Fluoxetine-Olanzapine

Fluoxetine-Olanzapine is a combination of prescription medicines used for treating depression associated with bipolar I disorder or resistant depression.

• Fluoxetine-Olanzapine is available under the following different brand names: Symbyax

Adult and pediatric dosage

Capsule

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

Depression Associated with Bipolar I Disorder

Adult dosage

• Initial: 25 mg/6 mg orally every day in the evening
• If needed, may titrate with 25-50 mg fluoxetine/6-12 mg olanzapine; not to exceed 75 mg/18 mg per day

Pediatric dosage

• Children below 10 years: Safety and efficacy not established
• Children between 10-17 years
• Initial: 25 mg/3 mg orally every day in the evening
• If needed, may titrate with 25-50 mg fluoxetine/6-12 mg olanzapine; not to exceed 50 mg/12 mg per day

Geriatric dosage

• Initiate with 25 mg/3 mg to 25 mg/6 mg orally every day

Dosage Considerations – Should be Given as Follows: 

• See “Dosages”

Common side effects of the Fluoxetine-Olanzapine include:

• increased appetite,
• weight gain,
• trouble concentrating,
• feeling tired,
• vision changes, and
• swelling in the hands or feet

Serious side effects of the Fluoxetine-Olanzapine include:

• hives,
• difficulty breathing,
• swelling of the face, lips, tongue, or throat,
• skin rash,
• fever,
• swollen glands,
• flu-like symptoms,
• unusual bruising,
• yellowing of your skin or eyes,
• uncontrollable muscle movements of the lips, tongue, eyes, face, arms, or legs,
• mood or behavior changes,
• anxiety,
• panic attacks,
• trouble sleeping,
• impulsive behavior,
• irritableness,
• agitation,
• hostility,
• aggression,
• restlessness,
• hyperactivity (mentally or physically),
• increased depression,
• thoughts of suicide
• lightheadedness,
• blurred vision,
• tunnel vision,
• eye pain or swelling,
• seeing halos around lights,
• chest pain,
• severe dizziness,
• fast or pounding heartbeats,
• feeling increased thirst or hot,
• being unable to urinate,
• heavy sweating,
• hot and dry skin,
• agitation,
• hallucinations,
• fast heart rate,
• overactive reflexes,
• nausea,
• vomiting,
• diarrhea,
• loss of coordination,
• very stiff (rigid) muscle,
• high fever,
• sweating,
• confusion,
• uneven heartbeats,
• tremors,
• headache,
• slurred speech,
• vomiting,
• severe weakness,
• feeling unsteady,
• shallow breathing,
• increased thirst,
• increased urination,
• hunger,
• fruity breath odor,
• confusion, and
• upset stomach.

Rare side effects of the Fluoxetine-Olanzapine include:

• none 

This is not a complete list of side effects and other serious side effects or health problems that may occur as a result of the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may report side effects or health problems to FDA at 1-800-FDA-1088.

If your medical doctor is using this medicine to treat your pain, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider, or pharmacist first.

• Fluoxetine-Olanzapine has severe interactions with the following drugs:
  • amisulpride
  • artemether/lumefantrine
• Fluoxetine-Olanzapine has serious interactions with at least 151 other drugs.
• Fluoxetine-Olanzapine has moderate interactions with at least 539 other drugs.
• Fluoxetine-Olanzapine has minor interactions with at least 43 other drugs:

This information does not contain all possible interactions or adverse effects. Visit the RxList Drug Interaction Checker for any drug interactions. Therefore, before using this product, tell your doctor or pharmacist about all the products you use. Keep a list of all your medications with you and share this information with your doctor and pharmacist. Check with your health care professional or doctor for additional medical advice, or if you have health questions or concerns.

Contraindications

• Hypersensitivity to any component
• Concomitant thioridazine, pimozide
• Coadministration with MAOIs
• Within 14 days of taking MAOIs
• Increased risk of serotonin syndrome when MAOIs coadministered
• MAOIs coadministered with fluoxetine or within 5 weeks of discontinuing fluoxetine-Olanzapine
• Starting fluoxetine in a patient who is being treated with linezolid or IV methylene blue

Effects of drug abuse

• None

Short-Term Effects

• See “What Are Side Effects Associated with Using Fluoxetine-Olanzapine?”

Long-Term Effects

• See “What Are Side Effects Associated with Using Fluoxetine-Olanzapine?”

Cautions

• This drug combination has the potential to impair judgment, thinking, or motor skills; patients should be cautioned about operating hazardous machinery, including automobiles until they are reasonably certain that therapy does not affect them adversely
• Pupillary dilation occurs following the use of many antidepressant drugs and may trigger an angle-closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy
• Cerebrovascular adverse events (eg, stroke, transient ischemic attack), including fatalities, are reported in patients in trials of olanzapine in elderly patients with dementia-related psychosis; this drug combination is not approved for the treatment of patients with dementia-related psychosis
• Olanzapine exhibits in vitro muscarinic receptor affinity; in premarketing clinical studies, this drug combination was associated with constipation, dry mouth, and tachycardia, all adverse reactions possibly related to cholinergic antagonism; such adverse reactions were not often the basis for study discontinuations; this drug combination should be used with caution in patients with a current diagnosis or prior history of urinary retention, clinically significant prostatic hypertrophy, constipation, a history of paralytic ileus, or related condition
• Potential for abnormal bleeding with concomitant ASA, NSAIDs, or other antiplatelet drugs; case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between the use of drugs that interfere with serotonin reuptake and occurrence of gastrointestinal bleeding; bleeding reactions related to SNRIs and SSRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages; patients should be cautioned about the risk of bleeding associated with concomitant use of this combination drug and NSAIDs, aspirin, or other drugs that affect coagulation
• The risk of mydriasis; may trigger angle closure attack in patients with angle-closure glaucoma with anatomically narrow angles without a patent iridectomy
• Therapy may induce orthostatic hypotension associated with dizziness, tachycardia, bradycardia, and in some patients, syncope, especially during the initial dose-titration period; treatment should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, or conditions that would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medication
• Clinical worsening and suicide ideation may occur despite medication; consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms; if the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with the recognition that abrupt discontinuation can be associated with certain symptoms
• 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
• May cause somnolence, postural hypotension, and 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
• Seizures occurred in 0.2% fluoxetine-Olanzapine-treated patients during open-label clinical studies; this drug combination should be used cautiously in patients with a history of seizures or with conditions that potentially lower seizure threshold, eg, Alzheimer’s dementia; this drug combination is not approved for treatment of patients with Alzheimer’s disease; conditions that lower seizure threshold may be more prevalent in a population of ≥65 years of age
• 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
• Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic drugs; appropriate care is advised when prescribing this drug combination for patients who will be experiencing conditions that may contribute to an elevation in core body temperature (eg, exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration
• Because of the long elimination half-lives of fluoxetine and its major active metabolite, changes in dose will not be fully reflected in plasma for several weeks, affecting both strategies for titration to final dose and withdrawal from treatment; this is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine following the discontinuation of fluoxetine
• Neuroleptic malignant syndrome
  • Neuroleptic malignant syndrome (NMS) is reported in association with the 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); additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure
  • The diagnostic evaluation of patients with this syndrome is complicated; in arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (eg, pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS); other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology
  • The management of NMS should include immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, intensive symptomatic treatment and medical monitoring, and treatment of any concomitant serious medical problems for which specific treatments are available; there is no general agreement about specific pharmacological treatment regimens for NMS
  • If after recovering from NMS, a patient requires treatment with an antipsychotic, the patient should be carefully monitored, since recurrences of NMS have been reported
• Allergic reactions
  • Since the introduction of fluoxetine, systemic reactions, possibly related to vasculitis, have developed in patients with rash; although these reactions are rare, they may be serious, involving the lung, kidney, or liver; death has been reported to occur in association with these systemic reactions
  • Anaphylactoid reactions, including bronchospasm, angioedema, and urticaria alone and in combination, reported
  • Pulmonary reactions, including inflammatory processes of varying histopathology and/or fibrosis, are reported rarely; these reactions occurred with dyspnea as the only preceding symptom; whether these systemic reactions and rash have a common underlying cause or are due to different etiologies or pathogenic processes is not known
  • Furthermore, a specific underlying immunologic basis for these reactions has not been identified; upon the appearance of rash or of other possible allergic phenomena for which an alternative etiology cannot be identified, therapy should be discontinued
• Activation of mania/hypomania
  • A major depressive episode may be the initial presentation of bipolar disorder; it is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a manic episode in patients at risk for bipolar disorder
  • Whether any of the symptoms described for clinical worsening and suicide risk represent such a conversion is unknown; however, before initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression; it should be noted that this drug combination is approved for acute treatment of depressive episodes associated with bipolar I disorder
  • Because of the cyclical nature of bipolar I disorder, patients should be monitored closely for the development of symptoms of mania/hypomania during therapy
• Tardive dyskinesia
  • A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs; although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, impossible to rely upon prevalence estimates to predict, the inception of antipsychotic treatment, which patients are likely to develop the syndrome; whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown
  • The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase; however, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses or may even arise after discontinuation of treatment.
  • Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is withdrawn; antipsychotic treatment itself, however, may suppress (or partially suppress) signs and symptoms of the syndrome and thereby may possibly mask the underlying process; the effect that symptomatic suppression has upon the long-term course of the syndrome is unknown
  • This drug combination should be prescribed in a manner that is most likely to minimize the risk of tardive dyskinesia; if signs and symptoms of tardive dyskinesia appear in a patient receiving this drug combination, drug discontinuation should be considered; however, some patients may require treatment with this drug combination despite the presence of syndrome; the need for continued treatment should be reassessed periodically
• Serotonin syndrome
  • Development of potentially life-threatening serotonin syndrome reported with SNRIs and SSRIs, including this drug combination, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John's Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue)
  • Serotonin syndrome symptoms may include mental status changes (eg, agitation, hallucinations, delirium, and coma), autonomic instability (eg, tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (eg, tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (eg, nausea, vomiting, diarrhea); patients should be monitored for the emergence of serotonin syndrome
  • Concomitant use of this drug in combination with MAOIs intended to treat psychiatric disorders is contraindicated; should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue; all reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg; no reports involved administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses
  • There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking this drug combination; therapy should be discontinued before initiating treatment with the MAOI
  • If concomitant use of this drug in combination with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamines, and St. John's Wort is clinically warranted, patients should be made aware of potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases
  • Treatment with this drug combination and any concomitant serotonergic agents should be discontinued immediately if adverse events occur and supportive symptomatic treatment should be initiated
• Leukopenia, neutropenia, agranulocytosis
  • In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia, and agranulocytosis have been reported temporally related to antipsychotic agents
  • Possible risk factors for leukopenia/neutropenia include preexisting low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia; patients with a history of clinically significant low WBC or drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during first few months of therapy and discontinuation of this drug combination should be considered at the first sign of clinically significant decline in WBC in absence of other causative factors
  • Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur; patients with severe neutropenia (absolute neutrophil count below 1000/mm3) should discontinue and have their WBC followed until recovery
• Hyponatremia
  • Hyponatremia is reported during treatment with SNRIs and SSRIs, including fluoxetine and this drug combination; in many cases, this hyponatremia appears to be the result of a syndrome of inappropriate antidiuretic hormone secret
  • Elderly patients may be at greater risk of developing hyponatremia with SNRIs and SSRIs; also, patients taking diuretics or who are otherwise volume depleted may be at greater risk; discontinuation of this drug combination should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted
  • Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls; more severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death
• QT prolongation
  • Post-marketing cases of QT interval prolongation and ventricular arrhythmia including Torsade de Pointes have been reported in patients treated with fluoxetine; therapy should be administered with caution in patients with congenital long QT syndrome; a previous history of QT prolongation; a family history of long QT syndrome or sudden cardiac death; and other conditions that predispose to QT prolongation and ventricular arrhythmia
  • Such conditions include concomitant use of drugs that prolong the QT interval; hypokalemia or hypomagnesemia; recent myocardial infarction, uncompensated heart failure, bradyarrhythmias, and other significant arrhythmias; and conditions that predispose to increased fluoxetine exposure (overdose, hepatic impairment, use of CYP2D6 inhibitors, CYP2D6 poor metabolizer status, or use of other highly protein-bound drugs)
  • Consider ECG assessment and periodic ECG monitoring if initiating therapy in patients with risk factors for QT prolongation and ventricular arrhythmia; consider discontinuing therapy and obtaining a cardiac evaluation if patients develop signs or symptoms consistent with ventricular arrhythmia
  • Clinicians should administer therapy with caution in those children or adolescents who are known to be particularly at risk for QT prolongation
• Hyperprolactinemia
  • As with other drugs that antagonize dopamine D2 receptors, this drug combination elevates prolactin levels, and the elevation persists during administration; hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion; this, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients
  • Galactorrhea, amenorrhea, gynecomastia, and erectile dysfunction were reported in patients receiving prolactin-elevating compounds; long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects
• Sexual dysfunction
  • Use may cause symptoms of sexual dysfunction in both male and female patients; inform patients that they should discuss any changes in sexual function and potential management strategies with their healthcare provider
  • Use of SSRIs may cause symptoms of sexual dysfunction; in male patients, SSRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction
  • In female patients, SSRI/SNRI use may result in decreased libido and delayed or absent orgasm
  • Important for prescribers to inquire about sexual function before initiation of therapy and to inquire specifically about changes in sexual function during treatment because the sexual function may not be spontaneously reported
  • When evaluating changes in sexual function, obtaining a detailed history (including the timing of symptom onset) is important because sexual symptoms may have other causes, including underlying psychiatric disorder
  • Discuss potential management strategies to support patients in making informed decisions about treatment
• Discontinuation adverse reactions
  • Adverse reactions occurring upon discontinuation of SNRIs and SSRIs were reported, particularly when done abruptly; reactions may include dysphoric mood, irritability, agitation, dizziness, sensory disturbances (eg, paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania
  • While these reactions are generally self-limiting, there have been reports of serious discontinuation symptoms; patients should be monitored for these symptoms when discontinuing treatment with fluoxetine; a gradual reduction in the dose rather than abrupt cessation is recommended whenever possible
  • If intolerable symptoms occur following a decrease in dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered; subsequently, the healthcare provider may continue decreasing the dose but at a more gradual rate
  • Plasma fluoxetine and norfluoxetine concentration decrease gradually after therapy, which may minimize the risk of discontinuation symptoms with this drug
• Metabolic changes
  • Atypical antipsychotic drugs have been associated with metabolic changes including hyperglycemia, dyslipidemia, and weight gain; metabolic changes may be associated with increased cardiovascular/cerebrovascular risk
  • Hyperglycemia/diabetes
    • Healthcare providers should consider the risks and benefits when prescribing this drug to patients with an established diagnosis of diabetes mellitus or having borderline increased blood glucose levels ting 100­-126 mg/dL, nonfasting 140-200 mg/dL)
    • Patients taking this drug combination should be monitored regularly for worsening glucose control; patients starting treatment should undergo fasting blood glucose testing at beginning of treatment and periodically during treatment
    • Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness; patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing
    • In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug
    • Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics, including olanzapine alone, as well as olanzapine taken concomitantly with fluoxetine
    • Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population
    • Epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse reactions in patients treated with atypical antipsychotics; while relative risk estimates are inconsistent, the association between atypical antipsychotics and increases in glucose levels appears to fall on a continuum and olanzapine appears to have a greater association than some other atypical antipsychotics
  • Dyslipidemia
    • Undesirable alterations in lipids observed with use; clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using this drug combination, recommended
  • Weight gain
    • Potential consequences of weight gain should be considered before initiating the therapy; patients receiving this drug combination should receive regular monitoring of weight
• Drug interaction overview
  • Fluoxetine is primarily metabolized by CYP2D; the use of CYP2D6 inhibitors may increase the risk of QT interval prolongation
  • Pimozide and thioridazine are contraindicated for use with this drug combination; avoid concomitant use of drugs known to prolong QT interval; these include specific antipsychotics (eg, ziprasidone, iloperidone, chlorpromazine, mesoridazine, droperidol); specific antibiotics (eg, erythromycin, gatifloxacin, moxifloxacin, sparfloxacin); Class 1A antiarrhythmic medications (eg, quinidine, procainamide); Class III antiarrhythmics (eg, amiodarone, sotalol); and others (eg, pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus)

Pregnancy and Lactation

• There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to psychiatric medications, during pregnancy; healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/
• 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 is associated with complications in newborns and may require prolonged hospitalization, respiratory support, and tube feeding
• Women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants; consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum
• Antipsychotic drug exposure
  • Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder reported in neonates who were exposed to antipsychotic drugs, including olanzapine, during the third trimester of pregnancy; these symptoms have varied in severity
  • Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately; some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization
• Fluoxetine drug exposure
  • Neonates exposed to fluoxetine and other SSRIs or SNRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding; such complications can arise immediately upon delivery; reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying
  • These findings are consistent with either a direct toxic effect of SSRIs and SNRIs or possibly a drug discontinuation syndrome; it should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome
• Females and males of reproductive potential
  • Females: Based on the pharmacologic action of olanzapine (dopamine D2 receptor blockade), treatment with a drug combination may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential
• Persistent pulmonary hypertension of the newborn
  • The 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 the 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
  • Consider developmental and health benefits of breastfeeding along with the mother’s clinical need for therapy and any potential adverse effects on the breastfed child from therapy or underlying maternal condition
  • Infants exposed to drug combinations should be monitored for agitation, irritability, poor feeding, poor weight gain, excess sedation, and extrapyramidal symptoms (tremors and abnormal muscle movements)
• Olanzapine
  • In a study in lactating, healthy women, olanzapine was excreted in breast milk
  • The mean infant dose at a 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; the concentration in the mother’s plasma was 295 ng/mL