Dosing and uses of Symbyax (fluoxetine/olanzapine)
Adult dosage forms and strengths
fluoxetine/olanzapine
capsule
- 25mg/3mg
- 25mg/6mg
- 50mg/6mg
- 25mg/12mg
- 50mg/12mg
Depression Associated with 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
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
Pediatric dosage forms and strengths
Safety and efficacy not established
Geriatric dosage forms and strengths
Initiate with 25 mg/3 mg to 25 mg/6 mg PO qDay
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 MAOIs, thioridazine, pimozide
Coadministration with serotonergic drugs
- Coadministration may cause serotonin syndrome
- Increased risk when MAOIs coadministered with fluoxetine or within 5 weeks of discontinuing fluoxetine/olanzapine
- Wait to initiate fluoxetine until 14 days after stopping an MAOI
- Seratonin 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
- If linezolid or IV methylene blue must be administered, discontinue fluoxetine immediately and monitor for CNS toxicity; may resume fluoxetine 24 hr after last linezolid or methylene blue dose or after 5 weeks of monitoring, whichever comes first
Cautions
Hypertension, hepatic impairment, slow metabolizers
Pregnancy: Conflicting evidence regarding use of SSRIs during pregnancy and increased risk of persistent pulmonary hypertension of the newborn (see Pregnancy)
Avoid alcohoL
Preascribe 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
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
Switching to/from MAOIs: start fluoxetine/olanzapine after at least 14 days of stopping MAOI; may begin MAOI after at least 5 weeks of stopping fluoxetine/olanzapine
Risk of serotonin syndrome when used with other strong serotonergic drugs
Hyperglycemia/diabetes
- Incr 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
Pregnancy and lactation
Pregnancy
Pregnancy category: C
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: Enters breast milk; not recommended
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.
Pharmacology of Symbyax (fluoxetine/olanzapine)
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
