VA Class:CN701

ATC Class:N05AC02

AHFS Class:

• Phenothiazines 28:16.08.24

Generic Name(s):

• Thioridazine Hydrochloride

Chemical Name:

• 10-[2-(1-methylpiperidin-2-yl)ethyl]-2-methylsulfanylphenothiazine

Molecular Formula:

• C₂₁H₂₆N₂S₂

Thioridazine hydrochloride is a phenothiazine antipsychotic agent. The drug is considered a conventional or first-generation antipsychotic agent.100

Psychotic Disorders

Thioridazine is used for the symptomatic management of psychotic disorders. However, because thioridazine has the potential for substantial, and possibly life-threatening, proarrhythmic effects and can precipitate sudden death, use of the drug is reserved for patients with schizophrenia whose disease fails to respond adequately to appropriate courses with at least 2 different antipsychotic agents, either because of insufficient efficacy or the inability to achieve an effective dosage due to intolerable adverse effects. In addition, use of thioridazine in patients with refractory schizophrenia has not been evaluated in controlled clinical trials and efficacy of the drug in such patients is not known.

Drug therapy is integral to the management of acute psychotic episodes in patients with schizophrenia and generally is required for long-term stabilization to improve symptoms between episodes and to minimize the risk of recurrent acute episodes. Antipsychotic agents are the principal class of drugs used for the management of all phases of schizophrenia and generally are effective in all subtypes of the disorder and subgroups of patients. Patient response and tolerance to antipsychotic agents are variable, and patients who do not respond to or tolerate one drug may be successfully treated with an agent from a different class or with a different adverse effect profile. For additional information on the symptomatic management of schizophrenia, see Uses: Psychotic Disorders, in the Phenothiazines General Statement 28:16.08.24.

Other Uses

Thioridazine is used for the short-term treatment of adults with major depression who have varying degrees of associated anxiety, and for the symptomatic management of agitation, anxiety, depressed mood, tension, sleep disturbances, and fears in geriatric patients (see Cautions).

Thioridazine also has been used for the treatment of severe behavioral problems in children marked by combativeness and/or explosive hyperexcitable behavior (out of proportion to immediate provocations), and for the short-term treatment of hyperactive children who exhibit excessive motor activity with accompanying conduct disorders. However, the possible risks of developing tardive dyskinesia, withdrawal dyskinesia, and other extrapyramidal reactions associated with the drug should be considered. Some clinicians recommend routine administration of the Abnormal Involuntary Movement Scale (AIMS) to all children receiving antipsychotic agents for this indication.

Administration

Thioridazine hydrochloride is administered orally.

Dosage

Dosage of thioridazine hydrochloride is expressed in terms of the hydrochloride salt. Dosage must be carefully adjusted according to individual requirements and response using the lowest possible effective dosage. Dosage should be increased more gradually in debilitated or geriatric patients.

Psychotic Disorders

For the symptomatic management of psychotic disorders, the usual initial adult dosage of thioridazine hydrochloride is 50-100 mg 3 times daily. Dosage may gradually be increased, depending on the patient's therapeutic response and tolerance. The manufacturers recommend that dosages greater than 300 mg daily be reserved for adults with severe neuropsychiatric conditions. Dosages up to 800 mg daily given in 2-4 divided doses may be required in hospitalized, institutionalized, or severely psychotic adults. Dosage during prolonged maintenance therapy with thioridazine should be kept at the lowest effective level; once an adequate response has been obtained, dosage should be gradually reduced and subsequently adjusted according to the patient's therapeutic response and tolerance. Because of the risk of adverse reactions associated with cumulative effects of phenothiazines, patients with a history of long-term therapy with thioridazine and/or other antipsychotic agents should be evaluated periodically to determine whether drug therapy could be discontinued.

For the management of hospitalized, severely disturbed, or psychotic children 2-12 years of age, the usual initial dosage of thioridazine is 0.5 mg/kg daily, administered in divided doses. Dosage may be gradually increased until optimum therapeutic effect is obtained. Dosage for children should not exceed 3 mg/kg daily.

Other Conditions

For the short-term treatment of adults with major depression who also have varying degrees of associated anxiety, or for the symptomatic management of agitation, anxiety, depressed mood, tension, sleep disturbances, and fears in geriatric patients (see Cautions), the usual initial dosage of thioridazine is 25 mg 3 times daily. Dosage ranges from 20-200 mg daily in these patients, depending on the severity of the condition.

Thioridazine shares the toxic potentials of other phenothiazines, and the usual precautions of phenothiazine therapy should be observed. (See Cautions in the Phenothiazines General Statement 28:16.08.24.) At recommended dosages, adverse effects of thioridazine are generally mild and transient.

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 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 also Cautions: Geriatric Precautions, in the Phenothiazines General Statement 28:16.08.24.

Arrhythmias and Associated Precautions and Contraindications

Dose-related serious cardiac effects, including prolongation of the QT interval corrected for rate (QT_c), arrhythmias (e.g., atypical ventricular tachycardia [torsades de pointes]), and/or sudden death, have been reported in patients receiving thioridazine. A causal relationship to the drug has not been established; however, since thioridazine and its major metabolite mesoridazine have been shown to prolong the QT_c interval, such a relationship is possible. Although thioridazine has been shown to prolong the QT_c interval in a dose-dependent manner, prolongation of the QT_c interval and sudden death have been reported occasionally at usual dosages. In a crossover study, healthy men receiving a single 50-mg dose of thioridazine hydrochloride had a greater increase in QT_c interval (mean maximum of about 23 msec) than those receiving either a 10-mg dose or placebo; however, the manufacturer states that even further prolongation of the QT_c interval may be observed in clinical practice.

The risk of atypical ventricular tachycardia (e.g., torsades de pointes) and/or sudden death may be increased in patients with bradycardia, hypokalemia, or congenital long QT syndrome and in those receiving thioridazine concomitantly with drugs that can prolong the QT_c interval. Use of antiarrhythmic agents (e.g., disopyramide, procainamide, quinidine) that can prolong the QT_c interval and potentially exacerbate the cardiotoxic effects of thioridazine should be avoided in treating arrhythmias associated with the antipsychotic agent. (See Acute Toxicity: Treatment.) In patients who experience symptoms of possible atypical ventricular tachycardia (torsades de pointes), such as dizziness, palpitations, or syncope, further cardiac evaluation (e.g., Holter monitoring) should be considered.

Cardiotoxic effects may be associated with increased plasma concentrations of thioridazine and its metabolites. Increased plasma concentrations of the drug are most likely to develop in patients with poor metabolizer phenotypes of the cytochrome P-450 (CYP) 2D6 isoenzyme; and in patients receiving drugs known to inhibit the CYP2D6 isoenzyme (e.g., fluoxetine, paroxetine) or reduce the clearance of thioridazine by other mechanisms (e.g., fluvoxamine, pindolol, propranolol).

Because thioridazine may be associated with serious adverse cardiac effects, ECG and serum potassium concentrations should be determined at baseline and periodically thereafter; such monitoring may be particularly useful during a period of dosage adjustment. Serum potassium concentrations should be within the normal range before thioridazine therapy is initiated; patients with a QT_c interval exceeding 450 msec should not receive thioridazine. Thioridazine should be discontinued if the QT_c interval exceeds 500 msec. Patients receiving thioridazine should be informed about the risk of developing adverse cardiac effects and the possibility of switching from thioridazine to another antipsychotic agent should be considered based on the possible risks and likely benefits associated with thioridazine.

Because thioridazine has been shown to be more cardiotoxic in overdosage than other antipsychotic agents, some clinicians caution against its use in actively suicidal patients.

Patients receiving thioridazine concomitantly with drugs that prolong the QT_c interval, inhibit the CYP2D6 isoenzyme (e.g., fluoxetine, paroxetine), or reduce clearance of the phenothiazine by other mechanisms (e.g., fluvoxamine, pindolol, propranolol); those with poor metabolizer phenotypes of the CYP2D6 isoenzyme; and those with underlying conditions that might prolong the QT_c interval (e.g., congenital long QT syndrome, history of arrhythmias) may be at increased risk of developing cardiac arrhythmias (e.g., atypical ventricular tachycardia [torsades de pointes]) that may be fatal. Therefore, use of thioridazine in such patients is contraindicated.

Drugs Affecting Hepatic Microsomal Enzymes

Drugs that inhibit the cytochrome P-450 (CYP) 2D6 isoenzyme (e.g., fluoxetine, paroxetine) appear to inhibit the metabolism of thioridazine, which has resulted in elevated plasma concentrations of the phenothiazine. Since thioridazine has been shown to prolong the QT interval corrected for rate (QT_c) in a dose-dependent manner, increased plasma concentrations of the drug may be expected to augment such prolongation and thus may increase the risk of serious, potentially fatal, cardiac arrhythmias (e.g., atypical ventricular tachycardia [torsades de pointes]). Therefore, concomitant use of thioridazine with drugs that inhibit the CYP2D6 isoenzyme is contraindicated.

Other Drugs that Reduce Clearance of Thioridazine

Fluvoxamine

In a limited number of male patients with schizophrenia, concomitant use of thioridazine and fluvoxamine (25 mg twice daily for 1 week) resulted in a threefold increase in steady-state plasma concentrations of thioridazine and its 2 active metabolites (mesoridazine and sulforidazine). Therefore, fluvoxamine and thioridazine should not be used concomitantly.

Propranolol

Concomitant use of propranolol (100-800 mg daily) and thioridazine reportedly resulted in increased plasma concentrations of thioridazine (approximately 50-400%) and its metabolites (approximately 80-300%). Therefore, propranolol and thioridazine should not be used concomitantly.

Pindolol

Concomitant use of pindolol and thioridazine has resulted in moderate, dose-related increases in serum concentrations of thioridazine and 2 of its metabolites in addition to higher than expected serum concentrations of pindolol. Therefore, pindolol and thioridazine should not be used concomitantly.

Drugs that Prolong QTc Interval

Although specific drug interaction studies have not been performed to evaluate the concomitant use of thioridazine with drugs that prolong the QT_c interval, the manufacturers state that additive effects of such concomitant therapy on the QT_c interval can be expected. Therefore, concomitant use of thioridazine with these drugs is contraindicated.

Acute Toxicity

Pathogenesis

Although the minimum toxic or lethal doses and blood concentrations of thioridazine remain to be definitely established, it has been suggested that blood thioridazine concentrations of 1 mg/dL or greater are toxic, and those of 2-8 mg/dL are potentially lethal.

Manifestations

Overdosage of phenothiazines (e.g., thioridazine) may be expected to produce effects that are extensions of common adverse effects. (See Acute Toxicity: Manifestations, in the Phenothiazines General Statement 28:16.08.24.) However, results of case reports and several studies suggest that overdosage of thioridazine may be associated with cardiotoxicity (e.g., prolongation of QT interval and QRS complex) more frequently than other antipsychotic agents.

Treatment

Management of thioridazine overdosage generally involves symptomatic and supportive care with cardiovascular (e.g., ECG) monitoring. A patent airway must be established and maintained, and adequate oxygenation and ventilation must be ensured.

Following acute ingestion of thioridazine, 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. In addition, emesis should not be induced in patients expected to deteriorate rapidly or in those with impaired consciousness.

To detect arrhythmias, continuous ECG monitoring may be necessary for at least 24 hours or for as long as the QT_c is prolonged. Management of thioridazine-induced arrhythmias may include ventricular pacing, defibrillation, administration of IV magnesium sulfate, lidocaine, phenytoin, or isoproterenol and correction of electrolyte abnormalities and/or acid-base balance. Lidocaine must be administered with caution in patients with overdosage of thioridazine since use of this antiarrhythmic in such patients may increase the risk of developing seizures. Antiarrhythmic agents that can prolong the QT interval (e.g., class IA [disopyramide, procainamide, quinidine] or III agents) should be avoided in treating overdosage-associated arrhythmias in which prolongation of the QT_c is a manifestation. For additional information on treatment of acute toxicity, see Acute Toxicity: Treatment, in the Phenothiazines General Statement 28:16.08.24.

Pharmacology

The principal pharmacologic effects of thioridazine are similar to those of chlorpromazine. On a weight basis, thioridazine is about as potent as chlorpromazine. Thioridazine has strong anticholinergic and sedative effects and weak extrapyramidal effects. Thioridazine has little antiemetic activity.

Chemistry and Stability

Chemistry

Thioridazine hydrochloride is a phenothiazine antipsychotic agent. The drug is an alkylpiperidine derivative of phenothiazine which differs structurally from other phenothiazine derivatives in the presence of a thiomethyl group at the 2 position of the phenothiazine nucleus. Thioridazine is commercially available as the hydrochloride salt.

Thioridazine hydrochloride occurs as a white to slightly yellow, granular powder with a faint odor and a very bitter taste, and is freely soluble in water.

Stability

Thioridazine hydrochloride tablets should be protected from light and stored in well-closed containers at a temperature less than 40°C, preferably at 15-30°C.

Additional Information

For further information on chemistry and stability, pharmacology, pharmacokinetics, uses, cautions, acute toxicity, drug interactions, and dosage and administration of thioridazine, see the Phenothiazines General Statement 28:16.08.24.

Please see the general statement for a list of references.