olanzapine and fluoxetine hydrochloride

Adult Starting Dose: 6 mg olanzapine with 25 mg fluoxetine (6 mg/25 mg, once daily in the evening ( 2.1 , 2.2 ) Adult Maximum Dose: 12 mg/50 mg once daily ( 2.1 , 2.2 ) Pediatric Bipolar Depression Starting Dose: 3 mg/25 mg once daily (for ages 10 to 17 years) ( 2.1 ) Pediatric Bipolar Depression Maximum Dose: 12 mg/50 mg ( 2.1 ) Starting dose in patients predisposed to hypotensive reactions, hepatic impairment, or with potential for slowed metabolism: 3 mg/25 mg to 6 mg/25 mg. Escalate dose cautiously ( 2.3 ) 2.1 Depressive Episodes Associated with Bipolar I Disorder Adults – Administer olanzapine and fluoxetine capsules once daily in the evening, generally beginning with the 6 mg/25 mg (mg olanzapine/mg equivalent fluoxetine) capsule. While food has no appreciable effect on the absorption of olanzapine and fluoxetine given individually, the effect of food on the absorption of olanzapine and fluoxetine capsules have not been studied. Make dosage adjustments, if indicated, according to efficacy and tolerability. Antidepressant efficacy was demonstrated with olanzapine and fluoxetine capsules in a dose range of olanzapine 6 mg to 12 mg and fluoxetine 25 mg to 50 mg [see Clinical Studies (14.1)] . The safety of doses above 18 mg of olanzapine and 75 mg of fluoxetine has not been evaluated in adult clinical studies. Periodically reexamine the need for continued pharmacotherapy.…

The following adverse reactions are discussed in more detail in other sections of the labeling: Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults [see Boxed Warning and Warnings and Precautions (5.1)] Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Warnings and Precautions (5.2)] Neuroleptic Malignant syndrome (NMS) [see Warnings and Precautions (5.3)] Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.4)] Hyperglycemia [see Warnings and Precautions (5.5)] Dyslipidemia [see Warnings and Precautions (5.5)] Weight Gain [see Warnings and Precautions (5.5)] Serotonin Syndrome [see Warnings and Precautions (5.6)] Angle-Closure Glaucoma [see Warnings and Precautions (5.7)] Allergic Reactions and Rash [see Warnings and Precautions (5.8)] Activation of Mania/Hypomania [see Warnings and Precautions (5.9)] Tardive Dyskinesia [see Warnings and Precautions (5.10)] Orthostatic Hypotension [see Warnings and Precautions (5.11)] Falls [see Warnings and Precautions (5.12)] Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions (5.13)] Dysphagia [see Warnings and Precautions (5.14)] Seizures [see Warnings and Precautions (5.15)] Increased Risk of Bleeding [see Warnings and Precautions (5.16)] Hyponatremia [see Warnings and Precautions (5.17)] Potential for Cognitive and Motor…

Monoamine Oxidase Inhibitors (MAOI) : Because of the risk of serotonin syndrome, do not use MAOIs intended to treat psychiatric disorders with olanzapine and fluoxetine capsules or within 5 weeks of stopping treatment with olanzapine and fluoxetine capsules. Do not use olanzapine and fluoxetine capsules within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start olanzapine and fluoxetine capsules in a patient who is being treated with linezolid or intravenous methylene blue. (4.1) P imozide : Do not use. Risk of QT interval prolongation (4.2, 5.20, 7.7, 7.8) Thioridazine : Do not use. Risk of QT interval prolongation. Do not use thioridazine within 5 weeks of discontinuing olanzapine and fluoxetine capsules (4.2, 5.20, 7.7, 7.8) 4.1 Monoamine Oxidase Inhibitors (MAOIs) The use of MAOIs intended to treat psychiatric disorders with olanzapine and fluoxetine capsules or within 5 weeks of stopping treatment with olanzapine and fluoxetine capsules is contraindicated because of an increased risk of serotonin syndrome. The use of olanzapine and fluoxetine capsules within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated [see Dosage and Administration (2.4) and Warnings and Precautions (5.6)]. Starting olanzapine and fluoxetine capsules in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome [see Dosage and Administration (2.5) and Warnings and Precautions (5.6)] . 4.2 Other Contraindications Pimozide [see Warnings and Precautions (5.20) and Drug Interactions (7.7, 7.8)] Thioridazine [see Warnings and Precautions (5.20) and Drug Interactions (7.7, 7.8)] Pimozide and thioridazine prolong the QT interval. Olanzapine and fluoxetine capsules can increase the levels of pimozide and thioridazine through inhibition of CYP2D6. Olanzapine and fluoxetine capsules can also prolong the QT interval.

Olanzapine and fluoxetine capsules — During premarketing clinical studies of olanzapine and fluoxetine in combination, overdose of both fluoxetine and olanzapine were reported in 5 study subjects. Four of the 5 subjects experienced loss of consciousness (3) or coma (1). No fatalities occurred. Adverse reactions involving overdose of fluoxetine and olanzapine in combination, and olanzapine and fluoxetine capsules, have been reported. An overdose of combination therapy is defined as confirmed or suspected ingestion of a dose of >20 mg olanzapine in combination with a dose of >80 mg fluoxetine. Adverse reactions associated with these reports included somnolence (sedation), impaired consciousness (coma), impaired neurologic function (ataxia, confusion, convulsions, dysarthria), arrhythmias, lethargy, essential tremor, agitation, acute psychosis, hypotension, hypertension, and aggression. Fatalities have been confounded by exposure to additional substances including alcohol, thioridazine, oxycodone, and propoxyphene. Olanzapine — In postmarketing reports of overdose with olanzapine alone, symptoms have been reported in the majority of cases. In symptomatic patients, symptoms with ≥10% incidence included agitation/aggressiveness, dysarthria, tachycardia, various extrapyramidal symptoms, and reduced level of consciousness ranging from sedation to coma. Among less commonly reported…

U.S. Poison Control: call or text 1-800-222-1222 (free, 24/7). In an emergency call 911. From the FDA label; not medical advice.

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) CN S Acting Drugs : Caution is advised if the concomitant administration of olanzapine and fluoxetine capsules and other CNS-active drugs is required (7.2) A n t ihypertensive Agent : Enhanced antihypertensive effect (7.7) Le v odopa and Dopa m ine Agonists : May antagonize levodopa/dopamine agonists (7.7) B e n z od iazepines : May potentiate orthostatic hypotension and sedation (7.6, 7.7) C lozapine : May elevate clozapine levels (7.7) Ha loperidol : Elevated haloperidol levels have been observed (7.7) Carba m a z ep ine : Potential for elevated carbamazepine levels and clinical anticonvulsant toxicity (7.7) P hen yt o in : Potential for elevated phenytoin levels and clinical anticonvulsant toxicity (7.7) A lcohol : May potentiate sedation and orthostatic hypotension (7.7) S ero t onerg ic 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 t hat 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 t hat 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 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 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 QT c 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. 7.8 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 cause QT prolongation. These include: specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, mesoridazine, droperidol); specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin); Class 1A antiarrhythmic medications (e.g., quinidine, procainamide); Class III antiarrhythmics (e.g., amiodarone, sotalol); and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus). Fluoxetine is primarily metabolized by CYP2D6. Concomitant treatment with CYP2D6 inhibitors can increase the concentration of fluoxetine. Concomitant use of other highly protein-bound drugs can increase the concentration of fluoxetine [see Contraindications (4.2), Warnings and Precautions (5.20), Drug Interactions (7.7), and Clinical Pharmacology (12.3)].