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olanzapine 10 mg tablet (generic zyprexa)

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Uses

Olanzapine is used orally for the symptomatic management of psychotic disorders (e.g., schizophrenia) in adults and adolescents 13-17 years of age. In addition, oral olanzapine is used alone in adults and adolescents 13-17 years of age or in conjunction with lithium or valproate in adults for the management of acute manic or mixed episodes associated with bipolar I disorder; the drug also is used for longer-term maintenance monotherapy in patients with this disorder. Short-acting olanzapine injection is used IM for the management of acute agitation in patients with bipolar disorder or schizophrenia. Long-acting olanzapine pamoate injection is used IM for the management of schizophrenia in adults.

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

Psychotic Disorders

Olanzapine is used orally and parenterally for the symptomatic management of psychotic disorders (e.g., schizophrenia). Drug therapy is integral to the management of acute psychotic episodes in patients with schizophrenia and generally is required for long-term stabilization to sustain symptom remission or control and to minimize the risk of relapse. Antipsychotic agents are the principal class of drugs used for the management of all phases of schizophrenia. Patient response and tolerance to antipsychotic agents are variable, and patients who do not respond to or tolerate one drug may be successfully treated with an agent from a different class or with a different adverse effect profile.

Schizophrenia

Olanzapine is used orally for the management of schizophrenia in adults and adolescents from 13 to 17 years of age. The long-acting pamoate ester of olanzapine is used parenterally for the management of schizophrenia in adults. Schizophrenia is a major psychotic disorder that frequently has devastating effects on various aspects of the patient's life and carries a high risk of suicide and other life-threatening behaviors. Manifestations of schizophrenia involve multiple psychologic processes, including perception (e.g., hallucinations), ideation, reality testing (e.g., delusions), emotion (e.g., flatness, inappropriate affect), thought processes (e.g., loose associations), behavior (e.g., catatonia, disorganization), attention, concentration, motivation (e.g., avolition, impaired intention and planning), and judgment. The principal manifestations of this disorder usually are described in terms of positive and negative (deficit) symptoms, and more recently, disorganized symptoms. Positive symptoms include hallucinations, delusions, bizarre behavior, hostility, uncooperativeness, and paranoid ideation, while negative symptoms include restricted range and intensity of emotional expression (affective flattening), reduced thought and speech productivity (alogia), anhedonia, apathy, and decreased initiation of goal-directed behavior (avolition). Disorganized symptoms include disorganized speech (thought disorder) and behavior and poor attention.

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

To compare the long-term effectiveness and tolerability of older, first-generation antipsychotic agents (i.e., perphenazine) with those of newer, atypical antipsychotic agents (i.e., olanzapine, quetiapine, risperidone, ziprasidone), a double-blind, multicenter study (the first phase of Clinical Antipsychotic Trials of Intervention Effectiveness [CATIE]) was sponsored by the National Institute of Mental Health. More than 1400 patients with schizophrenia received one of these antipsychotics for up to 18 months or until therapy was discontinued for any reason. Patients with tardive dyskinesia could enroll in this trial; however, the randomization scheme prevented their assignment to the perphenazine group. The primary outcome measure in this study was the discontinuance of treatment for any cause; this measure was selected because discontinuing or switching an antipsychotic agent occurs frequently and is an important problem in the management of schizophrenia. In addition, this measure integrates the patient's and clinician's judgments concerning efficacy, safety, and tolerability into a more comprehensive measure of effectiveness reflecting therapeutic benefits in relation to adverse effects. Overall, 74% of patients in this study discontinued their medication before receiving the full 18 months of therapy because of inadequate efficacy, intolerable adverse effects, or for other reasons, suggesting substantial limitations in the long-term clinical effectiveness of currently available antipsychotic agents. Olanzapine appeared to be more effective than the other drugs evaluated in this study with a lower (64%) discontinuance rate and a lower rate of hospitalization for exacerbation of schizophrenia, while no significant differences between the effectiveness of the conventional agent, perphenazine, and the other second-generation agents studied were observed (discontinuance rates were 75, 82, 74, and 79% for perphenazine, quetiapine, risperidone, and ziprasidone, respectively). The time to discontinuance of therapy for any cause was found to be longer in the olanzapine group than in the quetiapine, risperidone, perphenazine, and ziprasidone groups in this study; however, the differences between the olanzapine and perphenazine groups and between the olanzapine and ziprasidone groups did not achieve statistical significance. Although there were no significant differences in the time until discontinuance of therapy because of drug intolerance among the drugs studied, the incidences of discontinuance for certain adverse effects differed among the drugs with olanzapine discontinued more frequently because of weight gain or metabolic effects (e.g., increases in glycosylated hemoglobin [hemoglobin A1c; HbA1c], cholesterol, and triglycerides) and perphenazine discontinued more frequently because of adverse extrapyramidal effects.

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

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

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

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

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

Atypical antipsychotic agents, including olanzapine, generally appear less likely to induce adverse extrapyramidal effects and tardive dyskinesia than conventional, first-generation antipsychotic agents. In addition, stabilization of or improvement in tardive dyskinesia associated with conventional antipsychotic agents has been reported in some patients when they have been switched to second-generation antipsychotic therapy, including olanzapine. Therefore, the APA and some clinicians recommend that atypical antipsychotic agents be considered in patients with schizophrenia who have experienced tardive dyskinesia associated with conventional antipsychotic agents.

For additional information on the symptomatic management of schizophrenia, .

The efficacy of oral olanzapine for the management of psychotic disorders in adults has been established in hospital settings by 2 placebo-controlled studies of 6 weeks' duration in patients who met the DSM-III-R criteria for schizophrenia. 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).

In the first 6-week, placebo-controlled study, olanzapine was given in a fixed dosage of 1 or 10 mg once daily. 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. 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; the highest dosage also was superior to placebo on the SANS. There appeared to be no therapeutic advantage for the higher dosage of olanzapine compared with the medium dosage in this study. No race- or gender-related differences in outcome were noted in either of these studies.

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, 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. 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. 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. In addition, olanzapine was found to be superior to placebo on prolonging time to relapse, which was the primary outcome measure in this study. 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. If oral olanzapine is used for extended periods, the need for continued therapy should be reassessed periodically.

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. 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. Patients were discontinued from their previous antipsychotic regimen and underwent a washout period lasting 2-7 days. Supplementation with oral antipsychotics was not allowed throughout the study. 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). Total PANSS scores showed improvement from baseline to end point with each dosage of olanzapine pamoate compared with placebo. 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. There were no substantial differences in efficacy among the 3 olanzapine pamoate dosage groups at the study end point. The onset of antipsychotic efficacy for the long-acting olanzapine pamoate injection was evident within the first week of treatment. 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.

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. 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. No supplementation with oral antipsychotics was allowed throughout the study. The primary efficacy measure was time to exacerbation of symptoms of schizophrenia, which was defined as either increases in BPRS positive symptoms or hospitalization. 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. Olanzapine pamoate generally demonstrated a similar safety profile to oral olanzapine with the exception of injection-related adverse effects. If IM olanzapine pamoate injection is used for extended periods, the need for continued therapy should be reassessed periodically.

Parenteral antipsychotic therapy with a long-acting IM preparation may be particularly useful in patients with schizophrenia and a history of poor compliance. In addition, long-acting antipsychotic preparations may be useful in patients with suspected GI malabsorption or variable GI absorption of the drug. The principal disadvantage of long-acting parenteral antipsychotics is the inability to terminate the drug's action when severe adverse reactions occur. 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. 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.

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. Like other second-generation antipsychotic agents, olanzapine appears to improve both positive (florid symptomatology such as hallucinations, conceptual disorganization, and suspiciousness) and negative (''deficit'' symptomatology such as emotional withdrawal, motor retardation, blunted affect, and disorientation) manifestations of schizophrenia; conventional antipsychotic agents may have lesser effects on negative manifestations of the disorder. 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. 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.

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, 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. 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. 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. In other comparative studies, olanzapine usually was found to be at least as effective as or more effective than haloperidol and several other atypical antipsychotic agents, including quetiapine, risperidone, and ziprasidone. 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.

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. 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. 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. 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. 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. 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. 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. 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.

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

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

Pediatric Considerations

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

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

The short-term efficacy and tolerability of oral olanzapine in 107 adolescent inpatients and outpatients 13-17 years of age with schizophrenia were established in a randomized, double-blind, placebo-controlled, multicenter trial of 6 weeks' duration in which olanzapine was given in a flexible dosage range of 2.5-20 mg once daily. 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. 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. However, weight gain and hyperprolactinemia occurred more often in patients receiving olanzapine compared with those receiving placebo.

Olanzapine has been successfully used orally for the management of childhood-onset schizophrenia in a limited number of children and other adolescents. However, the manufacturers state that the safety and effectiveness of the drug in children younger than 13 years of age have not been established.

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

Based on the observed efficacy and tolerability of atypical antipsychotics in adults and the available clinical experience in pediatric patients, the American Academy of Child and Adolescent Psychiatry (AACAP) currently states that the use of atypical antipsychotic agents in children and adolescents with schizophrenia is justified, and many clinicians consider atypical antipsychotic agents, with the exception of clozapine, among the drugs of first choice in the management of childhood-onset schizophrenia. However, well-controlled studies are necessary to more clearly establish the efficacy and safety of atypical antipsychotics in pediatric patients, particularly during long-term therapy. For additional information on the symptomatic management of childhood-onset schizophrenia,

Acute Agitation

Short-acting olanzapine injection (e.g., Zyprexa IntraMuscular) is used IM for the management of acute agitation in adult patients with schizophrenia for whom treatment with olanzapine is appropriate and who require an IM antipsychotic agent for rapid control of behaviors that interfere with diagnosis and care (e.g., threatening behaviors, escalating or urgently distressing behavior, self-exhausting behavior). According to DSM-IV, psychomotor agitation is excessive motor activity associated with a feeling of inner tension. The efficacy of IM olanzapine for the management of acute agitation in patients with schizophrenia was established in 2 short-term (single-day), placebo-controlled trials in hospital settings; an active comparator treatment arm using haloperidol injection was included in both studies. The patients in this study exhibited a level of agitation that met or exceeded a threshold score of 14 on the 5 items comprising the Positive and Negative Syndrome Scale (PANSS) Excited Component (i.e., poor impulse control, tension, hostility, uncooperativeness, and excitement items) with at least one individual item score of 4 (''moderate'') or greater using a 1-7 scoring system, where scores of 1 or 7 indicate absent or extreme agitation, respectively. 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. 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.

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. All 4 IM olanzapine doses were found to be statistically superior to placebo in reducing the PANSS Excited Component score at 2 hours following injection; however, the effect was larger and more consistent for the 3 highest doses studied. There were no significant differences in efficacy noted for the 7.5- and 10-mg doses compared with the 5-mg dose in this study. 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. 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.

Bipolar Disorder

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

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

Acute Treatment of Manic or Mixed Episodes

Efficacy of oral olanzapine monotherapy in the acute treatment of manic or mixed episodes in adults has been demonstrated in 2 short-term (i.e., 3 or 4 weeks' duration), randomized, double-blind, placebo-controlled, parallel-group trials in patients who met DSM-IV criteria for bipolar I disorder (with or without a rapid-cycling course) and who met diagnostic criteria for an acute manic or mixed episode (with or without psychotic features). 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. The principal rating instrument used for assessing manic symptoms in these trials was the Y-MRS score, an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology (e.g., irritability, disruptive/aggressive behavior, sleep, elevated mood, speech, increased activity, sexual interest, language/thought disorder, thought content, appearance, insight) in a range from 0 (no manic features) to 60 (maximum score). All patients were hospitalized at the onset of these trials, but some patients were allowed to continue the studies on an outpatient basis after 1 week of hospitalization if their Clinical Global Impressions-Bipolar Version of severity of illness (CGI-BP) mania score was no greater than 3 (mild) and they had at least a 50% reduction in their Young Mania Rating Scale (Y-MRS) scores. 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. 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. 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.

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. 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. In addition, a substantially greater proportion of patients in the olanzapine group achieved remission compared with the divalproex group. 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.

Combined Therapy

Efficacy of oral olanzapine when used in combination with lithium or valproate in the short-term treatment of acute manic or mixed episodes has been demonstrated in 2 randomized, double-blind, placebo-controlled studies of 6 weeks' duration in adult patients who met the DSM-IV criteria for bipolar I disorder (with or without a rapid-cycling course) and who met diagnostic criteria for an acute manic or mixed episode (with or without psychotic features). 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. 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.

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.

Maintenance Monotherapy of Bipolar Disorder

Oral olanzapine is used for maintenance monotherapy in adults and adolescent patients 13-17 years of age with bipolar I disorder. 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. 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. Response during the open-label phase was defined as a reduction in the Y-MRS total score of 12 or more and in the 21-item Hamilton Depression Rating Scale (HAM-D 21) of 8 or more; relapse during the double-blind phase of the study was defined as an increase in the Y-MRS or HAM-D 21 total score to 15 or more or being hospitalized for either mania or depression. 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. 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. The relapse rate also was significantly lower in the olanzapine group (approximately 47%) than in the placebo group (approximately 80%). If olanzapine is used for extended periods, the need for continued therapy should be reassessed periodically.

In a double-blind, 52-week trial comparing olanzapine and lithium maintenance therapy in adults with bipolar disorder, olanzapine was found to be significantly more effective than lithium in preventing relapses and recurrences of manic and mixed episodes following initial stabilization with combined olanzapine and lithium therapy. Olanzapine and lithium demonstrated comparable efficacy in preventing relapses and recurrences of depression in this study. 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. 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. 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.

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. 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). 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. 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.

Rapid-Cycling Bipolar Disorder

In an analysis of pooled data from several trials comparing the clinical response to olanzapine therapy in rapid-cycling and non-rapid-cycling adult patients with bipolar disorder, relative clinical response to olanzapine was found to be similar in the 2 groups, although earlier responses were observed in the rapid-cycling group of patients, and long-term outcomes were more favorable in the non-rapid-cycling group. 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.

Depressive Episodes Associated with Bipolar Disorder

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

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

Pediatric Considerations

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

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

The short-term efficacy of oral olanzapine monotherapy in the acute treatment of bipolar I disorder in adolescents 13-17 years of age was established in a randomized, multicenter, double-blind, placebo-controlled trial of 3 weeks' duration in 161 patients who met DSM-IV-TR criteria for manic or mixed episodes associated with bipolar I disorder (with or without psychotic features). 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. 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. 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.

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

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

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

Acute Agitation

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

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. The patients in this study exhibited a level of agitation that met or exceeded a threshold score of 14 on the 5 items comprising the Positive and Negative Syndrome Scale (PANSS) Excited Component (i.e., poor impulse control, tension, hostility, uncooperativeness, and excitement items) with at least one individual item score of 4 (''moderate'') or greater using a 1-7 scoring system where scores of 1 or 7 indicate absent or extreme agitation, respectively. An active comparator treatment arm using IM lorazepam was included in this study. 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. 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. IM olanzapine was found to be statistically superior to placebo in reducing the PANSS Excited Component score at 2 hours and at 24 hours following the initial injection. 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.

Treatment-resistant Depression

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

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. Daily dosages evaluated in these studies ranged from 6-18 mg of olanzapine and 25-50 mg of fluoxetine. 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. 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. 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. 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. 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). 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).

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. Daily dosages evaluated in these studies ranged from 6-18 mg of olanzapine and 25-50 mg of fluoxetine. Patients were initially treated with open-label olanzapine and fluoxetine in fixed combination (Symbyax). 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. 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. 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. If combined olanzapine and fluoxetine therapy is used for an extended period, the continued need for maintenance therapy should be reassessed periodically.

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

Dosage and Administration

Reconstitution and Administration

Olanzapine is administered orally or by IM injection. Olanzapine pamoate is administered only by IM injection.

Restricted Distribution

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

Oral Administration

Olanzapine conventional tablets, orally disintegrating tablets, and capsules (in fixed combination with fluoxetine hydrochloride) are administered orally. 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. In patients who experience persistent or troublesome daytime sedation during oral olanzapine therapy, administration of the daily dosage in the evening at bedtime may be helpful.

Patients receiving olanzapine orally disintegrating tablets should be instructed not to remove a tablet from the blister until just prior to dosing. The tablet should not be pushed through the foil. With dry hands, the blister backing should be peeled completely off the blister. 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.

The fixed combination capsules of olanzapine with fluoxetine hydrochloride (e.g., Symbyax) are administered once daily in the evening. 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.

Dispensing and Administration Precautions

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

IM Administration

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

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. Other solutions should not be used to reconstitute olanzapine for injection.

Following reconstitution, olanzapine for injection should be used immediately (within 1 hour). 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. Olanzapine for injection should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

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

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).

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. The medication guide should be provided to the patient or legal guardian prior to each injection. After each injection, patients should be continuously monitored at the healthcare facility for at least 3 hours by a healthcare professional. Patients should be alert, oriented, and absent of any signs and symptoms of PDSS prior to being released. All patients receiving an IM injection of olanzapine pamoate must be accompanied to their destination upon leaving the facility.

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

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

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

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

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. If blood appears in the syringe, the dose should not be injected; the needle should be withdrawn and the syringe and dose discarded. A new convenience kit should be used for the new dose of olanzapine pamoate with a new syringe and needle. Following IM administration, the injection site should not be massaged.

Dosage

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

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

Dosage of olanzapine must be adjusted carefully according to individual requirements and response, using the lowest possible effective dosage.

Oral Dosage

Schizophrenia

For the management of schizophrenia in adults, the recommended initial oral dosage of olanzapine is 5-10 mg daily, usually given as a single daily dose. Dosage may be increased by 5 mg daily within several days, to a target dosage of 10 mg daily. 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.

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

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

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. When dosage adjustments are necessary, dosage increments or decrements of 2.5 or 5 mg daily are recommended. 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). The manufacturer states that the safety and effectiveness of dosages exceeding 20 mg daily have not been evaluated in clinical trials.

The optimum duration of olanzapine therapy currently is not known, but maintenance therapy with antipsychotic agents is well established. 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. 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.

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. 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.

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

Bipolar Disorder

As monotherapy for the management of acute manic or mixed episodes associated with bipolar I disorder in adults, the usual initial oral dosage of olanzapine is 10 or 15 mg daily, given as a single dose. 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. The effective dosage of olanzapine in short-term clinical studies generally has ranged from 5-20 mg daily. Safety of dosages exceeding 20 mg daily has not been established.

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. When dosage adjustments are necessary, the manufacturer recommends dosage increments or decrements of 2.5 or 5 mg daily. 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). The manufacturer states that the safety and effectiveness of dosages exceeding 20 mg daily have not been evaluated in clinical trials.

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. The effective dosage of olanzapine as adjunctive therapy for up to 6 weeks in clinical studies generally ranged from 5-20 mg daily. Safety of dosages exceeding 20 mg daily has not been established in clinical trials.

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. 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. In other patients, dosage can be increased according to patient response and tolerance as indicated. 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. Dosages exceeding 18 mg of olanzapine and 75 mg of fluoxetine daily have not been evaluated in clinical studies.

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. 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. An initial dosage of 2.5-5 mg of olanzapine and 20 mg of fluoxetine should be used in patients with a predisposition to hypotensive reactions, patients with hepatic impairment, those with factors that may slow metabolism of the drugs(s) (e.g., female gender, geriatric age, nonsmoking status), or those who may be pharmacodynamically sensitive to olanzapine; when indicated, dosage adjustments should be made with caution in these patients. Dosages exceeding 18 mg of olanzapine and 75 mg of fluoxetine daily have not been evaluated in clinical studies.

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). Dosage of the fixed-combination preparation ranges from olanzapine 3-12 mg and fluoxetine 25-50 mg daily. The following table provides the appropriate individual component dosages of olanzapine and fluoxetine compared with the fixed-combination preparation. If dosage adjustments are indicated, they should be made with the individual components according to efficacy and tolerability.

Table 1. Approximate Dosage Correspondence between Olanzapine in Fixed Combination with Fluoxetine (e.g., Symbyax®) and Combined Olanzapine (e.g., Zyprexa®) and Fluoxetine Therapy (Given Individually).[1 ]
For fixed-combination dosages of: Use in combination: Olanzapine (mg/day) Fluoxetine (mg/day)
3 mg olanzapine/25 mg fluoxetine 2.5 20
6 mg olanzapine/25 mg fluoxetine 5 20
12 mg olanzapine/25 mg fluoxetine 10 + 2.5 20
6 mg olanzapine/50 mg fluoxetine 5 40 + 10
12 mg olanzapine/50 mg fluoxetine 10 + 2.5 40 + 10

When used in fixed combination with fluoxetine hydrochloride (e.g., as the fixed combination Symbyax) for acute depressive episodes in children and adolescents 10-17 years of age with bipolar disorder, olanzapine is administered once daily in the evening, usually initiating therapy with a dosage of 3 mg of olanzapine and 25 mg of fluoxetine. 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. Concurrent administration of dosages exceeding 12 mg of olanzapine and 50 mg of fluoxetine daily has not been evaluated in pediatric clinical studies.

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. Dosage adjustments, if indicated, may be made based on efficacy and tolerability. Concurrent administration of dosages exceeding 12 mg of olanzapine and 50 mg of fluoxetine daily has not been evaluated in pediatric clinical studies.

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

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. If olanzapine is used for an extended period, the need for maintenance therapy should be reassessed periodically.

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

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. 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. In other patients, dosage can be increased according to patient response and tolerance as indicated. 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. Dosages exceeding 18 mg of olanzapine and 75 mg of fluoxetine daily have not been evaluated in clinical studies. Clinicians who elect to use the fixed combination for extended periods should periodically reevaluate the long-term risks and benefits of the drug for the individual patient.

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. 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. An initial dosage of 2.5-5 mg of olanzapine and 20 mg of fluoxetine should be used in patients with a predisposition to hypotensive reactions, patients with hepatic impairment, those with factors that may slow metabolism of the drugs(s) (e.g., female gender, geriatric age, nonsmoking status), or those who may be pharmacodynamically sensitive to olanzapine; when indicated, dosage adjustment should be made with caution in these patients. Dosages exceeding 18 mg of olanzapine and 75 mg of fluoxetine daily have not been evaluated in clinical studies. Clinicians who elect to use the combination for extended periods should periodically reevaluate the long-term risks and benefits of the drug for the individual patient.

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). Dosage of the fixed-combination preparation ranges from olanzapine 3-12 mg and fluoxetine 25-50 mg daily. Table 1 provides the appropriate individual component dosages of olanzapine and fluoxetine compared with the fixed-combination preparation. If dosage adjustments are indicated, they should be made with the individual components according to efficacy and tolerability.

IM Dosage

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

For the prompt control of acute agitation in patients with schizophrenia or bipolar mania, the recommended initial adult IM dose of olanzapine injection (e.g., Zyprexa IntraMuscular) is 10 mg given as a single dose. A lower initial IM dose (2.5, 5, or 7.5 mg) may be considered when clinically warranted. 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.

If agitation necessitating additional IM doses of olanzapine persists following the initial dose, subsequent single doses of up to 10 mg may be given. 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. 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.

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. 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.(See Orthostatic Hypotension under Cautions: Precautions and Contraindications.)

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

A lower initial IM olanzapine dose of 5 mg may be considered for geriatric patients or when other clinical factors warrant. 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.

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.

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.

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. 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.

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. 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.

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.

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.

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.

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. In addition, long-term use of oral olanzapine has been shown to be effective in maintaining treatment response in patients with schizophrenia. If olanzapine pamoate is used for an extended period, the need for continued treatment should be reassessed periodically.

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.

Dosage in Renal and Hepatic Impairment

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

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

Cautions

Adverse Effects

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

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

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

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

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

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

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

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

Nervous System Effects

Seizures

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

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

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

Extrapyramidal Reactions

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

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

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal symptom complex, has been reported in patients receiving antipsychotic agents, including olanzapine. 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). Additional signs of NMS may include increased serum creatine kinase (CK, creatine phosphokinase, CPK), myoglobinuria (rhabdomyolysis), and acute renal failure. NMS attributable to olanzapine therapy alone has been reported in some patients, and there also have been reports of NMS in olanzapine-treated patients concomitantly receiving other drugs, including antipsychotic agents, antidepressants, lithium, or valproate. Extrapyramidal reactions were present in approximately two-thirds of the olanzapine-treated patients diagnosed with NMS. Atypical presentations of NMS (e.g., absence of or lessened rigidity, presenting as fever of unknown origin) and less severe presentations of NMS also have been reported in some patients receiving olanzapine or other atypical antipsychotic agents.

The diagnostic evaluation of patients with NMS is complicated. 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. In addition, clinical features of NMS and serotonin syndrome sometimes overlap, and it has been suggested that these 2 syndromes may share certain underlying pathophysiologic mechanisms. Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary CNS pathology.

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. There currently is no specific drug therapy for NMS, although dantrolene, bromocriptine, amantadine, and benzodiazepines have been used in a limited number of patients. If a patient requires antipsychotic therapy following recovery from NMS, the potential reintroduction of drug therapy after several weeks should be carefully considered. If antipsychotic therapy is reintroduced, the dosage generally should be increased gradually and an antipsychotic agent other than the agent believed to have precipitated NMS generally is chosen. In addition, tolerability with oral olanzapine should be established prior to initiating treatment with extended-release IM olanzapine pamoate. Such patients should be carefully monitored since recurrences of NMS have been reported in some patients. For additional information on NMS, .

Tardive Dyskinesia

Use of antipsychotic agents may be associated with tardive dyskinesia, a syndrome of potentially irreversible, involuntary, dyskinetic movements. 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. Tardive dyskinesia has been reported in less than 1% of patients receiving olanzapine therapy. Although the manufacturer states that it is not yet known whether antipsychotic agents differ in their potential to cause tardive dyskinesia, available evidence suggests that the risk appears to be substantially less with second-generation antipsychotic agents, including olanzapine, than with conventional, first-generation antipsychotic agents. Analyses from controlled, long-term trials have found an approximately 12-fold lower risk of tardive dyskinesia with olanzapine therapy compared with haloperidol therapy. In addition, stabilization of or improvement in tardive dyskinesia associated with conventional antipsychotic agents has been reported in some patients when they have been switched to second-generation antipsychotic therapy, including olanzapine. However, a transient increase in dyskinetic movements (sometimes referred to as withdrawal-emergent dyskinesia) occasionally may occur when a patient is switched from a first-generation to a second-generation antipsychotic agent or upon dosage reduction of an antipsychotic agent.

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. 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. There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic therapy is discontinued. However, antipsychotic therapy itself may suppress or partially suppress the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that such symptomatic suppression has upon the long-term course of tardive dyskinesia is unknown. There also is some evidence that vitamin E administration may reduce the risk of development of tardive dyskinesia; therefore, the American Psychiatric Association (APA) currently states that patients receiving antipsychotic agents may be advised to take 400-800 units of vitamin E daily for prophylaxis.

Olanzapine should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. 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. 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.

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

Post-injection Delirium/Sedation Syndrome

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

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

Other Nervous System Effects

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

Insomnia occurred in about 12%, dizziness in about 11%, asthenia in about 10%, and abnormal gait in about 6% of adult patients receiving oral olanzapine in short-term controlled clinical trials. The incidence of asthenia appears to be dose related. In addition, articulation impairment was reported in about 2% of patients receiving oral olanzapine in short-term, controlled clinical trials.

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

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

Cardiovascular Effects

Hemodynamic Effects

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

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

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

ECG Effects

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

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

Other Cardiovascular Effects

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

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

Hepatic Effects

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

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

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

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

Endocrine and Metabolic Effects

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

Weight Gain

Like some conventional (first-generation) and atypical (second-generation) antipsychotic agents, olanzapine therapy may result in weight gain. In placebo-controlled studies of 6 weeks' duration in adults, weight gain occurred in approximately 6% of patients receiving oral olanzapine, and increased appetite occurred in 6% of patients receiving oral olanzapine in short-term controlled trials. 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). 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. Discontinuance of olanzapine therapy because of weight gain occurred in 0.2% of olanzapine-treated patients compared with none of the placebo recipients. 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.

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. In short-term, placebo-controlled studies in adolescent patients with schizophrenia or bipolar disorder, weight gain occurred in approximately 30% of adolescents and increased appetite occurred in approximately 24% of adolescents receiving oral olanzapine. 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). 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). 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. 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). 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. 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. Discontinuance because of weight gain occurred in 2.2% of olanzapine-treated adolescents following at least 24 weeks of olanzapine exposure.

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.

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

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. 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.(See Hyperglycemia and Diabetes Mellitus under Cautions: Precautions and Contraindications.)

Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics currently are not available. While relative risk estimates are inconsistent, the association between atypical antipsychotics and increases in glucose concentrations appears to fall on a continuum, and olanzapine appears to have a greater association with hyperglycemia than some other atypical antipsychotic agents (e.g., quetiapine, risperidone).

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). 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.

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). The difference in mean changes between olanzapine and placebo was greater in patients with evidence of glucose dysregulation at baseline (e.g., patients diagnosed with diabetes mellitus or related adverse reactions, patients treated with antidiabetic agents, patients with a random baseline glucose concentration of 200 mg/dL or more and/or a baseline fasting glucose level of 126 mg/dL). 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). 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. 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. The mean change in fasting glucose for patients exposed to at least 48 weeks of olanzapine therapy was 4.2 mg/dL. 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.

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. 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). The average increase in fasting glucose concentrations for adolescents exposed to at least 24 weeks of olanzapine therapy was 3.1 mg/dL. 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.

Diabetic coma and diabetic ketoacidosis have been reported in olanzapine-treated patients during postmarketing surveillance.

Dyslipidemia

Like some other antipsychotic agents, particularly clozapine, olanzapine therapy has been associated with undesirable changes in lipid parameters, including elevations in serum triglyceride and cholesterol concentrations. Clinically important, and sometimes very high (greater than 500 mg/dL), elevations in triglyceride concentrations have been observed with olanzapine therapy. Modest average increases in total cholesterol concentrations also have occurred with olanzapine use.

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. For fasting high-density lipoprotein (HDL)-cholesterol, no clinically important differences were observed between olanzapine-treated patients and patients receiving placebo. 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). 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. 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. 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. 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.

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. 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. For fasting HDL-cholesterol, no clinically important differences were observed between adolescents receiving olanzapine compared with adolescents receiving placebo. 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. 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.

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

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

Hyperprolactinemia

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

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. 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).

Adolescents treated with olanzapine had a higher incidence of elevated prolactin concentrations compared with adults; the incidence of galactorrhea and gynecomastia also was higher in adolescents compared with adults. 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. 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).

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.

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

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

Other Endocrine and Metabolic Effects

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

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

GI Effects

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

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

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

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

Respiratory Effects

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

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

Dermatologic and Sensitivity Reactions

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

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

Drug Reaction with Eosinophilia and Systemic Symptoms

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

FDA has identified 23 cases of DRESS, including one fatal case, associated with olanzapine use worldwide that were reported to its adverse event reporting system between 1996 and May 10, 2016. The median time to onset of symptoms in these cases was 19 days after initiation of olanzapine therapy and the median duration of olanzapine therapy was 2 months. The median reported olanzapine dosage was 20 mg daily; however, DRESS has been reported at olanzapine dosages as low as 5 mg daily. The 22 non-fatal cases all reported serious outcomes, including 18 that required hospitalization. Complete resolution of symptoms was reported in 9 cases after discontinuance of olanzapine. In one case, symptoms of DRESS recurred after reinitiation of the drug. In the fatal case, death was attributed to acute cardiac failure related to olanzapine; during hospitalization, the patient had an initial episode of DRESS, followed by a recurrence of DRESS. However, the patient in this case was taking multiple other drugs that may have contributed to death.

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

Local Effects

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

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

Genitourinary Effects

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

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

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

Musculoskeletal Effects

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

Ocular Effects

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

Hematologic Effects

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

Possible risk factors for leukopenia and neutropenia include a preexisting low leukocyte count and a history of drug-induced leukopenia or neutropenia. Therefore, patients with a history of clinically important low leukocyte count or drug-induced leukopenia and/or neutropenia should have their complete blood count monitored frequently during the first few months of olanzapine therapy. 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.

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. In patients with severe neutropenia (absolute neutrophil count [ANC] less than 1000/mm), olanzapine should be discontinued and the leukocyte count monitored until recovery occurs.

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

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

Other Adverse Effects

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

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

Precautions and Contraindications

Olanzapine shares many of the toxic potentials of other antipsychotic agents (e.g., other atypical antipsychotic agents, phenothiazines), and the usual precautions associated with therapy with these agents should be observed.

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

Laboratory Test Monitoring

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

Hyperprolactinemia

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

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.

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. 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.

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. 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.

Seizures

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

Body Temperature Regulation

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

Hepatic Effects

Because clinically important serum ALT elevations (3 or more times the upper limit of the normal range) were observed in adults and adolescents exposed to oral olanzapine and adults exposed to extended-release IM olanzapine pamoate in placebo-controlled clinical studies, the manufacturer states that olanzapine should be used with caution in patients with signs and symptoms of hepatic impairment, in patients with preexisting conditions associate

Drug Interactions

Drugs Affecting Hepatic Microsomal Enzymes

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

Carbamazepine

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

Selective Serotonin-reuptake Inhibitors

Concomitant administration of fluoxetine (60 mg as a single dose or 60 mg daily for 8 days) with a single 5-mg dose of oral olanzapine caused a small increase in peak plasma olanzapine concentrations (averaging 16%) and a small decrease (averaging 16%) in olanzapine clearance in one study; the elimination half-life was not substantially affected. 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. Fluoxetine is an inhibitor of CYP2D6, and thereby may affect a minor metabolic pathway for olanzapine. 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.

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. 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. Symptoms of olanzapine toxicity also have been reported in at least one patient during combined therapy. The manufacturer and some clinicians state that a lower olanzapine dosage should therefore be considered in patients receiving concomitant treatment with fluvoxamine. Preliminary data indicate that concurrent fluvoxamine administration may potentially be used to therapeutic advantage by reducing the daily dosage of olanzapine and thereby the cost of therapy; further controlled studies are needed to more fully evaluate this approach. Although combined therapy with olanzapine and fluvoxamine generally has been well tolerated and may be associated with clinical benefit, some clinicians recommend that caution be exercised and monitoring of plasma olanzapine concentrations be considered in patients receiving these drugs concurrently.

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

Warfarin

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

Drugs Metabolized by Hepatic Microsomal Enzymes

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

Anticholinergic Agents

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

Levodopa and Dopamine Agonists

Olanzapine may antagonize the effects of levodopa and dopamine agonists.

Lamotrigine

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

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. 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.

Benzodiazepines

Because of the prominent CNS actions of olanzapine, the manufacturer states that caution should be exercised when olanzapine is administered concomitantly with benzodiazepines. 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. However, administration of multiple doses of olanzapine did not substantially alter the pharmacokinetics of diazepam or its active metabolite N-desmethyldiazepam.

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. Hypotension also has been reported when short-acting IM olanzapine and IM lorazepam have been administered concurrently. 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.

Tricyclic Antidepressants

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

Lithium

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

Valproic Acid

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

Alcohol

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

Hypotensive Agents

Olanzapine therapy potentially may enhance the effects of certain hypotensive agents during concurrent use. 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.(See Acute Toxicity: Treatment.)

Antacids or Cimetidine

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

Activated Charcoal

Concurrent administration of activated charcoal (1 g) reduced peak plasma concentrations and the AUC of a single, 7.5-mg oral dose of olanzapine by approximately 60%. 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.(See Acute Toxicity: Treatment.)

Smoking

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

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

Other Drugs

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

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

Pharmacokinetics

Absorption

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

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.(See Selective Serotonin-reuptake Inhibitors under Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes.)

Following oral administration, peak plasma olanzapine concentrations occur in approximately 6 hours (range: 5-8 hours). 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.

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

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. An IM injection every 2 or 4 weeks provides plasma olanzapine concentrations that are similar to those achieved with daily doses of oral olanzapine. 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. Plasma olanzapine concentrations generally reach a peak within the first week following each injection.

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

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

Distribution

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

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

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

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

Elimination

Although the exact metabolic fate has not been clearly established, it appears that olanzapine is extensively metabolized. Following a single oral dose of radiolabeled olanzapine, 7% of the dose was recovered in urine as unchanged drug. Approximately 57 and 30% of the dose was recovered in the urine and feces, respectively. In plasma, olanzapine accounted for only 12% of the AUC for total radioactivity, suggesting substantial exposure to metabolites. 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. Both of these metabolites lack pharmacologic activity at the concentrations observed.

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

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. 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. Following IM administration of extended-release olanzapine pamoate injection (Zyprexa Relprevv), the elimination half-life is approximately 30 days. Therefore, exposure to olanzapine may persist for months after a single extended-release IM injection of the drug.

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

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

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

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

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

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

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

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

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

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