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Thioridazine (Thioridazine Hydrochloride) - Warnings and Precautions

 
 



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).

 

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 monitor ECG’s and serum potassium during thioridazine treatment, especially during a period of dose adjustment. Thioridazine should be discontinued in patients who are found to have a QTc interval over 500 msec.

Patients taking thioridazine who experience symptoms that may be associated with the occurrence of Torsades de pointes (e.g., dizziness, palpitations, or syncope) may warrant further cardiac evaluation; in particular, Holter monitoring should be considered.

Tardive Dyskinesia

Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

Both the risk of developing the syndrome and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.

There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying disease process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, antipsychotics should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that, 1) is known to respond to antipsychotic drugs, and, 2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient on antipsychotics, drug discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome.

(For further information about the description of tardive dyskinesia and its clinical detection, please refer to the sections on Information for Patients and ADVERSE REACTIONS.)

It has been suggested in regard to phenothiazines in general, that people who have demonstrated a hypersensitivity reaction (e.g., blood dyscrasias, jaundice) to one may be more prone to demonstrate a reaction to others. Attention should be paid to the fact that phenothiazines are capable of potentiating central nervous system depressants (e.g., anesthetics, opiates, alcohol, etc.) as well as atropine and phosphorus insecticides. Physicians should carefully consider benefit versus risk when treating less severe disorders.

Reproductive studies in animals and clinical experience to date have failed to show a teratogenic effect with thioridazine. However, in view of the desirability of keeping the administration of all drugs to a minimum during pregnancy, thioridazine should be given only when the benefits derived from treatment exceed the possible risks to mother and fetus.

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.

Neuroleptic Malignant Syndrome (NMS)

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. 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).

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system (CNS) pathology.

The management of NMS should include, 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.

Central Nervous System Depressants

As in the case of other phenothiazines, thioridazine is capable of potentiating central nervous system depressants (e.g., alcohol, anesthetics, barbiturates, narcotics, opiates, other psychoactive drugs, etc.) as well as atropine and phosphorus insecticides. Severe respiratory depression and respiratory arrest have been reported when a patient was given a phenothiazine and a concomitant high dose of a barbiturate.

PRECAUTIONS

Leukopenia and/or agranulocytosis and convulsive seizures have been reported but are infrequent. In schizophrenic patients with epilepsy, anticonvulsant medication should be maintained during treatment with thioridazine. Pigmentary retinopathy, which has been observed primarily in patients taking larger than recommended doses, is characterized by diminution of visual acuity, brownish coloring of vision, and impairment of night vision; examination of the fundus discloses deposits of pigment. The possibility of this complication may be reduced by remaining within the recommended limits of dosage.

Where patients are participating in activities requiring complete mental alertness (e.g., driving) it is advisable to administer the phenothiazines cautiously and to increase the dosage gradually. Female patients appear to have a greater tendency to orthostatic hypotension than male patients. The administration of epinephrine should be avoided in the treatment of drug-induced hypotension in view of the fact that phenothiazines may induce a reversed epinephrine effect on occasion. Should a vasoconstrictor be required, the most suitable are levarterenol and phenylephrine.

Antipsychotic drugs elevate prolactin levels; the elevation persists during chronic administration. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with a previously detected breast cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported, the clinical significance of elevated serum prolactin levels is unknown for most patients. An increase in mammary neoplasms has been found in rodents after chronic administration of neuroleptic drugs. Neither clinical studies nor epidemiologic studies conducted to date, however, have shown an association between chronic administration of these drugs and mammary tumorigenesis; the available evidence is considered too limited to be conclusive at this time.

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 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.

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 and, thus, such use is contraindicated.

Information for Patients

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.

Pediatric Use

See DOSAGE AND ADMINISTRATION: Pediatric Patients.

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.

Page last updated: 2011-02-04

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