Olanzapine and fluoxetine

The risks of using olanzapine and fluoxetine capsules in combination with other drugs have not been extensively evaluated in systematic studies. The drug-drug interactions sections of fluoxetine and olanzapine are applicable to olanzapine and fluoxetine capsules. As with all drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic drug inhibition or enhancement, etc.) is a possibility. In evaluating individual cases, consideration should be given to using lower initial doses of the concomitantly administered drugs, using conservative titration schedules, and monitoring of clinical status [see Clinical Pharmacology ( 12.3 )] .

Monoamine Oxidase Inhibitor (MAOI) : ( 2.4 , 2.5 , 4.1 , 5.6 , 7.1 ) Drugs Metabolized by CYP2D6 : Fluoxetine is a potent inhibitor of CYP2D6 enzyme pathway ( 7.7 ) Tricyclic Antidepressants (TCAs) : Monitor TCA levels during coadministration with olanzapine and fluoxetine capsules or when olanzapine and fluoxetine capsules have been recently discontinued ( 5.6 , 7.7 ) CNS Acting Drugs : Caution is advised if the concomitant administration of olanzapine and fluoxetine capsules and other CNS-active drugs is required ( 7.2 ) Antihypertensive Agent : Enhanced antihypertensive effect ( 7.7 ) Levodopa and Dopamine Agonists : May antagonize levodopa/dopamine agonists ( 7.7 ) Benzodiazepines : May potentiate orthostatic hypotension and sedation ( 7.6 , 7.7 ) Clozapine : May elevate clozapine levels ( 7.7 ) Haloperidol : Elevated haloperidol levels have been observed ( 7.7 ) Carbamazepine : Potential for elevated carbamazepine levels and clinical anticonvulsant toxicity ( 7.7 ) Phenytoin : Potential for elevated phenytoin levels and clinical anticonvulsant toxicity ( 7.7 ) Alcohol : May potentiate sedation and orthostatic hypotension ( 7.7 ) Serotonergic Drugs : ( 2.4 , 2.5 , 4.1 , 5.6 , 7.3 ) Fluvoxamine : May increase olanzapine levels; a lower dose of the olanzapine component of olanzapine and fluoxetine capsules should be considered ( 7.6 ) Drugs that Interfere with Hemostasis : (e.g., NSAIDs, Aspirin, Warfarin, etc.): May potentiate the risk of bleeding ( 7.4 ) Drugs Tightly Bound to Plasma Proteins : Fluoxetine may cause shift in plasma concentrations ( 7.7 ) Drugs that Prolong the QT Interval : Do not use olanzapine and fluoxetine capsules in combination with thioridazine or pimozide. Use olanzapine and fluoxetine capsules with caution in combination with other drugs that prolong the QT interval ( 4.2 , 5.20 , 7.7 , 7.8 )

7.1 Monoamine Oxidase Inhibitors (MAOIs) [See Dosage and Administration ( 2.4 , 2.5 ), Contraindications ( 4.1 ), and Warnings and Precautions ( 5.6 )] .

7.2 CNS Acting Drugs Caution is advised if the concomitant administration of olanzapine and fluoxetine capsules and other CNS-active drugs is required. In evaluating individual cases, consideration should be given to using lower initial doses of the concomitantly administered drugs, using conservative titration schedules, and monitoring of clinical status [see Clinical Pharmacology ( 12.3 )] .

7.3 Other Serotonergic Drugs The concomitant use of serotonergic drugs (including other SSRIs, SNRIs, triptans, tricyclic antidepressants, opioids, lithium, buspirone, amphetamines, tryptophan, and St. John's Wort) with olanzapine and fluoxetine capsules increases the risk of serotonin syndrome. Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of olanzapine and fluoxetine capsules and/or concomitant serotonergic drugs [see Warnings and Precautions ( 5.6 )] .

7.4 Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, Warfarin) Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SNRIs or SSRIs are coadministered with warfarin [see Warnings and Precautions ( 5.16 )] .

Warfarin (20 mg single dose) did not affect olanzapine pharmacokinetics. Single doses of olanzapine did not affect the pharmacokinetics of warfarin. Patients receiving warfarin therapy should be carefully monitored when olanzapine and fluoxetine capsules are initiated or discontinued.

7.5 Electroconvulsive Therapy (ECT) There are no clinical studies establishing the benefit of the combined use of ECT and fluoxetine. There have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment [see Warnings and Precautions ( 5.15 )] .

7.6 Potential for Other Drugs to Affect Olanzapine and Fluoxetine Capsules Benzodiazepines — Co-administration of diazepam with olanzapine potentiated the orthostatic hypotension observed with olanzapine [see Drug Interactions ( 7.7 )] . Inducers of 1A2 — Carbamazepine therapy (200 mg BID) causes an approximate 50% increase in the clearance of olanzapine. This increase is likely due to the fact that carbamazepine is a potent inducer of CYP1A2 activity. Higher daily doses of carbamazepine may cause an even greater increase in olanzapine clearance [see Drug Interactions ( 7.7 )] .

Alcohol — Ethanol (45 mg/70 kg single dose) did not have an effect on olanzapine pharmacokinetics [see Drug Interactions ( 7.7 )] . Inhibitors of CYP1A2 — Fluvoxamine decreases the clearance of olanzapine. This results in a mean increase in olanzapine C max following fluvoxamine administration of 54% in female nonsmokers and 77% in male smokers. The mean increase in olanzapine AUC is 52% and 108%, respectively. Lower doses of the olanzapine component of olanzapine and fluoxetine capsules should be considered in patients receiving concomitant treatment with fluvoxamine.

The Effect of Other Drugs on Olanzapine — Fluoxetine, an inhibitor of CYP2D6, decreases olanzapine clearance a small amount [see Clinical Pharmacology ( 12.3 )]. Agents that induce CYP1A2 or glucuronyl transferase enzymes, such as omeprazole and rifampin, may cause an increase in olanzapine clearance. The effect of CYP1A2 inhibitors, such as fluvoxamine and some fluoroquinolone antibiotics, on olanzapine and fluoxetine capsules has not been evaluated. Although olanzapine is metabolized by multiple enzyme systems, induction or inhibition of a single enzyme may appreciably alter olanzapine clearance.

Therefore, a dosage increase (for induction) or a dosage decrease (for inhibition) may need to be considered with specific drugs.

7.7 Potential for Olanzapine and Fluoxetine Capsules to Affect Other Drugs 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 QT c prolongation.

While a specific study with pimozide and olanzapine and fluoxetine capsules has not been conducted, the potential for drug interactions or QT c 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 C max 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…

8.1 Pregnancy Risk Summary Based on data from published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Warnings and Precautions ( 5.16 ) and Clinical Considerations] . Neonates exposed to antipsychotic drugs, including the olanzapine component of olanzapine and fluoxetine capsules, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations) .

Overall available data from published epidemiologic studies and postmarketing reports of pregnant women exposed to olanzapine or fluoxetine have not established a drug-associated increased risk of major birth defects or miscarriage (see Data) . Some studies in pregnant women exposed to fluoxetine have reported an increased incidence of cardiovascular malformations; however, these studies results do not establish a causal relationship (see Data) .

There are risks associated with untreated depression in pregnancy and risks of persistent pulmonary hypertension (PPHN) (see Data) and poor neonatal adaptation with exposure to selective serotonin reuptake inhibitors (SSRIs), including fluoxetine, during pregnancy (see Clinical Considerations). Neonates exposed to antipsychotic drugs, including the olanzapine component of olanzapine and fluoxetine capsules, during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations).

In animal studies, administration of the combination of olanzapine and fluoxetine during the period of organogenesis resulted in adverse effects on development (decreased fetal body weights in rats and rabbits and retarded skeletal ossification in rabbits) at maternally toxic doses greater than those used clinically. When administered to rats throughout pregnancy and lactation, an increase in early postnatal mortality was observed at doses similar to those used clinically (see Data). The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defects, miscarriage, or another adverse outcomes.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Women who discontinue antidepressants during pregnancy are more likely to experience a relapse…

8.3 Females and Males of Reproductive Potential Infertility Females Based on the pharmacologic action of olanzapine (dopamine D 2 receptor blockade), treatment with olanzapine and fluoxetine capsules may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential [see Warnings and Precautions ( 5.22) ].