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Olanzapine / Fluoxetine Hydrochloride

Pronunciation: oh-LAN-za-peen/floo-OX-e-teen HYE-droe-KLOR-ide
Class: Antipsychotic/Antidepressant combination

Trade Names

- Capsules, oral olanzapine 3 mg/fluoxetine hydrochloride 25 mg
- Capsules, oral olanzapine 6 mg/fluoxetine hydrochloride 25 mg
- Capsules, oral olanzapine 6 mg/fluoxetine hydrochloride 50 mg
- Capsules, oral olanzapine 12 mg/fluoxetine hydrochloride 25 mg
- Capsules, oral olanzapine 12 mg/fluoxetine hydrochloride 50 mg


Unknown; however, it is suspected that activation of 3 monoaminergic neural systems (dopamine, norepinephrine, and serotonin) is responsible for an enhanced antidepressant effect.

Indications and Usage

Acute treatment of depressive episodes associated with bipolar I disorder in adults; acute treatment of treatment-resistant depression in adults who do not respond to 2 separate trials of different antidepressants of adequate dose and duration in the current episode.


Coadministration with thioridazine (or within 5 wk of stopping olanzapine/fluoxetine), an MAOI (or within 14 days of discontinuing an MAOI and at least 5 wk after stopping olanzapine/fluoxetine), or pimozide.

Dosage and Administration

Depressive Episodes Associated With Bipolar I Disorder

PO Start with olanzapine 6 mg/fluoxetine 25 mg daily in the evening. Adjust the dosage as needed. Usual dose is olanzapine 6 to 12 mg/fluoxetine 15 to 50 mg.

Treatment-Resistant Depression

PO Start with olanzapine 6 mg/fluoxetine 25 mg daily in the evening. Adjust the dosage as needed. Usual dose is olanzapine 6 to 18 mg/fluoxetine 25 to 50 mg.

Special Populations

PO Start with olanzapine 3 mg/fluoxetine 25 mg to olanzapine 6 mg/fluoxetine 25 mg for patients with a predisposition to hypotensive reactions, patients with hepatic impairment, patients who exhibit a combination of factors that may slow metabolism (eg, elderly patients, nonsmoking status, women), or patients who may be pharmacodynamically sensitive to olanzapine. If indicated, perform dose escalation with caution.

General Advice

  • Administer once daily in the evening without regard to meals
  • Periodically reexamine the need for continued pharmacotherapy.
  • If discontinuing treatment or reducing the dose, gradually taper the dose and monitor the patient for withdrawal symptoms.


Store between 59° and 86°F. Protect from moisture.

Drug Interactions

5-HT 1 agonists (eg, sumatriptan)

Increased risk of serotonin syndrome (eg, hyperreflexia, incoordination, weakness) has been reported. Observe patients closely.

Antiarrhythmics (eg, propafenone)

Metabolism may be inhibited by fluoxetine, resulting in elevated plasma concentrations and increasing the pharmacologic effects and risk of adverse reactions. Closely monitor the clinical response.

Antihypertensives (eg, beta-blockers, calcium channel blockers)

Antihypertensive effects may be enhanced by olanzapine. Monitor BP and adjust the antihypertensive dose as needed.

Antipsychotic agents (eg, aripiprazole, clozapine, haloperidol, pimozide, risperidone, thioridazine)

Elevated serum antipsychotic levels and/or QTc prolongation may occur. Pimozide and thioridazine are contraindicated with fluoxetine; do not administer thioridazine with fluoxetine or within a minimum of 5 wk of fluoxetine discontinuation. Monitor the clinical response and adjust the aripiprazole dose as needed.


Atomoxetine plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. Closely monitor the clinical response and adjust the atomoxetine dose as needed.

Benzodiazepines (eg, alprazolam, diazepam)

Orthostatic hypotension of olanzapine may be potentiated by diazepam, half-life of diazepam may be prolonged by fluoxetine, and plasma concentrations of alprazolam may be increased. Monitor the clinical response and adjust the benzodiazepine dose as needed.


Unexpected adverse effects, including serotonin syndrome, may occur. Closely monitor the patient.


Effects of buspirone may be decreased. Paradoxical worsening of obsessive-compulsive disorder or serotonin syndrome has been reported. If coadministration cannot be avoided, closely monitor the patient for worsening clinical status as well as serotonin syndrome.


Clopidogrel plasma concentrations and pharmacologic effects may be decreased. Avoid coadministration.

CNS-active drugs (eg, alcohol)

Use with caution; titrate the dose and monitor the clinical status of the patient. Concurrent use of alcohol is not recommended.

Cyclosporine, phenytoin, tricyclic antidepressants (eg, desipramine, imipramine)

Blood levels of these agents may be increased by fluoxetine. Monitor the clinical response of the patient and the concentrations of these agents when appropriate.


Pharmacologic effects of fluoxetine may be decreased. If coadministration cannot be avoided, closely monitor the clinical response. If an interaction is suspected, consider discontinuing cyproheptadine.


Dextromethorphan plasma concentrations and risk of toxicity may be increased. If coadministration cannot be avoided, closely monitor the clinical response and adjust the dextromethorphan dose as needed.


Digoxin plasma concentrations may be elevated, increasing the pharmacologic effect and risk of toxicity. If coadministration cannot be avoided, closely monitor the clinical response and digoxin concentrations.

Dopamine agonists, levodopa

Effects of levodopa and dopamine agonists may be antagonized by olanzapine. Use with caution.

Drugs that induce CYP1A2 (eg, carbamazepine, omeprazole, rifampin)

May decrease olanzapine concentrations. In addition, carbamazepine levels may be increased. Monitor the clinical response and concentrations of the CYP1A2 inducer and olanzapine when coadministration of either agent is started or stopped.

Drugs that inhibit CYP1A2 (eg, estrogens, fluvoxamine, fluoroquinolone antibiotics)

May elevate olanzapine plasma levels, increasing the risk of adverse reactions. Monitor the clinical response and adjust the olanzapine/fluoxetine dose as needed.

Drugs that interfere with hemostasis (eg, aspirin, NSAIDs, warfarin)

Risk of bleeding may be increased. Caution patients about the increased risk of bleeding and the signs of GI bleeding.


Serotonin syndrome may occur because of additive serotonergic effects. Concurrent use is not recommended.


Pharmacologic effects and plasma concentrations of galantamine may be increased. Consider close clinical monitoring and galantamine dosage adjustment.


Iloperidone plasma concentrations and pharmacologic effects may be increased. A modification of the iloperidone dosage is recommended.


Serotonin syndrome may occur. Allow at least 2 wk after stopping linezolid before administering fluoxetine.


Fluoxetine may increase or decrease lithium levels. Lithium toxicity and increased serotonergic effects have been reported. Monitor plasma lithium concentrations following initiation of therapy.

Macrolide and related antibiotics (eg, clarithromycin)

Fluoxetine plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. Serotonin syndrome may result. Closely monitor the clinical response.

MAOIs (eg, isocarboxazid, phenelzine)

Administration with olanzapine/fluoxetine (or administration within 14 days of discontinuing an MAOI and at least 5 wk after stopping olanzapine/fluoxetine) is contraindicated; death has been reported with coadministration of MAOIs and fluoxetine.

Methylene blue

The risk of CNS toxicity, including serotonin syndrome, may be increased. Use an alternative agent for methylene blue.

Methylphenidate, nefazodone, opioid analgesics (eg, meperidine, tramadol), St. John's wort

Serotonin syndrome may occur because of additive serotonergic effects. Closely monitor the patient for adverse reactions.


Metoclopramide plasma concentrations may be increased by fluoxetine. Serotonin syndrome may occur. Monitor for adverse reactions and adjust the metoclopramide dose as needed.

Phosphodiesterase type 5 (PDE5) inhibitors (eg, sildenafil)

Fluoxetine may inhibit PDE5 inhibitor metabolism. If concurrent use cannot be avoided, coadminister with caution and reduce the initial dose of PDE5 inhibitor.


Plasma levels of ritonavir and fluoxetine may be elevated, increasing the pharmacologic effects and adverse reactions of both agents. Fluoxetine and ritonavir may inhibit the metabolism of each other. Ritonavir has also been reported to decrease olanzapine concentrations and pharmacologic effects. Monitor the clinical response and adjust the dose of one or both agents as needed.


Serotonin syndrome may occur. Concurrent use is not recommended.


Olanzapine clearance is approximately 40% higher in smokers than nonsmokers; however, no dosage adjustment is needed.

SNRIs (eg, venlafaxine), SSRIs (eg, fluoxetine)

Serotonin syndrome has occurred. Concurrent use is not recommended.

Sympathomimetics (eg, amphetamine)

Coadministration may cause increased sympathomimetic effects and an increased risk of serotonin syndrome. Monitor for increased CNS effects and adjust dose as needed.


Clinical response to tamoxifen may be reduced. Avoid coadministration. If an antidepressant is needed, citalopram, escitalopram, or venlafaxine are less likely to interact.


Fluoxetine plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. Monitor the clinical response and adjust the olanzapine/fluoxetine dose as needed.


Tetrabenazine plasma concentrations and pharmacologic effects may be increased. Use with caution.


Serotonin syndrome may occur. Use with caution.


Risk of adverse reactions (eg, agitation, GI distress, restlessness) may be increased. Concomitant use is not recommended.


Vinblastine metabolism may be decreased; consider giving a reduced dose.


Altered anticoagulant effects, including increased bleeding, may occur. Monitor PT.


Fluoxetine may shorten the onset of action and increase the effect of zolpidem. Monitor the clinical response and adjust the zolpidem dose as needed.

Adverse Reactions


Vasodilatation (at least 1%); bradycardia; orthostatic hypotension; QT interval prolongation; tachycardia; venous thromboembolic events, including deep venous thrombosis and pulmonary embolism (postmarketing).


Somnolence (14%); fatigue (12%); tremor (9%); sedation (8%); disturbances in attention, hypersomnia (5%); restlessness (4%); asthenia, lethargy (3%); abnormal thinking, nervousness (2%); amnesia (at least 1%); decreased libido; dystonic symptoms; extrapyramidal symptoms.


Blurred vision (5%).


Increased appetite (20%); dry mouth (15%); flatulence (3%); abdominal distention (2%); diarrhea, taste perversion (at least 1%).


Glycosuria (4%); erectile dysfunction (2%); breast pain, menorrhagia, urinary frequency, urinary incontinence (at least 1%); abnormal ejaculation, anorgasmia.


Ecchymosis (at least 1%).


Elevated hepatic transaminases (ALT, AST, GGT) and alkaline phosphatase; cholestatic or mixed liver injury, hepatitis (postmarketing).

Lab Tests

Elevated prolactin (28%); low total bilirubin (15%); low bicarbonate (14%); elevated ALT (5%); elevated urea nitrogen, elevated uric acid, low albumin, low Hgb (3%); low inorganic phosphorus, low lymphocytes (2%).


Increased triglycerides (68%); elevated glucose levels (37%); increased cholesterol (36%); increased weight (25%); generalized edema, weight loss (at least 1%).


Arthralgia (4%); pain in extremity (3%); musculoskeletal stiffness (2%); neck rigidity (at least 1%).


Sinusitis (2%).


Peripheral edema (9%); edema (3%); pain, pyrexia (2%); chills, photosensitivity reaction (at least 1%); rhabdomyolysis (postmarketing).



Increased mortality

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death compared with those taking placebo. Although the causes of death were varied, most of the deaths appeared to be CV (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Olanzapine/fluoxetine is not approved for the treatment of dementia-related psychosis.


Compared with placebo, antidepressants increased the risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants for major depressive disorder and other psychiatric disorders. Appropriately monitor and closely observe patients of all ages who are started on antidepressant therapy for clinical worsening, suicidality, or unusual changes in behavior. Advise families and caregivers of the need for close observation and communication with the health care provider.


Monitor for clinical worsening, suicidality, and unusual changes in behavior, especially during the first few months of therapy, or at times of dose increases or decreases. Monitor patients for development of mania/hypomania symptoms. Regularly monitor patient's weight. Monitor fasting blood glucose and lipid profile at the beginning of and periodically during treatment. Monitor patients for worsening of glucose control and for symptoms of hyperglycemia, including polydipsia, polyuria, polyphagia, and weakness. Frequently monitor CBC in patients with a history of clinically significant low WBC or drug-induced leukopenia/neutropenia during the first few months of therapy. Monitor patients with clinically significant neutropenia for fever or other signs or symptoms of infection. Monitor patients for the emergence of serotonin syndrome or NMS-like signs and symptoms.


Category C . Neonates exposed to fluoxetine late in the third trimester have developed persistent pulmonary hypertension of the newborn and other complications requiring prolonged hospitalization, respiratory support, and tube feeding. Consider potential risks and benefits of treatment when treating women during the third trimester. Consider tapering fluoxetine in the third trimester.


Fluoxetine and olanzapine are excreted in breast milk. The manufacturer recommends that women receiving olanzapine/fluoxetine do not breast-feed.


Not approved for use in children.


Use with caution, usually starting at the lower end of the dosing range, because of the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant diseases or other drug therapy.


Anaphylactoid reactions, including bronchospasm, angioedema, and urticaria, have been reported. Rarely, pulmonary reactions, including inflammatory processes of varying histopathology and/or fibrosis, have been reported.

Hepatic Function

Use with caution.

Special Risk Patients

Use with caution in patients with clinically significant prostatic hypertrophy, narrow-angle glaucoma, a history of paralytic ileus, or related conditions, or with diseases or conditions that could affect hemodynamic responses.

Abnormal bleeding

SSRIs, including fluoxetine, may increase the risk of bleeding.

Body temperature regulation

Antipsychotics may disrupt the ability to reduce core body temperature. Use with caution in patients who will experience conditions that may contribute to an elevation in core body temperature (eg, concomitant anticholinergic therapy, exposure to extreme heat, strenuous exercise, subject to dehydration).

Cognitive and motor impairment

Caution patients about operating potentially hazardous machinery (eg, driving) until it is known if the drug impairs their ability.

Discontinuation of treatment

Withdrawal symptoms have been reported after rapid discontinuation of therapy. If discontinuing treatment or reducing the dose, gradually taper the dose and monitor the patient for withdrawal symptoms. If significant withdrawal symptoms develop, reinstitute previous dosing schedule and attempt a less-rapid tapering regimen after the patient has stabilized.


Esophageal dysmotility and aspiration have been associated with antipsychotic drug use.

Electroconvulsive therapy

Prolonged seizures have been rarely reported in patients receiving concurrent electroconvulsive therapy treatment.

Hematologic effects

Leukopenia/neutropenia has been reported temporally related to antipsychotic agents, including olanzapine. Agranulocytosis has also been reported.

Hyperglycemia and diabetes mellitus

Hyperglycemia, in some cases extreme and associated with ketoacidosis, hyperosmolar coma, or death, has occurred.


Undesirable alterations in lipids have been observed. Very high (eg, more than 500 mg/dL) triglyceride elevations have occurred.


Elevated prolactin levels may occur; the elevation persists during administration.


Hyponatremia has occurred during SSRI treatment and is often the result of SIADH. Use with caution in patients who are elderly or volume-depleted, or who are taking diuretics.


May be precipitated by fluoxetine in patients at risk of bipolar disorder.

Neuroleptic malignant syndrome

Has occurred in association with olanzapine and is potentially fatal.

Orthostatic hypotension

Orthostatic hypotension, associated with bradycardia, dizziness, tachycardia, and, in some patients, syncope, may occur. Use caution in patients with CV disease, cerebrovascular disease, or conditions predisposing to hypotension (eg, concurrent treatment with antihypertensives, dehydration, hypovolemia).

Screening for bipolar disorder

A major depressive episode may be the initial presentation of bipolar disorder, and treating such an episode with an antidepressant alone may increase the likelihood of precipitating a manic episode in patients at risk for bipolar disorder. Screen patients with depression for risk of bipolar disorder prior to initiating therapy with an antidepressant.


May occur. Use with caution in patients with a history of seizures or with conditions that potentially lower the seizure threshold (eg, Alzheimer dementia).

Serotonin syndrome or neuroleptic malignant syndrome–like reactions

Development of a potentially life-threatening serotonin syndrome or NMS-like reactions may occur with SSRIs, including fluoxetine, but particularly with coadministration of serotonergic drugs (eg, triptans), drugs that impair metabolism of serotonin (eg, MAOIs), or antipsychotics or other dopamine antagonists.


Supervise depressed patients at risk during initial therapy. Prescribe the smallest quantity consistent with good patient management in order to reduce the risk of overdose.

Tardive dyskinesia

Syndrome of potentially irreversible, involuntary dyskinetic movements may develop. Prevalence is highest among elderly patients, especially women.

Weight gain

There is a potential for weight gain with treatment.



Acute psychosis, aggression, agitation, arrhythmias, essential tremor, hypertension, hypotension, impaired consciousness (coma), impaired neurologic function (ataxia, confusion, convulsions, dysarthria), lethargy, somnolence (sedation).

Patient Information

  • Advise patients that a low dose will be started and then increased until max benefit is obtained.
  • Instruct patients not to stop taking the medication when they feel better.
  • Advise patients that if medication needs to be discontinued, it will be slowly withdrawn unless safety concerns (eg, rash) require a more rapid withdrawal.
  • Caution patients not to take aspirin or aspirin-containing products, NSAIDs, Ginkgo biloba , or any other medication or herb that can affect coagulation unless advised by their health care provider because of an increased risk of serious bleeding.
  • Instruct patients to contact their health care provider if symptoms do not appear to be getting better or are getting worse, or if bothersome adverse reactions (eg, changes in sexual function, diarrhea, excessive drowsiness, nausea, nervousness, tremors) occur.
  • Advise patients of symptoms of serotonin syndrome or NMS-like reactions, including agitation, coma, diarrhea, hallucinations, hyperthermia, incoordination, muscle rigidity, nausea, tachycardia, and vomiting. Instruct patients to seek immediate medical care if these occur.
  • Advise patients to report symptoms of hyponatremia, including confusion, difficulty concentrating, headache, memory impairment, unsteadiness that may lead to falls, and weakness. More severe symptoms include coma, hallucinations, respiratory arrest, seizure, and syncope.
  • Advise patients to take frequent sips of water, suck on ice chips or sugarless hard candy, or chew sugarless gum if dry mouth occurs.
  • Instruct patients with diabetes to monitor blood glucose more frequently when drug is started or dose is changed and to inform their health care provider of significant changes in readings.
  • Advise patients being treated for depression and families or caregivers of patients to be alert for abnormal changes in mood or thinking and to immediately report any of the following to their health care provider: agitation, akathisia (psychomotor restlessness), anxiety, change in mood, change in personality, hostility or aggressiveness, hypomania, impulsivity, insomnia, irritability, mania, panic attacks, suicidal thoughts or behavior, or worsening of depression. Advise families and caregivers to observe patients for emergence of these symptoms on a day-to-day basis because changes may be abrupt.
  • Instruct patients to immediately report altered mental status, frequent urination, high fever, hives, irregular pulse, irritability, mood swings, muscle rigidity, racing thoughts, rash, seizures, sweating, unquenchable thirst, or unusual hunger to their health care provider.
  • Advise patients to notify their health care provider if excessive drowsiness, swelling in the feet or ankles, weight gain, involuntary body or facial movements, or rapid pulse occurs.
  • Advise patients to avoid strenuous activity during periods of high temperature or humidity.
  • Instruct patients to avoid alcoholic beverages and sedatives or depressants (eg, diazepam) while taking olanzapine/fluoxetine.
  • Instruct patients to get up slowly from a lying or sitting position and to avoid sudden position changes to prevent postural hypotension. Advise patient to report dizziness with position changes to their health care provider. Caution patients that hot tubs and hot showers or baths may make dizziness worse.
  • Advise patients taking antihypertensives to monitor BP at regular intervals.
  • Advise patients that olanzapine/fluoxetine therapy may impair judgment, thinking, or motor skills, or cause drowsiness, and to use caution while driving or performing other tasks requiring mental alertness or coordination until tolerance is determined.
  • Advise patients to notify their health care provider if they become pregnant or intend to become pregnant during therapy.
  • Advise patients not to breast-feed during therapy.

Further information

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