fluoxetine/olanzapine (Rx)

Brand and Other Names:Symbyax
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Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & Strengths

fluoxetine/olanzapine

capsule

  • 25mg/3mg
  • 25mg/6mg
  • 50mg/6mg
  • 25mg/12mg
  • 50mg/12mg

Depression Associated with Bipolar I Disorder

Indicated for acute depressive episodes in bipolar I disorder

Initial: 25 mg/6 mg PO qDay in evening

If needed, may titrate with 25-50 mg fluoxetine/6-12 mg olanzapine; not to exceed 75 mg/18 mg per day

Treatment of Resistant Depression

Indicated for treatment resistant depression (ie, major depressive disorder in patients who do not respond to 2 separate trials of different antidepressants of adequate dose and duration in the current episode)

Initial: 25 mg/6 mg PO qDay in evening

If needed, may titrate with 25-50 mg fluoxetine/6-12 mg olanzapine; not to exceed 75 mg/18 mg per day

Dosage Modifications

Hypotensive diathesis, hepatic impairment, or slow metabolism: Initiate with 25 mg/3 mg to 25 mg/6 mg PO qDay

Slow metabolism observed in females, elderly, and nonsmokers

Discontinue gradually

Coadministration with other monoamine oxidase inhibitor (MAOI)s (eg, linezolid or methylene blue)

  • Do not start fluoxetine/olanzapine in patients treated with linezolid or IV methylene blue due to the increased risk of serotonin syndrome
  • If alternatives to linezolid or IV methylene blue treatment are not available and potential benefits of linezolid or intravenous methylene blue are judged to outweigh risks of serotonin syndrome, promptly stop fluoxetine/olanzapine, and linezolid or intravenous methylene blue can be administered
  • Monitor for symptoms of serotonin syndrome for 5 weeks or until 24 hr after the last dose of linezolid or IV methylene blue, whichever comes first; resume 24 hr after the last dose of linezolid or IV methylene blue

Dosing Considerations

Switching to or from a MAOIs to treat psychiatric disorders

  • Allow at least 14 days to elapse prior to starting fluoxetine/olanzapine after discontinuation of an MAOI intended to treat psychiatric disorders
  • Conversely, allow at least 5 weeks after stopping fluoxetine/olanzapine before starting an MAOI intended to treat psychiatric disorders

Dosage Forms & Strengths

fluoxetine/olanzapine

capsule

  • 25mg/3mg
  • 25mg/6mg
  • 50mg/6mg
  • 25mg/12mg
  • 50mg/12mg

Depression Associated with Bipolar I Disorder

Indicated for acute depressive episodes in bipolar I disorder in children and adolescents aged 10-17 years

<10 years: Safety and efficacy not established

10-17 years

  • Initial: 25 mg/3 mg PO qDay in evening
  • If needed, may titrate with 25-50 mg fluoxetine/6-12 mg olanzapine; not to exceed 50 mg/12 mg per day

Clinical studies of fluoxetine/olanzapine did not include sufficient numbers of patients ≥65 year; use with caution

Initiate with 25 mg/3 mg to 25 mg/6 mg PO qDay

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Interactions

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            Warnings

            Black Box Warnings

            Children and antidepressants

            • In short-term studies, antidepressants increased the risk of suicidal thinking and behavior in children, adolescents, and young adults (<24 years of age) taking antidepressants for major depressive disorders and other psychiatric illnesses
            • This increase was not seen in patients >24 years of age
            • A slight decrease in suicidal thinking was seen in adults >65 years
            • Risks must be weighed in children and young adults against the benefits of taking antidepressants
            • Patients should be monitored closely for changes in behavior, clinical worsening, and suicidal tendencies; this should be done during the initial 1-2 months of therapy and dosage adjustments
            • The patient’s family should communicate to the healthcare provider any abrupt changes in behavior; worsening behavior and suicidal tendencies that are not part of the presenting symptoms may require discontinuation of therapy
            • This drug is not approved for use in pediatric patients

            Antipsychotics & Dementia

            • Patients with dementia-related psychosis that are treated with antipsychotic drugs are at an increased risk of death as shown in short-term controlled trials
            • The deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature
            • This drug is not approved for the treatment of patients with dementia-related psychosis (See WARNINGS in package insert)

            Contraindications

            Hypersensitivity to any component

            Concomitant thioridazine, pimozide

            Coadministration with MAOIs

            • Coadministration may cause serotonin syndrome
            • Increased risk when MAOIs coadministered with fluoxetine or within 5 weeks of discontinuing fluoxetine/olanzapine
            • Serotonin syndrome symptoms include tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome, seizures, rigidity, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma
            • Starting fluoxetine in a patient who is being treated with linezolid or IV methylene blue is contraindicated because of an increased risk of serotonin syndrome
            • See Dosing Considerations and Dosage Modifications

            Cautions

            Hypertension, hepatic impairment, slow metabolizers

            Conflicting evidence regarding use of SSRIs during pregnancy and increased risk of persistent pulmonary hypertension of the newborn (see Pregnancy)

            Pupillary dilation occurs following use of many antidepressant drugs may trigger an angle-closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy

            Anaphylactoid reactions (eg, bronchospasm, angioedema, and urticaria) alone and in combination, reported

            Avoid alcohol

            Prescribe the smallest quantity consistent with good patient care

            Risk of orthostatic hypotension

            Potential for abnormal bleeding with concomitant ASA, NSAIDs, or other antiplatelet drugs

            Risk of mydriasis; may trigger angle closure attack in patients with angle closure glaucoma with anatomically narrow angles without a patent iridectomy

            Neonates exposed to SNRIs or SSRIs late in third trimester of pregnancy have developed complications requiring prolonged hospitalization, respiratory support, & tube feeding

            Clinical worsening and suicide ideation may occur despite medication

            Postmarketing cases of QT interval prolongation and ventricular arrhythmia including torsade de pointes have been reported in patients treated with fluoxetine

            Neuroleptic malignant syndrome (NMS) reported in association with administration of antipsychotic drugs (eg, olanzapine); clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia)

            Drug reaction with eosinophilia and systemic symptoms (DRESS) reported with olanzapine exposure; DRESS may present with a cutaneous reaction (eg, rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis; discontinue treatment if DRESS is suspected

            Not approved in treatment of dementia-related psychosis; may increase incidence of CVA, TIA

            FDA Warning regarding off-label use for dementia in elderly

            Prolactin levels: Changes from normal to high prolactin levels observed in 3 controlled studies; incidence ranging from 28-47%

            May cause decreased libido, anorgasmia, erectile dysfunction, and abnormal ejaculation; priapism reported with SSRIs

            May cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries; for patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long- term antipsychotic therapy

            Risk of developing tardive dyskinesia and likelihood that it will become irreversible are believed to increase as treatment duration and the total cumulative dose of antipsychotic drugs administered to the patient increase

            Seizures occurred in 0.2% fluoxetine/olanzapine-treated patients during open-label clinical studies

            In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents

            Esophageal dysmotility and aspiration associated with antipsychotic drug use; aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer’s disease

            Risk of serotonin syndrome when used with other strong serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John's Wort)

            Disruption of body’s ability to reduce core body temperature has been attributed to antipsychotic drugs

            Owing to the long elimination half-lives of fluoxetine and its major active metabolite, dosage changes will not fully be reflected in plasma for several weeks, affecting both strategies for titration to final dose and withdrawal from treatment

            Hyperglycemia/diabetes

            • Increased risk of hyperglycemia and diabetes; in some cases, hyperglycemia concomitant with use of atypical antipsychotics (of which olanzapine is a member) has been associated with ketoacidosis, hyperosmolar coma, or death
            • Monitor blood glucose of high-risk patients
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            Pregnancy & Lactation

            Pregnancy

            Neonates exposed to antipsychotic drugs during the 3rd trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery

            These complications vary in severity; in some cases, symptoms have been self-limited, while in other cases neonates have required intensive care unit support and prolonged hospitalization

            Treatment of Pregnant Women during the First Trimester with Fluoxetine: There are no adequate and well-controlled clinical studies on the use of fluoxetine in pregnant women, but 1 prospective cohort study conducted by the European Network of Teratology Information Services reported an increased risk of cardiovascular malformations in infants born to women (N = 253) exposed to fluoxetine during the first trimester of pregnancy compared to infants of women (N = 1,359) who were not exposed to fluoxetine

            SSRI use late in the third trimester associated with complications in newborns and may require prolonged hospitalization, respiratory support, and tube feeding

            Persistent pulmonary hypertension of the newborn

            • Potential risk of persistent pulmonary hypertension of the newborn (PPHN) when used during pregnancy
            • Initial Public Health Advisory in 2006 was based on a single published study; since then, there have been conflicting findings from new studies, making it unclear whether use of SSRIs during pregnancy can cause PPHN
            • FDA has reviewed the additional new study results and has concluded that, given the conflicting results from different studies, it is premature to reach any conclusion about a possible link between SSRI use in pregnancy and PPHN
            • FDA recommendation: FDA advises health care professionals not to alter their current clinical practice of treating depression during pregnancy and to report any adverse events to the FDA MedWatch program

            Lactation

            Not recommended in breastfeeding women

            Olanzapine

            • In a study in lactating, healthy women, olanzapine was excreted in breast milk
            • Mean infant dose at steady state was estimated to be 1.8% of the maternal olanzapine dose
            • It is recommended that women receiving olanzapine should not breastfeed

            Fluoxetine

            • Excreted in human breast milk
            • In 1 breast milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 ng/mL; concentration in the mother’s plasma was 295 ng/mL

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Fluoxetine: Inhibits CNS neuron setotonin reuptake with minimal or no effect on norepinephrine or dopamine reuptake; does not bind to alpha-adrenergic, histamine, or cholinergic receptors

            Olanzapine: Potent antagonist of dopamine 1-3, histamine H1, serotonin 5-HT2A and 5-HT2C, and alpha1-adrenergic receptors; shows moterate antagonism for 5-HT3, and muscarinic M1-5 receptors; binds to GABA-A, benzodiazepine, and beta-adrenergic receptors

            Absorption

            Peak plasma time: 4-6 hr (50 mg/12 mg-dose); 6 hr (olanzapine); 6-8 hr (fluoxetine)

            Peak plasma concentration: 15-55 ng/mL (fluoxetine)

            Distribution

            Vd: ~1,000 L (olanzapine)

            Protein binding: 93% (olanzapine); ~94.5% (fluoxetine)

            Mechanism

            Direct glucuronidation and CYP450-mediated oxidation are the primary metabolic pathways for olanzapine

            CYP2D6-mediated oxidation appears to be a minor metabolic pathway in vivo, because clearance of olanzapine is not reduced in subjects who are deficient in this enzyme

            Fluoxetine is extensively metabolized in the liver to its active metabolite, norfluoxetine, via CYP2D6 pathway

            Excretion

            Half-life: 21-54 hr (olanzapine)

            Clearance: 12-47 L/hr (olanzapine)

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            Administration

            Oral Administration

            Administer orally once daily in the evening

            If missed dose, take the missed dose as soon possible; if it is almost time for the next dose, skip the missed dose and take next dose at the regular time; do not take two doses at once

            Storage

            Tablets: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F); keep tightly closed and protect from moisture

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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
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            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
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