Olanzapine + Fluoxetine

Oral
Treatment resistant depression

Oral
Depressive phase of bipolar disorder

Patients with a predisposition to hypotension, combined factors for reduced metabolism (e.g. females, nonsmokers), or those who may be pharmacodynamically sensitive to olanzapine: Initially, 3 mg/25 mg to 6 mg/25 mg once daily in the evening, may be adjusted with caution based on response and tolerability. Individual agents may provide lower dose strengths; consider using fixed-dose combination products or individual components based on the patient's dose requirements. Refer to the detailed local official guidelines when using the individual components of olanzapine and fluoxetine.

Pharmacogenomics:

Fluoxetine is extensively metabolised in the liver by CYP2D6 into the active metabolite, norfluoxetine. It is a racemic mixture of 2 enantiomers, specifically R-fluoxetine and S-fluoxetine, with the latter being slightly more potent.

CYP2D6 poor metabolisers have demonstrated to have increased concentrations of S-fluoxetine and decreased concentrations of S-norfluoxetine, as well as unchanged metabolism of R-fluoxetine. However, when compared with the normal metabolisers, the total sum of the plasma concentrations of the 4 enantiomers was not significantly higher among the poor metabolisers. This suggests that the net pharmacodynamic activities were essentially similar between the 2 groups. Approx 7% of the population is considered CYP2D6 poor metabolisers.

The US Food and Drug Administration (US FDA) drug labelling states that because of the metabolism of fluoxetine involving the CYP2D6 system, concurrent treatment with agents metabolised via CYP2D6 (e.g. TCAs) may result in drug interactions. Therefore, caution should be exercised when considering the coadministration of fluoxetine with agents metabolised via CYP2D6.

Initially, 3 mg/25 mg to 6 mg/25 mg once daily in the evening, may be adjusted with caution based on response and degree of hepatic impairment.

May be taken with or without food.

Concomitant use with MAOIs, within 14 days of discontinuing MAOIs, or within 5 weeks of discontinuing olanzapine + fluoxetine. Initiation of treatment in patients receiving linezolid or IV methylthioninium chloride. Concurrent use with thioridazine or within at least 5 weeks of discontinuing olanzapine + fluoxetine. Concomitant use with pimozide.

Patient with history of seizures and risk factors for seizures, including head trauma, brain damage, alcoholism, or conditions that may decrease the seizure threshold (e.g. Alzheimer's disease); severe cardiac disease, ischaemic heart disease, haemodynamic instability, hypercholesterolaemia or pre-existing dyslipidaemia; risk factors for QT prolongation (e.g. congenital long QT syndrome, history of prolonged QT, family history of prolonged QT or sudden cardiac death), other conditions predisposing to cardiac arrhythmias (e.g. hypokalaemia, hypomagnesaemia, bradyarrhythmias or other arrhythmias, uncompensated heart failure, recent MI); predisposition for orthostatic hypotension or those who would not tolerate transient hypotensive episodes (e.g. cerebrovascular disease, dehydration, hypovolaemia); pre-existing low WBC or history of drug-induced leucopenia or neutropenia; reduced gastrointestinal motility, history of paralytic ileus, urinary retention, benign prostatic hyperplasia, narrow-angle glaucoma; diabetes or other glucose regulation disorders; strenuous exercise or extreme heat exposure. Smokers and those at risk for aspiration pneumonia. Patients with combined factors for reduced metabolism (e.g. females, nonsmokers) or enhanced sensitivity to olanzapine. CYP2D6 poor metabolisers. Not approved for dementia-related psychosis. Avoid abrupt withdrawal. Concomitant use with NSAIDs, aspirin, and other anticoagulants. Hepatic impairment. Children and elderly. Pregnancy and lactation.

Significant: Suicidal thinking and behaviour in children, adolescents and young adults; hypersensitivity reactions (e.g. lupus-like syndrome, vasculitis, laryngospasm, anaphylactoid reactions, pulmonary inflammatory disease); precipitation of mania or hypomania (in patients with bipolar disorder); extrapyramidal symptoms (e.g. dystonia, akathisia, tardive dyskinesia, pseudoparkinsonism); impaired platelet aggregation leading to increased risk of bleeding events (e.g. gastrointestinal bleeding, haematomas, epistaxis, postpartum bleeding [particularly when used in the month before delivery]); oesophageal dysmotility or aspiration, orthostatic hypotension, CNS depression, increased risk of fall due to somnolence and motor or sensory instability, consequently bone fractures; ocular effects (e.g. mild pupillary dilation which may result to an episode of narrow-angle glaucoma); impaired core body temperature regulation, anticholinergic effects (e.g. blurred vision, constipation, xerostomia, urinary retention); dose-related hyperprolactinaemia, SIADH (leading to hyponatraemia), metabolic changes (e.g. hyperglycaemia, dyslipidaemia, significant weight gain [≥7% of baseline weight]), transaminase elevations; sexual dysfunction; withdrawal syndrome.
Cardiac disorders: Bradycardia.
Gastrointestinal disorders: Nausea, vomiting, diarrhoea, flatulence, dyspepsia, abdominal distention.
General disorders and administration site conditions: Oedema, fatigue, fever.
Investigations: Decreased serum bicarbonate, decreased serum bilirubin; increased BUN and uric acid levels.
Metabolism and nutrition disorders: Increased appetite.
Musculoskeletal and connective tissue disorders: Back pain, limb pain, arthralgia, musculoskeletal stiffness.
Nervous system disorders: Disturbance in attention, hypersomnia, lethargy.
Reproductive system and breast disorders: Dysmenorrhoea, erectile dysfunction.
Respiratory, thoracic and mediastinal disorders: Sinusitis.
Skin and subcutaneous tissue disorders: Photosensitivity reaction, alopecia, pruritus, dry skin, ecchymoses.
Vascular disorders: Vasodilatation.
Potentially Fatal: Serotonin syndrome, neuroleptic malignant syndrome (NMS); altered cardiac conduction, QT prolongation, ventricular arrhythmia including torsades de pointes; drug reaction with eosinophilia and systemic symptoms (DRESS); severe hyperglycaemia associated with ketoacidosis or hyperosmolar coma; blood dyscrasias (e.g. leucopenia, neutropenia, agranulocytosis), haemorrhage; cerebrovascular effects (e.g. stroke, TIA).

PO: C

This drug may cause somnolence, if affected, do not drive or operate machinery.

Evaluate for history of metabolic syndrome annually. Monitor renal function, LFTs, TSH and serum electrolytes annually (check serum Na as needed in at-risk patients); vital signs at least weekly during the 1st 3-4 weeks of therapy and 4 weeks after dose changes; weight, height, or BMI 8-12 weeks after treatment initiation or dose changes and quarterly thereafter; CBC and ECG as clinically indicated. Obtain fasting plasma glucose, HbA_1C, and lipid panel 12 weeks after treatment initiation or dose changes and annually thereafter; prolactin level (if with symptoms). Closely monitor for signs of clinical worsening, depression, suicidal tendencies, unusual behavioural changes, and serotonin syndrome. Assess for fall risk, extrapyramidal symptoms (every visit, 4 weeks after starting treatment or dose changes and annually thereafter), and signs of hyperglycaemia.

Symptoms: Confusion, ataxia, dysarthria, impaired consciousness, convulsions, somnolence, lethargy, agitation, aggression, acute psychosis, essential tremor, arrhythmias, hypo- or hypertension, and coma. Management: Maintain clear airway and adequate ventilation. Initiate CV monitoring with ECG to detect possible arrhythmias.

Increased risk of bleeding with NSAIDs, aspirin, and warfarin. Increased risk of QT prolongation with antipsychotics (e.g. chlorpromazine, droperidol, iloperidone, mesoridazine), antibiotics (e.g. erythromycin, gatifloxacin, moxifloxacin, sparfloxacin), class Ia antiarrhythmics (e.g. procainamide, quinidine), class III antiarrhythmics (e.g. amiodarone, sotalol), pentamidine, methadone, halofantrine, mefloquine, dolasetron, or tacrolimus.
Olanzapine: May antagonise the effects of levodopa and dopamine agonists. May enhance the effects of certain antihypertensives. May potentiate orthostatic hypotension with benzodiazepines (e.g. diazepam). Increased clearance with CYP1A2 inducers (e.g. carbamazepine). Decreased clearance with CYP1A2 inhibitors (e.g. fluvoxamine).
Fluoxetine: May increase the serum levels of clozapine, alprazolam, and haloperidol. Increased serum concentration with CYP2D6 inhibitors. May increase serum levels and toxicity of phenytoin.
Potentially Fatal: Increased risk of serotonin syndrome with MAOIs (including methylthioninium chloride and linezolid) and other serotonergic agents (e.g. other SSRIs, SNRIs, triptans, TCAs, fentanyl, lithium, tramadol, pethidine, buspirone, methadone, tryptophan). Increased serum levels and risk of QT prolongation with pimozide and thioridazine.

May potentiate sedation and orthostatic hypotension with alcohol. Increased risk of serotonin syndrome with St. John's wort.

Description:
Mechanism of Action: The enhanced antidepressant action of the olanzapine and fluoxetine combination may be due to the synergistic increases in serotonin, norepinephrine and dopamine.
Olanzapine is an atypical or 2nd generation thienobenzodiazepine antipsychotic agent. The exact mechanism of action is unknown; however, it may be facilitated by combined antagonism of dopamine and serotonin type 2 receptor sites. It shows a potent antagonistic effect in the serotonin 5-HT_2A and 5-HT_2C, dopamine D_1-4, histamine H₁ and α₁-adrenergic receptors, moderate antagonistic effect in the serotonin 5-HT₃ and muscarinic M_1-5 receptors, and weakly binds to GABA_A, benzodiazepine and β-adrenergic receptors.
Fluoxetine is an antidepressant that selectively inhibits the reuptake of CNS neuron serotonin, leading to increased synaptic serotonin concentrations in the CNS. It has minimal to no effect on norepinephrine or dopamine reuptake and a relatively low affinity for α-adrenergic, histamine, or cholinergic receptors.
Pharmacokinetics:
Absorption: Well absorbed from the gastrointestinal tract.
Olanzapine: Time to peak plasma concentration: Approx 6 hours.
Fluoxetine: Time to peak plasma concentration: 6-8 hours.
Distribution: Crosses the placenta and enters breast milk.
Olanzapine: Extensively distributed throughout the body. Volume of distribution: 1,000 L. Plasma protein binding: 93%, mainly to albumin and α₁-acid glycoprotein.
Fluoxetine: Widely distributed into the body. Readily crosses the blood-brain barrier. Volume of distribution: 12-43 L/kg. Plasma protein binding: 95%, mainly to albumin and α₁-acid glycoprotein.
Metabolism: Olanzapine: Extensively metabolised in the liver via direct glucuronidation and oxidation by CYP450 isoenzymes (CYP1A2, CYP2D6 [lesser extent]) into 10-N-glucuronide and 4'-N-desmethyl olanzapine (major inactive metabolites). Undergoes extensive first-pass metabolism.
Fluoxetine: Extensively metabolised in the liver via demethylation by CYP2D6 and CYP2C19 into norfluoxetine (primary active metabolite).
Excretion: Olanzapine: Via urine (57% as metabolites, 7% as unchanged drug); faeces (30%). Elimination half-life: 30 hours (range: 21-54 hours [5th to 95th percentile]).
Fluoxetine: Via urine (10% as norfluoxetine, 2.5-5% as fluoxetine). Elimination half-life: Fluoxetine: 1-3 days (acute use); 4-6 days (chronic use). Norfluoxetine: 9.3 days (range: 4-16 days).

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 135398745, Olanzapine. https://pubchem.ncbi.nlm.nih.gov/compound/Olanzapine. Accessed Jan. 31, 2024.

Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 3386, Fluoxetine. https://pubchem.ncbi.nlm.nih.gov/compound/Fluoxetine. Accessed Jan. 31, 2024.

Store at between 15-30°C. Protect from moisture.

Antidepressants / Antipsychotics

N06CA03 - fluoxetine and psycholeptics ; Belongs to the class of antidepressants in combination with psycholeptics.

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