Drug Interactions between aluminum hydroxide / diphenhydramine / lidocaine / magnesium hydroxide / simethicone topical and thioridazine

CONTRAINDICATED: Coadministration with inhibitors of CYP450 2D6 may increase the plasma concentrations and adverse effects of thioridazine and its two active metabolites, mesoridazine and sulforidazine, all of which are substrates of the isoenzyme. A study in 19 healthy male patients reviewed thioridazine metabolism in 6 slow and 13 rapid hydroxylators of debrisoquin (the rate of which is believed to be dependent upon the level of CYP450 2D6 activity). A single oral dose of thioridazine (25 mg) produced a 2.4-fold higher peak plasma concentration (Cmax) and a 4.5-fold higher systemic exposure (AUC) for thioridazine in the slow hydroxylators, which is predicted to be similar to what would be seen in patients on CYP450 2D6 inhibitors. Additionally, significant increases (up to severalfold) have been observed during coadministration with fluvoxamine, propranolol, and pindolol in pharmacokinetic studies, although these reductions in clearance may be via other currently unknown mechanisms. The use of thioridazine has been associated with dose-related prolongation of the QT interval, thus elevated plasma levels of the drug may potentiate the risk of ventricular arrhythmias such as ventricular tachycardia and torsade de pointes as well as cardiac arrest and sudden death. Several cases of torsade de pointes have been reported.

MANAGEMENT: The use of thioridazine with fluvoxamine, propranolol, pindolol and/or drugs that inhibit CYP450 2D6 is considered contraindicated. Depending on the elimination half-life of these drugs, a considerable waiting period may be appropriate following their discontinuation before thioridazine is initiated. For example, the manufacturer of fluoxetine recommends that thioridazine not be administered within 5 weeks after discontinuing fluoxetine because of the drug's long half-life. In addition, the prolonged duration of CYP450 2D6 inhibition by the moderate CYP450 2D6 inhibitor rolapitant of at least 28 days after its administration should also be taken into account.

MONITOR: Overuse of certain laxatives including magnesium hydroxide may cause electrolyte loss and increase the risk of torsade de pointes ventricular arrhythmia in patients treated with drugs that prolong the QT interval. Electrolyte disturbances including hypokalemia and hypomagnesemia have been reported with laxative abuse and are known risk factors for torsade de pointes associated with QT interval prolongation.

ADJUST DOSING INTERVAL: Coadministration with aluminum- or magnesium-containing antacids may decrease the serum concentrations of orally administered phenothiazines. The proposed mechanism is antacid adsorption resulting in reduced phenothiazine bioavailability. The interaction has been reported for chlorpromazine but may occur with other phenothiazines. In a study of ten patients treated with chlorpromazine, 30 mL of an antacid containing aluminum and magnesium hydroxide reduced the urinary excretion of chlorpromazine by 10% to 45%. In another study with six psychiatric patients, coadministration of chlorpromazine oral suspension with 30 mL of an antacid containing aluminum hydroxide and magnesium trisilicate resulted in a 20% reduction in serum chlorpromazine level two hours later. The clinical significance is unknown. Psychiatric relapse occurred in a chlorpromazine-treated patient following the addition of antacid therapy according to a single case report. Separating the times of administration by 2 to 3 hours may help if an interaction is suspected.

MANAGEMENT: Patients treated with drugs that prolong the QT interval should exercise caution when self-medicating with laxatives including magnesium hydroxide. The recommended dosage and duration of use should not be exceeded. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope.

Coadministration with aluminum- or magnesium-containing antacids may decrease the serum concentrations of orally administered phenothiazines. The proposed mechanism is antacid adsorption resulting in reduced phenothiazine bioavailability. The interaction has been reported for chlorpromazine but may occur with other phenothiazines. In a study of ten patients treated with chlorpromazine, 30 mL of an antacid containing aluminum and magnesium hydroxide reduced the urinary excretion of chlorpromazine by 10% to 45%. In another study with six psychiatric patients, coadministration of chlorpromazine oral suspension with 30 mL of an antacid containing aluminum hydroxide and magnesium trisilicate resulted in a 20% reduction in serum chlorpromazine level two hours later. The clinical significance is unknown. Psychiatric relapse occurred in a chlorpromazine-treated patient following the addition of antacid therapy according to a single case report. Separating the times of administration by 2 to 3 hours may help if an interaction is suspected.