Trifluoperazine

Pronunciation

(trye floo oh PER a zeen)

U.S. Brand Names

Stelazine® [DSC]

Synonyms

Trifluoperazine Hydrochloride

Generic Available

Yes: Tablet

Canadian Brand Names

Apo-Trifluoperazine®; Novo-Trifluzine; PMS-Trifluoperazine; Terfluzine

Use

Treatment of schizophrenia

Use - Unlabeled/Investigational

Management of psychotic disorders

Pregnancy Risk Factor

Lactation

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

Contraindications

Hypersensitivity to trifluoperazine or any component of the formulation (cross-reactivity between phenothiazines may occur); severe CNS depression; bone marrow suppression; blood dyscrasias; severe hepatic disease; coma

Warnings/Precautions

May result in hypotension, particularly after I.M. administration. May be 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; predisposition to seizures; subcortical brain damage; hepatic impairment; severe cardiac, renal, or respiratory disease. Esophageal dysmotility and aspiration have been associated with antipsychotic use - use with caution in patients at risk of 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 phenothiazines. 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). Safety in children <6 months of age has not been established.

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 antipsychotics, trifluoperazine has a low potency of cholinergic blockade.

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

Adverse Reactions

Frequency not defined.

Cardiovascular: Hypotension, orthostatic hypotension, cardiac arrest

Central nervous system: Extrapyramidal symptoms (pseudoparkinsonism, akathisia, dystonias, tardive dyskinesia), dizziness, headache, neuroleptic malignant syndrome (NMS), impairment of temperature regulation, lowering of seizure threshold

Dermatologic: Increased sensitivity to sun, rash, discoloration of skin (blue-gray), photosensitivity

Endocrine & metabolic: Changes in menstrual cycle, libido (changes in), breast pain, hyperglycemia, hypoglycemia, gynecomastia, lactation, galactorrhea

Gastrointestinal: Constipation, weight gain, nausea, vomiting, stomach pain, xerostomia

Genitourinary: Difficulty in urination, ejaculatory disturbances, urinary retention, priapism

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

Hepatic: Cholestatic jaundice, hepatotoxicity

Neuromuscular & skeletal: Tremor

Ocular: Pigmentary retinopathy, cornea and lens changes

Respiratory: Nasal congestion

Overdosage/Toxicology

Symptoms of overdose include deep sleep, coma, extrapyramidal symptoms, abnormal involuntary muscle movements, hypo- or hypertension, and cardiac arrhythmias. Treatment is symptom-directed and supportive.

Drug Interactions

Substrate of CYP1A2 (major)

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

CYP1A2 inducers: May decrease the levels/effects of trifluoperazine. Example inducers include aminoglutethimide, carbamazepine, phenobarbital, and rifampin.

CYP1A2 inhibitors: May increase the levels/effects of trifluoperazine. Example inhibitors include amiodarone, ciprofloxacin, fluvoxamine, ketoconazole, norfloxacin, ofloxacin, and rofecoxib.

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.

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

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

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

Trazodone: Phenothiazines and trazodone may produce additive hypotensive effects

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

Valproic acid: Serum levels may be increased by phenothiazines

Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (may increase CNS depression).

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

Stability

Store injection at room temperature; protect from heat and from freezing; use only clear or slightly yellow solutions

Mechanism of Action

Trifluoperazine is a piperazine phenothiazine antipsychotic which blocks postsynaptic mesolimbic dopaminergic receptors in the brain; exhibits alpha-adrenergic blocking effect and depresses the release of hypothalamic and hypophyseal hormones

Pharmacodynamics/Kinetics

Metabolism: Extensively hepatic

Half-life elimination: >24 hours with chronic use

Dosage

Children 6-12 years: Schizophrenia/psychoses:

Oral: Hospitalized or well-supervised patients: Initial: 1 mg 1-2 times/day, gradually increase until symptoms are controlled or adverse effects become troublesome; maximum: 15 mg/day

I.M.: 1 mg twice daily

Adults:

Schizophrenia/psychoses:

Outpatients: Oral: 1-2 mg twice daily

Hospitalized or well-supervised patients: Initial: 2-5 mg twice daily with optimum response in the 15-20 mg/day range; do not exceed 40 mg/day

I.M.: 1-2 mg every 4-6 hours as needed up to 10 mg/24 hours maximum

Nonpsychotic anxiety: Oral: 1-2 mg twice daily; maximum: 6 mg/day; therapy for anxiety should not exceed 12 weeks; do not exceed 6 mg/day for longer than 12 weeks when treating anxiety; agitation, jitteriness, or insomnia may be confused with original neurotic or psychotic symptoms

Elderly:

Schizophrenia/psychoses:

Oral: Refer to adult dosing. Dose selection should start at the low end of the dosage range and titration must be gradual.

I.M.: Initial: 1 mg every 4-6 hours; increase at 1 mg increments; do not exceed 6 mg/day

Behavioral symptoms associated with dementia behavior: Oral: Initial: 0.5-1 mg 1-2 times/day; increase dose at 4- to 7-day intervals by 0.5-1 mg/day; increase dosing intervals (bid, tid, etc) as necessary to control response or side effects. Maximum daily dose: 40 mg. Gradual increases (titration) may prevent some side effects or decrease their severity.

Hemodialysis: Not dialyzable (0% to 5%)

Administration

Administer I.M. injection deep in upper outer quadrant of buttock

Monitoring Parameters

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

Reference Range

Therapeutic response and blood levels have not been established

Test Interactions

False-positive for phenylketonuria

Dietary Considerations

May be taken with food to decrease GI distress.

Patient Education

Use exactly as directed; do not increase dose or frequency. Do not discontinue without consulting prescriber. Tablets/capsules may be taken with food. Do not take within 2 hours of any antacid. 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. 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); nausea or vomiting (small, frequent meals, frequent mouth care, chewing gum, or sucking lozenges 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 (eg, trembling fingers, altered gait or balance, excessive sedation, seizures, unusual movements, anxiety, abnormal thoughts, confusion, personality changes); chest pain, palpitations, rapid heartbeat, severe dizziness; unresolved urinary retention or changes in urinary pattern; altered menstrual pattern, changes 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.

Nursing Implications

Watch for hypotension when administering I.M.; observe for extrapyramidal symptoms

Additional Information

Do not exceed 6 mg/day for longer than 12 weeks when treating anxiety. Agitation, jitteriness, or insomnia may be confused with original neurotic or psychotic symptoms.

Anesthesia and Critical Care Concerns/Other Considerations

Do not exceed 6 mg/day for >12 weeks when treating anxiety; agitation, jitteriness or insomnia may be confused with original neurotic or psychotic symptoms.

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, 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.

Dosage Forms

[DSC] = Discontinued product

Injection, solution, as hydrochloride (Stelazine®): 2 mg/mL (10 mL) [contains benzyl alcohol] [DSC]

Tablet, as hydrochloride: 1 mg, 2 mg, 5 mg, 10 mg

Stelazine®: 5 mg [DSC]

References

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

Beighton PH and Wilkinson DJ, "Trifluoperazine Overdosage," Practitioner , 1967, 199(189):73-4.

FitzGerald MX and FitzGerald O, "Reaction to Trifluoperazine Abuse," Lancet , 1969, 1(7605):1100.

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

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

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

Apo-Trifluoperazine® (CA, PL, SG); Eskazine® (ES); Flupazine® [tabs] (MX); Flurazine® (IL); Modalina® (IT); Modiur® (CO); Novo-Trifluzine (CA); PMS-Trifluoperazine (CA); Psyrazine® (TH); Sedizine® (IL); Stelazine® (AR, AU, BR, GB, HK, ID, IE, KW, MX, NZ, PL, ZA); Stelazine Spansules® (GB); Stilizan® (TR); Telazine® (BD); Terflurazine® (ZA); Terfluzine (CA, NL); Trazine® (RU); Triflumed® (TH); Trifluoperazine® (CY, GB); Trifluoperazin® (RO); Trinicalm® (IN); Triplex® (TH)

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