Olanzapine / Fluoxetine Hydrochloride

Trade Names:Symbyax- Capsules olanzapine 3 mg/fluoxetine hydrochloride 25 mg- 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

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

Indications and Usage

Treatment of depressive episodes associated with bipolar I disorder; treatment of treatment-resistant depression.

Contraindications

Coadministration with thioridazine (or within at least 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

PO Start with olanzapine 6 mg/fluoxetine 25 mg daily in the evening. If indicated, dosage adjustments can be made based on efficacy and tolerability. Antidepressant efficacy has been demonstrated up to 12 mg/50 mg. Safety of doses above 18 mg/75 mg has not been evaluated.

PO Start with olanzapine 6 mg/fluoxetine 25 mg. If indicated, dosage adjustments can be made according to efficacy and tolerability. Antidepressant efficacy has been demonstrated up to 18 mg/50 mg. Safety of doses above 18 mg/75 mg has not been evaluated.

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, female gender), 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.

Storage/Stability

Store capsules at 59° to 86°F. Protect from moisture.

Drug Interactions

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

Inhibition of metabolism by fluoxetine, resulting in elevated plasma concentrations and increasing the pharmacologic effects and risk of adverse reactions.

Antihypertensive effects may be enhanced by olanzapine.

The orthostatic hypotension of olanzapine may be potentiated by diazepam; the half-life of diazepam may be prolonged by fluoxetine; plasma concentrations of alprazolam may be increased.

Effects of buspirone may be decreased.

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

Absorption of fluoxetine and olanzapine may be decreased.

Blood levels of these agents may be increased by fluoxetine.

Use with caution; titrate the dose and monitor the clinical status of the patient.

Pharmacologic effects of fluoxetine may be decreased.

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

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.

May decrease olanzapine concentrations.

May elevate olanzapine plasma levels, increasing the risk of adverse reactions.

Risk of bleeding may be increased.

Effects of levodopa and dopamine agonist may be antagonized by olanzapine.

Serotonin syndrome may occur.

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

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.

Serotonin syndrome may occur.

Fluoxetine may inhibit PDE5 inhibitor metabolism.

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.

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.

Plasma levels of ritonavir and fluoxetine may be elevated, increasing the pharmacologic effects and adverse reactions of both agents; risk of serotonin syndrome may be increased.

Serotonin syndrome may occur.

Serotonin syndrome has occurred.

Serotonin syndrome may occur.

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

Increased sympathomimetic effects and increased risk of serotonin syndrome.

Clinical response to tamoxifen may be reduced

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

Serotonin syndrome may occur.

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

Plasma concentrations of zolpidem may be increased.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

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

CNS

Increased appetite (20%); somnolence (14%); fatigue (12%); tremor (9%); sedation (8%); disturbances in attention, hypersomnia (5%); restlessness (4%); asthenia, lethargy (3%); abnormal thinking, nervousness, pyrexia (2%); amnesia (at least 1%).

EENT

Blurred vision (5%).

GI

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%).

Hematologic-Lymphatic

Ecchymosis (at least 1%).

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 (2%); chills, photosensitivity (at least 1%); rhabdomyolysis (postmarketing).

Precautions

Pregnancy

Category C .

Lactation

Undetermined; however, fluoxetine and olanzapine are excreted in breast milk.

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 concomitant diseases or other drug therapy.

Hypersensitivity

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

Hepatic Function

Use lower dose or less frequent dosing of fluoxetine in patients with cirrhosis.

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 patient, female gender).

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 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. Avoid use of alcohol.

Concomitant illness

Use with caution in cardiac patients and in patients with diseases or conditions that could affect hemodynamic responses.

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.

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 reported in patients receiving concurrent electroconvulsive therapy treatment and fluoxetine.

Hyperlipidemia

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

Hyperglycemia and diabetes mellitus

Hyperglycemia, in some cases extreme and associated with ketoacidosis, hyperosmolar coma, or death, may occur. Monitor blood sugar in patients with diabetes when drug is started or dose is changed. Ensure fasting blood glucose is evaluated before starting therapy and periodically thereafter during therapy in patients 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.

Hyponatremia

Hyponatremia may occur as a result of SSRI treatment, often the hyponatremia appears to be the result of SIADH.

Mania/Hypomania

May be precipitated by fluoxetine in susceptible patients.

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. 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 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.

Serotonin syndrome

Development of a potentially life-threatening serotonin syndrome may occur with SSRIs, including fluoxetine, particularly with coadministration of serotonergic drugs (eg, triptans) and with 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 higher among elderly patients, especially women. Use smallest effective dose for shortest period of time needed.

Transaminase elevations

Asymptomatic elevations may occur.

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

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, 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.
• Instruct patient not to stop taking the medication when they feel better.
• Caution patient 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 patient to contact health care provider if symptoms do not appear to be getting better, are getting worse, or if bothersome adverse reactions (eg, changes in sexual function, diarrhea, excessive drowsiness, nausea, nervousness, tremors) occur.
• Advise patient to take frequent sips of water, suck on ice chips or sugarless hard candy, or chew sugarless gum if dry mouth occurs.
• Instruct patient 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 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: agitation, akathisia (psychomotor restlessness), anxiety, change in mood, change in personality, hostility or aggressiveness, impulsivity, insomnia, irritability, panic attacks, 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 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 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.

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