Thioridazine is 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 should be used only in patients who have failed to respond adequately to treatment with appropriate courses of other antipsychotic drugs.
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 Cmax 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.
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.
Concurrent administration of propranolol (100 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.
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.
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 and, thus, such use is contraindicated.
Patients should be informed that thioridazine has been associated with potentially fatal heart rhythm disturbances. The risk of such events may be increased when certain drugs are given together with thioridazine. Therefore, patients should inform the prescriber that they are receiving thioridazine treatment before taking any new medication.
Given the likelihood that some patients exposed chronically to antipsychotics will develop tardive dyskinesia, it is advised that all patients in whom chronic use is contemplated be given, if possible, full information about this risk. The decision to inform patients and/or their guardians must obviously take into account the clinical circumstances and the competency of the patient to understand the information provided.
Leukopenia, Neutropenia and Agranulocytosis
In clinical trial and post-marketing experience, events of leukopenia/neutropenia and agranulocytosis have been reported temporally related to antipsychotic agents.
Possible risk factors for leukopenia/neutropenia include preexisting low white blood cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a preexisting low WBC or a history of drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue thioridazine hydrochloride tablets, USP at the first sign of a decline in WBC in the absence of other causative factors.
Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms occur. Patients with severe neutropenia (absolute neutrophil count < 1000 mm3) should discontinue thioridazine hydrochloride tablets, USP and have their WBC followed until recovery.
In the recommended dosage ranges with thioridazine hydrochloride most side effects are mild and transient.
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.
Dryness of mouth, blurred vision, constipation, nausea, vomiting, diarrhea, nasal stuffiness, and pallor have been seen.
Galactorrhea, breast engorgement, amenorrhea, inhibition of ejaculation, and peripheral edema have been described.
Dermatitis and skin eruptions of the urticarial type have been observed infrequently. Photosensitivity is extremely rare.
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).
Rare cases described as parotid swelling have been reported following administration of thioridazine.
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.
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 involuntary choreoathetoid movements which variously involve the tongue, face, mouth, lips, or jaw (e.g., protrusion of the tongue, puffing of cheeks, puckering of the mouth, chewing movements), trunk, and extremities. The severity of the syndrome and the degree of impairment produced vary widely.
The syndrome may become clinically recognizable either during treatment, upon dosage reduction, or upon withdrawal of treatment. Movements may decrease in intensity and may disappear altogether if further treatment with antipsychotics is withheld. It is generally believed that reversibility is more likely after short rather than long-term antipsychotic exposure. Consequently, early detection of tardive dyskinesia is important. To increase the likelihood of detecting the syndrome at the earliest possible time, the dosage of antipsychotic drug should be reduced periodically (if clinically possible) and the patient observed for signs of the disorder. This maneuver is critical, for antipsychotic drugs may mask the signs of the syndrome.
Neuroleptic Malignant Syndrome (NMS): Chronic use of antipsychotics may be associated with the development of Neuroleptic Malignant Syndrome. The salient features of this syndrome are described in the WARNINGS section and subsequently. 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).
Endocrine Disturbances: Menstrual irregularities, altered libido, gynecomastia, lactation, weight gain, edema. False positive pregnancy tests have been reported.
Urinary Disturbances: Retention, incontinence.
Others: Hyperpyrexia. Behavioral effects suggestive of a paradoxical reaction have been reported. These include excitement, bizarre dreams, aggravation of psychoses, and toxic confusional states. More recently, a peculiar skin-eye syndrome has been recognized as a side effect following long-term treatment with phenothiazines. This reaction is marked by progressive pigmentation of areas of the skin or conjunctiva and/or accompanied by discoloration of the exposed sclera and cornea. Opacities of the anterior lens and cornea described as irregular or stellate in shape have also been reported. Systemic lupus erythematosus-like syndrome.
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.
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.
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 thioridazine and should be avoided (see WARNINGS and CONTRAINDICATIONS). 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. The potent α adrenergic blocking properties of the phenothiazines makes the use of vasopressors with mixed α and β adrenergic agonist properties inappropriate, including epinephrine and dopamine. Paradoxical vasodilation may result. In addition, it is reasonable to expect that the α adrenergic-blocking properties of bretylium might be additive to those of thioridazine, resulting in problematic hypotension.
In managing overdosage, the physician should always consider the possibility of multiple drug involvement. 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. Emesis should not be induced in patients expected to deteriorate rapidly, or those with impaired consciousness.
Acute extrapyramidal symptoms may be treated with diphenhydramine hydrochloride or benztropine mesylate.
Avoid the use of barbiturates when treating seizures, as they may potentiate phenothiazine-induced respiratory depression.
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.
Up-to-date information about the treatment of overdose can often be obtained from a certified Regional Poison Control Center. Telephone numbers of certified Regional Poison Control Centers are listed in the Physicians’ Desk Reference®1.
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Since thioridazine is 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).
The usual starting dose for adult schizophrenic patients is 50 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 to 800 mg, divided into two to four doses.
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.
Thioridazine HCl tablets, USP are supplied as follows:
|Thioridazine tablets 10 mg, yellow, film-coated tablet debossed MP 12|
|Bottles of 100||NDC 53489-148-01|
|Bottles of 1000||NDC 53489-148-10|
|Thioridazine tablets 25 mg, yellow, film-coated tablet debossed MP 14|
|Bottles of 100||NDC 53489-149-01|
|Bottles of 1000||NDC 53489-149-10|
|Thioridazine tablets 50 mg, yellow, film-coated tablet debossed MP 17|
|Bottles of 100||NDC 53489-150-01|
|Bottles of 1000||NDC 53489-150-10|
|Thioridazine tablets 100 mg, yellow, film-coated tablet debossed MP 160|
|Bottles of 20||NDC 53489-500-60|
|Bottles of 50||NDC 53489-500-02|
|Bottles of 60||NDC 53489-500-06|
|Bottles of 100||NDC 53489-500-01|
|Bottles of 250||NDC 53489-500-03|
|Bottles of 500||NDC 53489-500-05|
|Bottles of 1000||NDC 53489-500-10|
Store at 20° to 25°C (68° to 77°F).
[See USP Controlled Room Temperature]
DISPENSE IN TIGHT, LIGHT-RESISTANT CONTAINER.
MUTUAL PHARMACEUTICAL COMPANY, INC.
Philadelphia, PA 19124 USA
Rev 02, August 2010