(9Z)-N,N-Dimethyl-9-[3-(4-methyl-1-piperazinyl)propylidene]-9H-thioxanthene-2-sulfonamide

443.63

443.63

227-001-0

7318FJ13YJ

DTXSID6023658|DTXSID2091542|DTXSID30109999

C47752

White to tan crystals cis-, trans- mixture)|White to tan crystalline powder

N - Nervous system

2935904000

77.5

3.78

Solid

1.269 g/cm3

cis isomer: 147.5-149 deg C; trans isomer 123-124.5 deg C; cis-trans mixture: 114-118 deg C

599ºC at 760 mmHg

316.1ºC

1.643

>66.5 [ug/mL]

2-8°C

2.56X10-12 mm Hg at 25 °C (est)

Practically odorless

Has very bitter taste

pH: ready-to-use injection: from 2.5-3.5; constituted powder: from 2.3-3.7 /Thiothixene hydrochloride/

Henry's Law constant = 3.70X10-16 atm-cu m/mol at 25 °C (est)

201.9 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

pH: ready-to-use injection: from 2.5-3.5; constituted powder: from 2.3-3.7 /Thiothixene hydrochloride/|White to nearly white crystalline powder. Has slight odor. Soluble in water; slightly soluble in chloroform. Practically insoluble in benzene, acetone, ether /Thiothixene hydrochloride/|Hydroxyl radical reaction reaction rate constant = 2.92X10-10 cu cm/molec-sec at 25 °C (est)|Ozone reaction rate constant = 1.63X10-15 cu cm/molec-sec at 25 °C (est)

NONH for all modes of transport

22

XO1420000

Xn

The constituted powder for injection is stable for 48 hr at room temperature. /Thiothixene HCl/

P301 + P312 + P330

H302

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including thiothixene, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

|Warning|H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]|P201, P202, P264, P270, P281, P301+P312, P308+P313, P330, P405, and P501|The GHS information provided by 1 company from 1 notification to the ECHA C&L Inventory.|P264, P270, P301+P312, P330, and P501|Aggregated GHS information provided by 38 companies from 1 notifications to the ECHA C&L Inventory.

Symptoms of overdose include central nervous system depression, coma, difficulty swallowing, dizziness, drowsiness, head tilted to the side, low blood pressure, muscle twitching, rigid muscles, salivation, tremors, walking disturbances, and weakness.|IDENTIFICATION AND USE: Thiothixene is a solid. It is antipsychotic agent and dopamine antagonist. Thiothixene capsules are effective in the management of schizophrenia. HUMAN STUDIES: Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs, including thiothixene. A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs, including thiothixene. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). Manifestations of overdose include muscular twitching, drowsiness and dizziness. Symptoms of gross overdosage may include CNS depression, rigidity, weakness, torticollis, tremor, salivation, dysphagia, hypotension, disturbances of gait, or coma. Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Thiothixene may be additive with or may potentiate the action of other CNS depressants (including alcohol), anticholinergics, or hypotensive agents. ANIMAL STUDIES: In animal reproduction studies with thiothixene, there was some decrease in conception rate and litter size, and an increase in resorption rate in rats and rabbits. After repeated oral administration of thiothixene to rats (5 to 15 mg/kg/day), rabbits (3 to 50 mg/kg/day), and monkeys (1 to 3 mg/kg/day) before and during gestation, no teratogenic effects were seen.

Hepatic microsomal enzyme inducing agents, such as carbamazepine, were found to significantly increase the clearance of thiothixene. Patients receiving these drugs should be observed for signs of reduced thiothixene effectiveness.|In this study healthy volunteers received thiothixene with and without a 3-day pretreatment with paroxetine to determine if paroxetine decreased the clearance of thiothixene. Ten healthy medication-free volunteers (4 women and 6 men, mean age 38 +/- 12 years) were randomized to receive a single 20 mg oral dose of thiothixene on two separate occasions. On one occasion thiothixene was given concurrently, and following 3 days of pre-treatment with oral paroxetine (20 mg/day). On the other occasion thiothixene was given without paroxetine pre-treatment. The two study days were separated by a minimum period of 2 weeks. On both study days, after the administration of thiothixene, 10 mL blood samples were collected over the next 72 hr. None of the pharmacokinetic parameters of thiothixene were significantly altered by a 3-day treatment with paroxetine. It is likely that the CYP2D6 isoenzyme is not responsible for a high proportion of thiothixene clearance, but one cannot exclude the possibility that a longer paroxetine pretreatment might have caused some inhibition of thiothixene clearance.|Thiothixene may be additive with or may potentiate the action of other CNS depressants (including alcohol), anticholinergics, or hypotensive agents.|Due to a possible additive effect with hypotensive agents, patients receiving these drugs should be observed closely for signs of excessive hypotension when thiothixene is added to their drug regimen.

LD50 Rat oral 720 mg/kg|LD50 Rat sc 2 g/kg|LD50 Mouse oral 400 mg/kg|LD50 Mouse sc 4 g/kg

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Thiothixene is not approved for the treatment of patients with dementia-related psychosis.|Thiothixene should be used with caution in patients with cardiovascular disease. ...|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. 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. 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. In patients with severe neutropenia (absolute neutrophil count [ANC] less than 1000/cu mm), thiothixene should be discontinued and the leukocyte count monitored until recovery occurs.|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 ... .|For more Populations at Special Risk (Complete) data for Thiothixene (6 total), please visit the HSDB record page.

For the management of schizophrenia.

Antipsychotic Agents; Dopamine Antagonists|/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Thiothixene is included in the database.|Thiothixene capsules are effective in the management of schizophrenia. /Included in US product label/|Experience with the drug in treating neurotic conditions is limited and does not indicate that thiothixene is likely to have advantages over anxiolytic agents, butyrophenones, phenothiazines, or chlorprothixene (no longer commercially available in the US). Thiothixene has not been evaluated in the management of behavioral complications in mentally retarded patients.

/BOXED WARNING/ Increased Mortality in Elderly Patients with Dementia-Related Psychosis: Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Thiothixene is not approved for the treatment of patients with dementia-related psychosis.|Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs, including thiothixene. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.|A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs, including thiothixene. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias).|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.|For more Drug Warnings (Complete) data for Thiothixene (21 total), please visit the HSDB record page.

Thiothixene is an antipsychotic of the thioxanthene series. Navane possesses certain chemical and pharmacological similarities to the piperazine phenothiazines and differences from the aliphatic group of phenothiazines. Although widely used in the treatment of schizophrenia for several decades, thiothixene is seldom used today in favor of atypical antipsychotics such as risperidone.

Agents that control agitated psychotic behavior, alleviate acute psychotic states, reduce psychotic symptoms, and exert a quieting effect. They are used in SCHIZOPHRENIA; senile dementia; transient psychosis following surgery; or MYOCARDIAL INFARCTION; etc. These drugs are often referred to as neuroleptics alluding to the tendency to produce neurological side effects, but not all antipsychotics are likely to produce such effects. Many of these drugs may also be effective against nausea, emesis, and pruritus. (See all compounds classified as Antipsychotic Agents.)|Drugs that bind to but do not activate DOPAMINE RECEPTORS, thereby blocking the actions of dopamine or exogenous agonists. Many drugs used in the treatment of psychotic disorders (ANTIPSYCHOTIC AGENTS) are dopamine antagonists, although their therapeutic effects may be due to long-term adjustments of the brain rather than to the acute effects of blocking dopamine receptors. Dopamine antagonists have been used for several other clinical purposes including as ANTIEMETICS, in the treatment of Tourette syndrome, and for hiccup. Dopamine receptor blockade is associated with NEUROLEPTIC MALIGNANT SYNDROME. (See all compounds classified as Dopamine Antagonists.)

Fifty-nine plasma thiothixene concentrations were measured in 42 patients as part of routine therapeutic drug monitoring. Data collection included concomitant medications, smoking history, and demographic variables. A retrospective analysis was performed to assess the effect of these parameters on oral thiothixene clearance. When groups of patients were categorized by concomitant medications (i.e., no interacting drugs, enzyme/clearance inducers, and enzyme/clearance inhibitors), thiothixene clearance was found to be significantly increased by enzyme inducing drugs (e.g., anticonvulsants) and decreased by clearance inhibiting agents (e.g., cimetidine). Tobacco smoking significantly increased the hepatic clearance of thiothixene within the no interactions and inhibitor groups, but not in the inducer group. Significantly more patients in the inducer group had nondetectable plasma concentrations of thiothixene than the other groups. When the entire patient population was dichotomized by age, patients less than 50 years old had a significantly greater mean clearance (48.2 +/- 37.8 liters/min) versus those greater than or equal to 50 (20.0 +/- 12.6 liters/min). Men in this cohort exhibited a significantly higher clearance (49.2 +/- 38.7 liters/min) than did the women (22.0 +/- 13.5 liters/min). By taking into account these potential sources of pharmacokinetic variability when monitoring plasma thiothixene concentrations, more appropriate dosing of thiothixene may be achieved. Controlled, prospective studies are needed to validate these findings.|Thiothixene is widely distributed into body tissues and may remain in the body for several weeks following administration.|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.|Two experiments are reported in which acute single test dose levels of thiothixene (Navane) were correlated with age. In the first study 20 mg oral doses were given to 28 male subjects and serum levels were drawn 2 hr later. Mean age was 30 and correlation of serum level with age was 0.43, P less than 0.02. In a second older group with a mean age of 41, 10 mg oral doses were given to 25 subjects. A correlation with age of 0.41, P less than 0.05 was obtained with age. In prior work such acute levels have been found to correlate with steady-state serum levels and with clinical response to the medication. ...

Hepatic.|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.

10-20 hours

Thiothixene acts as an antagonist (blocking agent) on different postsysnaptic receptors -on dopaminergic-receptors (subtypes D1, D2, D3 and D4 - different antipsychotic properties on productive and unproductive symptoms), on serotonergic-receptors (5-HT1 and 5-HT2, with anxiolytic, antidepressive and antiaggressive properties as well as an attenuation of extrapypramidal side-effects, but also leading to weight gain, fall in blood pressure, sedation and ejaculation difficulties), on histaminergic-receptors (H1-receptors, sedation, antiemesis, vertigo, fall in blood pressure and weight gain), alpha1/alpha2-receptors (antisympathomimetic properties, lowering of blood pressure, reflex tachycardia, vertigo, sedation, hypersalivation and incontinence as well as sexual dysfunction, but may also attenuate pseudoparkinsonism - controversial) and finally on muscarinic (cholinergic) M1/M2-receptors (causing anticholinergic symptoms like dry mouth, blurred vision, obstipation, difficulty/inability to urinate, sinus tachycardia, ECG-changes and loss of memory, but the anticholinergic action may attenuate extrapyramidal side-effects).

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/|Emergency and supportive measures: 1. Maintain an open airway and assist ventilation if necessary. Administer supplemental oxygen. 2. Treat coma, seizures, hypotension, and hyperthermia if they occur. 3. Monitor vital signs ECG for at least 6 hours and admit the patient for at least 24 hours if there are signs of significant intoxication. Children with antipsychotic intoxication should be evaluated for possible intentional abuse. /Antipsychotic drugs/|For more Antidote and Emergency Treatment (Complete) data for Thiothixene (7 total), please visit the HSDB record page.

/SIGNS AND SYMPTOMS/ Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs, including thiothixene. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.|/SIGNS AND SYMPTOMS/ A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs, including thiothixene. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias).|/SIGNS AND SYMPTOMS/ Manifestations /of overdose/ include muscular twitching, drowsiness and dizziness. Symptoms of gross overdosage may include CNS depression, rigidity, weakness, torticollis, tremor, salivation, dysphagia, hypotension, disturbances of gait, or coma.|/CASE REPORTS/ A 27-yr-old paranoid schizophrenic male manifested chewing movements of the mouth and choreiform movements of the tongue and face following a one-yr trial with 10 mg daily of thiothixene. During the yr period, the patient had received 2 mg of benztropine daily for 6 weeks and occasional supplements of diazepam and flurazepam. For therapeutic reasons, thiothixene was continued and the patient continued to experience symptoms of tardive dyskinesia in varying degrees of intensity. The need for conservatism in the use of thiothixene as well as other neuroleptics, in order to prevent dyskinesia is emphasized.|For more Human Toxicity Excerpts (Complete) data for Thiothixene (8 total), please visit the HSDB record page.

Navane

Table: Thiothixene Preparations [Table#4575]

A high-performance thin-layer chromatography method is available for quantitation of thiothixene plasma values. Sensitivity is about 0.1 ng/mL.

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients