Olanzapine - Olanzapine tablet, Orally Disintegrating

 Warnings and Precautions (

Olanzapine is an atypical antipsychotic indicated:

• Treatment of schizophrenia. (
  1.1 Schizophrenia

  Olanzapine orally disintegrating tablets are indicated for the treatment of schizophrenia. Efficacy was established in three clinical trials in adult patients with schizophrenia: two 6-week trials and one maintenance trial. In adolescent patients with schizophrenia (ages 13-17), efficacy was established in one 6-week trial

  [see Clinical Studies ].

  
  
  

  When deciding among the alternative treatments available for adolescents, clinicians should consider the increased potential (in adolescents as compared with adults) for weight gain and dyslipidemia. Clinicians should consider the potential long-term risks when prescribing to adolescents, and in many cases this may lead them to consider prescribing other drugs first in adolescents

  [see Warnings and Precautions ]

  .

  
  
  
  )
  • Adults: Efficacy was established in three clinical trials in patients with schizophrenia: two 6-week trials and one maintenance trial. (
    14.1 Schizophrenia

    Adults

    
    
    The efficacy of oral olanzapine in the treatment of schizophrenia was established in 2 short-term (6-week) controlled trials of adult inpatients who met DSM III-R criteria for schizophrenia. A single haloperidol arm was included as a comparative treatment in 1 of the 2 trials, but this trial did not compare these 2 drugs on the full range of clinically relevant doses for both.
    
    Several instruments were used for assessing psychiatric signs and symptoms in these studies, among them the Brief Psychiatric Rating Scale (BPRS), a multi-item inventory of general psychopathology traditionally used to evaluate the effects of drug treatment in schizophrenia. The BPRS psychosis cluster (conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content) is considered a particularly useful subset for assessing actively psychotic schizophrenic patients. A second traditional assessment, the Clinical Global Impression (CGI), reflects the impression of a skilled observer, fully familiar with the manifestations of schizophrenia, about the overall clinical state of the patient. In addition, 2 more recently developed scales were employed; these included the 30-item Positive and Negative Symptoms Scale (PANSS), in which are embedded the 18 items of the BPRS, and the Scale for Assessing Negative Symptoms (SANS). The trial summaries below focus on the following outcomes: PANSS total and/or BPRS total; BPRS psychosis cluster; PANSS negative subscale or SANS; and CGI Severity. The results of the trials follow:
    
    
    
    (1) In a 6-week, placebo-controlled trial (n=149) involving 2 fixed olanzapine doses of 1 and 10 mg/day (once daily schedule), olanzapine, at 10 mg/day (but not at 1 mg/day), was superior to placebo on the PANSS total score (also on the extracted BPRS total), on the BPRS psychosis cluster, on the PANSS Negative subscale, and on CGI Severity.
    
    (2) In a 6-week, placebo-controlled trial (n=253) involving 3 fixed dose ranges of olanzapine (5 ± 2.5 mg/day, 10 ± 2.5 mg/day, and 15 ± 2.5 mg/day) on a once daily schedule, the 2 highest olanzapine dose groups (actual mean doses of 12 and 16 mg/day, respectively) were superior to placebo on BPRS total score, BPRS psychosis cluster, and CGI severity score; the highest olanzapine dose group was superior to placebo on the SANS. There was no clear advantage for the high-dose group over the medium-dose group.
    
    (3) In a longer-term trial, adult outpatients (n=326) who predominantly met DSM-IV criteria for schizophrenia and who remained stable on olanzapine during open-label treatment for at least 8 weeks were randomized to continuation on their current olanzapine doses (ranging from 10 to 20 mg/day) or to placebo. The follow-up period to observe patients for relapse, defined in terms of increases in BPRS positive symptoms or hospitalization, was planned for 12 months, however, criteria were met for stopping the trial early due to an excess of placebo relapses compared to olanzapine relapses, and olanzapine was superior to placebo on time to relapse, the primary outcome for this study. Thus, olanzapine was more effective than placebo at maintaining efficacy in patients stabilized for approximately 8 weeks and followed for an observation period of up to 8 months.
    
    Examination of population subsets (race and gender) did not reveal any differential responsiveness on the basis of these subgroupings.

    Adolescents

    
    
    The efficacy of oral olanzapine in the acute treatment of schizophrenia in adolescents (ages 13 to 17 years) was established in a 6-week double-blind, placebo-controlled, randomized trial of inpatients and outpatients with schizophrenia (n=107) who met diagnostic criteria according to DSM-IV-TR and confirmed by the Kiddie Schedule for Affective Disorders and Schizophrenia for School Aged Children-Present and Lifetime Version (K-SADS-PL).
    
    The primary rating instrument used for assessing psychiatric signs and symptoms in this trial was the Anchored Version of the Brief Psychiatric Rating Scale for Children (BPRS-C) total score.
    
    In this flexible-dose trial, olanzapine 2.5 to 20 mg/day (mean modal dose 12.5 mg/day, mean dose of 11.1 mg/day) was more effective than placebo in the treatment of adolescents diagnosed with schizophrenia, as supported by the statistically significantly greater mean reduction in BPRS-C total score for patients in the olanzapine treatment group than in the placebo group.
    
    While there is no body of evidence available to answer the question of how long the adolescent patient treated with olanzapine should be maintained, maintenance efficacy can be extrapolated from adult data along with comparisons of olanzapine pharmacokinetic parameters in adult and adolescent patients. It is generally recommended that responding patients be continued beyond the acute response, but at the lowest dose needed to maintain remission. Patients should be periodically reassessed to determine the need for maintenance treatment.
    )
  • Adolescents (ages 13-17): Efficacy was established in one 6-week trial in patients with schizophrenia (
    14.1 Schizophrenia

    Adults

    
    
    The efficacy of oral olanzapine in the treatment of schizophrenia was established in 2 short-term (6-week) controlled trials of adult inpatients who met DSM III-R criteria for schizophrenia. A single haloperidol arm was included as a comparative treatment in 1 of the 2 trials, but this trial did not compare these 2 drugs on the full range of clinically relevant doses for both.
    
    Several instruments were used for assessing psychiatric signs and symptoms in these studies, among them the Brief Psychiatric Rating Scale (BPRS), a multi-item inventory of general psychopathology traditionally used to evaluate the effects of drug treatment in schizophrenia. The BPRS psychosis cluster (conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content) is considered a particularly useful subset for assessing actively psychotic schizophrenic patients. A second traditional assessment, the Clinical Global Impression (CGI), reflects the impression of a skilled observer, fully familiar with the manifestations of schizophrenia, about the overall clinical state of the patient. In addition, 2 more recently developed scales were employed; these included the 30-item Positive and Negative Symptoms Scale (PANSS), in which are embedded the 18 items of the BPRS, and the Scale for Assessing Negative Symptoms (SANS). The trial summaries below focus on the following outcomes: PANSS total and/or BPRS total; BPRS psychosis cluster; PANSS negative subscale or SANS; and CGI Severity. The results of the trials follow:
    
    
    
    (1) In a 6-week, placebo-controlled trial (n=149) involving 2 fixed olanzapine doses of 1 and 10 mg/day (once daily schedule), olanzapine, at 10 mg/day (but not at 1 mg/day), was superior to placebo on the PANSS total score (also on the extracted BPRS total), on the BPRS psychosis cluster, on the PANSS Negative subscale, and on CGI Severity.
    
    (2) In a 6-week, placebo-controlled trial (n=253) involving 3 fixed dose ranges of olanzapine (5 ± 2.5 mg/day, 10 ± 2.5 mg/day, and 15 ± 2.5 mg/day) on a once daily schedule, the 2 highest olanzapine dose groups (actual mean doses of 12 and 16 mg/day, respectively) were superior to placebo on BPRS total score, BPRS psychosis cluster, and CGI severity score; the highest olanzapine dose group was superior to placebo on the SANS. There was no clear advantage for the high-dose group over the medium-dose group.
    
    (3) In a longer-term trial, adult outpatients (n=326) who predominantly met DSM-IV criteria for schizophrenia and who remained stable on olanzapine during open-label treatment for at least 8 weeks were randomized to continuation on their current olanzapine doses (ranging from 10 to 20 mg/day) or to placebo. The follow-up period to observe patients for relapse, defined in terms of increases in BPRS positive symptoms or hospitalization, was planned for 12 months, however, criteria were met for stopping the trial early due to an excess of placebo relapses compared to olanzapine relapses, and olanzapine was superior to placebo on time to relapse, the primary outcome for this study. Thus, olanzapine was more effective than placebo at maintaining efficacy in patients stabilized for approximately 8 weeks and followed for an observation period of up to 8 months.
    
    Examination of population subsets (race and gender) did not reveal any differential responsiveness on the basis of these subgroupings.

    Adolescents

    
    
    The efficacy of oral olanzapine in the acute treatment of schizophrenia in adolescents (ages 13 to 17 years) was established in a 6-week double-blind, placebo-controlled, randomized trial of inpatients and outpatients with schizophrenia (n=107) who met diagnostic criteria according to DSM-IV-TR and confirmed by the Kiddie Schedule for Affective Disorders and Schizophrenia for School Aged Children-Present and Lifetime Version (K-SADS-PL).
    
    The primary rating instrument used for assessing psychiatric signs and symptoms in this trial was the Anchored Version of the Brief Psychiatric Rating Scale for Children (BPRS-C) total score.
    
    In this flexible-dose trial, olanzapine 2.5 to 20 mg/day (mean modal dose 12.5 mg/day, mean dose of 11.1 mg/day) was more effective than placebo in the treatment of adolescents diagnosed with schizophrenia, as supported by the statistically significantly greater mean reduction in BPRS-C total score for patients in the olanzapine treatment group than in the placebo group.
    
    While there is no body of evidence available to answer the question of how long the adolescent patient treated with olanzapine should be maintained, maintenance efficacy can be extrapolated from adult data along with comparisons of olanzapine pharmacokinetic parameters in adult and adolescent patients. It is generally recommended that responding patients be continued beyond the acute response, but at the lowest dose needed to maintain remission. Patients should be periodically reassessed to determine the need for maintenance treatment.
    ). The increased potential (in adolescents compared with adults) for weight gain and dyslipidemia may lead clinicians to consider prescribing other drugs first in adolescents. (
    1.1 Schizophrenia

    Olanzapine orally disintegrating tablets are indicated for the treatment of schizophrenia. Efficacy was established in three clinical trials in adult patients with schizophrenia: two 6-week trials and one maintenance trial. In adolescent patients with schizophrenia (ages 13-17), efficacy was established in one 6-week trial

    [see Clinical Studies ].

    
    
    

    When deciding among the alternative treatments available for adolescents, clinicians should consider the increased potential (in adolescents as compared with adults) for weight gain and dyslipidemia. Clinicians should consider the potential long-term risks when prescribing to adolescents, and in many cases this may lead them to consider prescribing other drugs first in adolescents

    [see Warnings and Precautions ]

    .

    
    
    
    )
• Acute treatment of manic or mixed episodes associated with bipolar I disorder and maintenance treatment of bipolar I disorder. (
  1.2 Bipolar I Disorder (Manic or Mixed Episodes)

  Monotherapy

  — Olanzapine orally disintegrating tablets are indicated for the acute treatment of manic or mixed episodes associated with bipolar I disorder and maintenance treatment of bipolar I disorder. Efficacy was established in three clinical trials in adult patients with manic or mixed episodes of bipolar I disorder: two 3- to 4-week trials and one monotherapy maintenance trial. In adolescent patients with manic or mixed episodes associated with bipolar I disorder (ages 13-17), efficacy was established in one 3-week trial

  [see Clinical Studies ].

  
  
  

  When deciding among the alternative treatments available for adolescents, clinicians should consider the increased potential (in adolescents as compared with adults) for weight gain and dyslipidemia. Clinicians should consider the potential long-term risks when prescribing to adolescents, and in many cases this may lead them to consider prescribing other drugs first in adolescents

  [see Warnings and Precautions ]

  .

  
  
  

  Adjunctive Therapy to Lithium or Valproate

  — Oral olanzapine is indicated for the treatment of manic or mixed episodes associated with bipolar I disorder as an adjunct to lithium or valproate. Efficacy was established in two 6-week clinical trials in adults. The effectiveness of adjunctive therapy for longer-term use has not been systematically evaluated in controlled trials

  [see Clinical Studies ]

  .

  
  
  
  )
  • Adults: Efficacy was established in three clinical trials in patients with manic or mixed episodes of bipolar I disorder: two 3- to 4-week trials and one maintenance trial. (
    14.2 Bipolar I Disorder (Manic or Mixed Episodes)

    Adults

    
    
    
    
    

    Monotherapy

    — The efficacy of oral olanzapine in the treatment of manic or mixed episodes was established in 2 short-term (one 3-week and one 4-week) placebo-controlled trials in adult patients who met the DSM-IV criteria for bipolar I disorder with manic or mixed episodes. These trials included patients with or without psychotic features and with or without a rapid-cycling course.
    
    The primary rating instrument used for assessing manic symptoms in these trials was the Young Mania Rating Scale (Y-MRS), an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology (irritability, disruptive/aggressive behavior, sleep, elevated mood, speech, increased activity, sexual interest, language/thought disorder, thought content, appearance, and insight) in a range from 0 (no manic features) to 60 (maximum score). The primary outcome in these trials was change from baseline in the Y-MRS total score. The results of the trials follow:
    
    (1) In one 3-week placebo-controlled trial (n=67) which involved a dose range of olanzapine (5-20 mg/day, once daily, starting at 10 mg/day), olanzapine was superior to placebo in the reduction of Y-MRS total score. In an identically designed trial conducted simultaneously with the first trial, olanzapine demonstrated a similar treatment difference, but possibly due to sample size and site variability, was not shown to be superior to placebo on this outcome.
    
    (2) In a 4-week placebo-controlled trial (n=115) which involved a dose range of olanzapine (5-20 mg/day, once daily, starting at 15 mg/day), olanzapine was superior to placebo in the reduction of Y-MRS total score.
    
    (3) In another trial, 361 patients meeting DSM-IV criteria for a manic or mixed episode of bipolar I disorder who had responded during an initial open-label treatment phase for about 2 weeks, on average, to olanzapine 5 to 20 mg/day were randomized to either continuation of olanzapine at their same dose (n=225) or to placebo (n=136), for observation of relapse. Approximately 50% of the patients had discontinued from the olanzapine group by day 59 and 50% of the placebo group had discontinued by day 23 of double-blind treatment. Response during the open-label phase was defined by having a decrease of the Y-MRS total score to ≤12 and HAM-D 21 to ≤8. Relapse during the double-blind phase was defined as an increase of the Y-MRS or HAM-D 21 total score to ≥15, or being hospitalized for either mania or depression. In the randomized phase, patients receiving continued olanzapine experienced a significantly longer time to relapse.
    
    
    
    

    Adjunct to Lithium or Valproate

    — The efficacy of oral olanzapine with concomitant lithium or valproate in the treatment of manic or mixed episodes was established in 2 controlled trials in patients who met the DSM-IV criteria for bipolar I disorder with manic or mixed episodes. These trials included patients with or without psychotic features and with or without a rapid-cycling course. The results of the trials follow:
    
    (1) In one 6-week placebo-controlled combination trial, 175 outpatients on lithium or valproate therapy with inadequately controlled manic or mixed symptoms (Y-MRS ≥16) were randomized to receive either olanzapine or placebo, in combination with their original therapy. Olanzapine (in a dose range of 5-20 mg/day, once daily, starting at 10 mg/day) combined with lithium or valproate (in a therapeutic range of 0.6 mEq/L to 1.2 mEq/L or 50 μg/mL to 125 μg/mL, respectively) was superior to lithium or valproate alone in the reduction of Y-MRS total score.
    
    (2) In a second 6-week placebo-controlled combination trial, 169 outpatients on lithium or valproate therapy with inadequately controlled manic or mixed symptoms (Y-MRS ≥16) were randomized to receive either olanzapine or placebo, in combination with their original therapy. Olanzapine (in a dose range of 5-20 mg/day, once daily, starting at 10 mg/day) combined with lithium or valproate (in a therapeutic range of 0.6 mEq/L to 1.2 mEq/L or 50 μg/mL to 125 μg/mL, respectively) was superior to lithium or valproate alone in the reduction of Y-MRS total score.
    
    
    
    

    Adolescents

    
    
    

    Acute Monotherapy

    — The efficacy of oral olanzapine in the treatment of acute manic or mixed episodes in adolescents (ages 13 to 17 years) was established in a 3-week, double-blind, placebo-controlled, randomized trial of adolescent inpatients and outpatients who met the diagnostic criteria for manic or mixed episodes associated with bipolar I disorder (with or without psychotic features) according to the DSM-IV-TR (n=161). Diagnosis was confirmed by the K-SADS-PL.
    
    The primary rating instrument used for assessing manic symptoms in this trial was the Adolescent Structured Young-Mania Rating Scale (Y-MRS) total score.
    
    In this flexible-dose trial, olanzapine 2.5 to 20 mg/day (mean modal dose 10.7 mg/day, mean dose of 8.9 mg/day) was more effective than placebo in the treatment of adolescents with manic or mixed episodes associated with bipolar I disorder, as supported by the statistically significantly greater mean reduction in Y-MRS total score for patients in the olanzapine treatment group than in the placebo group.
    
    While there is no body of evidence available to answer the question of how long the adolescent patient treated with olanzapine should be maintained, maintenance efficacy can be extrapolated from adult data along with comparisons of olanzapine pharmacokinetic parameters in adult and adolescent patients. It is generally recommended that responding patients be continued beyond the acute response, but at the lowest dose needed to maintain remission. Patients should be periodically reassessed to determine the need for maintenance treatment.
    )
  • Adolescents (ages 13-17): Efficacy was established in one 3-week trial in patients with manic or mixed episodes associated with bipolar I disorder (
    14.2 Bipolar I Disorder (Manic or Mixed Episodes)

    Adults

    
    
    
    
    

    Monotherapy

    — The efficacy of oral olanzapine in the treatment of manic or mixed episodes was established in 2 short-term (one 3-week and one 4-week) placebo-controlled trials in adult patients who met the DSM-IV criteria for bipolar I disorder with manic or mixed episodes. These trials included patients with or without psychotic features and with or without a rapid-cycling course.
    
    The primary rating instrument used for assessing manic symptoms in these trials was the Young Mania Rating Scale (Y-MRS), an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology (irritability, disruptive/aggressive behavior, sleep, elevated mood, speech, increased activity, sexual interest, language/thought disorder, thought content, appearance, and insight) in a range from 0 (no manic features) to 60 (maximum score). The primary outcome in these trials was change from baseline in the Y-MRS total score. The results of the trials follow:
    
    (1) In one 3-week placebo-controlled trial (n=67) which involved a dose range of olanzapine (5-20 mg/day, once daily, starting at 10 mg/day), olanzapine was superior to placebo in the reduction of Y-MRS total score. In an identically designed trial conducted simultaneously with the first trial, olanzapine demonstrated a similar treatment difference, but possibly due to sample size and site variability, was not shown to be superior to placebo on this outcome.
    
    (2) In a 4-week placebo-controlled trial (n=115) which involved a dose range of olanzapine (5-20 mg/day, once daily, starting at 15 mg/day), olanzapine was superior to placebo in the reduction of Y-MRS total score.
    
    (3) In another trial, 361 patients meeting DSM-IV criteria for a manic or mixed episode of bipolar I disorder who had responded during an initial open-label treatment phase for about 2 weeks, on average, to olanzapine 5 to 20 mg/day were randomized to either continuation of olanzapine at their same dose (n=225) or to placebo (n=136), for observation of relapse. Approximately 50% of the patients had discontinued from the olanzapine group by day 59 and 50% of the placebo group had discontinued by day 23 of double-blind treatment. Response during the open-label phase was defined by having a decrease of the Y-MRS total score to ≤12 and HAM-D 21 to ≤8. Relapse during the double-blind phase was defined as an increase of the Y-MRS or HAM-D 21 total score to ≥15, or being hospitalized for either mania or depression. In the randomized phase, patients receiving continued olanzapine experienced a significantly longer time to relapse.
    
    
    
    

    Adjunct to Lithium or Valproate

    — The efficacy of oral olanzapine with concomitant lithium or valproate in the treatment of manic or mixed episodes was established in 2 controlled trials in patients who met the DSM-IV criteria for bipolar I disorder with manic or mixed episodes. These trials included patients with or without psychotic features and with or without a rapid-cycling course. The results of the trials follow:
    
    (1) In one 6-week placebo-controlled combination trial, 175 outpatients on lithium or valproate therapy with inadequately controlled manic or mixed symptoms (Y-MRS ≥16) were randomized to receive either olanzapine or placebo, in combination with their original therapy. Olanzapine (in a dose range of 5-20 mg/day, once daily, starting at 10 mg/day) combined with lithium or valproate (in a therapeutic range of 0.6 mEq/L to 1.2 mEq/L or 50 μg/mL to 125 μg/mL, respectively) was superior to lithium or valproate alone in the reduction of Y-MRS total score.
    
    (2) In a second 6-week placebo-controlled combination trial, 169 outpatients on lithium or valproate therapy with inadequately controlled manic or mixed symptoms (Y-MRS ≥16) were randomized to receive either olanzapine or placebo, in combination with their original therapy. Olanzapine (in a dose range of 5-20 mg/day, once daily, starting at 10 mg/day) combined with lithium or valproate (in a therapeutic range of 0.6 mEq/L to 1.2 mEq/L or 50 μg/mL to 125 μg/mL, respectively) was superior to lithium or valproate alone in the reduction of Y-MRS total score.
    
    
    
    

    Adolescents

    
    
    

    Acute Monotherapy

    — The efficacy of oral olanzapine in the treatment of acute manic or mixed episodes in adolescents (ages 13 to 17 years) was established in a 3-week, double-blind, placebo-controlled, randomized trial of adolescent inpatients and outpatients who met the diagnostic criteria for manic or mixed episodes associated with bipolar I disorder (with or without psychotic features) according to the DSM-IV-TR (n=161). Diagnosis was confirmed by the K-SADS-PL.
    
    The primary rating instrument used for assessing manic symptoms in this trial was the Adolescent Structured Young-Mania Rating Scale (Y-MRS) total score.
    
    In this flexible-dose trial, olanzapine 2.5 to 20 mg/day (mean modal dose 10.7 mg/day, mean dose of 8.9 mg/day) was more effective than placebo in the treatment of adolescents with manic or mixed episodes associated with bipolar I disorder, as supported by the statistically significantly greater mean reduction in Y-MRS total score for patients in the olanzapine treatment group than in the placebo group.
    
    While there is no body of evidence available to answer the question of how long the adolescent patient treated with olanzapine should be maintained, maintenance efficacy can be extrapolated from adult data along with comparisons of olanzapine pharmacokinetic parameters in adult and adolescent patients. It is generally recommended that responding patients be continued beyond the acute response, but at the lowest dose needed to maintain remission. Patients should be periodically reassessed to determine the need for maintenance treatment.
    ).The increased potential (in adolescents compared with adults) for weight gain and dyslipidemia may lead clinicians to consider prescribing other drugs first in adolescents. (
    1.2 Bipolar I Disorder (Manic or Mixed Episodes)

    Monotherapy

    — Olanzapine orally disintegrating tablets are indicated for the acute treatment of manic or mixed episodes associated with bipolar I disorder and maintenance treatment of bipolar I disorder. Efficacy was established in three clinical trials in adult patients with manic or mixed episodes of bipolar I disorder: two 3- to 4-week trials and one monotherapy maintenance trial. In adolescent patients with manic or mixed episodes associated with bipolar I disorder (ages 13-17), efficacy was established in one 3-week trial

    [see Clinical Studies ].

    
    
    

    When deciding among the alternative treatments available for adolescents, clinicians should consider the increased potential (in adolescents as compared with adults) for weight gain and dyslipidemia. Clinicians should consider the potential long-term risks when prescribing to adolescents, and in many cases this may lead them to consider prescribing other drugs first in adolescents

    [see Warnings and Precautions ]

    .

    
    
    

    Adjunctive Therapy to Lithium or Valproate

    — Oral olanzapine is indicated for the treatment of manic or mixed episodes associated with bipolar I disorder as an adjunct to lithium or valproate. Efficacy was established in two 6-week clinical trials in adults. The effectiveness of adjunctive therapy for longer-term use has not been systematically evaluated in controlled trials

    [see Clinical Studies ]

    .

    
    
    
    )
• Medication therapy for pediatric patients with schizophrenia or bipolar I disorder should be undertaken only after a thorough diagnostic evaluation and with careful consideration of the potential risks. (
  1.3 Special Considerations in Treating Pediatric Schizophrenia and Bipolar I Disorder

  
  
  Pediatric schizophrenia and bipolar I disorder are serious mental disorders; however, diagnosis can be challenging. For pediatric schizophrenia, symptom profiles can be variable, and for bipolar I disorder, pediatric patients may have variable patterns of periodicity of manic or mixed symptoms. It is recommended that medication therapy for pediatric schizophrenia and bipolar I 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 for both pediatric schizophrenia and bipolar I disorder should be part of a total treatment program that often includes psychological, educational and social interventions.
  )
• Adjunct to valproate or lithium in the treatment of manic or mixed episodes associated with bipolar I disorder. (
  1.2 Bipolar I Disorder (Manic or Mixed Episodes)

  Monotherapy

  — Olanzapine orally disintegrating tablets are indicated for the acute treatment of manic or mixed episodes associated with bipolar I disorder and maintenance treatment of bipolar I disorder. Efficacy was established in three clinical trials in adult patients with manic or mixed episodes of bipolar I disorder: two 3- to 4-week trials and one monotherapy maintenance trial. In adolescent patients with manic or mixed episodes associated with bipolar I disorder (ages 13-17), efficacy was established in one 3-week trial

  [see Clinical Studies ].

  
  
  

  When deciding among the alternative treatments available for adolescents, clinicians should consider the increased potential (in adolescents as compared with adults) for weight gain and dyslipidemia. Clinicians should consider the potential long-term risks when prescribing to adolescents, and in many cases this may lead them to consider prescribing other drugs first in adolescents

  [see Warnings and Precautions ]

  .

  
  
  

  Adjunctive Therapy to Lithium or Valproate

  — Oral olanzapine is indicated for the treatment of manic or mixed episodes associated with bipolar I disorder as an adjunct to lithium or valproate. Efficacy was established in two 6-week clinical trials in adults. The effectiveness of adjunctive therapy for longer-term use has not been systematically evaluated in controlled trials

  [see Clinical Studies ]

  .

  
  
  
  )
  • Efficacy was established in two 6-week clinical trials in adults (
    14.2 Bipolar I Disorder (Manic or Mixed Episodes)

    Adults

    
    
    
    
    

    Monotherapy

    — The efficacy of oral olanzapine in the treatment of manic or mixed episodes was established in 2 short-term (one 3-week and one 4-week) placebo-controlled trials in adult patients who met the DSM-IV criteria for bipolar I disorder with manic or mixed episodes. These trials included patients with or without psychotic features and with or without a rapid-cycling course.
    
    The primary rating instrument used for assessing manic symptoms in these trials was the Young Mania Rating Scale (Y-MRS), an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology (irritability, disruptive/aggressive behavior, sleep, elevated mood, speech, increased activity, sexual interest, language/thought disorder, thought content, appearance, and insight) in a range from 0 (no manic features) to 60 (maximum score). The primary outcome in these trials was change from baseline in the Y-MRS total score. The results of the trials follow:
    
    (1) In one 3-week placebo-controlled trial (n=67) which involved a dose range of olanzapine (5-20 mg/day, once daily, starting at 10 mg/day), olanzapine was superior to placebo in the reduction of Y-MRS total score. In an identically designed trial conducted simultaneously with the first trial, olanzapine demonstrated a similar treatment difference, but possibly due to sample size and site variability, was not shown to be superior to placebo on this outcome.
    
    (2) In a 4-week placebo-controlled trial (n=115) which involved a dose range of olanzapine (5-20 mg/day, once daily, starting at 15 mg/day), olanzapine was superior to placebo in the reduction of Y-MRS total score.
    
    (3) In another trial, 361 patients meeting DSM-IV criteria for a manic or mixed episode of bipolar I disorder who had responded during an initial open-label treatment phase for about 2 weeks, on average, to olanzapine 5 to 20 mg/day were randomized to either continuation of olanzapine at their same dose (n=225) or to placebo (n=136), for observation of relapse. Approximately 50% of the patients had discontinued from the olanzapine group by day 59 and 50% of the placebo group had discontinued by day 23 of double-blind treatment. Response during the open-label phase was defined by having a decrease of the Y-MRS total score to ≤12 and HAM-D 21 to ≤8. Relapse during the double-blind phase was defined as an increase of the Y-MRS or HAM-D 21 total score to ≥15, or being hospitalized for either mania or depression. In the randomized phase, patients receiving continued olanzapine experienced a significantly longer time to relapse.
    
    
    
    

    Adjunct to Lithium or Valproate

    — The efficacy of oral olanzapine with concomitant lithium or valproate in the treatment of manic or mixed episodes was established in 2 controlled trials in patients who met the DSM-IV criteria for bipolar I disorder with manic or mixed episodes. These trials included patients with or without psychotic features and with or without a rapid-cycling course. The results of the trials follow:
    
    (1) In one 6-week placebo-controlled combination trial, 175 outpatients on lithium or valproate therapy with inadequately controlled manic or mixed symptoms (Y-MRS ≥16) were randomized to receive either olanzapine or placebo, in combination with their original therapy. Olanzapine (in a dose range of 5-20 mg/day, once daily, starting at 10 mg/day) combined with lithium or valproate (in a therapeutic range of 0.6 mEq/L to 1.2 mEq/L or 50 μg/mL to 125 μg/mL, respectively) was superior to lithium or valproate alone in the reduction of Y-MRS total score.
    
    (2) In a second 6-week placebo-controlled combination trial, 169 outpatients on lithium or valproate therapy with inadequately controlled manic or mixed symptoms (Y-MRS ≥16) were randomized to receive either olanzapine or placebo, in combination with their original therapy. Olanzapine (in a dose range of 5-20 mg/day, once daily, starting at 10 mg/day) combined with lithium or valproate (in a therapeutic range of 0.6 mEq/L to 1.2 mEq/L or 50 μg/mL to 125 μg/mL, respectively) was superior to lithium or valproate alone in the reduction of Y-MRS total score.
    
    
    
    

    Adolescents

    
    
    

    Acute Monotherapy

    — The efficacy of oral olanzapine in the treatment of acute manic or mixed episodes in adolescents (ages 13 to 17 years) was established in a 3-week, double-blind, placebo-controlled, randomized trial of adolescent inpatients and outpatients who met the diagnostic criteria for manic or mixed episodes associated with bipolar I disorder (with or without psychotic features) according to the DSM-IV-TR (n=161). Diagnosis was confirmed by the K-SADS-PL.
    
    The primary rating instrument used for assessing manic symptoms in this trial was the Adolescent Structured Young-Mania Rating Scale (Y-MRS) total score.
    
    In this flexible-dose trial, olanzapine 2.5 to 20 mg/day (mean modal dose 10.7 mg/day, mean dose of 8.9 mg/day) was more effective than placebo in the treatment of adolescents with manic or mixed episodes associated with bipolar I disorder, as supported by the statistically significantly greater mean reduction in Y-MRS total score for patients in the olanzapine treatment group than in the placebo group.
    
    While there is no body of evidence available to answer the question of how long the adolescent patient treated with olanzapine should be maintained, maintenance efficacy can be extrapolated from adult data along with comparisons of olanzapine pharmacokinetic parameters in adult and adolescent patients. It is generally recommended that responding patients be continued beyond the acute response, but at the lowest dose needed to maintain remission. Patients should be periodically reassessed to determine the need for maintenance treatment.
    ). Maintenance efficacy has not been systematically evaluated.

• Treatment of depressive episodes associated with bipolar I disorder. (
  1.5 Olanzapine orally disintegrating tablets and Fluoxetine in Combination: Depressive Episodes Associated with Bipolar I Disorder

  Oral olanzapine and fluoxetine in combination is indicated for the treatment of depressive episodes associated with bipolar I disorder, based on clinical studies. When using olanzapine orally disintegrating tablets and fluoxetine in combination, refer to the Clinical Studies section of the package insert for Symbyax.
  
  Olanzapine orally disintegrating tablets monotherapy is not indicated for the treatment of depressive episodes associated with bipolar I disorder.

  
  
  
  )
  • Efficacy was established with Symbyax (olanzapine and fluoxetine in combination); refer to the product label for Symbyax.
• Treatment of treatment resistant depression. (
  1.6 Olanzapine orally disintegrating tablets and Fluoxetine in Combination: Treatment Resistant Depression

  Oral olanzapine and fluoxetine in combination is indicated for the treatment of treatment resistant depression (major depressive disorder in patients who do not respond to 2 separate trials of different antidepressants of adequate dose and duration in the current episode), based on clinical studies in adult patients. When using olanzapine orally disintegrating tablets and fluoxetine in combination, refer to the Clinical Studies section of the package insert for Symbyax.
  
  Olanzapine orally disintegrating tablets monotherapy is not indicated for the treatment of treatment resistant depression.

  
  
  
  )
  • Efficacy was established with Symbyax (olanzapine and fluoxetine in combination) in adults; refer to the product label for Symbyax.

• Lower starting dose recommended in debilitated or pharmacodynamically sensitive patients or patients with predisposition to hypotensive reactions, or with potential for slowed metabolism. (
  2.1 Schizophrenia

  Adults

  Dose Selection

  — Oral olanzapine should be administered on a once-a-day schedule without regard to meals, generally beginning with 5 to 10 mg initially, with a target dose of 10 mg/day within several days. Further dosage adjustments, if indicated, should generally occur at intervals of not less than 1 week, since steady state for olanzapine would not be achieved for approximately 1 week in the typical patient. When dosage adjustments are necessary, dose increments/decrements of 5 mg QD are recommended.

  
  
  

  Efficacy in schizophrenia was demonstrated in a dose range of 10 to 15 mg/day in clinical trials. However, doses above 10 mg/day were not demonstrated to be more efficacious than the 10 mg/day dose. An increase to a dose greater than the target dose of 10 mg/day (i.e., to a dose of 15 mg/day or greater) is recommended only after clinical assessment. Olanzapine is not indicated for use in doses above 20 mg/day.

  Dosing in Special Populations

  — The recommended starting dose is 5 mg in patients who are debilitated, who have a predisposition to hypotensive reactions, who otherwise exhibit a combination of factors that may result in slower metabolism of olanzapine (e.g., nonsmoking female patients ≥65 years of age), or who may be more pharmacodynamically sensitive to olanzapine

  [see Warnings and Precautions , Drug Interactions , and Clinical Pharmacology ]

  . When indicated, dose escalation should be performed with caution in these patients.

  Maintenance Treatment

  — The effectiveness of oral olanzapine, 10 mg/day to 20 mg/day, in maintaining treatment response in 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 trial

  [see Clinical Studies ]

  . The healthcare provider who elects to use olanzapine for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.

  Adolescents

  Dose Selection

  — Oral olanzapine should be administered on a once-a-day schedule without regard to meals with a recommended starting dose of 2.5 or 5 mg, with a target dose of 10 mg/day. Efficacy in adolescents with schizophrenia was demonstrated based on a flexible dose range of 2.5 to 20 mg/day in clinical trials, with a mean modal dose of 12.5 mg/day (mean dose of 11.1 mg/day). When dosage adjustments are necessary, dose increments/decrements of 2.5 or 5 mg are recommended.

  The safety and effectiveness of doses above 20 mg/day have not been evaluated in clinical trials

  [see Clinical Studies ]

  .

  Maintenance Treatment

  — The efficacy of olanzapine for the maintenance treatment of schizophrenia in the adolescent population has not been systematically evaluated; however, maintenance efficacy can be extrapolated from adult data along with comparisons of olanzapine pharmacokinetic parameters in adult and adolescent patients. Thus, it is generally recommended that responding patients be continued beyond the acute response, but at the lowest dose needed to maintain remission. Patients should be periodically reassessed to determine the need for maintenance treatment.

  
  
  
  )
• Olanzapine may be given without regard to meals. (
  2.1 Schizophrenia

  Adults

  Dose Selection

  — Oral olanzapine should be administered on a once-a-day schedule without regard to meals, generally beginning with 5 to 10 mg initially, with a target dose of 10 mg/day within several days. Further dosage adjustments, if indicated, should generally occur at intervals of not less than 1 week, since steady state for olanzapine would not be achieved for approximately 1 week in the typical patient. When dosage adjustments are necessary, dose increments/decrements of 5 mg QD are recommended.

  
  
  

  Efficacy in schizophrenia was demonstrated in a dose range of 10 to 15 mg/day in clinical trials. However, doses above 10 mg/day were not demonstrated to be more efficacious than the 10 mg/day dose. An increase to a dose greater than the target dose of 10 mg/day (i.e., to a dose of 15 mg/day or greater) is recommended only after clinical assessment. Olanzapine is not indicated for use in doses above 20 mg/day.

  Dosing in Special Populations

  — The recommended starting dose is 5 mg in patients who are debilitated, who have a predisposition to hypotensive reactions, who otherwise exhibit a combination of factors that may result in slower metabolism of olanzapine (e.g., nonsmoking female patients ≥65 years of age), or who may be more pharmacodynamically sensitive to olanzapine

  [see Warnings and Precautions , Drug Interactions , and Clinical Pharmacology ]

  . When indicated, dose escalation should be performed with caution in these patients.

  Maintenance Treatment

  — The effectiveness of oral olanzapine, 10 mg/day to 20 mg/day, in maintaining treatment response in 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 trial

  [see Clinical Studies ]

  . The healthcare provider who elects to use olanzapine for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.

  Adolescents

  Dose Selection

  — Oral olanzapine should be administered on a once-a-day schedule without regard to meals with a recommended starting dose of 2.5 or 5 mg, with a target dose of 10 mg/day. Efficacy in adolescents with schizophrenia was demonstrated based on a flexible dose range of 2.5 to 20 mg/day in clinical trials, with a mean modal dose of 12.5 mg/day (mean dose of 11.1 mg/day). When dosage adjustments are necessary, dose increments/decrements of 2.5 or 5 mg are recommended.

  The safety and effectiveness of doses above 20 mg/day have not been evaluated in clinical trials

  [see Clinical Studies ]

  .

  Maintenance Treatment

  — The efficacy of olanzapine for the maintenance treatment of schizophrenia in the adolescent population has not been systematically evaluated; however, maintenance efficacy can be extrapolated from adult data along with comparisons of olanzapine pharmacokinetic parameters in adult and adolescent patients. Thus, it is generally recommended that responding patients be continued beyond the acute response, but at the lowest dose needed to maintain remission. Patients should be periodically reassessed to determine the need for maintenance treatment.

  
  
  
  )
• Olanzapine Orally Disintegrating Tablets and Fluoxetine in Combination:
•  
  Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability. (
  2.5 Olanzapine Orally Disintegrating Tablets and Fluoxetine in Combination: Depressive Episodes Associated with Bipolar I Disorder

  When using olanzapine orally disintegrating tablets and fluoxetine in combination, also refer to the Clinical Studies section of the package insert for Symbyax.

  Adults

  
  
  Oral olanzapine should be administered in combination with fluoxetine once daily in the evening, without regard to meals, generally beginning with 5 mg of oral olanzapine and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability within dose ranges of oral olanzapine 5 to 12.5 mg and fluoxetine 20 to 50 mg.
  
  Antidepressant efficacy was demonstrated with olanzapine orally disintegrating tablets and fluoxetine in combination in adult patients with a dose range of olanzapine 6 to 12 mg and fluoxetine 25 to 50 mg. Safety of co-administration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in clinical studies.
  
  
  
  

  Children and Adolescents (10-17 years of age)

  
  
  Oral olanzapine should be administered in combination with fluoxetine once daily in the evening, without regard to meals, generally beginning with 2.5 mg of oral olanzapine and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability. Safety of co-administration of doses above 12 mg olanzapine with 50 mg fluoxetine has not been evaluated in pediatric clinical studies.

  Safety and efficacy of olanzapine orally disintegrating tablets and fluoxetine in combination was determined in clinical trials supporting approval of Symbyax (fixed dose combination of olanzapine orally disintegrating tablets and fluoxetine). Symbyax is dosed between 3 mg/25 mg (olanzapine/fluoxetine) per day and 12 mg/50 mg (olanzapine/fluoxetine) per day. The following table demonstrates the appropriate individual component doses of olanzapine orally disintegrating tablets and fluoxetine versus Symbyax. Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability.

  Table 1: Approximate Dose Correspondence Between Symbyaxa and the Combination of Olanzapine Orally Disintegrating Tablets and Fluoxetine

  
  
  
  
  

  For Symbyax (mg/day)	Use in Combination
  	Olanzapine Orally Disintegrating Tablets (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

  
  
  

  ^aSymbyax (olanzapine/fluoxetine HCl) is a fixed-dose combination of olanzapine orally disintegrating tablets and fluoxetine.

  
  
  

  While there is no body of evidence to answer the question of how long a patient treated with olanzapine and fluoxetine in combination should remain on it, it is generally accepted that bipolar I disorder, including the depressive episodes associated with bipolar I disorder, is a chronic illness requiring chronic treatment. The healthcare provider should periodically reexamine the need for continued pharmacotherapy.

  Olanzapine orally disintegrating tablets monotherapy is not indicated for the treatment of depressive episodes associated with bipolar I disorder.
  ,
  2.6 Olanzapine Orally Disintegrating Tablets and Fluoxetine in Combination: Treatment Resistant Depression

  When using olanzapine orally disintegrating tablets and fluoxetine in combination, also refer to the Clinical Studies section of the package insert for Symbyax.
  
  Oral olanzapine should be administered in combination with fluoxetine once daily in the evening, without regard to meals, generally beginning with 5 mg of oral olanzapine and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability within dose ranges of oral olanzapine 5 to 20 mg and fluoxetine 20 to 50 mg.

  Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in combination in adult patients with a dose range of olanzapine 6 to 18 mg and fluoxetine 25 to 50 mg.

  Safety and efficacy of olanzapine in combination with fluoxetine was determined in clinical trials supporting approval of Symbyax (fixed dose combination of olanzapine and fluoxetine). Symbyax is dosed between 3 mg/25 mg (olanzapine/fluoxetine) per day and 12 mg/50 mg (olanzapine/fluoxetine) per day. Table 1 above demonstrates the appropriate individual component doses of olanzapine and fluoxetine versus Symbyax. Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability.

  While there is no body of evidence to answer the question of how long a patient treated with olanzapine and fluoxetine in combination should remain on it, it is generally accepted that treatment resistant depression (major depressive disorder in adult patients who do not respond to 2 separate trials of different antidepressants of adequate dose and duration in the current episode) is a chronic illness requiring chronic treatment. The healthcare provider should periodically reexamine the need for continued pharmacotherapy.

  Safety of co-administration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in clinical studies.

  Olanzapine orally disintegrating tablets  monotherapy is not indicated for treatment of treatment resistant depression (major depressive disorder in patients who do not respond to 2 antidepressants of adequate dose and duration in the current episode).
  )
• Olanzapine monotherapy is not indicated for the treatment of depressive episodes associated with bipolar I disorder or treatment resistant depression. (
  2.5 Olanzapine Orally Disintegrating Tablets and Fluoxetine in Combination: Depressive Episodes Associated with Bipolar I Disorder

  When using olanzapine orally disintegrating tablets and fluoxetine in combination, also refer to the Clinical Studies section of the package insert for Symbyax.

  Adults

  
  
  Oral olanzapine should be administered in combination with fluoxetine once daily in the evening, without regard to meals, generally beginning with 5 mg of oral olanzapine and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability within dose ranges of oral olanzapine 5 to 12.5 mg and fluoxetine 20 to 50 mg.
  
  Antidepressant efficacy was demonstrated with olanzapine orally disintegrating tablets and fluoxetine in combination in adult patients with a dose range of olanzapine 6 to 12 mg and fluoxetine 25 to 50 mg. Safety of co-administration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in clinical studies.
  
  
  
  

  Children and Adolescents (10-17 years of age)

  
  
  Oral olanzapine should be administered in combination with fluoxetine once daily in the evening, without regard to meals, generally beginning with 2.5 mg of oral olanzapine and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability. Safety of co-administration of doses above 12 mg olanzapine with 50 mg fluoxetine has not been evaluated in pediatric clinical studies.

  Safety and efficacy of olanzapine orally disintegrating tablets and fluoxetine in combination was determined in clinical trials supporting approval of Symbyax (fixed dose combination of olanzapine orally disintegrating tablets and fluoxetine). Symbyax is dosed between 3 mg/25 mg (olanzapine/fluoxetine) per day and 12 mg/50 mg (olanzapine/fluoxetine) per day. The following table demonstrates the appropriate individual component doses of olanzapine orally disintegrating tablets and fluoxetine versus Symbyax. Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability.

  Table 1: Approximate Dose Correspondence Between Symbyaxa and the Combination of Olanzapine Orally Disintegrating Tablets and Fluoxetine

  
  
  
  
  

  For Symbyax (mg/day)	Use in Combination
  	Olanzapine Orally Disintegrating Tablets (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

  
  
  

  ^aSymbyax (olanzapine/fluoxetine HCl) is a fixed-dose combination of olanzapine orally disintegrating tablets and fluoxetine.

  
  
  

  While there is no body of evidence to answer the question of how long a patient treated with olanzapine and fluoxetine in combination should remain on it, it is generally accepted that bipolar I disorder, including the depressive episodes associated with bipolar I disorder, is a chronic illness requiring chronic treatment. The healthcare provider should periodically reexamine the need for continued pharmacotherapy.

  Olanzapine orally disintegrating tablets monotherapy is not indicated for the treatment of depressive episodes associated with bipolar I disorder.
  ,
  2.6 Olanzapine Orally Disintegrating Tablets and Fluoxetine in Combination: Treatment Resistant Depression

  When using olanzapine orally disintegrating tablets and fluoxetine in combination, also refer to the Clinical Studies section of the package insert for Symbyax.
  
  Oral olanzapine should be administered in combination with fluoxetine once daily in the evening, without regard to meals, generally beginning with 5 mg of oral olanzapine and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability within dose ranges of oral olanzapine 5 to 20 mg and fluoxetine 20 to 50 mg.

  Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in combination in adult patients with a dose range of olanzapine 6 to 18 mg and fluoxetine 25 to 50 mg.

  Safety and efficacy of olanzapine in combination with fluoxetine was determined in clinical trials supporting approval of Symbyax (fixed dose combination of olanzapine and fluoxetine). Symbyax is dosed between 3 mg/25 mg (olanzapine/fluoxetine) per day and 12 mg/50 mg (olanzapine/fluoxetine) per day. Table 1 above demonstrates the appropriate individual component doses of olanzapine and fluoxetine versus Symbyax. Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability.

  While there is no body of evidence to answer the question of how long a patient treated with olanzapine and fluoxetine in combination should remain on it, it is generally accepted that treatment resistant depression (major depressive disorder in adult patients who do not respond to 2 separate trials of different antidepressants of adequate dose and duration in the current episode) is a chronic illness requiring chronic treatment. The healthcare provider should periodically reexamine the need for continued pharmacotherapy.

  Safety of co-administration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in clinical studies.

  Olanzapine orally disintegrating tablets  monotherapy is not indicated for treatment of treatment resistant depression (major depressive disorder in patients who do not respond to 2 antidepressants of adequate dose and duration in the current episode).
  )
• Safety of co-administration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in adults. (
  2.5 Olanzapine Orally Disintegrating Tablets and Fluoxetine in Combination: Depressive Episodes Associated with Bipolar I Disorder

  When using olanzapine orally disintegrating tablets and fluoxetine in combination, also refer to the Clinical Studies section of the package insert for Symbyax.

  Adults

  
  
  Oral olanzapine should be administered in combination with fluoxetine once daily in the evening, without regard to meals, generally beginning with 5 mg of oral olanzapine and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability within dose ranges of oral olanzapine 5 to 12.5 mg and fluoxetine 20 to 50 mg.
  
  Antidepressant efficacy was demonstrated with olanzapine orally disintegrating tablets and fluoxetine in combination in adult patients with a dose range of olanzapine 6 to 12 mg and fluoxetine 25 to 50 mg. Safety of co-administration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in clinical studies.
  
  
  
  

  Children and Adolescents (10-17 years of age)

  
  
  Oral olanzapine should be administered in combination with fluoxetine once daily in the evening, without regard to meals, generally beginning with 2.5 mg of oral olanzapine and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability. Safety of co-administration of doses above 12 mg olanzapine with 50 mg fluoxetine has not been evaluated in pediatric clinical studies.

  Safety and efficacy of olanzapine orally disintegrating tablets and fluoxetine in combination was determined in clinical trials supporting approval of Symbyax (fixed dose combination of olanzapine orally disintegrating tablets and fluoxetine). Symbyax is dosed between 3 mg/25 mg (olanzapine/fluoxetine) per day and 12 mg/50 mg (olanzapine/fluoxetine) per day. The following table demonstrates the appropriate individual component doses of olanzapine orally disintegrating tablets and fluoxetine versus Symbyax. Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability.

  Table 1: Approximate Dose Correspondence Between Symbyaxa and the Combination of Olanzapine Orally Disintegrating Tablets and Fluoxetine

  
  
  
  
  

  For Symbyax (mg/day)	Use in Combination
  	Olanzapine Orally Disintegrating Tablets (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

  
  
  

  ^aSymbyax (olanzapine/fluoxetine HCl) is a fixed-dose combination of olanzapine orally disintegrating tablets and fluoxetine.

  
  
  

  While there is no body of evidence to answer the question of how long a patient treated with olanzapine and fluoxetine in combination should remain on it, it is generally accepted that bipolar I disorder, including the depressive episodes associated with bipolar I disorder, is a chronic illness requiring chronic treatment. The healthcare provider should periodically reexamine the need for continued pharmacotherapy.

  Olanzapine orally disintegrating tablets monotherapy is not indicated for the treatment of depressive episodes associated with bipolar I disorder.
  ,
  2.6 Olanzapine Orally Disintegrating Tablets and Fluoxetine in Combination: Treatment Resistant Depression

  When using olanzapine orally disintegrating tablets and fluoxetine in combination, also refer to the Clinical Studies section of the package insert for Symbyax.
  
  Oral olanzapine should be administered in combination with fluoxetine once daily in the evening, without regard to meals, generally beginning with 5 mg of oral olanzapine and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability within dose ranges of oral olanzapine 5 to 20 mg and fluoxetine 20 to 50 mg.

  Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in combination in adult patients with a dose range of olanzapine 6 to 18 mg and fluoxetine 25 to 50 mg.

  Safety and efficacy of olanzapine in combination with fluoxetine was determined in clinical trials supporting approval of Symbyax (fixed dose combination of olanzapine and fluoxetine). Symbyax is dosed between 3 mg/25 mg (olanzapine/fluoxetine) per day and 12 mg/50 mg (olanzapine/fluoxetine) per day. Table 1 above demonstrates the appropriate individual component doses of olanzapine and fluoxetine versus Symbyax. Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability.

  While there is no body of evidence to answer the question of how long a patient treated with olanzapine and fluoxetine in combination should remain on it, it is generally accepted that treatment resistant depression (major depressive disorder in adult patients who do not respond to 2 separate trials of different antidepressants of adequate dose and duration in the current episode) is a chronic illness requiring chronic treatment. The healthcare provider should periodically reexamine the need for continued pharmacotherapy.

  Safety of co-administration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in clinical studies.

  Olanzapine orally disintegrating tablets  monotherapy is not indicated for treatment of treatment resistant depression (major depressive disorder in patients who do not respond to 2 antidepressants of adequate dose and duration in the current episode).
  )
• Safety of co-administration of doses above 12 mg olanzapine with 50 mg fluoxetine has not been evaluated in children and adolescents ages 10 to 17. (
  2.5 Olanzapine Orally Disintegrating Tablets and Fluoxetine in Combination: Depressive Episodes Associated with Bipolar I Disorder

  When using olanzapine orally disintegrating tablets and fluoxetine in combination, also refer to the Clinical Studies section of the package insert for Symbyax.

  Adults

  
  
  Oral olanzapine should be administered in combination with fluoxetine once daily in the evening, without regard to meals, generally beginning with 5 mg of oral olanzapine and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability within dose ranges of oral olanzapine 5 to 12.5 mg and fluoxetine 20 to 50 mg.
  
  Antidepressant efficacy was demonstrated with olanzapine orally disintegrating tablets and fluoxetine in combination in adult patients with a dose range of olanzapine 6 to 12 mg and fluoxetine 25 to 50 mg. Safety of co-administration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in clinical studies.
  
  
  
  

  Children and Adolescents (10-17 years of age)

  
  
  Oral olanzapine should be administered in combination with fluoxetine once daily in the evening, without regard to meals, generally beginning with 2.5 mg of oral olanzapine and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability. Safety of co-administration of doses above 12 mg olanzapine with 50 mg fluoxetine has not been evaluated in pediatric clinical studies.

  Safety and efficacy of olanzapine orally disintegrating tablets and fluoxetine in combination was determined in clinical trials supporting approval of Symbyax (fixed dose combination of olanzapine orally disintegrating tablets and fluoxetine). Symbyax is dosed between 3 mg/25 mg (olanzapine/fluoxetine) per day and 12 mg/50 mg (olanzapine/fluoxetine) per day. The following table demonstrates the appropriate individual component doses of olanzapine orally disintegrating tablets and fluoxetine versus Symbyax. Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability.

  Table 1: Approximate Dose Correspondence Between Symbyaxa and the Combination of Olanzapine Orally Disintegrating Tablets and Fluoxetine

  
  
  
  
  

  For Symbyax (mg/day)	Use in Combination
  	Olanzapine Orally Disintegrating Tablets (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

  
  
  

  ^aSymbyax (olanzapine/fluoxetine HCl) is a fixed-dose combination of olanzapine orally disintegrating tablets and fluoxetine.

  
  
  

  While there is no body of evidence to answer the question of how long a patient treated with olanzapine and fluoxetine in combination should remain on it, it is generally accepted that bipolar I disorder, including the depressive episodes associated with bipolar I disorder, is a chronic illness requiring chronic treatment. The healthcare provider should periodically reexamine the need for continued pharmacotherapy.

  Olanzapine orally disintegrating tablets monotherapy is not indicated for the treatment of depressive episodes associated with bipolar I disorder.
  )

Olanzapine orally disintegrating tablets, USP are yellow, round and debossed. Tablets are not scored. The tablets are available as follows:

When using olanzapine and fluoxetine in combination, also refer to the Use in Specific Populations section of the package insert for Symbyax.