(oh LAN za peen & floo OKS e teen)
Depression, acute (associated with bipolar I disorder): Treatment of acute depressive episodes associated with bipolar I disorder
Depression, treatment-resistant: Treatment of treatment-resistant depression (eg, unresponsive to 2 trials of different antidepressants in the current episode)
Use of MAO inhibitors intended to treat psychiatric disorders (concurrently, within 5 weeks of discontinuing olanzapine/fluoxetine, or within 2 weeks of discontinuing the MAO inhibitor); initiation of olanzapine/fluoxetine in a patient receiving linezolid or intravenous methylene blue; use with pimozide or thioridazine (Note: Thioridazine should not be initiated until 5 weeks after the discontinuation of fluoxetine.)
Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients older than 24 years; there was a reduction in risk with antidepressant use in patients 65 years and older. In patients of all ages who are started on antidepressant therapy, monitor closely for worsening and emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the health care provider. Olanzapine/fluoxetine is not approved for use in children younger than 10 years.
Increased mortality in elderly patients with dementia-related psychosis:Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Olanzapine/fluoxetine is not approved for the treatment of patients with dementia-related psychosis.
Lower doses (olanzapine 3 to 6 mg/fluoxetine 25 mg) should be used in patients predisposed to hypotension, with hepatic impairment, with combined factors for reduced metabolism (females, the elderly, nonsmokers), or enhanced sensitivity to olanzapine; dose adjustments should be made with caution in this patient population.
Depression associated with bipolar I disorder: Initial: Olanzapine 6 mg/fluoxetine 25 mg once daily in the evening. Adjust dose based on response and tolerability. Usual dose: Olanzapine 6 to 12 mg/fluoxetine 25 to 50 mg. Safety of daily doses of olanzapine >18 mg/fluoxetine >75 mg have not been evaluated.
Treatment-resistant depression: Initial: Olanzapine 6 mg/fluoxetine 25 mg once daily in the evening. Adjust dose based on response and tolerability. Usual dose: Olanzapine 6 to 18 mg/fluoxetine 25 to 50 mg. Safety of daily doses of olanzapine >18 mg/fluoxetine >75 mg have not been evaluated.
Note: When using individual components of fluoxetine with olanzapine rather than fixed dose combination product (Symbyax ‚ ®), approximate dosage correspondence is as follows:
Olanzapine 2.5 mg + fluoxetine 20 mg = Symbyax ‚ ® 3/25
Olanzapine 5 mg + fluoxetine 20 mg = Symbyax ‚ ® 6/25
Olanzapine 12.5 mg + fluoxetine 20 mg = Symbyax ‚ ® 12/25
Olanzapine 5 mg + fluoxetine 50 mg = Symbyax ‚ ® 6/50
Olanzapine 12.5 mg + fluoxetine 50 mg = Symbyax ‚ ® 12/50
Discontinuation of therapy: Upon discontinuation of antidepressant therapy, gradually taper the dose to minimize the incidence of withdrawal symptoms and allow for the detection of re-emerging symptoms. Evidence supporting ideal taper rates is limited. APA and NICE guidelines suggest tapering therapy over at least several weeks with consideration to the half-life of the antidepressant; antidepressants with a shorter half-life may need to be tapered more conservatively. In addition for long-term treated patients, WFSBP guidelines recommend tapering over 4 to 6 months. If intolerable withdrawal symptoms occur following a dose reduction, consider resuming the previously prescribed dose and/or decrease dose at a more gradual rate (APA, 2010; Bauer, 2002; Haddad, 2001; NCCMH, 2010; Schatzberg, 2006; Shelton, 2001; Warner, 2006).
MAO inhibitor recommendations:
Switching to or from an MAO inhibitor intended to treat psychiatric disorders:
Allow 14 days to elapse between discontinuing an MAO inhibitor intended to treat psychiatric disorders and initiation of olanzapine/fluoxetine.
Allow 5 weeks to elapse between discontinuing olanzapine/fluoxetine and initiation of an MAO inhibitor intended to treat psychiatric disorders.
Use with other MAO inhibitors (linezolid or IV methylene blue):
Do not initiate olanzapine/fluoxetine in patients receiving linezolid or IV methylene blue; consider other interventions for psychiatric condition.
If urgent treatment with linezolid or IV methylene blue is required in a patient already receiving olanzapine/fluoxetine and potential benefits outweigh potential risks, discontinue olanzapine/fluoxetine promptly and administer linezolid or IV methylene blue. Monitor for serotonin syndrome for 5 weeks or until 24 hours after the last dose of linezolid or IV methylene blue, whichever comes first. May resume olanzapine/fluoxetine 24 hours after the last dose of linezolid or IV methylene blue.
Oral: Initial: Olanzapine 3 to 6 mg/fluoxetine 25 mg once daily in the evening; use caution adjusting dose (metabolism may be decreased).
Discontinuation of therapy: Refer to adult dosing.
MAO inhibitor recommendations: Refer to adult dosing.
Lower doses (olanzapine 3 to 6 mg/fluoxetine 25 mg) should be used in patients predisposed to hypotension, with hepatic impairment, with combined factors for reduced metabolism (females, nonsmokers), or enhanced sensitivity to olanzapine; dose adjustments should be made with caution in this patient population.
Depression associated with bipolar I disorder: Initial: Children and Adolescents 10 to 17 years: Oral: Olanzapine 3 mg /fluoxetine 25 mg in the evening. Adjust dose based on response and tolerability. Usual dose: Olanzapine 6 to 12 mg/fluoxetine 25 to 50 mg; safety of fluoxetine doses >50 mg in combination with olanzapine doses >12 mg has not been studied in pediatrics.
Note: When using individual components of fluoxetine with olanzapine rather than fixed-dose combination product (Symbyax ‚ ®), approximate dosage correspondence is as follows:
Olanzapine 2.5 mg + fluoxetine 20 mg = Symbyax 3/25
Olanzapine 5 mg + fluoxetine 20 mg = Symbyax 6/25
Olanzapine 12.5 mg + fluoxetine 20 mg = Symbyax 12/25
Olanzapine 5 mg + fluoxetine 50 mg = Symbyax 6/50
Olanzapine 12.5 mg + fluoxetine 50 mg = Symbyax 12/50
Discontinuation of therapy: Refer to adult dosing.
MAO inhibitor recommendations: Refer to adult dosing.
No dosage adjustment necessary.
Initial: Olanzapine 3 to 6 mg/fluoxetine 25 mg once daily in the evening; use caution adjusting dose (metabolism may be decreased).
Administer capsules once daily in the evening; may be taken without regard to meals.
May be taken without regard to meals.
Store at 25 ‚ °C (77 ‚ °F); excursions are permitted between 15 ‚ °C and 30 ‚ °C (59 ‚ °F and 86 ‚ °F). Protect from moisture.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, oral: 3/25: Olanzapine 3 mg and fluoxetine 25 mg; 6/25: Olanzapine 6 mg and fluoxetine 25 mg; 6/50: Olanzapine 6 mg and fluoxetine 50 mg; 12/25: Olanzapine 12 mg and fluoxetine 25 mg; 12/50: Olanzapine 12 mg and fluoxetine 50 mg
Symbyax 3/25: Olanzapine 3 mg and fluoxetine 25 mg
Symbyax 6/25: Olanzapine 6 mg and fluoxetine 25 mg
Symbyax 6/50: Olanzapine 6 mg and fluoxetine 50 mg
Symbyax 12/25: Olanzapine 12 mg and fluoxetine 25 mg
Symbyax 12/50: Olanzapine 12 mg and fluoxetine 50 mg
Abiraterone Acetate: May increase the serum concentration of CYP2D6 Substrates. Management: Avoid concurrent use of abiraterone with CYP2D6 substrates that have a narrow therapeutic index whenever possible. When concurrent use is not avoidable, monitor patients closely for signs/symptoms of toxicity. Consider therapy modification
AbobotulinumtoxinA: Anticholinergic Agents may enhance the anticholinergic effect of AbobotulinumtoxinA. Monitor therapy
Acetylcholinesterase Inhibitors: May diminish the therapeutic effect of Anticholinergic Agents. Anticholinergic Agents may diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Monitor therapy
Acetylcholinesterase Inhibitors (Central): May enhance the neurotoxic (central) effect of Antipsychotic Agents. Severe extrapyramidal symptoms have occurred in some patients. Monitor therapy
Aclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination
Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the antiplatelet effect of other Agents with Antiplatelet Properties. Monitor therapy
Alcohol (Ethyl): May enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Management: Patients receiving selective serotonin reuptake inhibitors should be advised to avoid alcohol. Monitor for increased psychomotor impairment in patients who consume alcohol during treatment with selective serotonin reuptake inhibitors. Consider therapy modification
Amisulpride: Antipsychotic Agents may enhance the adverse/toxic effect of Amisulpride. Avoid combination
Amphetamines: Antipsychotic Agents may diminish the stimulatory effect of Amphetamines. Monitor therapy
Analgesics (Opioid): Anticholinergic Agents may enhance the adverse/toxic effect of Analgesics (Opioid). Specifically, the risk for constipation and urinary retention may be increased with this combination. Monitor therapy
Analgesics (Opioid): May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy
Anticholinergic Agents: May enhance the adverse/toxic effect of other Anticholinergic Agents. Monitor therapy
Anticoagulants: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants. Monitor therapy
Antidepressants (Serotonin Reuptake Inhibitor/Antagonist): Selective Serotonin Reuptake Inhibitors may enhance the serotonergic effect of Antidepressants (Serotonin Reuptake Inhibitor/Antagonist). This may cause serotonin syndrome. Management: Consider alternatives, and use conservative initial dosing. Monitor patients receiving these combinations for signs/symptoms of serotonin toxicity. Consider therapy modification
Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy
Antiemetics (5HT3 Antagonists): May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy
Antihepaciviral Combination Products: May decrease the serum concentration of OLANZapine. Monitor therapy
Anti-Parkinson Agents (Dopamine Agonist): Antipsychotic Agents (Second Generation [Atypical]) may diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Management: Consider using an alternative antipsychotic agent when possible in patients with Parkinson disease. If an atypical antipsychotic is necessary, consider using clozapine or quetiapine, which may convey the lowest interaction risk. Consider therapy modification
Antipsychotic Agents: Serotonin Modulators may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy
Apixaban: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Apixaban. Specifically, the risk for bleeding may be increased. Management: Carefully consider risks and benefits of this combination and monitor closely. Monitor therapy
ARIPiprazole: FLUoxetine may enhance the adverse/toxic effect of ARIPiprazole. Specifically, the risk of neuroleptic malignant syndrome may be increased. ARIPiprazole may enhance the serotonergic effect of FLUoxetine. This could result in serotonin syndrome. FLUoxetine may increase the serum concentration of ARIPiprazole. Management: Aripiprazole dose should be reduced by at least half, except when used adjunctively for depression. Consult full interaction monograph or aripiprazole prescribing information for complete details. Consider therapy modification
ARIPiprazole Lauroxil: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of ARIPiprazole Lauroxil. Management: Please refer to the full interaction monograph for details concerning the recommended dose adjustments. Consider therapy modification
Aspirin: Selective Serotonin Reuptake Inhibitors may enhance the antiplatelet effect of Aspirin. Monitor therapy
Asunaprevir: May increase the serum concentration of CYP2D6 Substrates. Consider therapy modification
AtoMOXetine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of AtoMOXetine. Management: Initiate atomoxetine at a reduced dose (adult doses -- patients up to 70kg: 0.5mg/kg/day; patients 70kg or more: 40mg/day) in patients receiving a strong CYP2D6 inhibitor. Consider therapy modification
Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination
Benzodiazepines: OLANZapine may enhance the adverse/toxic effect of Benzodiazepines. Management: Avoid concomitant use of parenteral benzodiazepines and IM olanzapine due to risks of additive adverse events (e.g., cardiorespiratory depression). Olanzapine prescribing information provides no specific recommendations regarding oral administration. Avoid combination
Beta-Blockers: Selective Serotonin Reuptake Inhibitors may increase the serum concentration of Beta-Blockers. Exceptions: Acebutolol; Atenolol; Betaxolol (Ophthalmic); Betaxolol (Systemic); Bisoprolol; Carteolol (Ophthalmic); Esmolol; Labetalol; Levobunolol; Metipranolol; Nadolol; Penbutolol; Sotalol. Monitor therapy
Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification
Blood Glucose Lowering Agents: Selective Serotonin Reuptake Inhibitors may enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy
Blood Pressure Lowering Agents: May enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy
Brexpiprazole: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Brexpiprazole. Management: Reduce brexpiprazole dose to 50% of usual with a strong CYP2D6 inhibitor; this recommendation does not apply if treating major depressive disorder. Reduce to 25% of usual if used with both a strong CYP2D6 inhibitor and a CYP3A4 inhibitor. Consider therapy modification
Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
BuPROPion: May enhance the adverse/toxic effect of FLUoxetine. BuPROPion may increase the serum concentration of FLUoxetine. Monitor therapy
BusPIRone: May enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This may cause serotonin syndrome. Selective Serotonin Reuptake Inhibitors may decrease the metabolism of BusPIRone. Management: The combination of a selective serotonin reuptake inhibitor and buspirone should be undertaken with great caution. When combined treatment is clinically indicated, monitor closely for signs of serotonin toxicity/serotonin syndrome. Consider therapy modification
Cannabis: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy
Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
CarBAMazepine: Selective Serotonin Reuptake Inhibitors may decrease the metabolism of CarBAMazepine. Specifically those SSRIs that inhibit CYP3A4 isoenzymes. CarBAMazepine may increase the metabolism of Selective Serotonin Reuptake Inhibitors. Specifically those agents metabolized via CYP1A2, 2C, and/or 3A4 isoenzymes. Consider therapy modification
Cephalothin: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Cephalothin. Specifically, the risk for bleeding may be increased. Monitor therapy
Cilostazol: CYP2C19 Inhibitors may increase the serum concentration of Cilostazol. Management: Consider reducing the cilostazol dose to 50 mg twice daily in patients who are also receiving inhibitors of CYP2C19. Consider therapy modification
Cimetidine: May decrease the metabolism of Selective Serotonin Reuptake Inhibitors. Consider therapy modification
Cimetropium: Anticholinergic Agents may enhance the anticholinergic effect of Cimetropium. Avoid combination
Clarithromycin: May enhance the QTc-prolonging effect of FLUoxetine. Clarithromycin may increase the serum concentration of FLUoxetine. Avoid combination
Clopidogrel: CYP2C19 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Clopidogrel. Management: Due to a risk for impaired clopidogrel effectiveness with such a combination, carefully consider the need for a moderate CYP2C19 inhibitor in patients receiving clopidogrel. Monitor patients closely for evidence of a diminished response to clopidogrel. Consider therapy modification
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Monitor therapy
CNS Depressants: May enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy
Cobicistat: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy
Codeine: CYP2D6 Inhibitors (Strong) may diminish the therapeutic effect of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine. Consider therapy modification
Collagenase (Systemic): Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased. Monitor therapy
CYP1A2 Inducers (Strong): May increase the metabolism of CYP1A2 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification
CYP1A2 Inhibitors (Moderate): May decrease the metabolism of CYP1A2 Substrates. Monitor therapy
CYP1A2 Inhibitors (Strong): May decrease the metabolism of CYP1A2 Substrates. Consider therapy modification
CYP2C19 Substrates: CYP2C19 Inhibitors (Moderate) may decrease the metabolism of CYP2C19 Substrates. Monitor therapy
CYP2C9 Inducers (Strong): May increase the metabolism of CYP2C9 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification
CYP2C9 Inhibitors (Moderate): May decrease the metabolism of CYP2C9 Substrates. Monitor therapy
CYP2C9 Inhibitors (Strong): May decrease the metabolism of CYP2C9 Substrates. Consider therapy modification
CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates. Monitor therapy
CYP2D6 Inhibitors (Strong): May decrease the metabolism of CYP2D6 Substrates. Consider therapy modification
CYP2D6 Substrates: CYP2D6 Inhibitors (Strong) may decrease the metabolism of CYP2D6 Substrates. Exceptions: Ajmaline; Dapoxetine; Tamoxifen; Timolol (Ophthalmic); Tropisetron. Consider therapy modification
Cyproheptadine: May diminish the therapeutic effect of Selective Serotonin Reuptake Inhibitors. Monitor therapy
Cyproterone: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy
Dabigatran Etexilate: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Dabigatran Etexilate. Agents with Antiplatelet Properties may increase the serum concentration of Dabigatran Etexilate. This mechanism applies specifically to clopidogrel. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Monitor therapy
Dabrafenib: May decrease the serum concentration of CYP2C9 Substrates. Management: Seek alternatives to the CYP2C9 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification
Dapoxetine: May enhance the adverse/toxic effect of Serotonin Modulators. Avoid combination
Darunavir: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy
Deferasirox: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy
Deoxycholic Acid: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased. Monitor therapy
Desmopressin: Selective Serotonin Reuptake Inhibitors may enhance the adverse/toxic effect of Desmopressin. Monitor therapy
Dextromethorphan: Selective Serotonin Reuptake Inhibitors may enhance the serotonergic effect of Dextromethorphan. Selective Serotonin Reuptake Inhibitors may increase the serum concentration of Dextromethorphan. Management: Avoid the concurrent use of dextromethorphan and SSRIs, particularly fluoxetine and paroxetine, when possible. The risk for this interaction may persist for several weeks following discontinuation of fluoxetine or paroxetine. Consider therapy modification
Dimethindene: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Dosulepin: Selective Serotonin Reuptake Inhibitors may increase the serum concentration of Dosulepin. Avoid combination
DOXOrubicin (Conventional): CYP2D6 Inhibitors (Strong) may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to strong CYP2D6 inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification
Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Monitor therapy
Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
DULoxetine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of DULoxetine. Monitor therapy
Edoxaban: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Edoxaban. Specifically, the risk of bleeding may be increased. Monitor therapy
Eluxadoline: Anticholinergic Agents may enhance the constipating effect of Eluxadoline. Avoid combination
Enzalutamide: May decrease the serum concentration of CYP2C9 Substrates. Management: Concurrent use of enzalutamide with CYP2C9 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP2C9 substrate should be performed with caution and close monitoring. Consider therapy modification
Fesoterodine: CYP2D6 Inhibitors may increase serum concentrations of the active metabolite(s) of Fesoterodine. Monitor therapy
FluvoxaMINE: May decrease the metabolism of OLANZapine. Consider therapy modification
Fosphenytoin: May enhance the QTc-prolonging effect of FLUoxetine. FLUoxetine may increase the serum concentration of Fosphenytoin. Consider therapy modification
Gastrointestinal Agents (Prokinetic): Anticholinergic Agents may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Monitor therapy
Glucagon: Anticholinergic Agents may enhance the adverse/toxic effect of Glucagon. Specifically, the risk of gastrointestinal adverse effects may be increased. Avoid combination
Glucosamine: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy
Glycopyrrolate (Oral Inhalation): Anticholinergic Agents may enhance the anticholinergic effect of Glycopyrrolate (Oral Inhalation). Avoid combination
Haloperidol: FLUoxetine may enhance the QTc-prolonging effect of Haloperidol. FLUoxetine may increase the serum concentration of Haloperidol. Avoid combination
Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Bleeding may occur. Consider therapy modification
Highest Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of other Highest Risk QTc-Prolonging Agents. Avoid combination
Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification
HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Consider starting with a 20% to 30% lower hydrocodone dose when using together with any other CNS depressant. Dose reductions in the other CNS depressant may also be warranted. Consider therapy modification
Ibritumomab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Ibritumomab. Both agents may contribute to impaired platelet function and an increased risk of bleeding. Monitor therapy
Ibrutinib: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Monitor therapy
Iobenguane I 123: Selective Serotonin Reuptake Inhibitors may diminish the therapeutic effect of Iobenguane I 123. Avoid combination
Ioflupane I 123: Selective Serotonin Reuptake Inhibitors may diminish the diagnostic effect of Ioflupane I 123. Monitor therapy
Ipratropium (Oral Inhalation): May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination
Itopride: Anticholinergic Agents may diminish the therapeutic effect of Itopride. Monitor therapy
Ivabradine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination
Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy
LamoTRIgine: May enhance the sedative effect of OLANZapine. Monitor therapy
Levosulpiride: Anticholinergic Agents may diminish the therapeutic effect of Levosulpiride. Avoid combination
Limaprost: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy
Linezolid: May enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This could result in serotonin syndrome. Avoid combination
Lithium: May enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This could increase the risk of serotonin toxicity/serotonin syndrome. Management: This combination should be undertaken with great caution. When combined treatment is clinically indicated, monitor closely for signs of serotonin toxicity/serotonin syndrome. Consider therapy modification
Lumacaftor: May decrease the serum concentration of CYP2C9 Substrates. Lumacaftor may increase the serum concentration of CYP2C9 Substrates. Monitor therapy
Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
MAO Inhibitors: May enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This may cause serotonin syndrome. While methylene blue and linezolid are expected to interact via this mechanism, management recommendations differ from other monoamine oxidase inhibitors. Refer to monographs specific to those agents for details. Exceptions: Linezolid; Methylene Blue; Tedizolid. Avoid combination
Mequitazine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Mequitazine. Avoid combination
Metaxalone: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification
Methylene Blue: Selective Serotonin Reuptake Inhibitors may enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. Avoid combination
Methylene Blue: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Avoid combination
Methylphenidate: Antipsychotic Agents may enhance the adverse/toxic effect of Methylphenidate. Methylphenidate may enhance the adverse/toxic effect of Antipsychotic Agents. Monitor therapy
Metoclopramide: May enhance the adverse/toxic effect of Antipsychotic Agents. Avoid combination
Metoprolol: CYP2D6 Inhibitors may increase the serum concentration of Metoprolol. Management: Consider an alternative for one of the interacting drugs in order to avoid metoprolol toxicity. If the combination must be used, monitor response to metoprolol closely. Metoprolol dose reductions may be necessary. Consider therapy modification
MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy
MetyroSINE: May enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Monitor therapy
MetyroSINE: May enhance the adverse/toxic effect of Antipsychotic Agents. Monitor therapy
Mexiletine: Selective Serotonin Reuptake Inhibitors may decrease the metabolism of Mexiletine. Consider therapy modification
MiFEPRIStone: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination
Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Moderate Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination
Multivitamins/Fluoride (with ADE): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy
Multivitamins/Minerals (with ADEK, Folate, Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy
Multivitamins/Minerals (with AE, No Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy
Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Nebivolol: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Nebivolol. Monitor therapy
Nicergoline: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Nicergoline. Specifically, concentrations of the MMDL metabolite may be increased. CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Nicergoline. Specifically, concentrations of the MDL metabolite may be decreased. Monitor therapy
NIFEdipine: FLUoxetine may enhance the adverse/toxic effect of NIFEdipine. Monitor therapy
NiMODipine: FLUoxetine may increase the serum concentration of NiMODipine. Monitor therapy
NSAID (COX-2 Inhibitor): Selective Serotonin Reuptake Inhibitors may enhance the antiplatelet effect of NSAID (COX-2 Inhibitor). NSAID (COX-2 Inhibitor) may diminish the therapeutic effect of Selective Serotonin Reuptake Inhibitors. Monitor therapy
NSAID (Nonselective): Selective Serotonin Reuptake Inhibitors may enhance the antiplatelet effect of NSAID (Nonselective). NSAID (Nonselective) may diminish the therapeutic effect of Selective Serotonin Reuptake Inhibitors. Management: Consider using alternative analgesics, when appropriate, and/or addition of a gastroprotective agent. Monitor patients closely for signs/symptoms of bleeding, and for evidence of diminished SSRI effectiveness with concurrent use. Consider therapy modification
Obeticholic Acid: May increase the serum concentration of CYP1A2 Substrates. Monitor therapy
Obinutuzumab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Monitor therapy
Omega-3 Fatty Acids: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy
OnabotulinumtoxinA: Anticholinergic Agents may enhance the anticholinergic effect of OnabotulinumtoxinA. Monitor therapy
Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination
Oxatomide: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination
OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: When oxycodone is combined with another CNS depressant, a dose reduction of one or both agents should be considered. The extended release oxycodone starting dose should be reduced 50% to 67% when initiated in patients already receiving CNS depressants. Consider therapy modification
Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination
Peginterferon Alfa-2b: May decrease the serum concentration of FLUoxetine. Monitor therapy
Pentosan Polysulfate Sodium: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Specifically, the risk of bleeding may be increased by concurrent use of these agents. Monitor therapy
Pentoxifylline: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy
Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification
Perhexiline: CYP2D6 Inhibitors may increase the serum concentration of Perhexiline. Management: Consider alternatives to this combination if possible. If combined, monitor for increased perhexiline serum concentrations and toxicities (eg, hypoglycemia, neuropathy, liver dysfunction). Perhexiline dose reductions will likely be required. Consider therapy modification
Phenytoin: FLUoxetine may increase the serum concentration of Phenytoin. Monitor therapy
Pimozide: FLUoxetine may enhance the QTc-prolonging effect of Pimozide. FLUoxetine may increase the serum concentration of Pimozide. Avoid combination
Piribedil [INT]: Antipsychotic Agents may diminish the therapeutic effect of Piribedil [INT]. Piribedil [INT] may diminish the therapeutic effect of Antipsychotic Agents. Management: Use of piribedil with antiemetic neuroleptics is contraindicated, and use with antipsychotic neuroleptics, except for clozapine, is not recommended. Avoid combination
Potassium Chloride: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Chloride. Management: Patients on drugs with substantial anticholinergic effects should avoid using any solid oral dosage form of potassium chloride. Avoid combination
Pramlintide: May enhance the anticholinergic effect of Anticholinergic Agents. These effects are specific to the GI tract. Consider therapy modification
Propafenone: May enhance the QTc-prolonging effect of FLUoxetine. FLUoxetine may increase the serum concentration of Propafenone. Avoid combination
Prostacyclin Analogues: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy
QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying): May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification
Quinagolide: Antipsychotic Agents may diminish the therapeutic effect of Quinagolide. Monitor therapy
Ramosetron: Anticholinergic Agents may enhance the constipating effect of Ramosetron. Monitor therapy
RimabotulinumtoxinB: Anticholinergic Agents may enhance the anticholinergic effect of RimabotulinumtoxinB. Monitor therapy
Rivaroxaban: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Rivaroxaban. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Monitor therapy
Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy
Salicylates: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Salicylates. Increased risk of bleeding may result. Monitor therapy
Secretin: Anticholinergic Agents may diminish the therapeutic effect of Secretin. Management: Avoid using drugs with substantial anticholinergic effects in patients receiving secretin whenever possible. If such agents must be used in combination, monitor closely for a diminished response to secretin. Consider therapy modification
Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy
Serotonin Modulators: May enhance the adverse/toxic effect of other Serotonin Modulators. The development of serotonin syndrome may occur. Exceptions: Nicergoline; Tedizolid. Monitor therapy
Serotonin Modulators: May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonin modulators may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Exceptions: Nicergoline. Monitor therapy
Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification
Sulpiride: Antipsychotic Agents may enhance the adverse/toxic effect of Sulpiride. Avoid combination
Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification
Tamoxifen: CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Tamoxifen. Specifically, strong CYP2D6 inhibitors may decrease the metabolic formation of highly potent active metabolites. Avoid combination
Tamsulosin: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Tamsulosin. Monitor therapy
Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Start tapentadol at a dose of one-third to one-half of the normal dose if being initiated in a patient who is taking another drug with CNS depressant effects. Monitor closely for evidence of excessive CNS depression. Consider therapy modification
Tedizolid: May enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy
Teriflunomide: May decrease the serum concentration of CYP1A2 Substrates. Monitor therapy
Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination
Thiazide and Thiazide-Like Diuretics: Selective Serotonin Reuptake Inhibitors may enhance the hyponatremic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy
Thiazide and Thiazide-Like Diuretics: Anticholinergic Agents may increase the serum concentration of Thiazide and Thiazide-Like Diuretics. Monitor therapy
Thioridazine: FLUoxetine may enhance the QTc-prolonging effect of Thioridazine. FLUoxetine may increase the serum concentration of Thioridazine. Avoid combination
Thrombolytic Agents: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Thrombolytic Agents. Monitor therapy
Thyroid Products: Selective Serotonin Reuptake Inhibitors may diminish the therapeutic effect of Thyroid Products. Thyroid product dose requirements may be increased. Monitor therapy
Timolol (Ophthalmic): CYP2D6 Inhibitors (Strong) may increase the serum concentration of Timolol (Ophthalmic). Monitor therapy
Tiotropium: Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium. Avoid combination
TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use cannot be avoided, initiate tizanidine at an adult dose of 2 mg and increase in 2-4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification
Topiramate: Anticholinergic Agents may enhance the adverse/toxic effect of Topiramate. Monitor therapy
Tositumomab and Iodine I 131 Tositumomab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Tositumomab and Iodine I 131 Tositumomab. Specifically, the risk of bleeding-related adverse events may be increased. Monitor therapy
TraMADol: CYP2D6 Inhibitors (Strong) may diminish the therapeutic effect of TraMADol. CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of TraMADol. CYP2D6 Inhibitors (Strong) may increase the serum concentration of TraMADol. Monitor therapy
TraMADol: Serotonin Modulators may enhance the adverse/toxic effect of TraMADol. The risk of seizures may be increased. TraMADol may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Monitor therapy
Tricyclic Antidepressants: FLUoxetine may enhance the adverse/toxic effect of Tricyclic Antidepressants. FLUoxetine may increase the serum concentration of Tricyclic Antidepressants. Management: Consider alternatives to this combination when possible. Monitor for adverse effects of tricyclic antidepressants (TCAs), including serotonin syndrome and QT-interval prolongation, when a TCA is being used in combination with fluoxetine. Consider therapy modification
Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy
Tryptophan: May enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors. This may cause serotonin syndrome. Avoid combination
Umeclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Avoid combination
Urokinase: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Urokinase. Avoid combination
Valproate Products: May decrease the serum concentration of OLANZapine. Monitor therapy
Vinflunine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination
Vitamin E (Systemic): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy
Vitamin K Antagonists (eg, warfarin): Selective Serotonin Reuptake Inhibitors may enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy
Vortioxetine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Vortioxetine. Management: The vortioxetine dose should be reduced by 50% when used together with a strong CYP2D6 inhibitor. Following cessation of the strong CYP2D6 inhibitor, the vortioxetine dose should be returned to the normal level. Consider therapy modification
Ziprasidone: FLUoxetine may enhance the QTc-prolonging effect of Ziprasidone. Ziprasidone may enhance the serotonergic effect of FLUoxetine. This could result in serotonin syndrome. Avoid combination
Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification
Vital signs; lipid profile, fasting blood glucose/HbA1c; BMI; mental status; abnormal involuntary movement scale (AIMS), extrapyramidal symptoms (EPS); signs and symptoms of depression, anxiety, suicidal ideation (especially at the beginning of therapy or when doses are increased or decreased), sleep; signs/symptoms of serotonin syndrome and/or NMS; liver function tests in patients with hepatic disease; complete blood count in patients at risk for neutropenia; ECG assessment and periodic monitoring in patients with risk factors for QT prolongation and ventricular arrhythmia
As reported with combination product (also see individual agents); percentages listed for adults unless otherwise noted:
>10%:
Cardiovascular: Edema (15%)
Central nervous system: Drowsiness (adults 27%; children and adolescents 10 to 17 years 24%), fatigue (12%)
Endocrine & metabolic: Hyperprolactinemia (children and adolescents 10 to 17 years 85%; adults 28%), increased serum triglycerides (children and adolescents 10 to 17 years [fasting] 52% to 70%; adults [nonfasting] 68%), weight gain ( ≥7% of body weight: Children and adolescents 52%; adults 22% to 66%; ≥15% of body weight: Children and adolescents 14%; adults 3% to 33%), increased serum cholesterol (children and adolescents 10 to 17 years [fasting] 30% to 53%; adults [nonfasting] 12% to 56%), increased LDL cholesterol (children and adolescents 10 to 17 years [fasting] 20% to 54%), decreased serum bicarbonate (14%)
Gastrointestinal: Increased appetite (children, adolescents, and adults 17% to 20%), xerostomia (15%)
Hepatic: Increased serum ALT (children and adolescents 10 to 17 years 46%; adults ≥3 times ULN 3% to 5%; ≥5 times ULN 2%), increased serum AST (children and adolescents 10 to 17 years 34%), decreased serum bilirubin (15%)
1% to 10%:
Cardiovascular: Orthostatic hypotension (4%), vasodilatation ( ≥1%)
Central nervous system: Manic reaction (adults 7%; children and adolescents 10 to 17 years 1%), disturbance in attention (5%), restlessness (children, adolescents, and adults 3% to 4%), anxiety (children and adolescents 10 to 17 years 3%), abnormality in thinking (2%), nervousness (2%), pain (2%), suicidal ideation (children and adolescents 10 to 17 years 2%), amnesia ( ≥1%), chills ( ≥1%)
Dermatologic: Ecchymoses ( ≥1%), skin photosensitivity ( ≥1%)
Endocrine & metabolic: Glycosuria (4%), hypoalbuminemia (3%), increased uric acid (3%), hypophosphatemia (2%), hypermenorrhea ( ≥1%), weight loss ( ≥1%)
Gastrointestinal: Dyspepsia (children and adolescents 10 to 17 years 3%), flatulence (3%), abdominal distension (2%), diarrhea ( ≥1%), dysgeusia ( ≥1%)
Genitourinary: Dysmenorrhea (children and adolescents 10 to 17 years 2%), erectile dysfunction (2%), mastalgia ( ≥1%), urinary frequency ( ≥1%), urinary incontinence ( ≥1%)
Hematologic & oncologic: Decreased hemoglobin (3%), lymphocytopenia (2%)
Hepatic: Increased liver enzymes (children and adolescents 10 to 17 years 9%)
Neuromuscular & skeletal: Tremor (children, adolescents, and adults 9%), arthralgia (4%), limb pain (3%), weakness (3%), back pain (children and adolescents 10 to 17 years 2%), stiffness (2%), neck stiffness ( ≥1%)
Ophthalmic: Blurred vision (5%)
Renal: Increased blood urea nitrogen (3%)
Respiratory: Sinusitis (2%)
Miscellaneous: Fever (2%)
<1% (Limited to important or life-threatening): Agranulocytosis, amenorrhea, anemia, angle-closure glaucoma, anorgasmia, ataxia, bradycardia, breast hypertrophy, coma, decreased libido, deep vein thrombosis, dysarthria, dystonia, exfoliative dermatitis, galactorrhea, gastrointestinal hemorrhage, hyperbilirubinemia, hypokinesia, hypomenorrhea, increased creatine phosphokinase, increased serum creatinine, intestinal obstruction, lethargy, leukopenia, myoclonus, neutropenia, osteoporosis, pancreatitis, prolonged Q-T interval on ECG, pulmonary embolism, purpura, rhabdomyolysis, tachycardia, thrombocytopenia, urinary retention
Major psychiatric warnings:
- Suicidal thinking/behavior: [U.S. Boxed Warning]: Antidepressants increase the risk of suicidal thinking and behavior in children, adolescents, and young adults in short-term studies Short-term studies did not show an increased risk in patients >24 years of age and showed a decreased risk in patients ≥65 years. Closely monitor patients for clinical worsening, and emergence of suicidal thoughts and behaviors, particularly during the initial 1 to 2 months of therapy or during periods of dosage adjustments (increases or decreases); the patient 's family or caregiver should be instructed to closely observe the patient and communicate condition with healthcare provider. A medication guide concerning the use of antidepressants should be dispensed with each prescription.
- The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Worsening depression and severe abrupt suicidality that are not part of the presenting symptoms may require discontinuation or modification of drug therapy. Use caution in high-risk patients during initiation of therapy.
- Prescriptions should be written for the smallest quantity consistent with good patient care. The patients family or caregiver should be alerted to monitor patients for the emergence of suicidality and associated behaviors such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania; patients should be instructed to notify their healthcare provider if any of these symptoms or worsening depression or psychosis occur.
Concerns related to adverse effects:
- Allergic reactions and rash: Fluoxetine use has been associated with occurrences of significant rash and allergic reactions, including vasculitis, lupus-like syndrome, laryngospasm, anaphylactoid reactions, and pulmonary inflammatory disease. Discontinue if underlying cause of rash cannot be identified.
- Altered cardiac conduction: May alter cardiac conduction; life-threatening arrhythmias have occurred with therapeutic doses of antipsychotics.
- Anticholinergic effects: Olanzapine may cause anticholinergic effects (constipation, xerostomia, blurred vision, urinary retention); use with caution in patients with decreased gastrointestinal motility, urinary retention, BPH, xerostomia, or visual problems (including narrow-angle glaucoma). Relative to other neuroleptics, olanzapine has a moderate potency of cholinergic blockade.
- Bleeding risk: May impair platelet aggregation resulting in increased risk of bleeding events, particularly if used concomitantly with aspirin, NSAIDs, warfarin or other anticoagulants. Bleeding related to SSRI use has been reported to range from relatively minor bruising and epistaxis to life-threatening hemorrhage.
- Blood dyscrasias: Leukopenia, neutropenia, and agranulocytosis (sometimes fatal) have been reported in clinical trials and postmarketing reports with antipsychotic use; presence of risk factors (eg, pre-existing low WBC or history of drug-induced leuko-/neutropenia) should prompt periodic blood count assessment. Discontinue therapy at first signs of blood dyscrasias or if absolute neutrophil count <1000/mm3.
- Cerebrovascular effects: An increased incidence of cerebrovascular effects (eg, transient ischemic attack, stroke), including fatalities, has been reported in placebo-controlled trials of olanzapine for the unapproved use in elderly patients with dementia-related psychosis.
- CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving). Olanzapine may be moderate to highly sedating in comparison to other antipsychotics (APA [Lehman, 2004]); dose-related effects have been observed.
- Dyslipidemia: Dose-related increases in cholesterol and triglycerides have been noted with olanzapine use. Use olanzapine with caution in patients with preexisting abnormal lipid profile.
- Esophageal dysmotility/Aspiration: Has been associated with antipsychotic use; use with caution in patients at risk of pneumonia (eg, Alzheimer 's disease).
- Extrapyramidal symptoms (EPS): May cause extrapyramidal symptoms, including pseudoparkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia (risk of these reactions is generally much lower relative to typical/conventional antipsychotics). Risk of dystonia (and probably other EPS) may be greater with increased doses, use of conventional antipsychotics, males, and younger patients.
- Fractures: Bone fractures have been associated with antidepressant treatment. Consider the possibility of a fragility fracture if an antidepressant-treated patient presents with unexplained bone pain, point tenderness, swelling, or bruising (Rabenda, 2013; Rizzoli, 2012).
- Hyperglycemia: Atypical antipsychotics have been associated with development of hyperglycemia; in some cases, may be extreme and associated with ketoacidosis, hyperosmolar coma, or death. Olanzapine may have a greater association with hyperglycemia than other atypical antipsychotics. Use with caution in patients with diabetes or other disorders of glucose regulation; monitor for worsening of glucose control. Patients with risk factors for diabetes (eg, obesity or family history) should have a baseline fasting blood sugar (FBS) and periodic assessment of glucose regulation.
- Hyperprolactinemia: May cause dose-related increases in prolactin levels; clinical significance of hyperprolactinemia in patients with breast cancer or other prolactin-dependent tumors is unknown. Clinical manifestations of increased prolactin levels included menstrual-, sexual- and breast-related events.
- Neuroleptic malignant syndrome (NMS): Use may be associated with NMS; monitor for mental status changes, fever, muscle rigidity, and/or autonomic instability.
- Ocular effects: May cause mild pupillary dilation which in susceptible individuals can lead to an episode of narrow-angle glaucoma. Consider evaluating patients who have not had an iridectomy for narrow-angle glaucoma risk factors.
- Orthostatic hypotension: May cause orthostatic hypotension; use with caution in patients at risk of this effect or in those who would not tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, hypovolemia, or concurrent medication use which may predispose to hypotension/bradycardia).
- QT prolongation: Fluoxetine may cause QT prolongation and ventricular arrhythmia including torsade de pointes. Use with caution in patients with risk factors for QT prolongation (eg, congenital long QT syndrome, history of prolonged QT, family history of prolonged QT or sudden cardiac death), other conditions that predispose to arrhythmias (eg, hypokalemia, hypomagnesemia, recent MI, uncompensated heart failure, bradyarrhythmias or other arrhythmias, concomitant use of other agents that prolong QT interval), or increased fluoxetine exposure (eg, overdose, hepatic impairment, use of CYP2D6 inhibitors, poor CYP2D6 metabolizer status, concomitant use of other highly protein-bound drugs). Consider ECG monitoring when initiating therapy in patients with risk factors for QT prolongation and ventricular arrhythmia. Consider discontinuing therapy if ventricular arrhythmia suspected and initiate cardiac evaluation.
- Serotonin syndrome: Potentially life-threatening serotonin syndrome (SS) has occurred with serotonergic agents (eg, SSRIs, SNRIs), particularly when used in combination with other serotonergic agents (eg, triptans, TCAs, fentanyl, lithium, tramadol, buspirone, St John 's wort, tryptophan) or agents that impair metabolism of serotonin (eg, MAO inhibitors intended to treat psychiatric disorders, other MAO inhibitors [ie, linezolid and intravenous methylene blue]). Monitor patients closely for signs of SS such as mental status changes (eg, agitation, hallucinations, delirium, coma); autonomic instability (eg, tachycardia, labile blood pressure, diaphoresis); neuromuscular changes (eg, tremor, rigidity, myoclonus); GI symptoms (eg, nausea, vomiting, diarrhea); and/or seizures. Discontinue treatment (and any concomitant serotonergic agent) immediately if signs/symptoms arise.
- Sexual dysfunction: May cause or exacerbate sexual dysfunction.
- SIADH and hyponatremia: SSRIs and SNRIs have been associated with the development of SIADH; hyponatremia has been reported rarely (including severe cases with serum sodium <110 mmol/L), predominately in the elderly. Volume depletion and/or concurrent use of diuretics likely increases risk. Consider discontinuation if symptomatic hyponatremia occurs.
- Temperature regulation: Impaired core body temperature regulation may occur; caution with strenuous exercise, heat exposure, dehydration, and concomitant medication possessing anticholinergic effects.
- Weight gain: Significant weight gain ( ≥7% of baseline weight) has been observed with antipsychotic therapy; incidence varies with product. Dose-related changes have been observed with olanzapine. Monitor waist circumference and BMI.
Disease-related concerns:
- Cardiovascular disease: Use with caution in patients with severe cardiac disease, hemodynamic instability, prior myocardial infarction, ischemic heart disease, or hypercholesterolemia.
- Dementia: [U.S. Boxed Warning]: Elderly patients with dementia-related behavioral disorders treated with antipsychotics are at an increased risk of death compared to placebo. Most deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Olanzapine and fluoxetine are not approved for the treatment of dementia-related psychosis.
- Hepatic impairment: Use with caution in patients with hepatic disease or impairment; lowest starting dose recommended; may increase transaminases (primarily ALT).
- Mania/hypomania: May worsen psychosis in some patients or precipitate a shift to mania or hypomania in patients with bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. Patients presenting with depressive symptoms should be screened for bipolar disorder. This combination is FDA approved for the treatment of depressive episodes associated with bipolar disorder.
- Parkinson's disease: Use with caution in patients with Parkinson's disease.
- Renal impairment: Use with caution in patients with renal disease; a lower dosage may be needed.
- Seizure disorder: Use with caution in patients at risk of seizures, including those with a history of seizures, head trauma, brain damage, alcoholism, or concurrent therapy with medications which may lower seizure threshold, or conditions that potentially lower the seizure threshold (eg Alzheimer 's dementia). Elderly patients may be at increased risk of seizures due to an increased prevalence of predisposing factors.
Concurrent drug therapy issues:
- Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
Special populations:
- Smokers: Olanzapine levels may be lower in patients who smoke.
Other warnings/precautions:
- Discontinuation syndrome: Abrupt discontinuation or interruption of antidepressant therapy has been associated with a discontinuation syndrome. Symptoms arising may vary with antidepressant however commonly include nausea, vomiting, diarrhea, headaches, lightheadedness, dizziness, diminished appetite, sweating, chills, tremors, paresthesias, fatigue, somnolence, and sleep disturbances (eg, vivid dreams, insomnia). Less common symptoms include electric shock-like sensations, cardiac arrhythmias (more common with tricyclic antidepressants), myalgias, parkinsonism, arthralgias, and balance difficulties. Psychological symptoms may also emerge such as agitation, anxiety, akathisia, panic attacks, irritability, aggressiveness, worsening of mood, dysphoria, mood lability, hyperactivity, mania/hypomania, depersonalization, decreased concentration, slowed thinking, confusion, and memory or concentration difficulties. Greater risks for developing a discontinuation syndrome have been associated with antidepressants with shorter half-lives, longer durations of treatment, and abrupt discontinuation. For antidepressants of short or intermediate half-lives, symptoms may emerge within 2 to 5 days after treatment discontinuation and last 7 to 14 days (APA, 2010; Fava, 2006; Haddad, 2001; Shelton, 2001; Warner, 2006).
- Duration of therapy: Antidepressant efficacy with treatment >8 weeks duration has not been established.
- Electroconvulsive therapy: May increase the risks associated with electroconvulsive therapy; consider discontinuing, when possible, prior to ECT treatment.
- Long half-life: Due to the long half-life of fluoxetine and its metabolites, the effects and interactions noted may persist for prolonged periods following discontinuation.
C
Adverse events were observed in animal reproduction studies using this combination. Refer to individual agents for additional information.
Olanzapine is a second generation thienobenzodiazepine antipsychotic which displays potent antagonism of serotonin 5-HT2A and 5-HT2C, dopamine D1-4, histamine H1 and alpha1-adrenergic receptors. Olanzapine shows moderate antagonism of 5-HT3 and muscarinic M1-5 receptors, and weak binding to GABA-A, BZD, and beta-adrenergic receptors. Fluoxetine inhibits CNS neuron serotonin reuptake; minimal or no effect on reuptake of norepinephrine or dopamine; does not significantly bind to alpha-adrenergic, histamine, or cholinergic receptors. The enhanced antidepressant effect of the combination may be due to synergistic increases in serotonin, norepinephrine, and dopamine.
- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
- Patient may experience dry mouth, loss of strength and energy, or fatigue. Have patient report immediately to prescriber signs of infection, signs of depression (suicidal ideation, anxiety, emotional instability, or confusion), signs of high blood sugar (confusion, fatigue, more thirst, hunger, polyuria, flushing, fast breathing, or breath that smells like fruit), signs of low sodium (headache, difficulty focusing, memory problems, confusion, weakness, seizures, or change in balance), bruising, bleeding, irritability, panic attacks, agitation, passing out, severe dizziness, swelling of arms or legs, enlarged breasts, nipple discharge, sexual dysfunction, amenorrhea, lack of sweating, difficult urination, swollen glands, signs of serotonin syndrome (dizziness, severe headache, agitation, hallucinations, tachycardia, abnormal heartbeat, flushing, tremors, sweating a lot, change in balance, severe nausea, or severe diarrhea), signs of neuroleptic malignant syndrome (fever, muscle cramps or stiffness, dizziness, severe headache, confusion, change in thinking, tachycardia, abnormal heartbeat, or sweating a lot), signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain) signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of a severe pulmonary disorder (lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse), or signs of tardive dyskinesia (unable to control body movements; tongue, face, mouth, or jaw sticking out; mouth puckering; or puffing cheeks) (HCAHPS).
- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.