Professional Information

Olanzapine / Fluoxetine Hydrochloride

Pronouncation: (oh-LAN-zah-peen/flew-OX-uh-tee HIGH-droe-KLOR-ide)
Class: Antidepressant

Trade Names:
Symbyax
- Capsules olanzapine 6 mg/fluoxetine hydrochloride 25 mg
- Capsules olanzapine 6 mg/fluoxetine hydrochloride 50 mg
- Capsules olanzapine 12 mg/fluoxetine hydrochloride 25 mg
- Capsules olanzapine 12 mg/fluoxetine hydrochloride 50 mg

Pharmacology

Feedback for Olanzapine/Fluoxetine Hydrochloride

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Compare with other drugs.

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

Indications and Usage

Treatment of depressive episodes associated with bipolar disorder.

Contraindications

Coadministration with thioridazine (or within at least 5 wk of stopping olanzapine/fluoxetine) or an MAOI (or within 14 days of discontinuing an MAOI and at least 5 wk after stopping olanzapine/fluoxetine); hypersensitivity to any component of the product.

Dosage and Administration

Adults

PO Start with olanzapine 6 mg/fluoxetine 25 mg daily in the evening. Administer without regard to meals but administer with food if GI upset occurs. If indicated, dosage adjustments can be made based on efficacy and tolerability. Antidepressant efficacy has been demonstrated up to olanzapine 12 mg/fluoxetine 50 mg. Safety of doses above olanzapine 18 mg/fluoxetine 75 mg have not been evaluated.

Storage/Stability

Store capsules at controlled room temperature (59° to 86°F). Protect from moisture.

Drug Interactions

Antihypertensives

Antihypertensive effects may be enhanced by olanzapine.

Antiparkinsonian agents (eg, dopamine antagonists, levodopa)

Effects may be antagonized by olanzapine.

Benzodiazepines (eg, alprazolam, diazepam)

The orthostatic hypotensive effects of olanzapine may be potentiated by diazepam; the t _½ of diazepam may be prolonged by fluoxetine; plasma concentrations of alprazolam may be increased.

Carbamazepine

Plasma concentrations of olanzapine may be decreased by carbamazepine, and plasma levels of carbamazepine may be increased by fluoxetine.

Clozapine, haloperidol, phenytoin, tricyclic antidepressants (eg, desipramine, imipramine)

Blood levels of these agents may be increased by fluoxetine.

Digoxin, warfarin

May be displaced from protein binding site by fluoxetine, increasing the risk of adverse effects.

Ethanol

May potentiate sedation and orthostatic hypotension of olanzapine/fluoxetine combination.

Fluvoxamine

May inhibit the metabolism of olanzapine, elevating olanzapine plasma levels and increasing the risk of side effects.

Lithium

Fluoxetine may increase or decrease lithium levels. Lithium toxicity and increased serotonergic effects have been reported.

MAOIs (eg, isocarboxazid)

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.

Drugs that induce CYP1A2 (eg, omeprazole, rifampin)

May decrease olanzapine concentrations.

Pimozide

Bradycardia has been reported during coadministration with fluoxetine.

Sumatriptan

Hyperreflexia, incoordination, and weakness have been reported with coadministration of sumatriptan and an SSRI (eg, fluoxetine).

Thioridazine

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

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

Risk of bleeding may be increased.

Tryptophan

Risk of adverse reactions (eg, agitation, GI distress, restlessness) may be increased.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Hypertension, tachycardia (at least 2%); bradycardia, increase in QTc interval, migraine, orthostatic hypotension, vasodilation (postmarketing).

CNS

Abnormal thinking, somnolence, tremor (at least 5%); amnesia, decreased libido, hyperkinesias, personality disorder, sleep disorder (at least 2%).

EENT

Pharyngitis (at least 5%); amblyopia, ear pain, otitis media (at least 2%); abnormal vision, taste perversion, tinnitus (postmarketing).

GI

Increased appetite (at least 5%); diarrhea, dry mouth, tooth disorder (at least 2%); increased salivation, thirst (postmarketing).

Genitourinary

Abnormal ejaculation, anorgasmia, impotence (at least 2%); breast pain, menorrhagia, priapism, urinary frequency, urinary incontinence, UTI (postmarketing).

Lab Tests

Increases in alkaline phosphatase, cholesterol, glucose tolerance test, uric acid, serum prolactin decrease in hemoglobin (postmarketing); abnormal ejaculation.

Metabolic-Nutritional

Edema, peripheral edema, weight gain (at least 5%); weight loss, generalized edema (postmarketing).

Musculoskeletal

Joint disorder, twitching, arthralgia (at least 2%).

Respiratory

Dyspnea (at least 2%); bronchitis; lung disorder (postmarketing).

Miscellaneous

Asthenia (at least 5%); accidental injury, fever, speech disorder (at least 2%); chest pain (at least 1%); chills, infection, neck pain and rigidity, photosensitivity reaction (postmarketing).

Precautions

Warnings

Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with major depressive disorder and other psychiatric disorders. When considering the use of any antidepressant in a child or adolescent balance this risk with clinical need. Closely observe children or adolescents for clinical worsening, suicidality, or unusual changes in behavior during the initial few months of therapy, or at times of dose changes, either increases or decreases. Advise families and caregivers of the need for close observation and communication with the prescriber.

Monitor

Monitor pediatric and adult patients for clinical worsening, suicidality, and unusual changes in behavior, especially during the first few months of therapy, or at times of dose changes, either increases or decreases. Evaluate pediatric patients at least weekly with face-to-face contact with the patient or their family members or caregiver during the first 4 wk of therapy, then every other week for the next 4 wk, then at 12 wk, and as clinically indicated thereafter.

Suicidality

The following symptoms may represent precursors to suicidality and should be reported to health care provider 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. Notify health care provider if condition does not appear to be improving or is worsening, or if bothersome side effects are noted. 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 complications requiring prolonged hospitalization, respiratory support, and tube feeding. Consider potential risks and benefits of treatment when treating women during the third trimester.

Lactation

Undetermined; however, fluoxetine is excreted in breast milk.

Children

Safety and efficacy not established.

Elderly

Use with caution because of the greater frequency of decreased hepatic, renal, or cardiac function and concomitant diseases or other drug therapy.

Special Risk Patients

Use lower starting dose (eg, olanzapine 6 mg/fluoxetine 25 mg) and slower dose escalation in patients with hepatic impairment, predisposition to hypotensive reactions, or combination of factors that may slow metabolism of medication (eg, nonsmoker, elderly, women).

Body temperature regulation

Antipsychotics 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, strenuous exercise, exposure to extreme heat, concomitant anticholinergic therapy, subject toߙdehydration).

Cerebrovascular adverse events (CVAE)

CVAE (eg, stroke, transient ischemic attack), including fatalities, may occur.

Cognitive and motor impairment

Caution patients about operating potentially hazardous machinery (eg, driving) until it is known if the drug impairs ability. Avoid 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 patient for withdrawal symptoms (eg, abnormal skin sensations, agitation, anxiety, confusion, dizziness, dysphoric mood, emotional lability, headaches, hypomania, insomnia, irritability, lethargy). If significant withdrawal symptoms develop, reinstitute previous dosing schedule and attempt a less rapid tapering regimen after patient has stabilized.

Dose changes

Because of the long elimination t _½ 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.

Hyperglycemia and diabetes mellitus

Hyperglycemia, in some cases extreme and associated with ketoacidosis, hyperosmolar coma, or death, may occur. Monitor blood sugar in diabetic patient when drug is started or dose is changed. Report significant changes to health care provider. Ensure fasting blood glucose is evaluated before starting therapy and periodically thereafter during therapy in patient with risk factors for diabetes mellitus (eg, family history of diabetes, obesity).

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.

Mania/Hypomania

May be precipitated by fluoxetine in susceptible patients.

Neuroleptic malignant syndrome (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). Inform health care provider immediately if NMS is noted or suspected.

Orthostatic hypotension

Orthostatic hypotension, associated with bradycardia, diaphoresis, dizziness, and tachycardia may occur. Monitor patients with CV disease, cerebrovascular disease, or conditions predisposing to hypotension (eg, concurrent treatment with antihypertensives, dehydration, hypovolemia) during initiation of therapy, and following dose increases, for orthostatic hypotension; implement safety precautions and inform health care provider 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 mixed/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

May occur; use with caution in patients with a history of seizures or with conditions that potentially lower the seizure threshold.

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 higher among elderly, especially women. Use smallest effective dose for shortest period of time needed.

Transaminase elevations

Asymptomatic elevations may occur; use with caution in patients with signs and symptoms of hepatic impairment, pre-existing conditions associated with limited hepatic functional reserve, and in patients being treated with potentially hepatotoxic drugs. Assess liver enzymes prior to and periodically during therapy in patient with liver disease; inform health care provider if elevations are noted.

Weight gain

May occur; document patient weight prior to and periodically during prolonged treatment.

Overdosage

Symptoms

Important overdose adverse reactions with single or multiple drugs include coma, delirium, ECG abnormalities (eg, QT-interval prolongation, ventricular tachycardia [eg, torsades de pointes]), hypotension, mania, NMS, pyrexia, stupor, syncope.

Olanzapine

Agitation, aggressiveness, aspiration, cardiac arrhythmias (eg, supraventricular tachycardia), cardiopulmonary arrest, convulsion, delirium, dysarthria, hypertension, hypotension, possible NMS, reduced level of consciousness (from sedation to coma), respiratory arrest, tachycardia, various extrapyramidal symptoms.

Fluoxetine

Abnormal accommodation, abnormal gait, confusion, death, elevated BP, hypomania, impotence, movement disorder, nausea, nervousness, pulmonary dysfunction, seizures, somnolence, tachycardia, tremor, unresponsiveness, vertigo, vomiting.

Patient Information

Advise patient or caregiver to read patient information before starting therapy and with each refill.
If patient is a child or adolescent, advise patient, their family, or caregiver to read the Medication Guide About Using Antidepressants in Children and Teenagers before starting therapy and with each refill.
Advise patient that a low dose will be started and then increased until max benefit is obtained.
Advise patient that if a dose is missed to take it as soon as possible and then return to the normal schedule. However, if it is almost time for the next dose, to skip the missed dose and take the next dose at the regularly scheduled time. Instruct patient that if a dose is skipped not to double the dose to catch up.
Instruct patient not to change the dose or stop taking unless advised by health care provider.
Instruct patient not to stop taking the medication when they feel better.
Caution patient not to take aspirin or aspirin-containing products, NSAIDS, Gingko 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 patient to contact health care provider if symptoms do not appear to be getting better, are getting worse, or if bothersome side effects (eg, excessive drowsiness, diarrhea, tremors, nausea, diarrhea, nervousness, changes in sexual function) occur.
Advise patient to take frequent sips of water, suck on ice chips, sugarless hard candy, or chew sugarless gum if dry mouth occurs.
Instruct diabetic patient 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 patient 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: change in personality; change in mood; anxiety; agitation; panic attacks; insomnia; irritability; hostility or aggressiveness; impulsivity; akathisia (psychomotor restlessness); suicidal thoughts or behavior. Advise families and caregivers of patients to observe for emergence on a day-to-day basis, because changes may be abrupt.
Advise patient that if medication needs to be discontinued it will be slowly withdrawn unless safety concerns (eg, rash) require a more rapid withdrawal.
Instruct patient to immediately report high fever, muscle rigidity, altered mental status, irregular pulse, sweating, seizures, racing thoughts, mood swings, irritability, unquenchable thirst, frequent urination, unusual hunger, rash, or hives to health care provider.
Advise patient 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 patient to avoid strenuous activity during periods of high temperature or humidity.
Instruct patient to avoid alcoholic beverages and sedatives or depressants (eg, diazepam) while taking medication.
Instruct patient to get up slowly from 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 patient that hot tubs and hot showers or baths may make dizziness worse.
Advise patient taking antihypertensives to monitor BP at regular intervals.
Advise patient 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.