Description: Thiothixene is an antipsychotic drug that is structurally similar to trifluoperazine and shares some of the pharmacological properties of the high-potency antipsychotics. It is used in the treatment of psychotic disorders and schizophrenia. Five milligrams of thiothixene is equivalent to 100 mg of chlorpromazine, the prototype antipsychotic. Thiothixene was approved by the FDA in 1967. Mechanism of Action: Thiothixene blocks postsynaptic dopamine receptors in the mesolimbic system and increases dopamine turnover by blockade of the D2 somatodendritic autoreceptor. After approximately 12 weeks of chronic therapy, depolarization blockade of dopamine tracts occurs. The decrease in dopamine neurotransmission has been found to correlate with the antipsychotic effects. This D2 blockade is also responsible for the potent extrapyramidal effects observed with this drug. Dopamine blockade in the chemoreceptor trigger zone accounts for the antiemetic effects. Thiothixene possesses weak anticholinergic and alpha-adrenergic receptor blocking effects. Blockade of alpha1-adrenergic receptors produces sedation; muscle relaxation; and cardiovascular effects such as hypotension, reflex tachycardia, and minor changes in ECG patterns. Pharmacokinetics: Following oral administration, thiothixene is rapidly and well absorbed. Peak concentrations occur 1—3 hours following a dose. Distribution is extensive, and the drug can be detected in the body for several weeks after use. Metabolism takes place in the liver, but large amounts of drug are excreted with metabolites in the feces, via the bile. Profound increases in clearance of thiothixene can be observed in the presence of carbamazepine. The elimination is biphasic, with an initial half-life of 3.4 hours and a terminal half-life of 34 hours.

Indications...Dosage For the treatment of psychotic disorders such as schizophrenia, acute psychosis, or psychotic depression and severe behavioral disturbances (e.g., agitation†) related to psychiatric or neurodevelopmental disorders: •for the routine management of psychotic disorders: Oral dosage: Adults and adolescents: Initially, 2 mg PO three times per day or 5 mg PO twice daily, depending on severity of the condition. Increase gradually at weekly intervals, as needed and tolerated. The usual optimal dosage is in the range 10—30 mg/day PO given in divided doses, but doses up to 60 mg/day PO may be necessary for severe conditions. For maintenance therapy, the lowest effective dosage should be used. For some patients on maintenance therapy, a single daily dose may be effective. Elderly and debilitated patients: See adult dosage. In general, lower dosage and slower titration are needed. Children: Safe and effective use has not been established; data are limited. A dose of 0.25 mg/kg/day PO, given in divided doses, has been suggested as an effective dose. Intramuscular dosage (for acute, severe agitation; or for patients unable to take oral preparations): Adults: Initially, in acute psychosis, may give 4 mg IM every 1 hour according to patient need, not to exceed 6 doses per 24 hours. The usual dosage is 4 mg IM 2—4 times per day. Most patients are controlled with 16—20 mg/day given in divided doses. Do not exceed 30 mg/day IM. Oral dosage should replace parenteral administration as soon as possible. Children: Safe and effective use has not been established. •for the treatment of severe behavioral disturbances (e.g., agitation†, aggression, psychosis, etc.) due to organic brain syndromes or dementia†( e.g., Alzheimer's disease, late-stage Parkinson's disease, or dementia with Lewy bodies): Oral dosage: Elderly: Initially, 1—2 mg PO once daily or twice per day. May gradually increase every 4—7 days by 1—2 mg/day as needed and tolerated. Dosage may range from 2—30 mg/day given in 1—3 divided doses. Federal OBRA guidelines for nursing homes recommend that dosage not exceed 7 mg/day PO given in 1—3 divided doses, except when higher doses are necessary to maintain or improve the resident's functional status. Maximum Dosage Limits: •Adults: 60 mg/day PO. Debilitated patients require lower dosages. •Elderly: 60 mg/day PO. Debilitated patients require lower dosages. •Adolescents: 60 mg/day PO. Debilitated patients require lower dosages. •Children: Safe and effective use has not been established. Patients with hepatic impairment: Specific guidelines for dosage adjustments in hepatic impairment are not available but decreased drug metabolism may occur. Patients who develop jaundice secondary to thiothixene use should have therapy discontinued. Patients with renal impairment: Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed. Thiothixene is not removed by hemodialysis. †non-FDA-approved indication

Administration NOTE: Dosage must be individualized according to the degree of mental and emotional disturbance exhibited by the patient. In all cases, the lowest effective dosage should be determined for each patient. Oral Administration •Capsules: Administer with food or milk to minimize GI irritation. Do not administer within 1 hour of an antacid dose. •Oral concentrate solution: Dilute with 60—120 ml of milk, tomato or fruit juice, soup, water, or a carbonated beverage before administering. Administer using a calibrated measuring device. Avoid spilling the solution on the skin and clothing. Intramuscular Administration •Thiothixene injection is administered via IM injection only, do not administer intravenously. Dilution for intramuscular administration: •Dilute each 10 mg vial with 2.2 ml of sterile water for injection to give a concentration of 5 mg/ml of thiothixene. •Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Intramuscular (IM) injection: •Inject slowly and deeply into a large muscle (i.e., upper outer quadrant of the gluteus maximus or lateral part of the thigh). Aspirate prior to injection to avoid injection into a blood vessel. •Keep patient in a recumbent position for at least 30 minutes following injection to minimize hypotensive effects.

Contraindications Thiothixene should be used with extreme caution in patients with thyroid disease such as thyrotoxicosis or hyperthyroidism. Antipsychotic agents can cause extremely severe extrapyramidal symptoms such as dystonias or rigidity. Laryngospasm can prevent breathing and could be life-threatening. Patients with hypocalcemia may be at an increased risk for having dystonic reactions, so thiothixene should be used with caution in this patient population. Rarely, thiothixene can cause hypotension or precipitate angina; therefore, it should be used with extreme caution in patients with cardiac disease. Thiothixene is classified as a pregnancy category C drug. It is likely that thiothixene crosses the placenta. Studies in humans have not been performed. No birth defects have been reported to be caused by thiothixene, but use of the drug in pregnant rats and rabbits showed an increase in resorption rate. To be safe, thiothixene should be used during pregnancy only when the benefits outweigh the potential risks to the fetus. It is not known if thiothixene is excreted into breast milk. Potential adverse effects to the nursing infant, if any, remain unknown. Therefore, thiothixene should be used during breast-feeding only when a benefit-to-risk assessment shows that it is clearly needed. Oral solutions of thiothixene should not come in contact with the skin. Contact dermatitis has been reported with similar medications. Severe adverse CNS reactions induced by thiothixene may appear similar to neurologic symptoms of CNS disorders such as encephalitis, Reye's syndrome, encephalopathy, meningitis, brain tumor, and tetanus. In addition, the drug can suppress the symptoms of these disorders, if they are present. Thiothixene is contraindicated in patients who are in a coma or who exhibit severe toxic CNS depression. Patients with a history of hepatic encephalopathy secondary to cirrhosis may be at an increased risk for potentiation of the CNS effects of thiothixene. Although preexisting hepatic disease does not appear to increase the probability of jaundice occurring in patients receiving antipsychotic agents, thiothixene should be used with caution in this patient population. Children with acute illnesses, including varicella-zoster infections, CNS infections, measles, gastroenteritis, or dehydration, can be more susceptible to developing extrapyramidal symptoms, particularly dystonias. Elderly patients can be more susceptible to the actions and adverse effects of phenothiazines. Lower initial doses should be considered. Hematologic reactions have been reported following administration of antipsychotic agents. Although these reactions are rare, thiothixene should be used with caution in patients with preexisting hematological disease. If sore throat or other signs or symptoms of infection occur, obtain a complete blood count and consider discontinuing thiothixene treatment. Patients receiving anticonvulsant agents or who have a history of seizures, epilepsy, or EEG abnormalities should be carefully monitored during therapy with thiothixene due to its potential lowering of seizure threshold. Adequate anticonvulsant therapy should prevent an increase in seizure frequency during treatment with thiothixene. High doses and large changes in dose of thiothixene should be avoided in patients with a known seizure disorder. The anticholinergic effects of thiothixene or concomitant antiparkinsonian agent can worsen angle closure glaucoma, so they should be used with caution in patients with preexisting angle closure glaucoma. Thiothixene should be used cautiously in patients with prostatic hypertrophy because the anticholinergic effects of thiothixene or concomitant antiparkinsonian agent can worsen urinary retention. Thiothixene is contraindicated in patients with Parkinson's disease. Blockade of dopamine receptors centrally by thiothixene will dramatically worsen Parkinson's disease, possibly incapacitating the patient. Thiothixene can disrupt the hypothalamic mechanism for temperature regulation. Patients therefore should avoid exposure to extreme temperature variations to prevent hyperthermia or hypothermia. Antipsychotics stimulate the release of prolactin and should be used extremely cautiously in patients who have a history of breast cancer. Cigarette smoking can induce hepatic metabolism and reduce plasma concentrations of thiothixene compared with those of nonsmokers receiving the same dose. Dosage adjustments may be required in patients who start or stop smoking while receiving phenothiazines.

Interactions Thiothixene can potentiate the actions of other CNS depressants such as opiate agonists, barbiturates, ethanol, tramadol, or general anesthetics. Caution should be exercised with simultaneous use of these agents due to potential excessive CNS effects. In addition, thiothixene therapy may be associated with an increased risk of seizures when given concurrently with tramadol. Carbamazepine is a potent inducer of the cytochrome P-450 mixed-function hepatic oxidase system. Carbamazepine can reduce plasma concentrations of thiothixene to undetectable levels. Carbamazepine either should be avoided or an antipsychotic other than a phenothiazine should be used. If thiothixene and carbamazepine must be used together, then dosage adjustments of thiothixene may be required. Limited data suggest that rifampin can increase the metabolism or reduce the bioavailability of thiothixene. Patient response, adverse effects, and plasma thiothixene concentrations should be monitored following addition or deletion of rifampin during treatment with thiothixene. Erythromycin can inhibit metabolism of thiothixene. Dosage adjustments of the phenothiazine may be necessary in patients receiving erythromycin. Propranolol can inhibit the metabolism of phenothiazines. In addition, concomitant administration of propranolol with phenothiazines can lead to additive hypotension. Seizures also have been reported during concomitant use of propranolol with thiothixene. While coadministration is not contraindicated, patients should be monitored carefully for exaggerated responses to the phenothiazine. Although a causal relationship has not been established, administration of thioridazine to patients with lithium serum levels in excess of 1.2 mEq/L can lead to an encephalopathic syndrome. This syndrome is characterized by weakness, lethargy, fever, confusion, extrapyramidal symptoms, leukocytosis, elevated serum enzymes, BUN, and fasting blood glucose. Additive extrapyramidal effects have also been noted in patients receiving both agents. Although this reaction has been associated with thioridazine, it is also possible during concomitant therapy with thiothixene. In addition, pharmacokinetic interactions have been noted during therapy with lithium and chlorpromazine (e.g., lithium-induced reductions in chlorpromazine plasma concentrations, and chlorpromazine-induced acceleration of lithium renal clearance). Phenothiazines possess anticholinergic properties to varying degrees. Concomitant use of a phenothiazine with other anticholinergic agents can lead to additive anticholinergic effects. Thiothixene should be used cautiously with any of the following drugs: atropine, benztropine, dicyclomine, H1-blockers, tricyclic antidepressants, or other anticholinergics. Severe constipation, increased intraocular pressure, or paralytic ileus can result from additive anticholinergic effects. Phenothiazines should be used cautiously in patients receiving certain antihypertensive agents. Concurrent administration of haloperidol and methyldopa has been reported to cause dementia in some cases. The clinical importance of this interaction has not been established, but caution is reasonable during simultaneous use of thiothixene and methyldopa. In addition, phenothiazines can antagonize the pharmacologic actions of guanethidine. Both guanethidine and guanadrel should be avoided in patients receiving a phenothiazine. Patients taking thiothixene can have reduced pressor response to ephedrine, methoxamine, phenylephrine, metaraminol, or norepinephrine, but these drugs are preferred over epinephrine if a vasopressor agent is required. The alpha-adrenergic effects of epinephrine can be blocked during concurrent administration of phenothiazines, possibly causing an apparently paradoxical condition called "epinephrine reversal." Epinephrine reversal can lead to severe hypotension, tachycardia, and, potentially, myocardial infarction. The vasoconstrictive properties of dopamine infusion can be decreased due to the alpha-adrenergic blocking capability of thiothixene. Dopamine infusions intended to improve renal perfusion can be ineffective due to thiothixeneis dopamine receptor blockade. Thiothixene is a direct antagonist of levodopa, cabergoline, bromocriptine, or pergolide at the D2-receptor. In theory, thiothixene should inhibit the clinical response to these agents, but there is a paucity of clinical data to support this. Nevertheless, in general, phenothiazines should generally not be used in patients requiring therapy with levodopa, bromocriptine, cabergoline, or pergolide. The combination of quinidine with a phenothiazine could lead to additive orthostatic hypotension or, if either agent is used in high doses, prolonged QT syndrome. While concomitant use is not contraindicated, patients receiving both agents should be monitored for ECG changes. Antacids can significantly reduce the oral bioavailability of chlorpromazine. Until additional data are available, other neuroleptics should not be administered within 2 hours of antacid doses. Conflicting data exist for the combination of MAOIs and neuroleptics. The combination of tranylcypromine and trifluoperazine leads to a reduction of side effects from either agent. In other cases, however, extrapyramidal reactions were increased when an MAOI was added. In general, these two classes of drugs can be used together safely, although clinicians should monitor these patients carefully for exaggerated reactions. Dextroamphetamine and neuroleptics can interfere with the therapeutic actions of the other. One should avoid this drug combination whenever possible. In the absence of relevant data and as a precaution, drugs that cause hyperprolactinemia, such as antipsychotics, should not be administered concomitantly with gonadotropin releasing hormone (GnRH) analogs (cetrorelix, ganirelix, goserelin, leuprolide, or triptorelin) since hyperprolactinemia downregulates the number of pituitary GnRH receptors.

Adverse Reactions Thiothixene is structurally similar to the phenothiazines, and all known adverse reactions to the phenothiazines should be considered. The adverse effects of phenothiazines can affect all organ systems and may be attributed either to the drug's effects on the central and autonomic nervous system, or to hypersensitivity reactions to the drug. Thiothixene is structurally similar to the phenothiazines which frequently cause extrapyramidal symptoms (EPS) during treatment and appear to be the result of D2-receptor blockade. These symptoms occur with greater severity and frequency during high-dose therapy. Extrapyramidal symptoms are categorized as dystonic reaction, akathisia (subjective and objective motor restlessness), and pseudoparkinsonism. Parkinsonian symptoms are more common in the elderly, whereas children most often develop dystonic reactions, which can be worsened by acute infections or severe dehydration. Dystonic reactions are seen during the first week of treatment. Akathisia and parkinsonian symptoms usually develop several days to weeks into therapy. Dystonia and pseudoparkinsonism usually are easily treated with concomitant benztropine, diphenhydramine, lorazepam, or amantadine. Akathisia may respond to dosage reduction or concomitant administration of a benzodiazepine (usually lorazepam) or propranolol. In rare patients, an alternate antipsychotic may be necessary. Neuroleptic malignant syndrome (NMS) can occur in patients receiving phenothiazines and may also occur with thiothixene. NMS is characterized by hyperthermia, severe extrapyramidal dysfunction, alterations in consciousness, altered mental status, and autonomic instability (sinus tachycardia, low blood pressure or hypertension, diaphoresis). Increased serum creatine phosphokinase (CPK), acute renal failure, and leukocytosis also have occurred. NMS does not appear to be dose-related. Severe cases have resulted in death 3—30 days after the onset of the syndrome. Several predisposing factors may contribute to the development of NMS including heat stress, physical exhaustion, dehydration, and organic brain disease. NMS occurs more frequently in young men. The antipsychotic should be immediately discontinued and appropriate supportive therapy initiated as soon as symptoms of NMS are discovered. Hypothermia and hyperthermia have been reported with antipsychotic therapy independent of the neuroleptic malignant syndrome and may be caused by the effect of the phenothiazine (and possibly thiothixene) on the hypothalamic control of temperature regulation. Hyperpyrexia and heat stroke unrelated to NMS also have occurred. Tardive dyskinesia (TD) is characterized by involuntary movements of the perioral region (tongue, mouth, jaw, eyelids, or face) or choreoathetoid movements in the extremities. It can develop during long-term therapy or following discontinuation of phenothiazine therapy ( this may also be true for thiothixene), and it is observed more frequently in elderly women. The incidence of TD may be higher in patients with bipolar disorder than with schizophrenia. Some cases can be irreversible. While contradictory evidence exists, it has been suggested that the likelihood of developing TD increases with prolonged treatment and cumulative doses. Although this complication often occurs following prolonged treatment or with administration of high dosages, it also has been reported to occur after short periods of time and with low dosages. Routine monitoring (at 3- to 6-month intervals) of movement disorders is considered the standard practice when using antipsychotics and should also be considered for thiothixene. If signs or symptoms of TD develop, the neuroleptic should be reevaluated and possibly discontinued. Thiothixene is structurally similar to the phenothiazines which can cause a variety of CNS effects. Drowsiness occurs occasionally during initial treatment with some antispychotics. Tolerance usually develops with continued therapy. Dizziness may occur as a result of orthostatic hypotension. Other CNS effects reported less frequently include restlessness, insomnia, depression, headache, and cerebral edema. Seizures can occur and are of special significance in patients with preexisting seizure disorders or EEG abnormalities. Thiothixene is structurally similar to the phenothiazines whose anticholinergic effects include blurred vision, xerostomia, mydriasis, nausea, adynamic ileus, urinary retention, impotence, and constipation. These effects can be enhanced by the concomitant administration of anticholinergic antiparkinsonian drugs, antidepressants, or other anticholinergic agents. Leukopenia including agranulocytosis is the most common hematologic disturbance that has been reported during phenothiazine (and possibly thiothixene) administration. Agranulocytosis has occurred rarely and has been associated with combination treatment with other agents. Other hematologic abnormalities that have been associated with phenothiazine therapy include leukocytosis (usually in association with the neuroleptic malignant syndrome), eosinophilia, thrombocytopenia, pancytopenia, aplastic anemia, and anemia. Thiothixene is structurally similar to the phenothiazines which, after prolonged therapy, can cause skin hyperpigmentation. Hyperpigmentation generally is restricted to areas of the body exposed to sunlight. Photosensitivity can result, and patients should be warned either to keep out of the sun or to use effective sunscreens (SPF 15+) on exposed areas of the body. Withdrawal of the drug can reverse the effects. Contact dermatitis is also possible in predisposed individuals if they come in contact with liquid dosage forms of phenothiazines (and possibly thiothixene.) Thiothixene is structurally similar to the phenothiazines which can cause ocular changes. Pigmentary retinopathy can occur with or without pigmentary changes in the skin during therapy with phenothiazines. Symptoms of blurred vision, difficulty with nighttime vision, or defective color vision should be investigated promptly. Wearing protective dark glasses can reduce the possibility of this reaction. Phenothiazines (and possibly thiothixene) have been associated with deposition of fine particles in the lens and cornea, which can lead to corneal opacification and visual impairment. Liver impairment in the form of cholestasis has been reported rarely with administration of phenothiazines (this may be true for thiothixene which is structurally similar.) Jaundice is also possible and may even occur in neonates of mothers who received phenothiazines during pregnancy. Cholestatic jaundice from phenothiazines (and possibly thiothixene) is generally considered a hypersensitivity reaction. Adverse cardiovascular reactions that have occurred during antipsychotic therapy include hypotension, hypertension, ventricular tachycardia, ECG changes such as QT prolongation, and other cardiac arrhythmias such as torsade de pointes. Cardiac arrhythmias such as torsade de pointes secondary to antipsychotic therapy have mainly been associated with thioridazine[334] and haloperidol.[336] Dopamine blockade can lead to hyperprolactinemia. As a result, neuroleptics can cause galactorrhea. Other endocrine changes that can occur during therapy with neuroleptics include amenorrhea or other menstrual irregularity, breast enlargement or mastalgia, libido decrease, impotence, ejaculation dysfunction (no ejaculation), and priapism. Weight gain may also occur during therapy with phenothiazines (and possibly thiothixene which is structurally similar.)

Thiothixene Navane®, Thiothixene by Mylan | Noxene™

334. Raehl CL, Patel AK, LeRoy M. Drug-induced torsade de pointes. Clin Pharm 1985;4:675—90.

336. Kriwisky M, Perry GY, Tarchitsky D, et al. Haloperidol-induced torsades de pointes. Chest 1990;98:482—3.