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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.
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 torsade de pointes-type arrhythmias, a potentially fatal polymorphic ventricular tachycardia, and sudden death (see WARNINGS). Both torsade 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:
Cutaneous Reactions: Erythema, exfoliative dermatitis, contact dermatitis.
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.
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).
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.
Read the Thioridazine (thioridazine) Side Effects Center for a complete guide to possible side effects
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 torsade de pointes-type arrhythmias. Such an increased risk may result also from the additive effect of co-administering 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 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 co-administration 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
The effect of fluvoxamine (25 mg b.i.d. for one week) on thioridazine steady state concentration was evaluated in 10 male in-patients with schizophrenia. Concentrations of thioridazine and its two active metabolites, mesoridazine and sulforidazine, increased three-fold following co-administration of fluvoxamine. Fluvoxamine and thioridazine should not be co-administered.
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 co-administered.
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 co-administered.
Drugs That Prolong the QTc Interval
There are no studies of the co-administration of thioridazine and other drugs that prolong the QTc interval. However, it is expected that such co-administration would produce additive prolongation of the QTc interval and, thus, such use is contraindicated.
See DOSAGE AND ADMINISTRATION: Pediatric Patients.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 5/5/2009
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