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Olanzapine: Drug information

Olanzapine: Drug information
(For additional information see "Olanzapine: Patient drug information" and see "Olanzapine: Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Special Alerts
REMS Drugs COVID-19 Safety Alert March 2020

Due to challenges with completion of required laboratory testing or imaging studies for REMS drugs because of self-isolation or quarantine during the COVID-19 public health emergency, the FDA is recommending health care providers prescribing and/or dispensing REMS drugs consider whether there are compelling reasons or not to complete these requirements during this public health emergency and weigh with the patient the benefits and risks of continuing treatment in the absence of the laboratory testing and imaging studies. The FDA will not take action against sponsors and others during the public health emergency for failing to adhere to REMS requirements.

Further information may be found at https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-provides-update-patient-access-certain-rems-drugs-during-covid-19.

ALERT: US Boxed Warning
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. Analyses of 17 placebo-controlled trials (modal duration, 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients between 1.6 and 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was approximately 4.5%, compared with a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patient is not clear. Olanzapine is not approved for treatment of patients with dementia-related psychosis.

Postinjection delirium/sedation syndrome (Zyprexa Relprevv):

Adverse reactions with signs and symptoms consistent with olanzapine overdose, in particular, sedation (including coma) and/or delirium, have been reported following injections of olanzapine extended release (ER). Olanzapine ER must be administered in a registered health care facility with ready access to emergency response services. After each injection, patients must be observed at the health care facility by a health care provider for at least 3 hours. Because of this risk, olanzapine ER is available only through a restricted distribution program called Zyprexa Relprevv Patient Care Program, and requires health care provider, health care facility, patient, and pharmacy enrollment.

Brand Names: US
  • ZyPREXA;
  • ZyPREXA Relprevv;
  • ZyPREXA Zydis
Brand Names: Canada
  • ACT OLANZapine ODT [DSC];
  • ACT OLANZapine [DSC];
  • AG-Olanzapine FC;
  • APO-OLANZapine;
  • APO-OLANZapine ODT;
  • Auro-Olanzapine ODT;
  • JAMP OLANZapine FC;
  • JAMP OLANZapine ODT;
  • Mar-OLANZapine ODT [DSC];
  • Mar-OLANZapine [DSC];
  • Mint-Olanzapine;
  • MINT-OLANZapine ODT;
  • MYLAN-OLANZapine [DSC];
  • PMS-OLANZapine;
  • PMS-OLANZapine ODT;
  • RAN-OLANZapine;
  • RAN-OLANZapine ODT;
  • RIVA-OLANZapine;
  • RIVA-OLANZapine ODT [DSC];
  • SANDOZ OLANZapine;
  • SANDOZ OLANZapine ODT;
  • TEVA-OLANZapine;
  • VAN-OLANZapine [DSC];
  • ZyPREXA;
  • ZyPREXA Zydis
Pharmacologic Category
  • Antimanic Agent;
  • Second Generation (Atypical) Antipsychotic
Dosing: Adult

Note: In patients who are medically ill, at risk for postural hypotension, or may metabolize more slowly (eg, nonsmoking, female, ≥65 years of age), a low starting dose (eg, 2.5 mg) and more gradual titration may be better tolerated. Due to the drug's sedating effect, bedtime dosing is preferred; alternatively, divided doses may improve tolerability (Jibson 2019).

Agitation/Aggression associated with psychiatric disorders, substance intoxication, or other organic causes

Agitation/Aggression (severe, acute) associated with psychiatric disorders (eg, schizophrenia, bipolar disorder) (labeled use), substance intoxications (off-label use), or other organic causes (off-label use): Note: Antipsychotics are appropriate when psychosis is suspected to be the primary cause of agitation/aggression. Avoid in suspected or confirmed intoxications with anticholinergic substances; other agents are used preferentially in some intoxications (eg, stimulants) or alcohol withdrawal. Depending on presentation, may combine oral administration with a benzodiazepine; parenteral administration with a benzodiazepine is not recommended due to risk of respiratory depression (Klein 2018; Moore 2020; WFSBP [Hasan 2012]; Wilson 2012a; Wilson 2012b).

IM: Short-acting injection: Initial: 5 to 10 mg; may repeat based on response and tolerability 2 hours after initial dose and 4 hours after second dose; maximum: 30 mg/day (including oral olanzapine) (Wilson 2012b; manufacturer's labeling).

Oral (off-label route): Initial: 5 to 10 mg; may repeat based on response and tolerability every 2 hours up to 20 mg/day (Wilson 2012b).

IV: Short-acting injection (alternative agent) (off-label route): Note: IM administration is preferred in most clinical situations. If IV administration is used, limit to settings where patients can be closely monitored for respiratory depression (eg, emergency department) (Chan 2013; Cole 2017; Khorassani 2019; Martel 2016; Taylor 2017).

Initial: 5 to 10 mg single dose; if needed, may repeat once with an additional 2.5 to 5 mg dose ≥10 minutes after initial dose based on response and tolerability; total maximum dose: 10 mg (Cole 2017; Martel 2016; Taylor 2017).

Agitation/Aggression and psychosis associated with dementia, severe or refractory

Agitation/Aggression and psychosis associated with dementia, severe or refractory (alternative agent) (off-label use): Note: Patients with dementia with Lewy bodies are at increased risk for severe adverse reactions; caution is required even with low doses (APA [Reus 2016]).

IM: Short-acting injection: Initial dose: 2.5 or 5 mg; may repeat based on response and tolerability with up to 2 additional 1.25 to 5 mg doses at intervals ≥2 hours after the initial dose and ≥1 hour after the second dose; maximum: 12.5 mg per episode (Meehan 2002).

Oral: Initial: 2.5 mg once daily, may increase dose based on response and tolerability in increments of 2.5 to 5 mg/day at intervals ≥1 week up to 10 mg/day (De Deyn 2004; Street 2000; Verhey 2006). In patients without a clinically significant response after an adequate trial (eg, up to 4 weeks), taper and withdraw therapy. Only continue in patients with demonstrated benefit; attempt to taper and withdraw at regular intervals (eg, within 4 months of initiation) (APA [Reus 2016]).

Anorexia nervosa

Anorexia nervosa (off-label use): Note: For acutely ill patients who do not gain weight with nutritional rehabilitation plus psychotherapy (Walsh 2021; WFSBP [Aigner 2011]).

Oral: Initial: 2.5 mg once daily; may increase dose based on response and tolerability in increments of 2.5 mg every 1 to 2 weeks up to 10 mg/day (Attia 2011; Attia 2019; Bissada 2008).

Bipolar disorder

Bipolar disorder:

Acute mania, acute episodes with mixed features (labeled use), and acute hypomania (off-label use) (monotherapy or adjunctive therapy): Oral: Initial: 10 to 15 mg once daily; may increase dose based on response and tolerability in 5 mg increments at intervals of ≥1 day up to 20 mg/day (maximum per manufacturer's labeling); however, experts suggest some patients may require doses up to 50 mg/day for optimal response (CANMAT [Yatham 2018]; Citrome 2009; Stovall 2019).

Bipolar major depression, acute (alternative agent; monotherapy or adjunctive therapy) (off-label, except labeled use as adjunctive to fluoxetine): Oral: Initial: 5 mg once daily; may increase dose based on response and tolerability in 5 mg increments at intervals of every 1 to 7 days up to 15 mg/day (adjunctive therapy) or up to 20 mg/day (monotherapy) (Brown 2006; Shelton 2021; Tohen 2003, Tohen 2012; Wang 2014; WFSBP [Grunze 2010]). A fixed-dose olanzapine/fluoxetine combination may be used instead of separate components. See “Dosing Conversion” below.

Maintenance treatment (monotherapy [labeled use for mania or episodes with mixed features; off-label use for depression episodes] or adjunctive therapy [off-label use]): Note: Continue dose and combination regimen that was used to achieve control of the acute episode (CANMAT [Yatham 2018]).

Oral: Usual dose: 5 to 20 mg/day; maximum dose: 20 mg/day (manufacturer's labeling); however, for patients who required doses up to 50 mg/day to achieve remission, continue remission-achieving dose, as tolerated (Stovall 2021).

Chemotherapy-induced acute and delayed nausea or vomiting, prevention

Chemotherapy-induced acute and delayed nausea or vomiting (high emetic risk [>90%]), prevention (off-label use): Oral: 5 or 10 mg on day of chemotherapy (day 1), followed by 5 or 10 mg once daily on days 2 to 4, in combination with antiemetics used for high emetic risk agents (Hashimoto 2020; Navari 2011; Navari 2016; Sutherland 2018). For cisplatin-based high emetic-risk therapy, the 5 mg dose (in combination with triplet antiemetic therapy) is effective and may be associated with less daytime sedation (Hashimoto 2020).

Chemotherapy-induced breakthrough nausea or vomiting, treatment

Chemotherapy-induced breakthrough nausea or vomiting, treatment (off-label use): Oral: 5 to 10 mg once daily for 3 days (Navari 2013; Sutherland 2018).

Delirium, hyperactive

Delirium, hyperactive (treatment): Note: Nonpharmacologic interventions and treatment of underlying conditions are initial steps to prevent and manage delirium. Antipsychotics may be used as short-term adjunctive treatment if distressing symptoms (eg, agitation, anxiety, combative behavior) are present (SCCM [Devlin 2018]). Reassess daily for continued need; consider discontinuation and/or taper as symptoms resolve, especially at transitions of care to prevent unnecessary continuation of therapy (D’Angelo 2019; Marshall 2016; Tietze 2020).

ICU (off-label use):

Oral or via NG tube: Initial: 5 to 10 mg once daily (or 2.5 mg once daily in patients >60 years of age); titrate daily as needed in 2.5 to 5 mg increments up to 20 mg/day (Skrobik 2004; Tietze 2020).

IM: Short-acting injection: 5 to 10 mg once; may repeat if needed after 2 to 4 hours; maximum total dose including oral: 30 mg/day (Tietze 2020).

Non-ICU (off-label use):

Oral: Initial: 1.25 to 5 mg once daily or as needed; titrate daily based on symptoms in 2.5 to 5 mg increments up to 20 mg/day (Grover 2011; Roy-Byrne 2021).

IM: Short-acting injection: Initial: 2.5 to 5 mg once daily or as needed. Maximum dose (including oral): 20 mg/day (Grover 2011; Roy-Byrne 2021).

Delusional infestation

Delusional infestation (delusional parasitosis) (off-label use): Oral: Initial: 2.5 mg once daily; increase dose based on response and tolerability at intervals ≥1 week up to 7.5 mg/day (Campbell 2019; Suh 2019). Further increases up to 20 mg/day may be necessary in some patients for optimal response (Freudenmann 2008; Heller 2013). After achieving adequate response, maintain for ≥1 to 3 months before attempting to taper (Suh 2019).

Huntington disease–associated chorea, moderate to severe

Huntington disease–associated chorea, moderate to severe (alternative agent) (off-label use): Oral: Initial: 2.5 mg once daily; may increase dose based on response and tolerability in 2.5 to 5 mg increments at intervals ≥3 days up to 10 mg/day (Paleacu 2002; Suchowersky 2021). Further increases up to 30 mg/day may be necessary in some patients for optimal response (Bonelli 2002; Paleacu 2002).

Major depressive disorder

Major depressive disorder (unipolar):

Psychotic depression (adjunctive therapy with an antidepressant) (off-label use): Oral: Initial: 5 mg once daily; may increase dose based on response and tolerability in increments of 5 mg at intervals of 3 to 7 days up to 20 mg/day (Meyers 2009; Rothschild 2004; WFSBP [Bauer 2013]). After 4 to 6 months of sustained recovery, some experts suggest discontinuing the antipsychotic and continuing antidepressant monotherapy (Rothschild 2003; Rothschild 2021; Wijkstra 2010).

Treatment-resistant depression (adjunctive therapy with an antidepressant) (off-label, except labeled use as adjunctive to fluoxetine): Oral: Initial: 5 mg once daily; may gradually increase dose based on response and tolerability up to 20 mg/day (CANMAT [Kennedy 2016]; Nelson 2019). A fixed-dose olanzapine/fluoxetine combination may be used instead of separate components. See “Dosing Conversion below.

Nausea and vomiting associated with advanced cancer

Nausea and vomiting (persistent) associated with advanced cancer (off-label use): Oral: 5 mg once daily for 7 days; treatment may be continued beyond 7 days if clinically beneficial (Navari 2020).

Schizophrenia

Schizophrenia (alternative agent) (PORT [Kreyenbuhl 2010]):

Oral: Initial: 5 mg once daily increasing to 10 mg once daily within several days or 10 mg once daily. Thereafter may increase dose based on response and tolerability in increments of 5 mg/day at intervals ≥1 week up to 20 mg/day; maximum dose: 20 mg/day (manufacturer's labeling). Further increases up to 30 mg/day may be necessary in some patients for optimal response (Stroup 2019). Note: Doses up to 50 mg/day have been evaluated in clinical studies; however, doses >30 mg/day are associated with increased adverse effects and generally not recommended (Citrome 2009).

IM: ER injection (olanzapine pamoate): Note: Establish tolerability using oral olanzapine prior to changing to ER injection. Overlap of oral olanzapine with initial dose of ER injection is not necessary. Due to the potential for a severe adverse reaction, patients must be observed for at least 3 hours after every injection. Maximum dose: 300 mg every 2 weeks or 405 mg every 4 weeks.

Conversion of oral olanzapine to ER IM olanzapine:

Oral olanzapine 10 mg daily: Initial dose: 210 mg every 2 weeks for 4 doses or 405 mg every 4 weeks for 2 doses; Maintenance dose: 150 mg every 2 weeks or 300 mg every 4 weeks.

Oral olanzapine 15 mg daily: Initial dose: 300 mg every 2 weeks for 4 doses; Maintenance dose: 210 mg every 2 weeks or 405 mg every 4 weeks.

Oral olanzapine 20 mg daily: Initial and maintenance dose: 300 mg every 2 weeks.

Dosage adjustment in elevated-risk patients: Initial: A lower starting dose of 150 mg every 4 weeks is recommended in patients who are debilitated, at risk for orthostatic hypotension, may metabolize olanzapine more slowly (eg, nonsmoking, female, patients ≥65 years of age), or who may be more sensitive to adverse effects; increase dose with caution as clinically indicated.

Dosing conversion:

Olanzapine/fluoxetine fixed-dose combination: When using individual components of olanzapine with fluoxetine rather than the fixed-dose combination product, corresponding approximate dosage equivalents are as follows:

Olanzapine 2.5 mg + fluoxetine 20 mg = combination strength 3/25

Olanzapine 5 mg + fluoxetine 20 mg = combination strength 6/25

Olanzapine 12.5 mg + fluoxetine 20 mg = combination strength 12/25

Olanzapine 5 mg + fluoxetine 50 mg = combination strength 6/50

Olanzapine 12.5 mg + fluoxetine 50 mg = combination strength 12/50

Discontinuation of therapy:

Oral: In the treatment of chronic psychiatric disease switching therapy rather than discontinuation is generally advised if side effects are intolerable or treatment is not effective. If patient insists on stopping treatment, gradual dose reduction (ie, over several weeks to months) is advised to detect a re-emergence of symptoms and to avoid withdrawal reactions (eg, agitation, alternating feelings of warmth and chill, anxiety, diaphoresis, dyskinesias, GI symptoms, insomnia, irritability, myalgia, paresthesia, psychosis, restlessness, rhinorrhea, tremor, vertigo) unless discontinuation is due to significant adverse effects. Monitor closely to allow for detection of prodromal symptoms of disease recurrence (APA [Keepers 2020]; Lambert 2007; Moncrieff 2020; Post 2021).

Long-acting injectable: Switching to other treatments is generally advised if side effects are intolerable or treatment is not effective. However, if a patient insists on stopping treatment, gradual dose reduction to avoid withdrawal reactions is generally not needed with long-acting injectable antipsychotics. The risk of withdrawal symptoms from discontinuation of long-acting injectables is low because the rate of drug elimination is slow. Monitor closely to allow for detection of prodromal symptoms of disease recurrence (APA [Keepers 2020]; Spanarello 2014; Steinman 2021).

Switching antipsychotics: An optimal universal strategy for switching antipsychotic drugs has not been established. Strategies include: Cross-titration (gradually discontinuing the first antipsychotic while gradually increasing the new antipsychotic) and abrupt change (abruptly discontinuing the first antipsychotic and either increasing the new antipsychotic gradually or starting it at a treatment dose). In patients with schizophrenia at high risk of relapse, the current medication may be maintained at full dose as the new medication is increased (ie, overlap); once the new medication is at therapeutic dose, the first medication is gradually decreased and discontinued over 1 to 2 weeks (Cerovecki 2013; Remington 2005; Takeuchi 2017). Based upon clinical experience, some experts generally prefer cross-titration and overlap approaches rather than abrupt change (Stroup 2019).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.

Injection, Oral:

Altered kidney function: No dosage adjustment necessary for any degree of kidney impairment (Callaghan 1999; manufacturer's labeling).

Hemodialysis, intermittent (thrice weekly): Not dialyzed (Callaghan 1999): No supplemental dose or dosage adjustment necessary (expert opinion).

Peritoneal dialysis: Unlikely to be significantly dialyzed: No dosage adjustment necessary (expert opinion).

CRRT: Unlikely to be significantly dialyzed: No dosage adjustment necessary (expert opinion).

PIRRT (eg, sustained, low-efficiency diafiltration): Unlikely to be significantly dialyzed: No dosage adjustment necessary (expert opinion).

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the manufacturer’s labeling except when used in combination with fluoxetine (as separate components) the initial olanzapine dose should be limited to 2.5 to 5 mg daily. Use with caution (cases of hepatitis and liver injury have been reported with olanzapine use).

Dosing: Pediatric

(For additional information see "Olanzapine: Pediatric drug information")

Agitation: Limited data available: Note: Due to risk of sedation and respiratory depression, separate parenteral olanzapine and benzodiazepine doses by at least 1 hour (oral dosing may need longer separation of doses due to delayed onset and peak effect relative to parenteral) (AAEP [Gerson 2019]).

Oral (preferred): Recommended for psychiatric emergencies in patients who are developmentally delayed or have been diagnosed with autism for severe or refractory agitation and in patients with oppositional defiant or conduct disorder (AAEP [Gerson 2019]).

Children and Adolescents: Oral: Tablet, orally-disintegrating tablet: 2.5 to 10 mg. Dosing based on expert recommendations and very limited retrospective data (AAEP [Gerson 2019]; Cole 2020; Hilt 2008).

Parenteral: Recommended for psychiatric emergencies in patients who are developmentally delayed or have been diagnosed with autism for severe or refractory agitation (although ideally want to avoid IM in these patients) and in patients with oppositional defiant or conduct disorder, mania, or psychosis (AAEP [Gerson 2019]).

Children <10 years: IM (short acting): 1.25 mg to 5 mg (Cole 2020; Khan 2006).

Children ≥10 years and Adolescents: IM (short acting): 5 to 10 mg; dose may be repeated >2 hours post initial injection based on pharmacokinetic data and experience in adults (Cole 2020; Khan 2006; manufacturer's labeling).

Dosing based on retrospective reports of IM olanzapine use in an emergency department (n=124; age range: 10 to 18 years) which showed efficacy in 77% of patients (ie, no further sedation required) (Cole 2020); and in an inpatient psychiatric setting to treat acute agitation associated with bipolar disorder or schizophrenia which included 50 pediatric patients (children [n=15; mean age: 11 years]; adolescents [n=35; mean age: 15 years]) and evaluated 163 doses administered; results showed a 90.2% response rate (Khan 2006).

Anorexia nervosa : Limited data available; efficacy results variable; in trials, poor tolerability reported (AACAP [Lock 2015]; Couturier 2020; Kafantaris 2011):

Note: Olanzapine role in management of anorexia nervosa not defined; some suggest a short-term trial in patients with severe anxiety, obsessive thinking, extreme agitation, or hyperactivity, and resistance to refeeding or weight phobia as adjunct therapy (AACAP [Lock 2015]; Couturier 2020; Resmark 2019).

Children ≥9 years and Adolescents: Oral: Initial: 0.625 to 1.25 mg once daily; may titrate; reported range: 1.25 to 12.5 mg/day; however, it has been suggested that higher doses (>2.5 mg once daily) may not be associated with greater efficacy. In small trials and several case reports, 1.25 to 2.5 mg once daily was shown to improve BMI and other disease-related symptoms (eg, eating attitudes, anxiety, sleep); another case series used initial doses of 2.5 mg once daily and final doses of 5 to 10 mg once daily (Boachie 2003; Couturier 2020; Dunican 2007; Leggero 2010; Mehler 2001; Mehler-Wex 2008).

Bipolar I disorder (acute mania or episodes with mixed features): Note: Olanzapine is not considered first-line therapy due to increased incidence of adverse effects identified in adolescent trials including weight gain and other metabolic abnormalities; neurological side effects may also occur; consider risks versus benefits prior to therapy initiation (CANMAT [Yatham 2018]; Lee 2018).

Children 4 to <6 years: Limited data available: Oral: Initial: 1.25 mg once daily; increase at weekly intervals according to response and tolerability to target dose: 10 mg/day. Dosing based on an open-label trial in 15 children (mean age: 5 ± 0.8 years; mean weight: 20.8 kg; mean required dose: 6.3 ± 2.3 mg/day) that showed significant improvement in manic symptoms (Biederman 2005).

Children 6 to 12 years: Limited data available: Oral: Initial: 2.5 mg once daily; increase dose in 2.5 or 5 mg increments at weekly intervals to target dose of 10 mg once daily; maximum dose: 20 mg/day (Frazier 2001; Kowatch 2005; Wozniak 2009).

Adolescents: Oral: Initial: 2.5 to 5 mg once daily; increase dose in 2.5 or 5 mg increments at weekly intervals to target dose of 10 mg once daily; maximum dose: 20 mg/day. In adolescent flexible-dosing (2.5 to 20 mg/day) clinical trials, the mean modal dose was 10.7 mg/day (mean dose: 8.9 mg/day) (Kowatch 2005; Tohen 2007).

Chemotherapy-induced nausea and vomiting (CINV); breakthrough, refractory: Limited data available: Note: For highly emetogenic chemotherapy, evidenced-based clinical practice guidelines suggest the addition of olanzapine to existing CINV regimen for treatment of breakthrough CINV and for prevention of CINV in patients who have refractory CINV (Flank 2016).

Children ≥3 years and Adolescents: Oral: Tablet, orally-disintegrating tablet: 0.1 to 0.14 mg/kg/dose once or twice daily; round dose to nearest 1.25 mg; in trials, olanzapine was combined with standard CINV regimens that included aprepitant, dexamethasone, and ondansetron or granisetron (Flank 2015; Flank 2016; Naik 2020). Dosing based on a prospective, open-label, parallel group trial in 231 pediatric patients ≥5 years of age (n=115 olanzapine treatment group; median age: 12.5 years; median weight: 34 kg). In the olanzapine treatment group, patients received olanzapine throughout the chemotherapy block and for 3 days at the conclusion; results showed a significantly higher proportion of patients had a complete response (no nausea and no rescue medication) (Naik 2020). A retrospective evaluation of 60 pediatric patients (128 chemotherapy blocks; median age: 13.2 years; range: 3 to ~18 years) with poorly controlled CINV received olanzapine and reported complete vomiting control in the acute phase in 65% of the evaluated chemotherapy blocks (Flank 2015).

Delirium, ICU setting:

Infants ≥7 months to Children <3 years: Very limited data available: Oral: Orally disintegrating tablets: Reported range: 0.625 to 1.25 mg once daily (at bedtime) or twice daily; based on experience in older pediatric patients, therapy should be initiated at low dose and then titrated as needed (Madden 2011; Turkel 2013).

Children ≥3 years and Adolescents: Limited data available: Oral: Tablets, orally disintegrating tablets: Usual initial range: 1.25 to 5 mg once daily (at bedtime) or twice daily; doses on the higher end of the range should be reserved for larger or extremely agitated patients; therapy should be initiated at low dose and then titrated as needed (Sassano-Higgins 2013; Turkel 2012). In trials, once symptoms were controlled, doses were decreased over time; average reported duration of therapy was 26.5 days (range: 1 to 132 days) (Sassano-Higgins 2013; Turkel 2012; Turkel 2013; Turkel 2014). In the largest reported experience (n=78, age range: 1 to 18 years), a retrospective, descriptive trial reported a mean initial total daily dose of 4 mg/day and a mean maximum total daily dose of 10 mg/day (Turkel 2012).

Schizophrenia: Note: Olanzapine may not be considered first-line therapy by clinicians due to increased incidence of adverse effects identified in adolescent trials including weight gain and other metabolic abnormalities; neurological side effects may also occur; consider risks versus benefits prior to therapy initiation (AACAP [McClellan 2013]).

Children ≥8 years (limited data available in ages <13 years) and Adolescents: Oral: Initial: 2.5 to 5 mg once daily; increase dose in 2.5 or 5 mg increments at weekly intervals to target dose of 10 mg once daily; maximum dose: 20 mg/day. Note: Doses up to 30 mg/day were used in one study of adolescents who were treatment refractory; however, some patients did not tolerate doses >20 mg/day (Kumra 2008); safety and efficacy of doses >20 mg/day have not been fully evaluated. In adolescent flexible-dosing (2.5 to 20 mg/day) clinical trials, the mean modal dose was 12.5 mg/day (mean dose: 11.1 mg/day). Dosing in children is based on 2 double-blind comparison studies which included both children and adolescents (n=35, age: 8 to 19 years with seven children; n=13, age: 7 to 16 years [mean age: 12.8 + 2.4 years]) (Shaw 2006; Sikich 2008).

Tourette syndrome, tic disorder: Limited data available: Note: Not considered a therapeutic option in expert guidelines (AAN [Pringsheim 2019]; AAP [Wolraich 2019]) due to increased incidence of adverse effects identified in pediatric patients including weight gain and other metabolic abnormalities and neurological side effects; consider risks versus benefits prior to therapy initiation (TSFC [Pringsheim 2012]).

Children ≥7 years and Adolescents:

Patient weight ≤40 kg: Oral: Initial: 2.5 mg every other day for 3 days, increase to 2.5 mg every day for remainder of week; increase to 5 mg/day by second week if needed; then increase in 5 mg increments at weekly intervals as tolerated; maximum dose: 20 mg/day.

Patient weight >40 kg: Oral: Initial: 2.5 mg every day for 3 days; increase to 5 mg every day for remainder of week if needed, then increase in 5 mg increments at weekly intervals as tolerated; maximum dose: 20 mg/day.

An open-label study of 10 pediatric patients (7 to 13 years of age) reported significant reductions in tic severity (Yale Global Tic Severity Scale [YGTSS]) from baseline at a mean final dose of 14.5 mg/day after 8 weeks of treatment (Stephens 2004). An open-label trial of 12 children and adolescents (7 to 14 years of age) reported a significant reduction (30%) in total tic severity (YGTSS) at a final mean dose of 11.3 mg/day (range: 2.5 to 20 mg/day) (McCracken 2008).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Pediatric

Adolescents: No dosage adjustment required. Not removed by dialysis.

Dosing: Hepatic Impairment: Pediatric

Adolescents: Use with caution. Dosage adjustment may be necessary; however, no specific recommendations exist. Monitor closely.

Dosing: Older Adult

Refer to adult dosing. Dosages in the lower range of recommended adult dosing are generally sufficient for patient with late-onset-schizophrenia or psychosis (Howard 2020).

Short-acting IM, Oral: Consider lower starting dose of 2.5 to 5 mg daily for elderly patients; may increase as clinically indicated and tolerated with close monitoring of orthostatic blood pressure.

ER IM: Consider lower starting dose of 150 mg every 4 weeks for elderly patients; increase dose with caution as clinically indicated.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution Reconstituted, Intramuscular:

ZyPREXA: 10 mg (1 ea)

Generic: 10 mg (1 ea)

Suspension Reconstituted, Intramuscular:

ZyPREXA Relprevv: 210 mg (1 ea [DSC]); 300 mg (1 ea [DSC]); 405 mg (1 ea [DSC]) [contains polysorbate 80]

Suspension Reconstituted, Intramuscular [preservative free]:

ZyPREXA Relprevv: 210 mg (1 ea); 300 mg (1 ea); 405 mg (1 ea) [contains polysorbate 80]

Tablet, Oral:

ZyPREXA: 2.5 mg, 5 mg, 7.5 mg, 10 mg

ZyPREXA: 15 mg [contains fd&c blue #2 aluminum lake]

ZyPREXA: 20 mg

Generic: 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg

Tablet Disintegrating, Oral:

ZyPREXA Zydis: 5 mg, 10 mg, 15 mg, 20 mg [contains aspartame, methylparaben sodium, propylparaben sodium]

Generic: 5 mg, 10 mg, 15 mg, 20 mg

Generic Equivalent Available: US

May be product dependent

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intramuscular:

ZyPREXA: 10 mg (1 ea)

Generic: 10 mg (1 ea)

Tablet, Oral:

ZyPREXA: 2.5 mg, 5 mg, 7.5 mg, 10 mg [contains polysorbate 80]

ZyPREXA: 15 mg [contains fd&c blue #2 aluminum lake]

ZyPREXA: 20 mg

Generic: 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg

Tablet Disintegrating, Oral:

ZyPREXA Zydis: 5 mg, 10 mg, 15 mg, 20 mg [contains aspartame, methylparaben sodium, propylparaben sodium]

Generic: 5 mg, 10 mg, 15 mg, 20 mg

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:

Zyprexa and Zyprexa Zydis: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020592s075,021086s049,021253s062lbl.pdf#page=37

Zyprexa Relprevv: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/022173s036lbl.pdf#page=29

Administration: Adult

Short-acting injection: May be administered IM or IV (off-label route); do not administer injection subcutaneously. For IM administration, inject slowly, deep into muscle. For off-label IV route, administer by rapid IV push (Taylor 2017). If dizziness and/or drowsiness are noted, patient should remain recumbent until examination indicates postural hypotension and/or bradycardia are not a problem.

Extended-release injection: For IM gluteal injection only; do not administer IV or subcutaneously. After needle insertion into muscle, aspirate to verify that no blood appears. Do not massage injection site. Use diluent, syringes, and needles provided in convenience kit; obtain a new kit if aspiration of blood occurs.

Tablet: May be administered without regard to meals.

Orally-disintegrating: Remove from foil blister by peeling back (do not push tablet through the foil); place tablet in mouth immediately upon removal; tablet dissolves rapidly in saliva and may be swallowed with or without liquid. May be administered with or without food/meals.

Administration: Pediatric

Oral:

Tablet: May be administered with or without food.

Orally disintegrating tablet: Remove from foil blister by peeling back foil (do not push tablet through the foil); place tablet in mouth immediately upon removal; tablet dissolves rapidly in saliva and may be swallowed with or without liquid. May be administered with or without food/meals.

Parenteral: IM (short-acting): For IM administration only; do not administer IV or subcutaneously; inject slowly, deep into muscle mass. If dizziness and/or drowsiness are noted, patient should remain recumbent until examination indicates postural hypotension and/or bradycardia are not a problem.

Use: Labeled Indications

Agitation/Aggression (acute) associated with psychiatric disorders (short-acting IM): Treatment of acute agitation associated with schizophrenia and bipolar I mania.

Bipolar disorder (oral): Treatment of acute mania, acute episodes with mixed features of bipolar I disorder (as monotherapy or in combination with lithium or valproate), and maintenance treatment; treatment of bipolar depression in combination with fluoxetine.

Major depressive disorder (unipolar), treatment resistant (oral): Treatment of treatment-resistant depression in combination with fluoxetine.

Schizophrenia (oral, ER IM): Treatment of the manifestations of schizophrenia.

Use: Off-Label: Adult

Agitation/Aggression and psychosis associated with dementia; Anorexia nervosa; Bipolar disorder, hypomania; Chemotherapy-induced acute and delayed nausea or vomiting (high emetic risk [>90%]), prevention; Chemotherapy-induced breakthrough nausea or vomiting, treatment; Delirium, hyperactive (ICU treatment); Delirium, hyperactive (non-ICU treatment); Delusional infestation (delusional parasitosis); Huntington disease-associated chorea; Major depressive disorder (unipolar) with psychotic features; Nausea and vomiting associated with advanced cancer

Medication Safety Issues
Sound-alike/look-alike issues:

OLANZapine may be confused with olsalazine, QUEtiapine

ZyPREXA may be confused with CeleXA, Reprexain, Zestril, ZyrTEC

ZyPREXA Zydis may be confused with Zelapar, zolpidem, zapelon

ZyPREXA Relprevv may be confused with ZyPREXA IntraMuscular

Geriatric Patients: High-Risk Medication:

Beers Criteria: Antipsychotics are identified in the Beers Criteria as a potentially inappropriate medication to be avoided in patients 65 years and older due to an increased risk of cerebrovascular accidents (stroke) and a greater rate of cognitive decline and mortality in patients with dementia. Antipsychotics may be appropriate for schizophrenia, bipolar disorder, other mental health conditions or short-term use as antiemetic during chemotherapy but should be given in the lowest effective dose for the shortest duration possible. In addition, antipsychotics should be used with caution in older adults due to their potential to cause or exacerbate syndrome of inappropriate antidiuretic hormone secretion (SIADH) or hyponatremia; monitor sodium closely with initiation or dosage adjustments in older adults (Beers Criteria [AGS 2019]).

Pediatric patients: High-risk medication:

KIDs List: Olanzapine, when used long term (>24 weeks) in pediatric patients <18 years of age, is identified on the Key Potentially Inappropriate Drugs in Pediatrics (KIDs) list and should be used with caution due to risk of metabolic syndrome (weight gain, hyperlipidemia, hyperglycemia) (strong recommendation; high quality of evidence) (PPA [Meyers 2020]).

Adverse Reactions (Significant): Considerations
Anticholinergic effects

Anticholinergic activity at usual therapeutic doses is generally considered to be moderate, relative to other second-generation antipsychotics (other than clozapine) (Ref). However, dose-dependent increases in anticholinergic activity have been observed (Ref). Anticholinergic effects include constipation, urinary retention, and xerostomia. In older adults, some scales have classified olanzapine as having a high anticholinergic burden which may lead to new-onset delirium, cognitive dysfunction, and falling. However, there is no standardized tool for measuring anticholinergic burden in older adults and varying scales have also ranked olanzapine as low or moderate (Ref).

Mechanism: Dose-related; believed to be mediated primarily through antagonism at muscarinic receptors (Ref).

Risk factors:

Variable and dependent upon:

• Total cumulative anticholinergic burden (Ref)

• Baseline cognitive function (Ref)

• Comorbidities (Ref)

• Older adults (Ref)

• Interindividual variability of the pharmacokinetic and pharmacodynamic parameters (Ref)

Dyslipidemia

Olanzapine is strongly associated with dyslipidemia in adult and adolescent patients, which is a component of the metabolic syndrome observed with this pharmacologic class. Dyslipidemia observed with olanzapine primarily manifests as hypercholesterolemia and/or hypertriglyceridemia, including cases of severe hypertriglyceridemia (>600 mg/dL) and acute pancreatitis (Ref).

Mechanism: The mechanism is not entirely understood and is likely multifactorial (Ref).

Onset: Varied; metabolic alterations from antipsychotics can develop in as short as 3 months after initiation (Ref). One case series observed olanzapine-induced hypertriglyceridemia occurred with a time to peak as early as 2 months following initiation in some patients (Ref). Increases in fasting total cholesterol, LDL cholesterol, and triglycerides were generally greater in adolescent patients when compared to adults.

Risk factors:

• Family history of hyperlipidemia (Ref)

• BMI >25 kg/m2 (Ref)

• Adolescents (Ref)

• Schizophrenia (regardless of medication use) is associated with a higher rate of morbidity/mortality compared to the general population primarily due to cardiovascular disease (Ref).

• Specific antipsychotics: Risk of dyslipidemia and overall metabolic disturbances appears to be high with olanzapine (Ref).

Extrapyramidal symptoms

Olanzapine may cause extrapyramidal symptoms (EPS), also known as drug-induced movement disorders. Antipsychotics can cause four main extrapyramidal reactions: Acute dystonia, drug-induced parkinsonism, akathisia, and tardive dyskinesia (Ref). EPS presenting as dysphagia, esophageal dysmotility, or aspiration have also been reported with antipsychotics, which may not be recognized as EPS (Ref).

Mechanism: EPS: Dose-related; due to antagonism of dopaminergic D2 receptors in nigrostriatal pathways (Ref). Tardive dyskinesia: Time related (delayed); results from chronic exposure to dopamine 2 receptor antagonists leading to up-regulation of these receptors over time (Ref).

Onset:

Antipsychotics in general:

Acute dystonia: Rapid; in the majority of cases, dystonia usually occurs within the first 5 days after initiating antipsychotic therapy (even with the first dose, particularly in patients receiving parenteral antipsychotics) or a dosage increase (Ref).

Drug-induced parkinsonism: Varied; onset may be delayed from days to weeks, with 50% to 75% of cases occurring within 1 month and 90% within 3 months of antipsychotic initiation, a dosage increase, or a change in the medication regimen (such as adding another antipsychotic agent or discontinuing an anticholinergic medication) (Ref).

Akathisia: Varied; may begin within several days after antipsychotic initiation but usually increases with treatment duration, occurring within 1 month in up to 50% of cases, and within 3 months in 90% of cases (Ref).

Tardive dyskinesia: Delayed; symptoms usually appear after 1 to 2 years of continuous exposure to a dopamine 2 receptor antagonist and almost never before 3 months, with an insidious onset, evolving into a full syndrome over days and weeks, followed by symptom stabilization, and then a chronic waxing and waning of symptoms (Ref).

Esophageal dysfunction (associated with extrapyramidal symptoms): Varied; ranges from weeks to months following initiation (Ref).

Risk factors:

EPS (in general):

• Prior history of EPS (Ref)

• Higher doses (Ref)

• Younger age (in general, children and adolescents are usually at higher risk for EPS compared to adults) (Ref)

• Specific antipsychotic: Olanzapine has a mild to moderate propensity to cause EPS; however, risk is dose-dependent (Ref)

Acute dystonia:

• Males (Ref)

• Young age (Ref).

Drug-induced parkinsonism:

• Females (Ref)

• Older patients (Ref)

Akathisia:

• Higher antipsychotic dosages (Ref)

• Polypharmacy (Ref)

• Mood disorders (Ref)

• Females (Ref)

• Older patients (Ref)

Tardive dyskinesia:

• Age >55 years (Ref)

• Cognitive impairment (Ref)

• Concomitant treatment with anticholinergic medications (Ref)

• Diabetes (Ref)

• Diagnosis of schizophrenia or affective disorders (Ref)

• Females (Ref)

• Greater total antipsychotic exposure (especially first-generation antipsychotics) (Ref)

• History of extrapyramidal symptoms (Ref)

• Substance misuse or dependence (Ref)

• Race (White or African descent). Note: Although early literature supported race as a potential risk factor for tardive dyskinesia (Ref), newer studies have challenged this assertion (Ref).

Esophageal dysfunction (associated with EPS):

• Certain comorbidities such as neurologic degenerative disease, dementia, stroke, Parkinson disease, or myasthenia gravis (Ref)

• Older adults >75 years of age (may be risk factor due to age-related muscle atrophy, cognitive impairment, reduced esophageal peristalsis) (Ref)

Hematologic abnormalities

Leukopenia, neutropenia, and thrombocytopenia have rarely been reported with olanzapine (Ref). Agranulocytosis and pancytopenia have also been very rarely reported (Ref).

Mechanism: Unknown; olanzapine has a chemical structure similar to clozapine (which also has hematologic side effects) (Ref).

Onset: Varied; in general, drug-induced neutropenia usually manifests after 1 or 2 weeks of exposure and agranulocytosis usually appears 3 to 4 weeks following initiation of therapy; however, the onset may be insidious (Ref).

Risk factors:

• History of drug-induced leukopenia/neutropenia or low white blood cell count/absolute neutrophil count

• Older adults (Ref)

Hyperglycemia

Olanzapine is strongly associated with hyperglycemia in adult and pediatric patients, which is a component of the metabolic syndrome observed with this pharmacologic class. Glycemic abnormalities range from mild insulin resistance to new-onset diabetes mellitus, hyperglycemic hyperosmolar coma, and diabetic ketoacidosis, including fatal cases (Ref).

Mechanism: The mechanism is not entirely understood and is likely multifactorial (Ref).

Onset: Varied; new-onset diabetes has been observed within the first 3 months to a median onset of 3.9 years (Ref)

Risk factors:

• African American race (Ref)

• Males (Ref)

• Younger adults (Ref)

• Patients with preexisting obesity, poor exercise habits, or other risk factors for diabetes, including family history of diabetes (Ref)

• Exposures to other agents that also increase the risk of hyperglycemia (Ref)

• Specific antipsychotic: Risk of metabolic disturbances appears to be high with olanzapine (Ref).

Hyperprolactinemia

In adults, olanzapine is typically associated with a lower risk of causing significant effects on prolactin compared to other second-generation antipsychotics with a higher risk (such as risperidone), although there are case reports of hyperprolactinemia in olanzapine-treated adults (Ref). However, in pediatric patients, the risk may be higher. A higher incidence of increased serum prolactin has been observed in adolescents receiving olanzapine compared to adults. Studies involving both children and adolescents (mostly short-term data) have also observed a statistically significant increase in serum prolactin levels during therapy compared to baseline levels. Hyperprolactinemia may lead to gynecomastia, galactorrhea not associated with childbirth, amenorrhea, sexual disorder, and infertility (Ref). Although long-term effects of elevated prolactin levels have not been fully evaluated, some studies have also suggested a possible association between hyperprolactinemia and an increased risk for breast and/or pituitary tumors and osteopenia/osteoporosis (Ref).

Mechanism: Dose-related (although some data involving olanzapine are inconsistent); antagonism of dopamine D2 receptors in the tuberoinfundibular dopaminergic pathway which causes disinhibition of prolactin release resulting in hyperprolactinemia (Ref).

Onset: Varied; onset of antipsychotic-induced hyperprolactinemia is typically within a few weeks following initiation or dosage increase but may also arise after long-term stable use (Ref). Data involving children and adolescents receiving olanzapine showed significantly higher prolactin levels at months 3 and 6 compared to month 1, and a lower level at month 12 compared to month 1 (although that difference was not statistically significant) (Ref). Although data are limited, a study involving patients 15 to 60 years suggests olanzapine does not significantly affect serum prolactin levels in the long term (eg, >1 year) (Ref).

Risk factors:

Antipsychotics in general:

• Higher doses (Ref) Note: Some data with olanzapine show inconsistent evidence for a dose relationship (Ref)

• Females (particularly those of reproductive age) (Ref)

• Children and adolescents (Ref)

Olanzapine specifically:

• Some D2 receptor and 5-HT2A receptor gene polymorphisms (potential risk factor affecting prolactin levels with olanzapine therapy) (Ref)

Hypersensitivity reactions

Delayed hypersensitivity reactions range from benign skin photosensitivity, purpuric rash, and fixed drug eruptions to more serious reactions, such as vasculitis and severe cutaneous adverse reactions (SCARs), including acute generalized exanthematous pustulosis and drug reaction with eosinophilia and systemic symptoms (DRESS) (Ref).

Mechanism: Non-dose-related; immunologic. Delayed hypersensitivity reactions, including fixed drug eruptions and SCARs are T-cell-mediated (Ref). Olanzapine can form N-oxide metabolites, which may contribute to the development of these reactions (Ref).

Onset: Delayed hypersensitivity reactions: Fixed drug eruptions: Intermediate; occur 7 to 10 days after initiation. Other reactions (including SCARs): Varied; usually occur between 7 to 14 days and up to 3 months (Ref) but may also occur within 4 to 5 days (Ref).

Risk factors:

• Although potential cross-reactivity has been postulated between olanzapine and carbamazepine in a patient who developed DRESS to both agents, this may represent a reaction to 2 unrelated drugs (Ref) or neosensitization to multiple drugs (Ref). Despite the chemical similarity between clozapine, olanzapine, and quetiapine, no cross-reactions have been reported between these atypical antipsychotics to date.

Mortality in older patients

Older adults with dementia-related psychosis treated with antipsychotics are at an increased risk of death compared to placebo. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature (Ref). In addition, an increased incidence of cerebrovascular effects (eg, cerebrovascular accident, transient ischemic attacks), including fatalities, have been reported in placebo-controlled olanzapine trials in elderly patients with dementia-related psychosis (Ref). Of note, olanzapine is not approved for the treatment of dementia-related psychosis.

Mechanism: Unknown; possible mechanisms include arrhythmia, cardiac arrest, and extrapyramidal effects that may increase the risk of falls, aspirations, and pneumonia (Ref).

Risk factors:

• Higher antipsychotic dosage (Ref)

• Dementia-related psychosis (eg, Lewy body dementia, Parkinson disease dementia)

• Older adults

Neuroleptic malignant syndrome

All antipsychotics have been associated with neuroleptic malignant syndrome (NMS), although the incidence is less with second-generation (atypical) antipsychotics compared to first-generation (typical) antipsychotics. There are case reports of NMS with olanzapine, including monotherapy (Ref).

Mechanism: Non-dose-related; idiosyncratic. Believed to be due to a reduction in CNS dopaminergic tone, along with the dysregulation of autonomic nervous system activity (Ref).

Onset: Varied; in general, most patients develop NMS within 2 weeks of initiating an antipsychotic, and in some patients, prodromal symptoms emerge within hours of initiation; once the syndrome starts, the full syndrome usually develops in 3 to 5 days (Ref). However, there are many cases of NMS occurring months after stable therapy (Ref).

Risk factors:

Antipsychotics in general:

• Males are twice as likely to develop NMS compared to females (Ref)

• Dehydration (Ref)

• High-dose antipsychotic treatment (Ref)

• Concomitant lithium or a benzodiazepine (potential risk factors) (Ref)

• Catatonia (Ref)

• Disorganized speech or behavior (Ref)

• Polypharmacy (Ref)

• Pharmacokinetic interactions (Ref)

• Intramuscular administration of an antipsychotic (Ref)

• Rapid dosage escalation (Ref)

• Psychomotor agitation (Ref)

Orthostatic hypotension

Olanzapine may cause orthostatic hypotension (although at a lower prevalence compared to first generation antipsychotics and certain atypicals, such as clozapine, risperidone, and quetiapine) and accompanying tachycardia and dizziness in adults, particularly with rapid titration (Ref). Orthostatic hypotension may result in a subsequent falling and fracture, particularly in older adults (Ref).

Mechanism: Orthostatic hypotension is attributed to alpha-1 adrenergic receptor antagonism (Ref).

Onset: Rapid; per the manufacturer’s labeling, orthostatic hypotension is most common during the initial dose titration but can also occur following subsequent dose increases.

Risk factors:

• Known cardiovascular diseases (history of myocardial infarction or ischemic heart disease, heart failure, or conduction abnormalities) or cerebrovascular disease

• Known predisposing conditions (eg, hypovolemia/dehydration)

• Concomitant medications that also cause or exacerbate orthostatic hypotension (eg, tricyclic antidepressants, antihypertensive medications)

• Older adults

• Rapid dose titration (Ref)

Post-injection delirium/sedation syndrome

Olanzapine pamoate, the long-acting intramuscular injectable formulation, is associated with rare cases of post-injection delirium/sedation syndrome (PDSS), characterized by sedation (ranging from mild in severity to a coma-like state) and/or delirium (eg, agitation disorientation, confusion, irritability). Recovery is expected by 72 hours. Due to the risk of PDSS, a risk evaluation and mitigation strategy (REMS) program, called the Patient Care Program, is required with olanzapine pamoate use (Ref).

Mechanism: Since patients with PDSS exhibit symptoms consistent with an oral overdose of olanzapine, the mechanism is believed to be due to accidental intravascular entry of a portion of the dose, likely following vessel injury during the injection (Ref).

Onset: Rapid; the vast majority of patients (80% to 90%) experience PDSS within the first hour of IM injection (median onset: 25 minutes postinjection), with most of the remainder of patients experiencing an onset between 1 hour and ≤3 hours; however, some patients have a time to onset at >3 hours (Ref). PDSS may occur with any injection; one case report describes PDSS following a patient’s 31st scheduled injection (patient previously received 1.5 years of injections without PDSS) (Ref).

Risk factors:

Note: No clear risk factors have been identified (Detke 2010), although the following have been suggested:

• Although PDSS can occur even with proper injection technique, improper injection technique and/or improper aspiration (to verify blood is not visible prior to injection) may increase the risk (Ref)

• Decreased BMI (weak evidence) (Ref)

• Older patients (weak evidence) (Ref)

• Higher doses (weak evidence) (Ref)

• Males (weak evidence) (Ref)

QT prolongation

Olanzapine has been associated with a mild degree of prolonged QT interval on ECG. In a study of 24 healthy psychiatric patients reaching steady state on olanzapine 20 mg/day, the mean change in QTc was 1.7 ms (Ref).

Mechanism: Likely dose-related (but some evidence is inconsistent/conflicting); olanzapine prolongs cardiac repolarization by blocking the rapid component of the delayed rectifier potassium current (Ref)

Risk factors:

Drug-induced QTc prolongation/torsades de pointes (TdP) (in general):

• Females (Ref)

• Age >65 years (Ref)

• Structural heart disease (eg, history of myocardial infarction or heart failure with a reduced ejection fraction) (Ref)

• History of drug-induced TdP (Ref)

• Genetic defects of cardiac ion channels (Ref)

• Congenital long QT syndrome (Ref)

• Baseline QTc interval prolongation (eg, >500 msec) or lengthening of the QTc by ≥60 msec (Ref)

• Electrolyte disturbances (eg, hypokalemia, hypocalcemia, hypomagnesemia) (Ref)

• Bradycardia (Ref)

• Hepatic impairment (Ref)

• Kidney impairment (Ref)

• Coadministration of multiple medications (≥2) that prolong the QT interval or increase drug interactions that increase serum drug concentrations of QTc prolonging medications (Ref)

• Substance use (Ref)

Sedation

Sedated state (drowsiness) is common with use in all ages and may cause nonadherence, impair physical and mental abilities, and may result in subsequent falling and fracture, particularly in older adults (Ref).

Mechanism: Sedation is believed to be due to H1 antagonism, leading to potential CNS depressant effects; olanzapine is considered a potent H1 receptor blocker (Ref).

Risk factors:

• Pediatric patients (sedation appears to be more prevalent compared to adults) (Ref)

• Higher doses (may increase risk) (Ref)

Sexual dysfunction

Antipsychotics have been associated with sexual disorder in both males and females. Antipsychotic treatment has been associated with effects on all phases of sexual activity (libido, arousal, and orgasm); however, many patients with schizophrenia experience more frequent sexual dysfunction, with or without antipsychotic treatment. Decreased libido, erectile dysfunction, and abnormal orgasm have been reported with olanzapine (Ref). Conversely, there are also rare case reports of increased libido occurring with use (Ref).

Mechanism: Antipsychotic-induced sexual dysfunction has been attributed to many potential mechanisms, including dopamine receptor antagonism, dopamine D2 receptor antagonism in the infundibular dopaminergic pathway causing hyperprolactinemia, histamine receptor antagonism, cholinergic receptor antagonism, and alpha-adrenergic receptor antagonism (Ref). Of note, in adults, olanzapine is associated with a lower propensity for hyperprolactinemia compared to certain other antipsychotics with a high risk, such as risperidone (Ref).

Risk factors:

• Hyperprolactinemia (although a correlation with sexual dysfunction has been observed, a relationship has not been confirmed) (Ref)

• Schizophrenia (the prevalence of antipsychotic-induced sexual dysfunction in patients with schizophrenia is high [~50% to 60% compared with 31% of men in the general population]) (Ref)

• Specific antipsychotic: Contrasting evidence; some studies have found a high prevalence of sexual dysfunction with olanzapine, while other studies have reported lower rates (Ref)

Temperature dysregulation

Antipsychotics may impair the body’s ability to regulate core body temperature, which may cause a potentially life-threatening heatstroke during predisposing conditions such as a heat wave or strenuous exercise. There are also several case reports of potentially life-threatening hypothermia associated with olanzapine use (Ref).

Mechanism: Non-dose-related; idiosyncratic. Exact mechanism is unknown; however, body temperature is regulated by the hypothalamus with involvement of the dopamine, serotonin, and norepinephrine neurotransmitters. D2 antagonism may cause an increase in body temperature, while 5-HT2a (serotonin) receptor antagonism may cause a decrease in body temperature. Of note, olanzapine has a stronger affinity for serotonin 5-HT2a receptors compared to D2 receptors. In addition, antagonism of peripheral alpha-adrenergic receptors has also been suggested as a factor in the hypothermic effect by inhibiting peripheral responses to cooling (vasoconstriction and shivering) (Ref).

Onset: Hypothermia: Varied; antipsychotic-induced hypothermia cases indicate a typical onset in the period shortly after initiation of therapy or a dosage increase (first 7 to 10 days) (Ref)

Risk factors:

Heat stroke:

• Psychiatric illness (regardless of medication) (Ref)

• Strenuous exercise, heat exposure, dehydration, and concomitant medication possessing anticholinergic effects (Ref).

Hypothermia:

• In general, predisposing risk factors include advanced age, a cerebrovascular accident or preexisting brain damage, hypothyroidism, malnutrition, shock, sepsis, adrenal insufficiency, diabetes, disability, burns, exfoliative dermatitis benzodiazepine use, alcohol intoxication, or kidney or liver failure (Ref)

• Schizophrenia (regardless of antipsychotic use) (Ref)

Weight gain

Olanzapine is strongly associated with significant weight gain (increase of ≥7% from baseline) in children, adolescents, and adults, which is a component of the metabolic syndrome observed with this pharmacologic class (Ref). Compared to adult patients, adolescent patients had both greater magnitude of weight gain and greater proportion of patients with clinically significant weight gain.

Mechanism: Multiple proposed mechanisms, including actions at serotonin, dopamine, histamine, and muscarinic receptors, with differing effects on weight gain by the different antipsychotic agents explained by differing affinity at these receptors. (Ref).

Onset: Varied; antipsychotic-induced weight gain usually occurs rapidly in the period following initiation, then gradually decreases and flattens over several months with patients continuing to gain weight in the long term (Ref).

Risk factors:

• Family history of obesity; parental BMI (Ref)

• Children and adolescents (Ref)

• Factors associated with rapid weight gain in the initial period include: Younger age, lower BMI, more robust response to antipsychotic and increase in appetite; rapid weight gain of >5% in the first month has been observed as the best predictor for significant long-term weight gain (Ref)

• Duration of therapy (although weight gain plateaus, patients continue to gain weight over time) (Ref)

• Schizophrenia (regardless of medication) is associated with a higher prevalence of obesity compared to the general population due to components of the illness, such as negative symptoms, sedentary lifestyles, and unhealthy diets (Ref)

• Specific antipsychotic: Olanzapine is considered to have a high propensity for causing weight gain in children, adolescents, and adults (Ref).

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

Oral:

>10%:

Cardiovascular: Orthostatic hypotension (adults: 3% to 21%) (table 1)

Olanzapine: Adverse Reaction: Orthostatic Hypotension

Drug (Olanzapine)

Placebo

Population

Dose

Dosage Form

Indication

Number of Patients (Olanzapine)

Number of Patients (Placebo)

5%

2%

Adults

N/A

Immediate-release oral

Schizophrenia

248

118

21%

N/A

Adults

N/A

Immediate-release oral

N/A

6,030

N/A

3%

1%

Adults

N/A

Immediate-release oral

N/A

532

294

Endocrine & metabolic: Increased LDL cholesterol (fasting, increase by ≥30 mg/dL or from baseline normal [<100 mg/dL] or borderline [≥100 mg/dL and <160 mg/dL] to high [≥160 mg/dL]: 7% to 48%); increased serum cholesterol (fasting, increase by ≥40 mg/dL or from baseline normal [<200 mg/dL] or borderline [≥200 mg/dL to <240 mg/dL] to high [≥240 mg/dL]: 3% to 58%), increased serum glucose (fasting, from baseline normal [<100 mg/dL] or borderline [≥100 and <126 mg/dL] to high [≥126 mg/dL]: ≤26%), increased serum prolactin (adolescents: 47%; adults: 30%) (table 2), increased serum triglycerides (fasting, increase by ≥50 mg/dL or from baseline normal [<150 mg/dL] or borderline [<150 mg/dL to <200 mg/dL) to high [≥200 mg/dL]: 9% to 71%), weight gain (adolescents: 29% to 31%, has been reported as high as 89%; adults: 5% to 6%, has been reported as high as 64%) (table 3)

Olanzapine: Adverse Reaction: Increased Serum Prolactin

Drug (Olanzapine)

Placebo

Population

Indication

47%

7%

Adolescents

Schizophrenia or bipolar I disorder

30%

11%

Adults

N/A

Olanzapine: Adverse Reaction: Weight Gain

Drug (Olanzapine)

Placebo

Population

Dose

Dosage Form

Indication

Number of Patients (Olanzapine)

Number of Patients (Placebo)

29%

4%

Adolescents

N/A

Immediate-release oral

Bipolar I Disorder

107

54

31%

9%

Adolescents

N/A

Immediate-release oral

Schizophrenia

72

35

6%

1%

Adults

N/A

Immediate-release oral

Schizophrenia

248

118

5%

3%

Adults

N/A

Immediate-release oral

N/A

532

294

Gastrointestinal: Constipation (4% to 11%) (table 4), dyspepsia (adolescents: 3%; adults: 7% to 11%), increased appetite (adolescents: 17% to 29%; adults: 3% to 6%), xerostomia (dose dependent: adolescents: 4% to 7%; adults: 3% to 22%) (table 5)

Olanzapine: Adverse Reaction: Constipation

Drug (Olanzapine)

Placebo

Population

Dose

Dosage Form

Indication

Number of Patients (Olanzapine)

Number of Patients (Placebo)

4%

0%

Adolescents

N/A

Immediate-release oral

Schizophrenia or Bipolar I Disorder

179

89

11%

5%

Adults

N/A

Immediate-release oral

Bipolar I Disorder

125

129

9%

3%

Adults

N/A

Immediate-release oral

Schizophrenia

248

118

9%

4%

Adults

N/A

Immediate-release oral

N/A

532

294

Olanzapine: Adverse Reaction: Xerostomia

Drug (Olanzapine)

Placebo

Population

Dose

Dosage Form

Indication

Number of Patients (Olanzapine)

Number of Patients (Placebo)

7%

0%

Adolescents

N/A

Immediate-release oral

Bipolar I Disorder

107

54

4%

0%

Adolescents

N/A

Immediate-release oral

Schizophrenia

72

35

22%

7%

Adults

N/A

Immediate-release oral

Bipolar I Disorder

125

129

13%

4%

Adults

15 ± 2.5 mg/day

Immediate-release oral

Schizophrenia

69

68

5%

4%

Adults

10 ± 2.5 mg/day

Immediate-release oral

Schizophrenia

64

68

3%

4%

Adults

5 ± 2.5 mg/day

Immediate-release oral

Schizophrenia

65

68

9%

5%

Adults

N/A

Immediate-release oral

N/A

532

294

Hepatic: Decreased serum bilirubin (adolescents: 22%), increased serum alanine aminotransferase (≥3 x ULN: 5% to 12%), increased serum aspartate aminotransferase (adolescents: 28%)

Nervous system: Akathisia (3% to 27%) (table 6), dizziness (adolescents: 7% to 8%; adults: 11% to 18% (table 7)); drowsiness (dose dependent: 20% to 48%) (table 8), extrapyramidal reaction (dose dependent: adolescents: 10%; adults: 15% to 32%) (table 9); fatigue (dose dependent: 2% to 14%), headache (adolescents: 17%), insomnia (12%), parkinsonism (8% to 20%; includes akinesia, cogwheel rigidity, hypokinesia, and mask-like face) (table 10), sedated state (adolescents: 39% to 48%) (table 11)

Olanzapine: Adverse Reaction: Akathisia

Drug (Olanzapine)

Placebo

Population

Dose

Dosage Form

Indication

Number of Patients (Olanzapine)

Number of Patients (Placebo)

6%

4%

Adolescents

N/A

Immediate-release oral

Schizophrenia or Bipolar I Disorder

179

89

27%

23%

Adults

15 ± 2.5 mg/day

Immediate-release oral

Schizophrenia

N/A

N/A

19%

23%

Adults

10 ± 2.5 mg/day

Immediate-release oral

Schizophrenia

N/A

N/A

16%

23%

Adults

5 ± 2.5 mg/day

Immediate-release oral

Schizophrenia

N/A

N/A

11%

1%

Adults

10 ± 2.5 mg/day

Immediate-release oral

Schizophrenia

64

68

10%

1%

Adults

15 ± 2.5 mg/day

Immediate-release oral

Schizophrenia

69

68

5%

1%

Adults

N/A

Immediate-release oral

Schizophrenia

248

118

5%

1%

Adults

5 ± 2.5 mg/day

Immediate-release oral

Schizophrenia

65

68

3%

2%

Adults

N/A

Immediate-release oral

N/A

532

294

Olanzapine: Adverse Reaction: Dizziness

Drug (Olanzapine)

Placebo

Population

Dose

Dosage Form

Indication

Number of Patients (Olanzapine)

Number of Patients (Placebo)

7%

2%

Adolescents

N/A

Immediate-release oral

Bipolar I Disorder

107

54

8%

3%

Adolescents

N/A

Immediate-release oral

Schizophrenia

72

35

18%

6%

Adults

N/A

Immediate-release oral

Bipolar I Disorder

125

129

11%

4%

Adults

N/A

Immediate-release oral

Schizophrenia

248

118

11%

4%

Adults

N/A

Immediate-release oral

N/A

532

294

Olanzapine: Adverse Reaction: Drowsiness

Drug (Olanzapine)

Placebo

Population

Dose

Dosage Form

Indication

Number of Patients (Olanzapine)

Number of Patients (Placebo)

48%

9%

Adolescents

N/A

Immediate-release oral

Bipolar I Disorder

107

54

39%

9%

Adolescents

N/A

Immediate-release oral

Schizophrenia

72

35

35%

13%

Adults

N/A

Immediate-release oral

Bipolar I Disorder

125

129

39%

16%

Adults

15 ± 2.5 mg/day

Immediate-release oral

Schizophrenia

69

68

30%

16%

Adults

10 ± 2.5 mg/day

Immediate-release oral

Schizophrenia

64

68

20%

16%

Adults

5 ± 2.5 mg/day

Immediate-release oral

Schizophrenia

65

68

29%

13%

Adults

N/A

Immediate-release oral

N/A

532

294

Olanzapine: Adverse Reaction: Extrapyramidal Reaction

Drug (Olanzapine)

Placebo

Population

Dose

Dosage Form

Indication

Number of Patients (Olanzapine)

Number of Patients (Placebo)

10%

6%

Adolescents

N/A

Immediate-release oral

Schizophrenia or Bipolar I Disorder

179

89

32%

16%

Adults

15 ± 2.5 mg/day

Immediate-release oral

Schizophrenia

69

68

25%

16%

Adults

10 ± 2.5 mg/day

Immediate-release oral

Schizophrenia

64

68

15%

16%

Adults

5 ± 2.5 mg/day

Immediate-release oral

Schizophrenia

65

68

Olanzapine: Adverse Reaction: Parkinsonism

Drug (Olanzapine)

Placebo

Population

Dose

Dosage Form

Indication

Number of Patients (Olanzapine)

Number of Patients (Placebo)

20%

10%

Adults

15 ± 2.5 mg/day

Immediate-release oral

Schizophrenia

69

68

14%

10%

Adults

10 ± 2.5 mg/day

Immediate-release oral

Schizophrenia

64

68

8%

10%

Adults

5 ± 2.5 mg/day

Immediate-release oral

Schizophrenia

65

68

Olanzapine: Adverse Reaction: Sedated State

Drug (Olanzapine)

Placebo

Population

Dose

Dosage Form

Indication

Number of Patients (Olanzapine)

Number of Patients (Placebo)

48%

9%

Adolescents

N/A

Immediate-release oral

Bipolar I Disorder

107

54

39%

9%

Adolescents

N/A

Immediate-release oral

Schizophrenia

72

35

Neuromuscular & skeletal: Asthenia (dose dependent: 8% to 20%)

Miscellaneous: Accidental injury (12%)

1% to 10%:

Cardiovascular: Chest pain (3%), hypertension (2%), peripheral edema (3%), tachycardia (3%) (table 12)

Olanzapine: Adverse Reaction: Tachycardia

Drug (Olanzapine)

Placebo

Population

Dose

Dosage Form

Indication

Number of Patients (Olanzapine)

Number of Patients (Placebo)

3%

1%

Adults

N/A

Immediate-release oral

N/A

532

294

Dermatologic: Ecchymoses (5%)

Endocrine & metabolic: Breast changes (male and female adolescents: ≤2%; including discharge, enlargement, galactorrhea not associated with childbirth, gynecomastia, lactation disorder), increased gamma-glutamyl transferase (adolescents: 10%; adults: 2%), increased uric acid (4%), menstrual disease (2%; including amenorrhea, delayed menstruation, hypomenorrhea, oligomenorrhea)

Gastrointestinal: Abdominal pain (adolescents: 6%), diarrhea (adolescents: 3%), vomiting (≤4%)

Genitourinary: Sexual disorder (≤2%; literature suggests an incidence up to 35% [Bobes 2003]; dysfunction includes: Anorgasmia, delayed ejaculation, erectile dysfunction, decreased libido, loss of libido, and orgasm abnormal), urinary incontinence (adults and older adults: ≥2%), urinary tract infection (2%)

Hepatic: Increased liver enzymes (adolescents: ≤8%), increased serum alkaline phosphatase (≥1%)

Nervous system: Abnormal gait (6%), articulation impairment (2%), falling (older adults: ≥2%), hypertonia (3%), personality disorder (5% to 8%), restlessness (adolescents: 3%)

Neuromuscular & skeletal: Arthralgia (adults: 5%; adolescents: 2%), back pain (5%), dyskinesia (1%), limb pain (5% to 6%), muscle rigidity (adolescents: 2%), tremor (dose dependent: 4% to 7%)

Ophthalmic: Amblyopia (3%)

Respiratory: Cough (6%), epistaxis (adolescents: 3%), nasopharyngitis (adolescents: 4%), pharyngitis (4%), respiratory tract infection (adolescents: 3%), rhinitis (7%), sinusitis (adolescents: 3%)

Miscellaneous: Fever (≤6%)

<1%:

Cardiovascular: Cerebrovascular accident (Gareri 2014), facial edema, syncope, transient ischemic attacks (Layton 2005), vasodilation

Dermatologic: Alopecia, skin photosensitivity

Endocrine & metabolic: Heavy menstrual bleeding

Gastrointestinal: Abdominal distension, intestinal obstruction, nausea

Genitourinary: Difficulty in micturition, impotence, mastalgia, urinary frequency, urinary retention, urinary urgency

Hematologic & oncologic: Hypoproteinemia, leukocytosis (eosinophilia), neutropenia (Lander 2011), pancytopenia (Pang 2017), thrombocytopenia (Carrillo 2004)

Hepatic: Hyperbilirubinemia, liver steatosis

Hypersensitivity: Tongue edema

Nervous system: Ataxia, chills, coma, dysarthria, hangover effect, seizure (Uvais 2018), stupor, suicidal tendencies

Neuromuscular & skeletal: Osteoporosis

Ophthalmic: Accommodation disturbance, dry eye syndrome, mydriasis

Renal: Polyuria

Respiratory: Pulmonary edema

Injection: Adverse events are reported for the extended-release suspension for injection (olanzapine pamoate [Zyprexa Relprevv]) unless otherwise indicated.

>10%: Nervous system: Headache (13% to 18%), sedated state (8% to 13%) (table 13)

Olanzapine: Adverse Reaction: Sedated State

Drug (Olanzapine)

Placebo

Population

Dose

Dosage Form

Indication

Number of Patients (Olanzapine)

Number of Patients (Placebo)

13%

7%

Adults

405 mg/4 weeks

Extended-release IM

Schizophrenia

100

98

13%

7%

Adults

300 mg/2 weeks

Extended-release IM

Schizophrenia

100

98

8%

7%

Adults

210 mg/2 weeks

Extended-release IM

Schizophrenia

106

98

1% to 10%:

Cardiovascular: Hypertension (2% to 3%), hypotension (short-acting: 2%), orthostatic hypotension (short-acting: 1%) (table 14), prolonged QT interval on ECG (≤2%) (table 15)

Olanzapine: Adverse Reaction: Orthostatic Hypotension

Drug (Olanzapine)

Placebo

Population

Dose

Dosage Form

Indication

Number of Patients (Olanzapine)

Number of Patients (Placebo)

1%

0%

Adults

N/A

Short-acting IM

Schizophrenia or Bipolar I Mania

415

150

Olanzapine: Adverse Reaction: Prolonged QT Interval on ECG

Drug (Olanzapine)

Placebo

Population

Dose

Dosage Form

Indication

Number of Patients (Olanzapine)

Number of Patients (Placebo)

2%

1%

Adults

300 mg/2 weeks

Extended-release IM

Schizophrenia

100

98

0%

1%

Adults

405 mg/4 weeks

Extended-release IM

Schizophrenia

100

98

0%

1%

Adults

210 mg/2 weeks

Extended-release IM

Schizophrenia

106

98

Dermatologic: Acne vulgaris (2%)

Endocrine & metabolic: Weight gain (short-term 8-week trial: 5% to 7%) (table 16)

Olanzapine: Adverse Reaction: Weight Gain

Drug (Olanzapine)

Placebo

Population

Dose

Dosage Form

Indication

Number of Patients (Olanzapine)

Number of Patients (Placebo)

7%

5%

Adults

300 mg/2 weeks

Extended-release IM

Schizophrenia

100

98

6%

5%

Adults

210 mg/2 weeks

Extended-release IM

Schizophrenia

106

98

5%

5%

Adults

405 mg/4 weeks

Extended-release IM

Schizophrenia

100

98

Gastrointestinal: Abdominal pain (3%), diarrhea (5% to 7%), flatulence (1% to 2%), increased appetite (1% to 6%), nausea (long-acting: 4% to 5%; short-acting: <1%), vomiting (6%), xerostomia (2% to 6%) (table 17)

Olanzapine: Adverse Reaction: Xerostomia

Drug (Olanzapine)

Placebo

Population

Dose

Dosage Form

Indication

Number of Patients (Olanzapine)

Number of Patients (Placebo)

6%

1%

Adults

210 mg/2 weeks

Extended-release IM

Schizophrenia

106

98

4%

1%

Adults

300 mg/2 weeks

Extended-release IM

Schizophrenia

100

98

2%

1%

Adults

405 mg/4 weeks

Extended-release IM

Schizophrenia

100

98

Genitourinary: Vaginal discharge (4%)

Hepatic: Increased liver enzymes (3% to 4%)

Infection: Viral infection (2%)

Local: Injection site reaction (4%, including abscess at injection site), pain at injection site (both formulations: 1% to 4%)

Nervous system: Abnormal dreams (2%), abnormality in thinking (3%), akathisia (short-acting: 2% to 5%) (table 18), auditory hallucination (3%), dizziness (both formulations: 1% to 4%) (table 19), drowsiness (short-acting: 6%) (table 20), dysarthria (1% to 2%), extrapyramidal reaction (short-acting: 2% to 4%) (table 21), fatigue (3% to 4%), pain (2% to 3%), parkinsonism (short-acting: 2% to 4%) (table 22), restlessness (3%), sleep disorder (2%)

Olanzapine: Adverse Reaction: Akathisia

Drug (Olanzapine)

Placebo

Population

Dose

Dosage Form

Indication

Number of Patients (Olanzapine)

Number of Patients (Placebo)

5%

0%

Adults

5 mg

Short-acting IM

Schizophrenia

N/A

N/A

2%

0%

Adults

2.5 mg

Short-acting IM

Schizophrenia

48

45

Olanzapine: Adverse Reaction: Dizziness

Drug (Olanzapine)

Placebo

Population

Dose

Dosage Form

Indication

Number of Patients (Olanzapine)

Number of Patients (Placebo)

4%

2%

Adults

405 mg/4 weeks

Extended-release IM

Schizophrenia

100

98

4%

2%

Adults

210 mg/2 weeks

Extended-release IM

Schizophrenia

106

98

1%

2%

Adults

300 mg/2 weeks

Extended-release IM

Schizophrenia

100

98

4%

2%

Adults

N/A

Short-acting IM

Schizophrenia or Bipolar I Mania

415

150

Olanzapine: Adverse Reaction: Drowsiness

Drug (Olanzapine)

Placebo

Population

Dose

Dosage Form

Indication

Number of Patients (Olanzapine)

Number of Patients (Placebo)

6%

3%

Adults

N/A

Short-acting IM

Schizophrenia or Bipolar I Mania

415

150

Olanzapine: Adverse Reaction: Extrapyramidal Reaction

Drug (Olanzapine)

Placebo

Population

Dose

Dosage Form

Indication

Number of Patients (Olanzapine)

Number of Patients (Placebo)

4%

0%

Adults

2.5 mg

Short-acting IM

Schizophrenia

48

45

2%

0%

Adults

5 mg

Short-acting IM

Schizophrenia

45

45

Olanzapine: Adverse Reaction: Parkinsonism

Drug (Olanzapine)

Placebo

Population

Dose

Dosage Form

Indication

Number of Patients (Olanzapine)

Number of Patients (Placebo)

4%

0%

Adults

2.5 mg

Short-acting IM

Schizophrenia

48

45

2%

0%

Adults

5 mg

Short-acting IM

Schizophrenia

45

45

Neuromuscular & skeletal: Arthralgia (3%), asthenia (short-acting: 2%), back pain (5%), muscle spasm (1% to 3%), stiffness (4%), tremor (long-acting: 3%; short-acting: 1%)

Otic: Otalgia (4%)

Respiratory: Cough (9%), nasal congestion (7%), nasopharyngitis (3% to 6%), pharyngolaryngeal pain (3%), sneezing (2%), upper respiratory tract infection (3% to 4%)

Miscellaneous: Fever (2%)

<1%:

Cardiovascular: Syncope (short-acting)

Nervous system: Confusion, postinjection delirium/sedation syndrome (Meyers 2010), speech disturbance

Neuromuscular & skeletal: Increased creatine phosphokinase in blood specimen (short-acting)

Postmarketing (all formulations):

Cardiovascular: Atrial fibrillation (Chou 2017), atrial flutter (Chou 2017), pulmonary embolism, venous thrombosis

Dermatologic: Eruptive xanthoma (Chang 2003), fixed drug eruption (rare: <1%) (Chawla 2017), pruritus, purpuric rash (rare: <1%) (Lin 2018), skin photosensitivity (benign, rare: <1%) (Reddy 2019), skin rash, urticaria

Endocrine & metabolic: Diabetes mellitus (new-onset) (Koller 2002), diabetic ketoacidosis (rare: <1%) (Avella 2004), hypercholesterolemia (common: >10%) (Olfson 2006), hyperglycemia (Bloch 2003; Solmi 2017), hyperglycemic hyperosmolar coma (rare: <1%) (Ahuja 2008), hypertriglyceridemia (Kimmel 2013), increased libido (Stefanou 2020), insulin resistance (Chiu 2010)

Gastrointestinal: Dysphagia (rare: <1%) (Crouse 2018), necrotizing pancreatitis (rare: <1%), pancreatitis (rare: <1%) (Buszek 2016; Doucette 2000; Kerr 2007), sialorrhea

Genitourinary: Priapism (Farag 2019)

Hematologic & oncologic: Agranulocytosis (rare: <1%) (Tolosa-Vilella 2002), leukopenia (rare: <1%) (Lander 2011)

Hepatic: Hepatic injury (cholestatic or mixed), hepatitis, jaundice

Hypersensitivity: Angioedema, nonimmune anaphylaxis

Immunologic: Acute generalized exanthematous pustulosis (rare: <1%) (Christen 2006), drug reaction with eosinophilia and systemic symptoms (rare: <1%) (Raz 2001), vasculitis (rare: <1%) (Duggal 2005)

Nervous system: Cognitive dysfunction (Morrens 2007), delirium (less frequent: ≥1% to <4%) (Pasina 2019), dystonia (less frequent: ≥1% to <4%) (Hill 2014), heatstroke (rare: <1%) (Jafferany 2008), hypothermia (rare: <1%) (Parris 2011), neuroleptic malignant syndrome (rare: <1%) (Kogoj 2003), restless leg syndrome, sleep apnea (obstructive) (Health Canada 2016; Shirani 2011), tardive dyskinesia (rare: <1%) (Hill 2014), withdrawal syndrome

Neuromuscular & skeletal: Rhabdomyolysis

Ophthalmic: Oculogyric crises (tardive) (Bavle 2013)

Respiratory: Respiratory depression (Cole 2007)

Contraindications

There are no contraindications listed in the manufacturer’s labeling.

Canadian labeling: Hypersensitivity to olanzapine or any component of the formulation

Warnings/Precautions

Concerns related to adverse effects:

• 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.

• Suicidal ideation: The possibility of a suicide attempt is inherent in psychotic illness or bipolar disorder; use with caution in high-risk patients during initiation of therapy. Prescriptions should be written for the smallest quantity consistent with good patient care.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with severe cardiac disease, hemodynamic instability, prior myocardial infarction, ischemic heart disease, or hypercholesterolemia.

• GI motility: Use with caution in patients with decreased GI motility (eg, paralytic ileus) as anticholinergic effects may exacerbate underlying condition.

• Hepatic impairment: Use with caution in patients with hepatic disease or impairment; dose adjustment may be required.

• Parkinson disease: Use with caution in patients with Parkinson disease; antipsychotic may aggravate motor disturbances (APA [Reus 2016]).

• Seizures: 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 that may lower seizure threshold. Elderly patients may be at increased risk of seizures because of an increased prevalence of predisposing factors.

• Urinary retention (eg, benign prostatic hyperplasia): Use with caution in patients with urinary retention as anticholinergic effects may exacerbate underlying condition.

Special populations:

• Tobacco smokers: Olanzapine levels may be lower in patients who smoke. Smokers may require an increased daily dose (Tsuda 2014). Discontinuation of smoking should also merit a dose reduction as olanzapine levels may be higher be smoking cessations occurs.

Dosage form-specific concerns:

• IM formulations: There are two Zyprexa formulations for IM injection: Zyprexa Relprevv is an ER formulation and Zyprexa IntraMuscular is short-acting.

ER IM injection (Zyprexa Relprevv):

Postinjection delirium/sedation syndrome: Upon determining alert status, patient should be escorted to their destination and not drive or operate heavy machinery for the remainder of the day.

Unexplained deaths: Two unexplained deaths in patients who received Zyprexa Relprevv have been reported. The patients died 3 to 4 days after receiving an appropriate dose of the drug. Both patients were found to have high blood concentrations of olanzapine postmortem. It is unclear if these deaths were the result of postinjection delirium sedation syndrome (PDSS) (FDA Safety Communication 2013).

Short-acting IM injection (Zyprexa IntraMuscular): Patients should remain recumbent if drowsy/dizzy until hypotension, bradycardia, and/or hypoventilation have been ruled out. Closely monitor for orthostasis prior to any repeat dosing. Concurrent use of IM/IV benzodiazepines is not recommended (fatalities have been reported, though causality not determined).

• Phenylalanine: Some products may contain phenylalanine.

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer’s labeling.

Other warnings/precautions:

• Discontinuation of therapy: When discontinuing antipsychotic therapy, gradually taper antipsychotics to avoid physical withdrawal symptoms and rebound symptoms (APA [Keepers 2020]; WFSBP [Hasan 2012]). Withdrawal symptoms may include agitation, alternating feelings of warmth and cold, anxiety, diaphoresis, dyskinesia, GI symptoms, insomnia, irritability, myalgia, paresthesia, psychosis, restlessness, rhinorrhea, tremor and vertigo (Lambert 2007; Moncrieff 2020). The risk of withdrawal symptoms is highest following abrupt discontinuation of highly anticholinergic or dopaminergic antipsychotics (Cerovecki 2013). Patients with chronic symptoms, repeated relapses, and clear diagnostic features of schizophrenia are at risk for poor outcomes if medications are discontinued (APA [Keepers 2020]).

• IV administration: IV administration has only been studied in emergency department settings, where patients can be closely monitored for respiratory depression (ie, pulse oximetry) (Chan 2013; Cole 2017; Martel 2016; Taylor 2017).

Warnings: Additional Pediatric Considerations

Pediatric psychiatric disorders are frequently serious mental disorders which present with variable symptoms that do not always match adult diagnostic criteria. Conduct a thorough diagnostic evaluation and carefully consider risks of psychotropic medication before initiation in pediatric patients. Medication therapy for pediatric patients with bipolar disorder and schizophrenia is indicated as part of a total treatment program that frequently includes educational, psychological, and social interventions.

Metabolism/Transport Effects

Substrate of CYP1A2 (major), CYP2D6 (minor), UGT1A4; Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions

Acetylcholinesterase Inhibitors: May diminish the therapeutic effect of Anticholinergic Agents. Anticholinergic Agents may diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Risk C: Monitor therapy

Acetylcholinesterase Inhibitors (Central): May enhance the neurotoxic (central) effect of Antipsychotic Agents. Severe extrapyramidal symptoms have occurred in some patients. Risk C: Monitor therapy

Aclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Amifampridine: Agents With Seizure Threshold Lowering Potential may enhance the neuroexcitatory and/or seizure-potentiating effect of Amifampridine. Risk C: Monitor therapy

Amisulpride (Oral): May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk of neuroleptic malignant syndrome may be increased. Risk X: Avoid combination

Amphetamines: Antipsychotic Agents may diminish the stimulatory effect of Amphetamines. Risk C: Monitor therapy

Anticholinergic Agents: May enhance the adverse/toxic effect of other Anticholinergic Agents. Risk C: Monitor therapy

Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy

Antihepaciviral Combination Products: May decrease the serum concentration of OLANZapine. Risk C: 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 avoiding atypical antipsychotic use in patients with Parkinson disease. If an atypical antipsychotic is necessary, consider using clozapine, quetiapine, or ziprasidone at lower initial doses, or a non-dopamine antagonist (eg, pimavanserin). Risk D: Consider therapy modification

Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Benzodiazepines: May enhance the adverse/toxic effect of OLANZapine. Management: Monitor closely for hypotension, respiratory or central nervous system depression, and bradycardia if olanzapine is combined with benzodiazepines. Use of parenteral benzodiazepines with IM olanzapine is not recommended. Risk C: Monitor therapy

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modification

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Risk C: Monitor therapy

Botulinum Toxin-Containing Products: May enhance the anticholinergic effect of Anticholinergic Agents. Risk C: Monitor therapy

Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Broccoli: May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers). Risk C: Monitor therapy

Bromopride: May enhance the adverse/toxic effect of Antipsychotic Agents. Risk X: Avoid combination

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider therapy modification

BuPROPion: May enhance the neuroexcitatory and/or seizure-potentiating effect of Agents With Seizure Threshold Lowering Potential. Risk C: Monitor therapy

Cabergoline: May diminish the therapeutic effect of Antipsychotic Agents. Risk X: Avoid combination

Cannabinoid-Containing Products: Anticholinergic Agents may enhance the tachycardic effect of Cannabinoid-Containing Products. Risk C: Monitor therapy

Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy

Cannabis: May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers). Risk C: Monitor therapy

CarBAMazepine: May decrease the serum concentration of OLANZapine. Risk C: Monitor therapy

Ceritinib: May enhance the QTc-prolonging effect of QT-prolonging Antipsychotics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

Chloral Betaine: May enhance the adverse/toxic effect of Anticholinergic Agents. Risk C: Monitor therapy

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy

Cimetropium: Anticholinergic Agents may enhance the anticholinergic effect of Cimetropium. Risk X: Avoid combination

Clarithromycin: QT-prolonging Antipsychotics (Moderate Risk) may enhance the QTc-prolonging effect of Clarithromycin. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

CloZAPine: Anticholinergic Agents may enhance the constipating effect of CloZAPine. Management: Consider alternatives to this combination whenever possible. If combined, monitor closely for signs and symptoms of gastrointestinal hypomotility and consider prophylactic laxative treatment. Risk D: Consider therapy modification

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy

CYP1A2 Inducers (Moderate): May decrease the serum concentration of OLANZapine. Risk C: Monitor therapy

CYP1A2 Inducers (Weak): May decrease the serum concentration of OLANZapine. Risk C: Monitor therapy

CYP1A2 Inhibitors (Moderate): May increase the serum concentration of OLANZapine. Risk C: Monitor therapy

CYP1A2 Inhibitors (Strong): May increase the serum concentration of OLANZapine. Risk C: Monitor therapy

Daridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification

Deutetrabenazine: May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk for akathisia, parkinsonism, or neuroleptic malignant syndrome may be increased. Risk C: Monitor therapy

Dexmethylphenidate-Methylphenidate: Antipsychotic Agents may enhance the adverse/toxic effect of Dexmethylphenidate-Methylphenidate. Dexmethylphenidate-Methylphenidate may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk of extrapyramidal symptoms may be increased when these agents are combined. Risk C: Monitor therapy

Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Domperidone: QT-prolonging Agents (Moderate Risk) may enhance the QTc-prolonging effect of Domperidone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk D: 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. Risk C: Monitor therapy

Droperidol: QT-prolonging Antipsychotics (Moderate Risk) may enhance the QTc-prolonging effect of Droperidol. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

Eluxadoline: Anticholinergic Agents may enhance the constipating effect of Eluxadoline. Risk X: Avoid combination

Esketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Fexinidazole: May enhance the QTc-prolonging effect of OLANZapine. Fexinidazole may increase the serum concentration of OLANZapine. Management: Monitor for increased olanzapine toxicities, including QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification

Flupentixol: QT-prolonging Antipsychotics (Moderate Risk) may enhance the QTc-prolonging effect of Flupentixol. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

Gastrointestinal Agents (Prokinetic): Anticholinergic Agents may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Risk C: Monitor therapy

Glucagon: Anticholinergic Agents may enhance the adverse/toxic effect of Glucagon. Specifically, the risk of gastrointestinal adverse effects may be increased. Risk C: Monitor therapy

Glycopyrrolate (Oral Inhalation): Anticholinergic Agents may enhance the anticholinergic effect of Glycopyrrolate (Oral Inhalation). Risk X: Avoid combination

Glycopyrronium (Topical): May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination

Guanethidine: Antipsychotic Agents may diminish the therapeutic effect of Guanethidine. Risk C: Monitor therapy

Haloperidol: QT-prolonging Antipsychotics (Moderate Risk) may enhance the QTc-prolonging effect of Haloperidol. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Iohexol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iohexol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iohexol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modification

Iomeprol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iomeprol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iomeprol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modification

Iopamidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iopamidol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iopamidol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modification

Ipratropium (Oral Inhalation): May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination

Itopride: Anticholinergic Agents may diminish the therapeutic effect of Itopride. Risk C: Monitor therapy

Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

LamoTRIgine: May enhance the sedative effect of OLANZapine. Risk C: Monitor therapy

Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modification

Levosulpiride: Anticholinergic Agents may diminish the therapeutic effect of Levosulpiride. Risk X: Avoid combination

Lithium: May enhance the neurotoxic effect of Antipsychotic Agents. Lithium may decrease the serum concentration of Antipsychotic Agents. Specifically noted with chlorpromazine. Risk C: Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Mequitazine: Antipsychotic Agents may enhance the arrhythmogenic effect of Mequitazine. Management: Consider alternatives to one of these agents when possible. While this combination is not specifically contraindicated, mequitazine labeling describes this combination as discouraged. Risk D: Consider therapy modification

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modification

Metoclopramide: May enhance the adverse/toxic effect of Antipsychotic Agents. Risk X: Avoid combination

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy

MetyroSINE: May enhance the adverse/toxic effect of Antipsychotic Agents. Risk C: Monitor therapy

Mianserin: May enhance the anticholinergic effect of Anticholinergic Agents. Risk C: Monitor therapy

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Mirabegron: Anticholinergic Agents may enhance the adverse/toxic effect of Mirabegron. Risk C: Monitor therapy

Nitroglycerin: Anticholinergic Agents may decrease the absorption of Nitroglycerin. Specifically, anticholinergic agents may decrease the dissolution of sublingual nitroglycerin tablets, possibly impairing or slowing nitroglycerin absorption. Risk C: Monitor therapy

Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Ondansetron: May enhance the QTc-prolonging effect of QT-prolonging Antipsychotics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination

Oxatomide: May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Oxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider therapy modification

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination

Pentamidine (Systemic): May enhance the QTc-prolonging effect of QT-prolonging Antipsychotics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Pimozide: May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Risk X: Avoid combination

Piribedil: Antipsychotic Agents may diminish the therapeutic effect of Piribedil. Piribedil 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. Risk X: 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. Risk X: Avoid combination

Potassium Citrate: Anticholinergic Agents may enhance the ulcerogenic effect of Potassium Citrate. Risk X: Avoid combination

Pramlintide: May enhance the anticholinergic effect of Anticholinergic Agents. These effects are specific to the GI tract. Risk X: Avoid combination

QT-prolonging Agents (Highest Risk): May enhance the QTc-prolonging effect of OLANZapine. Management: Consider alternatives to this combination. Patients with other risk factors (eg, older age, female sex, bradycardia, hypokalemia, hypomagnesemia, heart disease, and higher drug concentrations) are likely at greater risk for these toxicities. Risk D: Consider therapy modification

QT-prolonging Antidepressants (Moderate Risk): QT-prolonging Antipsychotics (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Antidepressants (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

QT-prolonging Antipsychotics (Moderate Risk): May enhance the QTc-prolonging effect of OLANZapine. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

QT-prolonging Class IC Antiarrhythmics (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Antipsychotics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

QT-prolonging Kinase Inhibitors (Moderate Risk): OLANZapine may enhance the QTc-prolonging effect of QT-prolonging Kinase Inhibitors (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

QT-prolonging Miscellaneous Agents (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Antipsychotics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Antipsychotics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

QT-prolonging Quinolone Antibiotics (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Antipsychotics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

Quinagolide: Antipsychotic Agents may diminish the therapeutic effect of Quinagolide. Risk C: Monitor therapy

Ramosetron: Anticholinergic Agents may enhance the constipating effect of Ramosetron. Risk C: Monitor therapy

Revefenacin: Anticholinergic Agents may enhance the anticholinergic effect of Revefenacin. Risk X: Avoid combination

RifAMPin: May decrease the serum concentration of OLANZapine. Risk C: Monitor therapy

Ritonavir: May decrease the serum concentration of OLANZapine. Risk C: Monitor therapy

Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy

Saquinavir: QT-prolonging Antipsychotics (Moderate Risk) may enhance the QTc-prolonging effect of Saquinavir. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

Secretin: Anticholinergic Agents may diminish the therapeutic effect of Secretin. Management: Avoid concomitant use of anticholinergic agents and secretin. Discontinue anticholinergic agents at least 5 half-lives prior to administration of secretin. Risk D: Consider therapy modification

Serotonergic Agents (High Risk): May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonergic agents may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor therapy

Sulpiride: Antipsychotic Agents may enhance the adverse/toxic effect of Sulpiride. Risk X: 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. Risk D: Consider therapy modification

Tetrabenazine: May enhance the adverse/toxic effect of Antipsychotic Agents. Risk C: Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination

Thiazide and Thiazide-Like Diuretics: Anticholinergic Agents may increase the serum concentration of Thiazide and Thiazide-Like Diuretics. Risk C: Monitor therapy

Tiotropium: Anticholinergic Agents may enhance the anticholinergic effect of Tiotropium. Risk X: Avoid combination

Tobacco (Smoked): May diminish the therapeutic effect of OLANZapine. Tobacco (Smoked) may decrease the serum concentration of OLANZapine. Risk C: Monitor therapy

Topiramate: Anticholinergic Agents may enhance the adverse/toxic effect of Topiramate. Risk C: Monitor therapy

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Umeclidinium: May enhance the anticholinergic effect of Anticholinergic Agents. Risk X: Avoid combination

Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Valproate Products: May decrease the serum concentration of OLANZapine. Risk C: Monitor therapy

Voriconazole: May enhance the QTc-prolonging effect of QT-prolonging Antipsychotics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

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. Risk D: Consider therapy modification

Reproductive Considerations

Olanzapine may cause hyperprolactinemia, which may decrease reproductive function in both males and females.

Olanzapine may be used if treatment with an atypical antipsychotic is needed in a woman planning a pregnancy (Larsen 2015).

Pregnancy Considerations

Olanzapine crosses the placenta and can be detected in cord blood at birth (Newport 2007; Schoretsanitis 2019).

Based on available data, an increased risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes has not been observed following maternal use of olanzapine (Brunner 2013; Damkier 2018; Huybrechts 2016). Antipsychotic use during the third trimester of pregnancy has a risk for abnormal muscle movements (extrapyramidal symptoms) and/or withdrawal symptoms in newborns following delivery. Symptoms in the newborn may include agitation, feeding disorder, hypertonia, hypotonia, respiratory distress, somnolence, and tremor; these effects may be self-limiting or require hospitalization.

The pharmacokinetic properties of olanzapine are not significantly altered by pregnancy (Westin 2018); however, serum levels may change, even at a stable dose, possibly due to decreased CYP1A2 activity during the second and third trimesters (Stiegler 2014; Westin 2018). The ACOG recommends that therapy during pregnancy be individualized; treatment with psychiatric medications during pregnancy should incorporate the clinical expertise of the mental health clinician, obstetrician, primary health care provider, and pediatrician. Safety data related to atypical antipsychotics during pregnancy are limited, as such, routine use is not recommended. However, if a woman is inadvertently exposed to an atypical antipsychotic while pregnant, continuing therapy may be preferable to switching to an agent that the fetus has not yet been exposed to; consider risk:benefit (ACOG 2008). If treatment is initiated during pregnancy, olanzapine may be used (Larsen 2015). The potential for excessive maternal weight gain and the development of gestational diabetes associated with olanzapine therapy should be considered (Damkier 2018).

Health care providers are encouraged to enroll women 18 to 45 years of age exposed to olanzapine during pregnancy in the Atypical Antipsychotics Pregnancy Registry (1-866-961-2388 or https://www.womensmentalhealth.org/pregnancyregistry).

Breastfeeding Considerations

Olanzapine is present in breast milk.

Olanzapine can be detected in breast milk following maternal use of oral or injectable preparations and the concentrations in breast milk are variable (Schoretsanitis 2019). Relative infant doses (RID) of 0.3% to 4% have been reported in the literature (Pacchiarotti 2016). In general, breastfeeding is considered acceptable when the RID of a medication is <10% (Anderson 2016; Ito 2000). Some sources note breastfeeding should only be considered if the RID is <5% for psychotropic agents (Larsen 2015).

Using data from 6 women, the mean maximum breast milk concentration appeared 5.2 hours after the maternal dose (Gardiner 2003). Olanzapine has been detected in the serum of a breastfeeding infant; concentrations were highest when first measured at 4 months of age and decreased over the next 5 months, possibly due to CYP1A2 metabolism, which matures as the child ages. Maternal doses varied based on maternal symptoms, but ranged from 5 to 15 mg/day (Whitworth 2010).

In the majority of cases, adverse events have not been noted in breastfeeding infants (Pacchiarotti 2016). When observed, excess sedation, irritability, poor feeding, and extrapyramidal symptoms (tremors and abnormal muscle movements) have been reported in infants exposed to olanzapine through breast milk. In general, infants exposed to second generation antipsychotics via breast milk should be monitored weekly for the first month of exposure for symptoms such as appetite changes, insomnia, irritability, or lethargy (Uguz 2016). According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother. When an antipsychotic medication is needed in a breastfeeding woman, olanzapine is preferred (Larsen 2015; Pacchiarotti 2016; Uguz 2016).

Dietary Considerations

Tablets may be taken without regard to meals. Some products may contain phenylalanine.

Monitoring Parameters

Frequency of Antipsychotic Monitoringa,b

Monitoring parameter

Frequency of monitoring

Comments

a For all monitoring parameters, it is appropriate to check at baseline and when clinically relevant (based on symptoms or suspected adverse reactions) in addition to the timeline.

b ADA 2004b; APA [Keepers 2020]; De Hert 2011; Gugger 2011; manufacturer's labeling.

c Risk factors for extrapyramidal symptoms (EPS) include prior history of EPS, high doses of antipsychotics, young age (children and adolescents at higher risk than adults), and dopaminergic affinity of individual antipsychotic.

d Risk factors for tardive dyskinesia include >55 years of age; females; White or African ethnicity; presence of a mood disorder, intellectual disability, CNS injury, or past or current EPS.

Adherence

Every visit

Blood chemistries (electrolytes, renal function, liver function, TSH)

Annually

CBC

As clinically indicated

Check frequently during the first few months of therapy in patients with preexisting low WBC or history of drug-induced leukopenia/neutropenia.

Extrapyramidal symptoms

Every visit; 4 weeks after initiation and dose change; annually. Use a formalized rating scale at least annually or every 6 months if high risk.c

Fall risk

Every visit

Fasting plasma glucose/HbA1c

12 weeks after initiation and dose change; annually

Check more frequently than annually if abnormal. Follow diabetes guidelines.

Lipid panel

12 weeks after initiation and dose change; annually

Check more frequently than annually if abnormal. Follow lipid guidelines.

Mental status

Every visit

Metabolic syndrome history

Annually

Evaluate for personal and family history of obesity, diabetes, dyslipidemia, hypertension, or cardiovascular disease.

Prolactin

Ask about symptoms at every visit until dose is stable. Check prolactin level if symptoms are reported.

Hyperprolactinemia symptoms: changes in menstruation, libido, gynecomastia, development of galactorrhea, and erectile and ejaculatory function.

Tardive dyskinesia

Every visit; annually. Use a formalized rating scale at least annually or every 6 months if high risk.d

Vital signs (BP, orthostatics, temperature, pulse, signs of infection)

Every visit (at least weekly during first 3 to 4 weeks of treatment); 4 weeks after dose change.

Weight/Height/BMI

8 and 12 weeks after initiation and dose change; quarterly

Consider monitoring waist circumference at baseline and annually, especially in patients with or at risk for metabolic syndrome.

Consider changing antipsychotic if BMI increases by ≥1 unit.

Some experts recommend checking weight and height at every visit.

Additional monitoring parameters with administration of injection formulations:

IM, short-acting, and IV: Sedation; vital signs (BP, pulse, respiratory rate); ECG (in patients at risk for QT prolongation) (Cole 2017; Taylor 2017).

IM, extended release: Sedation/delirium for 3 hours after each dose.

Reference Range

Schizophrenia:

Timing of serum samples: Draw trough just before next dose (Hiemke 2018).

Therapeutic reference range: 20 to 80 ng/mL (SI: 64 to 256 nmol/L) (Hiemke 2018). Note: Dosing should be based on therapeutic response as opposed to serum concentrations, however therapeutic drug monitoring can be used to confirm adherence (APA [Keepers 2020]).

Laboratory alert level: 100 ng/mL (SI: 320 nmol/L) (Hiemke 2018).

Mechanism of Action

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. Although the precise mechanism of action in schizophrenia and bipolar disorder is not known, the efficacy of olanzapine is thought to be mediated through combined antagonism of dopamine and serotonin type 2 receptor sites. Olanzapine’s activity at the dopamine (D2), 5-HT2C, and 5-HT3 receptors may be responsible for the antiemetic effect (Navari 2016).

Pharmacokinetics

Onset of action:

Agitation:

IM: Initial effects within 15 minutes; continued effects for at least 2 hours (Huang 2015; Wright 2001).

IV: Initial effects within 5 to 10 minutes (Taylor 2017).

Bipolar disorder, acute mania: Oral and IR injection: Oral: Initial effects may be observed within days of treatment with continued improvements over 1 to 2 weeks (Goikolea 2013; Tohen 2000; Welten 2016).

Schizophrenia: Oral: Initial effects may be observed within 1 to 2 weeks of treatment with continued improvements through 4 to 6 weeks (Agid 2003; Levine 2010).

Absorption:

Oral: Well absorbed; not affected by food; tablets and orally disintegrating tablets are bioequivalent

Short-acting injection: Rapidly absorbed

Distribution: Vd: Extensive, 1,000 L

Protein binding, plasma: 93% bound to albumin and alpha1-glycoprotein

Metabolism: Highly metabolized via direct glucuronidation and cytochrome P450 mediated oxidation (CYP1A2, CYP2D6); 40% removed via first pass metabolism

Half-life elimination:

Oral and IM (short-acting): Children: (10 to 18 years; n=8): 37.2 ± 5.1 hours (Grothe 2000); Adults: 30 hours [21 to 54 hours (5th to 95th percentile)]; approximately 1.5 times greater in elderly

Extended-release injection: ~30 days

Time to peak, plasma: Maximum plasma concentrations after IM administration are 5 times higher than maximum plasma concentrations produced by an oral dose.

Extended-release injection: ~7 day

Short-acting injection: 15 to 45 minutes

Oral: Children (10 to 18 years; n=8): 4.7 ± 3.7 hours (Grothe 2000); Adults: ~6 hours

Excretion: Urine (57%, 7% as unchanged drug); feces (30%)

Clearance: Oral:

Children (10 to 18 years; n=8): Apparent: 9.6 ± 2.4 L/hour (Grothe 2000)

Adults: Apparent: 25 L/hour [12 to 47 L/hour (5th to 95th percentile)]; 40% increase in olanzapine clearance in smokers; 30% decrease in females

Pharmacokinetics: Additional Considerations

Geriatric: The half-life increases 1.5 times.

Gender: Clearance is approximately 30% lower in women.

Cigarette smoking: Clearance is approximately 40% higher in smokers.

Pricing: US

Solution (reconstituted) (OLANZapine Intramuscular)

10 mg (per each): $41.50 - $45.22

Solution (reconstituted) (ZyPREXA Intramuscular)

10 mg (per each): $58.56

Suspension (reconstituted) (ZyPREXA Relprevv Intramuscular)

210 mg (per each): $707.62

300 mg (per each): $1,010.88

405 mg (per each): $1,364.69

Tablet, orally-disintegrating (OLANZapine Oral)

5 mg (per each): $2.08 - $14.27

10 mg (per each): $3.05 - $20.97

15 mg (per each): $4.50 - $30.93

20 mg (per each): $5.94 - $40.89

Tablet, orally-disintegrating (ZyPREXA Zydis Oral)

5 mg (per each): $19.52

10 mg (per each): $28.82

15 mg (per each): $42.65

20 mg (per each): $56.47

Tablets (OLANZapine Oral)

2.5 mg (per each): $10.42 - $11.20

5 mg (per each): $12.29 - $13.22

7.5 mg (per each): $14.95 - $16.08

10 mg (per each): $18.53 - $19.92

15 mg (per each): $27.77 - $29.87

20 mg (per each): $37.05 - $39.83

Tablets (ZyPREXA Oral)

2.5 mg (per each): $15.55

5 mg (per each): $18.35

7.5 mg (per each): $22.32

10 mg (per each): $27.65

15 mg (per each): $41.47

20 mg (per each): $55.30

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Aedon (AT, CZ);
  • Arenbil (ES);
  • Benexafrina OD (CR, DO, GT, HN, NI, PA, SV);
  • Benzopain (JO);
  • Dozic (CO, PY);
  • Enolex (AR);
  • Expolid (BR);
  • Exzapine (PH);
  • Lanzek (AU);
  • Lanzine (TZ);
  • Lanzine ODT (ZW);
  • Lapozan (LV);
  • Lopez (BD);
  • Marathon (CR, DO, GT, HN, NI, PA, SV);
  • Meflax (EC);
  • Midax (AR, PY);
  • Nodoff (TW);
  • Nykob (CZ);
  • Okpine (TW);
  • Olan (LK);
  • Olankline (MY, SG);
  • Olanpin (KR);
  • Olanza (BD, BH, HK, PH, TH);
  • Olanza OD (KR);
  • Olanza ODT (BH);
  • Olanzamed (LB);
  • Olanzapro (PH);
  • Olanzax (LB);
  • Olapin-10 (KR, TH);
  • Olapine (BD);
  • Olawin (ZA);
  • Oleanz (IN, ZA);
  • Olmed (VN);
  • Olza (HK);
  • Onzapin (HK, ID, SG);
  • Ozapex (KR);
  • Ozin (AU);
  • Placet (PY, UY);
  • Prexal (JO);
  • Rolyprexa (IE);
  • Schisolazine (EG);
  • Simina (AR);
  • Tolanz (LK);
  • Torolan (VN);
  • Xytrex (BD);
  • Zalasta (ES, FR, IE, LV, MT, PL);
  • Zanprex (PH);
  • Zap (BR);
  • Zapilux (BG);
  • Zapine (LK);
  • Zappa (IL);
  • Zelta (CO);
  • Zeprex (PH);
  • Zolafren (ES, VN);
  • Zozapin (LK);
  • Zylena (ZA);
  • Zypadhera (AT, BE, DE, DK, EE, ES, FR, GB, HR, IE, IL, IS, LT, MT, NL, NO, PL, PT, RO, SE, SI, SK, TR);
  • ZypAdhera (QA);
  • Zypeace OD (KR);
  • Zypine (AU);
  • Zyprexa (AE, AR, AT, AU, BB, BE, BF, BH, BJ, BR, CH, CI, CL, CN, CO, CY, CZ, DE, DK, EE, EG, ES, ET, FI, FR, GB, GH, GM, GN, GR, HK, HR, IE, IL, IS, IT, JO, JP, KE, KW, LB, LR, LT, LU, LV, MA, ML, MR, MT, MU, MW, MX, MY, NE, NG, NL, NO, NZ, PE, PH, PK, PL, PT, QA, RO, RU, SA, SC, SD, SE, SG, SI, SK, SL, SN, TH, TN, TR, TW, TZ, UA, UG, VE, VN, ZA, ZM);
  • Zyprexa Velotab (AE, AT, BE, BG, BH, CH, CY, DE, DK, EE, EG, ES, FI, GB, GR, IE, IT, LB, MT, NL, NO, PL, PT, RU, SE, SK, TR);
  • Zyprexa Zydis (BB, CN, TH);
  • Zyrepin (KR)


For country abbreviations used in Lexicomp (show table)

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