Thioridazine Hydrochloride

FDA Drug Information • Also known as: Thioridazine Hydrochloride

Brand Names: Thioridazine Hydrochloride
Route: ORAL
Dosage Form: TABLET, FILM COATED
Product Type: HUMAN PRESCRIPTION DRUG

⚠ Boxed Warning (Black Box)

WARNING Thioridazine has been shown to prolong the QTc interval in a dose related manner, and drugs with this potential, including thioridazine, have been associated with Torsades de pointes type arrhythmias and sudden death. Due to its potential for significant, possibly life threatening, proarrhythmic effects, thioridazine should be reserved for use in the treatment of schizophrenic patients who fail to show an acceptable response to adequate courses of treatment with other antipsychotic drugs, either because of insufficient effectiveness or the inability to achieve an effective dose due to intolerable adverse effects from those drugs (see WARNINGS , CONTRAINDICATIONS , and INDICATIONS ). 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. Thioridazine hydrochloride is not approved for the treatment of patients with dementia-related psychosis (see WARNINGS ).

Description

DESCRIPTION Thioridazine hydrochloride is 2-methylmercapto-10-[2-(N-methyl-2-piperidyl) ethyl] phenothiazine. Its structural formula, molecular weight and molecular formula are: Thioridazine hydrochloride, USP is available as tablets for oral administration containing 10 mg, 25 mg, 50 mg or 100 mg. Each tablet for oral administration contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, FD&C Yellow No. 6 Aluminum Lake, hydroxypropyl cellulose, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sodium lauryl sulfate and titanium dioxide. Thioridazine Hydrochloride Structural Formula

What Is Thioridazine Hydrochloride Used For?

INDICATIONS AND USAGE Thioridazine hydrochloride tablets are indicated for the management of schizophrenic patients who fail to respond adequately to treatment with other antipsychotic drugs. Due to the risk of significant, potentially life threatening, proarrhythmic effects with thioridazine treatment, thioridazine hydrochloride tablets should be used only in patients who have failed to respond adequately to treatment with appropriate courses of other antipsychotic drugs, either because of insufficient effectiveness or the inability to achieve an effective dose due to intolerable adverse effects from those drugs. Consequently, before initiating treatment with thioridazine hydrochloride tablets, it is strongly recommended that a patient be given at least two trials, each with a different antipsychotic drug product, at an adequate dose, and for an adequate duration (see WARNINGS and CONTRAINDICATIONS ). However, the prescriber should be aware that thioridazine hydrochloride tablets have not been systematically evaluated in controlled trials in treatment refractory schizophrenic patients and its efficacy in such patients is unknown.

Dosage and Administration

DOSAGE AND ADMINISTRATION Since thioridazine hydrochloride tablets are associated with a dose related prolongation of the QTc interval, which is a potentially life threatening event, its use should be reserved for schizophrenic patients who fail to respond adequately to treatment with other antipsychotic drugs. Dosage must be individualized and the smallest effective dosage should be determined for each patient (see INDICATIONS and WARNINGS ). Adults The usual starting dose for adult schizophrenic patients is 50 mg to 100 mg three times a day, with a gradual increment to a maximum of 800 mg daily if necessary. Once effective control of symptoms has been achieved, the dosage may be reduced gradually to determine the minimum maintenance dose. The total daily dosage ranges from 200 mg to 800 mg, divided into two to four doses. Pediatric Patients For pediatric patients with schizophrenia who are unresponsive to other agents, the recommended initial dose is 0.5 mg/kg/day given in divided doses. Dosage may be increased gradually until optimum therapeutic effect is obtained or the maximum dose of 3 mg/kg/day has been reached.

Side Effects (Adverse Reactions)

ADVERSE REACTIONS In the recommended dosage ranges with thioridazine hydrochloride most side effects are mild and transient. Central Nervous System Drowsiness may be encountered on occasion, especially where large doses are given early in treatment. Generally, this effect tends to subside with continued therapy or a reduction in dosage. Pseudoparkinsonism and other extrapyramidal symptoms may occur but are infrequent. Nocturnal confusion, hyperactivity, lethargy, psychotic reactions, restlessness, and headache have been reported but are extremely rare. Autonomic Nervous System Dryness of mouth, blurred vision, constipation, nausea, vomiting, diarrhea, nasal stuffiness, and pallor have been seen. Endocrine System Galactorrhea, breast engorgement, amenorrhea, inhibition of ejaculation, and peripheral edema have been described. Skin Dermatitis and skin eruptions of the urticarial type have been observed infrequently. Photosensitivity is extremely rare. Cardiovascular System Thioridazine produces a dose related prolongation of the QTc interval, which is associated with the ability to cause Torsades de pointes type arrhythmias, a potentially fatal polymorphic ventricular tachycardia, and sudden death (see WARNINGS ). Both Torsades de pointes type arrhythmias and sudden death have been reported in association with thioridazine. A causal relationship between these events and thioridazine therapy has not been established but, given the ability of thioridazine to prolong the QTc interval, such a relationship is possible. Other ECG changes have been reported (see Phenothiazine Derivatives: Cardiovascular Effects ). Other Rare cases described as parotid swelling have been reported following administration of thioridazine. Post Introduction Reports These are voluntary reports of adverse events temporally associated with thioridazine that were received since marketing, and there may be no causal relationship between thioridazine use and these events: priapism. Phenothiazine Derivatives It should be noted that efficacy, indications, and untoward effects have varied with the different phenothiazines. It has been reported that old age lowers the tolerance for phenothiazines. The most common neurological side effects in these patients are parkinsonism and akathisia. There appears to be an increased risk of agranulocytosis and leukopenia in the geriatric population. The physician should be aware that the following have occurred with one or more phenothiazines and should be considered whenever one of these drugs is used: Autonomic Reactions: Miosis, obstipation, anorexia, paralytic ileus. Cutaneous Reactions: Erythema, exfoliative dermatitis, contact dermatitis. Blood Dyscrasias: Agranulocytosis, leukopenia, eosinophilia, thrombocytopenia, anemia, aplastic anemia, pancytopenia. Allergic Reactions: Fever, laryngeal edema, angioneurotic edema, asthma. Hepatotoxicity: Jaundice, biliary stasis. Cardiovascular Effects: Changes in the terminal portion of the electrocardiogram to include prolongation of the QT interval, depression and inversion of the T wave, and the appearance of a wave tentatively identified as a bifid T wave or a U wave have been observed in patients receiving phenothiazines, including thioridazine. To date, these appear to be due to altered repolarization, not related to myocardial damage, and reversible. Nonetheless, significant prolongation of the QT interval has been associated with serious ventricular arrhythmias and sudden death (see WARNINGS ). Hypotension, rarely resulting in cardiac arrest, has been reported. Extrapyramidal Symptoms: Akathisia, agitation, motor restlessness, dystonic reactions, trismus, torticollis, opisthotonus, oculogyric crises, tremor, muscular rigidity, akinesia. Tardive Dyskinesia: Chronic use of antipsychotics may be associated with the development of tardive dyskinesia. The salient features of this syndrome are described in the WARNINGS section and subsequently. The syndrome is characterized by...

Warnings and Precautions

WARNINGS 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. Thioridazine hydrochloride is not approved for the treatment of patients with dementia-related psychosis (see BOXED WARNING ). Potential for Proarrhythmic Effects DUE TO THE POTENTIAL FOR SIGNIFICANT, POSSIBLY LIFE THREATENING, PROARRHYTHMIC EFFECTS WITH THIORIDAZINE TREATMENT, THIORIDAZINE SHOULD BE RESERVED FOR USE IN THE TREATMENT OF SCHIZOPHRENIC PATIENTS WHO FAIL TO SHOW AN ACCEPTABLE RESPONSE TO ADEQUATE COURSES OF TREATMENT WITH OTHER ANTIPSYCHOTIC DRUGS, EITHER BECAUSE OF INSUFFICIENT EFFECTIVENESS OR THE INABILITY TO ACHIEVE AN EFFECTIVE DOSE DUE TO INTOLERABLE ADVERSE EFFECTS FROM THOSE DRUGS. CONSEQUENTLY, BEFORE INITIATING TREATMENT WITH THIORIDAZINE, IT IS STRONGLY RECOMMENDED THAT A PATIENT BE GIVEN AT LEAST TWO TRIALS, EACH WITH A DIFFERENT ANTIPSYCHOTIC DRUG PRODUCT, AT AN ADEQUATE DOSE, AND FOR AN ADEQUATE DURATION. THIORIDAZINE HAS NOT BEEN SYSTEMATICALLY EVALUATED IN CONTROLLED TRIALS IN THE TREATMENT OF REFRACTORY SCHIZOPHRENIC PATIENTS AND ITS EFFICACY IN SUCH PATIENTS IS UNKNOWN. A crossover study in nine healthy males comparing single doses of thioridazine 10 mg and 50 mg with placebo demonstrated a dose related prolongation of the QTc interval. The mean maximum increase in QTc interval following the 50 mg dose was about 23 msec; greater prolongation may be observed in the clinical treatment of unscreened patients. Prolongation of the QTc interval has been associated with the ability to cause Torsades de pointes type arrhythmias, a potentially fatal polymorphic ventricular tachycardia, and sudden death. There are several published case reports of Torsades de pointes and sudden death associated with thioridazine treatment. A causal relationship between these events and thioridazine therapy has not been established but, given the ability of thioridazine to prolong the QTc interval, such a relationship is possible. Certain circumstances may increase the risk of Torsades de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including 1) bradycardia, 2) hypokalemia, 3) concomitant use of other drugs that prolong the QTc interval, 4) presence of congenital prolongation of the QT interval, and 5) for thioridazine in particular, its use in patients with reduced activity of P450 2D6 or its coadministration with drugs that may inhibit P450 2D6 or by some other mechanism interfere with the clearance of thioridazine (see CONTRAINDICATIONS and PRECAUTIONS ). It is recommended that patients being considered for thioridazine treatment have a baseline ECG performed and serum potassium levels measured. Serum potassium should be normalized before initiating treatment and patients with a QTc interval greater than 450 msec should not receive thioridazine treatment. It may also be useful to periodically...

Drug Interactions

Drug Interactions Reduced cytochrome P450 2D6 isozyme activity, drugs which inhibit this isozyme (e.g., fluoxetine and paroxetine), and certain other drugs (e.g., fluvoxamine, propranolol, and pindolol) appear to appreciably inhibit the metabolism of thioridazine. The resulting elevated levels of thioridazine would be expected to augment the prolongation of the QTc interval associated with thioridazine and may increase the risk of serious, potentially fatal, cardiac arrhythmias, such as Torsades de pointes type arrhythmias. Such an increased risk may result also from the additive effect of coadministering thioridazine with other agents that prolong the QTc interval. Therefore, thioridazine is contraindicated with these drugs as well as in patients, comprising about 7% of the normal population, who are known to have a genetic defect leading to reduced levels of activity of P450 2D6 (see WARNINGS and CONTRAINDICATIONS ). Drugs That Inhibit Cytochrome P450 2D6 In a study of 19 healthy male subjects, which included 6 slow and 13 rapid hydroxylators of debrisoquin, a single 25 mg oral dose of thioridazine produced a 2.4-fold higher C max and a 4.5-fold higher AUC for thioridazine in the slow hydroxylators compared to rapid hydroxylators. The rate of debrisoquin hydroxylation is felt to depend on the level of cytochrome P450 2D6 isozyme activity. Thus, this study suggests that drugs that inhibit P450 2D6 or the presence of reduced activity levels of this isozyme will produce elevated plasma levels of thioridazine. Therefore, the coadministration of drugs that inhibit P450 2D6 with thioridazine and the use of thioridazine in patients known to have reduced activity of P450 2D6 are contraindicated. Drugs That Reduce the Clearance of Thioridazine Through Other Mechanisms Fluvoxamine The effect of fluvoxamine (25 mg b.i.d. for one week) on thioridazine steady-state concentration was evaluated in ten male inpatients with schizophrenia. Concentrations of thioridazine and its two active metabolites, mesoridazine and sulforidazine, increased 3-fold following coadministration of fluvoxamine. Fluvoxamine and thioridazine should not be coadministered. Propranolol Concurrent administration of propranolol (100 mg to 800 mg daily) has been reported to produce increases in plasma levels of thioridazine (approximately 50% to 400%) and its metabolites (approximately 80% to 300%). Propranolol and thioridazine should not be coadministered. Pindolol Concurrent administration of pindolol and thioridazine have resulted in moderate, dose related increases in the serum levels of thioridazine and two of its metabolites, as well as higher than expected serum pindolol levels. Pindolol and thioridazine should not be coadministered. Drugs That Prolong the QTc Interval There are no studies of the coadministration of thioridazine and other drugs that prolong the QTc interval. However, it is expected that such coadministration would produce additive prolongation of the QTc interval...

Contraindications

CONTRAINDICATIONS Thioridazine hydrochloride tablet use should be avoided in combination with other drugs that are known to prolong the QTc interval and in patients with congenital long QT syndrome or a history of cardiac arrhythmias. Reduced cytochrome P450 2D6 isozyme activity drugs that inhibit this isozyme (e.g., fluoxetine and paroxetine) and certain other drugs (e.g., fluvoxamine, propranolol, and pindolol) appear to appreciably inhibit the metabolism of thioridazine. The resulting elevated levels of thioridazine would be expected to augment the prolongation of the QTc interval associated with thioridazine and may increase the risk of serious, potentially fatal, cardiac arrhythmias, such as Torsades de pointes type arrhythmias. Such an increased risk may result also from the additive effect of coadministering thioridazine with other agents that prolong the QTc interval. Therefore, thioridazine is contraindicated with these drugs as well as in patients, comprising about 7% of the normal population, who are known to have a genetic defect leading to reduced levels of activity of P450 2D6 (see WARNINGS and PRECAUTIONS ). In common with other phenothiazines, thioridazine is contraindicated in severe central nervous system depression or comatose states from any cause including drug induced central nervous system depression (see WARNINGS ). It should also be noted that hypertensive or hypotensive heart disease of extreme degree is a contraindication of phenothiazine administration.

Pregnancy and Breastfeeding

Pregnancy Nonteratogenic Effects Neonates exposed to antipsychotic drugs, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization. Thioridazine hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Overdosage

OVERDOSAGE Many of the symptoms observed are extensions of the side effects described under ADVERSE REACTIONS . Thioridazine can be toxic in overdose, with cardiac toxicity being of particular concern. Frequent ECG and vital sign monitoring of overdosed patients is recommended. Observation for several days may be required because of the risk of delayed effects. 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. It has been suggested that the toxic blood concentration range for thioridazine begins at 1 mg/dL, and 2 to 8 mg/dL is the lethal concentration range. Treatment 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...

How Supplied

HOW SUPPLIED: Thioridazine Hydrochloride Tablets, USP are available containing 10 mg, 25 mg, 50 mg or 100 mg of thioridazine hydrochloride, USP. The 10 mg tablets are orange film-coated, round, unscored tablets debossed with M over 54 on one side and 10 on the other side. They are available as follows: NDC 51079-565-20 – Unit dose blister packages of 100 (10 cards of 10 tablets each). The 25 mg tablets are orange film-coated, round, unscored tablets debossed with M over 58 on one side and 25 on the other side. They are available as follows: NDC 51079-566-20 – Unit dose blister packages of 100 (10 cards of 10 tablets each). The 50 mg tablets are orange film-coated, round, unscored tablets debossed with M over 59 on one side and 50 on the other side. They are available as follows: NDC 51079-567-20 – Unit dose blister packages of 100 (10 cards of 10 tablets each). The 100 mg tablets are orange film-coated, round, unscored tablets debossed with M over 61 on one side and 100 on the other side. They are available as follows: NDC 51079-580-20 – Unit dose blister packages of 100 (10 cards of 10 tablets each). Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Protect from light. **Trademark of Medical Economics Company, Inc. Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A. Manufactured by: Mylan Laboratories Limited Hyderabad — 500 096, India Distributed by: Mylan Institutional Inc. Rockford, IL 61103 U.S.A. S-12700 R1 4/25

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.