Drug Interactions between fluoxetine / olanzapine and mexiletine

MONITOR: Coadministration with certain selective serotonin reuptake inhibitors (SSRIs) may increase the plasma concentrations of antiarrhythmic agents that are metabolized by CYP450 2D6 such as encainide, flecainide, mexiletine, and propafenone. The mechanism is decreased drug clearance due to inhibition of the isoenzyme by some SSRIs. The interaction has been studied specifically with fluoxetine and propafenone. In nine healthy 2D6-extensive metabolizers, fluoxetine pretreatment (20 mg once a day for 10 days) significantly increased the elimination half-life, peak plasma concentration (Cmax), and area under the concentration-time curve (AUC) of both the S- and R-enantiomers of propafenone (400 mg single dose). Oral clearance decreased by about 34% for both enantiomers. In vitro inhibition data suggest that fluoxetine and paroxetine have the most significant effects on 2D6 metabolism of propafenone, while fluvoxamine and sertraline have only modest effects.

MANAGEMENT: Caution is advised if certain SSRIs, particularly fluoxetine or paroxetine, must be used concomitantly with antiarrhythmic agents that are metabolized by CYP450 2D6. Lower initial dosages of the antiarrhythmic agent may be appropriate. Patients who are already stabilized on their antiarrhythmic regimen should be monitored for altered effects on myocardial conduction following addition or discontinuation of SSRI therapy (up to 2 weeks for most SSRIs and 5 weeks for fluoxetine due to its long half-life), and the antiarrhythmic dosage adjusted if necessary. Alternatively, an antidepressant that does not interfere with 2D6 metabolism may be considered, such as citalopram, escitalopram, or venlafaxine.

MONITOR: It is uncertain whether olanzapine causes clinically significant prolongation of the QT interval. In pooled studies of adults as well as pooled studies of adolescents, there were no significant differences between olanzapine and placebo in the proportion of patients experiencing potentially important changes in ECG parameters, including QT, QTcF (Fridericia-corrected), and PR intervals. In clinical trials, clinically meaningful QTc prolongations (QTcF >=500 msec at any time post-baseline in patients with baseline QTcF <500 msec) occurred in 0.1% to 1% of patients treated with olanzapine, with no significant differences in associated cardiac events compared to placebo. Published studies have generally reported no significant effect of olanzapine on QTc interval, although both QTc prolongation and QTc shortening have also been reported. There have been a few isolated case reports of QT prolongation in patients receiving olanzapine. However, causality is difficult to establish due to confounding factors such as concomitant use of drugs that cause QT prolongation and underlying conditions that may predispose to QT prolongation (e.g., hypokalemia, congenital long QT syndrome, preexisting conduction abnormalities).

MANAGEMENT: Some authorities recommend caution when olanzapine is used with drugs that are known to cause QT prolongation. ECG monitoring may be advisable in some cases, such as in patients with a history of cardiac arrhythmias or congenital or family history of long QT syndrome. 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.

MONITOR: Coadministration with inhibitors of CYP450 1A2 may increase the plasma concentrations of olanzapine. Data from available studies indicate that olanzapine is primarily metabolized by CYP450 1A2 and, to a lesser extent, by CYP450 2D6. When coadministered with fluvoxamine, a potent CYP450 1A2 inhibitor that also inhibits CYP450 2D6, olanzapine peak plasma concentration (Cmax) increased by an average of 54% in female nonsmokers and 77% in male smokers, while systemic exposure (AUC) increased by an average of 52% and 108%, respectively. The greater degree of interaction in smokers is likely due to induction of CYP450 1A2 by polycyclic aromatic hydrocarbons in cigarette smoke, resulting in increased expression of the isoenzyme. Similar results have been reported in several other pharmacokinetic studies. In 12 healthy male volunteers, administration of a single 10 mg dose of olanzapine during treatment with fluvoxamine 100 mg/day increased mean olanzapine Cmax, AUC and elimination half-life (T1/2) by 49%, 76% and 40%, respectively, compared to administration of olanzapine alone. In 10 male smokers with schizophrenia, olanzapine Cmax, AUC, and T1/2 increased by 12% to 64%, 30% to 55%, and 25% to 32%, respectively, when a single 10 mg dose of olanzapine was administered on day 10 of treatment with fluvoxamine 50 mg/day and 100 mg/day, each for 2 weeks. In 8 patients with schizophrenia who had been treated with olanzapine 10 to 20 mg/day for at least 3 months, the addition of fluvoxamine 100 mg/day for 8 weeks increased olanzapine plasma concentrations by 12% to 112%, with a mean of 81%, from baseline. In an analysis of data from a therapeutic drug monitoring service, patients treated concomitantly with fluvoxamine had olanzapine plasma concentration to daily dose (C/D) ratios that were on average 2.3-fold higher than those of patients receiving olanzapine alone. The difference was as high as 4.2-fold in some patients. In contrast, coadministration with sertraline was not associated with increased C/D ratios compared to olanzapine alone, and a pharmacokinetic study involving 15 healthy volunteers also demonstrated no significant interaction with fluoxetine. Another similar study conducted in a group of 250 patients receiving olanzapine daily doses ranging from 2.5 to 30 mg found that coadministration with fluvoxamine increased median C/D ratios by 74%. In an investigation to test the hypothesis that coadministration of a low subclinical dose of fluvoxamine (25 mg/day) can help reduce olanzapine therapeutic dose requirements, a 26% reduction in the mean olanzapine dosage taken by 10 male smokers with stable psychotic illness resulted in no significant changes in olanzapine plasma concentration, antipsychotic response, or metabolic indices (e.g., serum glucose, lipids) during treatment with fluvoxamine for up to 6 weeks. Clinical toxicity has been cited in a case report of a patient treated with fluvoxamine 150 mg/day and olanzapine 15 mg/day for several months. The patient had mydriasis, hand tremors, and muscle rigidity in association with toxic olanzapine plasma levels. Subsequent reduction of the olanzapine dosage to 5 mg/day resolved the toxicity but did not produce adequate therapeutic response, and the patient was switched to paroxetine with no further problems. The interaction has also been reported with ciprofloxacin, another CYP450 1A2 inhibitor. Doubling of olanzapine concentrations, akathisia, and QT prolongation have been described in various case reports.

MANAGEMENT: Pharmacologic response and olanzapine plasma levels should be monitored more closely whenever CYP450 1A2 inhibitors are added to or withdrawn from therapy in patients stabilized on their antipsychotic regimen, and the dosage adjusted as necessary.