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Droperidol

Droperidol is a synthetic butyrophenone derivative and a potent antagonist of dopamine D₂ receptors, primarily used as an antiemetic agent to prevent and treat nausea and vomiting associated with surgical and diagnostic procedures.^[1] Administered exclusively via intramuscular or intravenous injection under medical supervision, it also possesses sedative, tranquilizing, and antipsychotic properties due to its central nervous system depressant effects.^[2] Chemically designated as 1-[1-[3-(p-Fluorobenzoyl)propyl]-1,2,3,6-tetrahydro-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one with the molecular formula C₂₂H₂₂FN₃O₂, droperidol has a molecular weight of 379.4 g/mol and is marketed under the brand name Inapsine.^[3] Originally approved by the U.S. Food and Drug Administration in 1970 for its antiemetic and tranquilizing indications, droperidol gained widespread use in perioperative settings for over three decades, often as an adjunct to anesthesia.^[4] Its mechanism of action involves blocking dopamine receptors in the chemoreceptor trigger zone of the medulla, thereby inhibiting emetic stimuli, while also producing subcortical sedation without significant analgesia.^[2] Pharmacokinetically, it exhibits rapid onset (3-10 minutes) and a duration of action of 2-4 hours, primarily through hepatic metabolism.^[1] Typical adult dosing is an initial 2.5 mg IV or IM, with additional 1.25 mg doses as needed; pediatric doses (ages 2-12) are weight-based with a maximum initial dose of 0.1 mg/kg.^[1] In 2001, the FDA issued a black box warning for droperidol due to post-marketing reports of QT interval prolongation and potentially fatal torsades de pointes, mandating ECG monitoring before and for 2-3 hours after administration in patients without contraindications such as known QT prolongation or hypersensitivity.^[4] Common adverse effects include drowsiness, hypotension, extrapyramidal symptoms like dystonia, and tachycardia, with serious risks encompassing neuroleptic malignant syndrome and respiratory depression when combined with other CNS depressants.^[1] Despite the warning leading to decreased use, droperidol was reintroduced to the U.S. market in 2019 and remains a cost-effective option for postoperative nausea and vomiting prophylaxis, particularly when combined with other antiemetics like ondansetron.^[4] It is contraindicated in patients with congenital long QT syndrome and requires caution in those with cardiac, renal, or hepatic impairment.^[5]

Pharmacology

Mechanism of action

Droperidol is a butyrophenone derivative that functions primarily as a potent antagonist at dopamine D2 receptors in the central nervous system (CNS).^[6] This antagonism inhibits dopaminergic neurotransmission, particularly in areas involved in emesis and behavioral regulation.^[4] The drug's antiemetic effects stem from its blockade of D2 receptors in the chemoreceptor trigger zone (CTZ) of the medulla oblongata, a region lacking a blood-brain barrier that detects emetogenic stimuli.^[6] Droperidol also crosses the blood-brain barrier efficiently to exert additional central actions, including sedation. In addition to D2 antagonism, droperidol exhibits alpha-adrenergic receptor blockade, which contributes to its sedative properties and potential for hypotension through vasodilation and reduced sympathetic tone.^[7] It also displays mild antihistaminic activity via H1 receptor antagonism and weak anticholinergic effects at muscarinic receptors, though these are less pronounced than in many other antipsychotics.^[6] Structurally similar to haloperidol, another butyrophenone, droperidol shares its strong antidopaminergic profile, explaining overlapping therapeutic and adverse effects.^[4] Its actions are dose-dependent: low doses (typically 0.625–1.25 mg) primarily target antiemetic pathways with minimal broader CNS effects, while higher doses engage more extensive antipsychotic and sedative mechanisms via intensified receptor blockade.^[8]

Pharmacokinetics

Droperidol is administered primarily via intravenous (IV) or intramuscular (IM) routes, with rapid absorption leading to onset of action within 3-10 minutes for IV and IM administration.^[9] Peak effects may occur up to 30 minutes after dosing.^[9] For IM administration, droperidol exhibits rapid absorption with peak plasma concentrations achieved within approximately 10 minutes, supporting its use in acute settings.^[10] The drug demonstrates high plasma protein binding of 85-90% and a wide volume of distribution ranging from 99 to 168 liters, indicating extensive tissue penetration.^[9] Droperidol readily crosses the blood-brain barrier, facilitating its central nervous system effects.^[11] Droperidol undergoes extensive hepatic metabolism primarily via the cytochrome P450 enzyme CYP3A4, along with contributions from other enzymes, producing inactive metabolites.^[9] Elimination occurs mainly through renal excretion of metabolites, with approximately 75% of metabolites cleared via the kidneys and about 1% of unchanged drug excreted in urine; fecal excretion accounts for around 11%.^[9] The elimination half-life is approximately 134 minutes (about 2.2 hours), with a terminal half-life of around 3 hours observed in population pharmacokinetic studies.^[9]^[10] IV administration provides near-complete bioavailability of 100%, and the drug does not accumulate significantly with short-term use due to its relatively short half-life.^[11]

Medical uses

Antiemetic applications

Droperidol is primarily FDA-approved for the prophylaxis of postoperative nausea and vomiting (PONV) associated with surgical and diagnostic procedures.^[12] It is administered intravenously at low doses of 0.625 to 1.25 mg to effectively prevent PONV in adults undergoing surgery.^[13]^[8] Clinical trials have demonstrated droperidol's superior efficacy over placebo in reducing PONV incidence among surgical patients, with one randomized, double-blind study showing a decrease from 41% in the placebo group to 7% with 0.625 mg droperidol.^[13] A large factorial trial further confirmed that droperidol reduces the relative risk of PONV by approximately 26%, establishing its role as a reliable antiemetic option in perioperative settings.^[14] Droperidol is frequently combined with opioids, such as in morphine-based patient-controlled analgesia, or with other anesthetics to enhance antiemetic effects without increasing sedation levels.^[15] Beyond surgery, it is applied in diagnostic procedures like endoscopy and radiology to mitigate procedure-induced nausea and vomiting.^[12] Overall, evidence from multiple clinical trials indicates that low-dose droperidol can reduce PONV incidence by 20-30% compared to placebo or no prophylaxis in high-risk patients.^[14]^[16]

Sedation and agitation management

Droperidol serves as a short-acting sedative for managing acutely agitated patients in emergency departments (EDs), particularly in behavioral emergencies requiring rapid chemical restraint.^[17] It is administered at doses of 2.5-5 mg intramuscularly (IM) or intravenously (IV), providing effective sedation with an onset of action typically within 5-15 minutes and a duration of 2-4 hours.^[18]^[19] This pharmacokinetic profile makes it suitable for acute interventions where quick control is needed without prolonged effects.^[20] Although its use for agitation is off-label in many contexts, droperidol is commonly employed in EDs for patients experiencing delirium or acute psychosis, with multiple studies demonstrating its safety and efficacy at low doses.^[17] For instance, prospective observational research has shown that IM droperidol achieves adequate sedation in a high proportion of cases, comparable to alternatives like olanzapine, with minimal need for rescue dosing.^[21] Systematic reviews further confirm its rapid time to sedation, often within 14-15 minutes, supporting its role in behavioral emergencies.^[22] Droperidol is frequently combined with midazolam to enhance sedation depth while minimizing risks such as respiratory depression, as evidenced by trials showing superior outcomes at 10 minutes compared to either agent alone.^[23] Following the 2001 FDA black box warning for QT prolongation, droperidol's use declined but has re-emerged in ED practice due to accumulating evidence from post-warning studies indicating low arrhythmia risk at therapeutic doses below 5 mg.^[4]^[24] This resurgence is backed by large-scale reviews and ED-specific research affirming its safety profile for acute agitation management.^[25]

Other indications

Droperidol has been used as an adjunct in anesthesia, particularly for inducing tranquilization during the induction phase of general or regional procedures. It is administered intravenously at doses of 2.5 to 10 mg to facilitate smoother induction and maintenance of anesthesia.^[26] This application leverages its dopamine D2 receptor antagonism to provide rapid sedation without significant respiratory depression, complementing agents like fentanyl in neuroleptanalgesia techniques.^[3] Use for tranquilization is off-label under current FDA labeling.^[27] Investigational applications of low-dose droperidol have explored its role in chronic pain management, particularly for conditions like migraines and sickle cell crises. In acute migraine treatment, parenteral doses of 2.5 to 5 mg administered intramuscularly or intravenously have demonstrated efficacy comparable to prochlorperazine or olanzapine, achieving pain relief in a majority of patients within 30 to 60 minutes, though with risks of sedation and extrapyramidal symptoms.^[28] For sickle cell disease exacerbations, low doses (under 2.5 mg) have been used off-label as an opioid adjuvant in emergency settings to enhance analgesia in opioid-tolerant patients, reducing the need for higher narcotic doses and addressing breakthrough pain in vaso-occlusive crises.^[29] These uses stem from droperidol's central antiemetic and potential analgesic-modulating effects via sigma-1 receptor interactions, though larger trials are needed to confirm long-term safety. Historically, droperidol was employed as an antipsychotic for schizophrenia and related psychotic disorders due to its butyrophenone structure, akin to haloperidol, providing potent D2 blockade to alleviate hallucinations and delusions. Introduced in the 1960s, it was used in psychiatric settings for acute agitation and maintenance therapy, but its adoption waned with the rise of atypical antipsychotics offering reduced extrapyramidal and cardiac risks.^[30] Today, it is not FDA-approved for primary psychiatric indications and is reserved for short-term psychosis-induced agitation, supported by Cochrane reviews showing moderate efficacy against behavioral disturbances.^[31] In pediatric populations, droperidol shows potential for sedation in acute behavioral disturbances, with studies indicating rapid onset (within 10-15 minutes) and high success rates (over 85%) at doses of 0.05-0.1 mg/kg intravenously, particularly in emergency departments for non-psychotic agitation.^[22] This use requires careful monitoring for QT prolongation, similar to adult applications. Off-label, droperidol has been utilized for vertigo and motion sickness, extending its antiemetic properties to suppress vestibular disturbances. Intravenous doses of 1.25-2.5 mg effectively reduce symptoms in acute vertigo episodes, outperforming placebo by alleviating nausea and disequilibrium through central dopamine and histamine receptor modulation, though it is not first-line due to safer alternatives like antihistamines.^[32]^[33]

Adverse effects

Common side effects

Droperidol commonly causes drowsiness and sedation, which are among the most frequently reported adverse effects during clinical use, typically resolving within a few hours after administration.^[27] These effects stem from the drug's potent central nervous system depressant action as a butyrophenone antipsychotic.^[2] Dizziness, hypotension, and dry mouth are also frequent non-serious side effects. Hypotension arises primarily from droperidol's alpha-adrenergic blockade, with an incidence of approximately 5% in acute care settings, often mild and self-limiting.^[22] Dry mouth occurs due to mild anticholinergic activity and is generally transient.^[34] Extrapyramidal symptoms, such as akathisia or dystonia, may emerge particularly at higher doses used for sedation, with an incidence of around 2-6% depending on the dose and patient population.^[35]^[22] These movement disorders result from dopamine D2 receptor antagonism in the basal ganglia and can usually be managed effectively with anticholinergic agents like diphenhydramine or benztropine.^[27] Overall, sedation occurs in 10-20% of patients receiving droperidol for antiemetic or sedative purposes, while hypotension affects 5-10%, based on aggregated data from emergency and perioperative studies.^[22] Management of these common side effects generally involves dose reduction to the lowest effective level and supportive care, such as fluid administration for hypotension or monitoring for resolution of sedation.^[27]

Serious adverse effects

In 2001, the U.S. Food and Drug Administration (FDA) issued a black box warning for droperidol due to reports of QT interval prolongation and serious ventricular arrhythmias, including torsades de pointes, which can occur even at low doses such as 2.5 mg or less.^[12]^[36] This warning was prompted by post-marketing surveillance identifying cases of sudden cardiac death linked to these arrhythmias, particularly in patients with risk factors like electrolyte imbalances or concomitant QT-prolonging medications.^[37] Due to these risks, the FDA recommends obtaining a 12-lead electrocardiogram (ECG) prior to administration to assess baseline QT interval and continuous ECG monitoring for 2-3 hours post-dose, or longer if clinically indicated, to detect any prolongation exceeding 500 ms or arrhythmic events.^[12]^[38] Droperidol has also been associated with rare cases of neuroleptic malignant syndrome (NMS), a life-threatening condition characterized by hyperthermia, muscle rigidity, autonomic instability, and altered mental status, typically occurring shortly after initiation or dose increase.^[39]^[40] NMS requires immediate discontinuation of the drug and supportive care, including cooling measures and possible dantrolene or bromocriptine administration.^[5] With prolonged use, droperidol may rarely cause tardive dyskinesia, manifesting as involuntary choreoathetoid movements of the face, tongue, or extremities; however, this is uncommon given its typical short-term administration in clinical settings.^[9]^[41] Subsequent studies after 2001 have reported a low incidence of clinically significant QT prolongation (0% to 2.7%) and torsades de pointes (extremely rare, <0.1%) with low doses under 5 mg, particularly in emergency department settings, which has supported the drug's re-emergence in practice with appropriate precautions.^[42]^[43]^[25]

Contraindications and precautions

Contraindications

Droperidol is contraindicated in patients with known hypersensitivity to the drug or other butyrophenone derivatives, as severe allergic reactions may occur upon administration.^[9] The medication must not be used in individuals with known or suspected QTc interval prolongation, defined as greater than 440 milliseconds in males or greater than 450 milliseconds in females, or those with congenital long QT syndrome, due to the risk of torsades de pointes and sudden cardiac death.^[44]^[9] This contraindication extends to patients with a family history of congenital long QT syndrome.^[9] Droperidol is contraindicated in comatose patients or those with acute intoxication, as the drug may further impair central nervous system function and complicate management.^[9]^[45] Safety and efficacy of droperidol have not been established in children younger than 2 years of age; therefore, its use is not recommended in this population.^[1]

Precautions

Droperidol should be used with caution or avoided in patients with conditions that predispose to QT prolongation, such as recent myocardial infarction, congestive heart failure, clinically significant bradycardia, or electrolyte imbalances including hypokalemia and hypomagnesemia, as these may increase the risk of life-threatening arrhythmias.^[1]^[46] A 12-lead ECG should be performed prior to administration to assess QTc interval, with monitoring for 2-3 hours post-dose if used. In patients with Parkinson's disease, droperidol may exacerbate extrapyramidal symptoms through dopamine D2 receptor blockade; use with caution and monitor for worsening parkinsonian features.^[1]^[38] Caution is advised in patients with severe depression, as droperidol may aggravate symptoms according to some regional guidelines (e.g., New Zealand).^[9] Droperidol requires caution in individuals with hepatic or renal impairment due to potential for prolonged effects from reduced metabolism or clearance. Dose adjustments may be necessary, and monitoring for adverse effects is recommended.^[5]^[2] In elderly patients, droperidol may cause increased sensitivity to CNS effects; lower doses and careful monitoring are advised.^[1]

Drug interactions

Droperidol exhibits significant pharmacodynamic interactions with other QT interval-prolonging medications, increasing the risk of serious ventricular arrhythmias such as torsades de pointes. Concomitant use with agents like ondansetron, haloperidol, and certain antibiotics (e.g., erythromycin) requires caution due to additive effects on cardiac repolarization, as droperidol causes dose-dependent QT prolongation via blockade of the hERG potassium channel. ECG monitoring is recommended, and combination should be avoided in patients with baseline QTc prolongation greater than 440 ms in males or 450 ms in females.^[44]^[3]^[2] Similarly, class I or III antiarrhythmics, tricyclic antidepressants, and some antihistamines or antimalarials heighten this arrhythmogenic potential. Central nervous system (CNS) depressants, including opioids, benzodiazepines, barbiturates, and general anesthetics, potentiate droperidol's sedative effects, leading to enhanced respiratory depression, hypotension, and prolonged recovery from anesthesia. This additive CNS depression arises from synergistic inhibition of neurotransmitter activity, particularly in the reticular activating system, and requires dose reductions of either droperidol or the concomitant agent, with close monitoring of respiratory and cardiovascular status during co-administration. For instance, combining droperidol with fentanyl or lorazepam has been associated with excessive sedation in procedural settings, emphasizing the need for individualized dosing adjustments.^[47]^[2]^[48] As droperidol is primarily metabolized by the hepatic cytochrome P450 3A4 (CYP3A4) enzyme, strong inhibitors such as ketoconazole can prolong its half-life and intensify its therapeutic and adverse effects by reducing clearance. This pharmacokinetic interaction may elevate plasma concentrations, amplifying risks like QT prolongation and sedation, particularly in patients with hepatic impairment; dose adjustments and therapeutic drug monitoring are recommended when CYP3A4 inhibitors are unavoidable.^[2]^[3] Anticholinergic agents, such as benztropine, are commonly employed to counteract droperidol-induced extrapyramidal symptoms (EPS), including dystonia and akathisia, by restoring dopaminergic-cholinergic balance in the basal ganglia. However, their use warrants caution in patients with narrow-angle glaucoma due to the potential for increased intraocular pressure from additive anticholinergic effects. These interactions highlight the role of anticholinergics in EPS management without altering droperidol's primary antipsychotic action.^[44]^[49] Moderate interactions occur with beta-blockers and diuretics, which can exacerbate droperidol's hypotensive effects or contribute to electrolyte disturbances. Beta-blockers like metoprolol may intensify bradycardia and orthostatic hypotension through combined alpha-adrenergic blockade and negative chronotropy, while diuretics such as furosemide risk inducing hypokalemia or hypomagnesemia, further predisposing to QT prolongation and arrhythmogenesis. Electrolyte monitoring and cautious co-administration are advised to mitigate these cardiovascular complications.^[47]^[50]^[2]

Overdose

Symptoms

Overdose with droperidol typically manifests as an exaggeration of its pharmacological effects, including profound central nervous system depression and cardiovascular instability.^[9] Symptoms onset rapidly following intravenous administration, usually within 3 to 10 minutes, with peak effects occurring around 30 minutes post-dose.^[9] Common initial presentations include psychic indifference progressing to deep sedation or coma, accompanied by hypotension due to peripheral vasodilation and α-adrenergic blockade.^[9]^[38] Respiratory depression is a prominent feature, ranging from hypoventilation to apnea, which can exacerbate hypoxia and require immediate ventilatory support.^[9] Neurologically, severe extrapyramidal reactions such as muscle rigidity, dystonia, akathisia, and oculogyric crises may occur, alongside the potential for convulsions or progression to coma, particularly with doses exceeding recommended limits.^[38]^[51] In extreme cases, neuroleptic malignant syndrome may develop, contributing to additional complications like rhabdomyolysis.^[52] Cardiac toxicity is a critical concern in droperidol overdose, characterized by marked QT interval prolongation that can precipitate torsades de pointes or ventricular fibrillation, potentially leading to sudden death.^[38] These arrhythmias may emerge or worsen up to 24 hours after exposure.^[38] Other manifestations in severe overdoses include hypothermia from central thermoregulatory disruption.^[53]

Management

Management of droperidol overdose is primarily supportive, as there is no specific antidote available. Treatment focuses on stabilizing vital functions, addressing life-threatening complications, and providing symptomatic relief. Patients should be monitored in a setting equipped for advanced cardiac and respiratory support, with continuous ECG monitoring recommended to detect arrhythmias early. Activated charcoal may be administered if ingestion occurred within 1-2 hours, but its use should not delay other interventions.^[54]^[9]^[55] Respiratory depression is a key concern, necessitating airway protection and ventilation support. A patent airway must be ensured, with oropharyngeal airways or endotracheal intubation considered for patients with reduced level of consciousness or inadequate ventilation. Mechanical ventilation may be required in severe cases to maintain oxygenation and prevent aspiration.^[54]^[9]^[55] Cardiac monitoring is essential due to the risk of QT interval prolongation and torsades de pointes. A 12-lead ECG should be obtained on presentation and repeated at intervals, such as every 6 hours or until normalization. If QT prolongation is detected, serum electrolytes (particularly potassium and magnesium) should be corrected. For torsades de pointes, intravenous magnesium sulfate (1-2 g over 1-2 minutes) is the first-line treatment, even if serum levels are normal, followed by antiarrhythmic agents like lidocaine if the arrhythmia persists. Overdrive pacing or isoproterenol infusion may be used for recurrent episodes.^[54]^[9]^[56] Hypotension should be managed initially with intravenous crystalloid fluids (10-20 mL/kg bolus). If unresponsive, vasopressors such as noradrenaline (0.05-0.5 mcg/kg/min infusion) are indicated; adrenaline should be avoided due to potential exacerbation of arrhythmias.^[54]^[55] Seizures, if present, are treated with benzodiazepines such as lorazepam (0.1 mg/kg IV, maximum 4 mg), diazepam (0.15 mg/kg IV, maximum 10 mg), or midazolam (0.2 mg/kg IV, maximum 10 mg), administered every 5 minutes until controlled. Extrapyramidal symptoms, including dystonia or akathisia, respond to anticholinergic agents like benztropine (1-2 mg IV in adults, 0.02 mg/kg in pediatrics up to 1 mg), which may be repeated after 20 minutes if needed; benzodiazepines serve as an alternative.^[54]^[55] Hemodialysis is ineffective for droperidol elimination due to its high plasma protein binding (85-90%) and large volume of distribution. Patients require observation for at least 24 hours, with supportive measures continued as necessary.^[54]^[9]

History

Development and approval

Droperidol was developed in 1961 by Janssen Pharmaceutica in Beerse, Belgium, as part of the butyrophenone class of compounds, building on the earlier synthesis of haloperidol in 1958.^[4] This class of drugs was designed to exhibit potent dopamine D2 receptor antagonism, providing antipsychotic and sedative effects with rapid onset.^[4] During the 1960s, initial clinical studies evaluated droperidol's antiemetic and antipsychotic properties, particularly in surgical settings as an anesthetic adjuvant and in psychiatric patients for agitation control.^[19] These early investigations, conducted primarily in Europe, demonstrated its efficacy in reducing postoperative nausea and providing tranquilization when combined with opioids like fentanyl, leading to its introduction as an independent agent by the mid-1960s.^[57] The U.S. Food and Drug Administration (FDA) approved droperidol in 1970 for use as an antiemetic and tranquilizer in adults, marketed under the brand name Inapsine by McNeil Laboratories (a subsidiary of Johnson & Johnson).^[4] By the 1970s, it achieved widespread adoption in anesthesia practices worldwide for preventing postoperative nausea and vomiting, often at low doses of 0.625–1.25 mg intravenously.^[8] Prior to 2001, droperidol's safety profile was favorable, with millions of administrations reported globally and low incidence of serious adverse events at therapeutic doses; for instance, over a 15-month period in the late 1990s, approximately 5 million vials were sold with only about 200 adverse events documented, including 15 deaths mostly at high doses exceeding 25 mg.00647-X/fulltext)^[58]

Regulatory actions

In December 2001, the U.S. Food and Drug Administration (FDA) added a black box warning to droperidol's labeling, citing post-marketing surveillance reports of QT interval prolongation and torsades de pointes associated with the drug, including cases of sudden death at low doses (≤2.5 mg).^[36] This action was prompted by adverse event reports, including at least 8 deaths linked to low-dose use among 15 events submitted by the manufacturer in mid-2001, alongside broader data indicating 89 fatalities in 273 total reports over decades, though most occurred at higher doses.00974-0/fulltext) The warning recommended reserving droperidol for patients unresponsive to other therapies, initiating at the lowest effective dose, and monitoring for QT prolongation via electrocardiogram (ECG) in at-risk individuals. The black box warning led to a sharp decline in droperidol's clinical use, with many U.S. emergency departments removing it from formularies and contributing to periodic drug shortages by the mid-2000s.^[4] Expert panels and editorials in 2002–2003, including responses from anesthesiology and emergency medicine groups, questioned the warning's evidence base, arguing that the cited cases often involved confounding factors like high doses, polypharmacy, or underlying cardiac conditions, and that prospective studies showed minimal risk at therapeutic levels.^[59] In 2004, an FDA-convened expert panel reviewed the data and affirmed the warning but clarified it applied primarily to doses ≥2.5 mg, without extending formal review to lower doses commonly used in emergency settings. During the 2010s, accumulating evidence from observational studies and meta-analyses supported the safety of low-dose droperidol (typically 0.625–2.5 mg) for indications like agitation, nausea, and sedation, with rare instances of clinically significant QT prolongation or torsades de pointes.^[60] A 2020 review and subsequent guidelines, including those from the American College of Emergency Physicians, endorsed its re-emergence for emergency department use under monitored conditions, prompting broader adoption despite the persistent warning.^[24] Internationally, the European Medicines Agency (EMA) and equivalents in other regions maintained QT-related warnings but permitted low-dose formulations for postoperative nausea and vomiting since relaunching approvals around 2009, allowing more flexible use than in the U.S. without full market withdrawal.^[8] As of 2025, the FDA black box warning remains unchanged, with no formal removal or revision initiated. However, droperidol's utilization has increased in U.S. emergency protocols for acute agitation and nausea, often with mandatory pre-administration ECG screening for patients with cardiac risk factors to mitigate potential QT effects.^[60]

Chemistry and availability

Chemical properties

Droperidol is a member of the butyrophenone class of compounds, characterized by a core structure featuring a fluorophenyl ketone moiety and a piperidine ring system.^[2] Its chemical formula is C₂₂H₂₂FN₃O₂, with a molecular weight of 379.43 g/mol.^[3] The IUPAC name is 1-{1-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,6-tetrahydropyridin-4-yl}-2,3-dihydro-1H-1,3-benzodiazol-2-one; it is also described as 1-[1-[3-(p-fluorobenzoyl)propyl]-1,2,3,6-tetrahydro-4-pyridyl]-2-benzimidazolinone, consisting of a 1,2,3,6-tetrahydropyridine ring linked to a benzimidazolinone group and a propyl chain bearing a p-fluorobenzoyl substituent.^[3]^[2] This arrangement is synthesized through alkylation reactions coupling the tetrahydropyridyl component with the fluorobenzoylpropyl chain and benzimidazolinone, following standard butyrophenone derivatization methods.^[61] Physically, droperidol appears as a white to light tan, amorphous or microcrystalline powder.^[3] It exhibits low solubility in water (approximately 0.01 g/100 mL at 25°C), making it practically insoluble, but is highly soluble in chloroform (approximately 18 g/100 mL) and dimethylformamide, with sparing solubility in ethanol (approximately 0.17 g/100 mL) and methanol.^[3]^[62] Droperidol should be stored at controlled room temperature (20° to 25°C) and protected from light, though the powder may darken upon prolonged exposure to light. Its pKa is approximately 7.6, reflecting moderate basicity primarily associated with the piperidine nitrogen.^[47]

Formulations and legal status

Droperidol is formulated exclusively as an injectable solution at a concentration of 2.5 mg/mL, supplied in single-dose vials of 1 mL or 2 mL for intravenous or intramuscular administration; no oral dosage form exists.^[63]^[64] The product is preservative-free and latex-free in its vial closures.^[64] In the United States, the original brand name Inapsine was discontinued following the 2001 FDA black box warning, but generic equivalents remain available from manufacturers such as Hikma Pharmaceuticals USA and American Regent.^[65]^[66] Internationally, droperidol is marketed under brand names including Droleptan in Australia and parts of Europe, as well as Dehydrobenzperidol in some regions.^[67]^[68] Droperidol is classified as a prescription-only medication worldwide, including Schedule 4 in Australia, POM in the United Kingdom, and Rx-only in the United States and Canada.^[68]^[69]^[70] In the US, it carries an FDA black box warning for the risk of QT interval prolongation and torsades de pointes, particularly at doses of 2.5 mg or higher, though it remains approved for use with appropriate monitoring.^[27] It is not designated as a controlled substance under the DEA schedules due to limited abuse potential.^[27] Availability in the United States has been limited by periodic shortages, but as of November 2025, supplies from Hikma and American Regent are available, supporting its use in anesthesia and antiemetic applications.^[66] The drug is more routinely accessible in Europe, Canada, and Australia for similar indications.^[68]^[70] In some countries, droperidol is also approved for veterinary use, often in combination with fentanyl under names like Innovar-Vet for sedation in animals.^[71]

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Apr 13, 2021 · The starting dosing of droperidol for agitation is 2.5 to 5 mg IV or IM. Average time to sedation is 15-30 minutes.
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Droperidol Use in the Emergency Department – What's Old is New ...
Aug 1, 2019 · Duration of effect is approximately 2 to 4 hours, although reduced alertness may persist for up to 12 hours (2). Droperidol undergoes hepatic ...
[20]
Droperidol: Making a Comeback!!! - Emergency Medicine Blog
Jun 7, 2021 · Onset of Action: 5 to 10min (a bit faster with IV) · Peak Effect: 20 to 30min (a bit faster with IV) · Duration of Action: 2 to 4hrs.
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[PDF] A Prospective Study of Intramuscular Droperidol or Olanzapine for ...
Apr 9, 2021 · Methods: This was a prospective observational study of ED patients receiving intramuscular droperidol or olanzapine for acute agitation.
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A systematic review of the effectiveness and safety of droperidol for ...
The largest study reported a median time to sedation of 14 min (interquartile range 10–20 min); other studies reported a time to sedation of 15 min or less.
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[PDF] Droperidol for Acute Agitation Pharmacology1,2
Combination of IV midazolam and IV droperidol was more effective at providing adequate sedation at 10 minutes than either droperidol or olanzapine alone. More ...<|control11|><|separator|>
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[PDF] Use of Droperidol in the Emergency Department | ACEP
Droperidol is a butyrophenone with an approved indication for reducing the incidence of nausea and vomiting associated with surgical and diagnostic procedures ...
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a retrospective analysis of QTc prolongation and adverse events
Dec 18, 2024 · Droperidol is a first-generation antipsychotic medication that primarily acts as an antagonist at the dopamine-2 receptors, while also inducing ...
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The Psychopharmacology of Agitation - PubMed Central - NIH
Droperidol, another butyrophenone with D2 receptor–blocking effects, has not been approved for psychiatric use but is approved as a preanesthetic to reduce ...
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Droperidol for the treatment of acute migraine headaches - PubMed
Conclusions: Parenteral droperidol is an effective option for the treatment of acute migraine. The minimum effective dose is 2.5 mg given IM or IV.Missing: low- sickle cell
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Droperidol in the Emergency Department: is it safe? - ScienceDirect
Of interest, Droperidol has received FDA approval for only two indications, as an antiemetic and as an anxiolytic/amnestic agent before diagnostic or ...
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Droperidol for psychosis‐induced aggression or agitation - PMC
Droperidol may be taken orally (5 mg to 20 mg repeated every four to six hours, as necessary) or as an IM or intravenous (IV) injection (dosages: up ...Missing: anesthesia tranquilization
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Droperidol is one pharmaceutical agent which is remarkably effective in depressing vestibular disturbance regardless of etiology.Missing: off- label motion
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Management of Dizziness and Vertigo - U.S. Pharmacist
Jan 20, 2012 · Benzodiazepines are effective for vertigo, but they may be habit-forming. For acute cases of severe vertigo, IM promethazine or IV droperidol ...
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Mar 10, 2025 · Droperidol produces an antiemetic effect as evidenced by the antagonism of apomorphine in dogs. It lowers the incidence of nausea and vomiting ...
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[PDF] Droperidol, Solution for injection - Medsafe
• increased saliva, dry mouth. • nausea, vomiting, constipation or diarrhoea. Speak to your doctor if you have any of these less serious side effects and.
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Apr 23, 2019 · In 2001, the FDA issued a black box warning due to concerns about QT prolongation and torsade de pointes. The recommended ECG telemetry ...Missing: emergence | Show results with:emergence
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The FDA has recently received reports of deaths associated with QT prolongation and torsades de pointes in patients who had received droperidol.
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However, in 2001 the FDA issued a “black box” warning for droperidol, citing reports of severe cardiac arrhythmias (eg, torsades de pointes) and rare cases ...
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As a neuroleptic it has known adverse effects including sedation, extrapyramidal symptoms (restlessness, akathisia, dystonia and occulogyric crises) and ...
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Neuroleptic malignant syndrome induced by droperidol - PubMed
A case of droperidol-induced neuroleptic malignant syndrome during anaesthesia is presented. An 86-year-old man underwent spinal anaesthesia for open ...
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Neuroleptic malignant syndrome (NMS) is a life-threatening syndrome associated with the use of dopamine-receptor antagonist medications or with rapid withdrawal ...Continuing Education Activity · Introduction · Etiology · Differential Diagnosis
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TD most generally occurs in individuals who are on long-term treatment with dopaminergic antagonist medications (antipsychotic drugs [APDs]). In fact, TD occurs ...
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The Incidence of QT Prolongation and Torsades des Pointes in ... - NIH
Jul 2, 2020 · We found the incidence of QTc prolongation and TdP in ED patients receiving droperidol to be extremely rare. Our data suggest the FDA “black box warning” is ...
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Droperidol is a short-acting, potent dopamine D2 antagonist that can pass through the blood–brain barrier. A black box warning was issued for droperidol by ...
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DROPERIDOL INJECTION, USP - DailyMed
Droperidol is contraindicated in patients with known or suspected QT prolongation (i.e., QTc interval greater than 440 msec for males or 450 msec for females).
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caution: heart rate <50; caution: MI, recent; caution: CHF; caution: electrolyte abnormalities; caution: hypokalemia; caution: hypomagnesemia; caution: cardiac ...
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[PDF] DROPERIDOL INJECTION USP - E-lactancia
Droperidol is contraindicated in patients with known hypersensitivity or intolerance to the drug. Droperidol should not be used in children 2 years of age and ...
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Droperidol Panpharma - NPS MedicineWise
Like all medicines, Droperidol Panpharma can cause side effects. Tell your ... increased saliva or dry mouth; nausea, vomiting, constipation or ...
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Droperidol Injection, USP - DailyMed
Potentially Arrhythmogenic Agents: Any drug known to have the potential to prolong the QT interval should not be used together with droperidol. Possible ...
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Extrapyramidal side effects, also referred to as medication-induced movement disorders, are common adverse drug reactions caused by antipsychotic medications.
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Coma After Droperidol Administration: A Case Report - PMC - NIH
Aug 13, 2024 · We discuss potential ADR for droperidol. Multiple drugs are typically coadministered to induce and maintain anesthesia during a surgical ...
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Evidence-based Review of the Black-box Warning for Droperidol
NMS is often fatal and results from cardiovascular collapse, cardiac arrhythmias, respiratory failure, thromboembolism, or rhabdomyolysis. ... Hypothermia.
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Nov 3, 2020 · Rapidly absorbed but in overdose absorption can be slow and erratic. · Reduced GCS: Prompt intubation and ventilation · They all cause dose- ...
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Toxicity / Risk Assessment. Management. - Toxicity is dose dependent. - Maintain airway. Intubation may be required in large overdoses.
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The treatment of drug induced torsades de pointes includes identifying and withdrawing the offending drug(s), replenishing the potassium concentration to ...
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Mar 21, 2017 · Janssen and colleagues then produced even more potent drugs, the butyrophenone droperidol, and the opioid fentanyl [ 4 ]. In 1963, de Castro and ...
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Droperidol | Internet Book of Emergency Medicine
In 2001, the FDA issued a black box warning about droperidol indicating that ... For patients who are severely agitated, droperidol can be combined with midazolam ...Missing: re- | Show results with:re-
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Aug 6, 2025 · FDA further suggested the use of droperidol was contraindicated for patients with known or suspected QT prolongation, including patients with ...
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Droperidol Use in the Emergency Department: A Clinical Review
Mar 9, 2023 · Although the exact mechanism is unknown, droperidol may block dopamine receptors in the chemoreceptor zone of the medulla, thus contributing to ...
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The neuroleptic droperidol possesses antipsychotic, sedative, and antishock action. It potentiates the action of drugs for narcosis.Missing: studies | Show results with:studies
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Droperidol - an overview | ScienceDirect Topics
Although CYP 3A4 is the primary enzyme responsible for haloperidol metabolism, with CYP 2D6 appearing to play only a minor role, several studies have shown ...
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[PDF] 2025 Injectable Product Catalog - Hikma Pharmaceuticals
Droperidol Injection, USP. 0143-9515-25. 2.5 mg / mL. 1 mL. 2 mL. 25 vials ... ©2025 Hikma Pharmaceuticals USA Inc. All rights reserved. HK-1133-v6. 200 ...Missing: American Regent
[64]
Droperidol / Products / American Regent
WARNING Cases of QT prolongation and/or torsade de pointes have been reported in patients receiving droperidol at doses at or below recommended doses.
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Generic Inapsine Availability - Drugs.com
Last updated on Oct 8, 2025. Inapsine is a brand name of droperidol, approved by the FDA in the following formulation: INAPSINE (droperidol - injectable ...
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Drug Shortage Detail: Droperidol Injection - ASHP
7/9/2025. Droperidol Injection. Reason for the Shortage. American Regent has droperidol injection available. Hikma has droperidol injection available.Missing: generic | Show results with:generic
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[PDF] Droleptan®, Droperidol 2.5mg in 1ml, Injection - Phebra
ANAESTHESIA DROLEPTAN® INJECTION is indicated to produce tranquillisation and to reduce the incidence of nausea and vomiting in surgical and.
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Symptoms of accidental overdose are psychic indifference with a transition to sleep, sometimes in association with lowered blood pressure.
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Droleptan | healthdirect
These medicine packs are available from a pharmacist and requires a prescription. It is Schedule 4 : Prescription Only Medicine.Missing: Europe Canada
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Product information - Canada.ca
Product name: DROPERIDOL INJECTION. DIN : 02232449. Electronic product monograph is not available. Company: NOVOPHARM LIMITED. 30 Novopharm Court Toronto ...
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The Opioid Epidemic: What Veterinarians Need to Know - FDA
Mar 25, 2025 · Two opioids are approved and marketed for use in animals, butorphanol and buprenorphine. Another, droperidol fentanyl citrate, is approved but ...