Drug Monograph
Prochlorperazine
Brand name: Compazine (discontinued); generic available
Pharmacokinetic Profile
Half-Life
6–9 h (single dose); ~18 h (chronic dosing)
Bioavailability
Very low oral (~12–15%); high first-pass
Protein Binding
>90% (phenothiazine class)
Volume of Distribution
~12.9 L/kg (very large)
Metabolism
Hepatic CYP450; N-desmethyl metabolite
Clinical Information
Drug Class
First-generation antipsychotic (phenothiazine)
Available Doses
5 mg, 10 mg tablets; 25 mg suppository; 5 mg/mL injection
Route
PO, PR, IV, IM
Renal Adjustment
No specific adjustment in PI
Hepatic Adjustment
Use with caution; no specific guidelines in PI
Pregnancy
Use only if benefit justifies risk; phenothiazines excreted in breast milk
Elderly Warning
Increased mortality in dementia-related psychosis; use lowest dose
Pediatric
Contraindicated <2 y or <20 lbs; not for pediatric surgery
Schedule
Rx Only
Generic Available
Yes (Compazine brand discontinued)
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Severe nausea and vomiting (chemotherapy, radiation, pre/post-operative, other causes) | Adults; children ≥2 y and ≥20 lbs | Treatment / prophylaxis | FDA Approved |
| Schizophrenia and psychotic disorders | Adults; children ≥2 y and ≥20 lbs | Acute and chronic treatment | FDA Approved |
| Non-psychotic anxiety (generalized anxiety disorder) | Adults | Short-term (≤12 weeks; max 20 mg/day) | FDA Approved |
Prochlorperazine is a first-generation phenothiazine antipsychotic with potent antiemetic activity via central dopamine D2 receptor blockade in the chemoreceptor trigger zone. It has been a cornerstone antiemetic for over 60 years. For non-psychotic anxiety, it is not considered first-line due to the risk of tardive dyskinesia and other extrapyramidal effects; use should not exceed 20 mg/day or 12 weeks. One systematic review found prochlorperazine equally effective as ondansetron, metoclopramide, promethazine, and droperidol for emergency department nausea and vomiting.
Off-Label Uses
Acute migraine — Evidence quality: High. The American Headache Society recommends prochlorperazine (10 mg IV) as a first-line agent for acute migraine in the emergency department. Randomized controlled trials have shown prochlorperazine provides superior headache and nausea relief compared to metoclopramide in the ED setting.
Vertigo / labyrinthitis — Evidence quality: Moderate. Widely used in the UK for vestibular symptoms; buccal formulation available internationally.
Dosing
Adult Dosing by Indication and Route
| Clinical Scenario | Dose | Frequency | Maximum Dose | Notes |
|---|---|---|---|---|
| Severe N/V — oral | 5–10 mg PO | q6–8 h | 40 mg/day | Take 30 min before meals if possible |
| Severe N/V — rectal | 25 mg PR | q12 h | 50 mg/day | Useful when oral route not tolerated |
| Severe N/V — IM | 5–10 mg IM | q3–4 h | 40 mg/day | Deep IM injection; duration of action up to 12 h |
| Severe N/V — IV | 5–10 mg IV | Slow IV push or infusion | 10 mg per single dose; 40 mg/day total IV | Do NOT give IV bolus; may dilute in isotonic solution Hypotension risk; keep patient supine ≥30 min after injection |
| PONV prophylaxis — IM | 5–10 mg IM | 1–2 h before anesthesia | 10 mg per dose | May repeat once at 30 min if needed |
| PONV prophylaxis — IV | 5–10 mg IV | 15–30 min before induction | 10 mg per dose | May repeat once; or 20 mg/L infusion 15–30 min before induction |
| Schizophrenia — oral (mild/moderate) | 5–10 mg PO | q6–8 h | 150 mg/day | Titrate slowly q2–3 days based on response |
| Schizophrenia — IM (acute) | 10–20 mg IM | q2–4 h for acute agitation | 40 mg/day (parenteral) | 3–4 doses rarely needed; switch to oral once controlled |
| Non-psychotic anxiety | 5 mg PO TID–QID | q6–8 h | 20 mg/day; max 12 weeks | Not first-line for anxiety; TD risk limits duration Exceeding 20 mg/day or 12 weeks increases irreversible TD risk |
| Acute migraine (off-label) — IV | 10 mg IV | Single dose | 10 mg | AHS first-line in ED setting |
Pediatric Dosing (≥2 Years and ≥20 lbs)
| Indication / Route | Dose | Frequency | Maximum | Notes |
|---|---|---|---|---|
| N/V — oral or rectal | 2.5 mg PO/PR | q8–12 h (BID–TID) | First day: 10 mg; ages 2–5: 20 mg/day; ages 6–12: 25 mg/day | More than 1 day’s therapy seldom necessary; use lowest effective dose Children more prone to EPS than adults |
| N/V — IM | 0.06 mg/lb (0.132 mg/kg) deep IM | Single dose usually sufficient | As per age-based oral maximums | Switch to oral once control is achieved |
| Schizophrenia — oral (ages 2–12) | 2.5 mg PO BID–TID | q8–12 h | Ages 2–5: 20 mg/day; ages 6–12: 25 mg/day | Start low; increase gradually based on response |
Special Population Adjustments
| Population | Recommendation | Notes |
|---|---|---|
| Elderly | Start at lowest effective dose | More susceptible to hypotension, neuromuscular reactions, and TD; higher incidence of agranulocytosis reported post-marketing |
| Hepatic impairment | Use with caution | No specific dose adjustment in PI; avoid in Reye’s syndrome |
| Renal impairment | No specific adjustment | No quantitative guidelines in PI |
Clinical Pearl: IV Administration Safety
Prochlorperazine must never be given as an IV bolus. A single IV dose should not exceed 10 mg and total IV dosage should not exceed 40 mg/day. Subcutaneous administration is not advisable due to local irritation. After any parenteral dose, keep the patient supine for at least 30 minutes to minimize the risk of hypotension. If a vasopressor is needed, use norepinephrine or phenylephrine; epinephrine may cause a paradoxical further drop in blood pressure due to alpha-receptor blockade by the phenothiazine.
Pharmacology
Mechanism of Action
Prochlorperazine is a piperazine-type phenothiazine that antagonizes dopaminergic D2 receptors across multiple CNS pathways. Its antiemetic effect is mediated primarily through D2 blockade in the chemoreceptor trigger zone (CTZ) of the area postrema, which lies outside the blood–brain barrier. In the mesolimbic and mesocortical pathways, D2 antagonism accounts for its antipsychotic activity against positive symptoms (hallucinations, delusions, agitation). D2 blockade in the nigrostriatal pathway underlies its propensity for extrapyramidal symptoms, while blockade in the tuberoinfundibular pathway produces hyperprolactinemia. Prochlorperazine also blocks histamine H1 receptors (causing sedation), muscarinic cholinergic receptors (producing anticholinergic effects), and alpha-1 adrenergic receptors (causing orthostatic hypotension). Unlike ondansetron, prochlorperazine does not act primarily through 5-HT3 receptors, which gives it a broader but less selective antiemetic profile.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Oral absorption slow; bioavailability very low (~12–15%) due to extensive first-pass metabolism; food decreases Cmax by 23% and AUC by 13% (sustained-release); IM onset 5–10 min | IM route provides rapid, reliable onset for acute N/V; oral bioavailability is highly variable between patients |
| Distribution | Vd ~12.9 L/kg (very large); highly protein-bound (>90%, phenothiazine class); crosses blood–brain barrier | Extensive tissue distribution explains prolonged pharmacological effects; high protein binding means potential for displacement interactions in hypoalbuminemic patients |
| Metabolism | Hepatic via CYP450 system; N-desmethyl metabolite detected; prochlorperazine sulphoxide also formed; no significant effect of CYP2C19, CYP2D6, or CYP3A5 genotypes on plasma concentrations | Monitor for CYP450 interactions; hepatic impairment may affect clearance (no specific dose guidance available) |
| Elimination | t½ 6.8–9 h (single dose IV/oral); ~18 h after 14 days chronic dosing (accumulation); urinary recoveries of drug and metabolite are low; elderly t½ ~7.5 h IV | Accumulation occurs with repeated dosing; IM action lasts up to 12 h; oral duration ~6 h |
Side Effects
Prochlorperazine shares the adverse effect profile of phenothiazine-class drugs. Extrapyramidal symptoms are the dominant concern and are dose-related, affecting 2% of patients at low doses and up to 40% at higher doses.
≥10%Very Common
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Sedation / drowsiness | Very common | H1 receptor blockade; additive with CNS depressants; may manifest as over-sedation or deep sleep from which patient can be aroused |
1–10%Common
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Extrapyramidal symptoms (akathisia, dystonia, parkinsonism) | 2–40% (dose-dependent) | More common in children, young adults, and at higher doses; akathisia was the main AE in 5/8 volunteers receiving higher IV doses |
| Anticholinergic effects (dry mouth, constipation, blurred vision, urinary retention) | Common | Muscarinic receptor blockade; more problematic in elderly |
| Orthostatic hypotension | Common (especially parenteral) | Alpha-1 blockade; keep supine ≥30 min after injection; avoid epinephrine (paradoxical effect) |
| Dizziness | Common | Related to both hypotension and CNS effects |
SeriousSerious (Regardless of Frequency)
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Tardive dyskinesia | Risk increases with duration & dose; highest in elderly women | Months to years; can appear after brief treatment or after discontinuation | Discontinue; potentially irreversible; no known effective treatment; may be masked by drug itself |
| Neuroleptic malignant syndrome (NMS) | Rare | Days to weeks | Discontinue immediately; intensive supportive care; hyperpyrexia, muscle rigidity, altered mental status, autonomic instability |
| Acute dystonic reactions (torticollis, oculogyric crisis, trismus, laryngospasm) | More frequent at 30–40 mg/day; more common in children and young adults | First 24–48 hours; can be within minutes of IM injection | Diphenhydramine 25–50 mg IV/IM or benztropine 1–2 mg IV/IM; discontinue prochlorperazine |
| Seizure threshold lowering | Uncommon | Any time | Avoid in epilepsy (not currently contraindicated in prochlorperazine PI but listed for phenothiazines); use with caution in seizure-prone patients |
| Hyperprolactinemia (galactorrhea, amenorrhea, gynecomastia) | Uncommon | Weeks to months | Monitor; clinical significance of elevated prolactin unknown for most patients; consider discontinuation if symptomatic |
| Agranulocytosis / leukopenia | Rare; may be higher in elderly (post-marketing) | Weeks to months | Discontinue if ANC <1,000; consider discontinuing with unexplained WBC drop; monitor CBC |
| Sudden death (cardiac arrest / asphyxia from cough reflex failure) | Very rare; reported with phenothiazines | Unpredictable | Reported in phenothiazine class; causal relationship not always established |
WithdrawalWithdrawal Effects
Withdrawal Symptoms
Reported
Nausea, vomiting, loss of appetite, restlessness, increased sweating, and insomnia have been reported upon abrupt discontinuation. BNF recommends gradual withdrawal to avoid acute withdrawal syndrome or rapid relapse.
Unmasking TD
Possible
Prochlorperazine may mask tardive dyskinesia during treatment. TD movements may first become apparent upon dose reduction or discontinuation, giving the false impression that symptoms are caused by withdrawal rather than being pre-existing.
Critical: EPS Risk in Children
Children are significantly more prone to extrapyramidal reactions than adults, even at moderate doses. Use the lowest effective dose, do not exceed the prescribed dosage, and exercise particular caution in children with acute illness or dehydration, as these conditions increase EPS susceptibility. If a child reacts with restlessness or excitement, do not administer additional doses.
Drug Interactions
Prochlorperazine’s interaction profile reflects its broad receptor activity (D2, H1, muscarinic, alpha-1) and phenothiazine class effects.
MajorCNS depressants (opioids, benzodiazepines, alcohol, barbiturates)
MechanismAdditive CNS depression
EffectProfound sedation, respiratory depression, coma, death; contraindicated with large amounts of CNS depressants
ManagementAvoid use in comatose states or with large CNS depressant loads; limit doses and monitor closely if unavoidable
FDA PIMajorEpinephrine
MechanismPhenothiazine alpha-1 blockade leaves epinephrine’s beta-2 vasodilatory effect unopposed
EffectParadoxical further lowering of blood pressure
ManagementDo NOT use epinephrine as a vasopressor; use norepinephrine or phenylephrine instead
FDA PIMajorQT-prolonging drugs
MechanismPhenothiazines associated with possible QT prolongation risk
EffectAdditive QT prolongation; risk of Torsade de Pointes
ManagementMonitor ECG; avoid combinations when possible
Class effectModerateLevodopa / dopamine agonists
MechanismPharmacodynamic antagonism at D2 receptors
EffectDecreased efficacy of levodopa; worsening of Parkinson’s symptoms
ManagementAvoid combination; use alternative antiemetic (e.g., trimethobenzamide, domperidone where available)
FDA PIModerateAnticholinergic drugs
MechanismAdditive anticholinergic burden
EffectIncreased risk of constipation, urinary retention, confusion, heat stroke
ManagementMinimize anticholinergic combinations; monitor especially in elderly
Class effectModerateAntihypertensives
MechanismAdditive hypotensive effects from alpha-1 blockade
EffectExcessive hypotension, especially with parenteral prochlorperazine in patients with impaired cardiovascular systems
ManagementUse parenteral doses cautiously; monitor BP
FDA PIMonitoring
- Tardive DyskinesiaEvery visit; AIMS scale
RoutineScreen for involuntary movements of face, tongue, trunk, and extremities at every encounter. Risk highest in elderly women. TD may appear during treatment, after dose reduction, or after discontinuation. There is no known effective treatment for established TD. - Extrapyramidal SymptomsFirst 48 h; then ongoing
RoutineDystonia typically within first 24–48 h; akathisia and parkinsonism can occur at any time. Children are at higher risk. Treat acute dystonia with diphenhydramine or benztropine. - Blood PressureAfter each parenteral dose
RoutineKeep patient supine for ≥30 min after IM/IV injection. Orthostatic hypotension risk increased in patients with impaired cardiovascular systems and in elderly. - CBC / WBCBaseline; periodically
Trigger-basedAgranulocytosis and leukopenia reported. Discontinue if ANC <1,000. Consider discontinuation with unexplained WBC drop. Incidence may be higher in elderly (post-marketing data). - Hepatic FunctionAs clinically indicated
Trigger-basedCholestatic jaundice has been reported with phenothiazines. Avoid use in children with signs of Reye’s syndrome. Monitor LFTs if hepatic symptoms develop. - Body TemperatureAs clinically indicated
Trigger-basedMonitor for NMS (hyperpyrexia, rigidity, altered mental status) and impaired thermoregulation. Phenothiazines can impair the body’s ability to regulate temperature.
Contraindications & Cautions
Absolute Contraindications
- Known hypersensitivity to phenothiazines
- Comatose states or in the presence of large amounts of CNS depressants (alcohol, barbiturates, narcotics)
- Pediatric patients <2 years of age or <20 lbs
- Pediatric surgery — not to be used in children undergoing surgery
- Conditions where children’s dosage has not been established
Use with Caution
- Elderly patients with dementia-related psychosis — increased risk of death (1.6–1.7× placebo in meta-analysis of 17 trials; ~4.5% vs ~2.6% over 10 weeks)
- Impaired cardiovascular systems — risk of severe hypotension with large or parenteral doses; patients with mitral insufficiency or pheochromocytoma have experienced severe hypotension
- Seizure disorders — phenothiazines may lower seizure threshold
- Children with acute illness or dehydration — significantly increased EPS susceptibility
- Hepatic impairment — use cautiously; avoid in Reye’s syndrome
- Previously detected breast cancer — approximately one-third of breast cancers may be prolactin-dependent in vitro; clinical significance of prolactin elevation unknown
- Post-surgical patients — aspiration of vomitus reported; antiemetic effect may mask signs of overdosage of other drugs, brain tumor, intestinal obstruction, or Reye’s syndrome
FDA Warning
Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration 10 weeks) revealed a risk of death in drug-treated patients between 1.6 to 1.7 times the risk in placebo-treated patients. Over a typical 10-week trial, the rate of death in drug-treated patients was approximately 4.5% compared to approximately 2.6% in the placebo group. Prochlorperazine is not approved for the treatment of patients with dementia-related psychosis.
Patient Counselling
Purpose of Therapy
Prochlorperazine is prescribed to control severe nausea and vomiting. In some cases, it is used to treat symptoms of psychosis or severe anxiety on a short-term basis. It works by blocking a chemical messenger (dopamine) in the brain that triggers nausea and vomiting.
Involuntary Movements (Tardive Dyskinesia)
Tell patientThis medication can rarely cause involuntary, uncontrollable movements, most commonly of the face and tongue. These movements may become permanent even after stopping the medication. The risk increases with longer use and higher doses.
Call prescriberImmediately if you notice lip smacking, puckering, tongue protrusion, chewing movements, or any uncontrolled movements of the face, arms, or legs.
Muscle Spasms and Stiffness
Tell patientParticularly in younger patients and children, prochlorperazine can cause sudden muscle spasms, especially of the neck, face, or eyes. This can be frightening but is treatable. These reactions typically occur within the first 1–2 days of treatment.
Call prescriberUrgently if you develop neck stiffness or twisting, difficulty swallowing or speaking, eyes rolling upward, or muscle rigidity with high fever.
Drowsiness and Dizziness
Tell patientThis medication commonly causes drowsiness and may make you dizzy, especially when standing up quickly. Avoid driving or operating machinery until you know how it affects you. Avoid alcohol and other sedating medications.
Call prescriberIf you feel faint, experience a rapid heartbeat on standing, or have a fainting episode.
Suppository Use
Tell patientIf using the suppository form, unwrap and insert gently into the rectum. Remain lying down for a few minutes. Store suppositories in a cool place. The suppository dose is 25 mg and is given every 12 hours as needed.
Call prescriberIf symptoms are not controlled within 24 hours or if nausea and vomiting worsen.
Parents/Caregivers (Pediatric Use)
Tell parentDo not exceed the prescribed dose. Children are more likely than adults to experience muscle spasms and other movement side effects. More than 1 day of treatment is seldom needed for nausea and vomiting. If your child becomes unusually restless or excited, do not give additional doses.
Call prescriberIf your child develops neck or body stiffness, difficulty breathing, tongue protrusion, or high fever.
Sources
Regulatory (PI / SmPC)
- Compazine (prochlorperazine) — FDA-Approved Prescribing Information, 2005. GlaxoSmithKline. FDA Label (Compazine)Comprehensive Compazine label covering all formulations (tablets, Spansule, suppositories, injection); source for adult and pediatric dosing, contraindications, and adverse reactions.
- Prochlorperazine Edisylate Injection — FDA-Approved Prescribing Information, revised 2010. FDA Label (Injection)Injection PI specifying IV max single dose 10 mg, total IV 40 mg/day, no bolus injection, and post-injection hypotension management.
- Prochlorperazine Maleate Tablets, USP — FDA-Approved Prescribing Information, revised 2025. FDA Label (Tablets 2025)Most recent FDA tablet label with updated elderly dementia mortality warning, Reye’s syndrome caution, and agranulocytosis data in geriatric patients.
Key Clinical Evidence
- Orr SL, Friedman BW, Christie S, et al. Management of adults with acute migraine in the emergency department: The American Headache Society Evidence Assessment of Parenteral Pharmacotherapies. Headache. 2016;56(6):911–940. PubMed: 27300483AHS evidence assessment recommending prochlorperazine as a first-line parenteral agent for acute migraine in the ED, with high confidence in its efficacy.
- Coppola M, Yealy DM, Leibold RA. Randomized, placebo-controlled evaluation of prochlorperazine versus metoclopramide for emergency department treatment of migraine headache. Ann Emerg Med. 1995;26(5):541–546. PubMed: 7486359Placebo-controlled RCT demonstrating IV prochlorperazine provides superior headache and nausea relief compared to metoclopramide in ED migraine patients.
- Barrett TW, DiPersio DM, Jenkins CA, et al. A randomized, placebo-controlled trial of ondansetron, metoclopramide, and promethazine in adults. Am J Emerg Med. 2011;29(3):247–255. PubMed: 20825792RCT comparing common ED antiemetics; supports equivalent efficacy of prochlorperazine-class agents with generally mild side effect profiles.
Guidelines
- Gan TJ, Belani KG, Bergese S, et al. Fourth Consensus Guidelines for the Management of Postoperative Nausea and Vomiting. Anesth Analg. 2020;131(2):411–448. PubMed: 32467512PONV consensus guideline including prochlorperazine among perioperative antiemetic options with discussion of EPS risk profile.
- Din L, Preuss CV. Prochlorperazine. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023. Updated August 14, 2023. StatPearls: NBK537083Comprehensive StatPearls review covering indications, mechanism, dosing, adverse effects, and monitoring; key data source for clinical dosing by route and indication.
Pharmacokinetics / Basic Science
- Taylor WB, Bateman DN. Preliminary studies of the pharmacokinetics and pharmacodynamics of prochlorperazine in healthy volunteers. Br J Clin Pharmacol. 1987;23(2):137–142. PubMed: 3828192First detailed PK study: t½ 6.8–6.9 h IV; very low oral bioavailability; high Vd; akathisia as main adverse effect in 5/8 volunteers at higher IV dose.
- Isah AO, Rawlins MD, Bateman DN. Clinical pharmacology of prochlorperazine in healthy young males. Br J Clin Pharmacol. 1991;32(6):677–684. PubMed: 1768559Definitive PK study: t½ 9 h IV, 8 h oral single dose, 18 h after 14 days chronic; Vd 12.9 L/kg; clearance 0.98 L/kg/h; N-desmethyl metabolite detected; accumulation with repeated dosing.
- Isah AO, Rawlins MD, Bateman DN. The pharmacokinetics and effects of prochlorperazine in elderly female volunteers. Age Ageing. 1992;21(1):27–31. PubMed: 1553856Elderly PK study: t½ 7.5 h IV; oral bioavailability 14.7%; antidopaminergic (prolactin rise) and anticholinergic effects confirmed in elderly.
- Finn A, Collins J, Voyksner R, Lindley C. Bioavailability and metabolism of prochlorperazine administered via the buccal and oral delivery route. J Clin Pharmacol. 2005;45(12):1383–1390. PubMed: 16291713Demonstrated that buccal delivery doubles bioavailability compared to oral tablet by partially bypassing first-pass metabolism.
- Tashiro M, Naito T, Kagawa Y, Kawakami J. Influence of cytochrome P450 genotype on the plasma disposition of prochlorperazine metabolites. Ann Clin Biochem. 2018;55(3):385–393. PubMed: 28853295Pharmacogenomics study finding no significant effect of CYP2C19, CYP2D6, or CYP3A5 genotypes on prochlorperazine plasma concentrations in cancer patients.