death; and other conditions that predispose to QT prolongation and ventricular arrhythmia Such conditions include concomitant use of drugs that prolong the QT interval; hypokalemia or hypomagnesemia; recent myocardial infarction, uncompensated heart failure, bradyarrhythmias, and other significant arrhythmias; and conditions that predispose to increased fluoxetine exposure (overdose, hepatic impairment, use of CYP2D6 inhibitors, CYP2D6 poor metabolizer status, or use of other highly protein-bound drugs) Consider ECG assessment and periodic ECG monitoring if initiating therapy in patients with risk factors for QT prolongation and ventricular arrhythmia; consider discontinuing therapy and obtaining a cardiac evaluation if patients develop signs or symptoms consistent with ventricular arrhythmia Clinicians should administer therapy with caution in those children or adolescents who are known to be particularly at risk for QT prolongation Hyperprolactinemia As with other drugs that antagonize dopamine D2 receptors, this drug combination elevates prolactin levels, and the elevation persists during administration; hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion; this, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients Galactorrhea, amenorrhea, gynecomastia, and erectile dysfunction reported in patients receiving prolactin-elevating compounds; long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects Sexual dysfunction Use may cause symptoms of sexual dysfunction in both male and female patients; inform patients that they should discuss any changes in sexual function and potential management strategies with their healthcare provider Use of SSRIs, may cause symptoms of sexual dysfunction; in male patients, SSRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction In female patients, SSRI/SNRI use may result in decreased libido and delayed or absent orgasm Important for prescribers to inquire about sexual function prior to initiation of therapy and to inquire specifically about changes in sexual function during treatment because sexual function may not be spontaneously reported When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including underlying psychiatric disorder Discuss potential management strategies to support patients in making informed decisions about treatment Discontinuation adverse reactions Adverse reactions occurring upon discontinuation of SNRIs and SSRIs reported, particularly when done abruptly; reactions may include dysphoric mood, irritability, agitation, dizziness, sensory disturbances (eg, paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania While these reactions are generally self-limiting, there have been reports of serious discontinuation symptoms; patients should be monitored for these symptoms when discontinuing treatment with fluoxetine; a gradual reduction in dose rather than abrupt cessation is recommended whenever possible If intolerable symptoms occur following a decrease in dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered; subsequently, the healthcare provider may continue decreasing dose but at more gradual rate Plasma fluoxetine and norfluoxetine concentration decrease gradually at conclusion of therapy, which may minimize risk of discontinuation symptoms with this drug Metabolic changes Atypical antipsychotic drugs have been associated with metabolic changes including hyperglycemia, dyslipidemia, and weight gain; metabolic changes may be associated with increased cardiovascular/cerebrovascular risk Hyperglycemia/diabetes Healthcare providers should consider the risks and benefits when prescribing this drug to patients with an established diagnosis of diabetes mellitus, or having borderline increased blood glucose level ting 100­-126 mg/dL, nonfasting 140-200 mg/dL) Patients taking this drug combination should be monitored regularly for worsening of glucose control; patients starting treatment should undergo fasting blood glucose testing at beginning of treatment and periodically during treatment Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness; patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics, including olanzapine alone, as well as olanzapine taken concomitantly with fluoxetine Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population Epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse reactions in patients treated with atypical antipsychotics; while relative risk estimates are inconsistent, the association between atypical antipsychotics and increases in glucose levels appears to fall on a continuum and olanzapine appears to have a greater association than some other atypical antipsychotics Dyslipidemia Undesirable alterations in lipids observed with use; clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using this drug combination, recommended Weight gain Potential consequences of weight gain should be considered prior to initiating therapy; patients receiving this drug combination should receive regular monitoring of weight Drug interaction overview Fluoxetine is primarily metabolized by CYP2D; use of CYP2D6 inhibitors may increase risk of QT interval prolongation Pimozide and thioridazine are contraindicated for use with this drug combination; avoid concomitant use of drugs known to prolong QT interval; these include specific antipsychotics (eg, ziprasidone, iloperidone, chlorpromazine, mesoridazine, droperidol); specific antibiotics (eg, erythromycin, gatifloxacin, moxifloxacin, sparfloxacin); Class 1A antiarrhythmic medications (eg, quinidine, procainamide); Class III antiarrhythmics (eg, amiodarone, sotalol); and others (eg, pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus) Pregnancy There is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to psychiatric medications, during pregnancy; healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/ Neonates exposed to antipsychotic drugs during the 3rd trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery These complications vary in severity; in some cases, symptoms have been self-limited, while in other cases neonates have required intensive care unit support and prolonged hospitalization Treatment of Pregnant Women during the First Trimester with Fluoxetine: There are no adequate and well-controlled clinical studies on the use of fluoxetine in pregnant women, but 1 prospective cohort study conducted by the European Network of Teratology Information Services reported an increased risk of cardiovascular malformations in infants born to women (N = 253) exposed to fluoxetine during the first trimester of pregnancy compared to infants of women (N = 1,359) who were not exposed to fluoxetine SSRI use late in the third trimester associated with complications in newborns and may require prolonged hospitalization, respiratory support, and tube feeding Women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants; consider risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum Antipsychotic drug exposure Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder reported in neonates who were exposed to antipsychotic drugs, including olanzapine, during third trimester of pregnancy; these symptoms have varied in severity Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately; some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization Fluoxetine drug exposure Neonates exposed to fluoxetine and other SSRIs or SNRIs late in third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding; such complications can arise immediately upon delivery; reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying These findings are consistent with either a direct toxic effect of SSRIs and SNRIs or possibly a drug discontinuation syndrome; it should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome Females and males of reproductive potential Females: Based on pharmacologic action of olanzapine (dopamine D2 receptor blockade), treatment with drug combination may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential Persistent pulmonary hypertension of the newborn Potential risk of persistent pulmonary hypertension of the newborn (PPHN) when used during pregnancy Initial Public Health Advisory in 2006 was based on a single published study; since then, there have been conflicting findings from new studies, making it unclear whether use of SSRIs during pregnancy can cause PPHN FDA has reviewed the additional new study results and has concluded that, given the conflicting results from different studies, it is premature to reach any conclusion about a possible link between SSRI use in pregnancy and PPHN FDA recommendation: FDA advises health care professionals not to alter their current clinical practice of treating depression during pregnancy and to report any adverse events to the FDA MedWatch program Animal data In animal studies, administration of combination of olanzapine and fluoxetine during 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 Lactation Consider developmental and health benefits of breastfeeding along with mother’s clinical need for therapy and any potential adverse effects on breastfed child from therapy or underlying maternal condition Infants exposed to drug combination should be monitored for agitation, irritability, poor feeding, poor weight gain, excess sedation, and extrapyramidal symptoms (tremors and abnormal muscle movements) Olanzapine In a study in lactating, healthy women, olanzapine was excreted in breast milk Mean infant dose at steady state was estimated to be 1.8% of the maternal olanzapine dose It is recommended that women receiving olanzapine should not breastfeed Fluoxetine Excreted in human breast milk In 1 breast milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 ng/mL; concentration in the mother’s plasma was 295 ng/mL Pregnancy Categories A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk. B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available. Mechanism of Action Fluoxetine: Inhibits CNS neuron setotonin reuptake with minimal or no effect on norepinephrine or dopamine reuptake; does not bind to alpha-adrenergic, histamine, or cholinergic receptors Olanzapine: Potent antagonist of dopamine 1-3, histamine H1, serotonin 5-HT2A and 5-HT2C, and alpha1-adrenergic receptors; shows moterate antagonism for 5-HT3, and muscarinic M1-5 receptors; binds to GABA-A, benzodiazepine, and beta-adrenergic receptors Absorption Peak plasma time: 4-6 hr (50 mg/12 mg-dose); 6 hr (olanzapine); 6-8 hr (fluoxetine) Peak plasma concentration: 15-55 ng/mL (fluoxetine) Distribution Vd: ~1,000 L (olanzapine) Protein binding: 93% (olanzapine); ~94.5% (fluoxetine) Mechanism Direct glucuronidation and CYP450-mediated oxidation are the primary metabolic pathways for olanzapine CYP2D6-mediated oxidation appears to be a minor metabolic pathway in vivo, because clearance of olanzapine is not reduced in subjects who are deficient in this enzyme Fluoxetine is extensively metabolized in the liver to its active metabolite, norfluoxetine, via CYP2D6 pathway Excretion Half-life: 21-54 hr (olanzapine) Clearance: 12-47 L/hr (olanzapine) Oral Administration Administer orally once daily in the evening If missed dose, take the missed dose as soon possible; if it is almost time for the next dose, skip the missed dose and take next dose at the regular time; do not take two doses at once Storage Tablets: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F); keep tightly closed and protect from moisture No images available for this drug. No images available for this drug.A Patient Handout is not currently available for this monograph.Print FormularyPatient DiscountsAdding plans allows you to compare formulary status to other drugs in the same class.To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.Create Your List of PlansAdding plans allows you to:View the formulary and any restrictions for each plan.Manage and view all your plans together –