Olanzapine / Fluoxetine Hydrochloride

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

Trade Names

Symbyax
- 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

Pharmacology

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; treatment of treatment-resistant depression.

Contraindications

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 Disorder
Adults

PO Start with olanzapine 6 mg/fluoxetine 25 mg daily in the evening. Adjust the dosage as needed. Antidepressant efficacy has been demonstrated up to 12 mg/50 mg. Safety of doses above 18 mg/75 mg has not been evaluated.

Treatment-Resistant Depression
Adults

PO Start with olanzapine 6 mg/fluoxetine 25 mg. Adjust the dosage as needed. Antidepressant efficacy has been demonstrated up to 18 mg/50 mg. Safety of doses above 18 mg/75 mg has not been evaluated.

Special Populations
Adults

PO Start with 3mg/25 mg to 6 mg/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 those patients who may be pharmacodynamically sensitive to olanzapine. If indicated, perform dose escalation with caution.

General Advice

Administer without regard to meals, but administer with food if GI upset occurs.
If treatment is to be discontinued or the dose reduced, gradually taper the dose and monitor the patient for withdrawal symptoms.

Storage/Stability

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 rarely. Observe patient closely.

Antiarrhythmics (eg, propafenone), risperidone

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. Consider a dose reduction.

Antihypertensives (eg, propranolol)

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

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

Elevated serum antipsychotic levels may occur, increasing the pharmacologic effects and risk of adverse reactions. Monitor the clinical response and adjust the aripiprazole dose as needed.

Atomoxetine

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

Benzodiazepines (eg, alprazolam, diazepam)

The orthostatic hypotension of olanzapine may be potentiated by diazepam, the half-life of diazepam may be prolonged by fluoxetine, and plasma concentrations of alprazolam may be increased. Monitor the clinical response. If an interaction is suspected, adjust the benzodiazepine dose as needed.

Beta-blockers (eg, metoprolol)

Coadministration may increase the risk of cardiac (eg, bradycardia) and CNS toxicity. Close clinical and cardiac monitoring is indicated.

Bupropion

Unexpected adverse effects, including serotonin syndrome, may occur. Closely monitor the patient; if an interaction is suspected, stop one or both drugs.

Buspirone

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 for serotonin syndrome.

Carbamazepine

Plasma concentrations of olanzapine may be decreased by carbamazepine, and plasma levels of carbamazepine may be increased by fluoxetine. Monitor the clinical response and concentrations of carbamazepine and olanzapine when coadministration with either agent is started or stopped. Adjust treatment as needed.

Clopidogrel

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. Adjust the dose of these agents as needed.

Cyproheptadine

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

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

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. Adjust the digoxin dose as needed.

Dopamine agonists, levodopa

Effects of levodopa and dopamine agonists may be antagonized by olanzapine. Use with caution. If an interaction is suspected, it may be necessary to use alternative therapy for one of the agents.

Drugs metabolized by CYP2D6 (eg, amitriptyline, flecainide, vinblastine)

Fluoxetine inhibits CYP2D6 activity and makes patients with normal CYP2D6 metabolic activity resemble poor metabolizers. Coadminister fluoxetine with agents metabolized by this enzyme with caution. Adjust the dose of these agents as needed.

Drugs that induce CYP1A2 (eg, omeprazole, rifampin)

May decrease olanzapine concentrations. Monitor the clinical response and concentrations of olanzapine when coadministration of the CYP1A2 inducer is started or stopped. Adjust the olanzapine dose as needed.

Drugs that inhibit CYP1A2 (eg, mexiletine)

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.

Fenfluramine

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

Food

Food does not appear to affect systemic bioavailability of fluoxetine, although it may delay absorption by 1 to 2 h.

Galantamine

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

Linezolid

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

Lithium

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

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)

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

Metoclopramide

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

Nifedipine

The pharmacologic and toxic effects of nifedipine may be increased. Closely monitor the clinical response; if an interaction is suspected, consider lowering the dosage of nifedipine.

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

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

Pimozide

Coadministration of pimozide and fluoxetine is contraindicated because of the potential risk of increased QTc prolongation, which could result in life-threatening arrhythmias. Bradycardia has been reported during coadministration with fluoxetine.

Protein-bound drugs

Because fluoxetine is tightly bound to plasma protein, the risk of adverse reactions may be increased if fluoxetine is displaced from protein-binding sites by other tightly bound drugs. Monitor the clinical response and adjust treatment as needed.

Ritonavir

Plasma levels of ritonavir and fluoxetine may be elevated, increasing the pharmacologic effects and adverse reactions of both agents. Monitor the clinical response and adjust the dose of one or both agents as needed.

Sibutramine

Serotonin syndrome may occur. Concurrent use is not recommended.

Smoking

Olanzapine clearance is about 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.

St. John's wort

Serotonin syndrome may occur. Use with caution. Serotonin syndrome requires immediate medical attention, including withdrawal of the serotonergic agent and supportive care.

Sympathomimetics (eg, amphetamine)

Increased sympathomimetic effects and increased risk of serotonin syndrome. Monitor for increased CNS effects and adjust dose as needed.

Tamoxifen

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

Terbinafine

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

Tetrabenazine

Tetrabenazine plasma concentrations and pharmacologic effects may be increased. Use with caution. Tetrabenazine dosage adjustments are recommended.

Thioridazine

Administration with olanzapine/fluoxetine or within 5 wk after discontinuing olanzapine/fluoxetine is contraindicated.

Tramadol, trazodone

Serotonin syndrome may occur. Use with caution. Serotonin syndrome requires immediate medical attention, including withdrawal of the serotonergic agent and supportive care.

Tricyclic antidepressants (TCAs) (eg, imipramine)

Plasma TCA levels may be increased. This increase may persist for 3 weeks or longer after fluoxetine is discontinued. Monitor TCA levels temporarily when olanzapine/fluoxetine is coadministered or recently discontinued; TCA dose may need to be reduced.

Tryptophan

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

Zolpidem

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

Cardiovascular

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

CNS

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.

EENT

Blurred vision (5%).

GI

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

Genitourinary

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

Hematologic-Lymphatic

Ecchymosis (at least 1%).

Hepatic

Hepatitis, cholestatic or mixed liver injury (postmarketing).

Lab Tests

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

Metabolic-Nutritional

Increased weight (25%); generalized edema, weight loss (at least 1%).

Musculoskeletal

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

Respiratory

Sinusitis (2%).

Miscellaneous

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

Precautions

Warnings

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.

Suicidality

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. Families and caregivers should be advised of the need for close observation and communication with the prescriber.

Monitor

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. Frequently monitor CBC for 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.

Suicidality

The following symptoms may represent precursors to suicidality and should be reported to health care providers immediately if noted or suspected: aggressiveness, agitation, anxiety, hostility, hypomania, impulsivity, insomnia, irritability, mania, panic attacks, and psychomotor restlessness. Frequently assess patient for response to treatment. Ensure therapy is periodically reviewed to determine if therapy needs to be continued without change or if a dose change (eg, increase, decrease, discontinuation) is indicated.

Pregnancy

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.

Lactation

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

Children

Safety and efficacy not established.

Elderly

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.

Hypersensitivity

Anaphylactoid reactions, including bronchospasm, angioedema, and urticaria, have been reported.

Hepatic Function

Use a lower dose of fluoxetine in patients with hepatic impairment, including cirrhosis.

Special Risk Patients

Use a lower starting dose and slower dose escalation in patients with hepatic impairment, predisposition to hypotensive reactions, or any combination of factors that may slow metabolism of medication (eg, nonsmokers, elderly patients, women). Use with caution in patients with clinically significant prostatic hypertrophy, cerebrovascular disease, conditions that predispose patients to hypotension (eg, dehydration, hypovolemia), CV disease (eg, conduction abnormalities, heart failure, history of MI or ischemia), narrow-angle glaucoma, or a history of paralytic ileus.

Abnormal bleeding

SSRIs, including fluoxetine, may increase the risk of bleeding; coadministration of aspirin, NSAIDs, and warfarin may add to this risk.

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 ability. Advise patients to avoid the use of alcohol.

Discontinuation of treatment

Withdrawal symptoms have been reported after rapid discontinuation of therapy. If treatment is to be discontinued or the dose reduced, gradually taper the dose and monitor the patient for withdrawal symptoms (eg, agitation, anxiety, confusion, dizziness, dysphoric mood, emotional lability, headaches, hypomania, insomnia, irritability, lethargy, sensory disturbances). If significant withdrawal symptoms develop, reinstitute previous dosing schedule and attempt a less-rapid tapering regimen after patient has stabilized.

Dosage changes

Because of the long elimination half-life of fluoxetine, changes in dose will not be fully reflected in plasma for several weeks, affecting titration to final dose and withdrawal from treatment.

Dysphagia

Use with caution in patients at risk for aspiration pneumonia.

Electroconvulsive therapy

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

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.

Hyperlipidemia

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

Hyperprolactinemia

Olanzapine-treated patients often have elevation in prolactin levels. Associated clinical manifestations (eg, breast enlargement, galactorrhea) occur infrequently; however, there is no evidence of increased breast cancer risk.

Hyponatremia

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.

Mania/Hypomania

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

NMS

Has occurred and is potentially fatal. Monitor patient for symptoms of NMS (eg, altered mental status, diaphoresis, hyperpyrexia, irregular pulse and BP, muscle rigidity, tachycardia).

Orthostatic hypotension

Orthostatic hypotension, associated with bradycardia, diaphoresis, dizziness, and tachycardia, may occur. Use caution in patients with CV disease, cerebrovascular disease, or conditions predisposing to hypotension (eg, concurrent treatment with antihypertensives, dehydration, hypovolemia). Monitor these patients during initiation of therapy and following dose increases for orthostatic hypotension; implement safety precautions if noted.

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.

Seizures

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 NMS-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) or drugs that impair metabolism of serotonin (eg, MAOIs).

Suicide

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. Approximately 22% of patients receiving olanzapine/fluoxetine gained at least 7% of their baseline weight with a median exposure of 6 wk.

Overdosage

Symptoms

Acute psychosis, aggression, agitation, arrhythmias, essential tremor, hypertension, hypotension, impaired consciousness (coma), impaired neurologic function (ataxia, confusion, convulsions, dysarthria), lethargy, and 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 health care provider because of increased risk of serious bleeding.
Instruct patients to contact 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 health care provider of significant changes in readings.
Advise patients being treated for depression and family or caregiver of patient to be alert for abnormal changes in mood or thinking and to immediately report any of the following to 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 of patients to observe for emergence 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 health care provider.
Advise patients to notify 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 medication.
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 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 drug 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.