not follow the FDA’s black box warning. For example, on March 22, 2007, the agency cited Garden Grove Hospital and Medical Center for “failure to monitor patients on droperidol (Inapsine) for emergency of potentially fatal arrhythmias.”‡‡ The document is worth reading to understand how the FDA’s reasonable caution about droperidol is misunderstood and inappropriately applied by other regulatory agencies who are blind to the difference between 0.625 and 625 mg of droperidol. In summary, droperidol can cause QT prolongation. This has likely resulted in patient harm. However, there is scant evidence that the off-label doses used by anesthesiologists are associated with toxicity. The FDA has unambiguously stated that the black box warning does not apply to those doses. In our view, the black box warning is justified. However, the FDA also needs to clarify the existing black box warning. Specifically, the black box warning should be brought into line with the evidence, the regulatory guidelines, and the longstanding safety history of low dose droperidol by adding the following concluding sentence: “Doses of INAPSINE below 2.5 mg are considered off-label. The FDA has no position on the safety or efficacy of doses below 2.5 mg.”