Pimozide — Concomitant use of olanzapine and fluoxetine capsules and pimozide is contraindicated. Pimozide can prolong the QT interval. Olanzapine and fluoxetine capsules can increase the level of pimozide through inhibition of CYP2D6. Olanzapine and fluoxetine capsules can also prolong the QT interval. Clinical studies of pimozide with other antidepressants demonstrate an increase in drug interaction or QTc prolongation. While a specific study with pimozide and olanzapine and fluoxetine capsules has not been conducted, the potential for drug interactions or QTc prolongation warrants restricting the concurrent use of pimozide and olanzapine and fluoxetine capsules [see Contraindications (4.2), Warnings and Precautions (5.20), and Drug Interactions (7.8)].

Carbamazepine — Patients on stable doses of carbamazepine have developed elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following initiation of concomitant fluoxetine treatment. 

Alcohol — The coadministration of ethanol with olanzapine and fluoxetine capsules may potentiate sedation and orthostatic hypotension [see Drug Interactions (7.6)]. 

Thioridazine — Thioridazine should not be administered with olanzapine and fluoxetine capsules or administered within a minimum of 5 weeks after discontinuation of olanzapine and fluoxetine capsules because of the risk of QT prolongation [see Contraindications (4.2), Warnings and Precautions (5.20), and Drug Interactions (7.8)].

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 with the rapid hydroxylators. The rate of debrisoquin hydroxylation is felt to depend on the level of CYP2D6 isozyme activity. Thus, this study suggests that drugs that inhibit CYP2D6, such as certain SSRIs, including fluoxetine, will produce elevated plasma levels of thioridazine [see Contraindications (4.2)].

Thioridazine administration produces a dose-related prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as torsades de pointes-type arrhythmias and sudden death. This risk is expected to increase with fluoxetine-induced inhibition of thioridazine metabolism [see Contraindications (4.2)].

Due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated thioridazine plasma levels, thioridazine should not be administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued [see Contraindications (4.2)].

Tricyclic Antidepressants (TCAs) — Single doses of olanzapine did not affect the pharmacokinetics of imipramine or its active metabolite desipramine. 

In 2 fluoxetine studies, previously stable plasma levels of imipramine and desipramine have increased >2- to 10-fold when fluoxetine has been administered in combination. This influence may persist for 3 weeks or longer after fluoxetine is discontinued. Thus, the dose of TCA may need to be reduced and plasma TCA concentrations may need to be monitored temporarily when olanzapine and fluoxetine capsules are coadministered or has been recently discontinued [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)].

Antihypertensive Agents — Because of the potential for olanzapine to induce hypotension, olanzapine and fluoxetine capsules may enhance the effects of certain antihypertensive agents [see Warnings and Precautions (5.11)].

Levodopa and Dopamine Agonists — The olanzapine component of olanzapine and fluoxetine capsules may antagonize the effects of levodopa and dopamine agonists. 

Benzodiazepines — Multiple doses of olanzapine did not influence the pharmacokinetics of diazepam and its active metabolite N-desmethyldiazepam. 

When concurrently administered with fluoxetine, the half-life of diazepam may be prolonged in some patients [see Clinical Pharmacology (12.3)]. Coadministration of alprazolam and fluoxetine has resulted in increased alprazolam plasma concentrations and in further psychomotor performance decrement due to increased alprazolam levels. 

Clozapine — Elevation of blood levels of clozapine has been observed in patients receiving concomitant fluoxetine. 

Haloperidol — Elevation of blood levels of haloperidol has been observed in patients receiving concomitant fluoxetine. 

Phenytoin — Patients on stable doses of phenytoin have developed elevated plasma levels of phenytoin with clinical phenytoin toxicity following initiation of concomitant fluoxetine. 

Drugs Metabolized by CYP2D6 — In vitro studies utilizing human liver microsomes suggest that olanzapine has little potential to inhibit CYP2D6. Thus, olanzapine is unlikely to cause clinically important drug interactions mediated by this enzyme. 

Fluoxetine inhibits the activity of CYP2D6 and may make individuals with normal CYP2D6 metabolic activity resemble a poor metabolizer. Coadministration of fluoxetine with other drugs that are metabolized by CYP2D6, including certain antidepressants (e.g., TCAs), antipsychotics (e.g., phenothiazines and most atypicals), and antiarrhythmics (e.g., propafenone, flecainide, and others) should be approached with caution. Therapy with medications that are predominantly metabolized by the CYP2D6 system and that have a relatively narrow therapeutic index should be initiated at the low end of the dose range if a patient is receiving fluoxetine concurrently or has taken it in the previous 5 weeks. If fluoxetine is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need for a decreased dose of the original medication should be considered. Drugs with a narrow therapeutic index represent the greatest concern (including but not limited to, flecainide, propafenone, vinblastine, and TCAs). 

Drugs Metabolized by CYP3A — In vitro studies utilizing human liver microsomes suggest that olanzapine has little potential to inhibit CYP3A. Thus, olanzapine is unlikely to cause clinically important drug interactions mediated by these enzymes.

In an in vivo interaction study involving the coadministration of fluoxetine with single doses of terfenadine (a CYP3A substrate), no increase in plasma terfenadine concentrations occurred with concomitant fluoxetine. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A activity, to be at least 100 times more potent than fluoxetine or norfluoxetine as an inhibitor of the metabolism of several substrates for this enzyme, including astemizole, cisapride, and midazolam. These data indicate that fluoxetine’s extent of inhibition of CYP3A activity is not likely to be of clinical significance. 

Effect of Olanzapine on Drugs Metabolized by Other CYP Enzymes — In vitro studies utilizing human liver microsomes suggest that olanzapine has little potential to inhibit CYP1A2, CYP2C9, and CYP2C19. Thus, olanzapine is unlikely to cause clinically important drug interactions mediated by these enzymes. 

Lithium — Multiple doses of olanzapine did not influence the pharmacokinetics of lithium. 

There have been reports of both increased and decreased lithium levels when lithium was used concomitantly with fluoxetine. Cases of lithium toxicity and increased serotonergic effects have been reported. Lithium levels should be monitored in patients taking olanzapine and fluoxetine capsules concomitantly with lithium [see Warnings and Precautions (5.5)].

Drugs Tightly Bound to Plasma Proteins — The in vitro binding of olanzapine and fluoxetine capsules to human plasma proteins is similar to the individual components. The interaction between olanzapine and fluoxetine capsules and other highly protein-bound drugs has not been fully evaluated. Because fluoxetine is tightly bound to plasma protein, the administration of fluoxetine to a patient taking another drug that is tightly bound to protein (e.g., Coumadin, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect. Conversely, adverse effects may result from displacement of protein-bound fluoxetine by other tightly bound drugs [see Clinical Pharmacology (12.3)].

Valproate — In vitro studies using human liver microsomes determined that olanzapine has little potential to inhibit the major metabolic pathway, glucuronidation, of valproate. Further, valproate has little effect on the metabolism of olanzapine in vitro. Thus, a clinically significant pharmacokinetic interaction between olanzapine and valproate is unlikely. 

Biperiden — Multiple doses of olanzapine did not influence the pharmacokinetics of biperiden. 

Theophylline — Multiple doses of olanzapine did not affect the pharmacokinetics of theophylline or its metabolites.