Thioridazine: profile and news

Lilly Submits Cymbalta Supplemental New Drug Application for ...  May 9, 2006
If you have recently taken a type of antidepressant called a monoamine oxidase inhibitor (MAOI), are taking Mellaril(R) (thioridazine) or have uncontrolled ... - International News Service,

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 Mellaril 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 Mellaril with other agents that prolong the QTc interval. Therefore, Mellaril 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.

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 co-administration of drugs that inhibit P450 2D6 with Mellaril and the use of Mellaril in patients known to have reduced activity of P450 2D6 are contraindicated.

Drugs that Reduce the Clearance of Mellaril® through Other Mechanisms

Fluvoxamine: 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 Mellaril should not be co-administered.

Propranolol: Concurrent administration of propranolol (100-800 mg daily) has been reported to produce increases in plasma levels of thioridazine (approximately 50%-400%) and its metabolites (approximately 80%-300%). Propranolol and Mellaril should not be co-administered.

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 Mellaril should not be co-administered.

Drugs That Prolong the QTc Interval

There are no studies of the co-administration of Mellaril 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.