Olanzapine, Olanzapine Pamoate

[Section Outline]

Psychotic Disorders
Bipolar Disorder
Treatment-resistant Depression
Cancer Chemotherapy-induced Nausea and Vomiting

Olanzapine is used orally for the symptomatic management of psychotic disorders (e.g., schizophrenia) in adults and adolescents 13-17 years of age.1,2,3,4,6,7,14,16,20,21,22,26,98,102,105,205,206,223,225,226,239,305,311,315,334,337,354,357,358,359,360,361,362,369,382,383,384 In addition, oral olanzapine is used alone in adults and adolescents 13-17 years of age or in conjunction with lithium or valproate in adults for the management of acute manic or mixed episodes associated with bipolar I disorder; the drug also is used for longer-term maintenance monotherapy in patients with this disorder.1,36,37,41,100,244,245,246,247,248,249,250,251,252,308,370 Short-acting olanzapine injection is used IM for the management of acute agitation in patients with bipolar disorder or schizophrenia.1,98,99,102 Long-acting olanzapine pamoate injection is used IM for the management of schizophrenia in adults.382

Olanzapine is used orally in combination with fluoxetine for the treatment of acute depressive episodes associated with bipolar I disorder in adults and pediatric patients 10-17 years of age.1,312,313,397 The drug also is used orally in combination with fluoxetine for the acute and maintenance therapy of treatment-resistant depression.1,312

Olanzapine has been used orally in combination with other antiemetic agents for the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy†, including high-dose cisplatin therapy in adults.425,426,427,428 The drug also has been used as rescue antiemetic therapy in patients with breakthrough cancer chemotherapy-induced nausea and vomiting†.425,429

Psychotic Disorders

Olanzapine is used orally and parenterally for the symptomatic management of psychotic disorders (e.g., schizophrenia).1,2,3,4,6,7,14,16,20,21,22,26,105,205,206,223,225,226,227,228,239,305,311,315,334,337,354,357,358,359,360,361,362,369,382,383,384 Drug therapy is integral to the management of acute psychotic episodes in patients with schizophrenia and generally is required for long-term stabilization to sustain symptom remission or control and to minimize the risk of relapse.26 Antipsychotic agents are the principal class of drugs used for the management of all phases of schizophrenia.26 Patient response and tolerance to antipsychotic agents are variable, and patients who do not respond to or tolerate one drug may be successfully treated with an agent from a different class or with a different adverse effect profile.2,6,14,15,20,21,22,23,24,26,27,28,346,400

Schizophrenia

Olanzapine is used orally for the management of schizophrenia in adults and adolescents from 13 to 17 years of age.1,2,3,4,6,7,14,16,20,21,22,26,105,205,206,219,220,221,223,224,225,226,239,305,306,307,309,310,311,315,334,337,354,357,358,359,360,361,362,369 The long-acting pamoate ester of olanzapine is used parenterally for the management of schizophrenia in adults.382,383,384,385 Schizophrenia is a major psychotic disorder that frequently has devastating effects on various aspects of the patient's life and carries a high risk of suicide and other life-threatening behaviors.26,29 Manifestations of schizophrenia involve multiple psychologic processes, including perception (e.g., hallucinations), ideation, reality testing (e.g., delusions), emotion (e.g., flatness, inappropriate affect), thought processes (e.g., loose associations), behavior (e.g., catatonia, disorganization), attention, concentration, motivation (e.g., avolition, impaired intention and planning), and judgment.26,29 The principal manifestations of this disorder usually are described in terms of positive and negative (deficit) symptoms, and more recently, disorganized symptoms.26,29 Positive symptoms include hallucinations, delusions, bizarre behavior, hostility, uncooperativeness, and paranoid ideation, while negative symptoms include restricted range and intensity of emotional expression (affective flattening), reduced thought and speech productivity (alogia), anhedonia, apathy, and decreased initiation of goal-directed behavior (avolition).26,29 Disorganized symptoms include disorganized speech (thought disorder) and behavior and poor attention.26

The American Psychiatric Association (APA) considers most atypical antipsychotic agents (e.g., olanzapine, aripiprazole, quetiapine, risperidone, ziprasidone) first-line drugs for the management of the acute phase of schizophrenia (including first psychotic episodes), principally because of the decreased risk of adverse extrapyramidal effects and tardive dyskinesia, with the understanding that the relative advantages, disadvantages, and cost-effectiveness of conventional (first-generation) and atypical antipsychotic agents remain controversial.26 The APA states that, with the possible exception of clozapine for the management of treatment-resistant symptoms, there currently is no definitive evidence that one atypical antipsychotic agent will have superior efficacy compared with another agent in the class, although meaningful differences in response may be observed in individual patients.26 Conventional antipsychotic agents may be considered first-line in patients who have been treated successfully in the past with or who prefer conventional agents.26 The choice of an antipsychotic agent should be individualized, considering past response to therapy, adverse effect profile (including the patient's experience of subjective effects such as dysphoria), and the patient's preference for a specific drug, including route of administration.26

To compare the long-term effectiveness and tolerability of older, first-generation antipsychotic agents (i.e., perphenazine) with those of newer, atypical antipsychotic agents (i.e., olanzapine, quetiapine, risperidone, ziprasidone), a double-blind, multicenter study (the first phase of Clinical Antipsychotic Trials of Intervention Effectiveness [CATIE]) was sponsored by the National Institute of Mental Health.240 More than 1400 patients with schizophrenia received one of these antipsychotics for up to 18 months or until therapy was discontinued for any reason.240 Patients with tardive dyskinesia could enroll in this trial; however, the randomization scheme prevented their assignment to the perphenazine group.240 The primary outcome measure in this study was the discontinuance of treatment for any cause; this measure was selected because discontinuing or switching an antipsychotic agent occurs frequently and is an important problem in the management of schizophrenia.240 In addition, this measure integrates the patient's and clinician's judgments concerning efficacy, safety, and tolerability into a more comprehensive measure of effectiveness reflecting therapeutic benefits in relation to adverse effects.240,241 Overall, 74% of patients in this study discontinued their medication before receiving the full 18 months of therapy because of inadequate efficacy, intolerable adverse effects, or for other reasons, suggesting substantial limitations in the long-term clinical effectiveness of currently available antipsychotic agents.240 Olanzapine appeared to be more effective than the other drugs evaluated in this study with a lower (64%) discontinuance rate and a lower rate of hospitalization for exacerbation of schizophrenia, while no significant differences between the effectiveness of the conventional agent, perphenazine, and the other second-generation agents studied were observed (discontinuance rates were 75, 82, 74, and 79% for perphenazine, quetiapine, risperidone, and ziprasidone, respectively).240,243 The time to discontinuance of therapy for any cause was found to be longer in the olanzapine group than in the quetiapine, risperidone, perphenazine, and ziprasidone groups in this study; however, the differences between the olanzapine and perphenazine groups and between the olanzapine and ziprasidone groups did not achieve statistical significance.240 Although there were no significant differences in the time until discontinuance of therapy because of drug intolerance among the drugs studied, the incidences of discontinuance for certain adverse effects differed among the drugs with olanzapine discontinued more frequently because of weight gain or metabolic effects (e.g., increases in glycosylated hemoglobin [hemoglobin A_1c; HbA_1c], cholesterol, and triglycerides) and perphenazine discontinued more frequently because of adverse extrapyramidal effects.240

An open, multicenter, randomized, controlled trial comparing the relative long-term effectiveness (over a 1-year period) of a group of first-generation antipsychotic agents (e.g., chlorpromazine, flupentixol [not commercially available in the US], flupentixol decanoate [not commercially available in the US], fluphenazine decanoate, haloperidol, haloperidol decanoate, loxapine, methotrimeprazine [no longer commercially available in the US], pipothiazine palmitate [not commercially available in the US], sulpiride [not commercially available in the US], trifluoperazine, zuclopenthixol [not commercially available in the US], zuclopenthixol decanoate [not commercially available in the US]) with a group of second-generation antipsychotic agents other than clozapine (e.g., olanzapine, amisulpride [not commercially available in the US], quetiapine, risperidone, zotepine [not commercially available in the US]) in patients with schizophrenia was conducted throughout the United Kingdom by the National Health Service.334 In the Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1), the primary outcome measure was the Quality of Life Scale score, and secondary outcome measures included symptom improvement, adverse effects, patient satisfaction, and costs of health care.334 Patients in the first-generation antipsychotic group demonstrated a trend toward greater improvements in the Quality of Life Scale and symptom improvements scores in this study.334 In addition, the patients studied did not report a clear preference for either group of drugs and costs of health care in the 2 groups were found to be similar.334

Emerging data from the first phase of the pivotal CATIE trial and the CUtLASS 1 trial suggest that newer, atypical antipsychotics may not provide clinically important advantages over older, first-generation antipsychotics in patients with chronic schizophrenia and that several factors, including adequacy of symptom relief, tolerability of adverse effects, and cost of therapy, may influence a patient's ability and willingness to remain on long-term antipsychotic medication.240,241,242,243,334,335,336 In addition, these results suggest that it may often be necessary to try 2 or more different antipsychotic agents in an individual patient in order to provide optimal therapeutic benefit with an acceptable adverse effect profile.240,241,242,243

In a randomized, double-blind, second phase trial, patients with schizophrenia who had discontinued an atypical antipsychotic agent during the first phase of the CATIE trial were reassigned to treatment with a different atypical antipsychotic agent (olanzapine, quetiapine, risperidone, or ziprasidone).307 Similarly to the first phase of the CATIE trial, efficacy and tolerability in this second phase study were principally measured by time until drug discontinuance for any reason.307 The time until antipsychotic treatment was discontinued was longer for patients receiving risperidone and olanzapine than for those receiving quetiapine and ziprasidone (median: 7, 6.3, 4, and 2.8 months, respectively).307 Among patients who discontinued their prior antipsychotic agent because of lack of efficacy, olanzapine was found to be more effective than quetiapine and ziprasidone, while risperidone was more effective than quetiapine.307

In another study that was part of the second phase of the CATIE investigation, schizophrenic patients who had discontinued treatment with olanzapine, quetiapine, risperidone, or ziprasidone during the first phase of the CATIE investigation, principally because of inadequate efficacy, were randomized to receive open-label clozapine therapy or blinded treatment with another atypical antipsychotic agent not previously received in the trial.306 Clozapine was found to be more effective in this study than switching to another atypical antipsychotic agent.306 Patients receiving clozapine also were found to be less likely to discontinue treatment for any reason than patients receiving quetiapine or risperidone.306 In addition, the clozapine-treated patients were less likely to discontinue therapy because of an inadequate clinical response than were patients receiving the other atypical antipsychotic agents.306

Pending further data clarifying the relative effectiveness and tolerability of first- and second-generation antipsychotics in the treatment of schizophrenia, many clinicians recommend that the choice of an antipsychotic agent be carefully individualized taking into consideration the clinical efficacy and adverse effect profile (including the risk for extrapyramidal effects, weight gain, and adverse metabolic effects) of the antipsychotic agent as well as the individual patient's risk factors; the patient's previous experience of subjective effects such as dysphoria; the patient's preference for and willingness to take (i.e., compliance) a specific drug, including route of administration; and the relative cost of therapy.26,215,240,241,242,243,353 Olanzapine and clozapine may be reasonable alternatives in any patient with schizophrenia who has not achieved a full clinical remission with other antipsychotic agents; however, the risk of adverse metabolic effects with both drugs necessitates dietary and exercise counseling before therapy is initiated, monitoring during drug therapy, and possible discontinuance of therapy if these effects become troublesome during therapy.26,205,240,241,306,307 Additional analyses from data generated by the CATIE trial addressing other schizophrenia treatment-related issues such as quality of life and predictors of response are ongoing.242,243

Atypical antipsychotic agents, including olanzapine, generally appear less likely to induce adverse extrapyramidal effects and tardive dyskinesia than conventional, first-generation antipsychotic agents.26,209,210,211,213,215,216,217,218,225,316 In addition, stabilization of or improvement in tardive dyskinesia associated with conventional antipsychotic agents has been reported in some patients when they have been switched to second-generation antipsychotic therapy, including olanzapine.210,211,213,214,216,217 Therefore, the APA26 and some clinicians213,216,217 recommend that atypical antipsychotic agents be considered in patients with schizophrenia who have experienced tardive dyskinesia associated with conventional antipsychotic agents.26,213,216,217

For additional information on the symptomatic management of schizophrenia, see Schizophrenia and Other Psychotic Disorders under Uses: Psychotic Disorders, in the Phenothiazines General Statement 28:16.08.24.

The efficacy of oral olanzapine for the management of psychotic disorders in adults has been established in hospital settings by 2 placebo-controlled studies of 6 weeks' duration in patients who met the DSM-III-R criteria for schizophrenia.1,3,20,223,311 In these and several other studies, improvement in manifestations of schizophrenia was based principally on the results of various psychiatric rating scales, including the Brief Psychiatric Rating Scale (BPRS) that assesses factors such as anergy, thought disturbances, activation, hostility/suspiciousness, and anxiety/depression; the Scale for the Assessment of Negative Symptoms (SANS); the Positive and Negative Symptoms Scale (PANSS); and the Clinical Global Impression (CGI).1,3,20,223,311

In the first 6-week, placebo-controlled study, olanzapine was given in a fixed dosage of 1 or 10 mg once daily.1,20,311 Results indicated that the 10-mg, but not the 1-mg, once-daily dosage was more effective than placebo in improving the scores on the PANSS total (also on the extracted BPRS total), the BPRS psychosis cluster, the PANSS Negative subscale, and the CGI Severity assessments.1,20,311 Results of the second 6-week, placebo-controlled study, which evaluated 3 fixed dosage ranges (5 ± 2.5 mg once daily, 10 ± 2.5 mg once daily, and 15 ± 2.5 mg once daily), found that the 2 highest dosages (actual mean dosages were 12 and 16 mg once daily, respectively) were more effective than placebo in reducing the BPRS total score, BPRS psychosis cluster, and CGI severity score;1,223 the highest dosage also was superior to placebo on the SANS.1 There appeared to be no therapeutic advantage for the higher dosage of olanzapine compared with the medium dosage in this study.1 No race- or gender-related differences in outcome were noted in either of these studies.1

The efficacy of oral olanzapine for long-term use (i.e., longer than 6 weeks) in schizophrenia has been established in one controlled study in adults,1,354 and the drug has been used in some other patients for prolonged periods (e.g., reportedly up to 1 year) without apparent loss of clinical effect.1,20,23,24,239,305,337 In the long-term clinical trial, adult outpatients who predominantly met DSM-IV criteria for schizophrenia and who remained stable on olanzapine therapy during an open-label treatment phase lasting at least 8 weeks were randomized to continue receiving their current olanzapine dosage (ranging from 10-20 mg daily) or to receive placebo.1,354 Although the follow-up period to observe patients for relapse, which was defined in terms of increases in BPRS positive symptoms or hospitalization, initially was planned for 12 months, criteria were met for stopping the trial early because of an excess of placebo relapses compared with olanzapine relapses.1,354 In addition, olanzapine was found to be superior to placebo on prolonging time to relapse, which was the primary outcome measure in this study.1,354 Therefore, olanzapine was more effective than placebo at maintaining efficacy in schizophrenic patients stabilized for approximately 8 weeks and followed for an observation period of up to 8 months.1,354 If oral olanzapine is used for extended periods, the need for continued therapy should be reassessed periodically.1,20,24,354

The short-term efficacy of long-acting IM olanzapine pamoate in schizophrenia has been established in a randomized, double-blind, placebo-controlled, multicenter study of 8 weeks' duration in 404 adults who were experiencing acute psychotic symptoms and met DSM-IV or DSM-IV-TR criteria for schizophrenia.382,385 Patients were randomized to receive IM injections of olanzapine pamoate (Zyprexa^® Relprevv) in dosages of 210 mg (of olanzapine) every 2 weeks, 405 mg every 4 weeks, or 300 mg every 2 weeks or placebo every 2 weeks.382,385 Patients were discontinued from their previous antipsychotic regimen and underwent a washout period lasting 2-7 days.382,385 Supplementation with oral antipsychotics was not allowed throughout the study.382,385 The primary efficacy measure in this study was the change from baseline to end point in the total PANSS score (the mean baseline total PANSS score was 101).382,385 Total PANSS scores showed improvement from baseline to end point with each dosage of olanzapine pamoate compared with placebo.382,385 At week 8, PANSS total scores decreased by a mean of 22.5, 22.6, or 26.3 points in patients receiving IM olanzapine pamoate 210 mg every 2 weeks, 405 mg every 4 weeks, or 300 mg every 2 weeks, respectively, compared with a mean decrease of 8.5 points in patients receiving placebo.385 There were no substantial differences in efficacy among the 3 olanzapine pamoate dosage groups at the study end point.385 The onset of antipsychotic efficacy for the long-acting olanzapine pamoate injection was evident within the first week of treatment.385 The manufacturer states that the effectiveness of olanzapine pamoate injection in the treatment of schizophrenia also is supported by the established effectiveness of orally administered olanzapine.382

Efficacy of long-acting IM olanzapine pamoate for long-term use (i.e., longer than 8 weeks) in the maintenance treatment of schizophrenia has been established in a randomized, double-blind, multicenter study in 1065 adults.382,383 Adult outpatients with schizophrenia who had remained stable on oral olanzapine therapy during an open-label treatment phase lasting 4-8 weeks were randomized to continue receiving their current olanzapine dosage orally (10, 15, or 20 mg daily) or to receive long-acting IM olanzapine pamoate (Zyprexa^® Relprevv) in a low-dosage regimen (150 mg [of olanzapine] every 2 weeks), a medium-dosage regimen (405 mg every 4 weeks), or a high-dosage regimen (300 mg every 2 weeks), or a very low reference dosage regimen (45 mg every 4 weeks) for 24 weeks in the double-blind maintenance phase.382,383 No supplementation with oral antipsychotics was allowed throughout the study.382,383 The primary efficacy measure was time to exacerbation of symptoms of schizophrenia, which was defined as either increases in BPRS positive symptoms or hospitalization.382,383 IM olanzapine pamoate was found to be effective in the maintenance treatment of schizophrenia for up to 24 weeks and IM olanzapine pamoate dosage regimens of 150 mg every 2 weeks, 405 mg every 4 weeks, or 300 mg every 2 weeks were found to be superior to 45 mg every 4 weeks.382,383 Olanzapine pamoate generally demonstrated a similar safety profile to oral olanzapine with the exception of injection-related adverse effects.383 If IM olanzapine pamoate injection is used for extended periods, the need for continued therapy should be reassessed periodically.382

Parenteral antipsychotic therapy with a long-acting IM preparation may be particularly useful in patients with schizophrenia and a history of poor compliance.384,388,393,394,395,396 In addition, long-acting antipsychotic preparations may be useful in patients with suspected GI malabsorption or variable GI absorption of the drug.393,395 The principal disadvantage of long-acting parenteral antipsychotics is the inability to terminate the drug's action when severe adverse reactions occur.382,393 The manufacturer of Zyprexa^® Relprevv recommends that patients first receive oral olanzapine therapy to establish tolerability of the drug before long-acting IM olanzapine pamoate is used.382 Long-acting IM olanzapine pamoate may be most useful in schizophrenic patients who respond well to oral olanzapine therapy and for whom a depot antipsychotic can improve compliance.384,388,392

Olanzapine has been shown to be an effective, relatively rapid-acting, broad-spectrum antipsychotic agent in both controlled and uncontrolled studies of patients with schizophrenia.1,26,205,207,219,239,305,306,307,355,356,357,358,359 Like other second-generation antipsychotic agents, olanzapine appears to improve both positive (florid symptomatology such as hallucinations, conceptual disorganization, and suspiciousness) and negative (“deficit” symptomatology such as emotional withdrawal, motor retardation, blunted affect, and disorientation) manifestations of schizophrenia; conventional antipsychotic agents may have lesser effects on negative manifestations of the disorder.2,14,20,21,22,223,305 Some evidence also suggests that atypical antipsychotic agents may be more effective in treating cognitive and mood symptoms as well as global psychopathology than conventional antipsychotic agents, but this is controversial and remains to be fully established.26,147,215,315,340,341,342,343,344,345 In addition, some patients with schizophrenia who have been stabilized on long-term conventional antipsychotic therapy have demonstrated further improvement following a switch to an atypical antipsychotic agent.304

Results from one comparative study in adults suggest that oral olanzapine dosages of 7.5-17.5 mg daily may be as effective as oral haloperidol dosages of 10-20 mg daily in reducing positive symptoms of schizophrenia,3,4 while oral olanzapine dosages of 12.5-17.5 mg daily may be more effective than oral haloperidol dosages of 10-20 mg daily in reducing negative symptoms of schizophrenia.3,4,20 A randomized, controlled trial comparing the long-term (i.e., 1 year) effectiveness and cost of olanzapine and haloperidol therapy in patients with schizophrenia or schizoaffective disorder did not reveal any important advantage of olanzapine compared with haloperidol on measures of compliance, symptom improvement, adverse extrapyramidal effects, overall quality of life, and cost; olanzapine also was more frequently associated with weight gain.337 However, olanzapine therapy was associated with reduced akathisia, less tardive dyskinesia in a secondary analysis, and small but significant improvements in measures of memory and motor function compared with haloperidol.337 In other comparative studies, olanzapine usually was found to be at least as effective as or more effective than haloperidol21,219 and several other atypical antipsychotic agents, including quetiapine,362 risperidone,205,305,357,358 and ziprasidone.206,359,360,361 In a comparative, double-blind trial conducted in patients with schizophrenia or schizoaffective disorder, both olanzapine and risperidone were found to be effective and well tolerated, although greater reductions in the severity of positive and affective symptoms were noted in the risperidone-treated patients compared with those receiving olanzapine.358

Olanzapine also has been studied in patients with treatment-refractory schizophrenia (i.e., patients who have demonstrated an inadequate response to prior antipsychotic therapy) in both open and comparative clinical trials.26,105,208,219,220,221,224,225,226,230,239,290,306,307 In an open trial of 6 weeks' duration, olanzapine (15-25 mg daily) was found to be effective and well tolerated in adult patients with treatment-refractory schizophrenia with 36% responding to the drug.105 In a double-blind trial of 8 weeks' duration, although olanzapine (25 mg daily) was found to be as effective as chlorpromazine (1.2 g daily with benztropine), the total amount of improvement with either drug was modest; olanzapine was better tolerated than chlorpromazine.224 In a double-blind trial of 14 weeks' duration comparing efficacy and safety of several atypical antipsychotics (olanzapine, clozapine, and risperidone) with each other and with haloperidol, olanzapine (mean dosage of approximately 30 mg daily) and clozapine produced greater clinical improvement in global psychopathology and negative symptoms than haloperidol (mean dosage of approximately 26 mg daily) in patients with chronic schizophrenia or schizoaffective disorder, but the effects of atypical antipsychotic agents were considered small and of limited clinical importance.219 In another study using the manufacturer's clinical trial database to retrospectively identify treatment-resistant schizophrenic patients, olanzapine (mean dosage of approximately 11 mg daily) was found to be more effective than haloperidol therapy (mean dosage of approximately 10 mg daily) in improving positive, negative, and mood symptoms and produced fewer extrapyramidal effects.225 The results of clinical trials to date suggest that olanzapine may be somewhat less effective than or similarly effective to clozapine in the management of resistant schizophrenia patients.26,219,226,230,306,307 Clozapine generally appears to be more effective in the management of treatment-refractory schizophrenia than most first-generation and other second-generation antipsychotic agents and may produce greater improvement in negative symptoms of schizophrenia than other antipsychotic agents; however, tolerability concerns (e.g., hematologic toxicity, hypotension, dizziness, sedation) limit its use in many patients.26,219,226,230,306,356 Although higher olanzapine dosages (i.e., up to 60 mg daily) have been used in some patients with treatment-resistant schizophrenia, it remains to be established whether higher dosages of the drug result in improved efficacy in such patients, and higher dosages may increase the risk of extrapyramidal and other adverse effects.26,105,219,220,221,224,230,290

Like some other atypical antipsychotic agents (e.g., clozapine, risperidone), olanzapine therapy appears to reduce the risk of violent behavior in patients with schizophrenia.309,310 Although the precise mechanism(s) for the antiaggressive effects are not known, improved compliance with atypical antipsychotic agents may play a role.309,310

Olanzapine also has been used with a variety of adjunctive agents, including other antipsychotic agents,227 antidepressants (including selective serotonin-reuptake inhibitors such as fluoxetine and fluvoxamine),152,227 valproate (e.g., divalproex sodium, valproic acid, valproate sodium),227,231,232,233 and topiramate,227,228,229 in some patients with treatment-refractory schizophrenia, inadequate response to antipsychotic therapy, or acute exacerbations of schizophrenia in both controlled and uncontrolled trials.152,227,228,229,231,232,233 Further controlled trials of olanzapine combined with these agents are necessary to more clearly determine the potential risks and benefits of such combined therapy.227,231,233

Pediatric Considerations

Olanzapine is used orally for the management of schizophrenia in adolescents 13 to 17 years of age.1,369 Clinicians treating pediatric patients with schizophrenia should be aware that pediatric schizophrenia is a serious mental disorder; however, its diagnosis can be challenging.1,373 Symptom profiles in such patients can be variable.1,373 Therefore, it is recommended that drug therapy for pediatric schizophrenia be initiated only after a thorough diagnostic evaluation has been performed and careful consideration given to the risks associated with medication treatment.1,373 Medication treatment should only be part of a total treatment program that often includes psychological, educational, and social interventions.1,373

When deciding among the alternative treatments available for adolescents with schizophrenia, clinicians should consider the increased potential for weight gain and dyslipidemia in adolescents treated with olanzapine (as compared with adults).1,373 Clinicians also should consider the potential long-term risks when prescribing olanzapine to adolescents; in many cases, this may lead them to consider prescribing other drugs first in adolescent patients.1,373 (See Cautions: Endocrine and Metabolic Effects, Cautions: Precautions and Contraindications, and see also Cautions: Pediatric Precautions.)

The short-term efficacy and tolerability of oral olanzapine in 107 adolescent inpatients and outpatients 13-17 years of age with schizophrenia were established in a randomized, double-blind, placebo-controlled, multicenter trial of 6 weeks' duration in which olanzapine was given in a flexible dosage range of 2.5-20 mg once daily.1,369 The principal rating instrument used for assessing psychiatric signs and symptoms in this trial was the Anchored Version of the BPRS for Children (BPRS-C) total score.1,369 Olanzapine (mean modal dosage: 12.5 mg daily; mean dosage: 11.1 mg daily) was found to be more effective than placebo in treating adolescents with schizophrenia, since the olanzapine-treated adolescents had a substantially greater mean reduction in the BPRS-C total score compared with those receiving placebo.1,369 However, weight gain and hyperprolactinemia occurred more often in patients receiving olanzapine compared with those receiving placebo.1,369

Olanzapine has been successfully used orally for the management of childhood-onset schizophrenia in a limited number of children† and other adolescents.148,149,234,235,236,237,238 However, the manufacturers state that the safety and effectiveness of the drug in children younger than 13 years of age have not been established.1,389

Although there is no body of evidence available to determine how long adolescent patients treated with oral olanzapine should be maintained on the drug, the manufacturer states that such efficacy can be extrapolated from adult data in addition to comparisons of olanzapine pharmacokinetic parameters in adult and adolescent patients.1 If olanzapine is used for an extended period, the continued need for maintenance therapy should be reassessed periodically.1

Based on the observed efficacy and tolerability of atypical antipsychotics in adults and the available clinical experience in pediatric patients, the American Academy of Child and Adolescent Psychiatry (AACAP) currently states that the use of atypical antipsychotic agents in children and adolescents with schizophrenia is justified,234 and many clinicians consider atypical antipsychotic agents, with the exception of clozapine, among the drugs of first choice in the management of childhood-onset schizophrenia.234,236 However, well-controlled studies are necessary to more clearly establish the efficacy and safety of atypical antipsychotics in pediatric patients, particularly during long-term therapy.234,235,237,238 For additional information on the symptomatic management of childhood-onset schizophrenia, see Pediatric Considerations under Psychotic Disorders: Schizophrenia, in Uses in the Phenothiazines General Statement 28:16.08.24.

Acute Agitation

Short-acting olanzapine injection (e.g., Zyprexa^® IntraMuscular) is used IM for the management of acute agitation in adult patients with schizophrenia for whom treatment with olanzapine is appropriate and who require an IM antipsychotic agent for rapid control of behaviors that interfere with diagnosis and care (e.g., threatening behaviors, escalating or urgently distressing behavior, self-exhausting behavior).1,98,102 According to DSM-IV, psychomotor agitation is excessive motor activity associated with a feeling of inner tension.1,29 The efficacy of IM olanzapine for the management of acute agitation in patients with schizophrenia was established in 2 short-term (single-day), placebo-controlled trials in hospital settings; an active comparator treatment arm using haloperidol injection was included in both studies.1,98,102 The patients in this study exhibited a level of agitation that met or exceeded a threshold score of 14 on the 5 items comprising the Positive and Negative Syndrome Scale (PANSS) Excited Component (i.e., poor impulse control, tension, hostility, uncooperativeness, and excitement items) with at least one individual item score of 4 (“moderate”) or greater using a 1-7 scoring system, where scores of 1 or 7 indicate absent or extreme agitation, respectively.1,98,102 The primary measure used for assessing efficacy in managing agitation in these trials was the change from baseline in the PANSS Excited Component at 2 hours post-injection.1,98,102 Patients could receive up to 3 injections of IM olanzapine; however, patients could not receive the second injection until after the initial 2-hour period when the primary efficacy measure was assessed.1,98,102

In the first placebo-controlled trial, short-acting IM olanzapine was given in fixed single doses of 2.5, 5, 7.5, or 10 mg in agitated hospitalized patients with schizophrenia.1,98 All 4 IM olanzapine doses were found to be statistically superior to placebo in reducing the PANSS Excited Component score at 2 hours following injection; however, the effect was larger and more consistent for the 3 highest doses studied.1,98 There were no significant differences in efficacy noted for the 7.5- and 10-mg doses compared with the 5-mg dose in this study.1,98 In the second placebo-controlled trial in agitated patients with schizophrenia, a fixed, 10-mg dose of short-acting IM olanzapine was evaluated and found to be superior to placebo on the PANSS Excited Component at 2 hours following injection.1,102 An analysis of these 2 controlled studies as well as an additional controlled study conducted in agitated patients with bipolar mania for possible age-, race-, or gender-related effects on treatment outcome did not suggest any difference in efficacy based on these patient characteristics.1,99,102

Bipolar Disorder

Oral olanzapine is used alone in adults and adolescents 13-17 years of age or in conjunction with lithium or valproate in adults for the acute management of manic or mixed episodes associated with bipolar I disorder; the drug also is used orally for longer-term maintenance monotherapy in adults and adolescents 13-17 years of age with this disorder.1,36,37,41,100,244,245,246,247,248,249,250,251,252,308,370 In addition, oral olanzapine is used in combination with fluoxetine hydrochloride for the treatment of acute depressive episodes associated with bipolar I disorder in adults and pediatric patients 10-17 years of age.1,312,313,397 According to DSM-IV criteria, manic episodes are distinct periods lasting 1 week or longer (or less than 1 week if hospitalization is required) of abnormally and persistently elevated, expansive, or irritable mood accompanied by at least 3 (or 4 if the mood is only irritability) of the following 7 symptoms: grandiosity, reduced need for sleep, pressure of speech, flight of ideas, distractability, increased goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation, and engaging in high-risk behavior (e.g., unrestrained buying sprees, sexual indiscretions, foolish business investments).29

For the initial management of less severe manic or mixed episodes in patients with bipolar disorder, current APA recommendations state that monotherapy with lithium, valproate (e.g., valproate sodium, valproic acid, divalproex), or an antipsychotic such as olanzapine may be adequate.42 For more severe manic or mixed episodes, combination therapy with an antipsychotic and lithium or valproate is recommended as first-line therapy.42 For further information on the management of bipolar disorder, see Uses: Bipolar Disorder, in Lithium Salts 28:28.

Acute Treatment of Manic or Mixed Episodes

Efficacy of oral olanzapine monotherapy in the acute treatment of manic or mixed episodes in adults has been demonstrated in 2 short-term (i.e., 3 or 4 weeks' duration), randomized, double-blind, placebo-controlled, parallel-group trials in patients who met DSM-IV criteria for bipolar I disorder (with or without a rapid-cycling course) and who met diagnostic criteria for an acute manic or mixed episode (with or without psychotic features).1,36,37 Olanzapine was given in an initial dosage of 10 mg once daily in the 3-week trial and 15 mg once daily in the 4-week trial; the dosage was subsequently adjusted within the range of 5-20 mg once daily in both of these trials.1,36,37 The principal rating instrument used for assessing manic symptoms in these trials was the Y-MRS score, an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology (e.g., irritability, disruptive/aggressive behavior, sleep, elevated mood, speech, increased activity, sexual interest, language/thought disorder, thought content, appearance, insight) in a range from 0 (no manic features) to 60 (maximum score).1,36,37 All patients were hospitalized at the onset of these trials, but some patients were allowed to continue the studies on an outpatient basis after 1 week of hospitalization if their Clinical Global Impressions-Bipolar Version of severity of illness (CGI-BP) mania score was no greater than 3 (mild) and they had at least a 50% reduction in their Young Mania Rating Scale (Y-MRS) scores.36,37 In the 3- and 4-week placebo-controlled trials, approximately 49-65% of patients receiving 5-20 mg of olanzapine once daily achieved a 50% or greater improvement in Y-MRS total score from baseline compared with approximately 24-43% of those who received placebo.36,37 In addition, unlike therapy with typical antipsychotic agents, patients receiving olanzapine in these clinical studies did not experience a worsening in depressive symptoms (defined as an increase in the Hamilton Psychiatric Rating Scale for Depression-21 item [HAMD-21] score of at least 3 points) compared with those receiving placebo.36,37 In another 3-week, placebo-controlled trial that was designed identically to the first 3-week trial and was conducted simultaneously, olanzapine demonstrated a similar treatment difference in reduction of the Y-MRS total score but was not found to be superior to placebo on this outcome measure, possibly due to sample size and site variability.1

Data from one limited comparative study suggest that oral olanzapine dosages of 10 mg daily may be as effective as lithium carbonate dosages of 400 mg twice daily in the treatment of manic episodes in adults with bipolar disorder.38,39 In a randomized, double-blind trial of 3 weeks' duration comparing olanzapine (5-20 mg daily) and divalproex sodium therapy in hospitalized adults with bipolar disorder experiencing acute manic or mixed episodes, olanzapine therapy was found to produce greater improvement in Y-MRS total scores, which was the primary efficacy measure in this trial.248 In addition, a substantially greater proportion of patients in the olanzapine group achieved remission compared with the divalproex group.248 In a randomized, double-blind study of 12 weeks' duration comparing olanzapine and divalproex sodium in patients with bipolar I disorder hospitalized for acute mania, the drugs were found to be equally effective although divalproex sodium was somewhat better tolerated than olanzapine.249

Combined Therapy

Efficacy of oral olanzapine when used in combination with lithium or valproate in the short-term treatment of acute manic or mixed episodes has been demonstrated in 2 randomized, double-blind, placebo-controlled studies of 6 weeks' duration in adult patients who met the DSM-IV criteria for bipolar I disorder (with or without a rapid-cycling course) and who met diagnostic criteria for an acute manic or mixed episode (with or without psychotic features).1,41 In these studies, patients with bipolar disorder experiencing manic or mixed episodes (Y-MRS scores of 16 or greater) who had not responded to at least 2 weeks of lithium or divalproex sodium monotherapy despite adequate plasma drug concentrations (in a therapeutic range of 0.6-1.2 mEq/L for lithium or 50-125 mcg/mL of valproate for divalproex sodium) were randomized to receive either olanzapine (initial dosage of 10 mg once daily; range: 5-20 mg once daily) or placebo, in combination with their original therapy.1,41 Addition of olanzapine to lithium or divalproex sodium was shown to be superior to continued monotherapy with lithium or divalproex sodium in the reduction of Y-MRS total score in both of these studies.1,41

The manufacturer states that efficacy of adjunctive therapy with olanzapine for longer-term use (i.e., longer than 6 weeks) in patients with bipolar I disorder has not been systematically evaluated in controlled trials.1

Maintenance Monotherapy of Bipolar Disorder

Oral olanzapine is used for maintenance monotherapy in adults and adolescent patients 13-17 years of age with bipolar I disorder.1,100,244,245,247,250 The long-term efficacy of oral olanzapine as maintenance monotherapy in adults with bipolar disorder has been demonstrated in a double-blind, placebo-controlled trial and in double-blind comparative trials.1,100,244,245,247,250 In the placebo-controlled study, adult patients who met DSM-IV criteria for bipolar I disorder and experienced manic or mixed episodes and who had responded during an initial open-label treatment phase to oral olanzapine therapy (5-20 mg daily) for an average of about 2 weeks were randomized either to continue olanzapine at the same dosage or to receive placebo for up to 48 weeks and were observed for relapse.1,100,244,245 Response during the open-label phase was defined as a reduction in the Y-MRS total score of 12 or more and in the 21-item Hamilton Depression Rating Scale (HAM-D 21) of 8 or more; relapse during the double-blind phase of the study was defined as an increase in the Y-MRS or HAM-D 21 total score to 15 or more or being hospitalized for either mania or depression.1,245 Approximately 50% of the patients in the olanzapine group had discontinued therapy by day 59, and approximately 50% of the patients in the placebo group had discontinued placebo by day 23 of the double-blind phase.1,245 A longer time until relapse was observed in the patients receiving olanzapine compared with those receiving placebo (median of 174 and 22 days, respectively, for relapse into any mood episode) during the randomized phase of this study.1,100,244,245 The relapse rate also was significantly lower in the olanzapine group (approximately 47%) than in the placebo group (approximately 80%).245 If olanzapine is used for extended periods, the need for continued therapy should be reassessed periodically. 1

In a double-blind, 52-week trial comparing olanzapine and lithium maintenance therapy in adults with bipolar disorder, olanzapine was found to be significantly more effective than lithium in preventing relapses and recurrences of manic and mixed episodes following initial stabilization with combined olanzapine and lithium therapy.250 Olanzapine and lithium demonstrated comparable efficacy in preventing relapses and recurrences of depression in this study.250 In a retrospective analysis from this trial, patients were subcategorized into illness stage (early, intermediate, or later) based on the number of prior manic or mixed episodes they had experienced.246 The rates of relapse or recurrence of manic or mixed episodes were approximately 2 and 26%, 13 and 24%, and 24 and 33% for olanzapine and lithium in the early, intermediate, and later stage groups of bipolar patients, respectively; no substantial treatment effect for treatment or illness stage for depressive relapse or recurrence was observed.246 Because olanzapine was associated with a lower rate of relapse or recurrence of manic and mixed episodes in early-stage patients, it was suggested that the drug may be particularly effective early in the course of bipolar disorder.246

In a double-blind, 47-week trial comparing monotherapy with olanzapine or divalproex sodium in adults with bipolar disorder experiencing manic or mixed episodes, mean improvement in Y-MRS scores was greater for olanzapine-treated patients.247 In addition, the median time to symptomatic mania remission was shorter for patients receiving olanzapine compared with those receiving divalproex sodium (14 days vs. 62 days, respectively).247 However, no significant differences in the rates of symptomatic mania remission and symptomatic relapse into mania or depression between the olanzapine- and divalproex-treated patients were observed in this study.247 In a double-blind, 18-month, relapse prevention trial comparing the efficacy of combined olanzapine plus lithium or valproate therapy with lithium or valproate therapy alone in patients with bipolar disorder, more sustained symptomatic remission (163 days vs 42 days, respectively) occurred in the group receiving combined olanzapine plus lithium or valproate therapy than in the group receiving lithium or valproate therapy alone.252

Rapid-Cycling Bipolar Disorder

In an analysis of pooled data from several trials comparing the clinical response to olanzapine therapy in rapid-cycling and non-rapid-cycling adult patients with bipolar disorder, relative clinical response to olanzapine was found to be similar in the 2 groups, although earlier responses were observed in the rapid-cycling group of patients, and long-term outcomes were more favorable in the non-rapid-cycling group.251 Rapid-cycling patients were found to be less likely to achieve an initial symptomatic remission, more likely to experience recurrences, especially of depression, and had more hospitalizations and suicide attempts than non-rapid-cycling patients in this study.251

Depressive Episodes Associated with Bipolar Disorder

Oral olanzapine is used in combination with fluoxetine for the treatment of acute depressive episodes associated with bipolar I disorder in adults and pediatric patients 10-17 years of age.1,312,313,397 In 2 randomized, double-blind studies of 8 weeks' duration comparing a fixed combination of olanzapine and fluoxetine hydrochloride (Symbyax^®) with olanzapine monotherapy and placebo in adults, the fixed combination (given in flexible daily dosages of 6 mg olanzapine with 25 or 50 mg of fluoxetine or 12 mg of olanzapine with 50 mg of fluoxetine) was more effective than olanzapine monotherapy (5-20 mg daily) or placebo in improvement in depressive symptoms as assessed by the Montgomery-Asberg Depression Rating Scale (MADRS).312,313 Although the manufacturer states that efficacy beyond 8 weeks' duration remains to be established, patients have received the fixed combination for up to 24 weeks in clinical trials.312,313,314 Clinicians who elect to extend therapy beyond 8 weeks should reevaluate the risks and benefits of continued therapy periodically.1,312

The manufacturers state that olanzapine monotherapy is not indicated for the treatment of depressive episodes associated with bipolar I disorder.1,389,390

Pediatric Considerations

Oral olanzapine is used as monotherapy in adolescents 13-17 years of age for the acute management of manic or mixed episodes associated with bipolar I disorder; the drug also is used orally for longer-term maintenance monotherapy in patients with this disorder.1,373 Oral olanzapine in combination with fluoxetine is used for the treatment of acute depressive episodes associated with bipolar I disorder in pediatric patients 10-17 years of age.1,312,397 When treating pediatric patients with bipolar I disorder, clinicians should be aware that pediatric bipolar I disorder is a serious mental disorder; however, its diagnosis can be challenging.1,253,373 Pediatric patients with bipolar disorder may have variable patterns of periodicity of manic or mixed symptoms.1,253,373 Therefore, it is recommended that drug therapy for pediatric bipolar disorder be initiated only after a thorough diagnostic evaluation has been performed and careful consideration given to the risks associated with medication treatment.1,253,373 Medication treatment should only be part of a total treatment program that often includes psychological, educational, and social interventions.1,253,373

When deciding among the alternative treatments available for adolescents with bipolar disorder, clinicians should consider the increased potential for weight gain and dyslipidemia in adolescents receiving olanzapine (as compared with adults).1,373 Clinicians also should consider the potential long-term risks when prescribing olanzapine to adolescents; in many cases, this may lead them to consider prescribing other drugs first in adolescent patients.1,373,373 (See Cautions: Endocrine and Metabolic Effects, Cautions: Precautions and Contraindications, and see also Cautions: Pediatric Precautions.)

The short-term efficacy of oral olanzapine monotherapy in the acute treatment of bipolar I disorder in adolescents 13-17 years of age was established in a randomized, multicenter, double-blind, placebo-controlled trial of 3 weeks' duration in 161 patients who met DSM-IV-TR criteria for manic or mixed episodes associated with bipolar I disorder (with or without psychotic features).1,370 In this flexible-dosage trial, outpatients and inpatients were randomized to receive either olanzapine 2.5-20 mg daily (mean modal dosage of 10.7 mg daily; mean dosage of 8.9 mg daily) or placebo.1,370 Olanzapine was found to be more effective than placebo as demonstrated by substantially greater reduction in the total score on the Adolescent Structured Y-MRS, which was the primary efficacy measure in this study.1,370 However, the olanzapine-treated adolescents had substantially greater weight gain and elevations in serum transaminases, prolactin, fasting glucose, fasting total cholesterol, and uric acid compared with those receiving placebo.1,370

The efficacy and safety of oral olanzapine in combination with fluoxetine hydrochloride for the acute treatment of depressive episodes associated with bipolar I disorder in pediatric patients 10-17 years of age were established in a randomized, double-blind, placebo-controlled trial of 8 weeks' duration in 255 patients who met the DSM-IV-TR criteria for bipolar I disorder, depressed episode.312,397 Patients randomized to receive olanzapine and fluoxetine were initially given 3 mg of olanzapine with 25 mg of fluoxetine and force-titrated to the maximum dosage of 12 mg of olanzapine with 50 mg of fluoxetine over 2 weeks; after 2 weeks, patients received flexible dosages of olanzapine 6-12 mg with fluoxetine 25-50 mg daily.312,397 At week 8, olanzapine in combination with fluoxetine was found to be substantially more effective than placebo in reducing the Children's Depression Rating Scale-Revised (CDRS-R) total score, which was the primary efficacy measure in this study.312,397 The average daily dosage was 7.7 mg of olanzapine and 37.6 mg of fluoxetine.312 The pediatric patients who received olanzapine in combination with fluoxetine had substantially greater weight gain and elevations in serum transaminases, serum lipids, and prolactin compared with those receiving placebo.312,397 The recommended initial dosage of the olanzapine/fluoxetine combination is lower in children and adolescents than in adults.312 In addition, the manufacturer states that flexible dosing is recommended in such patients instead of the forced-titration dosing initially used in this study.312 (See Bipolar Disorder under Dosage: Oral Dosage, in Dosage and Administration.)

Although there is no body of evidence available to determine how long adolescent patients with bipolar disorder treated with olanzapine should be maintained on the drug, the manufacturer states that such efficacy can be extrapolated from adult data in addition to comparisons of olanzapine pharmacokinetic parameters in adult and adolescent patients.1 If olanzapine is used for an extended period, the continued need for maintenance therapy should be reassessed periodically.1

Based on the observed efficacy and tolerability of mood stabilizers and atypical antipsychotic agents in clinical trials in adults and the available clinical experience in pediatric patients, the American Academy of Child and Adolescent Psychiatry (AACAP) currently states that mood stabilizers (e.g., lithium, valproic acid, carbamazepine) and atypical antipsychotics (e.g., olanzapine, aripiprazole, risperidone, quetiapine, ziprasidone) are among drugs of first choice in the acute management of pediatric patients with bipolar I disorder experiencing manic or mixed episodes with or without psychosis.253 Additional controlled studies are necessary to more clearly establish the efficacy and safety of atypical antipsychotics in pediatric patients with bipolar disorder, particularly during long-term therapy.253,254,370

Acute Agitation

Short-acting olanzapine injection (e.g., Zyprexa^® IntraMuscular) is used IM for the management of acute agitation in patients with bipolar I disorder for whom treatment with olanzapine is appropriate and who require an IM antipsychotic agent for rapid control of behaviors that interfere with their diagnosis and care (e.g., threatening behaviors, escalating or urgently distressing behavior, self-exhausting behavior).1,99 According to DSM-IV, psychomotor agitation is excessive motor activity associated with a feeling of inner tension.1,29

The efficacy of short-acting IM olanzapine for the management of acute agitation in adults with bipolar mania was established in a short-term (single-day), double-blind, placebo-controlled trial in agitated, hospitalized patients who met the DSM-IV criteria for bipolar I disorder and who displayed an acute manic or mixed episode with or without psychotic features.1,99 The patients in this study exhibited a level of agitation that met or exceeded a threshold score of 14 on the 5 items comprising the Positive and Negative Syndrome Scale (PANSS) Excited Component (i.e., poor impulse control, tension, hostility, uncooperativeness, and excitement items) with at least one individual item score of 4 (“moderate”) or greater using a 1-7 scoring system where scores of 1 or 7 indicate absent or extreme agitation, respectively.1,99 An active comparator treatment arm using IM lorazepam was included in this study.1,99 The primary measure used for assessing efficacy in managing agitation in this trial was the change from baseline in the PANSS Excited Component at 2 hours post-injection of a fixed, 10-mg IM dose of olanzapine.1,99 Patients in this study could receive up to 3 injections of IM olanzapine; however, patients could not receive the second injection until after the initial 2-hour period when the efficacy was assessed.1,99 IM olanzapine was found to be statistically superior to placebo in reducing the PANSS Excited Component score at 2 hours and at 24 hours following the initial injection.1,99 An analysis of this study as well as 2 additional controlled studies conducted in agitated patients with schizophrenia for possible age-, race-, or gender-related effects on treatment outcome did not suggest any difference in efficacy based on these patient characteristics.1,99,102

Treatment-resistant Depression

Oral olanzapine is used in combination with fluoxetine hydrochloride for the acute and maintenance therapy of treatment-resistant depression (i.e., major depressive disorder in patients who do not respond to 2 separate trials of different antidepressants of adequate dosage and duration in the current episode).1,312

The efficacy and safety of oral olanzapine in combination with fluoxetine for the acute treatment of treatment-resistant depression were demonstrated in 3 clinical studies conducted in 579 adults 18-85 years of age.312 Daily dosages evaluated in these studies ranged from 6-18 mg of olanzapine and 25-50 mg of fluoxetine.312 In the first study, efficacy of the fixed combination of olanzapine and fluoxetine (Symbyax^®) was evaluated in 300 patients who met DSM-IV criteria for major depressive disorder and did not respond to 2 different antidepressants after at least 6 weeks at or above the minimally effective labeled dosage in their current episode.312 Patients enrolled in this study entered an open-label fluoxetine lead-in phase in which the nonresponders were randomized to receive the fixed combination of olanzapine and fluoxetine, olanzapine alone, or fluoxetine alone for 8 weeks.312 The fixed combination of olanzapine and fluoxetine was flexibly dosed between 6-18 mg of olanzapine daily; all patients received 50 mg of fluoxetine daily.312 A substantially greater reduction in mean total MADRS scores from baseline to end point was observed in patients receiving olanzapine in fixed combination with fluoxetine compared with those receiving either fluoxetine or olanzapine alone.312 A second, smaller study with the same treatment-resistant depressed patient population also demonstrated a substantially greater reduction in MADRS scores in patients treated with the fixed combination compared with patients receiving fluoxetine or olanzapine monotherapy (when analyzed with change in MADRS score as the outcome measure).312 A third study demonstrated a substantially greater reduction in total MADRS scores in patients receiving the fixed combination of olanzapine and fluoxetine compared with those treated with fluoxetine or olanzapine alone, when data were analyzed in a subpopulation of 251 depressed patients who met the definition of treatment resistance (patients who had not responded to 2 antidepressants of adequate dosage and duration in the current episode).312

The efficacy of oral olanzapine in combination with fluoxetine in the maintenance therapy of treatment-resistant depression was demonstrated in a 47-week study in 892 adults (18-65 years of age) who met DSM-IV criteria for major depressive disorder and did not respond to 2 different antidepressants after at least 6 weeks at or above the minimally effective labeled dosage in their current episode.312 Daily dosages evaluated in these studies ranged from 6-18 mg of olanzapine and 25-50 mg of fluoxetine.312 Patients were initially treated with open-label olanzapine and fluoxetine in fixed combination (Symbyax^®).312 Patients who responded to and were stabilized on the fixed combination over approximately 20 weeks were randomized to continue receiving fixed-combination olanzapine and fluoxetine treatment or to receive fluoxetine alone for another 27 weeks.312 A total of 15.8% of patients receiving olanzapine and fluoxetine in fixed combination relapsed compared with 31.8% of patients receiving fluoxetine monotherapy; this difference was statistically significant.312 In addition, patients who continued to receive olanzapine and fluoxetine in fixed combination experienced a substantially longer time to relapse over the 27-week period compared with those receiving fluoxetine alone.312 If combined olanzapine and fluoxetine therapy is used for an extended period, the continued need for maintenance therapy should be reassessed periodically.312

The manufacturer states that olanzapine monotherapy is not indicated for the treatment of treatment-resistant depression.1

Cancer Chemotherapy-induced Nausea and Vomiting

Olanzapine has been used orally in combination with other antiemetic agents for the prevention of acute and delayed nausea and vomiting associated with highly emetogenic cancer chemotherapy†, including high-dose cisplatin therapy.425,426,427,428 The drug also has been used as rescue therapy in patients with breakthrough cancer chemotherapy-induced nausea and vomiting†.425,429

To prevent chemotherapy-induced nausea and vomiting associated with chemotherapy regimens with a high emetic risk (i.e., incidence of emesis exceeds 90% if no antiemetics are administered) in adults, the American Society of Clinical Oncology (ASCO) currently recommends a 4-drug antiemetic regimen consisting of a neurokinin 1 (NK₁) receptor antagonist (e.g., aprepitant, fosaprepitant, netupitant [in fixed combination with palonosetron], rolapitant), a type 3 serotonin (5-HT₃) receptor antagonist (e.g., dolasetron, granisetron, ondansetron, palonosetron, ramosetron [not commercially available in the US], tropisetron [not commercially available in the US]), dexamethasone, and olanzapine.425 If the fixed combination of netupitant and palonosetron is used as an NK₁ receptor antagonist, use of an additional 5-HT₃ receptor antagonist is not necessary.425 For adults receiving carboplatin with a target area under the plasma concentration-time curve (AUC) of 4 mg/mL per minute or more, ASCO recommends a 3-drug antiemetic regimen consisting of an NK₁ receptor antagonist, a 5-HT₃ receptor antagonist, and dexamethasone.425 For adults receiving other chemotherapy of moderate emetic risk (i.e., incidence of emesis without antiemetics exceeds 30% but does not exceed 90%), excluding carboplatin with a target AUC of 4 mg/mL per minute or more, ASCO recommends a 2-drug antiemetic regimen consisting of a 5-HT₃ receptor antagonist and dexamethasone.425 Because of the limited clinical experience with oral olanzapine in adults receiving moderately emetogenic chemotherapy,425,427 ASCO states that olanzapine is not recommended for routine prophylaxis in such patients.425 For adults receiving chemotherapy regimens with a low emetic risk (i.e., incidence of emesis without antiemetics exceeds 10% but does not exceed 30%), ASCO recommends a single dose of either a 5-HT₃ receptor antagonist or dexamethasone alone on the first day of chemotherapy.425 Routine antiemetic prophylaxis is not necessary in adults receiving chemotherapy with a minimal antiemetic risk (i.e., incidence of emesis is less than 10% without antiemetics).425

For patients with breakthrough chemotherapy-induced nausea or vomiting, ASCO recommends that clinicians reevaluate emetic risk, disease status, concomitant medical conditions, and concurrent medications and determine whether the best antiemetic regimen is being provided for the emetic risk.425 Adults who experience nausea and vomiting despite optimal antiemetic prophylaxis and who have not received olanzapine prophylactically should be offered olanzapine in addition to continuing the standard antiemetic regimen.425 Adults who experience nausea or vomiting despite optimal antiemetic prophylaxis and who have already received olanzapine may be offered a drug from a different class such as an NK₁ receptor antagonist, lorazepam or alprazolam, a dopamine receptor antagonist (e.g., metoclopramide), dronabinol, or nabilone in addition to continuing the standard antiemetic regimen.425

Clinical Experience

Efficacy of oral olanzapine for the prevention of nausea and vomiting associated with cancer chemotherapy was established in a randomized, double-blind, phase 3 study comparing olanzapine with placebo, in combination with an NK₁ receptor antagonist (either IV fosaprepitant or oral aprepitant), a 5-HT₃ receptor antagonist (e.g., oral or IV granisetron, oral or IV ondansetron, IV palonosetron), and oral dexamethasone, in 380 adults receiving highly emetogenic chemotherapy (cisplatin-containing regimens or anthracycline plus cyclophosphamide).426 Patients received olanzapine 10 mg or matching placebo orally once daily on days 1 through 4.426 The proportion of patients who experienced no chemotherapy-induced nausea was substantially higher with olanzapine than with placebo during the early assessment period (0-24 hours after chemotherapy; 74 versus 45%, respectively), the later assessment period (25-120 hours after chemotherapy; 42 versus 25%, respectively), and the overall period (0-120 hours after chemotherapy; 37 versus 22%, respectively).426 The proportion of patients with a complete response (no emetic episodes and no use of rescue medication) was also substantially higher in patients receiving olanzapine than in those receiving placebo in all 3 assessment periods (86 versus 65%, 67 versus 52%, and 64 versus 41% during the early, later, and overall assessment periods, respectively).426 Olanzapine was generally well tolerated and no serious adverse reactions to the drug were reported in this study; however, olanzapine-treated patients experienced more drowsiness on day 2 following chemotherapy than at baseline.426 The sedation generally resolved on days 3, 4, and 5 despite continued administration of olanzapine on days 3 and 4.426

Efficacy of antiemetic prophylactic regimens including oral olanzapine and antiemetic regimens not including olanzapine was compared in a meta-analysis of 10 randomized controlled trials in patients receiving either highly or moderately emetogenic chemotherapy.427 Six of these studies included patients receiving only highly emetogenic chemotherapy and 4 studies included patients receiving either highly emetogenic or moderately emetogenic chemotherapy.427 Antiemetic regimens containing olanzapine were found to be statistically superior in 5 of 6 end points and clinically superior in 4 of 6 end points compared with antiemetic regimens not containing olanzapine in this meta-analysis.427

In a randomized, multicenter, double-blind, phase 2, dose-finding study, efficacy and safety of 2 olanzapine dosage regimens (5 mg or 10 mg orally once daily on days 1 through 4) used in combination with standard antiemetic prophylaxis (e.g., aprepitant or fosaprepitant, palonosetron, and dexamethasone) for the prevention of nausea and vomiting associated with cancer chemotherapy were compared in 153 adults with malignant solid tumors who were receiving highly emetogenic chemotherapy with cisplatin.428 The primary end point in this study was complete response (no emesis and no use of rescue medications) in the delayed phase (24-120 hours after the start of cisplatin therapy).428 Both dosages of olanzapine produced a significant improvement in delayed emesis; complete response rates in the delayed phase were 85.7 and 77.6% in the 5- and 10-mg olanzapine dosage groups, respectively.428 Somnolence was the most commonly reported adverse effect in this study and occurred in 45.5 and 53.3% of patients in the 5- and 10-mg olanzapine dosage groups, respectively.428

Olanzapine has been shown to be an effective rescue antiemetic in patients who develop breakthrough chemotherapy-induced nausea and vomiting despite having received optimal antiemetic prophylaxis.425,429 In a randomized, double-blind, phase 3 study, efficacy and safety of orally administered olanzapine and metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting were compared in chemotherapy-naive adults receiving highly emetogenic chemotherapy (cisplatin or doxorubicin and cyclophosphamide) who did not receive antiemetic prophylaxis with olanzapine.429 All patients had initially received guideline-directed antiemetic prophylaxis with fosaprepitant, palonosetron, and dexamethasone.429 Of 276 enrolled patients, 112 developed breakthrough nausea and vomiting and were randomized to receive olanzapine (10 mg orally once daily for 3 days) or metoclopramide (10 mg orally 3 times daily for 3 days); 108 of these patients were evaluable.429 Patients were monitored for emesis and nausea for 72 hours after receiving olanzapine or metoclopramide.429 During the 72-hour observation period after the breakthrough nausea and vomiting occurred, 70% of the olanzapine-treated patients had no emesis compared with 31% of the metoclopramide-treated patients and 68% of the olanzapine-treated patients had no nausea compared with 23% of the metoclopramide-treated patients.429 Olanzapine was found to be significantly better than metoclopramide in controlling breakthrough nausea and vomiting in patients receiving highly emetogenic chemotherapy.429 No grade 3 or 4 toxicities occurred with either olanzapine or metoclopramide.429

Dosage and Administration ⬆ ⬇

[Section Outline]

Reconstitution and Administration
Dosage
Dosage in Renal and Hepatic Impairment

Reconstitution and Administration

Olanzapine is administered orally or by IM injection.1,312,382 Olanzapine pamoate is administered only by IM injection.382

Restricted Distribution

Because of the risk of post-injection delirium/sedation syndrome (PDSS), extended-release olanzapine pamoate injection is available only under a restricted distribution program, the Zyprexa^® Relprevv Patient Care Program.372,382 Zyprexa^® Relprevv must not be dispensed directly to a patient.372,382 For a patient to receive treatment, the prescriber, healthcare facility, patient, and pharmacy must all be enrolled in the Patient Care Program.372,382 Clinicians may contact 877-772-9390 for additional information and to enroll in the Zyprexa^® Relprevv Patient Care Program or consult the manufacturer's website ([Web]).372,382

Oral Administration

Olanzapine conventional tablets, orally disintegrating tablets, and capsules (in fixed combination with fluoxetine hydrochloride) are administered orally.1,312 Since food does not appear to affect GI absorption of olanzapine, the drug generally can be administered as conventional tablets or orally disintegrating tablets without regard to meals.1 In patients who experience persistent or troublesome daytime sedation during oral olanzapine therapy for psychiatric indications (e.g., psychotic disorders, bipolar disorder, treatment-resistant depression), administration of the daily dosage in the evening at bedtime may be helpful.26,259

Patients receiving olanzapine orally disintegrating tablets should be instructed not to remove a tablet from the blister until just prior to dosing.1 The tablet should not be pushed through the foil.1 With dry hands, the blister backing should be peeled completely off the blister.1 The tablet should then be gently removed and immediately placed on the tongue, where it rapidly disintegrates in saliva, and then subsequently swallowed with or without liquid.1

The fixed combination capsules of olanzapine with fluoxetine hydrochloride (e.g., Symbyax^®) are administered once daily in the evening.312 Although the manufacturer states that food has no appreciable effect on absorption of either drug when administered alone, absorption of the drugs when administered as the fixed combination with food has not been studied.312

Dispensing and Administration Precautions

Because of similarities in spelling, dosage intervals (once daily), and tablet strengths (5 and 10 mg) of Zyprexa^® (olanzapine) and Zyrtec^® (cetirizine hydrochloride, an antihistamine), extra care should be exercised in ensuring the accuracy of prescriptions for these drugs.97 (See Cautions: Precautions and Contraindications.)

IM Administration

Clinicians should be aware that there are 2 IM formulations of olanzapine with different indications and dosing schedules; the short-acting, immediate-release formulation (e.g., Zyprexa IntraMuscular®; 10 mg per vial) is used for agitation associated with schizophrenia and bipolar mania and should not be confused with Zyprexa® Relprevv, a long-acting formulation (available in 210-, 300-, and 405-mg vial strengths) used for the treatment of schizophrenia. 1,382

Short-acting Olanzapine Injection for Acute Agitation associated with Bipolar Disorder or Schizophrenia

Commercially available short-acting olanzapine for injection (e.g., Zyprexa^® IntraMuscular) must be reconstituted prior to administration by adding 2.1 mL of sterile water for injection to single-dose vials labeled as containing 10 mg of olanzapine to provide a solution containing approximately 5 mg/mL.1 Other solutions should not be used to reconstitute olanzapine for injection.1

Following reconstitution, olanzapine for injection should be used immediately (within 1 hour).1 If necessary, the reconstituted solution may be stored for up to 1 hour at 20-25°C; after 1 hour, any unused portion should be discarded.1 Olanzapine for injection should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.1

Olanzapine for injection is administered only by IM injection and should not be administered IV or subcutaneously.1 The drug should be injected slowly, deep into the muscle mass.1

Extended-release Olanzapine Pamoate Injection for Schizophrenia

The manufacturer states that tolerability with oral olanzapine therapy should be established prior to initiating IM therapy with extended-release olanzapine pamoate (Zyprexa^® Relprevv).382

Because of the risk of post-injection delirium/sedation syndrome (PDSS), Zyprexa^® Relprevv must be administered in a registered healthcare facility (e.g., hospital, clinic, residential treatment center, community healthcare center) with ready access to emergency response services.372,382 The medication guide should be provided to the patient or legal guardian prior to each injection.372,382 After each injection, patients should be continuously monitored at the healthcare facility for at least 3 hours by a healthcare professional.372,382 Patients should be alert, oriented, and absent of any signs and symptoms of PDSS prior to being released.372,382 All patients receiving an IM injection of olanzapine pamoate must be accompanied to their destination upon leaving the facility.372,382

Patients should not drive or operate heavy machinery for the remainder of the day following the injection.372,382 Patients should be advised to be vigilant for the symptoms of PDSS and to obtain medical assistance if needed.372,382 Close medical supervision and monitoring should be instituted in a facility capable of resuscitation if PDSS is suspected in any patient.372,382 (See Post-injection Delirium/Sedation Syndrome under Cautions: Nervous System Effects and also under Cautions: Precautions and Contraindications and see also Acute Toxicity.)

Extended-release olanzapine pamoate injection is administered only by deep IM injection into the gluteal area and should not be administered IV or subcutaneously.382 The injection should be administered by a healthcare professional every 2-4 weeks.382

Olanzapine pamoate is commercially available as the Zyprexa^® Relprevv Convenience Kit, which contains 2 single-use vials, needles, and a syrin one of the vials contains olanzapine pamoate powder for suspension and the other vial contains diluent.382 Olanzapine pamoate powder for suspension must be reconstituted using only the diluent provided in the convenience kit prior to IM administration; other diluents should not be substituted.382 Reconstitution and administration instructions included in the kit should be closely followed, and the suspension should be administered within 24 hours of mixing.382 Reconstituted olanzapine pamoate suspension remains stable for up to 24 hours in the vial.382 However, if the suspension is not used immediately, the vial should be shaken vigorously to resuspend the drug.382

The manufacturer recommends that gloves are used while reconstituting olanzapine pamoate powder for suspension since it may be irritating to the skin.382 If contact is made with skin, the affected area should be flushed with water.382

Following insertion of the needle into the gluteal muscle for the IM injection, the healthcare professional should aspirate for several seconds to ensure that no blood is drawn into the syringe.382 If blood appears in the syringe, the dose should not be injected; the needle should be withdrawn and the syringe and dose discarded.382 A new convenience kit should be used for the new dose of olanzapine pamoate with a new syringe and needle.382 Following IM administration, the injection site should not be massaged.382

Dosage

Olanzapine is commercially available as the base and as the pamoate salt; the dosage of olanzapine pamoate is expressed in terms of olanzapine.1,382

Conventional olanzapine tablets and orally disintegrating tablets of the drug are bioequivalent.1 However, IM administration of a 5-mg dose of the commercially available short-acting olanzapine injection results in a maximum plasma olanzapine concentration that is about fivefold higher than that resulting from a 5-mg oral dose of the drug.1

Dosage of olanzapine for psychiatric indications (e.g., psychotic disorders, bipolar disorder, treatment-resistant depression) must be adjusted carefully according to individual requirements and response, using the lowest possible effective dosage.1,20

Oral Dosage

Schizophrenia

For the management of schizophrenia in adults, the recommended initial oral dosage of olanzapine is 5-10 mg daily, usually given as a single daily dose.1,20,26 Dosage may be increased by 5 mg daily within several days, to a target dosage of 10 mg daily.1,20 Because steady-state plasma concentrations of olanzapine may not be attained for approximately 7 days at a given dosage, subsequent dosage adjustments generally should be made at intervals of not less than 7 days,1,20 usually in increments or decrements of 5 mg once daily.1

An initial adult olanzapine oral dosage of 5 mg daily is recommended in debilitated patients, in those predisposed to hypotension, in those who may be particularly sensitive to the effects of olanzapine, or in those who might metabolize olanzapine slowly (e.g., nonsmoking female patients who are 65 years of age or older).1,26 The manufacturers state that the presence of factors that might decrease the clearance or increase the pharmacodynamic response to olanzapine should lead to consideration of a lower initial dosage in all geriatric patients.1,389,390

While a relationship between dosage and antipsychotic effect has not been established, the effective oral dosage of olanzapine in clinical studies in adults generally ranged from 10-15 mg daily.1 The manufacturers state that increasing olanzapine dosages beyond 10 mg daily usually does not result in additional therapeutic effect and recommend that such increases generally should occur only after the patient's clinical status has been assessed.1,389,390 In addition, the manufacturers state that olanzapine is not indicated for use in dosages exceeding 20 mg daily.1,20,389,390 However, olanzapine occasionally has been used in controlled and uncontrolled trials and in individual patients in dosages of up to 40 mg daily; dosages of up to 60 mg daily have been used in some patients with treatment-resistant schizophrenia.26,105,219,220,221,224,287,290 It remains to be established whether higher dosages of the drug are safe and result in improved efficacy in such patients.26,219,220,221,224,287,290 Some clinicians state that olanzapine dosages of up to 30 mg daily may produce further clinical improvement in schizophrenia patients who did not respond adequately to dosages of up to 20 mg daily; however, they recommend that caution be exercised when dosage of the drug exceeds 40 mg daily because of the potential for serious adverse effects (e.g., extrapyramidal reactions, excitement, metabolic changes, weight gain, cardiovascular complications).287

For the management of schizophrenia in adolescents 13-17 years of age, the recommended initial oral dosage of olanzapine is 2.5 or 5 mg daily given as a single daily dose, and the recommended target dosage is 10 mg daily.1 When dosage adjustments are necessary, dosage increments or decrements of 2.5 or 5 mg daily are recommended.1 In clinical trials, efficacy of the drug in adolescents with schizophrenia was demonstrated based on a flexible dosage range of 2.5-20 mg daily, with a mean modal dosage of 12.5 mg daily (mean dosage of 11.1 mg daily).1,369 The manufacturer states that the safety and effectiveness of dosages exceeding 20 mg daily have not been evaluated in clinical trials.1

The optimum duration of olanzapine therapy currently is not known, but maintenance therapy with antipsychotic agents is well established.1,23,25,26,354 The effectiveness of oral olanzapine given in a daily dosage of 10-20 mg in maintaining treatment response in adult schizophrenic patients who had been stable on olanzapine for approximately 8 weeks and were then followed for relapse has been demonstrated in a placebo-controlled study.354,369 If olanzapine is used for an extended period in adults, the long-term usefulness of the drug for the individual patient should be reassessed periodically.1

Although there is no body of evidence available to determine how long adolescent patients treated with olanzapine should be maintained on the drug, the manufacturer states that such efficacy can be extrapolated from adult data in addition to comparisons of olanzapine pharmacokinetic parameters in adult and adolescent patients.1 Adolescent patients responding to olanzapine therapy should continue to receive the drug beyond the acute response, but at the lowest effective dosage, and the need for continued maintenance therapy with the drug should be reassessed periodically.1

The American Psychiatric Association (APA) states that prudent long-term treatment options in adult patients with schizophrenia with remitted first episodes or multiple episodes include either indefinite maintenance therapy or gradual discontinuance of the antipsychotic agent with close follow-up and a plan to reinstitute treatment upon symptom recurrence.26 Discontinuance of antipsychotic therapy should be considered only after a period of at least 1 year of symptom remission or optimal response while receiving the antipsychotic agent.26 In patients who have had multiple previous psychotic episodes or 2 psychotic episodes within 5 years, indefinite maintenance antipsychotic treatment is recommended.26

Bipolar Disorder

As monotherapy for the management of acute manic or mixed episodes associated with bipolar I disorder in adults, the usual initial oral dosage of olanzapine is 10 or 15 mg daily, given as a single dose.1 When dosage adjustments are necessary, the manufacturer recommends that dosage increments or decrements of 5 mg daily be made at intervals of not less than 24 hours, reflecting the procedures in the placebo-controlled trials.1 The effective dosage of olanzapine in short-term clinical studies generally has ranged from 5-20 mg daily.1,36,37,41,244,245,247,250,252 Safety of dosages exceeding 20 mg daily has not been established.1

As monotherapy for the management of acute manic or mixed episodes associated with bipolar I disorder in adolescents 13-17 years of age, the recommended initial oral dosage of olanzapine is 2.5 or 5 mg daily, given as a single dose, with a target dosage of 10 mg daily.1 When dosage adjustments are necessary, the manufacturer recommends dosage increments or decrements of 2.5 or 5 mg daily.1 In short-term clinical trials, efficacy was demonstrated in a dosage range of 2.5-20 mg daily, with a mean modal dosage of 10.7 mg daily (average dosage of 8.9 mg daily).1,370 The manufacturer states that the safety and effectiveness of dosages exceeding 20 mg daily have not been evaluated in clinical trials.1

When administered in conjunction with lithium or valproate for the management of acute manic or mixed episodes associated with bipolar I disorder in adults, the recommended initial oral dosage of olanzapine is 10 mg once daily.1,41 The effective dosage of olanzapine as adjunctive therapy for up to 6 weeks in clinical studies generally ranged from 5-20 mg daily.1,41 Safety of dosages exceeding 20 mg daily has not been established in clinical trials.1

When used in fixed combination with fluoxetine hydrochloride (e.g., as the fixed combination Symbyax^®) for acute depressive episodes in adults with bipolar disorder, olanzapine is administered once daily in the evening, usually initiating therapy with a dosage of 6 mg of olanzapine and 25 mg of fluoxetine.312 An initial dosage of 3 or 6 mg of olanzapine in fixed combination with 25 mg of fluoxetine should be used in patients with a predisposition to hypotensive reactions, patients with hepatic impairment, or those with factors that may slow metabolism of the drugs(s) (e.g., female gender, geriatric age, nonsmoking status); when indicated, dosage should be escalated with caution.312 In other patients, dosage can be increased according to patient response and tolerance as indicated.312 In clinical trials in adults, antidepressant efficacy was demonstrated at olanzapine dosages ranging from 6-12 mg daily and fluoxetine dosages ranging from 25-50 mg daily.1,312,313,314 Dosages exceeding 18 mg of olanzapine and 75 mg of fluoxetine daily have not been evaluated in clinical studies.1,312

When used in conjunction with fluoxetine (as individual components of olanzapine and fluoxetine hydrochloride rather than the fixed-combination preparation) for acute depressive episodes in adults with bipolar disorder, olanzapine is administered once daily in the evening, usually initiating therapy with a dosage of 5 mg of olanzapine and 20 mg of fluoxetine.1 Dosage adjustments, if indicated, may be made based on efficacy and tolerability within the dosage ranges of olanzapine 5-12.5 mg daily and fluoxetine 20-50 mg daily.1 An initial dosage of 2.5-5 mg of olanzapine and 20 mg of fluoxetine should be used in patients with a predisposition to hypotensive reactions, patients with hepatic impairment, those with factors that may slow metabolism of the drugs(s) (e.g., female gender, geriatric age, nonsmoking status), or those who may be pharmacodynamically sensitive to olanzapine; when indicated, dosage adjustments should be made with caution in these patients.1 Dosages exceeding 18 mg of olanzapine and 75 mg of fluoxetine daily have not been evaluated in clinical studies.1,312

The safety and efficacy of olanzapine and fluoxetine in combination (given as the individual components) were determined in clinical trials that supported the approval of Symbyax^® (the fixed combination of olanzapine and fluoxetine).1 Dosage of the fixed-combination preparation ranges from olanzapine 3-12 mg and fluoxetine 25-50 mg daily.1 The following table provides the appropriate individual component dosages of olanzapine and fluoxetine compared with the fixed-combination preparation.1 If dosage adjustments are indicated, they should be made with the individual components according to efficacy and tolerability.1

Table 1. Approximate Dosage Correspondence between Olanzapine in Fixed Combination with Fluoxetine (e.g., Symbyax^®) and Combined Olanzapine (e.g., Zyprexa^®) and Fluoxetine Therapy (Given Individually).1

For fixed-combination dosages of:	Use in combination:
	Olanzapine (mg/day)	Fluoxetine (mg/day)
3 mg olanzapine/25 mg fluoxetine	2.5	20
6 mg olanzapine/25 mg fluoxetine	5	20
12 mg olanzapine/25 mg fluoxetine	10 + 2.5	20
6 mg olanzapine/50 mg fluoxetine	5	40 + 10
12 mg olanzapine/50 mg fluoxetine	10 + 2.5	40 + 10

When used in fixed combination with fluoxetine hydrochloride (e.g., as the fixed combination Symbyax^®) for acute depressive episodes in children and adolescents 10-17 years of age with bipolar disorder, olanzapine is administered once daily in the evening, usually initiating therapy with a dosage of 3 mg of olanzapine and 25 mg of fluoxetine.312 Dosage can then be adjusted to a target dosage within the FDA-labeled dosage range of olanzapine 6-12 mg daily and fluoxetine 25-50 mg daily.1,312 Concurrent administration of dosages exceeding 12 mg of olanzapine and 50 mg of fluoxetine daily has not been evaluated in pediatric clinical studies.1,312

When used in conjunction with fluoxetine hydrochloride (as individual components of olanzapine and fluoxetine rather than the fixed-combination preparation) for acute depressive episodes in children and adolescents 10-17 years of age with bipolar disorder, olanzapine is administered once daily in the evening, usually initiating therapy with a dosage of 2.5 mg of olanzapine and 20 mg of fluoxetine.1 Dosage adjustments, if indicated, may be made based on efficacy and tolerability.1 Concurrent administration of dosages exceeding 12 mg of olanzapine and 50 mg of fluoxetine daily has not been evaluated in pediatric clinical studies.1,312

The long-term efficacy of oral olanzapine (dosage range: 5-20 mg daily) for maintenance monotherapy in adults with bipolar disorder has been demonstrated in a double-blind, placebo-controlled trial of 52 weeks' duration and in comparative studies of 47-52 weeks' duration.1,100,244,245,247,250 The mean modal dosage of olanzapine in the placebo-controlled study was 12.5 mg daily.244 The manufacturer states that patients receiving oral olanzapine for extended periods should be reassessed periodically to determine the need for continued therapy.1

Although the efficacy of oral olanzapine for maintenance treatment of adolescents with bipolar disorder has not been evaluated, the manufacturer states that such efficacy can be extrapolated from adult data in addition to comparisons of olanzapine pharmacokinetic parameters in adult and adolescent patients.1 If olanzapine is used for an extended period, the need for maintenance therapy should be reassessed periodically.1

Although the manufacturer states that efficacy of the fixed combination of olanzapine and fluoxetine beyond 8 weeks' duration remains to be established, patients have received the fixed combination for up to 24 weeks in clinical trials.312,313,314 Clinicians who elect to use the fixed combination for extended periods should periodically reevaluate the long-term risks and benefits of the drug for the individual patient.312

Treatment-resistant Depression

When used in fixed combination with fluoxetine hydrochloride (e.g., as the fixed combination Symbyax^®) for the acute and maintenance treatment of treatment-resistant depression in adults, olanzapine is administered once daily in the evening, usually initiating therapy with a dosage of 6 mg of olanzapine and 25 mg of fluoxetine.312 An initial dosage of 3 or 6 mg of olanzapine in fixed combination with 25 mg of fluoxetine should be used in patients with a predisposition to hypotensive reactions, patients with hepatic impairment, or those with factors that may slow metabolism of the drugs(s) (e.g., female gender, geriatric age, nonsmoking status); when indicated, dosage should be escalated with caution.312 In other patients, dosage can be increased according to patient response and tolerance as indicated.312 In clinical trials in adults, antidepressant efficacy was demonstrated at olanzapine dosages ranging from 6-18 mg daily and fluoxetine dosages ranging from 25-50 mg daily.1,312,313,314 Dosages exceeding 18 mg of olanzapine and 75 mg of fluoxetine daily have not been evaluated in clinical studies.1,312 Clinicians who elect to use the fixed combination for extended periods should periodically reevaluate the long-term risks and benefits of the drug for the individual patient.312

When used in conjunction with fluoxetine hydrochloride (as individual components of olanzapine and fluoxetine rather than the fixed-combination preparation) for the acute and maintenance treatment of treatment-resistant depression in adults, olanzapine is administered once daily in the evening, usually initiating therapy with a dosage of 5 mg of olanzapine and 20 mg of fluoxetine.1 Dosage adjustments, if indicated, may be made based on efficacy and tolerability within the dosage ranges of olanzapine 5-20 mg and fluoxetine 20-50 mg daily.1 An initial dosage of 2.5-5 mg of olanzapine and 20 mg of fluoxetine should be used in patients with a predisposition to hypotensive reactions, patients with hepatic impairment, those with factors that may slow metabolism of the drugs(s) (e.g., female gender, geriatric age, nonsmoking status), or those who may be pharmacodynamically sensitive to olanzapine; when indicated, dosage adjustment should be made with caution in these patients.1 Dosages exceeding 18 mg of olanzapine and 75 mg of fluoxetine daily have not been evaluated in clinical studies.1,312 Clinicians who elect to use the combination for extended periods should periodically reevaluate the long-term risks and benefits of the drug for the individual patient.1

The safety and efficacy of olanzapine and fluoxetine in combination (given as the individual components) were determined in clinical trials that supported the approval of Symbyax^® (the fixed combination of olanzapine and fluoxetine).1 Dosage of the fixed-combination preparation ranges from olanzapine 3-12 mg and fluoxetine 25-50 mg daily.1 Table 1 provides the appropriate individual component dosages of olanzapine and fluoxetine compared with the fixed-combination preparation.1 If dosage adjustments are indicated, they should be made with the individual components according to efficacy and tolerability.1

Cancer Chemotherapy-induced Nausea and Vomiting

For the prevention of acute and delayed nausea and vomiting associated with highly emetogenic cancer chemotherapy† in adults, the American Society of Clinical Oncology (ASCO) currently recommends an oral olanzapine dosage of 10 mg once daily on the first day of chemotherapy (day 1) and then 10 mg once daily on days 2-4 of chemotherapy.425,426 Olanzapine usually has been administered as part of a 4-drug combination antiemetic regimen that includes a neurokinin 1 (NK₁) receptor antagonist, a 5-HT₃ receptor antagonist, and dexamethasone.425,426 This is the same dosage regimen that was used in the pivotal clinical study evaluating olanzapine as an antiemetic in patients receiving highly emetogenic chemotherapy.425,426 There is some evidence that 5-mg once-daily doses of olanzapine may be as effective as 10-mg once-daily doses in preventing chemotherapy-induced nausea and vomiting and reduce the risk of sedation observed with 10-mg once-daily doses; additional controlled studies are needed to determine the optimal dosing of olanzapine in prophylactic antiemetic regimens.425,426,428

For the treatment of breakthrough nausea and vomiting† despite optimal antiemetic prophylaxis in adults receiving cancer chemotherapy, olanzapine has been given orally in a dosage of 10 mg orally once daily for 3 days in a pivotal clinical study.429 (See Uses: Cancer Chemotherapy-induced Nausea and Vomiting.)

IM Dosage

Immediate-release Olanzapine Injection for Acute Agitation associated with Bipolar Disorder or Schizophrenia

For the prompt control of acute agitation in patients with schizophrenia or bipolar mania, the recommended initial adult IM dose of olanzapine injection (e.g., Zyprexa^® IntraMuscular) is 10 mg given as a single dose.1,103 A lower initial IM dose (2.5, 5, or 7.5 mg) may be considered when clinically warranted.1 In clinical trials, the efficacy of IM olanzapine for controlling agitation in patients with schizophrenia or bipolar mania has been demonstrated in a dosage range of 2.5-10 mg.1,98,99,102

If agitation necessitating additional IM doses of olanzapine persists following the initial dose, subsequent single doses of up to 10 mg may be given.1,103 However, the manufacturer states that the efficacy of repeated doses of IM olanzapine in agitated patients has not been systematically evaluated in controlled clinical trials.1 In addition, the safety of IM dosages exceeding 30 mg daily or of 10-mg IM doses given more frequently than 2 hours after the initial dose and 4 hours after the second dose has not been evaluated in clinical trials.1

Maximal dosing of IM olanzapine (e.g., 3 doses of 10 mg administered 2-4 hours apart) may be associated with a substantial risk of clinically important orthostatic hypotension.1 Patients who experience drowsiness or dizziness after the IM injection should remain recumbent until an examination indicates that they are not experiencing orthostatic hypotension, bradycardia, and/or hypoventilation.1 (See Orthostatic Hypotension under Cautions: Precautions and Contraindications.)

If ongoing olanzapine therapy is clinically indicated, the manufacturer states that oral olanzapine may be initiated in a dosage range of 5-20 mg daily as soon as clinically appropriate.1 In one controlled study evaluating IM olanzapine in acutely agitated patients, patients initially received 1-3 IM injections of olanzapine 10 mg and were then switched to oral olanzapine therapy in dosages ranging from 5-20 mg daily for a period of 4 days.103

A lower initial IM olanzapine dose of 5 mg may be considered for geriatric patients or when other clinical factors warrant.1 In addition, a lower IM dose of 2.5 mg per injection should be considered for patients who are debilitated, who may be predisposed to hypotensive reactions, or who may be more sensitive to the pharmacodynamic effects of olanzapine.1

Extended-release Olanzapine Pamoate Injectable Suspension for Schizophrenia

The manufacturer recommends that patients first receive oral olanzapine to establish tolerability of the drug before the extended-release olanzapine pamoate injection is used IM.382

The clinical efficacy of extended-release olanzapine pamoate injectable suspension (Zyprexa^® Relprevv) in adults has been demonstrated within the dosage range of 150-300 mg administered every 2 weeks and with 405 mg administered every 4 weeks.382,383,385

For the management of schizophrenia in patients established on oral olanzapine 10 mg daily , the recommended initial IM dosage of extended-release olanzapine pamoate is 210 mg administered every 2 weeks or 405 mg administered every 4 weeks during the first 8 weeks of therapy.382 Following the initial 8 weeks, the recommended maintenance dosage of olanzapine pamoate is 150 mg given every 2 weeks or 300 mg given every 4 weeks.382

In patients established on oral olanzapine 15 mg daily , the recommended initial IM dosage of extended-release olanzapine pamoate is 300 mg administered every 2 weeks for the first 8 weeks of therapy.382 Following the initial 8 weeks, the recommended maintenance dosage of olanzapine pamoate is 210 mg given every 2 weeks or 405 mg given every 4 weeks.382

In patients established on oral olanzapine 20 mg daily , the recommended initial and maintenance IM dosage of extended-release olanzapine pamoate is 300 mg administered every 2 weeks.382

The manufacturer states that extended-release olanzapine pamoate IM dosages exceeding 405 mg every 4 weeks or 300 mg every 2 weeks have not been evaluated in clinical trials.382

A lower initial IM olanzapine pamoate dosage of 150 mg every 4 weeks is recommended in patients who are debilitated, who may be predisposed to hypotensive reactions, who exhibit a combination of factors that may result in slower metabolism of olanzapine (e.g., nonsmoking female patients 65 years of age or older), or who may be more sensitive to the pharmacodynamic effects of the drug.382

Although no controlled studies have been conducted to determine the optimum duration of extended-release olanzapine pamoate therapy in patients with stabilized schizophrenia, the long-term efficacy of the drug has been demonstrated over a 24-week period.382,383 In addition, long-term use of oral olanzapine has been shown to be effective in maintaining treatment response in patients with schizophrenia.354,382 If olanzapine pamoate is used for an extended period, the need for continued treatment should be reassessed periodically.382

The manufacturer states that there are no systematically collected data to specifically address how to switch patients with schizophrenia receiving other antipsychotic agents to extended-release IM olanzapine pamoate therapy.382

Dosage in Renal and Hepatic Impairment

The manufacturer states that because only minimal amounts of olanzapine (about 7%) are excreted in urine and because the pharmacokinetics of olanzapine appear not to be altered in patients with renal or hepatic impairment, dosage adjustment is not necessary in such patients.1

The manufacturer states that the extended-release IM formulation of olanzapine pamoate (Zyprexa^® Relprevv) has not been specifically studied in patients with renal and/or hepatic impairment.382

Cautions ⬆ ⬇

[Section Outline]

Adverse Effects
Precautions and Contraindications
Pediatric Precautions
Geriatric Precautions
Mutagenicity and Carcinogenicity
Pregnancy, Fertility, and Lactation

Adverse Effects

The adverse effect profile of olanzapine generally is similar to that of other atypical (second-generation) antipsychotic agents (e.g., aripiprazole, clozapine, quetiapine, risperidone, ziprasidone).26,211,215,283 Although olanzapine differs chemically from the phenothiazines, the drug also may be capable of producing many of the toxic manifestations of phenothiazine derivatives. 26,211,215,283 (See Cautions in the Phenothiazines General Statement 28:16.08.24.) Not all adverse effects of the phenothiazines have been reported with olanzapine, but the possibility that they may occur should be considered.26,211,215,283 Adverse effects of olanzapine, other atypical antipsychotics, and the phenothiazines are numerous and may involve nearly all body organ systems.1,26,211,215,283

In controlled studies in adults, the most common adverse effects occurring more frequently in patients receiving oral olanzapine for schizophrenia or bipolar mania than in those receiving placebo included central and autonomic nervous system effects such as somnolence, asthenia, dry mouth, dizziness, tremor, personality disorder, and akathisia; cardiovascular system effects such as postural hypotension; GI effects such as constipation, dyspepsia, and increased appetite; and weight gain.1,36,247,283 There was no clear relationship between the incidence of adverse events and dosage in patients receiving oral olanzapine for schizophrenia in placebo-controlled trials except for certain extrapyramidal symptoms, asthenia or fatigue, dry mouth, nausea, somnolence, tremor, weight gain, and elevated prolactin concentrations.1 Discontinuance of olanzapine therapy was required in 5% of adult patients with schizophrenia compared with 6% for placebo in controlled trials; however, discontinuance because of increased serum ALT (SGPT) concentrations was required in 2% of the olanzapine-treated patients compared with none of those receiving placebo, and this adverse effect was considered to be drug related.1 Similar between olanzapine and placebo discontinuance rates were observed in the controlled trials for oral olanzapine for bipolar mania (2% for olanzapine and 2% for placebo) and IM olanzapine for acute agitation (0.4% for IM olanzapine and 0% for placebo).1

Adverse effects occurring in 5% or more of adult patients with schizophrenia receiving oral olanzapine in short-term clinical studies and with an incidence of at least twice that of placebo included dizziness (11%),1 constipation (9%),1 personality disorder (i.e., nonaggressive objectionable behavior; 8%),1 weight gain (6%),1 postural hypotension (5%),1 and akathisia (5%).1

Adverse effects occurring in 6% or more of adult patients with acute mania associated with bipolar disorder receiving oral olanzapine in clinical studies and with an incidence of at least twice that of placebo included somnolence (35%),1 dry mouth (22%),1,247 dizziness (18%),1 asthenia (15%),1 constipation (11%),1,247 dyspepsia (11%),1 increased appetite (6%),1 and tremor (6%).1

When oral olanzapine was used in conjunction with lithium or divalproex sodium for treatment of acute mania associated with bipolar disorder in adults, adverse effects occurring in 5% or more of patients in clinical studies and with an incidence of at least twice that of placebo included dry mouth (32%),1 weight gain (26%),1 increased appetite (24%),1 dizziness (14%),1 back pain (8%),1 constipation (8%),1 speech disorder (7%),1 increased salivation (6%),1 amnesia (5%),1 and paresthesia (5%).1

Adverse effects occurring in 5% or more of adolescents (13-17 years of age) with schizophrenia or bipolar disorder receiving oral olanzapine in short-term, placebo-controlled clinical studies and with an incidence of at least twice that of placebo included sedation (39-48%),1 weight gain (29-31%),1 headache (17%),1 increased appetite (17-29%),1 dizziness (7-8%),1 abdominal pain (6%),1 pain in extremities (5-6%),1 fatigue (3-14%),1 and dry mouth (4-7%).1

When short-acting IM olanzapine was used for the management of acute agitation in short-term clinical studies, somnolence was the only adverse effect that occurred in 5% or more of patients with schizophrenia or bipolar mania and with an incidence at least twice that of placebo (6% and 3%, respectively).1

When extended-release olanzapine pamoate injection was used IM in adults with schizophrenia in a short-term, placebo-controlled clinical study, adverse effects occurring in 5% or more of patients and more frequently than with placebo included headache (13-18%),382,385 sedation (8-13%),382,385 weight gain (5-7%),382,385 cough (3-9%),382,385 diarrhea (2-7%),382,385 back pain (3-5%),382,385 nausea (4-5%),382,385 somnolence (1-6%),382,383,385 dry mouth (2-6%),382,385 nasopharyngitis (1-6%),382,385 increased appetite (1-6%),382,385 and vomiting (1-6%).382,385

Nervous System Effects

Seizures

Seizures occurred in about 0.9% of adult patients receiving oral olanzapine in controlled clinical trials during premarketing testing.1 During premarketing testing of extended-release olanzapine pamoate IM injection, seizures occurred in 0.15% of adult patients.382 Confounding factors that may have contributed to the occurrence of seizures were present in many of these cases.1,382

Myoclonic status reportedly occurred shortly after initiation of olanzapine in one patient with probable dementia of the Alzheimer's type (Alzheimer's disease) who was concurrently receiving citalopram and donepezil; the myoclonic jerks in this patient coincided with EEG changes indicative of seizure activity (spikes and polyspike/wave complexes), and the seizures subsided following discontinuance of olanzapine.171 A new-onset seizure also reportedly occurred in an adult female patient upon the addition of quetiapine to maintenance therapy with olanzapine and following discontinuance of clonazepam therapy.172 In addition, an apparent lowering of seizure threshold occurred in at least 2 epileptic patients who experienced increased seizure activity following initiation of olanzapine therapy that resolved upon discontinuance of the drug.174,175 Fatal status epilepticus also has been reported in a patient who had been receiving olanzapine therapy for 5 months.173

Olanzapine should be administered with caution to patients with a history of seizures or conditions known to lower the seizure threshold (e.g., dementia of the Alzheimer's type); conditions that lower the seizure threshold may be more prevalent in patients 65 years of age or older.1,20,24,171,172,174,175,315,382

Extrapyramidal Reactions

Like other atypical antipsychotic agents, olanzapine has a low potential for causing certain adverse extrapyramidal effects (e.g., dystonias).1,26,215,283 Results from controlled clinical trials suggest that extrapyramidal reactions associated with olanzapine therapy are dose related.1

Tremor1 was reported in about 4% of patients receiving oral olanzapine and in about 1% of patients receiving short-acting IM olanzapine in controlled clinical trials; the incidence of tremor appears to be dose related.1 In addition, akathisia1 occurred in about 3% of patients receiving oral olanzapine and in less than 1% of patients receiving short-acting IM olanzapine; hypertonia1 occurred in about 3% of patients receiving oral olanzapine in short-term controlled clinical trials.1 Oculogyric crisis also has been reported in a patient receiving olanzapine, lithium, and paroxetine concurrently.348 (See Drug Interactions: Other CNS-Active Agents and Alcohol.)

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal symptom complex, has been reported in patients receiving antipsychotic agents, including olanzapine.1,26,176,177,178,179,180,181,182,183,184,185,186,201,315,382 Clinical manifestations of NMS generally include hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac arrhythmias).1,26,176,177,178,179,183,184,185,186,201,382 Additional signs of NMS may include increased serum creatine kinase (CK, creatine phosphokinase, CPK), myoglobinuria (rhabdomyolysis), and acute renal failure.1,26,176,177,178,183,184,185,201 NMS attributable to olanzapine therapy alone has been reported in some patients,176,177,178,179,180,182,184,201 and there also have been reports of NMS in olanzapine-treated patients concomitantly receiving other drugs, including antipsychotic agents,177,201 antidepressants,201 lithium,201 or valproate.185 Extrapyramidal reactions were present in approximately two-thirds of the olanzapine-treated patients diagnosed with NMS.201 Atypical presentations of NMS (e.g., absence of or lessened rigidity, presenting as fever of unknown origin) and less severe presentations of NMS also have been reported in some patients receiving olanzapine or other atypical antipsychotic agents.26,179,180,181,182,201

The diagnostic evaluation of patients with NMS is complicated.1,26,179,181,382 In arriving at a diagnosis, serious medical illnesses (e.g., pneumonia, systemic infection) and untreated or inadequately treated extrapyramidal signs and symptoms must be excluded.1,382 In addition, clinical features of NMS and serotonin syndrome sometimes overlap, and it has been suggested that these 2 syndromes may share certain underlying pathophysiologic mechanisms.181 Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary CNS pathology.1,382

The management of NMS should include immediate discontinuance of antipsychotic agents and other drugs not considered essential to concurrent therapy, intensive symptomatic treatment and medical monitoring, and treatment of any concomitant serious medical problems for which specific treatments are available.1,26,177,179,181,183,186,382 There currently is no specific drug therapy for NMS,1,382 although dantrolene, bromocriptine, amantadine, and benzodiazepines have been used in a limited number of patients.26,179,186,201,234 If a patient requires antipsychotic therapy following recovery from NMS, the potential reintroduction of drug therapy after several weeks should be carefully considered.1,26,178,179,185,382 If antipsychotic therapy is reintroduced, the dosage generally should be increased gradually and an antipsychotic agent other than the agent believed to have precipitated NMS generally is chosen.26 In addition, tolerability with oral olanzapine should be established prior to initiating treatment with extended-release IM olanzapine pamoate.382 Such patients should be carefully monitored since recurrences of NMS have been reported in some patients.1,178,179,185,201,382 For additional information on NMS, see Neuroleptic Malignant Syndrome under Cautions: Nervous System Effects, in the Phenothiazines General Statement 28:16.08.24.

Tardive Dyskinesia

Use of antipsychotic agents may be associated with tardive dyskinesia, a syndrome of potentially irreversible, involuntary, dyskinetic movements.1,26,210,211,212,213,218,315,316 Although the incidence of tardive dyskinesia appears to be highest among geriatric individuals, particularly geriatric females, it is not possible to reliably predict at the beginning of antipsychotic therapy which patients are likely to develop this syndrome.1,26,211,212 Tardive dyskinesia1,211,212,218,316 has been reported in less than 1% of patients receiving olanzapine therapy.1,211,218,222,316 Although the manufacturer states that it is not yet known whether antipsychotic agents differ in their potential to cause tardive dyskinesia,1 available evidence suggests that the risk appears to be substantially less with second-generation antipsychotic agents, including olanzapine, than with conventional, first-generation antipsychotic agents.26,209,210,211,213,215,216,217,218,222,316 Analyses from controlled, long-term trials have found an approximately 12-fold lower risk of tardive dyskinesia with olanzapine therapy compared with haloperidol therapy.26,218,222 In addition, stabilization of or improvement in tardive dyskinesia associated with conventional antipsychotic agents has been reported in some patients when they have been switched to second-generation antipsychotic therapy, including olanzapine.210,211,213,214,216,217 However, a transient increase in dyskinetic movements (sometimes referred to as withdrawal-emergent dyskinesia) occasionally may occur when a patient is switched from a first-generation to a second-generation antipsychotic agent or upon dosage reduction of an antipsychotic agent.26

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase.1,26,211 However, the syndrome can develop, although much less commonly, following relatively brief treatment periods at low dosages or may even arise after discontinuance of treatment.1

Management of tardive dyskinesia generally consists of gradual discontinuance of the precipitating antipsychotic agent when possible, reducing the dosage of the first-generation (conventional) antipsychotic agent or switching to a second-generation (atypical) antipsychotic agent, or switching to clozapine therapy.26,417,418,419,420 The syndrome may remit, partially or completely, if antipsychotic therapy is discontinued.1,26,234 However, antipsychotic therapy itself may suppress or partially suppress the signs and symptoms of the syndrome and thereby may possibly mask the underlying process.1 The effect that such symptomatic suppression has upon the long-term course of tardive dyskinesia is unknown.1 Vesicular monoamine transporter 2 (VMAT2) inhibitors (e.g., deutetrabenazine, valbenazine tosylate) have been shown to be effective in reducing symptoms of tardive dyskinesia in controlled clinical studies and may allow some patients to continue receiving antipsychotic therapy.417,418,419,420,421,422,423,424 (See Deutetrabenazine 28:56 and Valbenazine Tosylate 28:56.) There also is some evidence that vitamin E administration may reduce the risk of development of tardive dyskinesia; therefore, the American Psychiatric Association (APA) currently states that patients receiving antipsychotic agents may be advised to take 400-800 units of vitamin E daily for prophylaxis.26 (See Cautions in Vitamin E 88:20.)

Olanzapine should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia.1 Chronic antipsychotic treatment generally should be reserved for patients who suffer from a chronic illness that is known to respond to antipsychotic agents, and for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate.1 In patients who do require chronic treatment, the smallest dosage and the shortest duration of treatment producing a satisfactory clinical response should be sought, and the need for continued treatment should be reassessed periodically.1,26

The APA currently recommends that all patients receiving second-generation antipsychotic agents be assessed clinically for abnormal involuntary movements every 12 months and that patients considered to be at increased risk for tardive dyskinesia be assessed every 6 months.26 If signs and symptoms of tardive dyskinesia appear in a patient receiving olanzapine, drug discontinuance or a reduction in dosage should be considered.1,234 However, some patients may require treatment with olanzapine or another antipsychotic agent despite the presence of the syndrome.1,216

For additional information on tardive dyskinesia, including manifestations and treatment, see Tardive Dyskinesia under Cautions: Nervous System Effects, in the Phenothiazines General Statement 28:16.08.24.

Post-injection Delirium/Sedation Syndrome

During premarketing studies of extended-release olanzapine pamoate (Zyprexa^® Relprevv), adverse events that presented with signs and symptoms consistent with olanzapine overdosage, particularly sedation (ranging from mild in severity to coma) and/or delirium, were reported following injection of the drug.372,382,383,386,387,392 Such cases of post-injection delirium/sedation syndrome (PDSS) occurred in less than 0.1% of injections382,386,387 and in approximately 2% of patients who received injections for up to 46 months.382 These events were correlated with an unintentional rapid increase in serum olanzapine concentrations to supratherapeutic ranges in some cases.382,387 Although a rapid and greater than expected increase in serum olanzapine concentrations has been noted in some patients with these adverse events, the precise mechanism by which the drug was unintentionally introduced into the bloodstream in these cases is not known.382

Clinical signs and symptoms of PDSS include dizziness, confusion, disorientation, malaise, slurred speech, altered gait, ambulation difficulties, weakness, agitation, extrapyramidal symptoms, hypertension, convulsions, and reduced levels of consciousness ranging from mild sedation to coma.382,383,386 The time after injection to PDSS in most reported cases ranged from soon after the injection to greater than 3 hours after the injection; patients had largely recovered by 72 hours.382,383,386 Because the risk of PDSS is the same at each injection, the risk per patient is cumulative (i.e., the risk increases with the number of injections).382,384 (See Post-injection Delirium/Sedation Syndrome under Cautions: Precautions and Contraindications and see also Acute Toxicity.)

Other Nervous System Effects

Somnolence or sedation,1,26,36,163,247 which usually appears to be moderate in severity compared with other antipsychotic agents and dose related, is among the most common adverse effects of olanzapine, occurring in approximately 29% of adults and 44% of adolescents receiving oral olanzapine in controlled clinical trials.1,26,36,215,283 In addition, sedation-related adverse events (defined as hypersomnia, lethargy, sedation, and somnolence) occurred more often in adolescents compared with adults.371 Sedation occurred in 8% of patients receiving extended-release olanzapine pamoate injection, and somnolence and sedation resulted in discontinuance of the drug in 0.6% of patients in the premarketing database.382 Somnolence associated with olanzapine and other antipsychotic agents generally is most pronounced during early therapy, since most patients develop some tolerance to the sedating effects with continued administration.26 Although sedation can have therapeutic benefits in some cases, persistent daytime drowsiness and increased sleep time can become troublesome in some patients and necessitate a lower dosage or evening administration of oral olanzapine.26,259 (See Reconstitution and Administration under Dosage and Administration, Cognitive and Motor Impairment under Cautions: Precautions and Contraindications, and see also Effects on Sleep under Pharmacology: Nervous System Effects.)

Insomnia1 occurred in about 12%, dizziness1 in about 11%, asthenia1,247 in about 10%, and abnormal gait1 in about 6% of adult patients receiving oral olanzapine in short-term controlled clinical trials.1 The incidence of asthenia appears to be dose related.1 In addition, articulation impairment1 was reported in about 2% of patients receiving oral olanzapine in short-term, controlled clinical trials.1

Ataxia,1 decreased libido,1 dysarthria,1 stupor,1 and suicide attempt1 have been reported in 1% or less of patients receiving oral olanzapine in clinical trials.1

In short-term (i.e., 24-hour), controlled clinical trials of short-acting IM olanzapine for acute agitation in adults, somnolence occurred in approximately 6%,1 dizziness in approximately 4%,1 and asthenia in about 2% of the patients.1

Cardiovascular Effects

Hemodynamic Effects

Oral olanzapine may produce orthostatic hypotension1 that may be associated with dizziness, tachycardia, bradycardia, and, in some patients, syncope, particularly during the initial period of dosage titration.1 These adverse hemodynamic effects probably are due to the drug's α₁-adrenergic blocking activity.1 In short-term, controlled clinical trials of oral olanzapine in adults, postural hypotension1 and tachycardia1 occurred in approximately 3%1 and hypertension1 occurred in approximately 2% of patients.1 In an analysis of vital sign data from 41 clinical trials conducted with oral olanzapine in adults, orthostatic hypotension was reported in 20% or more of patients.1,382 Vasodilatation1 has been reported in 1% or less of patients treated with oral olanzapine; this adverse effect has not been definitely attributed to the drug.1

Hypotension, bradycardia with or without hypotension, tachycardia, and syncope also were reported during the clinical trials with short-acting IM olanzapine.1 In an open trial in nonagitated patients with schizophrenia designed to evaluate the safety and tolerability of a dosage regimen of three 10-mg IM doses of olanzapine administered 4 hours apart, approximately one-third of the patients experienced a substantial orthostatic decrease in systolic blood pressure (i.e., decrease of 30 mm Hg or more).1

Syncope was reported in 0.6% of olanzapine-treated patients in phase 2 and 3 clinical trials of oral olanzapine, and in 0.3% of patients receiving short-acting IM olanzapine in the acute agitation clinical trials.1 In phase 1 trials of olanzapine, 3 healthy volunteers experienced hypotension, bradycardia, and sinus pauses of up to 6 seconds that spontaneously resolved; 2 of these cases occurred in association with short-acting IM olanzapine and one case involved oral olanzapine.1 In short-term, controlled clinical trials for short-acting IM olanzapine for acute agitation, hypotension occurred in approximately 2%1 and postural hypotension occurred in approximately 1% of patients.1 Syncope1 has been reported in 1% or less of patients receiving short-acting IM olanzapine in clinical trials.1 The manufacturer states that the risk for this sequence of hypotension, bradycardia, and sinus pause may be greater in nonpsychiatric patients compared with psychiatric patients, who may be more adapted to certain pharmacologic effects of psychotropic agents.1 Long-acting IM olanzapine pamoate also may cause orthostatic hypotension associated with dizziness, tachycardia, bradycardia, and syncope (in some cases).382 Syncope-related adverse effects have been reported in 0.1% of patients receiving long-acting IM olanzapine pamoate in clinical trials.382 (See Dosage and Administration and see also Orthostatic Hypotension, under Cautions: Precautions and Contraindications.)

ECG Effects

Pooled analyses from controlled clinical trials in adults as well as in adolescents did not reveal significant differences in the proportions of oral olanzapine-treated patients experiencing potentially important ECG changes, including QT, QT_c (Fridericia corrected), and PR intervals.1,202,283,382 Oral olanzapine was associated with a mean increase in heart rate of 2.4 beats/minute in adults and a mean increase of 6.3 beats/minute in adolescents compared with no change and a mean decrease of 5.1 beats/minute, respectively, among patients who received placebo in controlled trials.1,283,382 A comparison of extended-release IM olanzapine pamoate and oral olanzapine (in the 24-week study) did not reveal substantial differences in ECG changes between these formulations.382 The manufacturer states that the tendency to cause tachycardia may be related to olanzapine's potential for inducing orthostatic changes in blood pressure.1,382

Like some other antipsychotic agents, olanzapine has been associated with prolongation of the QT_c interval in some patients and there is some evidence that higher dosages of the drug may increase the risk of QT_c-interval prolongation; however, the clinical relevance of these findings remains to be established.203,247,285

Other Cardiovascular Effects

In short-term, controlled clinical trials for oral olanzapine, chest pain1 occurred in approximately 3% of patients.1 Cerebrovascular accident1 has been reported in 1% or less of patients.1

Venous thromboembolic effects, including pulmonary embolism and deep venous thrombosis, have been reported in patients receiving olanzapine during postmarketing surveillance.1

Hepatic Effects

During premarketing clinical trials, oral olanzapine therapy was associated with asymptomatic elevations in serum aminotransferase (transaminase) concentrations, including elevations in serum concentrations of ALT (SGPT), AST (SGOT), and γ-glutamyltransferase (GGT).1 Clinically important ALT elevations 3 or more times the upper limit of the normal range were observed in 5% (77 of 1426) of adult patients exposed to olanzapine in placebo-controlled clinical studies; none of these patients experienced jaundice.1 ALT elevations 5 or more times the upper limit of the normal range were observed in 2% (29 of 1438) of adult patients treated with olanzapine.1 ALT values returned to normal, or were decreasing, at last follow-up in the majority of patients who either continued olanzapine therapy or discontinued the drug.1 None of the patients with elevated ALT values experienced jaundice, liver failure, or met the criteria for Hy's rule.1 Within the larger premarketing database of about 2400 adult patients with baseline ALT values of 90 IU/L or less, the incidence of ALT elevation exceeding 200 IU/L was 2% (50 of 2381 patients).1 None of these patients experienced jaundice or other symptoms attributable to hepatic impairment, and most had transient changes that tended to normalize while olanzapine therapy was continued.1 (See Hepatic Effects under Cautions: Precautions and Contraindications.)

Changes in serum transaminase concentrations observed with extended-release IM olanzapine pamoate are similar to those reported with oral olanzapine.382 In placebo-controlled studies of the extended-release IM formulation, clinically important ALT elevations 3 or more times the upper limit of normal were observed in 2.7% (8 of 291) of adult patients exposed to the drug compared with 3.2% (3 of 94) of placebo recipients; none of these patients experienced jaundice.382 In 3 of the patients, transaminase concentrations returned to normal despite continuing IM olanzapine pamoate therapy; in the other 5 patients transaminase concentrations decreased but remained about the normal range at the end of therapy.382 Within the larger premarketing database of 1886 patients with baseline ALT values of 90 IU/L or less, the incidence of ALT elevation exceeding 200 IU/L was 0.8%.382 None of these patients experienced jaundice or other symptoms attributable to hepatic impairment, and most had transient changes that tended to normalize while olanzapine pamoate IM therapy was continued.382 (See Hepatic Effects under Cautions: Precautions and Contraindications.)

In clinical studies with oral olanzapine, adolescents were more likely to have greater increases in serum transaminase concentrations compared with adults.1,373 In placebo-controlled monotherapy studies, clinically important ALT elevations (3 or more times the upper limit of the normal range) were observed in 12% (22 of 192) of adolescent patients exposed to olanzapine.1 ALT elevations 5 or more times the upper limit of the normal range were observed in 4% (8 of 192) of adolescent patients treated with olanzapine.1 ALT values returned to normal, or were decreasing, at last follow-up in the majority of adolescent patients who either continued olanzapine therapy or discontinued the drug.1 None of the adolescents with elevated ALT values experienced jaundice, liver failure, or met the criteria for Hy's rule.1

Hepatitis1,382 and jaundice1 have rarely been reported in patients receiving different formulations of olanzapine during postmarketing experience, as well as very rare cases of cholestatic or mixed hepatic injury.1,382 In addition, fatty deposit in the liver1 has been reported in less than 0.1% of patients receiving oral olanzapine in short-term clinical trials, although a causal relationship to the drug remains to be established.1

Endocrine and Metabolic Effects

Atypical antipsychotic agents have been associated with metabolic changes, including hyperglycemia, dyslipidemia, and weight gain.1,382 Such metabolic changes may be associated with increased cardiovascular and cerebrovascular risk.1,382

Weight Gain

Like some conventional (first-generation) and atypical (second-generation) antipsychotic agents, olanzapine therapy may result in weight gain.1,36,129,130,131,132,133,140,247,253,280,350,351,369,371,373 In placebo-controlled studies of 6 weeks' duration in adults, weight gain occurred in approximately 6% of patients receiving oral olanzapine,1 and increased appetite occurred in 6% of patients receiving oral olanzapine in short-term controlled trials.1 In an analysis of 13 placebo-controlled monotherapy studies, adult patients receiving olanzapine gained an average of 2.6 kg compared with an average loss of 0.3 kg in those receiving placebo (with a median exposure of 6 weeks); 22.2% of the olanzapine-treated patients gained 7% or more of their baseline weight compared with 3% of placebo recipients (with a median exposure to event of 8 weeks).1 Dose group differences with regard to weight gain have been noted in a short-term, controlled study comparing fixed oral dosages of olanzapine in adults with schizophrenia or schizoaffective disorder; the mean baseline to end point increase in weight was 1.9 kg in patients receiving 10 mg of olanzapine daily, 2.3 kg in those receiving 20 mg daily, and 3 kg in those receiving 40 mg daily, with substantial differences between 10 and 40 mg daily.1,382 Discontinuance of olanzapine therapy because of weight gain occurred in 0.2% of olanzapine-treated patients compared with none of the placebo recipients.1 During long-term studies (at least 48 weeks' duration) with olanzapine in adults, mean weight gain was 5.6 kg (median exposure of 573 days); 64% of olanzapine-treated patients gained 7% or more of their baseline weight, 32% gained 15% or more of their baseline weight, and 12% gained 25% or more of their baseline weight.1

In olanzapine-treated adolescent patients, both the magnitude of weight gain and the proportion of patients who had clinically significant weight gain were greater than in adult patients with comparable exposures.1,373 In short-term, placebo-controlled studies in adolescent patients with schizophrenia or bipolar disorder, weight gain occurred in approximately 30% of adolescents and increased appetite occurred in approximately 24% of adolescents receiving oral olanzapine.1 In 4 short-term, placebo-controlled monotherapy studies, adolescents receiving olanzapine gained an average of 4.6 kg compared with an average loss of 0.3 kg in those receiving placebo (with a median exposure of 3 weeks); 40.6% of the olanzapine-treated patients gained 7% or more of their baseline weight compared with 9.8% of placebo recipients (with median exposures to event of 4 and 8 weeks, respectively).1 Of the olanzapine-treated adolescents, 7.1% gained 15% or more of their baseline body weight compared with 2.7% of the placebo recipients (with median exposures to event of 19 and 8 weeks, respectively).1 In placebo-controlled studies of olanzapine therapy in adolescents, discontinuance due to weight gain occurred in 1% of olanzapine-treated patients compared with none of the placebo recipients.1 During long-term studies (at least 24 weeks' duration) in adolescents, the average weight gain was 11.2 kg (with a median exposure of 201 days).1 The percentages of adolescents who gained at least 7, 15, or 25% of their baseline body weight with long-term exposure were 89, 55, and 29%, respectively.1,373 Among adolescent patients, average weight gain according to baseline BMI category was 11.5, 12.1, and 12.7 kg for normal, overweight, and obese adolescents, respectively.1 Discontinuance because of weight gain occurred in 2.2% of olanzapine-treated adolescents following at least 24 weeks of olanzapine exposure.1,373

In a 24-week, randomized, double-blind, fixed-dosage study that compared 3 different extended-release olanzapine pamoate IM dosage regimens in adult patients with schizophrenia, average weight gains of 0.7, 0.9, and 1.7 kg occurred in those receiving 150 mg of olanzapine every 2 weeks, 405 mg every 4 weeks, and 300 mg every 2 weeks, respectively.382

Although the precise mechanism(s) remains to be clearly established, weight gain may result at least in part from the drug's serotonergic-, histaminergic-, and adrenergic-blocking properties.129,132,350 Weight gain has been reported to be troublesome for some patients during long-term therapy with atypical antipsychotics, particularly olanzapine and clozapine, and may be an important cause of outpatient noncompliance.129,140 Some clinicians suggest regular physical exercise and nutritional counseling in the prevention and treatment of weight gain associated with these drugs.129,133 There currently are no well established pharmacologic treatments for antipsychotic agent-induced weight gain; however, a number of drugs, including amantadine,129,132,133,366 bupropion,350 histamine H₂-receptor antagonists (e.g., nizatidine),129,132,133,367 orlistat,129,132,133 metformin,129,132,133,140 and topiramate,129,130,131,132,133 have been used with limited success to date.129,132,133,140,350,351 Because the potential risk of adverse effects in patients receiving these drugs may outweigh their possible weight-reducing effects in some cases, routine use of pharmacologic therapy currently is not recommended by most clinicians, although individual patients may benefit.132,140,355,356 Additional controlled studies are needed to more clearly determine the optimum management of antipsychotic-associated weight gain during long-term therapy with these drugs.133,140,351

Hyperglycemia and Diabetes Mellitus

Hyperglycemia, sometimes severe and associated with ketoacidosis, hyperosmolar coma, or death, has been reported in patients receiving atypical antipsychotic agents, including olanzapine.1,44,45,47,48,49,50,51,52,53,54,55,56,70,71,72,73,77,95,265,266,267,268,269,270,377 While confounding factors such as an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population make it difficult to establish with certainty the relationship between use of agents in this drug class and glucose abnormalities, epidemiologic studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with atypical antipsychotic agents.1,42,44,45,46,47,48,49,50,51,52,53,54,55,57,58,94 (See Hyperglycemia and Diabetes Mellitus under Cautions: Precautions and Contraindications.)

Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics currently are not available.1,44,45,47,48,49,50,51,52,53,54,55 While relative risk estimates are inconsistent, the association between atypical antipsychotics and increases in glucose concentrations appears to fall on a continuum, and olanzapine appears to have a greater association with hyperglycemia than some other atypical antipsychotic agents (e.g., quetiapine, risperidone).1,23,24,42,43,56,57,58,59,60,61,63,64,65,66,67,68,69,74,75,76,78,79,80,81,82,83,84,85,86,87,88,89,90,91,93,94,262,263,264,356,377

In the first phase of Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), the mean increase in serum glucose concentration (fasting and nonfasting samples) from baseline to the average of the 2 highest serum concentrations was 15 mg/dL in olanzapine-treated adult patients (median exposure of about 9 months).1 In a study in healthy individuals, subjects who received olanzapine for 3 weeks had a mean increase in fasting blood glucose of 2.3 mg/dL compared with baseline; the subjects who received placebo had a mean increase in fasting blood glucose of 0.34 mg/dL compared with baseline.1

In an analysis of 5 placebo-controlled monotherapy studies in adults with a median treatment duration of about 3 weeks, olanzapine was associated with a greater average increase in fasting glucose concentrations compared with placebo (2.76 mg/dL versus 0.17 mg/dL, respectively).1 The difference in mean changes between olanzapine and placebo was greater in patients with evidence of glucose dysregulation at baseline (e.g., patients diagnosed with diabetes mellitus or related adverse reactions, patients treated with antidiabetic agents, patients with a random baseline glucose concentration of 200 mg/dL or more and/or a baseline fasting glucose level of 126 mg/dL).1 Olanzapine-treated patients had a mean glycosylated hemoglobin (hemoglobin A_1c [HbA_1c]) concentration increase from baseline of 0.04% (median exposure: 21 days) compared with a mean HbA_1c decrease of 0.06% in placebo-treated individuals (median exposure of 17 days).1 In an analysis of 8 placebo-controlled studies (median treatment exposure of 4-5 weeks), 6.1% of olanzapine-treated subjects had treatment-emergent glycosuria compared with 2.8% of those receiving placebo.1 In adults receiving olanzapine monotherapy for at least 48 weeks, fasting glucose concentrations changed from normal (less than 100 mg/dL) to high (126 mg/dL or higher) and from borderline (between 100 and less than 126 mg/dL) to high (126 mg/dL or higher) in 12.8% and 26% of the patients, respectively.1 The mean change in fasting glucose for patients exposed to at least 48 weeks of olanzapine therapy was 4.2 mg/dL.1 In analyses of patients who completed 9-12 months of olanzapine therapy, the average change in fasting and nonfasting glucose concentrations continued to increase over time.1

Although increases in fasting glucose concentrations were similar in adolescents and adults treated with olanzapine, the difference in these values between the olanzapine and placebo groups was greater in adolescents than in adults.1,373 In an analysis of 3 short-term, placebo-controlled olanzapine monotherapy studies of 3 or 6 weeks' duration in adolescent patients, olanzapine was associated with a greater mean change from baseline in fasting glucose concentrations compared with placebo (an increase of 2.68 mg/dL versus a decrease of 2.59 mg/dL, respectively).1 The average increase in fasting glucose concentrations for adolescents exposed to at least 24 weeks of olanzapine therapy was 3.1 mg/dL.1 In adolescents receiving olanzapine monotherapy for at least 24 weeks, fasting glucose concentrations changed from normal (less than 100 mg/dL) to high (126 mg/dL or higher) and from borderline (between 100 and less than 126 mg/dL) to high (126 mg/dL or higher) in 0.9% and 23.1% of the patients, respectively.1

Diabetic coma1 and diabetic ketoacidosis1 have been reported in olanzapine-treated patients during postmarketing surveillance.1

Dyslipidemia

Like some other antipsychotic agents, particularly clozapine, olanzapine therapy has been associated with undesirable changes in lipid parameters, including elevations in serum triglyceride and cholesterol concentrations.1,26,275,276,277,278,279,280,338,339,346,371,373 Clinically important, and sometimes very high (greater than 500 mg/dL), elevations in triglyceride concentrations have been observed with olanzapine therapy.1 Modest average increases in total cholesterol concentrations also have occurred with olanzapine use.1

In an analysis of 5 placebo-controlled olanzapine monotherapy studies of up to 12 weeks' duration in adults, olanzapine-treated patients had increases from baseline in mean fasting serum total cholesterol, low-density lipoprotein (LDL)-cholesterol, and triglyceride concentrations of 5.3 mg/dL, 3 mg/dL, and 20.8 mg/dL, respectively, compared with decreases from baseline in mean fasting total cholesterol, LDL-cholesterol, and triglyceride concentrations of 6.1 mg/dL, 4.3 mg/dL, and 10.7 mg/dL for patients receiving placebo.1 For fasting high-density lipoprotein (HDL)-cholesterol, no clinically important differences were observed between olanzapine-treated patients and patients receiving placebo.1 Mean increases in fasting lipid values (total cholesterol, LDL-cholesterol, and triglycerides) were greater in patients without evidence of lipid dysregulation at baseline (defined as patients diagnosed with dyslipidemia or related adverse reactions, patients receiving antilipemic agents, or patients with high baseline lipid levels).1 In long-term studies (at least 48 weeks) in adults, patients had increases from baseline in mean fasting serum total cholesterol, LDL-cholesterol, and triglyceride concentrations of 5.6 mg/dL, 2.5 mg/dL, and 18.7 mg/dL, respectively, and a mean decrease in fasting HDL-cholesterol of 0.16 mg/dL.1 In an analysis of patients who completed 12 months of therapy, the mean nonfasting total cholesterol concentration did not increase further after approximately 4-6 months.1 In adult monotherapy studies, fasting serum triglyceride increases of 50 mg/dL or more occurred in approximately 61% of patients, fasting total cholesterol increases of 40 mg/dL or more occurred in approximately 33% of patients, and fasting LDL-cholesterol increases of 30 mg/dL or more occurred in approximately 40% of patients.1 In the first phase of the CATIE program, the mean increase in serum triglyceride concentrations in patients receiving olanzapine was 40.5 mg/dL (median exposure of about 9 months) and the mean increase in total cholesterol was 9.4 mg/dL.1

In clinical studies, increases in fasting serum total cholesterol, LDL-cholesterol, and triglyceride concentrations were generally greater in adolescents than in adults treated with olanzapine.1,373 In an analysis of 3 placebo-controlled olanzapine monotherapy studies in adolescent patients, increases from baseline in mean fasting total cholesterol, LDL-cholesterol, and triglyceride concentrations of approximately 13 mg/dL, 7 mg/dL, and 28 mg/dL, respectively, occurred in adolescents receiving olanzapine compared with increases from baseline in mean fasting total cholesterol and LDL cholesterol of 1.3 mg/dL and 1 mg/dL and a decrease in triglycerides of 1.1 mg/dL in adolescents receiving placebo.1 For fasting HDL-cholesterol, no clinically important differences were observed between adolescents receiving olanzapine compared with adolescents receiving placebo.1 Adolescents receiving olanzapine monotherapy for at least 24 weeks had increases from baseline in mean fasting total cholesterol, LDL-cholesterol, and triglyceride concentrations of 5.5 mg/dL, 5.4 mg/dL, and 20.5 mg/dL, respectively, and a mean decrease in fasting HDL-cholesterol of 4.5 mg/dL.1 In adolescent monotherapy studies, fasting serum triglyceride increases of 50 mg/dL or more occurred in approximately 46% of adolescents, fasting total cholesterol increases of 40 mg/dL or more occurred in approximately 15% of patients, and fasting LDL-cholesterol increases of 30 mg/dL or more occurred in approximately 22% of patients.1

Cholesterol concentrations of 240 mg/dL or higher and triglyceride concentrations of 1000 mg/dL or higher have been reported rarely during postmarketing surveillance.1

The manufacturer recommends clinical monitoring, including baseline and periodic follow-up lipid evaluations, in all patients receiving olanzapine.1,373 In addition, some clinicians recommend that lipid profiles be monitored at baseline and periodically (e.g., every 3-6 months) in all patients receiving long-term therapy with atypical antipsychotic agents.275,277,278,279 There is some evidence from a study in individuals with developmental disabilities that the risk of dyslipidemia in patients receiving atypical antipsychotic agents may be minimized or avoided by careful monitoring, dietary management, and suitable physical activity.338 In patients who develop persistent and clinically important dyslipidemia during olanzapine therapy, nondrug therapies and measures (e.g., dietary management, weight control, an appropriate program of physical activity) and drug therapy (e.g., antilipemic agents) may be helpful.26,279,338,355,356 Consideration also may be given to switching to an alternative antipsychotic agent that is less frequently associated with dyslipidemia (such as aripiprazole, risperidone, or ziprasidone).26,279,280,346

Hyperprolactinemia

As with other drugs that antagonize dopamine D₂ receptors, olanzapine can elevate serum prolactin concentrations, and the elevation may persist during chronic administration of the drug.1,283,300,302 However, in contrast to conventional (first-generation) antipsychotic agents and similar to many other atypical antipsychotic agents, olanzapine therapy in usual dosages generally produces transient elevations in serum prolactin concentrations in humans.1,119,283,288,300,301,315,332 It has been suggested that the more transient effect of atypical antipsychotic agents on prolactin may be because these drugs appear to dissociate from dopamine receptors more rapidly than conventional antipsychotic agents.1,288,289,315,332

In placebo-controlled studies with olanzapine (up to 12 weeks) in adults, changes from normal to high serum prolactin concentrations were observed in 30% of olanzapine-treated adults compared with 10.5% of adults receiving placebo.1 In a pooled analysis from clinical studies involving 8136 adults treated with olanzapine, potentially associated clinical manifestations of hyperprolactinemia included menstrual-related events (2% of females), sexual function-related events (2% of females and males), and breast-related events (0.7% of females and 0.2% of males).1

Adolescents treated with olanzapine had a higher incidence of elevated prolactin concentrations compared with adults; the incidence of galactorrhea and gynecomastia also was higher in adolescents compared with adults.1,373 In placebo-controlled olanzapine monotherapy studies of up to 6 weeks' duration in adolescent patients with schizophrenia or bipolar disorder, changes from normal to high serum prolactin concentrations were observed in 47% of olanzapine-treated patients compared with 7% of those receiving placebo.1 In a pooled analysis from clinical trials that included 454 olanzapine-treated adolescents, potentially associated clinical manifestations included menstrual-related events (1% of females), sexual function-related events (0.7% of females and males), and breast-related events (2% of females and 2% of males).1

In premarketing studies with extended-release IM olanzapine pamoate, substantial differences in prolactin concentrations have been observed in patients receiving different dosage regimens of the drug.382

Olanzapine is considered by many experts to be relatively low to moderate among antipsychotic agents in its potential for inducing hyperprolactinemia in adults,26,281,377 and it has been recommended along with other prolactin-sparing atypical antipsychotics (e.g., aripiprazole, clozapine, quetiapine, ziprasidone) in patients with schizophrenia who are at risk of hyperprolactinemia.26,281 Although clinical disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been associated with prolactin-elevating drugs, the clinical importance of elevated prolactin concentrations is unknown for most patients.1,281,301

Like other drugs that increase prolactin, an increase in mammary gland neoplasia was observed in olanzapine carcinogenicity studies conducted in mice and rats.1 However, neither clinical studies nor epidemiologic studies have demonstrated an association between chronic administration of dopamine antagonists and tumorigenesis in humans; the available evidence is considered too limited to be conclusive.1 (See Hyperprolactinemia under Cautions: Precautions and Contraindications and see also Cautions: Mutagenicity and Carcinogenicity.) In patients who develop elevated prolactin concentrations during antipsychotic therapy, some clinicians recommend reducing the dosage of the current antipsychotic agent or switching to a more prolactin-sparing antipsychotic agent281 (e.g., aripiprazole, clozapine, quetiapine, ziprasidone).26,281,377 Dopamine receptor agonists (e.g., bromocriptine) also may be helpful, and estrogen replacement therapy may be considered in hypoestrogenic female patients.281

Other Endocrine and Metabolic Effects

Peripheral edema has been reported in approximately 3% of adult patients receiving oral olanzapine in short-term clinical trials; increased serum alkaline phosphatase concentrations have been reported in at least 1% of patients.1 Bilirubinemia1 and hypoproteinemia1 have been reported in 1% or less of patients receiving oral olanzapine in short-term trials.1

Increased serum creatine phosphokinase concentrations1 have been reported in less than 1% of patients receiving IM olanzapine in short-term clinical trials;1 however, a causal relationship remains to be established.1

GI Effects

Dryness of the mouth and constipation both occurred in about 9%,1 dyspepsia in about 7%,1 vomiting in about 4%,1 and increased appetite1 in about 3% of adult patients receiving oral olanzapine in short-term controlled clinical trials.1

Nausea (4-5%), vomiting (1-6%), dry mouth (2-6%), diarrhea (2-7%), and increased appetite (1-6%) occurred in adult patients receiving extended-release IM olanzapine pamoate therapy in a short-term controlled clinical trial.382

Nausea1 has been reported in less than 1% of patients receiving short-acting IM olanzapine in clinical trials.1

Tongue edema1 has been reported in 1% or less of oral olanzapine-treated patients.1 Ileus1 and intestinal obstruction1 have been reported in less than 0.1% of patients receiving oral olanzapine in short-term clinical trials.1

Respiratory Effects

Rhinitis1 occurred in about 7%, increased cough1 in about 6%, and pharyngitis1 in about 4% of adult patients receiving oral olanzapine in short-term controlled clinical trials.1 Dyspnea1,187 has been reported in at least 1% of patients receiving oral olanzapine in short-term clinical trials.1 Epistaxis1 has been reported in 1% or less of olanzapine-treated patients.1 In addition, dyspnea and hyperventilation, which appeared to be dose related, have been reported together in a patient treated with oral olanzapine.187

Lung edema1 has been reported in less than 0.1% of adult patients receiving oral olanzapine; however, a causal relationship to the drug has not been clearly established.1 Respiratory failure developed in a geriatric individual with chronic lung disease who was receiving olanzapine therapy; although not clearly established, it was suggested that the respiratory failure was due at least in part to the sedative effect of the drug.192

Dermatologic and Sensitivity Reactions

Alopecia1 and photosensitivity reaction1 have been reported in 1% or less of olanzapine-treated adults.1 Allergic/hypersensitivity reactions (e.g., anaphylactoid reaction, angioedema, pruritus, urticaria, rash) also have been reported during postmarketing surveillance of olanzapine.1 In addition, a case of Guillain-Barré syndrome associated with an apparent hypersensitivity reaction to olanzapine (manifested as rash and hepatic impairment) has been reported in at least one olanzapine-treated patient; the symptoms of the reaction gradually improved in this patient following discontinuance of the drug and plasma exchange.402

Eruptive xanthomas, which are associated with hyperlipidemia, have occurred in several patients receiving olanzapine therapy.195 Leukocytoclastic vasculitis also has been reported in a geriatric patient receiving olanzapine and warfarin concurrently; the vasculitis improved following discontinuance of olanzapine in this patient but recurred when the drug was subsequently reintroduced.196

Drug Reaction with Eosinophilia and Systemic Symptoms

Drug reaction with eosinophilia and systemic symptoms (DRESS; also known as multiorgan hypersensitivity and hypersensitivity syndrome), a rare and serious dermatologic reaction, has been reported in patients receiving olanzapine.193,401,403 DRESS, which can be fatal in up to 10% of cases, consists of a combination of 3 or more of the following manifestations: cutaneous reaction (e.g., rash, exfoliative dermatitis), eosinophilia, fever, lymphadenopathy, and one or more systemic complications such as hepatitis, myocarditis, pericarditis, pancreatitis, nephritis, and pneumonitis.401 DRESS may start as a rash that can spread all over the body and include fever, lymphadenopathy, facial swelling, and injury to organs (including the liver, kidneys, lungs, heart, or pancreas) and possibly death.401

FDA has identified 23 cases of DRESS, including one fatal case, associated with olanzapine use worldwide that were reported to its adverse event reporting system between 1996 and May 10, 2016.401 The median time to onset of symptoms in these cases was 19 days after initiation of olanzapine therapy and the median duration of olanzapine therapy was 2 months.401 The median reported olanzapine dosage was 20 mg daily; however, DRESS has been reported at olanzapine dosages as low as 5 mg daily.401 The 22 non-fatal cases all reported serious outcomes, including 18 that required hospitalization.401 Complete resolution of symptoms was reported in 9 cases after discontinuance of olanzapine.401 In one case, symptoms of DRESS recurred after reinitiation of the drug.401 In the fatal case, death was attributed to acute cardiac failure related to olanzapine; during hospitalization, the patient had an initial episode of DRESS, followed by a recurrence of DRESS.401 However, the patient in this case was taking multiple other drugs that may have contributed to death.401

A published case report describes a severe and generalized pruritic eruption, fever, eosinophilia, and toxic hepatitis that developed in an adult male patient 60 days after beginning olanzapine therapy.193 The manifestations of DRESS/hypersensitivity syndrome in this patient improved following discontinuance of the drug, and skin and liver biopsy results suggested that the syndrome was caused by olanzapine.193 Another case of DRESS/hypersensitivity syndrome, which was manifested as rash, edema, generalized lymphadenopathy, hepatomegaly, eosinophilia, fever, and cough and confirmed by patch testing, was reported in an olanzapine-treated patient.403 (See Drug Reaction with Eosinophilia and Systemic Symptoms under Cautions: Precautions and Contraindications.)

Local Effects

Pain at the injection site1 has been reported in at least 1% of patients receiving short-acting IM olanzapine in controlled clinical trials.1

Injection site reactions were reported in 3.6% of patients receiving extended-release olanzapine pamoate IM in a short-term, placebo-controlled clinical trial, which included pain at the injection site, buttock pain, injection site mass, induration, and injection site induration.382,385 Pain at the injection site was reported most frequently (in 2.3% of patients).382 The injection site reactions were generally mild to moderate in severity, and none of the affected patients discontinued therapy because of the reactions.385

Genitourinary Effects

Urinary incontinence1 has been reported in approximately 2% of adult patients receiving oral olanzapine in short-term controlled clinical trials, although a causal relationship to the drug remains to be established.1 Amenorrhea,1 breast pain,1 decreased menstruation,1 increased menstruation,1 menorrhagia,1 metrorrhagia,1 lactation disorder,1 and gynecomastia1 have been reported in 1% or less of olanzapine-treated patients.1

Impotence,1 polyuria,1 urinary frequency,1 urinary retention,1,352 urinary urgency,1 and impaired urination1 have been reported in 1% or less of adult patients receiving oral olanzapine in short-term clinical trials.1

Priapism has been reported in several male patients1,197,198,200 and at least one case of clitoral priapism has been reported in a female patient.199 The α-adrenergic blocking effect of olanzapine appears to be responsible for this rare but potentially serious adverse effect requiring immediate medical attention to prevent long-term consequences such as erectile dysfunction.197,198,200

Musculoskeletal Effects

Joint pain,1 back pain,1 and extremity (other than joint) pain1 have been reported in 5% of adult patients receiving oral olanzapine in short-term controlled clinical trials.1 Osteoporosis1 has been reported in less than 0.1% of patients receiving oral olanzapine.1 Rhabdomyolysis1,185,188,189,190,191 also has been reported rarely in olanzapine-treated patients and may be seen as one of the clinical features of NMS.1,185,382 (See Neuroleptic Malignant Syndrome in Cautions: Nervous System Effects.)

Ocular Effects

Amblyopia1 has been reported in 3% of adult patients receiving oral olanzapine in short-term clinical trials.1 Accommodation abnormality1 and dry eyes1 have been reported in 1% or less of oral olanzapine-treated patients.1 In addition, mydriasis has been reported in less than 0.1% of patients receiving oral olanzapine.1

Hematologic Effects

In clinical trial and/or postmarketing experience, leukopenia and neutropenia temporally related to antipsychotic agents, including olanzapine, have been reported.1,376,378,382 Agranulocytosis also has been reported.1,382

Possible risk factors for leukopenia and neutropenia include a preexisting low leukocyte count and a history of drug-induced leukopenia or neutropenia.1,382 Therefore, patients with a history of clinically important low leukocyte count or drug-induced leukopenia and/or neutropenia should have their complete blood count monitored frequently during the first few months of olanzapine therapy.1,382 Discontinuance of olanzapine should be considered at the first sign of a clinically important decline in leukocyte count in the absence of other causative factors.1,382

Patients with clinically significant neutropenia should be carefully monitored for fever or other signs or symptoms of infection and promptly treated if such signs or symptoms occur.1,382 In patients with severe neutropenia (absolute neutrophil count [ANC] less than 1000/mm³), olanzapine should be discontinued and the leukocyte count monitored until recovery occurs.1,382

Lithium reportedly has been used successfully in the treatment of several cases of leukopenia and neutropenia associated with aripiprazole, clozapine, olanzapine, and some other drugs; however, further clinical experience is needed to confirm these anecdotal findings.376,378

Ecchymosis1 has been reported in 5% of adult patients receiving oral olanzapine in short-term clinical trials; however, a causal relationship to the drug remains to be established.1 Leukopenia1 and thrombocytopenia1 have been reported in less than 1% of patients receiving oral olanzapine.1 During premarketing clinical trials, asymptomatic elevation of the eosinophil count was reported in approximately 0.3% of patients receiving oral olanzapine.1

Other Adverse Effects

Accidental injury has been reported in approximately 12% of adult patients,1 and fever1 has been reported in approximately 6% of adult patients1 receiving oral olanzapine in short-term clinical trials.1 Chills1 and facial edema1 have been reported in 1% or less of oral olanzapine-treated patients.1 In addition, chills accompanied by fever,1 hangover effect,1 and sudden death1 have been reported in less than 0.1% of patients receiving oral olanzapine; however, a causal relationship to the drug has not been clearly established.1 Discontinuation reaction (diaphoresis, nausea, or vomiting) also has been reported during postmarketing surveillance of olanzapine.1

Pancreatitis, which has been fatal in some cases, has occurred rarely in patients receiving atypical antipsychotic agents, including olanzapine, clozapine, and risperidone.1,271,272,273,274 In most of these cases, pancreatitis developed within 6 months of initiation of atypical antipsychotic therapy.272 Although the precise mechanism for this effect remains to be established, it has been suggested that it may be due at least in part to the adverse metabolic effects associated with these drugs.271,273

Precautions and Contraindications

Olanzapine shares many of the toxic potentials of other antipsychotic agents (e.g., other atypical antipsychotic agents, phenothiazines), and the usual precautions associated with therapy with these agents should be observed.26 (See Cautions in the Phenothiazines General Statement 28:16.08.24.)

When olanzapine is used in combination with fluoxetine, the usual cautions, precautions, and contraindications associated with fluoxetine must be considered in addition to those associated with olanzapine.1

Laboratory Test Monitoring

The manufacturer recommends fasting blood glucose testing and lipid profile determinations at the beginning of olanzapine therapy and periodically during treatment with the drug.1,382 (See Cautions: Endocrine and Metabolic Effects and see also Dyslipidemia and Hyperglycemia and Diabetes Mellitus under Cautions: Precautions and Contraindications.)

Hyperprolactinemia

Similar to other antipsychotic agents, olanzapine can cause elevated serum prolactin concentrations, which may persist during chronic use of the drug.1 (See Hyperprolactinemia under Cautions: Endocrine and Metabolic Effects.) Clinical disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been associated with prolactin-elevating drugs.1 In addition, chronic hyperprolactinemia associated with hypogonadism may lead to decreased bone density.1

If olanzapine therapy is considered in a patient with previously detected breast cancer, clinicians should consider that approximately one-third of human breast cancers are prolactin-dependent in vitro.1

Cognitive and Motor Impairment

Dose-related somnolence occurred in 26% of patients receiving oral olanzapine compared with 15% of those receiving placebo, and resulted in discontinuance of the drug in 0.4% of the patients in the premarketing database.1 Sedation occurred in 8% of patients receiving extended-release olanzapine pamoate injection; somnolence and sedation resulted in discontinuance of the drug in 0.6% of patients in the premarketing database.382

Because of olanzapine's sedative effects and because the drug potentially may impair judgment, thinking, and motor skills, olanzapine-treated patients should be cautioned about operating hazardous machinery, including driving a motor vehicle, until they are reasonably certain that the drug does not adversely affect them.1,290,315,382 In addition, because of the risk of post-injection delirium/sedation syndrome, patients receiving extended-release olanzapine pamoate injection should not drive or operate heavy machinery for the remainder of the day after each injection.382

Seizures

Although seizures occurred in about 0.9% of patients receiving oral olanzapine in controlled clinical trials and in 0.15% of patients receiving extended-release olanzapine pamoate injection during premarketing testing, it should be noted that confounding factors that may have contributed to the occurrence of seizures were present in many of these cases.1,382 Olanzapine should be administered with caution to patients with a history of seizures, patients with conditions known to lower the seizure threshold (e.g., dementia of the Alzheimer's type), and during concurrent therapy with drugs that may lower the seizure threshold.1,20,24,171,172,174,382

Body Temperature Regulation

Because disruption of the body's ability to reduce core body temperature has been associated with the use of antipsychotic agents, caution is advised when olanzapine is administered in patients exposed to conditions that may contribute to an elevation in core body temperature.1,382 Such conditions include strenuous exercise, exposure to extreme heat, concomitant use of drugs with anticholinergic activity, or dehydration.1,382 Patients receiving olanzapine should be advised regarding appropriate precautions to avoid overheating and dehydration.1 Patients also should be advised to contact their clinician immediately if they become severely ill and have some or all of the symptoms of dehydration, including sweating too much or not at all, dry mouth, feeling very hot or thirsty, and unable to produce urine.1,382

Hepatic Effects

Because clinically important serum ALT elevations (3 or more times the upper limit of the normal range) were observed in adults and adolescents exposed to oral olanzapine and adults exposed to extended-release IM olanzapine pamoate in placebo-controlled clinical studies, the manufacturer states that olanzapine should be used with caution in patients with signs and symptoms of hepatic impairment, in patients with preexisting conditions associated with limited hepatic functional reserve, and in patients who are being treated concurrently with potentially hepatotoxic drugs.1,382

Drug Reaction with Eosinophilia and Systemic Symptoms

Drug reaction with eosinophilia and systemic symptoms (DRESS; also known as multiorgan hypersensitivity and hypersensitivity syndrome) has been reported in olanzapine-treated patients.193,401,403 (See Drug Reaction with Eosinophilia and Systemic Symptoms under Cautions: Dermatologic and Sensitivity Reactions.) Patients receiving olanzapine should be informed about the risk of DRESS and advised to seek immediate medical care if symptoms suggestive of DRESS, including rash, fever, facial swelling, and/or lymphadenopathy, occur.401 There currently is no specific treatment for DRESS.401 Management of the syndrome involves early recognition, immediate discontinuance of olanzapine if DRESS is suspected, and initiation of supportive care.401 Corticosteroid therapy also should be considered in cases of DRESS with extensive organ involvement.401

Individuals with Phenylketonuria

Individuals with phenylketonuria (i.e., homozygous genetic deficiency of phenylalanine hydroxylase) and other individuals who must restrict their intake of phenylalanine should be warned that olanzapine orally disintegrating tablets contain aspartame (e.g., NutraSweet^®), which is metabolized in the GI tract to provide phenylalanine following oral administration; the respective manufacturer's labeling should be consulted for specific information regarding phenylalanine content of individual preparations and dosage strengths.1,30,31,32,33,34

Dysphagia

Esophageal dysmotility and aspiration have been associated with the use of antipsychotic agents.1 Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer's disease.1 The manufacturer states that olanzapine is not approved for the treatment of Alzheimer's disease.1

Patients with Concomitant Illness

Clinical experience with olanzapine in patients with certain concurrent systemic diseases is limited.1,382 Olanzapine has demonstrated anticholinergic activity in vitro and constipation, dryness of the mouth, and tachycardia, possibly related to the drug's anticholinergic effects, have occurred in premarketing clinical trials.1,382 Although these adverse effects did not often result in drug discontinuance, the manufacturer states that olanzapine should be used with caution in patients with clinically important prostatic hypertrophy, angle-closure glaucoma, or a history of paralytic ileus or related conditions.1,382

Olanzapine has not been adequately evaluated in patients with a recent history of myocardial infarction or unstable cardiovascular disease to date and patients with these conditions were excluded from premarketing clinical trials.1,382 Because of the risk of orthostatic hypotension associated with olanzapine, the manufacturer states that the drug should be used with caution in patients with cardiovascular disease.1,382 (See Cautions: Cardiovascular Effects and see also Orthostatic Hypotension under Cautions: Precautions and Contraindications.)

Concomitant Medication or Alcohol Use

Because of the potential for adverse drug interactions, the manufacturer recommends that patients receiving olanzapine be advised to notify their clinician if they are taking or plan to take other olanzapine-containing preparations (e.g., Symbyax^® [an olanzapine/fluoxetine combination]).1,382 Patients receiving olanzapine should also be advised to inform their clinician if they are taking, plan to take, or have stopped taking any prescription or nonprescription (over-the-counter) medications, including herbal supplements.1,382 The manufacturer also recommends that patients be advised to avoid alcohol while receiving the drug.1,382 (See Drug Interactions.)

Tardive Dyskinesia

Because use of antipsychotic agents may be associated with tardive dyskinesia, a syndrome of potentially irreversible, involuntary, dyskinetic movements,1,26,210 olanzapine should be prescribed in a manner that is most likely to minimize the occurrence of this syndrome.1 Chronic antipsychotic treatment generally should be reserved for patients who suffer from a chronic illness that is known to respond to antipsychotic agents, and for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate.1 In patients who do require chronic treatment, the smallest dosage and the shortest duration of treatment producing a satisfactory clinical response should be sought, and the need for continued treatment should be reassessed periodically.1

The APA currently recommends that patients receiving second-generation antipsychotic agents be assessed clinically for abnormal involuntary movements every 12 months and that patients considered to be at increased risk for tardive dyskinesia be assessed every 6 months.26 (See Tardive Dyskinesia under Cautions: Nervous System Effects.)

Falls

Olanzapine therapy may cause somnolence, postural hypotension, and motor and sensory instability, which may lead to falls; as a consequence, fractures or other injuries may occur.430 For patients with diseases or conditions or receiving other drugs that could exacerbate these effects, fall risk assessments should be completed when initiating antipsychotic treatment and periodically during long-term therapy.430

Dispensing and Administration Precautions

Because of similarities in spelling, dosage intervals (once daily), and tablet strengths (5 and 10 mg) of Zyprexa^® (the trade name for olanzapine) and Zyrtec^® (the trade name for cetirizine hydrochloride, an antihistamine), several dispensing or prescribing errors have been reported to the manufacturer of Zyprexa^®.97 These medication errors may result in unnecessary adverse events or a potential relapse in patients with schizophrenia or bipolar disorder.97 Therefore, the manufacturer of Zyprexa^® cautions that extra care should be exercised in ensuring the accuracy of written prescriptions for Zyprexa^® and Zyrtec^® such as printing both the proprietary (brand) and nonproprietary (generic) names on all prescriptions for these drugs. 97 The manufacturer also recommends that pharmacists assess various measures of avoiding dispensing errors and implement them as appropriate (e.g., placing drugs with similar names apart from one another on pharmacy shelves, patient counseling).97

Leukopenia, Neutropenia, and Agranulocytosis

In clinical trial and/or postmarketing experience, leukopenia and neutropenia temporally related to antipsychotic agents, including olanzapine, have been reported;378,376,378 agranulocytosis also has been reported.1

Because possible risk factors for leukopenia and neutropenia include a preexisting low leukocyte count and a history of drug-induced leukopenia and neutropenia, the manufacturer states that patients with a history of clinically important low leukocyte count or drug-induced leukopenia and/or neutropenia should have their complete blood count monitored frequently during the first few months of olanzapine therapy.1,382 Discontinuance of olanzapine should be considered at the first sign of a clinically important decline in leukocyte count in the absence of other causative factors.1,382

Orthostatic Hypotension

Orthostatic hypotension associated with dizziness, tachycardia, bradycardia, and/or syncope, particularly during the initial dosage titration period, has been reported in patients receiving oral olanzapine therapy.1 The risk of orthostatic hypotension and syncope may be minimized by initiating therapy with a dosage of 5 mg orally once daily.1 A more gradual titration to the target dosage should be considered if hypotension occurs.1 Patients should be cautioned about the risk of orthostatic hypotension, particularly during the initial dosage titration period and if the drug is given concurrently with drugs that may potentiate the orthostatic effect of olanzapine, including diazepam, or alcohol.1 Patients should be advised to change positions carefully to help prevent orthostatic hypotension and to lie down if they feel dizzy or faint until they feel better.1 Patients also should be advised to contact their clinician if they experience any of the following signs and symptoms associated with orthostatic hypotension: dizziness, fast or slow heart beat, or fainting.1

Hypotension, bradycardia with or without hypotension, tachycardia, and syncope have been reported in patients receiving short-acting IM olanzapine.1 The use of maximum recommended dosages of IM olanzapine (i.e., 3 doses of 10 mg each given IM 2-4 hours apart) may be associated with a substantial risk of clinically important orthostatic hypotension.1 Patients who experience drowsiness or dizziness after the IM injection should remain recumbent until an examination indicates that they are not experiencing orthostatic hypotension, bradycardia, and/or hypoventilation.1 Patients requiring additional IM injections of olanzapine should be assessed for orthostatic hypotension prior to administration of any subsequent doses.1 Administration of additional IM doses to patients with clinically important postural change in blood pressure is not recommended.1

Extended-release IM olanzapine pamoate therapy also may cause orthostatic hypotension associated with dizziness, tachycardia, bradycardia, and, in some cases, syncope.382

The manufacturer states that olanzapine should be used with particular caution in patients with known cardiovascular disease (e.g., history of myocardial infarction or ischemia, heart failure, conduction abnormalities), cerebrovascular disease, and/or other conditions that would predispose patients to hypotension (e.g., dehydration, hypovolemia, concomitant antihypertensive therapy) where the occurrence of syncope, hypotension, and/or bradycardia might put the patient at increased risk.1,382 The manufacturer also states that the drug should be used with caution in patients receiving other drugs that can induce hypotension, bradycardia, or respiratory and CNS depression.1,382 (See Drug Interactions.) In such patients who have never taken oral olanzapine, tolerability should be established with oral olanzapine before initiating extended-release IM olanzapine pamoate therapy.382

Concurrent administration of short-acting IM olanzapine and parenteral benzodiazepines is not recommended due to the potential for excessive sedation and cardiorespiratory depression.1 If use of short-acting IM olanzapine in combination with parenteral benzodiazepine therapy is considered, careful evaluation of the patient's clinical status for excessive sedation and cardiorespiratory depression is recommended.1

Weight Gain

Olanzapine therapy may result in weight gain.1,36,129,130,131,132,133,140,247,253,280,350,351,369,373,382 In olanzapine-treated adolescent patients, both the magnitude of weight gain and the proportion of patients who had clinically important weight gain were greater compared with adult patients with comparable exposures.1,373,382 (See Endocrine and Metabolic Effects under Cautions and see also Cautions: Pediatric Precautions.)

The potential consequences of weight gain should be considered in adults and adolescents prior to starting olanzapine therapy.1,373,382 All patients receiving the drug should be advised that weight gain has occurred during olanzapine treatment and receive regular monitoring of their weight.1,373,382

Dyslipidemia

Because undesirable changes in serum lipids have been observed with olanzapine therapy in both adults and adolescents, the manufacturer recommends appropriate clinical monitoring, including baseline and periodic follow-up lipid evaluations, in all patients receiving the drug.1,373,382 (See Endocrine and Metabolic Effects under Cautions and see also Cautions: Pediatric Precautions.)

Hyperglycemia and Diabetes Mellitus

Because hyperglycemia, sometimes severe and associated with ketoacidosis, hyperosmolar coma, or death, has been reported in patients receiving atypical antipsychotic agents, including olanzapine,1,44,45,46,47,48,49,50,51,52,53,54,55,56,70,71,72,73,77,95,265,266,267,268,269,270,373 the manufacturer states that clinicians should consider the risks and benefits when prescribing olanzapine to adult and adolescent patients with an established diagnosis of diabetes mellitus or in those having borderline increased blood glucose concentrations (i.e., fasting values of 100-126 mg/dL or nonfasting values of 140-200 mg/dL).1,371 The manufacturer recommends that all patients beginning olanzapine therapy undergo fasting blood glucose testing upon therapy initiation and periodically during treatment.1,373 The manufacturer also recommends that all patients receiving olanzapine be regularly monitored for worsening of glucose control.1,373 Any patient who develops manifestations of hyperglycemia (e.g., polydipsia, polyphagia, polyuria, weakness) during treatment with an atypical antipsychotic should undergo fasting blood glucose testing.1,44,45,46,47,48,49,50,51,52,53,54,55,266,373 In some cases, patients who developed hyperglycemia while receiving an atypical antipsychotic have required continuance of antidiabetic treatment despite discontinuance of the suspect drug; in other cases, hyperglycemia resolved with discontinuance of the antipsychotic or with continuance of both the suspect drug and initiation of antidiabetic treatment.1,45,46,47,48,49,50,51,52,53,54,55,77,266,373

Various experts have developed additional recommendations for the management of diabetes risks in patients receiving atypical antipsychotics; these include initial screening measures and regular monitoring (e.g., determination of diabetes risk factors; BMI determination using weight and height; waist circumference; blood pressure; fasting blood glucose; HbA_1c; fasting lipid profile), as well as provision of patient education and referral to clinicians experienced in the treatment of diabetes, when appropriate.56,57,59,61,62,66,129,266,269 Although some clinicians state that a switch from one atypical antipsychotic agent to another that has not been associated with substantial weight gain or diabetes should be considered in patients who experience weight gain (equal to or exceeding 5% of baseline body weight) or develop worsening glycemia or dyslipidemia at any time during therapy, such recommendations are controversial because differences in risk of developing diabetes associated with use of the different atypical antipsychotics remain to be fully established.56,57,63,64,65,66,67,77 Many clinicians consider antipsychotic efficacy the most important factor when making treatment decisions and suggest that detrimental effects of switching from a beneficial treatment regimen also should be considered in addition to any potential for exacerbation or development of medical conditions (e.g., diabetes). 24,59,63,64,65,66,75,90,91,93,95,262,263,346 Decisions to alter drug therapy should be made on an individual basis, weighing the potential risks and benefits of the particular drug in each patient.24,346

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome requiring immediate discontinuance of the drug and intensive symptomatic treatment, has been reported in patients receiving antipsychotic agents, including olanzapine.1,26,176,177,178,179,180,181,182,183,184,185,186,201,315,382 If a patient requires antipsychotic therapy following recovery from NMS, the potential reintroduction of drug therapy should be carefully considered.1,26,178,179,185,382 If antipsychotic therapy is reintroduced, the dosage generally should be increased gradually, and an antipsychotic agent other than the agent believed to have precipitated NMS generally should be chosen.26 In addition, such patients should be carefully monitored since recurrences of NMS have been reported in some patients.1,178,179,185,201,382 (See Neuroleptic Malignant Syndrome under Cautions: Nervous System Effects.)

Suicide

Because the possibility of a suicide attempt is inherent in patients with schizophrenia and bipolar disorder, close supervision of high-risk patients is recommended during olanzapine therapy.1,382 The manufacturer recommends that the drug be prescribed in the smallest quantity consistent with good patient management to reduce the risk of overdosage.1

Geriatric Patients with Dementia-related Psychosis

Geriatric patients with dementia-related psychosis treated with antipsychotic drugs are at increased risk of death compared with patients receiving placebo.1 Analyses of 17 placebo-controlled trials (modal duration of 10 weeks) revealed an approximate 1.6- to 1.7-fold increase in mortality among geriatric patients receiving atypical antipsychotic drugs (i.e., aripiprazole, olanzapine, quetiapine, risperidone) compared with that observed in patients receiving placebo.1,374 Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5% compared with a rate of about 2.6% in the placebo group.1,374 Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.1,374 Observational studies suggest that, similar to atypical antipsychotics, treatment with conventional (first-generation) antipsychotics 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 patients remains unclear.1 In placebo-controlled trials of geriatric patients with dementia-associated psychosis, the incidence of death was significantly greater in olanzapine-treated patients than in those receiving placebo (3.5 versus 1.5%, respectively).1

Adverse cerebrovascular events (e.g., stroke, transient ischemic attack), including fatalities, have been reported in clinical trials of olanzapine in geriatric patients with dementia-related psychosis.1,382 In placebo-controlled studies, a significantly higher incidence of adverse cerebrovascular events was observed in olanzapine-treated patients compared with those receiving placebo.1,382

The manufacturer states that olanzapine is not approved for the treatment of patients with dementia-related psychosis.1,382 (See Cautions: Geriatric Precautions.)

Post-injection Delirium/Sedation Syndrome

Clinicians should discuss the potential risk of post-injection delirium/sedation syndrome (PDSS) with patients each time they prescribe and administer extended-release olanzapine pamoate injection (Zyprexa^® Relprevv).382,386 (See Post-injection Delirium/Sedation Syndrome under Cautions: Nervous System Effects.)

Patients should be advised not to drive or operate heavy machinery for the remainder of the day following each injection, and should be vigilant for symptoms of PDSS and able to obtain medical assistance if needed.382 If PDSS is suspected, close medical supervision and monitoring should be instituted in a facility capable of resuscitation.382 For additional information concerning the pathogenesis, clinical manifestations, and management of possible PDSS and other types of olanzapine overdosage, see Acute Toxicity.

In March 2015, FDA concluded a review of 2 unexplained deaths that occurred 3-4 days after the patients received an appropriate dose of long-acting olanzapine pamoate injection (Zyprexa^® Relprevv), which is well beyond the 3-hour post-injection monitoring period required under the current REMS program.391,398 Both patients were found to have very high blood concentrations of olanzapine after death.391,398 High doses of olanzapine can cause delirium, cardiopulmonary arrest, cardiac arrhythmias, and reduced levels of consciousness, ranging from sedation to coma.391 The review suggested that much of the drug level increase could have occurred after death.398 It is unclear whether the patients in these 2 cases died from PDSS; FDA states that the results of their review were inconclusive, and that the possibility that the deaths were caused by rapid but delayed entry of the drug into the bloodstream following IM injection could not be excluded.391,398 In clinical trials, cases of PDSS were observed within 3 hours of administration of olanzapine pamoate; however, no deaths were reported.383,391 If therapy with extended-release olanzapine pamoate is initiated or continued in patients, the FDA recommends that clinicians continue to follow the REMS requirements as well as the recommendations in the prescribing information for Zyprexa^® Relprevv.391,398 The FDA states that patients should not discontinue therapy with extended-release olanzapine pamoate injection without consulting their clinician.398 (See Extended-release Olanzapine Pamoate Injection for Schizophrenia under Dosage and Administration: Reconstitution and Administration.)

Contraindications

The manufacturer states that there are no contraindications associated with oral or short-acting IM olanzapine monotherapy.1

When olanzapine is used in combination with fluoxetine, the usual contraindications associated with fluoxetine must be considered.1

When olanzapine is used as adjunctive therapy with lithium or valproate, the manufacturer advises clinicians to refer to prescribing information for those other drugs.1

The manufacturer states that there are no contraindications associated with use of the long-acting IM formulation of olanzapine pamoate.382

Pediatric Precautions

The safety and effectiveness of oral olanzapine in the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder were established in short-term clinical trials in adolescents (13-17 years of age).1,369,370 Use of oral olanzapine in such adolescents is supported by evidence from adequate and well-controlled clinical trials in which 268 adolescents received olanzapine in a dosage range of 2.5-20 mg daily.1,369,370 The recommended initial dosage for adolescents is lower than that for adults (see Dosage and Administration: Dosage).1 Compared with adults in clinical trials, adolescents were likely to gain more weight, experience increased sedation, and have greater increases in serum concentrations of total cholesterol, triglycerides, LDL-cholesterol, prolactin, and hepatic transaminases.1,369,370,373 (See Pediatric Considerations under Psychotic Disorders: Schizophrenia in Uses, Pediatric Considerations under Bipolar Disorder in Uses, and Cautions.)

When deciding among the alternative treatments available for adolescents with schizophrenia or bipolar disorder, clinicians should consider the increased potential for weight gain and dyslipidemia with olanzapine in adolescents as compared with adults.1,373 Clinicians also should consider the potential long-term risks when prescribing olanzapine to adolescents; in many cases, this may lead them to consider prescribing other drugs first in such patients.1,373

Adolescent patients and/or their caregivers should be advised that adolescent patients receiving olanzapine are likely to gain more weight and to develop sedation, dyslipidemia, higher prolactin elevations, and more elevated serum aminotransferase concentrations compared with adults.1 Adolescent patients and/or their caregivers also should be advised about the potential long-term risks associated with olanzapine therapy and that the risks may lead them to consider other drugs first.1

Pediatric patients with schizophrenia or bipolar disorder should be advised that olanzapine is indicated as an integral part of a total treatment program that may include other measures (e.g., psychological, educational, social) for patients with the disorder.1,373 In addition, pediatric patients should be informed that atypical antipsychotic agents are not intended for use in pediatric patients who exhibit symptoms secondary to environmental factors and/or other primary psychiatric disorders.1,373 Appropriate educational placement is essential and psychosocial intervention is often helpful.1,373 The decision whether to prescribe atypical antipsychotic medication in pediatric patients with schizophrenia or bipolar disorder will depend upon the clinician's assessment of the chronicity and severity of the patient's symptoms.1,373

Because adolescents receiving olanzapine are more likely to gain more weight and experience other metabolic problems compared with adults receiving the drug (see Cautions: Endocrine and Metabolic Effects),1,253,369,370 the American Academy of Child and Adolescent Psychiatry (AACAP) currently recommends that pediatric patients receiving atypical antipsychotic agents for the management of bipolar disorder have baseline body mass index (BMI), waist circumference, blood pressure, fasting glucose, and fasting lipid parameters determined at baseline.253 The AACAP also recommends that the BMI be followed monthly for the initial 3 months of therapy and then every 3 months thereafter.253 In addition, these experts recommend that blood pressure, fasting glucose, and lipid parameters be assessed after 3 months of therapy and then annually thereafter.253 (See Cautions: Precautions and Contraindications.)

The manufacturer states that safety and efficacy of oral olanzapine for the treatment of schizophrenia or manic or mixed episodes associated with bipolar I disorder in children and adolescents younger than 13 years of age have not been established.1,35 However, the drug has been used in a limited number of children and other adolescents with childhood-onset schizophrenia (see Pediatric Considerations under Psychotic Disorders: Schizophrenia, in Uses).148,149,234,235,236,237,238

The safety and efficacy of oral olanzapine in combination with fluoxetine for the treatment of acute depressive episodes associated with bipolar I disorder were established in a short-term clinical trial in pediatric patients 10-17 years of age.1,312,397 Use of oral olanzapine and fluoxetine in such children and adolescents is supported by evidence from a well-controlled clinical trial in which 255 pediatric patients received olanzapine in a dosage range of 3-12 mg daily.312,397 The recommended initial dosage of olanzapine in combination with fluoxetine for adolescents is lower than that for adults (see Dosage and Administration: Dosage).1,312

The manufacturer states that the safety and efficacy of oral olanzapine in combination with fluoxetine for the treatment of treatment-resistant depression have not been established in patients younger than 18 years of age.1,312

The manufacturer states that the safety and efficacy of oral olanzapine in combination with fluoxetine have not been established in pediatric patients younger than 10 years of age.1,312

Oral olanzapine also has been effective and well tolerated in a limited number of children† and adolescents with pervasive developmental disorder, including autistic disorder†.256,257,258,259,260,261 Additional controlled and longer-term studies are needed to confirm these initial findings and to evaluate the relative benefits and risks of olanzapine therapy in such patients.256,257,258,259,261

The manufacturer states that the safety and efficacy of short-acting IM olanzapine have not been established in patients younger than 18 years of age.1

The manufacturer states that the safety and efficacy of extended-release olanzapine pamoate IM injection in patients younger than 18 years of age have not been established.382

Geriatric Precautions

In premarketing clinical studies with oral olanzapine, 11% (263 of 2500) of the patients were 65 years of age or older.1 Clinical experience in patients with schizophrenia generally has not revealed differences in tolerability of oral olanzapine in geriatric patients compared with younger adults.1

The first phase of the large-scale Clinical Antipsychotic Trials of Intervention Effectiveness—Alzheimer's Disease (CATIE-AD) trial was designed to evaluate the overall effectiveness of atypical antipsychotic agents in the treatment of psychosis, aggression, and agitation associated with Alzheimer's disease.318 Patients in this multicenter, double-blind, placebo-controlled trial were randomized to receive either olanzapine, quetiapine, risperidone, or placebo for up to 36 weeks; the principal outcomes were the time from initial treatment until discontinuance of treatment for any reason and the number of patients with at least minimum improvement on the Clinical Global Impression of Change (CGIC) Scale at 12 weeks.318 No statistically significant differences were found among the 4 groups with regard to the time until discontinuation of treatment for any reason; patients remained on olanzapine, quetiapine, risperidone, and placebo for median times of approximately 8, 5, 7, and 8 weeks, respectively.318 In addition, no significant differences in CGIC Scale improvements were noted.318 However, patients receiving atypical antipsychotic therapy reportedly experienced more frequent adverse effects (e.g., drowsiness, weight gain, adverse extrapyramidal effects, confusion, and psychotic symptoms) compared with those receiving placebo.318 The authors stated that these results indicate that the overall therapeutic benefit of atypical antipsychotics in patients with Alzheimer's disease may be offset by the potential risk of adverse effects.318

Studies in patients with dementia-related psychosis have suggested that oral olanzapine may have a different tolerability profile in patients 65 years of age or older with this condition compared with younger patients with schizophrenia.1,26,101,317 Geriatric patients with dementia-related psychosis receiving antipsychotic agents, including olanzapine, are at an increased risk of death compared with that among patients receiving placebo.1,101,317 Analyses of 17 placebo-controlled trials (average duration of 10 weeks) revealed an approximate 1.6- to 1.7-fold increase in mortality among geriatric patients receiving atypical antipsychotic drugs (i.e., olanzapine, aripiprazole, quetiapine, risperidone) compared with that in patients receiving placebo.1,101 Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5% compared with a rate of about 2.6% in the placebo group.1,101 Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.1,101

In placebo-controlled trials with oral olanzapine in geriatric individuals with dementia-related psychosis, an increased incidence of death also was observed; the incidence of death in olanzapine-treated patients was significantly higher than in patients receiving placebo (3.5% and 1.5%, respectively). 1 In addition, a significantly higher incidence of adverse cerebrovascular events (e.g., stroke, transient ischemic attack), including fatalities, was observed in patients receiving olanzapine compared with those receiving placebo in these trials.1 In 5 placebo-controlled studies of olanzapine in geriatric individuals with dementia-related psychosis, certain treatment-emergent adverse effects, including falls, somnolence, peripheral edema, abnormal gait, urinary incontinence, lethargy, increased weight, asthenia, pyrexia, pneumonia, dry mouth, and visual hallucinations, occurred in at least 2% of the patients and the incidence was significantly higher than in patients receiving placebo.1 Discontinuance of therapy because of adverse effects occurred in a significantly higher number of olanzapine-treated patients than in those receiving placebo (13% and 7%, respectively) in these studies.1

The manufacturer states that olanzapine is not approved for the treatment of patients with dementia-related psychosis.1 Some clinicians recommend that the potential risks, therapeutic benefits, and individual needs of patients be carefully considered prior to prescribing olanzapine and other atypical antipsychotic agents for the management of behavioral problems associated with Alzheimer's disease.318,355,356 For additional information on the use of antipsychotic agents in the management of dementia-related psychosis, see Geriatric Considerations under Uses: Psychotic Disorders, in the Phenothiazines General Statement 28:16.08.24.

The manufacturer states that the presence of factors that might decrease the clearance of or increase the pharmacodynamic response to olanzapine should lead to consideration of a lower initial dosage of the drug in geriatric patients.1,312,382

Clinical studies of olanzapine in combination with fluoxetine did not include sufficient numbers of patients 65 years of age or older to determine whether they respond differently than younger patients.1,312

Clinical studies of extended-release IM olanzapine pamoate did not include sufficient numbers of patients 65 years of age or older to determine whether they respond differently than younger patients.382

Mutagenicity and Carcinogenicity

Olanzapine did not exhibit genotoxic potential in the Ames reverse mutation test, in vivo micronucleus mutation test in mice, the chromosomal aberration test in Chinese hamster ovary cells, unscheduled DNA synthesis test in rat hepatocytes, induction of forward mutation test in mouse lymphoma cells, or in vivo sister chromatid exchange test in bone marrow of Chinese hamsters.1

In oral carcinogenicity studies conducted in mice, olanzapine was administered in 2 studies of 78-weeks' duration at dosages of 3, 10, and 30 mg/kg initially then reduced to 20 mg/kg daily (equivalent to 0.8-5 times the maximum recommended human daily oral dosage on a mg/m² basis) and 0.25, 2, and 8 mg/kg daily (equivalent to 0.06-2 times the maximum recommended human daily oral dosage on a mg/m² basis).1,355 In oral carcinogenicity studies conducted in rats, olanzapine was administered for 2 years at dosages of 0.25, 1, 2.5, and 4 mg/kg daily in males (equivalent to 0.13-2 times the maximum recommended human daily oral dosage on a mg/m² basis) and 0.25, 1, 4, and 8 mg/kg daily in females (equivalent to 0.13-4 times the maximum recommended human daily oral dosage on a mg/m² basis).1 An increased incidence of liver hemangiomas and hemangiosarcomas was observed in one mouse study in female mice receiving 8 mg/kg of the drug daily (equivalent to 2 times the maximum recommended human daily oral dosage on a mg/m² basis).1 The incidence of these tumors was not increased in another study in female mice receiving 10 or 30 mg/kg (later reduced to 20 mg/kg) of olanzapine daily (equivalent to 2-5 times the maximum recommended human daily oral dosage on a mg/m² basis); in this study, there was a high incidence of early mortalities in males in the 30 mg/kg (later reduced to 20 mg/kg) daily group.1 The incidence of mammary gland adenomas and adenocarcinomas was increased in female mice receiving 2 mg/kg or more of olanzapine daily and in female rats receiving 4 mg/kg or more of the drug daily (equivalent to 0.5 and 2 times the maximum recommended human daily oral dosage on a mg/m² basis, respectively).1

Antipsychotic agents have been shown to chronically elevate prolactin concentrations in rodents.1 Serum prolactin concentrations were not measured during the olanzapine carcinogenicity studies; however, measurements during subchronic toxicity studies demonstrated that olanzapine administration produced up to a fourfold increase in serum prolactin concentrations in rats receiving the same dosages used in the carcinogenicity study.1 In addition, an increase in mammary gland neoplasms has been observed in rodents following chronic administration of other antipsychotic agents and generally is considered to be prolactin-mediated.1 However, the clinical importance in humans of this finding of prolactin-mediated endocrine tumors in rodents is unknown.1

Pregnancy, Fertility, and Lactation

Pregnancy

Limited experience to date with olanzapine administration during pregnancy has been encouraging and has not revealed evidence of any obvious teratogenic risks; however, additional cases of olanzapine exposure during pregnancy need to be evaluated to more fully determine the relative safety of olanzapine and other antipsychotic agents when administered during pregnancy.26,113,315,319,321,322,323,324,325,326 The manufacturer states that there have been 7 pregnancies reported during clinical trials with olanzapine, including 2 resulting in normal births, one resulting in neonatal death due to a cardiovascular defect, 3 therapeutic abortions, and one spontaneous abortion.1 In a separate compilation of pregnancy exposures to olanzapine reported to the manufacturer during clinical trials and from spontaneous reports worldwide, outcomes were available from 23 prospectively collected, olanzapine-exposed pregnancies.113,319 Spontaneous abortion occurred in 13% of these pregnancies, stillbirth in 5%, major malformations in 0%, and prematurity in 5%; these rates were all within the range of normal historical control rates.113,319 In 11 retrospectively collected, olanzapine-exposed pregnancies, there was one case of dysplastic kidney, one case of Down's syndrome, and one case of heart murmur and sudden infant death syndrome at 2 months of age.113,319 In another study, the majority of women with schizophrenia receiving atypical antipsychotic agents were found to be overweight and to have reduced folate intake and low serum folate concentrations, which may increase the potential risk of neural tube defects.26,327 In a prospective, comparative trial assessing pregnancy outcome in women receiving atypical antipsychotic agents (olanzapine, clozapine, risperidone, and quetiapine) during pregnancy, atypical antipsychotics did not appear to be associated with an increased risk of major congenital malformations.315 In addition, several case reports have described healthy infants born to women without complications despite prenatal exposure to olanzapine.319,321,322,323,324,325,326

Neonates exposed to antipsychotic agents, including olanzapine, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery.1,312,379,380,381,382 There have been reports of agitation, hypertonia, hypotonia, tardive dyskinetic-like symptoms, tremor, somnolence, respiratory distress, and feeding disorder in these neonates.1,312,379,380,381,382 The majority of cases were also confounded by other factors, including concomitant use of other drugs known to be associated with withdrawal symptoms, prematurity, congenital malformations, and obstetrical and perinatal complications; however, some cases suggested that neonatal extrapyramidal and withdrawal symptoms may occur with exposure to antipsychotic agents alone.379,381 Some of the cases described time of symptom onset, which ranged from birth to one month after birth.379,380,381 Any neonate exhibiting extrapyramidal or withdrawal symptoms following in utero exposure to antipsychotic agents should be monitored.381 Symptoms were self-limiting in some neonates but varied in severity; some infants required intensive care unit support and prolonged hospitalization.1,312,379,380,381,382 For further information on extrapyramidal and withdrawal symptoms in neonates, see Cautions: Pregnancy, Fertility, and Lactation, in the Phenothiazines General Statement 28:16.08.24.

The manufacturer and some clinicians state that there are no adequate and well-controlled studies to date using olanzapine in pregnant women,1 and the drug should be used during pregnancy only when the potential benefits justify the potential risks to the fetus.1,26,113 Women should be advised to notify their clinician if they become pregnant or plan to become pregnant during therapy with the drug.1,381,382 In addition, clinicians should advise women of childbearing potential about the benefits and risks of using antipsychotic agents during pregnancy.381 Patients should also be advised not to stop taking their antipsychotic agent if they become pregnant without first consulting with their clinician, since abruptly discontinuing the drugs can cause clinically important complications.381

Parturition in rats was not affected by olanzapine.1 The effect of olanzapine on labor and delivery is unknown.1

In oral reproduction studies in rats receiving dosages of up to 18 mg/kg daily and in rabbits at dosages of up to 30 mg/kg daily (equivalent to 9 and 30 times the maximum recommended human daily oral dosage on a mg/m² basis, respectively), no evidence of teratogenicity was observed.1 In an oral rat teratology study, early resorptions and increased numbers of nonviable fetuses were observed at a dosage of 18 mg/kg daily (9 times the maximum recommended human daily oral dosage on a mg/m² basis), and gestation was prolonged at a dosage of 10 mg/kg daily (equivalent to 5 times the maximum recommended human daily oral dosage on a mg/m² basis).1 In an oral rabbit teratology study, fetal toxicity, which was manifested as increased resorptions and decreased fetal weight, occurred at a maternally toxic dosage of 30 mg/kg daily (equivalent to 30 times the maximum recommended human daily oral dosage on a mg/m² basis).1

Fertility

In an oral fertility and reproductive performance study in rats, male mating performance, but not fertility, was impaired at an olanzapine dosage of 22.4 mg/kg daily, and female fertility was decreased at a dosage of 3 mg/kg daily (equivalent to 11 and 1.5 times the maximum recommended human daily oral dosage on a mg/m² basis, respectively).1 Discontinuance of olanzapine administration reversed the effects on male mating performance.1 In a female rat fertility study, the precoital period was increased, and the mating index reduced at a dosage of 5 mg/kg daily (equivalent to 2.5 times the maximum recommended human daily oral dosage on a mg/m² basis).1 Diestrus was prolonged and estrus was delayed at a dosage of 1.1 mg/kg daily (equivalent to 0.6 times the maximum recommended human daily oral dosage on a mg/m² basis). 1

Lactation

Olanzapine is distributed into milk.1,110,111,112,113 The mean dosage received by an infant at steady state is estimated to be about 1.8% of the maternal dosage.1 The manufacturer recommends that women receiving olanzapine not breast-feed. 1,113

Drug Interactions ⬆ ⬇

[Section Outline]

Drugs Affecting Hepatic Microsomal Enzymes
Drugs Metabolized by Hepatic Microsomal Enzymes
Anticholinergic Agents
Levodopa and Dopamine Agonists
Lamotrigine
Other CNS-Active Agents and Alcohol
Hypotensive Agents
Antacids or Cimetidine
Activated Charcoal
Smoking
Other Drugs

Drugs Affecting Hepatic Microsomal Enzymes

Olanzapine is a substrate for cytochrome P-450 (CYP) isoenzyme 1A2 and concomitant administration of drugs that induce CYP1A2 or glucuronyl transferase enzymes (e.g., carbamazepine, omeprazole, rifampin) may cause an increase in olanzapine clearance.1,116 Inhibitors of CYP1A2 (e.g., fluvoxamine) could potentially decrease olanzapine clearance.1,116 Although olanzapine is metabolized by multiple enzyme systems, induction or inhibition of a single enzyme may appreciably alter olanzapine clearance.1,116 Therefore, an increase or decrease in olanzapine dosage may be necessary during concomitant administration of olanzapine with specific drugs that induce or inhibit olanzapine metabolism, respectively.1,116

Carbamazepine

Carbamazepine therapy (200 mg twice daily for 2 weeks) causes an approximately 50% increase in the clearance of a single, 10-mg dose of olanzapine.1,116 The manufacturer of olanzapine states that higher dosages of carbamazepine may cause an even greater increase in olanzapine clearance.1,116 Increased clearance of olanzapine probably is caused by carbamazepine-induced induction of CYP1A2 activity.1,116

Selective Serotonin-reuptake Inhibitors

Concomitant administration of fluoxetine (60 mg as a single dose or 60 mg daily for 8 days) with a single 5-mg dose of oral olanzapine caused a small increase in peak plasma olanzapine concentrations (averaging 16%) and a small decrease (averaging 16%) in olanzapine clearance in one study; the elimination half-life was not substantially affected.1,116,312,330 A similar decrease in olanzapine clearance of 14% was observed in another study with concomitant administration of olanzapine doses of 6 or 12 mg and fluoxetine doses of 25 mg or more.312 Fluoxetine is an inhibitor of CYP2D6, and thereby may affect a minor metabolic pathway for olanzapine.116,330 Although the changes in pharmacokinetics are statistically significant when olanzapine and fluoxetine are given concurrently, the changes are unlikely to be clinically important in comparison to the overall variability observed between individuals; therefore, routine dosage adjustment is not recommended. 1,116,312,330

Fluvoxamine, a CYP1A2 inhibitor, has been shown to decrease the clearance of olanzapine, which is metabolized by CYP1A2; there is some evidence that fluvoxamine-induced CYP1A2 inhibition is dose dependent.1,151,152,153,155,156 In one pharmacokinetic study, peak plasma olanzapine concentrations increased by an average of 54 and 77% and area under the plasma concentration-time curve (AUC) increased by an average of 52 and 108% in female nonsmokers and male smokers, respectively, when fluvoxamine and olanzapine were administered concomitantly.1 Symptoms of olanzapine toxicity also have been reported in at least one patient during combined therapy.155 The manufacturer and some clinicians state that a lower olanzapine dosage should therefore be considered in patients receiving concomitant treatment with fluvoxamine.1,151 Preliminary data indicate that concurrent fluvoxamine administration may potentially be used to therapeutic advantage by reducing the daily dosage of olanzapine and thereby the cost of therapy; further controlled studies are needed to more fully evaluate this approach.151 Although combined therapy with olanzapine and fluvoxamine generally has been well tolerated and may be associated with clinical benefit, some clinicians recommend that caution be exercised and monitoring of plasma olanzapine concentrations be considered in patients receiving these drugs concurrently.151,152,153,156

Preliminary results from a therapeutic drug monitoring service suggest that concurrent administration of sertraline and olanzapine does not substantially affect the pharmacokinetics of olanzapine.156

Warfarin

Concomitant administration of a single 20-mg dose of warfarin (which has a potential CYP2C9 interaction) and a single oral 10-mg dose of olanzapine did not substantially alter the pharmacokinetics of olanzapine. 1,116

Drugs Metabolized by Hepatic Microsomal Enzymes

In vitro studies utilizing human liver microsomes suggest that olanzapine has little potential to inhibit metabolism of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A substrates.1,116 Therefore, clinically important drug interactions between olanzapine and drugs metabolized by these isoenzymes are considered unlikely.1,116

Anticholinergic Agents

Because of the potential for disruption of body temperature regulation, olanzapine should be used with caution in patients concurrently receiving other drugs with anticholinergic activity.1,382 (See Body Temperature Regulation under Cautions: Precautions and Contraindications.)

Levodopa and Dopamine Agonists

Olanzapine may antagonize the effects of levodopa and dopamine agonists.1

Lamotrigine

In a multiple-dose study in healthy individuals, the pharmacokinetics of olanzapine and lamotrigine were not substantially affected when the drugs were administered concomitantly.284 In another multiple-dose study conducted in healthy volunteers, olanzapine did not substantially alter lamotrigine pharmacokinetics when the drugs were administered concurrently.331 However, the time to reach maximal plasma concentrations of lamotrigine was substantially prolonged in this study, possibly because of olanzapine's anticholinergic activity.331 The tolerability of this combination was found to be similar to that of olanzapine alone, with mild sedative effects reported in some patients receiving the drugs concurrently.284,331 Although routine dosage adjustment does not appear to be necessary when olanzapine and lamotrigine are given concurrently, adjustment in lamotrigine dosage may be necessary in some patients for therapeutic reasons when olanzapine therapy is initiated or discontinued.284 In addition, careful monitoring of patients receiving high dosages of olanzapine and lamotrigine has been recommended by some clinicians.284

Other CNS-Active Agents and Alcohol

Because of the prominent CNS actions of olanzapine, the manufacturer states that caution should be exercised when olanzapine is administered concomitantly with other centrally acting drugs and alcohol.1,382 The manufacturer also states that concomitant use of olanzapine with CNS agents that are associated with hypotension (e.g., diazepam) may potentiate the orthostatic hypotension associated with olanzapine.1,382

Benzodiazepines

Because of the prominent CNS actions of olanzapine, the manufacturer states that caution should be exercised when olanzapine is administered concomitantly with benzodiazepines.1,382 The manufacturer also states that concomitant use of olanzapine and diazepam or other benzodiazepines that are associated with hypotension may potentiate the orthostatic hypotension associated with olanzapine.1,382 However, administration of multiple doses of olanzapine did not substantially alter the pharmacokinetics of diazepam or its active metabolite N -desmethyldiazepam.1,382

The pharmacokinetics of olanzapine, unconjugated lorazepam, and total lorazepam were not substantially affected when IM lorazepam (2 mg) was administered 1 hour after IM olanzapine (5 mg); however, increased somnolence was observed with this combination.1 Hypotension also has been reported when short-acting IM olanzapine and IM lorazepam have been administered concurrently.150 The manufacturer of olanzapine therefore states that concurrent use of short-acting IM olanzapine in conjunction with parenteral benzodiazepines is not recommended due to the potential for excessive sedation and cardiorespiratory depression.1

Tricyclic Antidepressants

Administration of single doses of olanzapine did not substantially affect the pharmacokinetics of imipramine or its active metabolite desipramine.1,282

Lithium

Multiple doses of oral olanzapine (10 mg for 8 days) did not affect the pharmacokinetics of a single dose of lithium.1,116 Although combined olanzapine and lithium therapy generally has been well tolerated in controlled clinical studies,1,41 rare cases of apparent lithium toxicity and adverse extrapyramidal effects, including oculogyric crisis, have been reported in patients receiving these drugs concurrently; the mechanism(s) for this potential drug interaction remains to be established.348 The manufacturer of olanzapine states that lithium dosage adjustment is not necessary during concurrent olanzapine administration.1

Valproic Acid

In vitro studies using human liver microsomes indicated that olanzapine has little potential to inhibit the major metabolic pathway (glucuronidation) of valproic acid.1 In addition, valproic acid has little potential effect on the metabolism of olanzapine in vitro.1 In a pharmacokinetic study, olanzapine administration (10 mg daily for 2 weeks) did not affect the steady-state plasma concentrations of valproic acid.1 However, substantially decreased plasma olanzapine concentrations have been reported in several patients following initiation of valproate in patients already receiving oral olanzapine; it was suggested that induction of the hepatic enzymes responsible for olanzapine's metabolism by valproate may have been responsible for these findings.349 Further studies are needed to determine whether a pharmacokinetic interaction exists between olanzapine and valproic acid since these drugs are frequently used in combination in clinical practice.349 The manufacturer of olanzapine currently states that routine dosage adjustment of valproic acid is not necessary during concurrent olanzapine administration.1

Alcohol

In a pharmacokinetic study, concomitant administration of a single dose of alcohol did not substantially alter the steady-state pharmacokinetics of olanzapine (given in dosages of up to 10 mg daily).1,116,382 However, concomitant use of olanzapine with alcohol potentiated the orthostatic hypotension associated with olanzapine.1 The manufacturer therefore states that alcohol should be avoided during olanzapine therapy.1,382

Hypotensive Agents

Olanzapine therapy potentially may enhance the effects of certain hypotensive agents during concurrent use.1 In addition, the administration of dopamine, epinephrine, and/or other sympathomimetic agents with β-agonist activity should be avoided in the treatment of olanzapine-induced hypotension, since such stimulation may worsen hypotension in the presence of olanzapine-induced α-blockade.1,128 (See Acute Toxicity: Treatment.)

Antacids or Cimetidine

In pharmacokinetic studies, single doses of cimetidine (800 mg) or aluminum- and magnesium-containing antacids (30 mL) did not substantially affect the oral bioavailability of a single, 7.5-mg dose of olanzapine.1,116

Activated Charcoal

Concurrent administration of activated charcoal (1 g) reduced peak plasma concentrations and the AUC of a single, 7.5-mg oral dose of olanzapine by approximately 60%.1,116 Since peak plasma concentrations are not usually obtained until about 6 hours after oral administration, activated charcoal may be useful in the management of olanzapine intoxication.1,116 (See Acute Toxicity: Treatment.)

Smoking

The manufacturer states that the clearance of olanzapine in smokers is approximately 40% higher than in nonsmokers.1 Therefore, plasma olanzapine concentrations generally are lower in smokers than in nonsmokers receiving the drug. 1,134,135,141,142 Adverse extrapyramidal effects have been reported in one olanzapine-treated patient after a reduction in cigarette smoking,134 while worsened delusions, hostility, and aggressive behavior have been reported in another olanzapine-treated patient following a marked increase in smoking (i.e., an increase from 12 up to 80 cigarettes per day). 138 Although the precise mechanism(s) for this interaction has not been clearly established, it has been suggested that induction of the CYP isoenzymes, particularly 1A2, by smoke constituents may be responsible at least in part for the reduced plasma olanzapine concentrations observed in smokers compared with nonsmokers.134,135,138,144

Although the manufacturer states that routine dosage adjustment is not recommended in patients who smoke while receiving olanzapine,1 some clinicians recommend that patients treated with olanzapine should be monitored with regard to their smoking consumption and that dosage adjustment be considered in patients who have reduced or increased their smoking and/or who are not responding adequately or who are experiencing dose-related adverse reactions to the drug.134,138 In addition, monitoring of plasma olanzapine concentrations may be helpful in patients who smoke and have other factors associated with substantial alterations in metabolism of olanzapine (e.g., geriatric patients, women, concurrent fluvoxamine administration).141

Other Drugs

Multiple doses of olanzapine did not substantially alter the pharmacokinetics of theophylline or its metabolites.1,116

Multiple doses of olanzapine did not substantially affect the pharmacokinetics of biperiden.1,116

Other Information ⬆ ⬇

[Section Outline]

Pathogenesis and Manifestation
Treatment
Nervous System Effects
Neuroendocrine Effects
Antiemetic Effects
Absorption
Distribution
Elimination
Chemistry
Stability

Acute Toxicity

Pathogenesis and Manifestation

The acute lethal dose of olanzapine in humans remains to be established.119,124 However, the toxic and lethal doses of olanzapine and other atypical antipsychotic agents appear to be highly variable and depend on concurrent administration of other drugs or toxic substances, patient age and habituation, and the time from exposure until treatment is initiated; pediatric and/or nonhabituated patients appear to be more sensitive to the toxic effects of these drugs.119

During premarketing clinical studies of extended-release olanzapine pamoate (Zyprexa^® Relprevv), adverse events that presented with signs and symptoms consistent with olanzapine overdosage, particularly sedation (ranging from mild in severity to coma) and/or delirium, were reported following IM injection of the drug.372,382,383,386,387,392,398 Such cases of post-injection delirium/sedation syndrome (PDSS) occurred in less than 0.1% of injections382,386,387 and in approximately 2% of patients who received injections for up to 46 months.382 These events were correlated with an unintentional rapid increase in serum olanzapine concentrations to supratherapeutic ranges in some cases.382,387 Although a rapid and greater than expected increase in serum olanzapine concentrations has been noted in some patients with these adverse events, the precise mechanism by which the drug was unintentionally introduced into the bloodstream in these cases is not known.382 Clinical signs and symptoms of PDSS include dizziness, confusion, disorientation, malaise, slurred speech, altered gait, ambulation difficulties, weakness, agitation, extrapyramidal symptoms, hypertension, convulsion, and reduced levels of consciousness ranging from mild sedation to coma.382,383,386 The time after injection to PDSS in the reported cases ranged from soon after the injection to greater than 3 hours after the injection.382,383,386 The majority of patients required hospitalization, and supportive care, including intubation, was necessary in several cases.382,386 All patients had largely recovered by 72 hours.382,383,386 Because the risk of PDSS is the same at each injection, the risk per patient is cumulative (i.e., the risk increases with the number of injections).382,384 (See Post-injection Delirium/Sedation Syndrome under Cautions: Nervous System Effects and also under Cautions: Precautions and Contraindications.)

In postmarketing reports of overdosage with oral olanzapine alone, symptoms have been reported in the majority of cases.121,303,329,382 Following acute overdosage of oral olanzapine or other atypical antipsychotic agents, toxic effects usually begin within 1-2 hours and maximal toxic effects usually are seen 4-6 hours following acute ingestion.119,120,126 In general, overdosage of olanzapine may be expected to produce effects that are extensions of its pharmacologic and adverse effects.118,119,303,329,382 The most commonly reported manifestations of olanzapine overdosage and those that have occurred in 10% or more of symptomatic patients following postmarketing overdosage reports with olanzapine alone are agitation and/or aggressiveness, dysarthria, tachycardia, anticholinergic syndrome, miosis, various extrapyramidal symptoms, jerking and myoclonus, hypersalivation, and reduced level of consciousness ranging in severity from sedation to coma.1,117,118,119,120,121,126,128,303,329,382 Less commonly reported but potentially medically serious events included aspiration, cardiopulmonary arrest, cardiac arrhythmias (e.g., supraventricular tachycardia), delirium, possible neuroleptic malignant syndrome, respiratory depression and/or arrest, convulsions, hypertension, and hypotension (including orthostatic hypotension); one patient experienced sinus pause with spontaneous resumption of normal rhythm.1,117,118,119,120,128,329,382 Fatalities in association with overdosage of oral olanzapine alone have been reported.1,119,124,127,382 In one such case, the amount of acutely ingested oral olanzapine was reported to be possibly as low as 450 mg of oral olanzapine; however, in another case, a patient reportedly survived an acute ingestion of approximately 2 g of oral olanzapine.1,119,127,382

In some cases of acute olanzapine intoxication, rapid fluctuation in mental status (i.e., between sedation and agitation or agitation despite sedation) has been reported.118,120,121,126,136,137 In addition, olanzapine overdosage may resemble opiate overdosage because CNS depression and miosis sometimes are observed.118,121,126,137,328,329 Increased creatine kinase (CK, creatine phosphokinase, CPK) concentrations also have occurred following acute olanzapine overdosage.137,329 Cardiac arrhythmias, persistent choreoathetosis, nonconvulsive status epilepticus, hypersalivation, and coma occurred in an adult following an intentional ingestion estimated to be 750 mg of olanzapine; both coma and choreoathetosis persisted until the patient's death 8 weeks later.329

The toxic effects of olanzapine and other atypical antipsychotic agents in pediatric patients appear to be similar to those seen in adults.117,119,120,125,126,328 In young children, marked CNS depression and anticholinergic delirium have occurred following ingestion of 7.5-15 mg of olanzapine (equivalent to 0.5-1 mg/kg).119,125,126 In an adolescent who ingested 275 mg of olanzapine and had an extremely high serum olanzapine concentration (1503 ng/mL), somnolence, agitation, and extrapyramidal symptoms developed initially, but the patient recovered without complications.117 A 400-mg olanzapine overdosage in another adolescent reportedly produced severe respiratory depression requiring intubation and mechanical ventilation; the patient recovered after 3 days.117 In addition, polyuria and other signs suggesting possible diabetes insipidus, including hypoosmolar urine, normoosmolar plasma, and increased serum sodium concentrations, have been reported in one adolescent following an overdosage of olanzapine and prazepam (a benzodiazepine; not commercially available in the US).136

Treatment

Clinicians should be aware that post-injection delirium/sedation syndrome (PDSS) may occur with any IM injection of extended-release olanzapine pamoate (Zyprexa^® Relprevv).382 Signs and symptoms consistent with olanzapine overdosage have been observed in such cases, and access to emergency response services must be readily available for safe use.382

Management of olanzapine overdosage generally involves symptomatic and supportive care, including continuous cardiovascular and respiratory monitoring and ensuring IV access.119,120,121,128,303,329,382 Cardiovascular monitoring should be initiated immediately and should include continuous ECG monitoring to detect possible arrhythmias.119,121,382 There is no specific antidote for olanzapine intoxication.128,329,382 In managing olanzapine overdosage, the clinician should consider the possibility of multiple drug intoxication.382

The manufacturer and many clinicians recommend establishing and maintaining an airway and ensuring adequate ventilation and oxygenation, which may include intubation.1,119,120,128,382 Gastric lavage (following intubation, if the patient is unconscious) and/or activated charcoal, which may be used with sorbitol, should be considered.1,119,120,121,329 (See Drug Interactions: Activated Charcoal.) The possibility that obtundation, seizures, or dystonic reaction of the head and neck following olanzapine overdosage may create a risk of aspiration with induction of emesis should be considered.1,382

Hypotension and circulatory collapse, if present, should be treated with appropriate measures, such as Trendelenburg's position, IV fluids, and/or sympathomimetic agents (e.g., norepinephrine, phenylephrine).1,119,128,329,382 However, dopamine, epinephrine, and/or other sympathomimetic agents with β-adrenergic agonist activity should be avoided, since such stimulation may worsen hypotension in the presence of olanzapine-induced α-adrenergic blockade.1,128,329,382 Tachycardia associated with olanzapine intoxication usually does not require specific therapy.119 Atrial and ventricular arrhythmias and conduction disturbances should be treated with appropriate measures; sodium bicarbonate may be helpful if QRS-interval prolongation is present.119 Seizures following olanzapine overdosage may be treated initially with a benzodiazepine followed by barbiturates, if necessary.119 Acute extrapyramidal reactions should be treated with anticholinergic agents (e.g., diphenhydramine, benztropine).119

Physostigmine salicylate or benzodiazepine therapy may be useful in the management of severe agitation and delirium in patients with severe anticholinergic toxicity and a narrow QRS complex on their ECG.119,120,121,303 Physostigmine has been used successfully in the treatment of anticholinergic toxicity associated with overdosages of olanzapine or clozapine, another atypical antipsychotic agent.119,121,303 However, experience with physostigmine in the management of atypical antipsychotic overdosage is limited, and some clinicians recommend that the drug be used only by experienced clinicians and in cases in which the potential therapeutic benefit outweighs the potential risks.119,121,303

Resolution of toxic effects following atypical antipsychotic intoxication generally occurs within 12-48 hours following acute overdosage, although it has taken up to 6 days.117,119,125,126,303 Patients should remain under close medical supervision and monitoring until fully recovered.1,121

Hemodialysis has not been shown to be useful for enhancing elimination of olanzapine in acute overdosage.116,119,146,329 Clinical experience with other enhanced elimination techniques, including multiple-dose activated charcoal, hemoperfusion, forced diuresis, and urinary alkalinization, is lacking; however, these treatments also are unlikely to be beneficial following olanzapine overdosage because of the drug's large volume of distribution and extensive protein binding.116,119

Chronic Toxicity

In animal studies prospectively designed to assess abuse and dependence potential, olanzapine was shown to produce acute CNS depressive effects but little or no potential for abuse or physical dependence in rats administered oral doses up to 15 times the maximum recommended human daily oral dosage (20 mg) and rhesus monkeys administered oral doses up to 8 times the maximum recommended human daily oral dosage on a mg/m² basis.1 Olanzapine has not been systematically evaluated in humans to date for its potential for abuse, tolerance, or physical dependence.1 While clinical trials did not reveal any tendency for drug-seeking behavior, these observations were not systematic, and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed.1 Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of misuse or abuse of olanzapine (e.g., development of tolerance, increases in dose, drug-seeking behavior).1

Pharmacology

Olanzapine is a thienobenzodiazepine-derivative antipsychotic agent.1,16,17,20,119,315 The drug shares some of the pharmacologic actions of other antipsychotic agents and has been described as an atypical or second-generation antipsychotic agent.1,2,4,7,14,16,17,18,19,20,22,26,147,315,333 Like other atypical or second-generation antipsychotics (e.g., aripiprazole, asenapine, clozapine, quetiapine, risperidone, ziprasidone), olanzapine is less likely to cause adverse extrapyramidal effects and tardive dyskinesia than conventional (first-generation) antipsychotic agents, and is effective in the treatment of positive, negative, and depressive manifestations of schizophrenia.26,147,215,288,289,290,315,333,375

Nervous System Effects

The exact mechanism of antipsychotic action of olanzapine and other atypical antipsychotic agents has not been fully elucidated but appears to be more complex than that of conventional, first-generation antipsychotic agents and may involve central antagonism at serotonin type 2 (5-hydroxytryptamine [5-HT_2A, 5-HT_2C]), type 3 (5-HT₃), and type 6 (5-HT₆) and dopamine receptors.1,4,6,7,16,17,18,19,20,21,22,164,288,289,290,315,333

The exact mechanism(s) of action of olanzapine in the treatment of acute manic or mixed episodes associated with bipolar disorder is not fully known.1,347 However, it has been suggested that the ability of olanzapine to block and downregulate 5-HT_2A receptors may play a role in its antimanic activity.347 In addition, olanzapine's mood-stabilizing action may be caused at least in part by antagonism of D₂ receptors.347 Further studies are needed to more clearly elucidate the potential mechanism(s) of the drug's antimanic activity.347,356

Although not clearly established, the efficacy of IM olanzapine in the treatment of acute agitation appears to be due at least in part to its distinct calming effects rather than solely to nonspecific sedation.104

Antidopaminergic Effects

The therapeutic effects of antipsychotic drugs are thought to be mediated by dopaminergic blockade in the mesolimbic and mesocortical areas of the CNS, while antidopaminergic effects in the neostriatum appear to be associated with extrapyramidal effects.7,13,15,18,20,22,295,296,297,298,315,333 The relatively low incidence of extrapyramidal effects associated with olanzapine therapy suggests that the drug is more active in the mesolimbic than the neostriatal dopaminergic system.13,18,20,164,295,296,297,298

Several (at least 5) different types or subtypes of dopamine receptors have been identified in animals or humans.1,290 The relative densities of these receptors and their distribution and function vary for different neuroanatomical regions, and olanzapine's effects may be secondary to regionally specific receptor interactions and/or other effects on dopaminergic neurons.164,290 Current evidence suggests that the clinical potency and antipsychotic efficacy of both typical and atypical antipsychotic drugs generally are related at least in part to their affinity for and blockade of central dopamine D₂ receptors.1,2,13,14,16,20,288,289,290,315 Some studies suggest that clinically effective dosages of most antipsychotic agents result in occupation of between 60 and 80% of central dopamine D₂ receptors.288,289 However, antagonism at D₂ receptors does not appear to account fully for the antipsychotic effects of olanzapine. 1,7,16,17,18,20,22,164,288,289,290 In vivo and in vitro studies have demonstrated that olanzapine is a comparatively weak antagonist at D₂ receptors.4,16,17,20,21 Although their role in eliciting the pharmacologic effects of antipsychotic agents remains to be fully elucidated, dopamine D₃, D₄, and D₅ receptors also have been identified. 1,2,4,7,13,18,20,288 Olanzapine may have a higher affinity for D₄ receptors than for D₂ or D₃ receptors.4,18 K_I values of olanzapine for dopamine D_1-4 receptors range from 11-31 nM.1

Atypical antipsychotic agents generally have demonstrated relatively loose binding to dopamine D₂ receptors.26,288,289,333 Compared with typical antipsychotic agents, atypical antipsychotics appear to have faster dissociation rates from and lower affinity for dopamine D₂ receptors, which may result in fewer adverse extrapyramidal effects and less risk of elevated prolactin concentrations; however, further studies are needed to confirm these initial findings.26,288,289,333

Serotonergic Effects

It has been suggested that schizophrenia may involve a dysregulation of serotonin- and/or dopamine-mediated neurotransmission, and olanzapine may at least partially restore a normal balance of neurotransmitter function, possibly through serotonergic modulation of dopaminergic tone.1,119,291,292,293,333 Olanzapine blocks serotonin type 2 (5-hydroxytryptamine [5-HT_2A and 5-HT_2C; K_I of 4 and 11 nM, respectively]), type 3 (5-HT₃; K_I of 57 nM), 1,16 and type 6 (5-HT₆; K_I of 5 nM) receptors. 1,4,18,19,20,21,164

Anticholinergic Effects

Olanzapine blocks muscarinic cholinergic receptors and has demonstrated moderate affinity for all 5 muscarinic receptor subtypes (K_I values for M_1-5 were 73, 96, 132, 32, and 48 nM, respectively).1,6,7,16,17,20,164,289,290 Anticholinergic activity in antipsychotic agents may contribute to certain adverse anticholinergic events associated with these drugs but also may help reduce the risk of adverse extrapyramidal reactions.1,6,7,16,17,20,164,289,290,352

Effects on Other Central Neurotransmitters

Antagonism at receptors other than dopamine and 5-HT₂ receptors may produce some of the therapeutic and adverse effects associated with olanzapine.1,2,6,7,16,20,164,290 Olanzapine exhibits α₁-adrenergic blocking activity (K_I of 19 nM), which may explain the occasional orthostatic hypotension associated with the drug.1,2,6,7,16,20 In addition, olanzapine blocks histamine H₁ receptors (K_I of 7 nM), which may explain the sedative effects associated with the drug; affinity for H₂ and H₃ receptors appears to be low.1,7,16,20,290

Olanzapine demonstrated weak binding affinity (K_I exceeding 10 µM) for β-adrenergic, γ-aminobutyric acid (GABA), and benzodiazepine receptors; the drug also has little or no affinity for opiate receptors.1,16,20,290

Neurophysiologic Effects

In vivo electrophysiologic studies demonstrate different sensitivities of various brain areas to antipsychotic-mediated postsynaptic receptor blockade.290,294,295,296,297,298,315 While conventional antipsychotics generally reduce spontaneous firing activity in both the mesolimbic (A10) and nigrostriatal regions (A9), chronic administration of atypical antipsychotics generally reduces the number of spontaneously active dopaminergic neurons in the mesolimbic region but not in the nigrostriatal region.290,294,295,296,297,298,299,315 Although not clearly established, it has been suggested that the ability to decrease A10 but not A9 neurons is associated clinically with a low potential to cause adverse extrapyramidal reactions and tardive dyskinesia.295,296,297,298,315 Olanzapine has demonstrated such mesolimbic selectivity in the in vivo studies conducted to date. 290,294,295,296,297,298,315

Cognitive Effects in Humans

Clinical experience suggests that second-generation antipsychotics, including olanzapine, improve cognition in patients with schizophrenia and that there may be differences between these drugs in their effects on neurocognitive functioning.147,215,315,340,341,342,343,344,345 In an initial clinical trial evaluating the short-term effects of atypical antipsychotic agents on cognitive function, olanzapine-treated schizophrenic patients demonstrated improved learning and memory, verbal fluency, and executive function.341 In a controlled clinical trial evaluating the neurocognitive effects of olanzapine, clozapine, risperidone, and haloperidol in patients with treatment-resistant schizophrenia or schizoaffective disorder, global neurocognitive function improved with olanzapine and risperidone treatment, and these improvements were found to be superior to those seen with haloperidol.342 Patients treated with olanzapine exhibited improvement in the general and attention domains but not more than that observed with the other antipsychotic agents.342 In another controlled trial, patients with schizophrenia receiving long-term (1 year) therapy with olanzapine demonstrated improved results on a general cognition index compared with those receiving haloperidol and risperidone.340 Neurocognition also improved in olanzapine- and risperidone-treated schizophrenic and schizoaffective patients receiving the drug for 1 year in another controlled study; improvements in executive function, learning and memory, processing speed, attention and vigilance, verbal working memory, and motor function were reported.344 The clinical relevance of these cognitive findings in the management of schizophrenia remains to be determined and requires further study.340,343,345

EEG Effects

Olanzapine may cause EEG changes.167,168,169,170 In one study, olanzapine-induced EEG slowing to a lesser extent than clozapine in patients with schizophrenia and did not appear to substantially alter epileptiform activity in most of the patients studied; further studies are needed to determine whether olanzapine can affect the seizure threshold.167 Similarly, a comparative study found that epileptiform activity did not increase during olanzapine therapy; however, EEG slowing and other nonspecific EEG changes did occur more frequently in olanzapine-treated patients than in those receiving certain other antipsychotic agents.169 In another study that was retrospective in design, EEG changes occurred more frequently in patients receiving olanzapine or clozapine than in those receiving typical antipsychotic agents, quetiapine, or risperidone.168 In a study in patients with schizophrenia, olanzapine therapy was associated with increased rates of slow waves, sharp waves, and paroxysmal slow wave discharges on EEG recordings in the patients evaluated; however, spike- and sharp-slow-wave complexes that indicate seizure risk were not observed in this study.170

Seizures have been reported rarely in olanzapine-treated patients but confounding factors were present in most of these cases.1,171,172,173,174,175 Further studies and postmarketing surveillance are needed to determine whether olanzapine can affect the seizure threshold and to evaluate the clinical relevance of the observed EEG findings in patients receiving the drug.167,169,174,175

Effects on Sleep

The available evidence suggests that atypical antipsychotics, including olanzapine, clozapine, and risperidone, substantially increase total sleep time and stage 2 sleep; both olanzapine and risperidone also have been shown to enhance slow-wave sleep.158,160 Olanzapine's beneficial effects on sleep quality are thought to be mediated principally via type 2 serotonergic (5-HT₂) receptors.157,158,159,161,163

In a controlled study, administration of single evening doses of olanzapine (5 or 10 mg orally) in healthy individuals significantly increased slow-wave sleep in a dose-related manner; sleep continuity measures and subjective sleep quality also increased significantly.157 Single 10-mg doses of the drug also suppressed rapid eye movement (REM) sleep and increased REM sleep latency in this study.157 In another study in healthy males and females, single 10-mg oral doses of olanzapine also were found to increase slow-wave sleep but preserved the normal structure of sleep; these effects were more prominent in females than in males.158

During subchronic administration of olanzapine (15-20 mg) in patients with schizophrenia with predominantly negative symptoms in an uncontrolled study, parameters of sleep efficiency improved and delta sleep and REM sleep increased.159 Acute olanzapine administration (10 mg orally) in schizophrenic patients improved sleep continuity variables and total sleep time in another study; the principal changes observed in sleep architecture were a reduction in stage 1 sleep, a significant enhancement in stage 2 and delta sleep, and an increase in REM density.161 In a study comparing the effect of aging on the improvement of subjective sleep quality in patients with schizophrenia receiving atypical antipsychotic agents, including olanzapine, the proportion of patients experiencing improved subjective sleep quality was significantly higher in geriatric patients than in middle-aged patients.162

Neuroendocrine Effects

In contrast to conventional (first-generation) antipsychotic agents and similar to many other atypical antipsychotic agents, olanzapine therapy in usual dosages generally produces transient elevations in serum prolactin concentrations in humans.1,119,283,288,300,301,315,332 This prolactin-elevating effect appears to be mediated by dopamine blockade.1,119,288,289,301,332 The effect of atypical antipsychotic agents on prolactin generally appears to be transient, possibly because the drugs appear to dissociate from dopamine receptors more rapidly than conventional antipsychotic agents. 1,288,289,315,332

Antiemetic Effects

Although the precise mechanism of olanzapine's antiemetic action has not been clearly established, its inhibitory activity at multiple dopaminergic and serotonergic receptors, particularly the D₂, 5-HT_2C, and 5-HT₃ receptors that may be involved in nausea and vomiting, may play a role in the drug's efficacy in both the prevention and rescue therapy of chemotherapy-induced nausea and vomiting†.426,427,428

Pharmacokinetics

Absorption

Olanzapine is well absorbed following oral administration.1,290 However, because of extensive first-pass metabolism, only about 60% of an orally administered dose reaches systemic circulation unchanged.1 Olanzapine exhibits linear and dose-proportional pharmacokinetics when given orally within the clinical dosage range.1,116,143,290 Food does not appear to affect the rate or the extent of GI absorption of the drug.1,290 The relative oral bioavailability of olanzapine has been shown to be equivalent following administration of the conventional and orally disintegrating tablets of the drug.1,115

When olanzapine and fluoxetine hydrochloride are administered as the fixed-combination oral capsules, the pharmacokinetic characteristics of the drugs are expected to resemble those of the individual components; olanzapine pharmacokinetics are slightly altered when administered with fluoxetine, but the effects were not deemed to be clinically important.312 (See Selective Serotonin-reuptake Inhibitors under Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes.)

Following oral administration, peak plasma olanzapine concentrations occur in approximately 6 hours (range: 5-8 hours).1,290 Steady-state plasma concentrations of olanzapine are achieved after approximately 7 days of continuous dosing and are approximately twice those observed following single-dose administration.1,116,290

Following IM administration of short-acting olanzapine injection (Zyprexa^® IntraMuscular), olanzapine is rapidly absorbed with peak plasma olanzapine concentrations occurring within 15-45 minutes.1,382 In one pharmacokinetic study performed in healthy individuals, a single 5-mg IM dose of olanzapine produced peak plasma concentrations that were an average of approximately fivefold higher than the peak plasma concentrations produced following a single 5-mg oral dose of the drug.1 In this study, the areas under the plasma concentration-time curve (AUCs) achieved following IM and oral administration of the same dose of the drug were similar.1 Olanzapine exhibits linear pharmacokinetics when given IM within the clinical dosage range.1 Preliminary evidence suggests that the onset of antipsychotic action following IM administration of the drug is evident within 24 hours but may be observed as early as 2 hours after IM administration.207

Following deep IM gluteal administration of extended-release olanzapine pamoate injection (Zyprexa^® Relprevv), slow dissolution of the pamoate ester (which is practically insoluble) results in prolonged plasma olanzapine concentrations over a period of weeks to months.382 An IM injection every 2 or 4 weeks provides plasma olanzapine concentrations that are similar to those achieved with daily doses of oral olanzapine.382 Steady-state plasma concentrations achieved with extended-release olanzapine pamoate injection in IM dosages of 150-405 mg every 2 or 4 weeks are within the range achieved with oral olanzapine dosages of 5-20 mg daily.382 Plasma olanzapine concentrations generally reach a peak within the first week following each injection.382

Plasma olanzapine concentrations may vary between individuals according to gender, smoking status, and age.1,143,145,148 There is limited evidence that gender may affect plasma olanzapine concentrations, with concentrations being somewhat higher, perhaps by as much as 30-40%, in females compared with males.1,143,145 Plasma concentrations of olanzapine also may be increased in geriatric individuals compared with younger individuals, possibly as a result of age-related decreases in hepatic elimination of the drug.1,143 Data from one limited study in children and adolescents 10-18 years of age with schizophrenia found that plasma olanzapine concentrations among adolescents were within the range reported in nonsmoking adult patients with schizophrenia.148 However, the manufacturer states that most adolescents (i.e., 13-17 years of age) in clinical studies were nonsmokers and had a lower average body weight, which resulted in higher average olanzapine exposure compared with adults.1 In vivo studies have shown that exposures to olanzapine are similar among Japanese, Chinese, and Caucasian individuals, particularly after normalization for body weight differences.1

The therapeutic range for plasma olanzapine concentrations and the relationship of plasma concentration to clinical response and toxicity have not been clearly established; however, acutely ill schizophrenic patients with 24-hour post-dose plasma olanzapine concentrations of 9.3 ng/mL or higher in one study or 12-hour post-dose concentrations of 23.2 ng/mL or higher in another study appeared to have a better clinical response to therapy than patients with lower plasma concentrations.364,365

Distribution

Distribution of olanzapine, a highly lipophilic drug, into human body tissues is extensive.1,146,290

The manufacturer states that the volume of distribution of olanzapine has been reported to be approximately 1000 L.1,146 In pharmacokinetic studies in healthy individuals, the apparent volume of distribution of the drug averaged 1150 L and ranged from 660 to 1790 L for the fifth to 95th percentiles.116 Olanzapine is 93% bound to plasma proteins over the concentration range of 7-1100 ng/mL, principally to albumin and α₁-acid glycoprotein.1,139,290

Olanzapine and its glucuronide metabolite have been shown to cross the placenta in humans.114,381 Placental transfer of olanzapine also has been shown to occur in rat pups.1

Olanzapine is distributed into milk.1,110,111,112,319 The manufacturer states that in a study in lactating, healthy women, the average infant dose of olanzapine at steady-state was estimated to be approximately 1.8% of the maternal olanzapine dose.1 In a separate study that evaluated the extent of infant exposure to olanzapine in 7 breastfeeding women who had been receiving 5-20 mg of olanzapine daily for periods ranging from 19-395 days, median and maximum relative infant doses of 1 and 1.2%, respectively, were observed.110 Olanzapine was not detected in the plasma of the breast-fed infants, and adverse effects possibly related to olanzapine exposure were not reported in the infants in this study.110 In addition, peak milk concentrations were achieved a median of 5.2 hours later than the corresponding maximal maternal plasma concentrations.110 In a case report, a relative infant dose of approximately 4% was estimated in one woman after 4 and 10 days (estimated to be at steady state) of olanzapine therapy at a dosage of 20 mg daily based on measurements of drug concentration in serum and in expressed breast milk.112 (See Cautions: Pregnancy, Fertility, and Lactation.)

Elimination

Although the exact metabolic fate has not been clearly established, it appears that olanzapine is extensively metabolized.1,116,139 Following a single oral dose of radiolabeled olanzapine, 7% of the dose was recovered in urine as unchanged drug.1,139 Approximately 57 and 30% of the dose was recovered in the urine and feces, respectively. 1,139,290 In plasma, olanzapine accounted for only 12% of the AUC for total radioactivity, suggesting substantial exposure to metabolites.1 After multiple doses of olanzapine, the principal circulating metabolites are the 10- N -glucuronide, which is present at steady state at 44% of the plasma concentration of the parent drug, and 4'- N -desmethyl olanzapine, which is present at steady state at 31% of the plasma concentration of olanzapine.1,116 Both of these metabolites lack pharmacologic activity at the concentrations observed.1,116

Direct glucuronidation and cytochrome P-450 (CYP)-mediated oxidation are the principal pathways for olanzapine metabolism.1,116 In vitro studies suggest that the CYP isoenzymes 1A2 and 2D6 and the flavin-containing monooxygenase system are involved in the oxidation of olanzapine. 1,116 However, CYP2D6-mediated oxidation appears to be a minor metabolic pathway for olanzapine in vivo since the clearance of the drug is not reduced in individuals deficient in this enzyme.1

Following oral administration, olanzapine has an elimination half-life ranging from 21 to 54 hours for the fifth to 95th percentiles of individual values with a mean of 30 hours.1,116,139 Following IM administration of short-acting olanzapine injection (Zyprexa^® IntraMuscular), the half-life and metabolic profile of olanzapine were similar to those observed with oral administration.1 Following IM administration of extended-release olanzapine pamoate injection (Zyprexa^® Relprevv), the elimination half-life is approximately 30 days.382 Therefore, exposure to olanzapine may persist for months after a single extended-release IM injection of the drug.382

The apparent plasma clearance of olanzapine ranges from 12 to 47 L/hour (mean: 25 L/hour).1,116,290

The clearance of olanzapine in smokers is approximately 40% higher than in nonsmokers. 1,144 (See Drug Interactions: Smoking.)

The clearance of olanzapine in females may be reduced by approximately 30% compared with males.1,144

In a single-dose pharmacokinetic study, the elimination half-life of orally administered olanzapine was 1.5 times longer in healthy geriatric individuals 65 years of age or older than in healthy younger adults.1 (See Dosage and Administration: Dosage and see also Cautions: Geriatric Precautions.)

In one pharmacokinetic study conducted in a limited number of children and adolescents 10-18 years of age with schizophrenia who were treated with oral olanzapine, the apparent plasma clearance at steady-state averaged 9.6 L/hr, which was approximately half of the clearance values reported in adult studies but similar to clearance values reported in nonsmoking male and female schizophrenic patients.1,116,148,290 The elimination half-life averaged 37.2 hours in this same study.148 (See Dosage and Administration: Dosage and see also Cautions: Pediatric Precautions.)

The combined effects of age, smoking, and gender could result in substantial pharmacokinetic differences in populations.1,116,141 The clearance in younger, smoking adult male patients may be 3 times higher than that in geriatric, nonsmoking females. 1 Dosage adjustment may be necessary in patients who exhibit a combination of factors that may result in slower metabolism of olanzapine.1 (See Dosage and Administration: Dosage.)

Because olanzapine is extensively metabolized before excretion and only 7% of the drug is excreted unchanged, renal impairment alone is unlikely to substantially alter the pharmacokinetics of olanzapine.1,116,290 The pharmacokinetics of olanzapine were similar in patients with severe renal impairment and healthy individuals, suggesting that dosage adjustment based upon the degree of renal impairment is not necessary.1,116,290 The effect of renal impairment on the elimination of olanzapine's metabolites has not been evaluated to date.1

Although the presence of hepatic impairment would be expected to reduce the clearance of olanzapine, a pharmacokinetic study evaluating the effect of impaired hepatic function in individuals with clinically important cirrhosis (Child-Pugh classification A and B) revealed little effect on the pharmacokinetics of olanzapine.1

Olanzapine is not appreciably removed by hemodialysis, probably due to its large volume of distribution and extensive protein binding.1,116,119,146 Clinical experience with other enhanced elimination techniques, including multiple-dose activated charcoal, hemoperfusion, forced diuresis, and urinary alkalinization, is lacking; however, these treatments are unlikely to be beneficial following olanzapine overdosage because of the drug's large volume of distribution and extensive protein binding.116,119

Chemistry and Stability

Chemistry

Olanzapine is a thienobenzodiazepine-derivative antipsychotic agent.1,16,17,20 The drug is considered an atypical or second-generation antipsychotic agent.1,2,4,7,14,16,17,18,19,20,22,26,119,315 Olanzapine is structurally similar to clozapine.3,14,16,20

Olanzapine occurs as a yellow crystalline solid that is practically insoluble in water. 1

Olanzapine for injection (short-acting) contains lactose monohydrate and tartaric acid; hydrochloric acid and/or sodium hydroxide may have been added to adjust pH.1 When olanzapine for injection is reconstituted as directed, the resulting solution should appear clear and yellow.1

Stability

Commercially available olanzapine conventional tablets, orally disintegrating tablets, and short-acting olanzapine for IM injection should be stored at a controlled room temperature of 20-25°C but may be exposed to temperatures ranging from 15-30°C.1 Olanzapine orally disintegrating tablets should be stored in their original sealed blister.1 The conventional and orally disintegrating tablets should be protected from light and moisture and olanzapine for injection should be protected from light and freezing.1 Extended-release olanzapine pamoate for IM injection should be stored at room temperature (not to exceed 30°C).382

Following reconstitution, olanzapine for injection (short-acting) may be stored at a controlled room temperature of 20-25°C for up to 1 hour if necessary,1 but immediate use is preferred.1

Following reconstitution, extended-release olanzapine pamoate injection suspension may be stored at room temperature for 24 hours.382 The vial should be agitated immediately prior to withdrawal of the suspension.382

Olanzapine orally disintegrating tablets contain aspartame (e.g., NutraSweet^®).1 (See Individuals with Phenylketonuria, under Cautions: Precautions and Contraindications.)

Olanzapine for IM injection (short-acting) should not be combined with diazepam injection in a syringe because precipitation occurs when these drugs are mixed.1 Olanzapine for IM injection also should not be combined in a syringe with haloperidol injection because the resulting pH has been shown to degrade olanzapine over time.1 In addition, lorazepam injection should not be used to reconstitute olanzapine for injection since this delays reconstitution time.1 Specialized references should be consulted for additional specific compatibility information.

Preparations ⬆ ⬇

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Long-acting IM olanzapine pamoate (Zyprexa^® Relprevv) is available only through a restricted distribution program.382 (See Restricted Distribution under Dosage and Administration: Reconstitution and Administration.)

OLANZapine

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	2.5 mg*	ZyPREXA^®	Lilly
		5 mg*	ZyPREXA^®	Lilly
		7.5 mg*	ZyPREXA^®	Lilly
		10 mg*	ZyPREXA^®	Lilly
		15 mg*	ZyPREXA^®	Lilly
		20 mg*	ZyPREXA^®	Lilly
	Tablets, orally disintegrating	5 mg*	ZyPREXA^® Zydis^®	Lilly
		10 mg*	ZyPREXA^® Zydis^®	Lilly
		15 mg*	ZyPREXA^® Zydis^®	Lilly
		20 mg*	ZyPREXA^® Zydis^®	Lilly
Parenteral	For injection, for IM use only	10 mg*	ZyPREXA^® IntraMuscular	Lilly

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

OLANZapine Combinations

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules	3 mg with Fluoxetine Hydrochloride 25 mg (of fluoxetine)*	Symbyax^®	Lilly
		6 mg with Fluoxetine Hydrochloride 25 mg (of fluoxetine)*	Symbyax^®	Lilly
		6 mg with Fluoxetine Hydrochloride 50 mg (of fluoxetine)*	Symbyax^®	Lilly
		12 mg with Fluoxetine Hydrochloride 25 mg (of fluoxetine)*	Symbyax^®	Lilly
		12 mg with Fluoxetine Hydrochloride 50 mg (of fluoxetine)*	Symbyax^®	Lilly

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

OLANZapine Pamoate

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injectable suspension, extended-release, for IM use only	210 mg (of olanzapine)	ZyPREXA^® Relprevv^® (available as a convenience kit containing single-use vial, needles, syringe, and diluent)	Lilly
		300 mg (of olanzapine)	ZyPREXA^® Relprevv^® (available as a convenience kit containing single-use vial, needles, syringe, and diluent)	Lilly
		405 mg (of olanzapine)	ZyPREXA^® Relprevv^® (available as a convenience kit containing single-use vial, needles, syringe, and diluent)	Lilly

AHFS^® Drug Information. © Copyright, 1959-2024, Selected Revisions November 12, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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section name header

Introduction ⬇

AHFS Class:

Generic Name(s):

Chemical Name:

Molecular Formula:

Uses ⬆ ⬇

Dosage and Administration ⬆ ⬇

Table 1. Approximate Dosage Correspondence between Olanzapine in Fixed Combination with Fluoxetine (e.g., Symbyax^®) and Combined Olanzapine (e.g., Zyprexa^®) and Fluoxetine Therapy (Given Individually).1

Cautions ⬆ ⬇

Drug Interactions ⬆ ⬇

Other Information ⬆ ⬇

Preparations ⬆ ⬇

OLANZapine

OLANZapine Combinations

OLANZapine Pamoate

Copyright ⬆ ⬇

References ⬆

section name header

Introduction ⬇

AHFS Class:

Generic Name(s):

Chemical Name:

Molecular Formula:

Uses ⬆ ⬇

Dosage and Administration ⬆ ⬇

Table 1. Approximate Dosage Correspondence between Olanzapine in Fixed Combination with Fluoxetine (e.g., Symbyax®) and Combined Olanzapine (e.g., Zyprexa®) and Fluoxetine Therapy (Given Individually).1

Cautions ⬆ ⬇

Drug Interactions ⬆ ⬇

Other Information ⬆ ⬇

Preparations ⬆ ⬇

OLANZapine

OLANZapine Combinations

OLANZapine Pamoate

Copyright ⬆ ⬇

References ⬆

Table 1. Approximate Dosage Correspondence between Olanzapine in Fixed Combination with Fluoxetine (e.g., Symbyax^®) and Combined Olanzapine (e.g., Zyprexa^®) and Fluoxetine Therapy (Given Individually).1