Trifluoperazine Hydrochloride

Pronunciation

Class: Phenothiazines
VA Class: CN701
Chemical Name: 10-[3-(4-methylpiperazin-1-yl)propyl]-2-(trifluoromethyl)-10H-phenothiazine
Molecular Formula: C21H24F3N3S
CAS Number: 117-89-5

Warning(s)

  • Increased Mortality in Geriatric Patients with Dementia-related Psychosis
  • Geriatric patients with dementia-related psychosis treated with antipsychotic agents are at an increased risk of death.a e l m o

  • Analyses of 17 placebo-controlled trials in geriatric patients mainly receiving atypical antipsychotic agents revealed an approximate 1.6- to 1.7-fold increase in mortality compared with that in patients receiving placebo.a l m

  • Most fatalities appeared to result from cardiovascular-related events (e.g., heart failure, sudden death) or infections (mostly pneumonia).a m

  • Observational studies suggest that conventional or first-generation antipsychotic agents also may increase mortality in such patients.a e l

  • Antipsychotic agents, including trifluoperazine, are not approved for the treatment of dementia-related psychosis.a l m

Introduction

Propylpiperazine-derivative phenothiazine; conventional (prototypical, first-generation) antipsychotic agent.a b c

Uses for Trifluoperazine Hydrochloride

Schizophrenia

Treatment of schizophrenia.a b c e

American Psychiatric Association (APA) considers most atypical antipsychotic agents first-line drugs for management of the acute phase of schizophrenia (including first psychotic episodes).e APA considers conventional antipsychotic agents first-line in patients with acute psychotic episodes who have been treated successfully in the past with, or who prefer, conventional agents.e

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Patients who do not respond to or tolerate one drug may be successfully treated with an agent from a different class or with a different adverse effect profile.e i p q

Nonpsychotic Anxiety

Short-term management of nonpsychotic anxiety in patients with generalized anxiety disorder.a b c

Not established whether trifluoperazine is useful for the management of other nonpsychotic conditions in which anxiety or manifestations that mimic anxiety are evident (e.g., physical illness, organic mental conditions, agitated depression, character pathologies).a b

Because of the risks of toxicity, use only as an alternative to other less toxic anxiolytic agents (e.g., benzodiazepines) in most patients.a b

Mental Retardation

Efficacy not established for the management of behavioral complications in patients with mental retardation.a b

Trifluoperazine Hydrochloride Dosage and Administration

General

  • Adjust dosage carefully according to individual requirements and response; use the lowest possible effective dosage.a b c

  • For symptomatic relief of psychotic disorders, optimum therapeutic response usually occurs within 2–3 weeks.a b

  • Periodically evaluate patients receiving long-term therapy to determine whether maintenance dosage can be decreased or drug therapy discontinued.a b c

Administration

Oral Administration

Administered orally.a b c Has been given parenterally as trifluoperazine hydrochloride, but a parenteral dosage form of the drug is no longer commercially available in the US.b

Because of the long duration of action, may be administered once or twice daily.a b

Dosage

Available as trifluoperazine hydrochloride; dosage expressed in terms of trifluoperazine.a b

Pediatric Patients

Psychotic Disorders
Oral

Adjust dosage based on weight and severity of symptoms.a b

Children 6–12 years of age: Initially, 1 mg once or twice daily for hospitalized or well-supervised children.a b Gradually increase dosage until symptoms are controlled or adverse effects become troublesome.a b Most children respond to a dosage of ≤15 mg daily.a b

Dosage for children <6 years of age not established.a b

Adults

Psychotic Disorders
Oral

Initially, 2–5 mg given twice daily.a b Gradually increase dosage until symptoms are controlled or adverse effects become troublesome.a b Although most patients exhibit optimum response with 15–20 mg daily, dosages up to 40 mg or more daily may be required in some patients.a b e

Nonpsychotic Anxiety
Oral

Usually, 1 or 2 mg twice daily for ≤12 weeks.a b

Prescribing Limits

Pediatric Patients

Psychotic Disorders
Oral

Maximum 15 mg daily for children 6–12 years of age.a b Dosages >15 mg daily should be used only in older children with severe symptoms.a b

Adults

Nonpsychotic Anxiety
Oral

Maximum 6 mg daily; do not administer for >12 weeks.a b

Special Populations

Geriatric Patients

Generally, select dose at the lower end of recommended range; increase dosage more gradually and monitor closely.a b e (See Geriatric Use under Cautions.)

Debilitated or Emaciated Patients

Increase dosage more gradually.a b

Cautions for Trifluoperazine Hydrochloride

Contraindications

  • Comatose states or in the presence of large amounts of CNS depressants (e.g., alcohol, barbiturates, opiates).a c (See Specific Drugs and Laboratory Tests under Interactions.)

  • Bone marrow depression or blood dyscrasias.a c

  • Liver damage.a c

  • Known hypersensitivity to phenothiazines.a c

Warnings/Precautions

Warnings

Shares the toxic potentials of other phenothiazines; observe the usual precautions of phenothiazine therapy.a b

Increased Mortality in Geriatric Patients with Dementia-related Psychosis

Increased risk of death with use of either conventional (first-generation) or atypical (second-generation) antipsychotics in geriatric patients with dementia-related psychosis.a e l m o

Antipsychotic agents, including trifluoperazine, are not approved for the treatment of dementia-related psychosis.a l m (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning.)

Tardive Dyskinesia

Tardive dyskinesia, a syndrome of potentially irreversible, involuntary, dyskinetic movements, reported with use of antipsychotic agents, including trifluoperazine.a c

Reserve long-term antipsychotic treatment for patients with chronic illness known to respond to antipsychotic agents, and for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate.a In patients requiring chronic treatment, use smallest dosage and shortest duration of treatment producing a satisfactory clinical response; periodically reassess need for continued therapy.a

APA recommends assessing patients receiving conventional antipsychotic agents for abnormal involuntary movements every 6 months; for patients at increased risk for tardive dyskinesia, assess every 3 months.e Consider discontinuance of trifluoperazine if signs and symptoms of tardive dyskinesia appear.a However, some patients may require treatment despite the presence of the syndrome.a

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome characterized by hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability, reported with antipsychotic agents.a

Immediately discontinue therapy and initiate supportive and symptomatic therapy if NMS occurs.a Careful monitoring recommended if therapy is reinstituted following recovery; the risk that NMS can recur must be considered.a

Concomitant Therapy with Lithium

Although most patients receiving lithium and an antipsychotic agent concurrently do not develop unusual adverse effects, an acute encephalopathic syndrome occasionally has occurred, especially when high serum lithium concentrations were present.a c (See Specific Drugs and Laboratory Tests under Interactions.)

Cognitive and Motor Impairment

May impair mental and/or physical abilities, especially during the first few days of therapy.a c (See Specific Drugs and Laboratory Tests under Interactions and see also Advice to Patients.)

Sensitivity Reactions

Possible sensitivity reactions (e.g., cholestatic jaundice, blood dyscrasias, skin reactions, photosensitivity).a c Use generally not recommended in patients who have previously demonstrated a hypersensitivity reaction (e.g., blood dyscrasias, jaundice) to a phenothiazine, unless potential benefits outweigh the possible risks.a c

Contact dermatitis occurs rarely following skin contact with trifluoperazine hydrochloride preparations; use care to avoid skin contact with preparations of the drug.a b c

General Precautions

Hematologic Effects

Leukopenia, neutropenia, and agranulocytosis temporally related to antipsychotic agents, including trifluoperazine.a r s Thrombocytopenia, anemia, and pancytopenia also reported in patients receiving trifluoperazine.a r

Possible risk factors for leukopenia and neutropenia include preexisting low WBC count and a history of drug-induced leukopenia or neutropenia.r s Monitor CBC frequently during the first few months of therapy in patients with such risk factors.r Discontinue trifluoperazine at the first sign of a decline in WBC count in the absence of other causative factors.r

Carefully monitor patients with clinically important neutropenia for fever or other signs and symptoms of infection and treat promptly if they occur.r (See Advice to Patients.) In patients with severe neutropenia (ANC <1000/mm3), discontinue trifluoperazine and monitor WBC until recovery occurs.r

Hepatic Effects

Cholestatic jaundice or liver damage reported.a c

Perform hepatic function tests immediately in patients who develop fever accompanied by flu-like symptoms (e.g., nausea, vomiting, anorexia) during therapy; if hepatic function test results are abnormal, discontinue drug.a c

Cardiovascular Effects

Possible hypotension and exacerbation of angina; avoid large dosages in patients with cardiovascular disorders.a c If severe hypotension occurs, may use norepinephrine or phenylephrine to alleviate; epinephrine should not be used.a c (See Specific Drugs and Laboratory Tests under Interactions.)

Ocular Effects

Consider possibility of pigmentary retinopathy and lenticular and corneal deposits in patients receiving prolonged therapy.a c Periodic ophthalmic examinations recommended in patients receiving prolonged phenothiazine therapy with moderate to high dosages.a c Discontinue drug if ophthalmic examination or visual field studies demonstrate retinal changes.a c

Hyperprolactinemia

May cause elevated serum prolactin concentrations, which may persist during chronic administration and cause clinical disturbances (e.g., galactorrhea, amenorrhea, gynecomastia, impotence).a c

If contemplating trifluoperazine therapy in patient with previously detected breast cancer, consider that approximately one-third of human breast cancers are prolactin-dependent in vitro.a

Mutagenicity

Chromosomal aberrations in spermatocytes and abnormal sperm have been demonstrated in rodents.a c

Body Temperature Regulation

Phenothiazines depress the hypothalamic mechanism for body temperature regulation; possible hyperthermia or hypothermia when exposed to temperature extremes.a c

Use with caution in patients exposed to extreme heat or cold.a c

Anticholinergic Effects

Possible anticholinergic effects (e.g., dry mouth, blurred vision, mydriasis, constipation, obstipation, nausea, adynamic ileus, atonic colon, urinary retention, decreased perspiration, impotence).a c

Use with caution in patients with glaucoma.a c

Other Precautions

Antiemetic effects may mask signs of overdosage of other drugs (e.g., antineoplastic agents) or obscure cause of vomiting in various disorders (e.g., intestinal obstruction, Reye’s syndrome, brain tumor).a c

Specific Populations

Pregnancy

Category C.d

Risk for extrapyramidal and/or withdrawal symptoms (e.g., agitation, hypertonia, hypotonia, tardive dyskinetic-like symptoms, tremor, somnolence, respiratory distress, feeding disorder) in neonates exposed to antipsychotic agents during the third trimester; monitor neonates exhibiting such symptoms.a h j k Symptoms were self-limiting in some neonates but varied in severity; some infants required intensive support and prolonged hospitalization.a h j k

Lactation

Phenothiazines are distributed into milk.a c d Discontinue nursing or the drug.a c

Pediatric Use

Safety and efficacy not established in children <6 years of age.a b

Geriatric Use

Geriatric patients appear to be particularly sensitive to adverse CNS (e.g., tardive dyskinesia, parkinsonian manifestations, akathisia, sedation), anticholinergic, and cardiovascular (e.g., orthostatic hypotension) effects of antipsychotic agents.a b c e

Common Adverse Effects

Extrapyramidal reactions (e.g., Parkinson-like symptoms, dystonia, akathisia), drowsiness, fatigue, muscular weakness, insomnia, blurred vision, skin reactions or rash, anorexia, dry mouth, hypotension, amenorrhea, galactorrhea.a b c e

Interactions for Trifluoperazine Hydrochloride

Specific Drugs and Laboratory Tests

Drug or Test

Interaction

Comments

Anticoagulants, oral

Potential decreased effect of oral anticoagulantsa

Anticonvulsants (e.g., phenytoin)

Trifluoperazine may lower seizure thresholda c

Trifluoperazine may interfere with phenytoin metabolism and precipitate phenytoin toxicitya

Dosage adjustments of anticonvulsants may be necessarya c

CNS depressants (e.g., alcohol, anesthetics, opiate analgesics, sedative/hypnotics)

Possible additive effects or potentiated action of other CNS depressantsa c

Use with caution to avoid excessive sedation or CNS depressiona c

Epinephrine

Possible further lowering of BPa c

Do not use epinephrine for phenothiazine-induced hypotensiona c (see Cardiovascular Effects under Cautions)

Guanethidine and related compounds

Potential for decreased effectiveness of guanethidine and related compoundsa

Lithium

An acute encephalopathic syndrome reported occasionally, especially when high serum lithium concentrations presenta c

Observe patients receiving combined therapy for evidence of adverse neurologic effects; promptly discontinue if such signs or symptoms appeara c

Propranolol

Increased plasma concentrations of trifluoperazine and propranolola

Test for phenylketonuria (PKU)

Potential false-positive test resultsa c

Thiazide diuretics

Potential for increased orthostatic hypotensiona

Trifluoperazine Hydrochloride Pharmacokinetics

Absorption

Bioavailability

Phenothiazines are generally well absorbed from the GI tract.c f Considerable interindividual variation in peak concentrations reported.c f g

Distribution

Extent

Not fully characterized.c

Crosses the placenta.c d Distributed into breast milk.a c d

Plasma Protein Binding

Phenothiazines are highly bound to plasma proteins.c

Elimination

Metabolism

Metabolic fate not fully elucidated.c f Appears to be extensively metabolized, principally in the liver.c f

Elimination Route

Phenothiazines and their metabolites are excreted in urine and feces.c

Half-life

12–24 hours.e f g

Stability

Storage

Oral

Tablets

Tight, light-resistant containers at 20–25°C; protect from moisture.a

Actions

  • Precise mechanism(s) of antipsychotic action not determined, but may be principally related to antidopaminergic effects.b c

  • Exhibits weak anticholinergic and sedative effects and strong extrapyramidal effects and antiemetic activity.b c

Advice to Patients

  • Importance of advising patients and caregivers that geriatric patients with dementia-related psychosis treated with antipsychotic agents are at an increased risk of death.a e l m Inform patients and caregivers that trifluoperazine is not approved for treating geriatric patients with dementia-related psychosis.a m

  • Potential for drug to impair mental alertness or physical coordination; use caution when driving or operating machinery until effects on individual are known.a c

  • Importance of clinicians informing patients in whom chronic trifluoperazine use is contemplated of risk of tardive dyskinesia, taking into account clinical circumstances and competency of patient to understand information provided.a c n Importance of informing patients to report any muscle movements that cannot be stopped.n

  • Importance of avoiding exposure to temperature extremes.a c

  • Importance of informing clinician if sore throat or other signs of infection occur.a c

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., cardiovascular disease).a c

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.a h Importance of clinicians informing patients about the benefits and risks of taking antipsychotics during pregnancy (see Pregnancy under Cautions).a h Importance of advising patients not to stop taking trifluoperazine if they become pregnant without consulting their clinician; abruptly stopping antipsychotic agents may cause complications.h

  • Importance of informing patients of other important precautionary information.a (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Trifluoperazine Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

1 mg (of trifluoperazine)*

Trifluoperazine Hydrochloride Tablets

2 mg (of trifluoperazine)*

Trifluoperazine Hydrochloride Tablets

5 mg (of trifluoperazine)*

Trifluoperazine Hydrochloride Tablets

10 mg (of trifluoperazine)*

Trifluoperazine Hydrochloride Tablets

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Trifluoperazine HCl 10MG Tablets (SANDOZ): 60/$55.99 or 180/$135.98

Trifluoperazine HCl 2MG Tablets (MYLAN): 60/$36.99 or 180/$86.97

Trifluoperazine HCl 5MG Tablets (SANDOZ): 60/$35.99 or 180/$98.98

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions June 13, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

HID. Trissel LA. Handbook on injectable drugs. 12th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2003:622-3.

a. Sandoz Inc. Trifluoperazine hydrochloride tablets prescribing information. Princeton, NJ; 2010 Sep.

b. AHFS drug information 2007. McEvoy GK, ed. Trifluoperazine hydrochloride. Bethesda, MD: American Society of Health-System Pharmacists; 2007:2457.

c. AHFS drug information 2007. McEvoy GK, ed. Phenothiazines general statement. Bethesda, MD: American Society of Health-System Pharmacists; 2007: 2439-50.

d. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 7th ed. Philadelphia, PA: Williams & Wilkins; 2005:1626-7.

e. American Psychiatric Association. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry. 2004; 161(Suppl):1-56.

f. Midha KK, Korchinski ED, Verbeeck RK et al. Kinetics of oral trifluoperazine disposition in man. Br J Clin Pharmacol. 1983; 15:380-2. [PubMed 6849769]

g. Midha KK, Hawes EM, Hubbard JW et al. A pharmacokinetic study of trifluoperazine in two ethnic populations. Psychopharmacol. 1988; 95:333-8.

h. US Food and Drug Administration. FDA drug safety communication: Antipsychotic drug labels updated in use during pregnancy and risk of abnormal muscle movements and withdrawal symptoms in newborns.. Rockville, MD; 2010 Feb 22. From the FDA website: .

i. Lahti AC, Tamminga CA. Recent developments in the neuropharmacology of schizophrenia. Am J Health-Syst Pharm. 1995; 52(Suppl 1):S5-8. [IDIS 341484] [PubMed 7749964]

j. Sexson WR, Barak Y. Withdrawal emergent syndrome in an infant associated with maternal haloperidol therapy. J Perinatol. 1989; 9:170-2. [PubMed 2738729]

k. Coppola D, Russo LJ, Kwarta RF Jr. et al. Evaluating the postmarketing experience of risperidone use during pregnancy: pregnancy and neonatal outcomes. Drug Saf. 2007; 30:247-64. [PubMed 17343431]

l. Food and Drug Administration. Information for Healthcare Professionals: Conventional antipsychotics. Rockville, MD; 2008 Jun 16. From the FDA website: .

m. Food and Drug Administration. Public health advisory: deaths with antipsychotics in elderly patients with behavioral disturbances. Rockville, MD; 2005 Apr 11. From the FDA website: ().

n. Food and Drug Administration. Patient information sheet: aripiprazole (marketed as Abilify). 2006 Sep 6.

o. Banerjee S. The use of antipsychotic medication for people with dementia: time for action. A report for the Minister of State for Care Services. United Kingdom Department of Health. From the website: .

p. Volavka J, Citrome L. Oral antipsychotics for the treatment of schizophrenia: heterogeneity in efficacy and tolerability should drive decision-making. Expert Opin Pharmacother. 2009; 10:1917-28. [PubMed 19558339]

q. Lieberman JA. Atypical antipsychotic drugs as a first-line treatment of schizophrenia: a rationale and hypothesis. J Clin Psychiatry. 1996; 57(Suppl 11):68-71. [IDIS 376650] [PubMed 8941173]

r. Mylan Pharmaceuticals Inc. Trifluoperazine hydrochloride tablets prescribing information. Morgantown, WV; 2010 Sep.

s. Qureshi SU, Rubin E. Risperidone- and aripiprazole-induced leukopenia: a case report. Prim Care Companion J Clin Psychiatry. 2008; 10:482-3. [PubMed 19287562]

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