Thioridazine

Water spray, dry chemical, carbon dioxide or foam as appropriate for surrounding fire and materials.

As with all fires, evacuate personnel to a safe area. Firefighters should use self-contained breathing equipment and protective clothing.

Wear approved respiratory protection, chemically compatible gloves and protective clothing. Wipe up spillage or collect spillage using a high efficiency vacuum cleaner. Avoid breathing dust. Place spillage in appropriately labeled container for disposal. Wash spill site.

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.

SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

This material is assumed to be combustible. As with all dry powders it is advisable to ground mechanical equipment in contact with dry material to dissipate the potential buildup of static electricity.

As a general rule, when handling USP Reference Standards avoid all contact and inhalation of dust, mists, and/or vapors associated with the material. Wash thoroughly after handling.

Use safety glasses or goggles and protect exposed skin.

Engineering controls such as exhaust ventilation are recommended.

Use a NIOSH approved respirator, if it is determined to be necessary by an industrial hygiene survey involving air monitoring. In the event that a respirator is not required, an approved dust mask should be used.

An airway must be established and maintained. Adequate oxygenation and ventilation must be ensured. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias. Treatment may include one or more of the following therapeutic interventions: correction of electrolyte abnormalities and acid-base balance, lidocaine, phenytoin, isoproterenol, ventricular pacing, and defibrillation. Disopyramide, procainamide, and quinidine may produce additive QT-prolonging effects when administered to patients with acute overdosage of Mellaril and should be avoided. Caution must be exercised when administering lidocaine, as it may increase the risk of developing seizures. Treatment of hypotension may require intravenous fluids and vasopressors. Phenylephrine, levarterenol, or metaraminol are the appropriate pressor agents for use in the management of refractory hypotension. Gastric lavage and repeated doses of activated charcoal should be considered. Induction of emesis is less preferable to gastric lavage because of the risk of dystonia and the potential for aspiration of vomitus. Acute extrapyramidal symptoms may be treated with diphenhydramine hydrochloride or benztropine mesylate. Forced diuresis, hemoperfusion, hemodialysis and manipulation of urine pH are of unlikely benefit in the treatment of phenothiazine overdose due to their large volume of distribution and extensive plasma protein binding. (L1712)

QT interval-prolonging medications, including cisapride, erythromycin, and quinidine /may produce/ additive QT interval prolongation increasing the risk of developing cardiac arrhythmias when /concurrently administered with phenothiazines/. /Phenothiazines/

Concurrent use /of other photosensitizing medications/ with phenothiazines may cause additive photosensitizing effects. In addition, concurrent use of systemic methoxsalen, trixsalen, or tetracyclines with phenothiazines may potentiate intraocular photochemical damage to the choroid, retina, or lens. /Phenothiazines/

Prior administration of phenothiazines may decrease the pressor effect and shorten the duration of action of phenylephrine. /Phenothiazines/

In addition to increased CNS and respiratory depression, concurrent use /of opiod (narcotic) analgesics/ with phenothiazines increases orthostatic hypotension and increases the risk of severe constipation, which may lead to paralytic ileus, and/or urinary retention. /Phenothiazines/

For more Interactions (Complete) data for Thioridazine (30 total), please visit the HSDB record page.

Liver test abnormalities have been reported to occur in a high proportion of patients on long term phenothiazine therapy, but elevations are uncommonly above 3 times the upper limit of normal. The aminotransferase abnormalities are usually mild, asymptomatic and transient, reversing even with continuation of medication. Rare instances of clinically apparent acute liver injury have been reported due to thioridazine, with some resemblance to cases of chlorpromazine jaundice. The onset of jaundice occurred within a few weeks to several months of therapy and the pattern of serum enzyme elevations was typically cholestatic, although hepatocellular patterns have also been reported. Immunoallergic manifestations (fever, rash and eosinophilia) were not prominent and autoantibodies were not detected. Some cases were associated with agranulocytosis which is a rare but known complication of the phenothiazines.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1.2X10+5(SRC), determined from a log Kow of 5.90(2) and a regression-derived equation(3), indicates that thioridazine is expected to be immobile in soil(SRC). The pKa of thioridazine is 9.5(4), indicating that this compound will almost entirely exist in cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(5). Volatilization from moist soil is not expected because the base exists as an cation and cations do not volatilize. Thioridazine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.69X10-8 mm Hg at 25 °C(SRC), determined from a fragment constant method(6). Biodegradation data in soil were not available(SRC, 2010).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1.2X10+5(SRC), determined from a log Kow of 5.90(2) and a regression-derived equation(3), indicates that thioridazine is expected to adsorb to suspended solids and sediment(SRC). A pKa of 9.5(4) indicates thioridazine will exist almost entirely in the cation form at pH values of 5 to 9 and therefore volatilization from water surfaces is not expected to be an important fate process(5). According to a classification scheme(6), an estimated BCF of 3,600(SRC), from its log Kow(2) and a regression-derived equation(3), suggests the potential for bioconcentration in aquatic organisms is very high, provided the compound is not metabolized by the organism(SRC). Biodegradation data in water were not available(SRC, 2010).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), thioridazine, which has an estimated vapor pressure of 3.69X10-8 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phases in the ambient atmosphere. Particulate-phase thioridazine may be removed from the air by wet or dry deposition(SRC). Thioridazine does not contain chromophores that absorb at wavelengths >290 nm(3), and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

Thioridazine is a low-potency typical antipsychotic, like chlorpromazine. Unlike higher-potency antipsychotics, thioridazine has a lower incidence of extrapyramidal side effects. However, lower-potency antipsychotics are more likely to be associated with antimuscarinic, antihistaminic, and antiadrenergic side effects. Thioridazine is metabolized through the liver with a half-life of 24 hours and is excreted in the urine, bile, and feces. The hepatic cytochrome P450 CYP2D6 metabolism of thioridazine is important because it assists in identifying different drug-drug interactions. Thus, it is necessary to evaluate patients and identify medications that may increase or decrease thioridazine levels.

Thioridazine blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors in the brain; blocks alpha-adrenergic effect, depresses the release of hypothalamic and hypophyseal hormones and is believed to depress the reticular activating system thus affecting basal metabolism, body temperature, wakefulness, vasomotor tone, and emesis.

LD₅₀=956-1034 mg/kg (Orally in rats); Agitation, blurred vision, coma, confusion, constipation, difficulty breathing, dilated or constricted pupils, diminished flow of urine, dry mouth, dry skin, excessively high or low body temperature, extremely low blood pressure, fluid in the lungs, heart abnormalities, inability to urinate, intestinal blockage, nasal congestion, restlessness, sedation, seizures, shock

The Koc of thioridazine is estimated as 1.2X10+5(SRC), using a log Kow of 5.90(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that thioridazine is expected to be immobile in soil. The pKa of thioridazine is 9.5(4), indicating that this compound will almost entirely exist in cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(5).

/HUMAN EXPOSURE STUDIES/ Thioridazine is a phenothiazine derivative that has been used as an antipsychotic; it rarely causes photosensitization. However, /investigators/ noticed that this drug induced an erythematous reaction in a photopatch test. Six volunteers were patch tested with various concentrations of thioridazine and irradiated with a range of UVA doses, and the time courses of the color of and blood flow to the test sites were monitored. The free-radical metabolites of thioridazine generated under UVA irradiation and its effects on ascorbate radical formation were examined with an electron paramagnetic resonance (EPR) spectrometer in vitro. As a result, immediate erythema developed during UVA irradiation in most subjects when 1% thioridazine was applied for 48 hr and irradiation doses were higher than 4 J cm(-2). Another peak of erythematous reaction was observed 8-12 hr after irradiation. ... Thioridazine-derived oxidants and/or thioridazine radicals generated during UVA irradiation seem to play an important role in this unique phototoxic reaction.

/SIGNS AND SYMPTOMS/ Effects and clinical complications of acute overdose involving phenothiazines may include: Cardiovascular: Cardiac arrhythmias, hypotension, shock, ECG changes, increased QT and PR intervals, non-specific ST and T wave changes, bradycardia, sinus tachycardia, atrioventricular block, ventricular tachycardia, ventricular fibrillation, Torsades de pointes, myocardial depression. Central Nervous System: Sedation, extrapyramidal effects, confusion, agitation, hypothermia, hyperthermia, restlessness, seizures, areflexia, coma. Autonomic Nervous System: Mydriasis, miosis, dry skin, dry mouth, nasal congestion, urinary retention, blurred vision. Respiratory: Respiratory depression, apnea, pulmonary edema. Gastrointestinal: Hypomotility, constipation, ileus. Renal: Oliguria, uremia. Toxic dose and blood concentration ranges for the phenothiazines have not been firmly established.

/SIGNS AND SYMPTOMS/ In general, overdosage of phenothiazines may be expected to produce effects that are extensions of common adverse reactions; severe extrapyramidal reactions, hypotension, and sedation have been the principal effects reported. CNS depression progressing to coma with areflexia or CNS stimulation with convulsions followed by respiratory depression may occur; patients with early or mild intoxication may experience drowsiness, restlessness, disorientation, confusion, and excitement. Other reported effects associated with acute phenothiazine overdosage have included shock (eg, ECG changes and cardiac arrhythmias), increased QT and PR intervals, non-specific ST and T wave changes, bradycardia, sinus tachycardia, bilateral bundle branch block, atrioventricular block, ventricular tachycardia, ventricular fibrillation, torsades de pointes, myocardial depression, agitation, dry skin, nasal congestion, urinary retention, oliguria, uremia, blurred vision, hypothermia, hyperthermia, mydriasis, miosis, tremor, muscle twitching, spasm or rigidity, seizures, muscular hypotonia, constipation, ileus, dry mouth, vomiting, difficulty in swallowing or breathing, cyanosis, and respiratory and/or vasomotor collapse, and pulmonary edema, possibly with sudden apnea. /Phenothiazine general Statement/

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

Indicated for the management of schizophrenic patients who fail to respond adequately to treatment with antipsychotic drugs

Used in the management of psychoses ... and in the control of severely distured or agitated behavior

THERAPEUTIC CATEGORY: Antipsychotic

MEDICATION

Use (kg; approx.) in Germany (2009): >250

For the treatment of schizophrenia and generalized anxiety disorder.