Thiothixene may be capable of producing all the toxic manifestations of phenothiazine derivatives. Although all adverse reactions of the phenothiazines have not been reported with thiothixene, the possibility that they may occur should be considered. Adverse effects of thiothixene and the phenothiazines are numerous and may involve nearly all organ systems; however, they are usually reversible when dosage is reduced or the drug is discontinued. Some adverse effects may be attributed to the actions of the drug on the central and autonomic nervous systems, whereas others are hypersensitivity reactions. Unexpected deaths have been reported during phenothiazine therapy. In some patients, cardiac arrest or asphyxia resulting from failure of the cough reflex appeared to be the cause of death. In other cases, the cause of death could not be determined nor definitely attributed to phenothiazine therapy. (See Cautions in the Phenothiazines General Statement 28:16.08.24.)
Nervous System Effects 
The most frequent adverse effects of thiothixene are drowsiness (which usually is mild and subsides with continuation of therapy) and extrapyramidal symptoms. Like propylpiperazine phenothiazines, thiothixene is more likely to produce akathisia and dystonia than parkinson-like syndromes. Generally, extrapyramidal effects can be controlled by reducing the dosage of thiothixene and/or administering an antiparkinsonian drug.
Because use of antipsychotic agents, including thiothixene, may be associated with tardive dyskinesia (a syndrome of potentially irreversible, involuntary, dyskinetic movements),101 thiothixene should be used in a manner that is most likely to minimize the occurrence of this syndrome.101 Chronic antipsychotic treatment generally should be reserved for patients with a chronic illness that is known to respond to antipsychotic agents, and for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate.101 In patients who do require chronic treatment, the lowest dosage and the shortest duration of treatment producing a satisfactory clinical response should be sought, and the need for continued treatment should be reassessed periodically.101 For additional information on tardive dyskinesia, see Tardive Dyskinesia under Cautions: Nervous System Effects, in the Phenothiazines General Statement 28:16.08.24.
Neuroleptic malignant syndrome (NMS) may occur in patients receiving thiothixene or other antipsychotic therapy. NMS is potentially fatal and requires immediate discontinuance of the drug and intensive symptomatic and supportive care. For additional information on NMS, see Extrapyramidal Reactions under Cautions: Nervous System Effects, in the Phenothiazines General Statement 28:16.08.24.
Adverse effects referable to the action of thiothixene on the autonomic nervous system include dryness of the mouth, blurred vision, constipation, increased sweating, nasal congestion, increased salivation, and impotence. Miosis, mydriasis, and adynamic ileus have been associated with phenothiazine therapy. Restlessness, agitation, and insomnia may occur in patients receiving thiothixene; seizures and paradoxical exacerbation of psychotic symptoms have been reported infrequently. Thiothixene may increase the frequency of seizures in epileptic patients or provoke epileptiform attacks in nonepileptic individuals. A withdrawal syndrome and severe delirium was reported in a patient following abrupt cessation of prolonged thiothixene therapy. Other reported adverse effects of thiothixene include hyperpyrexia, anorexia, nausea, vomiting, diarrhea, increase in appetite and weight, weakness, fatigue, leg cramps, polydypsia, and peripheral edema. Fine lenticular pigmentation has been reported in a few patients who received prolonged thiothixene therapy. Phenothiazine derivatives have been associated with cerebral edema and CSF abnormalities.
Cardiovascular Effects
The action of thiothixene on the cardiovascular system may cause hypotension, tachycardia, lightheadedness, dizziness, and syncope. Nonspecific ECG changes have been reported; however, their clinical importance has not been determined. ECG effects are usually reversible and may disappear with continued therapy. Hypotension occurs most frequently when phenothiazines are given parenterally. Because the same may be true with thiothixene, it may be advisable to have patients supine at the time of parenteral administration and for at least 1 hour following completion of the injection (an injectable preparation of thiothixene hydrochloride is no longer commercially available in the US). Severe hypotensive effects may be alleviated by the administration of norepinephrine or phenylephrine; epinephrine should not be used since thiothixene causes a reversal of its vasopressor effects and a further lowering of blood pressure.
Sensitivity Reactions
Hypersensitivity reactions, including rash, pruritus, urticaria, photosensitivity, and, rarely, anaphylaxis, have been reported in patients receiving thiothixene. Phenothiazine therapy has been associated with a syndrome resembling systemic lupus erythematosus.
Dermatologic Effects
Patients receiving thiothixene should avoid undue exposure to sunlight. Exfoliative dermatitis and contact dermatitis have been reported in persons who came in contact with certain phenothiazine derivatives. Long-term administration of high doses of phenothiazines has resulted in pigment deposition in various body tissues including skin.
Metabolic Effects
Lactation, moderate breast enlargement, and amenorrhea have been reported in a small percentage of women receiving thiothixene; these adverse effects may be alleviated by decreasing the dosage or withdrawing the drug. In one patient, hyponatremia that apparently resulted from inappropriate antidiuretic hormone secretion was attributed to thiothixene therapy. Premature ejaculation, gynecomastia, false-positive pregnancy test results, hypoglycemia, hyperglycemia, or glycosuria have been associated with phenothiazine therapy.
Hematologic Effects
In clinical trial and/or postmarketing experience, leukopenia and neutropenia have been temporally related to antipsychotic agents.101 Agranulocytosis (including fatal cases) also has been reported with other antipsychotic agents.101 Possible risk factors for leukopenia and neutropenia include preexisting low leukocyte count and a history of drug-induced leukopenia and neutropenia.101 (See Cautions: Precautions and Contraindications.)
Leukocytosis, which is usually transient, may occur in patients receiving thiothixene. Decreased prothrombin time has also been reported. Adverse hematologic effects reported in patients receiving other antipsychotic drugs include eosinophilia, hemolytic anemia, thrombocytopenia, and pancytopenia.101
Other Adverse Effects
Elevations of serum transaminase and alkaline phosphatase concentrations, which are usually transient, have been observed in some patients receiving thiothixene. Cholestatic jaundice has been reported in patients receiving related drugs. Increases in uric acid excretion have occurred in patients receiving chlorprothixene, and the possibility of this occurrence should be considered in patients receiving thiothixene.
Precautions and Contraindications
Thiothixene shares the toxic potentials of other antipsychotic agents (e.g., phenothiazines), and the usual precautions associated with therapy with these agents should be observed. (See Cautions in the Phenothiazines General Statement 28:16.08.24.)
Geriatric patients with dementia-related psychosis treated with either conventional (first-generation) or atypical (second-generation) antipsychotic agents are at an increased risk of mortality.101,102,103,104,105,106 For additional information on the use of antipsychotic agents for dementia-associated psychosis and other behavioral disturbances, see Geriatric Considerations under Psychotic Disorders: Schizophrenia and Other Psychotic Disorders, in Uses and see Cautions: Geriatric Precautions, in the Phenothiazines General Statement 28:16.08.24.
Thiothixene should be used with caution in patients with cardiovascular disease. Because of possible drowsiness, fatigue, ataxia, and syncope, thiothixene should be administered with caution to patients performing hazardous tasks requiring mental alertness or physical coordination, especially during the first few days of therapy; patients should be cautioned accordingly. It should be considered that the drug may have an antiemetic effect that may mask the signs of overdosage of toxic drugs or may obscure the cause of vomiting in various organic disorders such as intestinal obstruction or brain tumor.
Thiothixene should be administered with extreme caution in patients with a history of seizure disorders or those in alcohol withdrawal, since the drug may decrease the seizure threshold. The drug should be used with extreme caution in patients who develop akathisia and restlessness because these patients may exhibit increased tension, aggressiveness, anxiety, depression, and suicidal tendencies. Because of possible anticholinergic effects, thiothixene should be used with caution in patients with glaucoma or prostatic hypertrophy. Patients receiving thiothixene should be carefully observed for pigmentary retinopathy and lenticular pigmentation, and periodic slit-lamp examinations should be performed in patients on prolonged thiothixene therapy. The drug should be administered with caution to patients who might be exposed to extreme heat or who are receiving atropine or related drugs.
Patients with a history of clinically important low leukocyte count or drug-induced leukopenia and/or neutropenia should have their complete blood count monitored frequently during the first few months of therapy.101 Discontinuance of thiothixene should be considered at the first sign of a clinically important decline in leukocyte count in the absence of other causative factors.101 Patients with clinically important neutropenia should be carefully monitored for fever or other signs or symptoms of infection and promptly treated if such signs or symptoms occur.101 In patients with severe neutropenia (absolute neutrophil count [ANC] less than 1000/mm3), thiothixene should be discontinued and the leukocyte count monitored until recovery occurs.101 (See Cautions: Hematologic Effects.)
Thiothixene is contraindicated in comatose patients and in patients with circulatory collapse, CNS depression from any cause, blood dyscrasias, or hypersensitivity to the drug. It has not been determined if there is a cross-sensitivity between the thioxanthenes and the phenothiazines, but the possibility should be considered.
Pediatric Precautions
Pending further accumulation of clinical data on the use of this drug in children, thiothixene is not recommended for use in children younger than 12 years of age.
Carcinogenicity
Antipsychotic agents increase prolactin concentrations; this effect persists during long-term administration of the drugs. Because up to 33% of breast cancer may be prolactin dependent, the risk of using thiothixene in patients with previous or existing breast cancer should be considered. Although an increase in mammary neoplasms has occurred in rodents receiving antipsychotic agents for prolonged periods, available clinical or epidemiologic evidence is too limited to determine whether such an association exists in humans.
Pregnancy
Pregnancy
Although animal reproduction studies and clinical experience to date have not demonstrated any teratogenic effects, safe use of thiothixene during pregnancy has not been established.101
Neonates exposed to antipsychotic agents, including thiothixene, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery.101,107,108,109 Symptoms reported in these neonates to date include agitation, hypertonia, hypotonia, tardive dyskinetic-like symptoms, tremor, somnolence, respiratory distress, and feeding disorder.101,107,108,109 Any neonate exhibiting extrapyramidal or withdrawal symptoms following in utero exposure to antipsychotic agents should be monitored.109 Symptoms were self-limiting in some neonates, but varied in severity; some infants required intensive care unit support and prolonged hospitalization.101,107,108,109 For further information on extrapyramidal and withdrawal symptoms in neonates, see Cautions: Pregnancy, Fertility, and Lactation, in the Phenothiazines General Statement 28:16.08.24.
Thiothixene should only be used during pregnancy if the potential benefits to the woman outweigh the possible risks to the woman and fetus.101
Acute Toxicity
Manifestations
Overdosage of thiothixene may result in muscular twitching, drowsiness, and dizziness.101 In severe cases, rigidity, weakness, torticollis, tremor, salivation, dysphagia, hypotension, disturbance of gait, or CNS depression including coma may occur.101
Treatment
In the treatment of overdosage, general supportive measures such as maintenance of an adequate airway, oxygen uptake, and carbon dioxide removal should be maintained. Early gastric lavage may be useful in the treatment of oral thiothixene overdosage. Hypotension and circulatory collapse may be alleviated by administration of IV fluids and/or vasopressor agents such as norepinephrine or phenylephrine; epinephrine should not be used. Antiparkinsonian drugs may be used to treat extrapyramidal symptoms. The value of peritoneal dialysis and hemodialysis in the treatment of thiothixene overdosage has not been established; however, dialysis is of little value in acute phenothiazine toxicity.
Pharmacology
Thiothixene produces pharmacologic responses similar to those of the phenothiazines, the butyrophenones, and chlorprothixene (no longer commercially available in the US). Although the precise mechanism of action has not been determined, the drug probably acts principally at subcortical levels on the reticular formation, hypothalamus, and limbic system. In addition, thiothixene may be expected to act on the autonomic nervous system resulting in cholinergic and α-adrenergic blocking effects, adrenergic potentiating effects, antiserotonin effects, and prevention of uptake of biologic amines. The drug also decreases the seizure threshold. In animals, thiothixene has produced a blockade of conditioned avoidance and has exhibited weak anticholinergic, hypothermic, antihistaminic, hypotensive, and sedative properties. Although the antiemetic effect has not been clinically evaluated, thiothixene has had an antiemetic effect in animals. There appears to be a very narrow range between the effective therapeutic dose and doses causing extrapyramidal symptoms.
Pharmacokinetics
Absorption
Thiothixene is well absorbed from the GI tract. Therapeutic response may occur within a few days to several weeks following oral administration of the drug. Plasma concentrations required for therapeutic effects are not known.
Distribution
Thiothixene is widely distributed into body tissues and may remain in the body for several weeks following administration.
Elimination
Thiothixene is metabolized in the liver and is excreted mainly in feces via biliary elimination as unchanged drug and as the demethyl, sulfoxide, demethylated sulfoxide, and hydroxylated thiothixene derivatives.
Chemistry and Stability
Chemistry
Thiothixene is a thioxanthene-derivative antipsychotic agent. The drug is structurally and pharmacologically related to chlorprothixene and the propylpiperazine phenothiazine derivatives including trifluoperazine. Structurally, thiothixene differs from chlorprothixene in the replacement of a chlorine atom at the 2-position on the thioxanthene nucleus with a dimethylsulfamyl group and the replacement of a dimethyl group on the propylidene side chain with a methyl piperazinyl group.
Thiothixene occurs as white to tan, practically odorless crystals; the hydrochloride salt occurs as a white or nearly white crystalline powder, having a slight odor. Thiothixene is slightly soluble in alcohol and has a solubility of less than 0.1 mg/mL in water at 25°C. Thiothixene hydrochloride is slightly soluble in alcohol and has a solubility of approximately 125 mg/mL in water at 25°C.
Stability
Thiothixene preparations are affected by light and should be stored in light-resistant containers.
Only references cited for selected revisions after 1984 are available electronically.
100. American Psychiatric Association. Practice guideline for the treatment of patients with schizophrenia, second edition. From the APA website: [Web]
101. Pfizer Inc. Navane® (thiothixene) capsules and (thiothixene hydrochloride) concentrate prescribing information. New York, NY; 2010 Dec.
102. Food and Drug Administration. FDA Alert: Information for healthcare professionals: antipsychotics. Rockville, MD; 2008 Jun 16. From the FDA website: ([Web]).
103. Food and Drug Administration. FDA News: FDA requests boxed warnings on older class of antipsychotic drugs. Rockville, MD; 2008 Jun 16. From the FDA website ([Web]).
104. Schneeweiss S, Setoguchi S, Brookhart A et al. Risk of death associated with the use of conventional versus atypical antipsychotic drugs among elderly patients. CMAJ . 2007; 176:627-32. [PubMedCentral][PubMed 17325327]
105. Gill SS, Bronskill SE, Normand SL et al. Antipsychotic drug use and mortality in older adults with dementia. Ann Intern Med . 2007; 146:775-86. [PubMed 17548409]
106. 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: ([Web]).
107. Sexson WR, Barak Y. Withdrawal emergent syndrome in an infant associated with maternal haloperidol therapy. J Perinatol . 1989; 9:170-2. [PubMed 2738729]
108. 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]
109. 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; 2011 Feb 22. From the FDA website: [Web].