Published: June 2001

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Thioridazine and Arrhythmia: Prescribing Changes

Information on this subject has been updated. Read the most recent information.

Prescriber Update 21: 4-7
June 2001

Medsafe Editorial Team

Thioridazine (Melleril™, Aldazine™) increases the risk of arrhythmia from QT-prolongation. Consequently, the Medicines Adverse Reactions Committee has recommended the following changes to how thioridazine is prescribed in New Zealand.

Thioridazine is now contraindicated in the following circumstances, all of which are risk factors for arrhythmia:

• use with medicines which inhibit the metabolism of thioridazine (cimetidine, most antidepressants, pindolol, propranolol)
• use with medicines which prolong the QT-interval (some antiarrhythmics, most antipsychotics, cisapride)
• use in patients with predisposing factors for arrhythmia or pre-existing QT-prolongation (QTc ≥ 500ms).

Thioridazine should be initiated only by a specialist and only as third line therapy. In addition, the following precautions should be observed for new patients:

• assess for risk factors for arrhythmia
• check the QTc-interval and serum potassium
• use the minimum effective dose
• observe a maximum of 200mg daily ordinarily
• use dosages above 200mg daily up to a maximum of 600mg daily only under specialist supervision and only with QTc-interval monitoring following each increase.

For all patients currently taking thioridazine:

• assess for risk factors for arrhythmia
• check the QTc-interval and serum potassium
• doses above 200mg daily require review by a specialist
• reduce the dose if QTc-interval ≥ 500ms
• withdraw thioridazine if QTc-interval is persistently ≥ 500ms, or in the presence of any contraindication.

Any children taking thioridazine should also have their therapy reviewed by a specialist.

If thioridazine discontinuation is necessary, gradually reduce the dose over a period of one month and concurrently introduce alternative medication. Specialist supervision may be advisable for the withdrawal process.

MARC review resulted in changes to reduce risk of arrhythmia

The Medicines Adverse Reactions Committee (MARC) has reviewed data on the risk of QT-prolongation with thioridazine, a Medsafe-commissioned expert report and regulatory action taken by authorities overseas. The Committee noted that anecdotal evidence and CARM data suggested thioridazine was well tolerated by the overwhelming majority of patients using it in New Zealand. The Committee observed that the data on QT-prolongation were sparse, but considered it prudent to take steps to reduce the risk of arrhythmia from QT-prolongation in patients prescribed thioridazine.

Avoid thioridazine with interacting medicines or predisposing conditions

Thioridazine is now contraindicated in the following circumstances, all of which are risk factors for arrhythmia:

• A history of QT-prolongation, ventricular arrhythmia, torsade de pointes, and risk factors for arrhythmia, such as second or third degree atrioventricular block, clinically significant heart disease and congenital long QT-syndrome.
• Baseline QTc-interval ≥ 500ms.
• Abnormal serum potassium.
• Concomitant use of medicines which inhibit CYP 2D6 (e.g. cimetidine, fluoxetine, paroxetine, moclobemide, tricyclic antidepressants) or inhibit thioridazine metabolism by another mechanism (e.g. fluvoxamine, pindolol, propranolol).
• Concomitant use of medicines which may prolong the QT-interval including quinine, cisapride, some antiarrhythmic medicines (e.g. amiodarone, quinidine, flecainide, sotalol), tricyclic antidepressants and some other antipsychotic agents (e.g. droperidol, haloperidol, risperidone).

New patients to be initiated by a specialist

Thioridazine therapy should be initiated only by a specialist and only after the patient has failed to respond adequately to treatment with appropriate courses of at least two other suitable medicines. The patient should first be assessed for risk factors for arrhythmia (see above), and undergo an ECG to determine the QTc-interval and a check of serum potassium. Abnormal potassium levels should be corrected. If the patient is on interacting medicines, therapy must be adjusted to avoid these medicines or an alternative to thioridazine prescribed instead. Do not use thioridazine in patients with predisposing factors for arrhythmia or pre-existing QT-prolongation (QTc ≥ 500ms).

It is recommended that the initial dose of thioridazine be at the lower end of the range and be gradually increased until the desired effect is achieved or a maximum of 200mg daily is reached. Dosages above 200mg daily should be prescribed by a specialist and only in exceptional circumstances. The maximum dose of 600mg daily should be observed. Two weeks after every increase in dose, the QTc-interval should be measured with an ECG taken 12 hours after or immediately prior to a dose. The dosage should be reduced if the QTc-interval is ³ 500ms and the patient re-assessed for risk factors.

Patients on a maintenance dose of greater than 200mg daily need to be monitored. This involves repeating an ECG if the patient develops a disease state, or commences medication, that may increase the risk of QT-prolongation either directly or indirectly (e.g. by causing hypokalaemia). In all cases, if the QTc-interval is persistently ≥ 500ms, or if the patient now has a contraindication, thioridazine should be discontinued gradually (see below).

Review all patients currently taking thioridazine

Patients who are taking thioridazine at daily doses of more than 200mg should be evaluated by a specialist for their need to continue at high doses. These patients and all others already taking thioridazine should be reviewed for risk factors for arrhythmia (outlined above), undergo an ECG to determine the QTc-interval and a check of serum potassium. Conduct the ECG 12 hours after or immediately before a dose. Abnormal potassium levels should be corrected. If the patient is on interacting medicines, adjust therapy to avoid these medicines, or switch to an alternative to thioridazine.

Patients with QTc-interval ≥ 500ms should have their dose reduced and continuing use of thioridazine evaluated. If the QTc-interval is persistently ≥ 500ms thioridazine should be discontinued gradually (see below).

Patients who are at high risk of arrhythmias through either intrinsic (e.g. disease states) or extrinsic (e.g. concomitant medication) factors should be switched to an alternative to thioridazine. Discontinuation of thioridazine should be done by gradually reducing the dose over a period of one month and concurrently introducing the new medication. Depending on the severity of the patient's condition, it may be advisable to have the change in medication supervised by a psychiatrist.

Abrupt withdrawal of thioridazine may be associated with symptoms such as nausea, vomiting, gastric upset, trembling, dizziness, anxiety, agitation and insomnia, as well as transient dyskinesia or the re-emergence of psychotic symptoms. Patients on high doses or who have received long term therapy are particularly at risk for these symptoms.

Specialist involvement required for all paediatric patients

The same checks for contraindications, QT-prolongation and abnormal serum potassium should be conducted for new and existing paediatric patients, as for adults. The initiation of thioridazine for children should be by a specialist and only as third line therapy. Children who are currently taking thioridazine should have their therapy reviewed by a specialist (paediatrician or child psychiatrist). The maximum dose of 4 mg/kg/day should be observed (upper limit 200mg). Doses above 200mg daily should be used only in exceptional circumstances, under specialist supervision, and the patient monitored as outlined above.

Consult the data sheets for all details of the changes

The above changes have been incorporated into the data sheets for thioridazine (Melleril™, Aldazine™). It is recommended that prescribers of thioridazine read the data sheets for these products to familiarise themselves with all the details of the changes.