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Prochlorperazine


Pronunciation

 (proe klor PER a zeen)


U.S. Brand Names

 Compazine® [DSC]; Compro™


Synonyms

 Chlormeprazine; Prochlorperazine Edisylate; Prochlorperazine Maleate


Generic Available

 Yes: Injection, tablet, suppository


Canadian Brand Names

 Apo-Prochlorperazine®; Compazine®; Nu-Prochlor; Stemetil®


Use

 Management of nausea and vomiting; psychosis; anxiety


Use - Unlabeled/Investigational

 Behavioral syndromes in dementia


Pregnancy Risk Factor

 C


Pregnancy Implications

 Crosses the placenta. Isolated reports of congenital anomalies, however, some included exposures to other drugs. Available evidence with use of occasional low doses suggests safe use during pregnancy.


Lactation

 Enters breast milk/not recommended


Contraindications

 Hypersensitivity to prochlorperazine or any component of the formulation (cross-reactivity between phenothiazines may occur); severe CNS depression; coma; should not be used in children <2 years of age or <10 kg


Warnings/Precautions

 May be sedating; use with caution in disorders where CNS depression is a feature. May impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). Effects with other sedative drugs or ethanol may be potentiated. Avoid use in Reye's syndrome. Use with caution in Parkinson's disease; hemodynamic instability; bone marrow suppression; predisposition to seizures; subcortical brain damage; and in severe cardiac, hepatic, renal or respiratory disease. Caution in breast cancer or other prolactin-dependent tumors (may elevate prolactin levels). May alter temperature regulation or mask toxicity of other drugs due to antiemetic effects. May alter cardiac conduction - life threatening arrhythmias have occurred with therapeutic doses of phenothiazines. May cause orthostatic hypotension; use with caution in patients at risk of hypotension or where transient hypotensive episodes would be poorly tolerated (cardiovascular disease or cerebrovascular disease). Hypotension may occur following administration, particularly when parenteral form is used or in high dosages.

Phenothiazines may cause anticholinergic effects (constipation, xerostomia, blurred vision, urinary retention); therefore, they should be used with caution in patients with decreased gastrointestinal motility, urinary retention, BPH, xerostomia, or visual problems. Conditions which also may be exacerbated by cholinergic blockade include narrow-angle glaucoma (screening is recommended) and worsening of myasthenia gravis. May cause extrapyramidal symptoms, including pseudoparkinsonism, acute dystonic reactions, akathisia and tardive dyskinesia. May be associated with neuroleptic malignant syndrome (NMS).


Adverse Reactions

 Frequency not defined.

Cardiovascular: Hyper-/hypotension, orthostatic hypotension, tachycardia, bradycardia, dizziness, cardiac arrest

Central nervous system: Extrapyramidal symptoms (pseudoparkinsonism, akathisia, dystonias, tardive dyskinesia), dizziness, cerebral edema, seizure, headache, drowsiness, paradoxical excitement, restlessness, hyperactivity, insomnia, neuroleptic malignant syndrome (NMS), impairment of temperature regulation

Dermatologic: Rash, discoloration of skin (blue-gray), photosensitivity

Endocrine & metabolic: Hypoglycemia, hyperglycemia, galactorrhea, lactation, breast enlargement, gynecomastia, menstrual irregularity, amenorrhea, SIADH, libido (changes in)

Gastrointestinal: Constipation, weight gain, vomiting, stomach pain, nausea, xerostomia, salivation, diarrhea, anorexia, ileus

Genitourinary: Difficulty in urination, ejaculatory disturbances, incontinence, polyuria, ejaculating dysfunction, priapism

Hematologic: Agranulocytosis, leukopenia, eosinophilia, hemolytic anemia, thrombocytopenic purpura, pancytopenia

Hepatic: Cholestatic jaundice, hepatotoxicity

Neuromuscular & skeletal: Tremor

Ocular: Pigmentary retinopathy, blurred vision, cornea and lens changes

Respiratory: Nasal congestion

Miscellaneous: Diaphoresis


Overdosage/Toxicology

 Symptoms of overdose include deep sleep, coma, extrapyramidal symptoms, abnormal involuntary muscle movements, and hypotension. Treatment is symptom-directed and supportive.


Drug Interactions

Aluminum salts: May decrease the absorption of phenothiazines; monitor

Amphetamines: Efficacy may be diminished by antipsychotics; in addition, amphetamines may increase psychotic symptoms; avoid concurrent use

Anticholinergics: May inhibit the therapeutic response to phenothiazines and excess anticholinergic effects may occur; includes benztropine, trihexyphenidyl, biperiden, and drugs with significant anticholinergic activity (TCAs, antihistamines, disopyramide)

Antihypertensives: Concurrent use of phenothiazines with an antihypertensive may produce additive hypotensive effects (particularly orthostasis)

Bromocriptine: Phenothiazines inhibit the ability of bromocriptine to lower serum prolactin concentrations

CNS depressants: Sedative effects may be additive with phenothiazines; monitor for increased effect; includes barbiturates, benzodiazepines, narcotic analgesics, ethanol and other sedative agents

Epinephrine: Chlorpromazine (and possibly other low potency antipsychotics) may diminish the pressor effects of epinephrine

Guanethidine and guanadrel: Antihypertensive effects may be inhibited by phenothiazines

Levodopa: Phenothiazines may inhibit the antiparkinsonian effect of levodopa; avoid this combination

Lithium: Phenothiazines may produce neurotoxicity with lithium; this is a rare effect

Metoclopramide: May increase extrapyramidal symptoms (EPS) or risk.

Phenytoin: May reduce serum levels of phenothiazines; phenothiazines may increase phenytoin serum levels

Propranolol: Serum concentrations of phenothiazines may be increased; propranolol also increases phenothiazine concentrations

Polypeptide antibiotics: Rare cases of respiratory paralysis have been reported with concurrent use of phenothiazines

QTc-prolonging agents: Effects on QTc interval may be additive with phenothiazines, increasing the risk of malignant arrhythmias; includes type Ia antiarrhythmics, TCAs, and some quinolone antibiotics (sparfloxacin, moxifloxacin, and gatifloxacin)

Sulfadoxine-pyrimethamine: May increase phenothiazine concentrations

Tricyclic antidepressants: Concurrent use may produce increased toxicity or altered therapeutic response

Trazodone: Phenothiazines and trazodone may produce additive hypotensive effects

Valproic acid: Serum levels may be increased by phenothiazines


Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (may increase CNS depression).

Food: Limit caffeine.

Herb/Nutraceutical: Avoid dong quai, St John's wort (may also cause photosensitization). Avoid kava kava, gotu kola, valerian, St John's wort (may increase CNS depression).


Stability

Injection: Intact vials/ampuls for injection are stable at room temperature; protect from light; clear or slightly yellow solutions may be used.

I.V. infusion: Injection may be diluted in 50-100 mL NS or D5W.

Suppository: May require refrigeration

Tablet: Stable at room temperature.


Compatibility

 Stable in dextran 6% in dextrose, dextran 6% in NS, D5W, D10W, D5LR, D5 1 /4NS, D5 1 /2NS, D5NS, LR, 1 /2NS, NS.

Y-site administration: Compatible: Amsacrine, calcium gluconate, cisatracurium, cisplatin, cladribine, clarithromycin, cyclophosphamide, cytarabine, docetaxel, doxorubicin, doxorubicin liposome, fluconazole, gatifloxacin, granisetron, heparin, hydrocortisone sodium succinate, linezolid, melphalan, methotrexate, ondansetron, paclitaxel, potassium chloride, propofol, remifentanil, sargramostim, sufentanil, teniposide, thiotepa, topotecan, vinorelbine, vitamin B complex with C. Incompatible: Aldesleukin, allopurinol, amifostine, amphotericin B cholesteryl sulfate complex, aztreonam, cefepime, etoposide phosphate, fludarabine, foscarnet, filgrastim, gemcitabine, piperacillin/tazobactam

Compatibility in syringe: Compatible: Atropine, butorphanol, chlorpromazine, cimetidine, diamorphine, diphenhydramine, droperidol, fentanyl, glycopyrrolate, hydroxyzine, meperidine, metoclopramide, nalbuphine, pentazocine, perphenazine, promazine, promethazine, ranitidine, scopolamine, sufentanil. Incompatible: Dimenhydrinate, ketorolac, midazolam, morphine tartrate, pentobarbital, thiopental. Variable (consult detailed reference): Hydromorphone, morphine sulfate

Compatibility when admixed: Compatible: Amikacin, ascorbic acid injection, cephalothin, dexamethasone sodium phosphate, dimenhydrinate, erythromycin lactobionate, ethacrynate, lidocaine, nafcillin, sodium bicarbonate, vitamin B complex with C. Incompatible: Aminophylline, amphotericin B, ampicillin, chloramphenicol, chlorothiazide, floxacillin, furosemide, heparin, hydrocortisone sodium succinate, methohexital, penicillin G sodium, phenobarbital, phenytoin, thiopental. Variable (consult detailed reference): Calcium gluconate, penicillin G potassium


Mechanism of Action

 Prochlorperazine is a piperazine phenothiazine antipsychotic which blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors in the brain, including the medullary chemoreceptor trigger zone; exhibits a strong alpha-adrenergic and anticholinergic blocking effect and depresses the release of hypothalamic and hypophyseal hormones; believed to depress the reticular activating system, thus affecting basal metabolism, body temperature, wakefulness, vasomotor tone and emesis


Pharmacodynamics/Kinetics

Onset of action: Oral: 30-40 minutes; I.M.: 10-20 minutes; Rectal: ~60 minutes

Duration: I.M., oral extended-release: 12 hours; Rectal, immediate release: 3-4 hours

Distribution: Vd: 1400-1548 L; crosses placenta; enters breast milk

Metabolism: Primarily hepatic; N-desmethyl prochlorperazine (major active metabolite)

Bioavailability: Oral: 12.5%

Half-life elimination: Oral: 3-5 hours; I.V.: ~7 hours


Dosage

Antiemetic: Children (not recommended in children <10 kg or <2 years):

Oral, rectal: >10 kg: 0.4 mg/kg/24 hours in 3-4 divided doses; or

9-14 kg: 2.5 mg every 12-24 hours as needed; maximum: 7.5 mg/day

14-18 kg: 2.5 mg every 8-12 hours as needed; maximum: 10 mg/day

18-39 kg: 2.5 mg every 8 hours or 5 mg every 12 hours as needed; maximum: 15 mg/day

I.M.: 0.1-0.15 mg/kg/dose; usual: 0.13 mg/kg/dose; change to oral as soon as possible

Antiemetic: Adults:

Oral: 5-10 mg 3-4 times/day; usual maximum: 40 mg/day

I.M.: 5-10 mg every 3-4 hours; usual maximum: 40 mg/day

I.V.: 2.5-10 mg; maximum 10 mg/dose or 40 mg/day; may repeat dose every 3-4 hours as needed

Rectal: 25 mg twice daily

Surgical nausea/vomiting: Adults:

I.M.: 5-10 mg 1-2 hours before induction; may repeat once if necessary

I.V.: 5-10 mg 15-30 minutes before induction; may repeat once if necessary

Antipsychotic:

Children 2-12 years (not recommended in children <10 kg or <2 years):

Oral, rectal: 2.5 mg 2-3 times/day; increase dosage as needed to maximum daily dose of 20 mg for 2-5 years and 25 mg for 6-12 years

I.M.: 0.13 mg/kg/dose; change to oral as soon as possible

Adults:

Oral: 5-10 mg 3-4 times/day; doses up to 150 mg/day may be required in some patients for treatment of severe disturbances

I.M.: 10-20 mg every 4-6 hours may be required in some patients for treatment of severe disturbances; change to oral as soon as possible

Nonpsychotic anxiety: Oral: Adults: Usual dose: 15-20 mg/day in divided doses; do not give doses >20 mg/day or for longer than 12 weeks

Elderly: Behavioral symptoms associated with dementia (unlabeled use): Initial: 2.5-5 mg 1-2 times/day; increase dose at 4- to 7-day intervals by 2.5-5 mg/day; increase dosing intervals (twice daily, 3 times/day, etc) as necessary to control response or side effects; maximum daily dose should probably not exceed 75 mg in elderly; gradual increases (titration) may prevent some side effects or decrease their severity

Hemodialysis: Not dialyzable (0% to 5%)


Administration

 May be administered orally, I.M., or I.V.: I.V. doses should be given as a short (~30 minute) infusion or by slow (5-10 minutes) IVP to avoid orthostatic hypotension.


Monitoring Parameters

 Vital signs; lipid profile, fasting blood glucose/Hgb A1c; BMI; mental status, abnormal involuntary movement scale (AIMS); periodic ophthalmic exams (if chronically used); extrapyramidal symptoms (EPS)


Test Interactions

 False-positives for phenylketonuria, urinary amylase, uroporphyrins, urobilinogen


Dietary Considerations

 Increase dietary intake of riboflavin; should be administered with food or water. Rectal suppositories may contain coconut and palm oil.


Patient Education

 Take exact amount as prescribed. Do not change brand names. Do not crush or chew tablets or capsules. Do not discontinue without consulting prescriber. Avoid alcohol or other sedatives or sleep-inducing drugs. Avoid skin contact with drug; wash immediately with warm soapy water. You may experience appetite changes; small, frequent meals may help. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. May cause dizziness, tremors, or visual disturbance (especially during early therapy); use caution when driving or engaging in tasks that require alertness until response to drug is known. Do not change position rapidly (rise slowly). May cause photosensitivity reaction; use sunscreen, wear protective clothing and eyewear, and avoid direct sunlight. Report immediately any changes in gait or muscular tremors. Report unresolved changes in voiding or elimination (constipation or diarrhea), acute dizziness or unresolved sedation, vision changes, palpitations, yellowing of skin or eyes, or changes in color of urine or stool (pink or red brown urine is expected). Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Breast-feeding is not recommended.


Additional Information

 Not recommended as an antipsychotic due to inferior efficacy compared to other phenothiazines.


Anesthesia and Critical Care Concerns/Other Considerations

 Prochlorperazine is not recommended as an antipsychotic due to inferior efficacy compared to other phenothiazines.


Dental Health: Effects on Dental Treatment

 Key adverse event(s) related to dental treatment: Xerostomia and changes in salivation (normal salivary flow resumes upon discontinuation). Significant hypotension may occur, especially when the drug is administered parenterally; orthostatic hypotension is due to alpha-receptor blockade, the elderly are at greater risk for orthostatic hypotension.

Tardive dyskinesia: Prevalence rate may be 40% in elderly; development of the syndrome and the irreversible nature are proportional to duration and total cumulative dose over time. Extrapyramidal reactions are more common in elderly with up to 50% developing these reactions after 60 years of age. Drug-induced Parkinson's syndrome occurs often; akathisia is the most common extrapyramidal reaction in elderly.


Dental Health: Vasoconstrictor/Local Anesthetic Precautions

 Most pharmacology textbooks state that in presence of phenothiazines, systemic doses of epinephrine paradoxically decrease the blood pressure. This is the so called "epinephrine reversal" phenomenon. This has never been observed when epinephrine is given by infiltration as part of the anesthesia procedure.


Oncology: Emetic Potential

 Very low (<10%)


Oncology: Vesicant

 No


Dosage Forms

 [DSC] = Discontinued product

Injection, solution, as edisylate: 5 mg/mL (2 mL, 10 mL) [contains benzyl alcohol]

Suppository, rectal: 2.5 mg (12s), 5 mg (12s), 25 mg (12s) [may contain coconut and palm oil]

Compazine®: 2.5 mg (12s), 5 mg (12s), 25 mg (12s) [contains coconut and palm oils] [DSC]

Compro™: 25 mg (12s) [contains coconut and palm oils]

Tablet, as maleate: 5 mg, 10 mg


References

Goldstein D, Levi JA, Woods RL, et al, "Double-Blind Randomized Cross-Over Trial of Dexamethasone and Prochlorperazine as Antiemetics for Cancer Chemotherapy," Oncology , 1989, 46(2):105-8.

Hesketh PJ, Gandara DR, Hesketh AM, et al, "Improved Control of High-Dose-Cisplatin-Induced Acute Emesis With the Addition of Prochlorperazine to Granisetron/Dexamethasone," Cancer J Sci Am , 1997, 3(3):180-3.

Lapierre J, Amin M, and Hattangadi S, "Prochlorperazine - A Review of the Literature Since 1956," Can Psychiatr Assoc J , 1969, 14(3):267-74.

Olver IN, Webster LK, Bishop JF, et al, "A Dose Finding Study of Prochlorperazine as an Antiemetic for Cancer Chemotherapy," Eur J Cancer Clin Oncol , 1989, 25(10):1457-61.

Owens NH, Schauer AR, Nightingale CH, et al, "Antiemetic Efficacy of Prochlorperazine, Haloperidol, Droperidol in Cisplatin-Induced Emesis," Clin Pharm , 1984, 3(2):167-70.

Peabody CA, Warner MD, Whiteford HA, et al, "Neuroleptics and the Elderly," J Am Geriatr Soc , 1987, 35(3):233-8.


International Brand Names

 Apo-Prochlorperazine® (CA); Compazine® (CA); Emetiral® (RO); Emidoxyn® (IN); Nu-Prochlor (CA); Stemetil® (AU, BD, CA, DK, GB, ID, IE, IN, IT, NL, NO, NZ, SG, ZA)


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