Frequently Asked Questions

Olanzapine/Fluoxetine Hydrochloride

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

Psychotherapeutic combinations


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.

Slideshow: View Frightful (But Dead Serious) Drug Side Effects

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.

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 I Disorder
Adults

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
Adults

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
Adults

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.

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. 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

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.

Bupropion

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

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 serotonin syndrome.

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.

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.

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.

Fenfluramine

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

Galantamine

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

Iloperidone

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

Linezolid

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

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.

Ritonavir

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.

Sibutramine

Serotonin syndrome may occur. Concurrent use is not recommended.

Smoking

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.

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 adjust the olanzapine/fluoxetine dose as needed.

Tetrabenazine

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

Trazodone

Serotonin syndrome may occur. Use with caution.

Tryptophan

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

Vinblastine

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

Warfarin

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

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%); bradycardia; orthostatic hypotension; QT interval prolongation; tachycardia; venous thromboembolic events, including deep venous thrombosis and pulmonary embolism (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; dystonic symptoms; extrapyramidal symptoms.

EENT

Blurred vision (5%).

GI

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

Genitourinary

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

Hematologic-Lymphatic

Ecchymosis (at least 1%).

Hepatic

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%).

Metabolic-Nutritional

Increased triglycerides (68%); elevated glucose levels (37%); increased cholesterol (36%); 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 reaction (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. Advise families and caregivers of the need for close observation and communication with the health care provider.


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, 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.


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 do not breast-feed.

Children

Not approved for use in children.

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. 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.

Dysphagia

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.

Hyperlipidemia

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

Hyperprolactinemia

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

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.

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.

Seizures

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.

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 with treatment.

Overdosage

Symptoms

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.

Copyright © 2009 Wolters Kluwer Health.

Not all side effects for fluoxetine / olanzapine may be reported. You should always consult a doctor or healthcare professional for medical advice. Side effects can be reported to the FDA here.

For the Consumer

Applies to fluoxetine / olanzapine: oral capsule

In addition to its needed effects, some unwanted effects may be caused by fluoxetine / olanzapine. In the event that any of these side effects do occur, they may require medical attention.

You should check with your doctor immediately if any of these side effects occur when taking fluoxetine / olanzapine:

More common
  • Bloating or swelling of the face, arms, hands, lower legs, or feet
  • body aches or pain
  • confusion
  • congestion
  • cough
  • delusions
  • dementia
  • dryness or soreness of the throat
  • fever
  • hoarseness
  • rapid weight gain
  • runny nose
  • shakiness in the legs, arms, hands, or feet
  • tender, swollen glands in the neck
  • tingling of the hands or feet
  • trembling or shaking of the hands or feet
  • trouble with swallowing
  • unusual weight gain or loss
  • voice changes
Less common
  • Blurred vision
  • change in personality
  • change in vision
  • difficult or labored breathing
  • difficulty with sleeping
  • difficulty with speaking
  • dizziness
  • ear pain
  • headache
  • impaired vision
  • increase in body movements
  • loss of memory
  • nervousness
  • pounding in the ears
  • problems with memory
  • slow, fast, pounding, or irregular heartbeat or pulse
  • tightness in the chest
Rare
  • Inability to move the eyes
  • increased blinking or spasms of the eyelid
  • sticking out of the tongue
  • uncontrolled twisting movements of the neck, trunk, arms, or legs
  • unusual facial expressions
Incidence not known
  • Bloody or black, tarry stools
  • constipation
  • severe stomach pain
  • vomiting of blood or material that looks like coffee grounds

Some of the side effects that can occur with fluoxetine / olanzapine may not need medical attention. As your body adjusts to the medicine during treatment these side effects may go away. Your health care professional may also be able to tell you about ways to reduce or prevent some of these side effects. If any of the following side effects continue, are bothersome or if you have any questions about them, check with your health care professional:

More common
  • Diarrhea
  • dry mouth
  • increased appetite
  • lack or loss of strength
  • weight gain
Less common
  • Change or problem with discharge of semen
  • decreased interest in sexual intercourse
  • difficulty with moving
  • inability to have or keep an erection
  • loss in sexual ability, desire, drive, or performance
  • muscle pain or stiffness
  • not able to have an orgasm
  • pain, swelling, or redness in the joints
  • tooth disorder
  • twitching

For Healthcare Professionals

Applies to fluoxetine / olanzapine: oral capsule

General

Commonly reported side effects associated with fluoxetine-olanzapine treatment in short-term controlled studies at an incidence of at least 5% and double that of placebo were disturbance in attention, dry mouth, fatigue, hypersomnia, increased appetite, peripheral edema, sedation, somnolence, tremor, blurred vision, and increased weight.

Statistically significant differences in the incidence of weight gain, prolactin elevation, fatigue, and dizziness have been observed in a single 8-week randomized, double-blind, fixed dose study comparing 10 mg, 20 mg, and 40 mg olanzapine in patients with schizophrenia or schizoaffective disorder. Side effects associated with treatment discontinuation were increased weight and sedation.

In a single, 8-week, randomized, placebo-controlled clinical trial of fluoxetine-olanzapine for the treatment of bipolar I depression in patients aged 10 to 17 years, the side effects that lead to discontinuation that occurred at an incidence of at least 1% and greater than that of the placebo group were increased weight, suicidal ideation, bipolar disorder, and somnolence.[Ref]

Psychiatric

Antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. An increased risk of suicidal thinking and behavior in children, adolescents, and young adults (aged 18 to 24 years) with major depressive disorder (MDD) and other psychiatric disorders has been reported with short-term use of antidepressant drugs.

Adult and pediatric patients receiving antidepressants for MDD, as well as for psychiatric and nonpsychiatric indications, have reported symptoms that may be precursors to emerging suicidality, including anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and mania. Causality has not been established.

Placebo-controlled clinical trials in elderly patients with dementia-related psychosis showed a significantly increased risk of death in olanzapine-treated patients (3.5%) compared to placebo-treated patients (1.5%).

Anxiety, restlessness, and suicidal ideation were reported as a treatment-emergent side effect in an 8-week randomized, double-blind, placebo-controlled clinical trial in pediatric bipolar I depression in patients aged 10 to 17 years.[Ref]

Common (1% to 10%): Nervousness, restlessness, thinking abnormal
Uncommon (0.1% to 1%): Depersonalization, emotional lability, euphoria
Rare (less than 0.1%): Withdrawal syndrome
Frequency not reported: Bruxism, violent behaviors[Ref]

Nervous system

Very common (10% or more): Somnolence
Common (1% to 10%): Disturbance in attention, taste perversion, tremor
Uncommon (0.1% to 1%): Ataxia, coma, dysarthria, hypokinesia, movement disorder, myoclonus
Rare (less than 0.1%): Hyperkinesia
Frequency not reported: Dystonias, headache[Ref]

Dystonias may occur in the first few days of treatment; males and younger age groups appear to be at a greater risk for acute dystonia. The frequency and severity of symptoms appear greater with high potency and at higher doses of first generation antipsychotic drugs, but may occur at low doses.

One retrospective study of 23 outpatients with Parkinson's disease treated with 40 mg of fluoxetine a day reported that three patients experienced worsening of parkinsonism, two patients experienced improvement of parkinsonism, and 18 patients experienced no change. Another small study reported a series of four patients who experienced worsening of parkinsonism during treatment with fluoxetine.

Potentially life-threatening serotonin syndrome has been reported with SSRIs and SNRIs as monotherapy, but particularly with concomitant use of other serotonergic drugs and drugs that impair the metabolism of serotonin.

Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has been reported in connection to treatment with antipsychotic drugs, including olanzapine.

A number of case reports have implicated fluoxetine in causing seizures. Twelve of 6000 patients experienced convulsions during pre-marketing testing.

A case of dose-dependent exacerbation of preexisting, mild restless legs syndrome (which ultimately required discontinuation of fluoxetine) has been reported.

Somnolence and tremor were reported as a treatment-emergent side effect in an 8-week randomized, double-blind, placebo-controlled clinical trial in pediatric bipolar I depression in patients aged 10 to 17 years.[Ref]

Metabolic

Numerous cases of hyponatremia have been reported following treatment with an SSRI. Risk factors for the development of SSRI- associated hyponatremia including advanced age, female gender, concomitant use of diuretics, low body weight, and lower baseline serum sodium levels have been identified. Hyponatremia tends to develop within the first few weeks of treatment (range 3 to 120 days) and typically resolves within 2 weeks (range 48 hours to 6 weeks) after therapy has been discontinued with some patients requiring treatment. The proposed mechanism for the development of hyponatremia involves SIADH via release of antidiuretic hormone.

Hyperglycemia has been reported with olanzapine alone as well as in combination with fluoxetine. In an analysis of 7 controlled clinical studies, 2 of which were placebo controlled, with treatment duration up to 12 weeks, fluoxetine-olanzapine was associated with a greater mean change in random glucose compared to placebo (+8.65 mg/dL versus -3.86 mg/dL). The difference in mean changes was greater in patients with evidence of glucose dysregulation at baseline. Epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia in patients treated with atypical antipsychotics. The association between atypical antipsychotic therapy and increases in glucose levels appears greater with olanzapine than some other atypical antipsychotic agents.

Elevated uric acid, low albumin, low bicarbonate, and low inorganic phosphorus were observed at a statistically significant greater frequency in the fluoxetine-olanzapine group compared to the placebo group in adult clinical studies. Clinically meaningful increases in total cholesterol and triglyceride levels, sometimes greater than 500 mg/dL have also been observed in adults.

Clinically significant weight gain across all baseline BMI categories has been reported in clinical trials with fluoxetine-olanzapine. An analysis of 7 controlled clinical studies (2 of which were placebo-controlled) reported that, after a median exposure of eight weeks, 22% of patients treated with fluoxetine-olanzapine had gained at least 7% of their baseline weight. Long-term studies with fluoxetine-olanzapine (n=431), where patients were treated with this combination for at least 48 weeks, showed a mean weight gain of 6.7 kg.

Increased weight, appetite, blood triglycerides, and cholesterol were reported as treatment-emergent side effects in an 8 week randomized, double-blind, placebo-controlled clinical trial in pediatric bipolar I depression in patients aged 10 to 17 years. High fasting total cholesterol, high fasting LDL cholesterol, and high fasting triglycerides were observed at statistically significant greater frequencies in the fluoxetine-olanzapine group compared to the placebo group.[Ref]

Very common (10% or more): High fasting LDL cholesterol, high fasting triglycerides, high fasting total cholesterol, low bicarbonate, increased appetite, increased weight
Common (1% to 10%): Elevated uric acid, low albumin, low inorganic phosphorus, weight loss
Rare (less than 0.1%): Gout
Frequency not reported: Hyperglycemia, increased creatine phosphokinase, random triglyceride levels of 1000 mg/dL or more[Ref]

Cardiovascular

The mean standing pulse rate in patients treated with fluoxetine-olanzapine was reduced by 0.7 beats/minute.

QTcF interval prolongation of 450 milliseconds or more for males and 470 milliseconds for females was reported at an incidence of at least 1% in clinical trials. The mean increase in QTc interval was reported as significantly greater in fluoxetine-olanzapine treated patients than placebo-treated patients, olanzapine-treated, and fluoxetine-treated patients.

Mean increases in QTcF interval of 8.2 milliseconds was observed at a statistically significant greater frequency in the fluoxetine-olanzapine group compared to the placebo group in a single 8-week randomized, placebo-controlled clinical trial for bipolar I depression in children and adolescents aged 10 to 17 years.

One placebo-controlled study has suggested that fluoxetine has no effects on intraventricular conduction. Other case reports have suggested that fluoxetine may rarely provoke dysrhythmias. Other conflicting case reports have suggested that fluoxetine may have a propensity to provoke and alleviate vasoconstriction. Several cases of unexpected death occurring shortly after initiation of fluoxetine therapy have been reported in elderly patients with multiple medical problems.

In one case report, QTc prolongation and torsades de pointes developed in an elderly woman 6 months after starting therapy with fluoxetine 20 mg daily. The QTc interval returned to normal following discontinuation of fluoxetine. Four additional cases suggesting fluoxetine-associated QTc prolongation or torsades de pointes have been reported.[Ref]

Very common (10% or more): Edema
Common (1% to 10%): Generalized edema, vasodilatation
Frequency not reported: Bradycardia, hypotension, orthostatic hypotension, tachycardia
Postmarketing reports: Deep vein thrombosis[Ref]

Other

Accidental overdose was reported as a treatment-emergent side effect in an 8-week randomized, double-blind, placebo-controlled clinical trial in pediatric bipolar I depression in patients aged 10 to 17 years.[Ref]

Very common (10% or more): Fatigue
Common (1% to 10%): Asthenia, chills, neck rigidity, pain, pyrexia
Rare (less than 0.1%): Death
Frequency not reported: Body temperature dysregulation[Ref]

Genitourinary

Common (1% to 10%): Breast pain, erectile dysfunction, menorrhagia, urinary frequency, urinary incontinence
Uncommon (0.1% to 1%): Amenorrhea, female lactation, hypomenorrhea, metrorrhagia, urinary retention, urinary urgency, impaired urination
Rare (less than 0.1%): Breast engorgement, increased libido
Frequency not reported: Abnormal ejaculation, anorgasmia, decreased libido, dysuria, gynecological bleeding[Ref]

Urinary retention and galactorrhea have been reported with other SSRIs.

The estimates of the incidence of untoward sexual experience and performance may underestimate their actual incidence, partly because patients and physicians may be reluctant to discuss this issue. In placebo-controlled clinical trials ejaculation disorder (primarily ejaculation delay) was reported as a treatment-emergent side effect at an incidence of 6% and at least twice the incidence in placebo-treated male patients.

Dysmenorrhea was reported as a treatment-emergent side effect in an 8-week randomized, double-blind, placebo-controlled clinical trial in pediatric bipolar I depression in patients aged 10 to 17 years.[Ref]

Dermatologic

Common (1% to 10%): Ecchymosis
Uncommon (0.1% to 1%): Alopecia, dry skin, pruritus
Rare (less than 0.1%): Exfoliative dermatitis, purpura
Frequency not reported: Erythema multiforme, sweating[Ref]

Approximately 3% of fluoxetine-treated patients have been reported to develop a skin reaction.[Ref]

Endocrine

Very common (10% or more): Elevated prolactin
Frequency not reported: Diabetic coma[Ref]

Elevated prolactin levels were observed at a statistically significant greater frequency in the fluoxetine-olanzapine group compared to the placebo group in adult clinical studies and also in a single 8-week randomized, placebo-controlled clinical trial for bipolar I depression in children and adolescents aged 10 to 17 years.[Ref]

Gastrointestinal

A study of 26,005 antidepressant users has reported 3.6 times more upper GI bleeding episodes with the use of SSRIs relative to the population who did not receive antidepressant medications. Upper gastrointestinal tract bleeding was observed in 3.9 times more frequently in patients receiving fluoxetine.

Dyspepsia was reported as a treatment-emergent side effect in an 8-week randomized, double-blind, placebo-controlled clinical trial in pediatric bipolar I depression in patients aged 10 to 17 years.[Ref]

Very common (10% or more): Dry mouth
Common (1% to 10%): Abdominal distension, diarrhea, flatulence
Uncommon (0.1% to 1%): Buccoglossal syndrome, gastritis, gastroenteritis, nausea and vomiting, peptic ulcer
Rare (less than 0.1%): Gastrointestinal hemorrhage, intestinal obstruction, pancreatitis
Frequency not reported: Esophageal ulcer[Ref]

Hematologic

Common (1% to 10%): Low hemoglobin, low lymphocytes
Uncommon (0.1% to 1%): Anemia, thrombocytopenia
Rare (less than 0.1%): Leukopenia
Frequency not reported: Aplastic anemia, neutropenia[Ref]

Low lymphocytes and low hemoglobin were observed at a statistically significant greater frequency in the fluoxetine-olanzapine group compared to the placebo group in adult clinical studies[Ref]

Hepatic

ALT levels reported to return to normal, or were decreasing, at last follow-up in the majority of patients who either continued or discontinued treatment with fluoxetine-olanzapine.

Low total bilirubin levels were observed at a statistically significant greater frequency in the fluoxetine-olanzapine group compared to the placebo group in adult clinical studies. Elevated ALT and AST levels were observed at statistically significant greater frequencies in the fluoxetine-olanzapine group compared to the placebo group in a single 8-week randomized, placebo-controlled clinical trial for bipolar I depression in children and adolescents aged 10 to 17 years.[Ref]

Very common (10% or more): Elevated ALT and AST, low total bilirubin
Common (1% to 10%): Clinically significant ALT elevation less than 3 times the upper limit of normal (ULN), ALT elevations 5 times the ULN or more.
Rare (less than 0.1%): Bilirubinemia , liver fatty deposit
Frequency not reported: Cholestatic jaundice, increased alkaline phosphatase, jaundice
Postmarketing reports: Cholestatic or mixed liver injury, hepatitis[Ref]

Hypersensitivity

Common (1% to 10%): Photosensitivity reaction[Ref]

Musculoskeletal

Common (1% to 10%): Arthralgia, musculoskeletal stiffness, pain in extremity
Rare (less than 0.1%): Osteoporosis
Postmarketing reports: Rhabdomyolysis[Ref]

Epidemiological studies, primarily in patients aged 50 years or older, have shown an increased risk of bone fractures in patients receiving SSRIs or TCAs.

Back pain was reported as a treatment-emergent side effect in an 8-week randomized, double-blind, placebo-controlled clinical trial in pediatric bipolar I depression in patients aged 10 to 17 years.[Ref]

Ocular

Common (1% to 10%): Eye disorders
Uncommon (0.1% to 1%): Abnormality of accommodation, dry eyes[Ref]

Renal

Elevated urea nitrogen levels were observed at a statistically significant greater frequency in the fluoxetine-olanzapine group compared to the placebo group in adult clinical studies.

Glycosuria was reported at an incidence of 4.4% of patients treated with fluoxetine-olanzapine in an analysis of 6 controlled clinical studies, compared to 1.4% in the placebo group.[Ref]

Common (1% to 10%): Elevated urea nitrogen, glycosuria
Rare (less than 0.1%): Increased creatinine[Ref]

Respiratory

Common (1% to 10%): Sinusitis
Uncommon (0.1% to 1%): Epistaxis, yawn
Rare (less than 0.1%): Laryngismus
Frequency not reported: Eosinophilic pneumonia
Postmarketing reports: Pulmonary embolism[Ref]

References

1. "Product Information. Symbyax (fluoxetine-olanzapine)." Lilly, Eli and Company, Indianapolis, IN.

2. "Product Information. Zyprexa (olanzapine)." Lilly, Eli and Company, Indianapolis, IN.

3. "Product Information. Prozac (fluoxetine)." Dista Products Company, Indianapolis, IN.

4. Mann JJ, Kapur S "The emergence of suicidal ideation and behavior during antidepressant pharmacotherapy]." Arch Gen Psychiatry 48 (1991): 1027-33

5. Caley CF, Friedman JH "Does fluoxetine exacerbate Parkinson's disease?" J Clin Psychiatry 53 (1992): 278-82

6. Steur EN "Increase of Parkinson disability after fluoxetine medication." Neurology 43 (1993): 211-3

7. Vishwanath BM, Navalgund AA, Cusano W, Navalgund KA "Fluoxetine as a cause of SIADH." Am J Psychiatry 148 (1991): 542-3

8. Spigset O, hedenmalm K "Hyponatremia in relation to treatment with antidepressants: a survey of reports in the World Health Organization data base for spontaneous reporting of adverse drug reactions." Pharmacotherapy 17 (1997): 348-52

9. Jacob S, Spinler SA "Hyponatremia associated with selective serotonin-reuptake inhibitors in older adults." Ann Pharmacother 40 (2006): 1618-22

10. Schattner A, Skurnik Y "Fluoxetine-induced SIADH." J Am Geriatr Soc 44 (1996): 1413

11. FDA. U.S. Food and Drug Admiinistration. Center for Drug Evaluation and Research "FDA Public Health Advisory. Deaths and antipsychotics in elderly patients with behavioral disturbances. Available from: URL: http://www.fda.gov/cder/drug/advisory/antipsychotics.htm." ([2005 Apr 11]):

12. Wilting I, Smals OM, Holwerda NJ, Meyboom RH, De Bruin ML, Egberts TC "QTc prolongation and torsades de pointes in an elderly woman taking fluoxetine." Am J Psychiatry 163 (2006): 325

13. Herman JB, Brotman AW, Pollack MH, Falk WE, Biederman J, Rosenbaum JF "Fluoxetine-induced sexual dysfunction." J Clin Psychiatry 51 (1990): 25-7

14. Patterson WM "Fluoxetine-induced sexual dysfunction." J Clin Psychiatry 54 (1993): 71

15. Olfson M, Wilner MT "A family case history of fluoxetine-induced skin reactions." J Nerv Ment Dis 179 (1991): 504-5

16. deAbajo FJ, Rodriguez LAG, Montero D "Association between selective serotonin reuptake inhibitors and upper gastrointestinal bleeding: population based case-control study." Br Med J 319 (1999): 1106-9

17. Po AL "Antidepressants and upper gastrointestiinal bleeding: new results suggest a link." BMJ 319 (1999): 1081-2

18. Dalton SO, Johansen C, Mellemkjaer L, Norgard B, Sorensen HT, Olsen JH "Use of selective serotonin reuptake inhibitors and risk of upper gastrointestinal tract bleeding: a population-based cohort study." Arch Intern Med 163 (2003): 59-64

19. Aranth J, Lindberg C "Bleeding, a side effect of fluoxetine." Am J Psychiatry 149 (1992): 412

20. Alderman CP, Moritz CK, Ben-Tovim DI "Abnormal platelet aggregation associated with fluoxetine therapy." Ann Pharmacother 26 (1992): 1517-9

21. Cai Q, Benson MA, Talbot TJ, Devadas G, Swanson HJ, Olson JL, Kirchner JP "Acute hepatitis due to fluoxetine therapy." Mayo Clin Proc 74 (1999): 692-4

22. Liu B, Anderson G, Mittmann N, To Teresa, Axcell T, Shear N "Use of selective serotonin-reuptake inhibitors or tricyclic antidepressants and risk of hip fractures in elderly people." Lancet 351 (1998): 1303-7

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