REMS: FDA approved a REMS for olanzapine extended-release injectable suspension to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of olanzapine extended-release injectable suspension and consists of the following: medication guide, elements to assure safe use, communication plan, and implementation system. See the FDA REMS page ([Web]). |
Olanzapine is considered an atypical antipsychotic agent.1, 382
Olanzapine is commercially available in the US as olanzapine and olanzapine pamoate.1, 382 Olanzapine is also commercially available in fixed combination with fluoxetine and in fixed combination with samidorphan.1, 312, 431
Olanzapine is used orally for the treatment of schizophrenia in adults and adolescents 13—17 years of age, for the acute treatment of manic and mixed episodes associated with bipolar I disorder and maintenance treatment of bipolar I disorder in adults and adolescents 13—17 years of age, and as an adjunct to lithium or valproate in the treatment of manic or mixed episodes associated with bipolar I disorder in adults.1
Olanzapine (e.g., Zyprexa IntraMuscular®) is also used IM for the treatment of acute agitation associated with schizophrenia and bipolar I mania in adults.1
Olanzapine pamoate (e.g., Zyprexa Relprevv®) is used IM for the treatment of schizophrenia. 382
Olanzapine, in fixed combination with fluoxetine (Symbyax®), is used orally for acute depressive episodes associated with bipolar I disorder in adults and pediatric patients 10—17 years of age and for treatment-resistant depression in adults.312
Olanzapine, in fixed combination with samidorphan (Lybalvi®), is used orally for the treatment of schizophrenia, for the acute treatment of manic or mixed episodes as monotherapy and as an adjunct to lithium or valproate in bipolar I disorder, and for monotherapy maintenance treatment of bipolar I disorder in adults.431
Olanzapine is used orally for the treatment of schizophrenia in adults and adolescents 13—17 years of age.1
In pediatric patients with schizophrenia, symptom profiles can be variable.1 Medication therapy for pediatric patients with schizophrenia should only be initiated after a thorough diagnostic evaluation and careful consideration of the risks associated with pharmacologic treatment.1 Drug therapy in pediatric patients should be administered as part of a total treatment program that often includes psychological, educational, and social interventions.1
Short-acting olanzapine injection (e.g., Zyprexa® IntraMuscular) is used IM for the management of acute agitation in adults with schizophrenia.1, 98, 102
Olanzapine pamoate (Zyprexa®Relprevv) long-acting injectable is used IM for the treatment of schizophrenia in adults.382
Olanzapine, in fixed combination with samidorphan (Lybalvi®), is used orally for the treatment of schizophrenia in adults.431
The efficacy of oral olanzapine for the management of psychotic disorders in adults has been established in 2 placebo-controlled studies of 6 weeks' duration in hospitalized patients who met DSM-III-R criteria for schizophrenia.1, 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, 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, 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 outcomes 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, 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, 354
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
Although there is no 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
The efficacy of short-acting IM olanzapine for the management of acute agitation in adults 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 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 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 substantial 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
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, 357, 358, 359 Like other atypical 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.224 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 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
The American Psychiatric Association (APA) recommends that patients with schizophrenia be treated with an antipsychotic medication.26 The APA states that, with the possible exception of clozapine, 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 The choice of an antipsychotic agent should be individualized, considering patient preference, past response to therapy, concurrent medical conditions, and medication-specific factors (e.g., adverse effect profile, available formulations, potential drug interactions, receptor binding profiles, pharmacokinetic considerations).26 Patients whose symptoms improve on an antipsychotic medication should continue treatment with an antipsychotic medication long-term; in most patients, it is appropriate to continue the same antipsychotic medication rather than switch to another antipsychotic medication for maintenance therapy.26
Guidelines from the Department of Veterans Affairs and Department of Defense similarly recommend the use of antipsychotic medication for acute and maintenance treatment of schizophrenia.434 Choice of antipsychotic medication should be based on patient-specific factors and the adverse effect profiles of the different antipsychotic medications.434 Clozapine should generally be reserved for individuals with treatment-resistant schizophrenia.434
A practice parameter from the American Academy of Child and Adolescent Psychiatry (AACAP) recommends antipsychotic medication as a primary treatment for schizophrenia spectrum disorders in children and adolescents.234 The AACAP states that most atypical and typical antipsychotic medications, with the exception of clozapine, can be used as primary treatment in early-onset schizophrenia (i.e., onset of schizophrenia before 18 years of age).234 Depot antipsychotics (i.e., IM formulations) have not been studied in pediatric patients.234 Choice of antipsychotic medication in pediatric patients should be individualized based on FDA-labeling, adverse effect profiles, patient and family preferences, cost, and clinician familiarity.234
Olanzapine is used orally as monotherapy in adults and adolescents 13-17 years of age for the acute management of manic or mixed episodes associated with bipolar I disorder and for the maintenance treatment of bipolar I disorder.1, 30, 36, 37, 41, 100, 245, 246, 247, 248, 249, 250, 251, 252, 308, 370
For pediatric patients with schizophrenia, symptom profiles can be variable.1 Medication therapy for pediatric patients with schizophrenia should only be initiated after a thorough diagnostic evaluation and careful consideration of risks associated with pharmacologic treatment.1 Medication treatment for pediatric patients is indicated as part of a total treatment program that often includes psychological, educational, and social interventions.1
Short-acting olanzapine injection (e.g., Zyprexa® IntraMuscular) is used IM for the management of acute agitation in adult patients with bipolar I disorder.1
Olanzapine, in a fixed combination with fluoxetine (e.g., Symbyax®), is used orally for the treatment of acute depressive episodes in bipolar I disorder in adults and pediatric patients 10-17 years of age.312
Olanzapine, in a fixed combination with samidorphan (e.g., Lybalvi®), is used orally for the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults as monotherapy and as an adjunct to lithium or valproate, and for maintenance monotherapy of bipolar I disorder in adults.431
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 Young Mania Rating Scale (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 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
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
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 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 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 substantially 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
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
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 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 superior to placebo in reducing the PANSS Excited Component score at 2 hours and at 24 hours following the initial injection.1, 82, 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
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 Efficacy of oral olanzapine used in combination with fluoxetine for the treatment of acute depressive episodes in adults is based primarily on the results of 2 randomized, double-blind studies.312, 313 In these 8-week studies, a fixed combination of olanzapine and fluoxetine hydrochloride (Symbyax®) was compared 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
Legacy practice guidelines from APA recommend lithium plus an antipsychotic or valproate plus an antipsychotic for first-line treatment of patients with severe manic or mixed episodes associated with bipolar I disorder; patients with less severe symptoms may be treated with lithium, valproate, or antipsychotic monotherapy.42 Selection of a specific treatment should be based on clinical factors such as illness severity, associated features (e.g., rapid cycling, psychosis), and patient preference, with particular attention to adverse effect profiles.42 Manic or mixed episodes with psychotic features usually require treatment with an antipsychotic.42 Atypical antipsychotics are generally preferred over typical antipsychotics because of their more benign adverse effect profile.42 Following remission of an acute episode, maintenance pharmacologic treatment is recommended; first-line options for maintenance therapy include lithium and valproate.42 The guideline states that, for patients treated with an antipsychotic medication during the acute episode, the need for ongoing antipsychotic therapy should be reassessed upon entering the maintenance phase; antipsychotics should generally be discontinued, unless they are required to control persistent psychosis or prevent recurrence.42
Guidelines from the Department of Veterans Affairs and Department of Defense suggest lithium or quetiapine monotherapy for the treatment of acute mania in patients with bipolar disorder.435 If lithium or quetiapine is not selected based on patient preference or characteristics, olanzapine, paliperidone, and risperidone are recommended as alternative treatments.435 If none of these therapies are considered suitable based on patient preference or characteristics, other suggested options include aripiprazole, asenapine, carbamazepine, cariprazine, haloperidol, valproate, or ziprasidone.435 For patients who experience breakthrough episodes of mania or unsatisfactory response to initial treatment, lithium or valproate in combination with an antipsychotic (haloperidol, asenapine, quetiapine, olanzapine, or risperidone) is recommended.435 For prevention of mania recurrence, lithium or quetiapine is recommended; alternatives include olanzapine, paliperidone, or risperidone.435 Aripiprazole, olanzapine, quetiapine, or ziprasidone may also be used in combination with lithium or valproate for prevention of mania recurrence.435
A practice parameter from the AACAP recommends pharmacotherapy as primary treatment for mania in bipolar I disorder in children and adolescents.253 Standard therapies include lithium, valproate, and/or atypical antipsychotic agents.253 Choice of medication in pediatric patients should be based on evidence for efficacy, phase of illness, presence of confounding symptoms, adverse effect profiles, patient history of response to medication, and patient and family preferences.253
Treatment-resistant Depression
Oral olanzapine is used in combination with fluoxetine hydrochloride (e.g., Symbyax®) in adults for 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
Treatment options for major depressive disorder include pharmacologic and nonpharmacologic (e.g., psychotherapy) approaches.437, 438, 439, 440 Several classes of antidepressant drugs are available for the treatment of major depressive disorder.437, 438, 439, 440 In general, antidepressants have shown similar effectiveness; therefore, initial treatment is guided by specific patient- and drug-related factors.437, 438, 439, 440 For patients who did not response or with an inadequate response to initial treatment with an antidepressant, approaches to therapy may include changing to a different antidepressant or psychotherapy, or augmentation with psychotherapy or another pharmacological agent.437, 438, 439, 440
The Department of Veterans Affairs and Department of Defense have developed guidelines for the management of major depressive disorder.438 Treatment of major depressive disorder can be initiated with either psychotherapy (e.g., cognitive behavioral therapy) or pharmacotherapy, depending on patient preference; for patients with severe, persistent, or recurrent major depressive disorder, a combination of pharmacotherapy and psychotherapy is suggested.438 When pharmacotherapy is used as initial therapy, either bupropion, mirtazapine, a selective serotonin-reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI), trazodone, vilazodone, or vortioxetine is suggested.438 No evidence is available to suggest superiority of one agent over another.438 The guidelines recommend against using esketamine, ketamine, MAOIs, nefazodone, or TCAs as initial therapy.438 For patients not responding to initial therapy, recommendations include switching to another antidepressant (including MAOIs or TCAs), switching to or augmenting with psychotherapy, or augmenting with a second-generation antipsychotic (e.g., aripiprazole, brexpiprazole).438
Chemotherapy-induced Nausea and Vomiting
Olanzapine has been used orally in combination with other antiemetic agents for theprevention of acute and delayed nausea and vomiting associated with highly emetogenic cancer chemotherapy†, including high-dose cisplatin therapy.425, 426, 427, 428 Olanzapine also has been used as rescue therapy in patients with breakthrough cancer chemotherapy-induced nausea and vomiting†.425, 429
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 substantial 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
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], fosnetupitant [in fixed combination with palonosetron], rolapitant), a type 3 serotonin (5-HT3) receptor antagonist (e.g., dolasetron, granisetron, ondansetron, palonosetron), dexamethasone, and olanzapine.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 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 adults treated with high-dose chemotherapy and stem-cell or bone marrow transplantation, ASCO recommends a 3-drug antiemetic regimen, consisting of an NK1 receptor antagonist, a 5-HT3 receptor antagonist, and dexamethasone, be offered.425 A 4-drug combination antiemetic regimen that includes olanzapine may also be offered for this patient population.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, dronabinol, or nabilone in addition to continuing the standard antiemetic regimen.425
Olanzapine has been used in the management of cancer cachexia in adults with advanced cancer†.432, 433 A rapid guideline update on cancer cachexia from ASCO states that for adults with advanced cancer, clinicians may offer low-dose olanzapine once daily to improve weight gain and appetite.433 This recommendation is supported by a randomized controlled trial of 124 adults with untreated, locally advanced, or metastatic gastric, hepatopancreaticobiliary, and lung cancers receiving chemotherapy.432 After 12 weeks, there was a substantially greater proportion of patients who received low dose olanzapine (2.5 mg once daily) who had a weight gain >5% compared to patients who received placebo.432
Behavioral and Psychological Symptoms with Dementia
Olanzapine has been used as an IM injection for the management of behavioral and psychological symptoms associated with dementia (BPSD) in emergent situations†.441, 442, 443 The APA recommends that antipsychotic medications should only be used for the treatment of agitation or psychosis in patients with dementia when symptoms are severe, are dangerous, and/or cause significant distress to the patient.441 Prior to nonemergency treatment with an antipsychotic, review of clinical response to nonpharmacological interventions is recommended; a discussion of the risks and benefits of treatment with an antipsychotic with the patient, the patient's surrogate decision maker, or family or other caregivers is also recommended.441 In another treatment algorithm, for the diagnosis of emergent BPSD, first-line pharmacotherapy includes IM olanzapine.442 If there is an inadequate or no response, IM haloperidol is recommended, followed by IM benzodiazepines.442 The American Geriatrics Society (AGS) 2023 updated AGS Beers Criteria® for potentially inappropriate medication use in older adults states that antipsychotics should be avoided in patients with cognitive impairment or dementia due to increased risk of stroke and greater rate of cognitive decline and mortality.443 Antipsychotics should be avoided unless documented nonpharmacologic options have failed and/or the patient is threatening substantial harm to self and others; if used, use the lowest effective dose and consider periodic deprescribing attempts.443
Olanzapine has been used in adults for the management of refractory generalized anxiety disorder†, obsessive-compulsive disorder (OCD)†, and posttraumatic stress disorder (PTSD)†.444, 445, 446, 447
Guidelines from international experts state that olanzapine, as an add-on therapy with fluoxetine, may be used for treatment-refractory generalized anxiety disorder.444
Legacy guidelines from APA for OCD state that first-line pharmacotherapy treatment includes SSRIs (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline).445 If a patient does not respond to one SSRI, they may switch to a different SSRI, switch to clomipramine, augment their current SSRI with a second-generation antipsychotic, switch to venlafaxine, or switch to mirtazapine.445
A Cochrane review of pharmacological treatments for PTSD assessed the effects of several classes of medications, including alpha-blockers, anticonvulsants, antihistamines, SSRIs, SNRIs, and atypical antipsychotics for reducing PTSD symptoms in adults.446 This review found evidence of benefit following treatment with olanzapine compared to placebo in reducing total PTSD symptoms on the Clinician Administered PTSD Scale (CAPS), CGI Severity score, and in the reduction of depression symptoms.446 Guidelines from international experts state that olanzapine is effective in treatment-unresponsive PTSD as monotherapy and as an add-on to SSRIs based on double-blind, randomized, placebo-controlled trials; however, due to a higher rate of adverse effects, it should only be used when standard treatments have failed or have not been tolerated.447 The Department of Veterans Affairs and Department of Defense guidelines for the treatment of PTSD state that there is insufficient evidence to recommend for or against olanzapine for the treatment of PTSD and suggest against olanzapine as augmentation for the treatment of PTSD.448
Dispensing and Administration Precautions
Olanzapine is administered orally or by IM injection.1, 312, 382 Olanzapine pamoate is administered only by IM injection.382 Olanzapine is also available in fixed combination with fluoxetine or samidorphan.312, 431 Refer to the prescribing information for olanzapine/samidorphan (Lybalvi®) for specific information on its administration and dosing.431
Olanzapine conventional tablets and orally disintegrating tablets are administered orally.1 Olanzapine is also available as a fixed-combination tablet with samidorphan and a fixed-combination capsule with fluoxetine, both of which are administered orally.312, 431 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
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.1, 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
Store conventional olanzapine tablets and olanzapine orally disintegrating tablets at 20-25°C (excursions permitted between 15-30°C); protect from exposure to light and moisture.1 Store fixed-combination capsules of olanzapine with fluoxetine hydrochloride (e.g., Symbyax®) at 25°C (excursions permitted between 15-30°C); keep the container tightly closed and protect from moisture.312
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
Store unopened vials of short-acting olanzapine for injection (e.g., Zyprexa® IntraMuscular) at 20-25°C (excursions permitted between 15-30°C); protect from exposure to light and do not freeze.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 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 After each injection, patients should be continuously monitored at the healthcare facility for at least 3 hours by a healthcare professional.372, 382
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 Store unopened kits of olanzapine pamoate powder for suspension (e.g., Zyprexa® Relprevv) at ≤30°C.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
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 5 times higher than that resulting from a 5-mg oral dose of the drug.1
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 Dosage may be increased by 5 mg daily to a target dosage of 10 mg daily within several days.1 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, 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 more slowly (e.g., nonsmoking female patients who are ≥65 years of age).1 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 geriatric patients.1
The effective oral dosage of olanzapine in clinical studies in adults generally ranged from 10-15 mg daily.1 The manufacturer states 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 In addition, the manufacturer states that olanzapine is not indicated for use in dosages exceeding 20 mg daily.1
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 The manufacturer states that the safety and effectiveness of dosages exceeding 20 mg daily have not been evaluated in clinical trials.1
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.1 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
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 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 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 The effective dosage of olanzapine as adjunctive therapy for up to 6 weeks in clinical studies generally ranged from 5-20 mg daily.1 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 drug(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.312 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 drug(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
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, 312 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
For fixed-combination dosages of: | Use in combination: | |
|---|---|---|
Fixed-combination preparation (mg/day) | 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.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 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
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 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 need for continued treatment.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 drug(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 need for continued treatment.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
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 5-10 mg once daily on the first day of chemotherapy (day 1) and then 5-10 mg once daily on days 2-4 of chemotherapy.425 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
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
For the management of cachexia in adults with advanced cancer†, ASCO currently recommends low-dose oral olanzapine once daily to improve weight gain and appetite.432 This change in recommendations was largely based on a randomized, double-blind, placebo-controlled study where patients received olanzapine 2.5 mg once daily for 12 weeks.433
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 A lower initial IM dose (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
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 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
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
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
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 When indicated, dosage may be escalated with caution in such patients.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 In addition, long-term use of oral olanzapine has been shown to be effective in maintaining treatment response in patients with schizophrenia.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
When olanzapine is used in combination with fluoxetine in patients with hepatic impairment, an initial dose of oral olanzapine 2.5-5 mg and fluoxetine 20 mg is recommended.1
The manufacturer states that the extended-release IM formulation of olanzapine pamoate (Zyprexa® Relprevv) has not been specifically studied in patients with hepatic impairment.382
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 impairment, dosage adjustment is not necessary in such patients.1 Olanzapine is not removed by dialysis.1
The manufacturer states that the extended-release IM formulation of olanzapine pamoate (Zyprexa® Relprevv) has not been specifically studied in patients with renal impairment.382
The manufacturer suggests consideration of a lower starting dosage of oral olanzapine and extended-release IM olanzapine pamoate (e.g., Zyprexa® Relprevv) for any geriatric patient with factors present that could decrease pharmacokinetic clearance or increase pharmacodynamic response to olanzapine.1, 382 When short-acting olanzapine for injection (e.g., Zyprexa® IntraMuscular) is used IM to treat agitation associated with schizophrenia and bipolar I mania in geriatric patients, a dose of 5 mg per injection should be considered when other clinical factors warrant.1
Increased Mortality in Geriatric Patients with Dementia-related Psychosis
The prescribing information for all olanzapine products contains a boxed warning for the risk of increased mortality in geriatric patients with dementia-related psychosis.1, 382 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 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 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 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
Post-Injection Delirium/Sedation Syndrome Associated with Extended-release Injection
The prescribing information for extended-release olanzapine pamoate injection (Zyprexa® Relprevv) contains a boxed warning for post-injection delirium/sedation syndrome (PDSS).382 During premarketing studies of Zyprexa® Relprevv, adverse events consistent with olanzapine overdose, in particular, sedation (including coma) and/or delirium were reported in patients who received the drug.382 Such events occurred in <0.1% of injections administered and in about 2% of patients who received injections over 46 months.382 The events were correlated with an unintentional rapid increase in serum olanzapine concentrations, sometimes to supratherapeutic ranges.382 While a rapid and greater than expected increase in serum olanzapine concentration has occurred in some patients who experienced these events, the exact mechanism of this effect is not known.382 Clinical signs and symptoms of PDSS included dizziness, confusion, disorientation, slurred speech, altered gait, difficulty ambulating, weakness, agitation, extrapyramidal symptoms, hypertension, convulsions, and reduced consciousness ranging from mild sedation to coma.382 The timing of onset after injection ranged from soon after injection to >3 hours later.382 Most patients required hospitalization; some required additional supportive care, including intubation, and all patients largely recovered within 72 hours.382 The risk of PDSS is the same with each injection and the risk is cumulative (i.e., increases with the number of injections) for each individual patient.382
Because of the risk of 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.382 A copy of the medication guide should be provided to the patient or legal guardian prior to each injection.382 After each injection, patients should be monitored continuously at the healthcare facility for at least 3 hours by a healthcare professional.382 Patients should be alert, oriented, and absent of any signs and symptoms of PDSS prior to being released.382 All patients receiving an IM injection of olanzapine pamoate must be accompanied to their destination upon leaving the facility.382 Patients should not drive or operate heavy machinery for the remainder of the day following the injection.382 Patients should be advised to be vigilant for symptoms of PDSS and to obtain medical assistance if needed.382 Close medical supervision and monitoring should be instituted in a facility capable of resuscitation if PDSS is suspected in any patient.382
Other Warnings and Precautions
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
Neuroleptic Malignant Syndrome
Neuroleptic malignant syndrome (NMS), a potentially fatal symptom complex, has been reported in patients receiving antipsychotic agents, including olanzapine.1, 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, 382 Additional signs of NMS may include increased serum creatine kinase (CK, creatine phosphokinase, CPK), myoglobinuria (rhabdomyolysis), and acute renal failure.1, 382
The diagnostic evaluation of patients with NMS is complicated.1, 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 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, 382 There currently is no specific drug therapy for NMS.1, 382 If a patient requires antipsychotic therapy following recovery from NMS, the potential reintroduction of drug therapy should be carefully considered.1, 382 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, 382
Drug Reaction with Eosinophilia and Systemic Symptoms
Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported in olanzapine-treated patients.1, 382 Clinical presentation of DRESS may include a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis.1, 382 DRESS is sometimes fatal.1, 382 If DRESS is suspected, discontinue treatment with olanzapine.1, 382
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, 382 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, 382
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.1, 382
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, 382 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, 382
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, 382 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 and/or a baseline fasting glucose level of ≥126 mg/dL).1, 382 Olanzapine-treated patients had a mean glycosylated hemoglobin (hemoglobin A1c [HbA1c]) concentration increase from baseline of 0.04% (median exposure: 21 days) compared with a mean HbA1c decrease of 0.06% in placebo-treated individuals (median exposure of 17 days).1, 382 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, 382 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, 382 The mean change in fasting glucose for patients exposed to at least 48 weeks of olanzapine therapy was 4.2 mg/dL.1, 382 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, 382
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 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
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, 382 The manufacturer recommends that all patients beginning olanzapine therapy undergo fasting blood glucose testing upon therapy initiation and periodically during treatment.1, 382 The manufacturer also recommends that all patients receiving olanzapine be regularly monitored for worsening of glucose control.1, 382 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, 382 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, 382
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, 382 Clinically important, and sometimes very high (greater than 500 mg/dL), elevations in triglyceride concentrations have been observed with olanzapine therapy.1, 382 Modest average increases in total cholesterol concentrations also have occurred with olanzapine use.1, 382
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, 382 For fasting high-density lipoprotein (HDL)-cholesterol, no clinically important differences were observed between olanzapine-treated patients and patients receiving placebo.1, 382 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, 382 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, 382 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, 382 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, 382
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 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
The manufacturer recommends clinical monitoring, including baseline and periodic follow-up lipid evaluations, in all patients receiving olanzapine.1, 382
Like some conventional (first-generation) and atypical (second-generation) antipsychotic agents, olanzapine therapy may result in weight gain.1, 382 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, 382 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, 382 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, 382
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 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 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
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
The manufacturer states that the potential consequences of weight gain should be considered prior to initiating olanzapine therapy.1, 382 Patients receiving olanzapine should receive regular monitoring of weight.1, 382
Use of antipsychotic agents may be associated with tardive dyskinesia, a syndrome of potentially irreversible, involuntary, dyskinetic movements.1, 382 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, 382 It is not known whether the risk for development of tardive dyskinesia differs among antipsychotic drug products.1, 382
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, 382 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, 382
The syndrome may remit, partially or completely, if antipsychotic therapy is discontinued.1, 382 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, 382 The effect that such symptomatic suppression has upon the long-term course of tardive dyskinesia is unknown.1, 382
Olanzapine should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia.1, 382 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, 382 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, 382
If signs and symptoms of tardive dyskinesia appear in a patient receiving olanzapine, drug discontinuance or a reduction in dosage should be considered.1, 382 However, some patients may require treatment with olanzapine or another antipsychotic agent despite the presence of the syndrome.1, 382
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 olanzapine should be used with caution in patients receiving other drugs that can induce hypotension, bradycardia, or respiratory and CNS depression.1, 382 In such patients who have never taken oral olanzapine, establish tolerability 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
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.1, 382 For patients with diseases or conditions or receiving other drugs that could exacerbate these effects, complete a fall risk assessment when initiating antipsychotic treatment and periodically during long-term therapy.1, 382
Leukopenia, Neutropenia, and Agranulocytosis
In clinical trials and/or postmarketing experience, leukopenia and neutropenia temporally related to antipsychotic agents, including olanzapine, have been reported; agranulocytosis also has been reported.1, 382
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
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
Esophageal dysmotility and aspiration have been associated with the use of antipsychotic agents.1, 382 Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer's disease.1, 382 The manufacturer states that olanzapine is not approved for the treatment of Alzheimer's disease.1, 382
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 or with conditions known to lower the seizure threshold (e.g., dementia of the Alzheimer's type).1, 382 Conditions that lower the seizure threshold may be more prevalent in patients ≥65 years of age.1, 382
Potential for 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, 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
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
Anticholinergic (Antimuscarinic) Effects
Olanzapine has demonstrated anticholinergic activity in vitro and constipation, dry 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 a current diagnosis or prior history of urinary retention, clinically important prostatic hypertrophy, constipation, or a history of paralytic ileus or related conditions.1, 382 In postmarketing experience, concomitant use of anticholinergic medications increased the risk for severe adverse reactions, including fatalities.1, 382
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, 382 Clinical disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been associated with prolactin-elevating drugs.1, 382 In addition, chronic hyperprolactinemia associated with hypogonadism may lead to decreased bone density.1, 382
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, 382 Like other drugs that increase prolactin, an increase in mammary gland neoplasia was observed in olanzapine carcinogenicity studies conducted in mice and rats.1, 382 However, published epidemiologic studies have shown inconsistent results about the potential association between hyperprolactinemia and breast cancer.1, 382
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, 382 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, 382
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
Use in Combination with Other Agents
When preparations containing olanzapine in fixed combination with other drugs (e.g., fluoxetine, samidorphan) are used, the cautions, precautions, contraindications, and drug interactions associated with each drug in the fixed combination must be considered.1, 312, 431 When olanzapine is used in combination with lithium or valproate, the cautions, precautions, contraindications, and drug interactions associated with both drugs must be considered.1
A pregnancy exposure registry is available that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including olanzapine, during pregnancy.1, 382 Clinicians are encouraged to enroll patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 866-961-2388 or online at [Web].1, 382 Currently available data from published epidemiologic studies of pregnant women exposed to olanzapine have not established a drug-associated risk of major birth defects, miscarriage, or adverse outcomes in the mother or fetus.1, 382 However, there are risks to the mother (e.g., risk of relapse, hospitalization, suicide) associated with untreated schizophrenia or bipolar I disorder and with exposure to antipsychotics, including olanzapine, during pregnancy.1, 382 Schizophrenia and bipolar I disorder are associated with increased adverse perinatal outcomes, including preterm birth.1, 382
In pregnant rats and rabbits receiving oral olanzapine at doses 9 to 30 times the maximum recommended human dose based on mg/m2 body surface area, no teratogenicity was observed; however, some fetal toxicities (e.g., increased or early resorptions, increased numbers of nonviable fetuses, and decreased fetal weight) were observed.1
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, 382 Symptoms reported to date have included agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder.1, 382 Neonates exhibiting such symptoms should be monitored.1, 382 The complications have varied in severity; some neonates recovered within hours to days without specific treatment while others have required intensive care unit support and prolonged hospitalization.1, 382
Olanzapine is distributed into milk.1, 382 There are reports of excess sedation, irritability, poor feeding, and extrapyramidal symptoms (tremors and abnormal muscle movements) in infants exposed to olanzapine through breast milk.1, 382 There are no data on the effects of olanzapine on milk production.1, 382
Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for olanzapine and any potential adverse effects on the breast-fed child from the drug or from the mother's underlying condition.1, 382
Monitor infants exposed to olanzapine for excess sedation, irritability, poor feeding, and extrapyramidal symptoms (tremors and abnormal muscle movements).1, 382
Females and Males of Reproductive Potential
Based on the D2 antagonistic activity of olanzapine, treatment with the drug may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential.1, 382
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 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 The recommended initial dosage for adolescents is lower than that for adults.1 Compared with adults in clinical trials, adolescents treated with oral olanzapine 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
Clinicians should consider the potential long-term risks (including weight gain and dyslipidemia) when prescribing olanzapine to adolescents; in many cases, this may lead them to consider prescribing other drugs first in such patients.1
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
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 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 The recommended initial dosage of olanzapine in combination with fluoxetine for adolescents is lower than that for adults.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.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
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
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
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 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 In addition, a significantly higher incidence of adverse cerebrovascular events (e.g., stroke, transient ischemic attack) 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
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
Although the presence of hepatic impairment may be expected to reduce the clearance of olanzapine, a study of 6 patients with impaired hepatic function and clinically significant (Child-Pugh class A and B) cirrhosis revealed little effect on the pharmacokinetics of olanzapine.1
The manufacturer states that the extended-release IM formulation of olanzapine pamoate (Zyprexa® Relprevv) has not been specifically studied in patients with hepatic impairment.382
The manufacturer states that because olanzapine is highly metabolized and only minimal amounts of olanzapine (about 7%) are excreted in urine unchanged, renal dysfunction alone is unlikely to have a major impact on the pharmacokinetics of olanzapine.1 Olanzapine pharmacokinetics were similar in patients with severe renal impairment and normal subjects, indicating that dosage adjustment based upon renal impairment is not required.1 Olanzapine is not removed by dialysis.1 The effect of renal impairment on metabolite elimination has not been studied.1
The manufacturer states that the extended-release IM formulation of olanzapine pamoate (Zyprexa® Relprevv) has not been specifically studied in patients with renal impairment.382
Adverse effects occurring in 5% or more of adult patients with schizophrenia receiving oral olanzapine monotherapy in clinical studies and with an incidence of at least twice that of placebo included postural hypotension, constipation, weight gain, dizziness, personality disorder, and akathisia.1 In adolescents with schizophrenia, common adverse effects included sedation, increased weight, headache, increased appetite, dizziness, abdominal pain, pain in extremity, fatigue, and dry mouth.1
Adverse effects occurring in 5% or more of adult patients with manic or mixed episodes associated with bipolar I disorder receiving oral olanzapine monotherapy in clinical studies and with an incidence of at least twice that of placebo included asthenia, dry mouth, constipation, increased appetite, somnolence, dizziness, and tremor.1 In adolescents with manic or mixed episodes associated with bipolar I disorder, common adverse effects included sedation, increased weight, increased appetite, headache, fatigue, dizziness, dry mouth, abdominal pain, and pain in extremity.1
When oral olanzapine was used in conjunction with lithium or valproate for treatment of manic or mixed episodes associated with bipolar I 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, weight gain, increased appetite, dizziness, back pain, constipation, speech disorder, increased salivation, amnesia, and paresthesia.1
When short-acting IM olanzapine was used for the management of acute agitation in clinical studies in adults, somnolence was the only adverse effect that occurred in 5% or more of patients with schizophrenia or bipolar I mania and with an incidence at least twice that of placebo.1
When extended-release olanzapine pamoate injection was used IM in adults with schizophrenia in a clinical study, adverse effects occurring in 5% or more of patients and more frequently than with placebo included headache, sedation, weight gain, cough, diarrhea, back pain, nausea, somnolence, dry mouth, nasopharyngitis, increased appetite, and vomiting.382
Olanzapine is mainly metabolized via direct glucuronidation and cytochrome P-450 (CYP)-mediated oxidation.1 In vitro studies suggest that CYP isoenzymes 1A2 and 2D6 and the flavin-containing monooxygenase system are involved in oxidation; however, CYP2D6-mediated oxidation appears to be a minor pathway.1
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 Therefore, clinically important drug interactions between olanzapine and drugs metabolized by these isoenzymes are considered unlikely.1
Drugs Affecting Hepatic Microsomal Enzymes
Olanzapine is a substrate for CYP1A2 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 Inhibitors of CYP1A2 (e.g., fluvoxamine) could potentially decrease olanzapine clearance.1 Although olanzapine is metabolized by multiple enzyme systems, induction or inhibition of a single enzyme may appreciably alter olanzapine clearance.1 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
Carbamazepine therapy (200 mg twice daily) causes an approximately 50% increase in the clearance of olanzapine.1 The manufacturer of olanzapine states that higher dosages of carbamazepine may cause an even greater increase in olanzapine clearance.1 Increased clearance of olanzapine probably is caused by carbamazepine-induced induction of CYP1A2 activity.1
Selective Serotonin-reuptake Inhibitors
Concomitant administration of fluoxetine (60 mg as a single dose or 60 mg daily for 8 days) with 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, 312 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 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, 312
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 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 The manufacturer states that a lower olanzapine dosage should therefore be considered in patients receiving concomitant treatment with fluvoxamine.1
Concomitant administration of a single 20-mg dose of warfarin did not substantially alter the pharmacokinetics of olanzapine.1
Concomitant use of olanzapine with other drugs that have anticholinergic activity can increase the risk for severe GI adverse reactions related to hypomotility, disruption of body temperature regulation, and other signs and symptoms of anticholinergic toxicity, .1, 382 Use olanzapine with caution in patients receiving medications that have anticholinergic (antimuscarinic) effects.1, 382
Levodopa and Dopamine Agonists
Olanzapine may antagonize the effects of levodopa and dopamine agonists.1
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
In a pharmacokinetic study, concomitant administration of a single dose of alcohol did not substantially alter the steady-state pharmacokinetics of olanzapine.1, 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
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 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
Administration of single doses of olanzapine did not substantially affect the pharmacokinetics of imipramine or its active metabolite desipramine.1
Multiple doses of oral olanzapine (10 mg for 8 days) did not affect the pharmacokinetics of lithium.1 The manufacturer of olanzapine states that lithium dosage adjustment is not necessary during concurrent olanzapine administration.1
In a pharmacokinetic study, olanzapine administration (10 mg daily for 2 weeks) did not affect the steady-state plasma concentrations of valproate.1 The manufacturer of olanzapine states that routine dosage adjustment of valproate is not necessary during concurrent olanzapine administration.1
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
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
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 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
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
The manufacturer states that routine dosage adjustment is not recommended in patients who smoke while receiving olanzapine.1
Multiple doses of olanzapine did not substantially alter the pharmacokinetics of theophylline or its metabolites.1
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 and dopamine receptors.1 Olanzapine acts as an antagonist with high binding affinity for 5-HT2A/2C, 5-HT6, D1-4, histamine H1 receptors, and adrenergic α1 receptors.1 The drug has moderate affinity for 5-HT3 and muscarinic M1-5 receptors and low affinity for γ-aminobutyric acid (GABA) A, benzodiazepine, and β-adrenergic receptors.1
Olanzapine is well absorbed following oral administration.1 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 Food does not appear to affect the rate or the extent of GI absorption of the drug.1 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
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
Following oral administration, peak plasma olanzapine concentrations occur in approximately 6 hours.1 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
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 Olanzapine exhibits linear pharmacokinetics when given IM within the clinical dosage range.1
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
Olanzapine is 93% bound to plasma proteins over the concentration range of 7-1100 ng/mL, principally to albumin and α1-acid glycoprotein.1
Olanzapine appears to be extensively metabolized.1 Following a single oral dose of radiolabeled olanzapine, 7% of the dose was recovered in urine as unchanged drug.1 Approximately 57 and 30% of the dose was recovered in the urine and feces, respectively.1 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 Both of these metabolites lack pharmacologic activity at the concentrations observed.1
Direct glucuronidation and cytochrome P-450 (CYP)-mediated oxidation are the principal pathways for olanzapine metabolism.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 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 Plasma olanzapine concentrations may vary between individuals according to gender (clearance is approximately 30% lower in women vs. men), smoking status (clearance is 40% higher in smokers), and age.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
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
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 2.5 mg* | OLANZapine Tablets | |
ZyPREXA® | H2-Pharma | |||
5 mg* | OLANZapine Tablets | |||
ZyPREXA® | H2-Pharma | |||
7.5 mg* | OLANZapine Tablets | |||
ZyPREXA® | H2-Pharma | |||
10 mg* | OLANZapine Tablets | |||
ZyPREXA® | H2-Pharma | |||
15 mg* | OLANZapine Tablets | |||
ZyPREXA® | H2-Pharma | |||
20 mg* | OLANZapine Tablets | |||
ZyPREXA® | H2-Pharma | |||
Tablets, orally disintegrating | 5 mg* | OLANZapine Orally Disintegrating Tablets | ||
ZyPREXA® Zydis® | H2-Pharma | |||
10 mg* | OLANZapine Orally Disintegrating Tablets | |||
ZyPREXA® Zydis® | H2-Pharma | |||
15 mg* | OLANZapine Orally Disintegrating Tablets | |||
ZyPREXA® Zydis® | H2-Pharma | |||
20 mg* | OLANZapine Orally Disintegrating Tablets | |||
ZyPREXA® Zydis® | H2-Pharma | |||
Parenteral | For injection, for IM use only | 10 mg* | OLANZapine IM Injection | |
ZyPREXA® IntraMuscular | H2-Pharma |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | 3 mg with Fluoxetine Hydrochloride 25 mg (of fluoxetine)* | OLANZapine with Fluoxetine Capsules | |
Symbyax® | Lilly | |||
6 mg with Fluoxetine Hydrochloride 25 mg (of fluoxetine)* | OLANZapine with Fluoxetine Capsules | |||
Symbyax® | Lilly | |||
6 mg with Fluoxetine Hydrochloride 50 mg (of fluoxetine)* | OLANZapine with Fluoxetine Capsules | |||
Symbyax® | Lilly | |||
12 mg with Fluoxetine Hydrochloride 25 mg (of fluoxetine)* | OLANZapine with Fluoxetine Capsules | |||
Symbyax® | Lilly | |||
12 mg with Fluoxetine Hydrochloride 50 mg (of fluoxetine)* | OLANZapine with Fluoxetine Capsules | |||
Symbyax® | Lilly | |||
Tablets | 5 mg with Samidorphan 10 mg | Lybalvi® | Alkermes | |
10 mg with Samidorphan 10 mg | Lybalvi® | Alkermes | ||
15 mg with Samidorphan 10 mg | Lybalvi® | Alkermes | ||
20 mg with Samidorphan 10 mg | Lybalvi® | Alkermes |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
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) | H2-Pharma |
300 mg (of olanzapine) | ZyPREXA® Relprevv® (available as a convenience kit containing single-use vial, needles, syringe, and diluent) | H2-Pharma | ||
405 mg (of olanzapine) | ZyPREXA® Relprevv® (available as a convenience kit containing single-use vial, needles, syringe, and diluent) | H2-Pharma |
1. H2-Pharma, LLC. Zyprexa® (olanzapine) tablets and Zyprexa® Zydis® (olanzapine) orally disintegrating tablets and Zyprexa® IntraMuscular (olanzapine) for injection prescribing information. Montgomery, AL; 2025 Jan.
2. Lahti AC, Tamminga CA. Recent developments in the neuropharmacology of schizophrenia. Am J Health-Syst Pharm . 1995; 52(Suppl 1):S5-8. [PubMed 7749964]
3. Borison RL. Clinical efficacy of serotonin-dopamine antagonists relative to classic neuroleptics. J Clin Psychopharmacol . 1995; 15(Suppl 1):S24-29.
4. Meltzer HY. Clozapine and other atypical neuroleptics: efficacy, side effects, optimal utilization. J Clin Psychiatry . 1994; 12:38-42.
14. Keks N. Schizophrenia. Aust J Hosp Pharm . 1996; 26:93-6.
20. Fulton B, Goa KL. Olanzapine: a review of its pharmacological properties and therapeutic efficacy in the management of schizophrenia and related psychoses. Drugs . 1997; 53:282-98.
21. Tollefson GD, Beasley CM, Tran PV et al. Olanzapine versus haloperidol in the treatment of schizophrenia and schizoaffective and schizophreniform disorders: results of an international collaborative trial. Am J Psychiatry . 1997; 154:457-65. [PubMed 9090331]
22. Tollefson GD, Sanger TM. Negative symptoms: a path analytic approach to a double-blind, placebo- and haloperidol-controlled clinical trial with olanzapine. Am J Psychiatry . 1997; 154:466-74. [PubMed 9090332]
26. American Psychiatric Association. Practice guideline for the treatment of patients with schizophrenia, third edition. 2020. Accessed 2025 Feb 2025. [Web]
30. American Medical Association Council on Scientific Affairs. Aspartame: review of safety issues. JAMA . 1985; 254:400-2. [PubMed 2861297]
36. Tohen M, Jacobs TG, Grundy SL et al. Efficacy of olanzapine in acute bipolar mania: a double-blind, placebo-controlled study. The Olanzapine HGGW Study Group. Arch Gen Psychiatry . 2000; 57:841-9. [PubMed 10986547]
37. Tohen M, Sanger TM, McElroy SL et al. Olanzapine versus placebo in the treatment of acute mania. Olanzapine HGEH Study Group. Am J Psychiatry . 1999; 156:702-9. [PubMed 10327902]
38. Berk M, Segal J, Janet L et al. Emerging options in the treatment of bipolar disorders. Drugs . 2001; 61:1407-14. [PubMed 11558830]
39. Berk M, Ichim L, Brook S. Olanzapine compared to lithium in mania: a double-blind randomized controlled trial. Int Clin Psychopharmacol . 1999; 14:339-43. [PubMed 10565800]
41. Tohen M, Chengappa KNR, Suppes T et al. Efficacy of olanzapine in combination with valproate or lithium in the treatment of mania in patients partially nonresponsive to valproate or lithium monotherapy. Arch Gen Psychiatry . 2002; 59:62-9. (IDIS 474664) [PubMed 11779284]
42. American Psychiatric Association. Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry. 2002; 159(4 Suppl):1-50.
82. Gianfrancesco FD, Grogg AL, Mahmoud RA et al. Differential effects of risperidone, olanzapine, clozapine, and conventional antipsychotics on type 2 diabetes: findings from a large health plan database. J Clin Psychiatry . 2002; 63:920-30. [PubMed 12416602]
97. Institute for Safe Medication Practices. ISMP List of Confused Drug Names. Accessed 2025 Feb 25. [Web]
98. Jones B, Taylor CC, Meehan K. The efficacy of a rapid-acting intramuscular formulation of olanzapine for positive symptoms. J Clin Psychiatry . 2001; 62(Suppl. 2):22-4. [PubMed 11232747]
99. Meehan K, Zhang F, David S et al. A double-blind, randomized comparison of the efficacy and safety of intramuscular injections of olanzapine, lorazepam, or placebo in treating acutely agitated patients diagnosed with bipolar mania. J Clin Psychopharmacol . 2001; 21:389-97. [PubMed 11476123]
100. Eli Lilly and Company. Landmark, placebo-controlled trial suggests olanzapine may delay and reduce rates of manic and depressive relapse in patients with bipolar disorder. May 19, 2003. Press release.
102. Wright P, Birkett M, David SR et al. Double-blind, placebo-controlled comparison of intramuscular olanzapine and intramuscular haloperidol in the treatment of acute agitation in schizophrenia. Am J Psychiatry . 2001; 158:1149-51. [PubMed 11431240]
105. Martin J, Gomez JC, Garcia-Bernardo E et al. Olanzapine in treatment-refractory schizophrenia: results of an open-label study. The Spanish Group for the Study of Olanzapine in Treatment-Refractory Schizophrenia. J Clin Psychiatry . 1997; 58:479-83. [PubMed 9413413]
147. Freedman R. Schizophrenia. New Engl J Med . 2003; 349:1738-49. [PubMed 14585943]
152. Hiemke C, Peled S, Jabarin M et al. Fluvoxamine augmentation of olanzapine in chronic schizophrenia: pharmacokinetic interactions and clinical effects. J Clin Psychopharmacol . 2002; 22:502-6. [PubMed 12352274]
205. Kraus JE, Sheitman BB, Cook A et al. Olanzapine versus risperidone in newly admitted acutely ill psychotic patients. J Clin Psychiatry . 2005; 66:1564-8. [PubMed 16401158]
206. Breier A, Berg PH, Thakore JH et al. Olanzapine versus ziprasidone: results of a 28-week double-blind study in patients with schizophrenia. Am J Psychiatry . 2005; 162:1879-87. [PubMed 16199834]
207. Kapur S, Arenovich T, Agid O et al. Evidence for onset of antipsychotic effects within the first 24 hours of treatment. Am J Psychiatry . 2005; 162:939-46. [PubMed 15863796]
208. Kluge M, Wehmeier PM, Dittmann RW et al. A simple switching strategy for inadequately treated patients with schizophrenia to olanzapine: changes in psychopathology and subjective well being. Pharmacopsychiatry . 2005; 38:6-12. [PubMed 15706459]
215. Tandon R. Safety and tolerability: how do newer generation “atypical” antipsychotics compare? Psychiatr Q . 2002; 73:297-311.
219. Volavka J, Czobor P, Sheitman B et al. Clozapine, olanzapine, risperidone, and haloperidol in the treatment of patients with chronic schizophrenia and schizoaffective disorder. Am J Psychiatry . 2002; 159:255-62. [PubMed 11823268]
220. Sheitman BB, Lindgren JC, Early JE et al. High-dose olanzapine for treatment-refractory schizophrenia. Am J Psychiatry . 1997; 154:1626.
221. Mount Joy CQ, Baldacchino AM, Stubbs JH. British experience with high-dose olanzapine for treatment-refractory schizophrenia. Am J Psychiatry . 1999; 156:158-9. [PubMed 9892320]
223. Beasley CM Jr, Tollefson G, Tran P et al. Olanzapine versus placebo and haloperidol: acute phase results of the North American double-blind olanzapine trial. Neuropsychopharmacology . 1996; 14:111-23. [PubMed 8822534]
224. Conley RR, Tamminga CA, Bartko JJ et al. Olanzapine compared with chlorpromazine in treatment-resistant schizophrenia. Am J Psychiatry . 1998; 155:914-20. [PubMed 9659857]
225. Breier A, Hamilton SH. Comparative efficacy of olanzapine and haloperidol for patients with treatment-resistant schizophrenia. Biol Psychiatry . 1999; 45:403-11. [PubMed 10071708]
226. Tollefson GD, Birkett MA, Kiesler GM et al. Double-blind comparison of olanzapine versus clozapine in schizophrenic patients clinically eligible for treatment with clozapine. Biol Psychiatry . 2001; 49:52-63. [PubMed 11163780]
227. Zink M. Augmentation of olanzapine in treatment-resistant schizophrenia. J Psychiatry Neurosci . 2005; 30:409-15. [PubMed 16327874]
228. Tiihonen TJ, Halonen P, Wahlbeck K et al. Topiramate add-on in treatment-resistant schizophrenia: a randomized, double-blind, placebo-controlled, crossover trial. J Clin Psychiatry . 2005; 66:1012-5. [PubMed 16086616]
229. Dursun SM, Deakin JF. Augmenting antipsychotic treatment with lamotrigine or topiramate in patients with treatment-resistant schizophrenia: a naturalistic case-series outcome study. J Psychopharmacol . 2001; 15:297-301. [PubMed 11769825]
230. Conley RR, Kelly DL, Richardson CM et al. The efficacy of high-dose olanzapine versus clozapine in treatment-resistant schizophrenia: a double-blind crossover study. J Clin Psychopharmacol . 2003; 23:668-71. [PubMed 14624201]
231. Casey DE, Daniel DG, Wassef AA et al. Effect of divalproex combined with olanzapine or risperidone in patients with an acute exacerbation of schizophrenia. Neuropsychopharmacology . 2003; 28:182-92. [PubMed 12496955]
232. Citrome L, Casey DE, Daniel DG et al. Adjunctive divalproex and hostility among patients with schizophrenia receiving olanzapine or risperidone. Psychiatr Serv . 2004; 55:290-4. [PubMed 15001730]
233. Cramer JA, Sernyak M. Results of a naturalistic study of treatment options: switching atypical antipsychotic drugs or augmenting with valproate. Clin Ther . 2004; 26:905-14. [PubMed 15262461]
234. McClellan J, Stock S; American Academy of Child and Adolescent Psychiatry (AACAP) Committee on Quality Issues (CQI). Practice parameter for the assessment and treatment of children and adolescents with schizophrenia. J Am Acad Child Adolesc Psychiatry. 2013;52(9):976-990.
239. Rodriguez-Perez V, Lopez A, Blanco C et al. Olanzapine for the treatment of chronic refractory schizophrenia: a 12-month follow-up naturalistic study. Prog Neuropsychopharmacol Biol Psychiatry . 2002; 6:1055-62.
244. Now approved: Zyprexa for maintenance therapy for bipolar disorder. Accessed 2006 Mar 11. [Web]
245. Tohen M, Calabrese JR, Sachs GS et al. Randomized, placebo-controlled trial of olanzapine as maintenance therapy in patients with bipolar I disorder responding to acute treatment with olanzapine. Am J Psychiatry . 2006; 163:247-56. [PubMed 16449478]
246. Ketter TA, Houston JP, Adams DH et al. Differential efficacy of olanzapine and lithium in preventing manic or mixed recurrence in patients with bipolar I disorder based on number of previous manic or mixed episodes. J Clin Psychiatry . 2006; 67:95-101. [PubMed 16426094]
247. Tohen M, Ketter TA, Zarate CA et al. Olanzapine versus divalproex sodium for the treatment of acute mania and maintenance of remission: a 47-week study. Am J Psychiatry . 2003; 160:1263-71. [PubMed 12832240]
248. Tohen M, Baker RW, Altshuler LL et al. Olanzapine versus divalproex in the treatment of acute mania. Am J Psychiatry . 2002; 159:1011-7. [PubMed 12042191]
249. Zajecka JM, Weisler R, Sachs G et al. A comparison of the efficacy, safety, and tolerability of divalproex sodium and olanzapine in the treatment of bipolar disorder. J Clin Psychiatry . 2002; 63:1148-55. [PubMed 12523875]
250. Tohen M, Greil W, Calabrese JR et al. Olanzapine versus lithium in the maintenance treatment of bipolar disorder: a 12-month, randomized, double-blind, controlled clinical trial. Am J Psychiatry . 2005; 162:1281-90. [PubMed 15994710]
251. Vieta E, Calabrese JR, Hennen J et al. Comparison of rapid-cycling and non-rapid-cycling bipolar I manic patients during treatment with olanzapine: analysis of pooled data. J Clin Psychiatry . 2004; 65:1420-8. [PubMed 15491248]
252. Tohen M, Chengappa KNR, Suppes T et al. Relapse prevention in bipolar I disorder: 18-month comparison of olanzapine plus mood stabilizer v. mood stabilizer alone. Br J Psychiatry . 2004; 184:337-45. [PubMed 15056579]
253. McClellan J, Kowatch R, Findling RL et al. Practice parameter for the assessment and treatment of children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry . 2007; 46:107-25. [PubMed 17195735]
290. Stephenson CMA, Pilowsky LS. Psychopharmacology of olanzapine. Br J Psychiatry . 1999; 174(Suppl. 38):52-8.
304. Wang X, Savage R, Borisov A et al. Efficacy of risperidone versus olanzapine in patients with schizophrenia previously on chronic conventional antipsychotic therapy: a switch study. J Psychiatr Res . 2006 Jun 6 [Epub].
305. Alvarez E, Ciudad A, Olivares JM et al. A randomized, 1-year follow-up study of olanzapine and risperidone in the treatment of negative symptoms in outpatients with schizophrenia. J Clin Psychopharmacol . 2006; 26:238-49. [PubMed 16702888]
306. McEvoy JP, Lieberman JA, Stroup TS et al. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry . 2006; 163:600-10. [PubMed 16585434]
307. Stroup TS, Leiberman JA, McEvoy JP et al. Effectiveness of olanzapine, quetiapine, risperidone, and ziprasidone in patients with chronic schizophrenia following discontinuation of a previous atypical antipsychotic. Am J Psychiatry . 2006; 163:611-22. [PubMed 16585435]
308. Baker RW, Brown E, Akiskal HS et al. Efficacy of olanzapine combined with valproate or lithium in the treatment of dysphoric mania. Br J Psychiatry . 2004; 185:472-8. [PubMed 15572737]
309. Swanson JW, Swartz MS, Elbogen EB et al. Reducing violence risk in persons with schizophrenia: olanzapine versus risperidone. J Clin Psychiatry . 2004; 65:1666-73. [PubMed 15641872]
310. Krakowski MI, Czobor P, Citrome L et al. Atypical antipsychotic agents in the treatment of violent patients with schizophrenia and schizoaffective disorder. Arch Gen Psychiatry . 2006; 63:622-9. [PubMed 16754835]
311. Beasley CM, Sanger T, Satterlee W et al. Olanzapine versus placebo: results of a double-blind, fixed-dose olanzapine trial. Psychopharmacology (Berl) . 1996; 124:159-67. [PubMed 8935812]
312. Eli Lilly and Company. Symbyax® (olanzapine and fluoxetine) capsules prescribing information. Indianapolis, IN; 2025 Jan.
313. Tohen M, Vieta E, Calabrese J et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch J Psychiatry . 2003; 60:1079-88.
314. Corya SA, Perlis RH, Keck PE et al. A 24-week open-label extension study of olanzapine-fluoxetine combination and olanzapine monotherapy in the treatment of bipolar depression. J Clin Psychiatry . 2006; 67:798-806. [PubMed 16841630]
315. Bhana N, Foster RH, Olney R et al. Olanzapine: an updated review of its use in the management of schizophrenia. Drugs . 2001; 61:111-61. [PubMed 11217867]
337. Rosenheck R, Perlick D, Bingham S et al. for the Department of Veterans Affairs Cooperative Study Group on the Cost-Effectiveness of Olanzapine.. Effectiveness and cost of olanzapine and haloperidol in the treatment of schizophrenia: a randomized controlled trial. JAMA . 2003; 290:2693-702. [PubMed 14645311]
340. Peuskens J, Demily C, Thibaut F. Treatment of cognitive dysfunction in schizophrenia. Clin Ther . 2005; 27 (Suppl. A):S25-37. [PubMed 16198199]
341. Meltzer HY, McGurk SR. The effects of clozapine, risperidone, and olanzapine on cognitive function in schizophrenia. Schizophren Bull . 1999; 25:233-55.
342. Bilder RM, Goldman RS, Volavka J et al. Neurocognitive effects of clozapine, olanzapine, risperidone, and haloperidol in patients with chronic schizophrenia or schizoaffective disorder. Am J Psychiatry . 2002; 159:1018-28. [PubMed 12042192]
343. Purdon SE, Jones BD, Stip E et al. Neuropsychological change in early phase schizophrenia during 12 months of treatment with olanzapine, risperidone, or haloperidol. The Canadian Collaborative Group for research in schizophrenia. Arch Gen Psychiatry . 2000; 57:249-58. [PubMed 10711911]
344. Keefe RS, Young CA, Rock SL et al. One-year double-blind study of he neurocognitive efficacy of olanzapine, risperidone, and haloperidol in schizophrenia. Schizophr Res . 2006; 81:1-15. [PubMed 16202565]
345. Jann MW. Implications for atypical antipsychotics in the treatment of schizophrenia: neurocognition effects and a neuroprotective hypothesis. Pharmacotherapy . 2004; 24:1759-83. [PubMed 15585443]
354. Beasley CM Jr, Sutton VK, Hamilton SH et al. for the Olanzapine Relapse Prevention Study Group.. A double-blind, randomized, placebo-controlled trial of olanzapine in the prevention of psychotic relapse. J Clin Psychopharmacol . 2003; 23:582-94. [PubMed 14624189]
357. Tran PV, Hamilton SH, Kuntz AJ et al. Double-blind comparison of olanzapine versus risperidone in the treatment of schizophrenia and other psychotic disorders. J Clin Psychopharmacol . 1997; 17:407-18. [PubMed 9315992]
358. Conley RR, Mahmoud R. A randomized double-blind study of risperidone and olanzapine in the treatment of schizophrenia or schizoaffective disorder. m J Psychiatry . 2001; 158:765-74.
359. Kinon BJ, Lipkovich I, Edwards SB et al. A 24-week randomized study of olanzapine versus ziprasidone in the treatment of schizophrenia or schizoaffective disorder in patients with prominent depressive symptoms. J Clin Psychopharmacol . 2006; 26:157-62. [PubMed 16633144]
360. Simpson GM, Glick ID, Weiden PJ et al. Randomized, controlled, double-blind multicenter comparison of the efficacy and tolerability of ziprasidone and olanzapine in acutely ill inpatients with schizophrenia or schizoaffective disorder. Am J Psychiatry . 2004; 161:1837-47. [PubMed 15465981]
361. Simpson GM, Weiden P, Pigott T et al. Six-month, blinded, multicenter continuation study of ziprasidone versus olanzapine in schizophrenia. Am J Psychiatry . 2005; 162:1535-8. [PubMed 16055779]
362. Kinon BJ, Noordsy DL, Liu-Seifert H et al. Randomized, double-blind 6-month comparison of olanzapine and quetiapine in patients with schizophrenia or schizoaffective disorder with prominent negative symptoms and poor functioning. J Clin Psychopharmacol . 2006; 26:453-61. [PubMed 16974184]
369. Kryzhanovskaya L, Schulz SC, McDougle C et al. Olanzapine versus placebo in adolescents with schizophrenia: a 6-week, randomized, double-blind, placebo-controlled trial. J Am Acad Child Adolesc Psychiatry . 2009; 48:60-70. [PubMed 19057413]
370. Tohen M, Kryzhanovskaya L, Carlson G et al. Olanzapine versus placebo in the treatment of adolescents with bipolar mania. Am J Psychiatry . 2007; 164:1547-56. [PubMed 17898346]
372. Food and Drug Administration. Risk evaluation and mitigation strategy (REMS) for Zyprexa Relprevv. Available from FDA website. Accessed 2025 Feb 25. [Web]
382. H2 Pharma. Zyprexa® Relprevv (olanzapine) for extended release injectable suspension prescribing information. Montgomery, AL; 2025 Jan.
383. Kane JM, Detke HC, Naber D et al. Olanzapine long-acting injection: a 24-week, randomized, double-blind trial of maintenance treatment in patients with schizophrenia. Am J Psychiatry . 2010; 167:181-9. [PubMed 20008947]
384. Citrome L. Olanzapine pamoate: a stick in time? A review of the efficacy and safety profile of a new depot formulation of a second-generation antipsychotic. Int J Clin Pract . 2009; 63:140-50. [PubMed 18834452]
385. Lauriello J, Lambert T, Andersen S et al. An 8-week, double-blind, randomized, placebo-controlled study of olanzapine long-acting injection in acutely ill patients with schizophrenia. J Clin Psychiatry . 2008; 69:790-9. [PubMed 18452346]
388. Frampton JE. Olanzapine long-acting injection: a review of its use in the treatment of schizophrenia. Drugs . 2010; 70:2289-313. [PubMed 21080745]
392. McGlennon D, Bushe CJ. Olanzapine long-acting injection: insights from an early case series in the UK. Ther Adv Psychopharmacol . 2012; 2:189-93. [PubMed 23983974]
393. Ereshefsky L, Saklad SR, Jann MW et al. Future of depot neuroleptic therapy: pharmacokinetic and pharmacodynamic approaches. J Clin Psychiatry . 1984; 45:50-9. [PubMed 6143748]
394. Jann MW, Ereshefsky L, Saklad SR. Clinical pharmacokinetics of the depot antipsychotics. Clin Pharmacokinet . 1985; 10:315-33. [PubMed 2864156]
395. Knudsen P. Chemotherapy with neuroleptics. Acta Psychiatr Scand . 1985; 322(Suppl):51-75.
396. Kane JM. Dosage strategies with long-acting injectable neuroleptics, including haloperidol decanoate. J Clin Psychopharmacol . 1986; 1(Suppl):20-3S.
397. Detke HC, DelBello MP, Landry J et al. Olanzapine/fluoxetine combination in children and adolescents with bipolar I depression: a randomized, double-blind, placebo-controlled trial. J Am Acad Child Adolesc Psychiatry . 2015; 54:217-24. [PubMed 25721187]
425. Hesketh PJ, Kris MG, Basch E et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol . 2020; 38:2782-2797.
426. Navari RM, Qin R, Ruddy KJ et al. Olanzapine for the prevention of chemotherapy-induced nausea and vomiting. N Engl J Med . 2016; 375:134-42. [PubMed 27705262]
427. Chiu L, Chow R, Popovic M et al. Efficacy of olanzapine for the prophylaxis and rescue of chemotherapy-induced nausea and vomiting (CINV): a systematic review and meta-analysis. Support Care Cancer . 2016; 24:2381-92. [PubMed 26768437]
428. Yanai T, Iwasa S, Hashimoto H et al. A double-blind randomized phase II dose-finding study of olanzapine 10 mg or 5 mg for the prophylaxis of emesis induced by highly emetogenic cisplatin-based chemotherapy. Int J Clin Oncol . 2018; 23:382-8. [PubMed 29039073]
429. Navari RM, Nagy CK, Gray SE. The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy. Support Care Cancer . 2013; 21:1655-63. [PubMed 23314603]
431. Alkermes. Lybalvi® (olanzapine and samidorphan) tablets prescribing information. Waltham, MA; 2025 Jan.
432. Roeland EJ, Bohlke K, Baracos VE, Smith TJ, Loprinzi CL; Cancer Cachexia Expert Panel. Cancer Cachexia: ASCO Guideline Rapid Recommendation Update. J Clin Oncol. 2023;41(25):4178-4179.
433. Sandhya L, Devi Sreenivasan N, Goenka L, et al. Randomized Double-Blind Placebo-Controlled Study of Olanzapine for Chemotherapy-Related Anorexia in Patients With Locally Advanced or Metastatic Gastric, Hepatopancreaticobiliary, and Lung Cancer. J Clin Oncol. 2023;41(14):2617-2627.
434. Department of Veterans Affairs (VA) and Department of Defense (DoD). VA/DoD Clinical Practice Guideline for Management of First-Episode Psychosis and Schizophrenia, 2023. [Web]
435. Department of Veterans Affairs (VA) and Department of Defense (DoD). VA/DoD Clinical Practice Guideline for Management of Bipolar Disorder, 2023. [Web]
436. Shelton RC, Tollefson GD, Tohen M, et al. A novel augmentation strategy for treating resistant major depression. Am J Psychiatry. 2001;158(1):131-134.
437. American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder, third edition. Am J Psychiatry. 2010;167(suppl).
438. Department of Veterans Affairs (VA) and Department of Defense (DoD). VA/DoD Clinical Practice Guideline for the Management of Major Depressive Disorder, 2022. [Web]
439. American Psychological Association. (2019). Clinical practice guidelines for the treatment of depression across three age cohorts. [Web]
440. Drugs for depression. Med Lett Drugs Ther. 2023 Dec 11;65(1691):193-200.
441. Reus VI, Fochtmann LJ, Eyler AE, et al. The American Psychiatric Association Practice Guideline on the Use of Antipsychotics to Treat Agitation or Psychosis in Patients With Dementia. Am J Psychiatry. 2016;173(5):543-546.
442. Chen A, Copeli F, Metzger E, Cloutier A, Osser DN. The Psychopharmacology Algorithm Project at the Harvard South Shore Program: An update on management of behavioral and psychological symptoms in dementia. Psychiatry Res. 2021;295:113641.
443. By the 2023 American Geriatrics Society Beers Criteria® Update Expert Panel. American Geriatrics Society 2023 updated AGS Beers Criteria® for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2023;71(7):2052-2081.
444. Bandelow B, Allgulander C, Baldwin DS, et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for treatment of anxiety, obsessive-compulsive and posttraumatic stress disorders - Version 3. Part I: Anxiety disorders. World J Biol Psychiatry. 2023;24(2):79-117.
445. Koran LM, Hanna GL, Hollander E, Nestadt G, Simpson HB; American Psychiatric Association. Practice guideline for the treatment of patients with obsessive-compulsive disorder. Am J Psychiatry. 2007;164(7 Suppl):5-53.
446. Williams T, Phillips NJ, Stein DJ, Ipser JC. Pharmacotherapy for post traumatic stress disorder (PTSD). Cochrane Database Syst Rev. 2022;3(3):CD002795.
447. Bandelow B, Allgulander C, Baldwin DS, et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for treatment of anxiety, obsessive-compulsive and posttraumatic stress disorders - Version 3. Part II: OCD and PTSD. World J Biol Psychiatry. 2023;24(2):118-134.
448. Department of Veterans Affairs (VA) and Department of Defense (DoD). VA/DoD Clinical Practice Guideline for Management of Posttraumatic Stress Disorder and Acute Stress Disorder, 2023. [Web]