ChlorproMAZINE

Pronunciation

(klor PROE ma zeen)

U.S. Brand Names

Thorazine® [DSC]

Synonyms

Chlorpromazine Hydrochloride; CPZ

Generic Available

Yes: Tablet

Canadian Brand Names

Apo-Chlorpromazine®; Largactil®; Novo-Chlorpromazine

Use

Control of mania; treatment of schizophrenia; control of nausea and vomiting; relief of restlessness and apprehension before surgery; acute intermittent porphyria; adjunct in the treatment of tetanus; intractable hiccups; combativeness and/or explosive hyperexcitable behavior in children 1-12 years of age and in short-term treatment of hyperactive children

Use - Unlabeled/Investigational

Management of psychotic disorders

Pregnancy Risk Factor

Lactation

Enters breast milk/not recommended (AAP rates "of concern")

Contraindications

Hypersensitivity to chlorpromazine or any component of the formulation (cross-reactivity between phenothiazines may occur); severe CNS depression; coma

Warnings/Precautions

Highly sedating, use with caution in disorders where CNS depression is a feature. Use with caution in Parkinson's disease. Caution in patients with hemodynamic instability; bone marrow suppression; predisposition to seizures, subcortical brain damage, severe cardiac, hepatic, renal, or respiratory disease. Esophageal dysmotility and aspiration have been associated with antipsychotic use - use with caution in patients at risk of aspiration pneumonia (ie, Alzheimer's 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 neuroleptics. May cause orthostatic hypotension - use with caution in patients at risk of this effect or those who would tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, or other medications which may predispose). Significant hypotension may occur, particularly with parenteral administration. Injection contains sulfites and benzyl alcohol.

Phenothiazines may cause anticholinergic effects (confusion, agitation, 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. Relative to other neuroleptics, chlorpromazine has a moderate potency of cholinergic blockade.

May cause extrapyramidal symptoms, including pseudoparkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia (risk of these reactions is low-moderate relative to other neuroleptics). May be associated with neuroleptic malignant syndrome (NMS) or pigmentary retinopathy.

Adverse Reactions

Cardiovascular: Postural hypotension, tachycardia, dizziness, nonspecific QT changes

Central nervous system: Drowsiness, dystonias, akathisia, pseudoparkinsonism, tardive dyskinesia, neuroleptic malignant syndrome, seizure

Dermatologic: Photosensitivity, dermatitis, skin pigmentation (slate gray)

Endocrine & metabolic: Lactation, breast engorgement, false-positive pregnancy test, amenorrhea, gynecomastia, hyper- or hypoglycemia

Gastrointestinal: Xerostomia, constipation, nausea

Genitourinary: Urinary retention, ejaculatory disorder, impotence

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

Hepatic: Jaundice

Ocular: Blurred vision, corneal and lenticular changes, epithelial keratopathy, pigmentary retinopathy

Overdosage/Toxicology

Symptoms of overdose include deep sleep, coma, extrapyramidal symptoms, abnormal involuntary muscle movements, and hypotension. Following initiation of essential overdose management, toxic symptom treatment and supportive treatment should be initiated. Neuroleptics often cause extrapyramidal symptoms (eg, dystonic reactions) requiring management with anticholinergic agents such as benztropine mesylate 1-2 mg for adult patients (oral, I.M., I.V.) or diphenhydramine 25-50 mg (oral, I.M., I.V.) may be effective.

Drug Interactions

Substrate of CYP1A2 (minor), 2D6 (major), 3A4 (minor); Inhibits CYP2D6 (strong), 2E1 (weak)

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

CYP2D6 inhibitors: May increase the levels/effects of chlorpromazine. Example inhibitors include delavirdine, fluoxetine, miconazole, paroxetine, pergolide, quinidine, quinine, ritonavir, and ropinirole.

CYP2D6 substrates: Chlorpromazine may increase the levels/effects of CYP2D6 substrates. Example substrates include amphetamines, selected beta-blockers, dextromethorphan, fluoxetine, lidocaine, mirtazapine, nefazodone, paroxetine, risperidone, ritonavir, thioridazine, tricyclic antidepressants, and venlafaxine.

CYP2D6 prodrug substrates: Chlorpromazine may decrease the levels/effects of CYP2D6 prodrug substrates. Example prodrug substrates include codeine, hydrocodone, oxycodone, and tramadol.

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

Guanethidine and guanadrel: Antihypertensive effects may be inhibited by chlorpromazine

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

Lithium: Chlorpromazine 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).

Herb/Nutraceutical: Avoid St John's wort (may decrease chlorpromazine levels, increase photosensitization, or enhance sedative effect). Avoid dong quai (may enhance photosensitization). Avoid kava kava, gotu kola, valerian (may increase CNS depression).

Stability

Injection: Protect from light; a slightly yellowed solution does not indicate potency loss, but a markedly discolored solution should be discarded; diluted injection (1 mg/mL) with NS and stored in 5 mL vials remains stable for 30 days

Compatibility

Stable in dextran 6% in dextrose, dextran 6% in NS, D5LR, D5¹ /4NS, D5¹ /2NS, D5NS, D5W, D10W, LR, ¹ /2NS, NS

Y-site administration: Compatible: Amsacrine, cisatracurium, cisplatin, cladribine, cyclophosphamide, cytarabine, docetaxel, doxorubicin, doxorubicin liposome, famotidine, filgrastim, fluconazole, gatifloxacin, gemcitabine, granisetron, heparin, hydrocortisone sodium succinate, ondansetron, potassium chloride, propofol, teniposide, thiotepa, vinorelbine, vitamin B complex with C. Incompatible: Allopurinol, amifostine, amphotericin B cholesteryl sulfate complex, aztreonam, cefepime, etoposide phosphate, fludarabine, furosemide, linezolid, melphalan, methotrexate, paclitaxel, piperacillin/tazobactam, sargramostim. Variable (consult detailed reference): Remifentanil, TPN

Compatibility in syringe: Compatible: Atropine, benztropine, butorphanol, diphenhydramine, doxapram, droperidol, fentanyl, glycopyrrolate, hydromorphone, hydroxyzine, meperidine, metoclopramide, midazolam, morphine, pentazocine, perphenazine, prochlorperazine edisylate, promazine, promethazine, scopolamine. Incompatible: Cimetidine, dimenhydrinate, heparin, pentobarbital, thiopental. Variable (consult detailed reference): Ranitidine

Compatibility when admixed: Compatible: Ascorbic acid injection, ethacrynate, netilmicin, theophylline, vitamin B complex with C. Incompatible: Aminophylline, amphotericin B, ampicillin, chloramphenicol, chlorothiazide, floxacillin, furosemide, methohexital, penicillin G potassium, penicillin G sodium, phenobarbital. Variable (consult detailed reference): Pentobarbital

Mechanism of Action

Chlorpromazine is an aliphatic phenothiazine antipsychotic which blocks postsynaptic mesolimbic dopaminergic receptors in the brain; exhibits a strong alpha-adrenergic 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: I.M.: 15 minutes; Oral: 30-60 minutes

Absorption: Rapid

Distribution: Vd: 20 L/kg; crosses the placenta; enters breast milk

Protein binding: 92% to 97%

Metabolism: Extensively hepatic to active and inactive metabolites

Bioavailability: 20%

Half-life, biphasic: Initial: 2 hours; Terminal: 30 hours

Excretion: Urine (<1% as unchanged drug) within 24 hours

Dosage

Children 6 months:

Schizophrenia/psychoses:

Oral: 0.5-1 mg/kg/dose every 4-6 hours; older children may require 200 mg/day or higher

I.M., I.V.: 0.5-1 mg/kg/dose every 6-8 hours

<5 years (22.7 kg): Maximum: 40 mg/day

5-12 years (22.7-45.5 kg): Maximum: 75 mg/day

Nausea and vomiting:

Oral: 0.5-1 mg/kg/dose every 4-6 hours as needed

I.M., I.V.: 0.5-1 mg/kg/dose every 6-8 hours

<5 years (22.7 kg): Maximum: 40 mg/day

5-12 years (22.7-45.5 kg): Maximum: 75 mg/day

Adults:

Schizophrenia/psychoses:

Oral: Range: 30-2000 mg/day in 1-4 divided doses, initiate at lower doses and titrate as needed; usual dose: 400-600 mg/day; some patients may require 1-2 g/day

I.M., I.V.: Initial: 25 mg, may repeat (25-50 mg) in 1-4 hours, gradually increase to a maximum of 400 mg/dose every 4-6 hours until patient is controlled; usual dose: 300-800 mg/day

Intractable hiccups: Oral, I.M.: 25-50 mg 3-4 times/day

Nausea and vomiting:

Oral: 10-25 mg every 4-6 hours

I.M., I.V.: 25-50 mg every 4-6 hours

Elderly: Behavioral symptoms associated with dementia: Initial: 10-25 mg 1-2 times/day; increase at 4- to 7-day intervals by 10-25 mg/day. Increase dose intervals (bid, tid, etc) as necessary to control behavior response or side effects; maximum daily dose: 800 mg; gradual increases (titration) may prevent some side effects or decrease their severity.

Dosing comments in renal impairment: Hemodialysis: Not dialyzable (0% to 5%)

Dosing adjustment/comments in hepatic impairment: Avoid use in severe hepatic dysfunction

Administration

Note: Avoid skin contact with oral solution or injection solution; may cause contact dermatitis.

I.V.: Direct or intermittent infusion: Infuse 1 mg or portion thereof over 1 minute.

Monitoring Parameters

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

Reference Range

Therapeutic: 50-300 ng/mL (SI: 157-942 nmol/L)

Toxic: >750 ng/mL (SI: >2355 nmol/L); serum concentrations poorly correlate with expected response

Test Interactions

False-positives for phenylketonuria, amylase, uroporphyrins, urobilinogen. May cause false-positive pregnancy test.

Patient Education

Use exactly as directed; do not increase dose or frequency. Do not discontinue without consulting prescriber. Tablets may be taken with food. Do not take within 2 hours of any antacid. Store away from light. Avoid alcohol or caffeine and other prescription or OTC medications not approved by prescriber. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. May turn urine red-brown (normal). You may experience excess drowsiness, lightheadedness, dizziness, or blurred vision (use caution driving or when engaging in tasks requiring alertness until response to drug is known); dry mouth, upset stomach, nausea, vomiting, anorexia (small, frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help); constipation (increased exercise, fluids, fruit, or fiber may help); postural hypotension (use caution climbing stairs or when changing position from lying or sitting to standing); urinary retention (void before taking medication); ejaculatory dysfunction (reversible); decreased perspiration (avoid strenuous exercise in hot environments); or photosensitivity (use sunscreen, wear protective clothing and eyewear, and avoid direct sunlight). Report persistent CNS effects (trembling fingers, altered gait or balance, excessive sedation, seizures, unusual movements, anxiety, abnormal thoughts, confusion, personality changes); chest pain, palpitations, rapid heartbeat, or severe dizziness; unresolved urinary retention or changes in urinary pattern; altered menstrual pattern, change in libido, swelling or pain in breasts (male or female); vision changes, skin rash, irritation, or changes in color of skin (gray-blue); or worsening of condition. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Breast-feeding is not recommended.

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment:

Significant hypotension may occur, especially when the drug is administered parenterally. Orthostatic hypotension is due to alpha-receptor blockade; elderly are at greater risk.

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.

Increased confusion, memory loss, psychotic behavior, and agitation frequently occur as a consequence of anticholinergic effects. Antipsychotic-associated sedation in nonpsychotic patients is extremely unpleasant due to feelings of depersonalization, derealization, and dysphoria.

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

Dosage Forms

[DSC] = Discontinued product

Injection, solution, as hydrochloride (Thorazine® [DSC]): 25 mg/mL (10 mL) [contains benzyl alcohol, sodium bisulfite, and sodium sulfite]

Tablet, as hydrochloride: 10 mg, 25 mg, 50 mg, 100 mg, 200 mg

References

American Academy of Pediatrics Committee on Drugs, "Reappraisal of Lytic Cocktail/Demerol®, Phenergan®, and Thorazine® (DPT) for the Sedation of Children," Pediatrics , 1995, 95(4):598-602.

"American Academy of Pediatrics Committee on Drugs. The Transfer of Drugs and Other Chemicals Into Human Milk," Pediatrics , 2001, 108(3):776-89.

Fernandes CM, "Parenteral Chlorpromazine and a Meningitis Headache," J Emerg Med , 1995, 13(4):577-9.

Gez E, Ben-Yosef R, Catane R, et al, "Chlorpromazine and Dexamethasone Versus High-Dose Metoclopramide and Dexamethasone in Patients Receiving Cancer Chemotherapy, Particularly Cis-Platinum: A Prospective Randomized Crossover Study," Oncology , 1989, 46(3):150-4.

Gez E, Brufman G, Kaufman B, et al, "Methylprednisolone and Chlorpromazine in Patients Receiving Cancer Chemotherapy: A Prospective Nonrandomized Study," J Chemother , 1989, 1(2):140-3.

Hutcheon AW, Palmer JB, Soukop M, et al, "A Randomized Multicentre Single Blind Comparison of a Cannabinoid Antiemetic (Levonantradol) With Chlorpromazine in Patients Receiving Their First Cytotoxic Chemotherapy," Eur J Cancer Clin Oncol , 1983, 19(8):1087-90.

Knight ME and Roberts RJ, "Phenothiazine and Butyrophenone Intoxication in Children," Pediatr Clin North Am , 1986, 33(2):299-309.

Lipka LJ, Lathers CM, and Roberts J, "Does Chlorpromazine Produce Cardiac Arrhythmia Via the Central Nervous System," J Clin Pharmacol , 1988, 28(11):968-83.

Mitchell AC and Brown KW, "Chlorpromazine-Induced Retinopathy," Br J Psychiatry , 1995, 166(6):822-3.

Oshika T, "Ocular Adverse Effects of Neuropsychiatric Agents. Incidence and Management," Drug Saf , 1995, 12(4):256-63.

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

Relling MV, Mulhern RK, Fairclough D, et al, "Chlorpromazine With and Without Lorazepam as Antiemetic Therapy in Children Receiving Uniform Chemotherapy," J Pediatr , 1993, 123(5):811-6.

Risse SC and Barnes R, "Pharmacologic Treatment of Agitation Associated With Dementia," J Am Geriatr Soc , 1986, 34(5):368-76.

Rosenberg MR and Green M, "Neuroleptic Malignant Syndrome: Review of Response to Therapy," Arch Intern Med , 1989, 149(9):1927-31.

Saab GA, Shamseddine A, and Habbal Z, "Prolonged Chlorpromazine Infusion as Antiemetic in Patients on Daily Cisplating Infusion. A Pilot Study," Am J Clin Oncol , 1988, 11(4):470-3.

Saltz BL, Woerner MG, Kane JM, et al, "Prospective Study of Tardive Dyskinesia Incidence in the Elderly," JAMA , 1991, 266(17):2402-6.

Seifert RD, "Therapeutic Drug Monitoring: Psychotropic Drugs," J Pharm Pract , 1984, 6:403-16.

International Brand Names

Aminazin® (RU); Ampliactil® (AR); Amplictil® (BR); Apo-Chlorpromazine® (CA); Chloorpromazine FNA® (NL); Chloractil® (GB); Chlorazin® (BG, CH); Chlorpromazina HCl® (RO); Chlorpromazine® (AU, CY, GB, IN, RU); Chlorpromed® (TH); Clonazine® (IE); Clordelazin® (RO); Clorpromacina Luar® (AR); Clorpromazina Cevallos® (AR); Clorpromazina® (CL); Clorpromazina Clorhidrato® (CL); Clorpromazina Cloridrato® (IT); Clorpromazina Duncan® (AR); Clorpromazina Lando® (AR); Clorpromazina L.CH.® (CL); Conrax® (AR); Duncan® (TH); Fenactil® (PL); Hibernal-embonat® (SE); Hibernal® (HU, SE); Intramed Chlorpromazine Injection® (ZA); Klorproman® (CZ, FI); Largactil® (AU, BD, CA, CL, CR, DK, DO, ES, FR, GB, GT, HK, HN, ID, IE, IT, LU, MX, NL, NO, NZ, PA, PT, RO, SV, TR, YU, ZA); Longactil® (BR); Matcine® (SG, TH); Meprosetil® (ID); Novo-Chlorpromazine (CA); Opsonil® (BD); Plegomazin® (CZ, RO); Plegomazine® (CZ); Promactil® (ID); Propaphenin® (DE); Prozine® (TH); Prozin® (IT, RO); Taroctyl® (IL)

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