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Thiothixene

Class: Thioxanthenes
VA Class: CN709
Chemical Name: N,N-dimethyl-9-[3-(4-methyl-1-piperazinyl)-propylidene]thioxanthene-2-sulfonamide
Molecular Formula: C23H29N3O2S2
CAS Number: 5591-45-7
Brands: Navane

Medically reviewed by Drugs.com on Apr 12, 2021. Written by ASHP.

Warning

    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.

  • 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.

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

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

  • Antipsychotic agents, including thiothixene, are not approved for the treatment of dementia-related psychosis.

Introduction

Thioxanthene-derivative, conventional (prototypical, first-generation) antipsychotic agent; structurally and pharmacologically related to chlorprothixene (no longer commercially available in the US) and trifluoperazine.

Uses for Thiothixene

Psychotic Disorders

Symptomatic management of psychotic disorders (i.e., schizophrenia).

Has been used in the management of refractory or treatment-resistant schizophrenia.

Mental Retardation

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

Thiothixene Dosage and Administration

General

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

  • Periodically evaluate patients receiving long-term therapy to determine whether maintenance dosage can be decreased or drug therapy discontinued. (See Tardive Dyskinesia under Cautions.)

  • For symptomatic relief of psychotic disorders, initial therapeutic response to antipsychotic therapy usually occurs within 2–4 weeks and optimum therapeutic response occurs within 6 months or longer.

Administration

Oral Administration

Thiothixene is administered orally once daily or in divided doses 2 or 3 times daily. Thiothixene hydrochloride has been given orally and parenterally, but no longer is commercially available in the US.

Dosage

Pediatric Patients

Psychotic Disorders
Oral

Children ≥12 years of age: Initially, 2 mg 3 times daily for mild to moderate psychotic disorders; may gradually increase dosage, if necessary, up to 15 mg daily.

For more severe psychotic disorders in children ≥12 years of age: Initially, 5 mg twice daily; may then increase dosage until satisfactory response obtained.

Optimal maintenance dosage usually 20–30 mg daily; may be increased up to 60 mg daily, if necessary; once-daily administration may be adequate.

Daily dosages >60 mg rarely provide additional therapeutic effect.

Adults

Psychotic Disorders
Oral

For mild to moderate psychotic disorders: Initially, 2 mg 3 times daily; may gradually increase dosage, if necessary, up to 15 mg daily.

For more severe psychotic disorders: Initially, 5 mg twice daily; may then increase dosage until satisfactory response obtained.

Optimal maintenance dosage usually 20–30 mg daily; may be increased up to 60 mg daily, if necessary; once-daily administration may be adequate.

Daily dosages >60 mg rarely provide additional therapeutic effect.

Prescribing Limits

Pediatric Patients

Psychotic Disorders
Oral

Children ≥12 years of age: Maximum 60 mg daily.

Adults

Psychotic Disorders
Oral

Maximum 60 mg daily.

Special Populations

Geriatric Patients

No specific dosage recommendations for geriatric patients, but generally select dosage at the lower end of recommended range; increase dosage more gradually and monitor closely. (See Geriatric Use under Cautions and see Special Populations under Pharmacokinetics.)

Cautions for Thiothixene

Contraindications

  • Circulatory collapse.

  • Comatose states or CNS depression from any cause. (See Specific Drugs and Laboratory Tests under Interactions.)

  • Blood dyscrasias.

  • Known hypersensitivity to thiothixene. Not known if cross-sensitivity exists between thioxanthenes and phenothiazines; consider possibility that cross-sensitivity may occur.

Warnings/Precautions

Warnings

Shares the toxic potentials of other antipsychotic agents (e.g., phenothiazines); observe the usual precautions associated with therapy with these agents.

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.

Antipsychotic agents, including thiothixene, are not approved for the treatment of dementia-related psychosis. (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 thiothixene.

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. In patients requiring chronic treatment, use smallest dosage and shortest duration of treatment producing a satisfactory clinical response; periodically reassess need for continued therapy.

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. Consider discontinuance of thiothixene if signs and symptoms of tardive dyskinesia appear. However, some patients may require treatment despite presence of the syndrome.

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, including thiothixene.

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

CNS Depression

May impair mental and/or physical abilities, especially during the first few days of therapy; use caution with activities requiring alertness (e.g., operating vehicles or machinery).

Response to CNS depressants and alcohol may be potentiated. (See Specific Drugs and Laboratory Tests under Interactions.)

Sensitivity Reactions

Hypersensitivity and Cross-sensitivity

Possible sensitivity reactions reported with thiothixene (e.g., rash, pruritus, urticaria, anaphylactoid reactions) and related drugs (e.g., agranulocytosis, pancytopenia, thrombocytopenic purpura, jaundice, biliary stasis).

Not known if cross-sensitivity exists between thioxanthenes and phenothiazines; consider possibility that cross-sensitivity may occur.

Photosensitivity

Photosensitivity may occur; avoid excessive exposure to sunlight during therapy.

General Precautions

Seizures

Possible risk of seizures; may lower seizure threshold. Use with extreme caution in patients with a history of seizures or during alcohol withdrawal. (See Specific Drugs and Laboratory Tests under Interactions.)

Cardiovascular Effects

Possible hypotension, tachycardia, nonspecific ECG changes, dizziness, and/or syncope; use with caution in patients with cardiovascular disease.

If severe hypotension occurs, administer norepinephrine or phenylephrine; epinephrine or dopamine should not be used. (See Specific Drugs and Laboratory Tests under Interactions.)

Anticholinergic Effects

Possible anticholinergic effects (e.g., dry mouth, blurred vision, constipation, increased perspiration, urinary retention, impotence).

Use with caution in patients with glaucoma or prostatic hypertrophy. (See Specific Drugs and Laboratory Tests under Interactions.)

Ocular Effects

Pigmentary retinopathy and lenticular pigmentation reported with prolonged therapy with antipsychotic agents, including thiothixene. Observe carefully.

Prolactin Secretion

Elevated prolactin concentrations reported; elevation persists during chronic administration.

Clinical significance unknown; consider that approximately one-third of human breast cancers are prolactin dependent when prescribing thiothixene in patients with previously detected breast cancer.

Galactorrhea, amenorrhea, gynecomastia, and impotence reported.

Hematologic Effects

Leukopenia and neutropenia temporally related to antipsychotic agents reported during clinical trial and/or postmarketing experience. Agranulocytosis also reported with other antipsychotic agents.

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

Carefully monitor patients with clinically important neutropenia for signs and symptoms of infection (e.g., fever) and treat promptly if they occur. Discontinue thiothixene if severe neutropenia (ANC <1000/mm3) occurs; monitor WBC until recovery occurs.

Regulation of Body Temperature

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

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).

Specific Populations

Pregnancy

Category C.

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. Symptoms were self-limiting in some neonates but varied in severity; some infants required intensive support and prolonged hospitalization.

Use during pregnancy only if potential benefit justifies potential risk to the fetus.

Lactation

Not known but considered likely to distribute into human milk; possible effects on nursing infant unknown. Caution if used in nursing women; carefully assess potential benefits and risks.

Pediatric Use

Safety not established in children <12 years of age.

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.

Use with caution. (See Geriatric Patients under Dosage and Administration and see Special Populations under Pharmacokinetics.)

Geriatric patients with dementia-related psychosis treated with either conventional or atypical antipsychotic agents are at an increased risk of death. (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning.)

Common Adverse Effects

Drowsiness or sedation, extrapyramidal reactions (e.g., Parkinson-like symptoms, dystonia, akathisia, tardive dyskinesia), anticholinergic effects (e.g., dry mouth, blurred vision), hypotension.

Interactions for Thiothixene

Drugs Affecting Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction (increased or decreased plasma thiothixene concentrations) with concomitant use of CYP enzyme inhibitors or inducers. (See Specific Drugs and Laboratory Tests under Interactions.)

Specific Drugs and Laboratory Tests

Drug or Test

Interaction

Comments

Alcohol

Potential additive CNS effects and hypotension

Use with caution

Anticholinergic drugs (e.g., atropine)

Possible potentiation of anticholinergic effects

Use with caution

Anticonvulsants (e.g., carbamazepine, phenobarbital, phenytoin)

Anticonvulsants may decrease plasma thiothixene concentrations

Thiothixene may lower seizure threshold

Barbiturates: Thiothixene potentiates the anticonvulsant activity of barbiturates

Observe for signs and symptoms of reduced thiothixene effectiveness

Dosage adjustments of anticonvulsants may be necessary

Barbiturates: Do not reduce anticonvulsant dosage during concurrent use

Antidepressants, tricyclic (TCAs)

Possible increased plasma concentrations of thiothixene

β-Blockers (e.g., propranolol)

Possible decreased thiothixene clearance

Cimetidine

Possible decreased thiothixene clearance

CNS depressants (e.g., antihistamines, barbiturates, general anesthetics, opiate analgesics, sedative/hypnotics)

Possible additive CNS effects and hypotension

Use with caution to avoid excessive sedation or CNS depression; carefully adjust dosages of both agents as necessary

Epinephrine or dopamine

Possible further lowering of BP

Do not use epinephrine or dopamine for thiothixene-induced hypotension (see Cardiovascular Effects under Cautions)

Hypotensive agents

Possible additive hypotensive effect

Observe closely for signs of excessive hypotension

Isoniazid

Possible decreased thiothixene clearance

Lithium

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

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

Paroxetine

Pharmacokinetic interaction unlikely

Smoking

Possible decreased plasma thiothixene concentrations

Tests for pregnancy

False-positive results reported in some patients receiving phenothiazines; less likely to occur when serum test is used

Thiothixene Pharmacokinetics

Absorption

Bioavailability

Rapidly and well absorbed from GI tract following oral administration. Peak plasma concentrations usually occur within 1–3 hours.

Onset

Antipsychotic effects usually are apparent within 2–4 weeks after initiation of oral therapy and optimum therapeutic response usually occurs within 6 months or longer.

Plasma Concentrations

Optimal therapeutic plasma concentrations not well defined, but clinical improvement associated with peak plasma concentrations of 2–15 mcg/L.

Distribution

Extent

Widely distributed into body tissues.

Crosses placenta in animals; considered likely to cross placenta in humans. Not known if distributed into human milk but distribution into breast milk considered likely.

Plasma Protein Binding

>99%.

Elimination

Metabolism

Principally metabolized in the liver; undergoes extensive oxidative first-pass metabolism to form thiothixene sulfoxide and N-desmethylthiothixene.

Elimination Route

Excreted mainly in feces via biliary elimination as unchanged drug and as demethyl, sulfoxide, demethylated sulfoxide, and hydroxylated metabolites.

Unlikely to be removed by hemodialysis and peritoneal dialysis.

Half-life

34–35 hours.

Special Populations

Clearance is reduced in females and in patients >50 years of age.

Stability

Storage

Oral

Capsules

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

Actions

  • Produces pharmacologic effects similar to those of other conventional antipsychotic agents (e.g., phenothiazines, butyrophenones, chlorprothixene).

  • Precise mechanism(s) of antipsychotic action not determined, but may be principally related to antidopaminergic effects. Acts principally at subcortical levels on the reticular formation, hypothalamus, and limbic system.

  • Exhibits weak anticholinergic, antihistaminic, α-adrenergic, and sedative effects and strong extrapyramidal effects; appears to possess antiemetic activity.

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. Importance of informing patients and caregivers that thiothixene is not approved for treating geriatric patients with dementia-related psychosis.

  • Importance of informing patients and caregivers about the risk of NMS, which can cause high fever, stiff muscles, sweating, fast or irregular heart beat, change in BP, confusion, and kidney damage.

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

  • Importance of informing patients in whom chronic thiothixene use is contemplated of risk of tardive dyskinesia, taking into account clinical circumstances and competency of patient to understand information provided.

  • Importance of clinicians informing patients of risk of extrapyramidal reactions and providing reassurance that these reactions usually can be controlled by administration of antiparkinsonian drugs (e.g., benztropine) and by subsequent dosage reduction.

  • Risk of leukopenia/neutropenia. Importance of advising patients with a preexisting low WBC count or history of drug-induced leukopenia/neutropenia that their CBC count should be monitored during thiothixene therapy.

  • Advise patients to avoid excessive sunlight.

  • Importance of avoiding exposure to temperature extremes.

  • 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, seizures).

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

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

Preparations

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

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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

Thiothixene

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

1 mg*

Navane

Pfizer

Thiothixene Capsules

2 mg*

Navane

Pfizer

Thiothixene Capsules

5 mg*

Navane

Pfizer

Thiothixene Capsules

10 mg*

Navane

Pfizer

Thiothixene Capsules

20 mg

Navane

Pfizer

AHFS DI Essentials™. © Copyright 2021, Selected Revisions April 20, 2012. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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