General Information

Zyprexa (olanzapine) is an atypical antipsychotic.

Zyprexa is supplied as a tablet for oral administration, an orally disintegrating tablet or a solution for intramuscular injection. The indications for each formulation are as follows:

Schizophrenia:

Oral Zyprexa is indicated for the treatment of schizophrenia. 

• Adult dose: Start at 5-10 mg once daily; Target: 10 mg/day within several days
• Adolescents: Start at 2.5-5 mg once daily; Target: 10 mg/day

Bipolar I Disorder (Manic or Mixed Episodes)

• Monotherapy
  • Oral Zyprexa is indicated for the acute treatment of manic or mixed episodes associated with bipolar I disorder and maintenance treatment of bipolar I disorder
    • Adults: Start at 10 or 15 mg once daily
    • Pediatrics: Start at 2.5-5 mg once daily; Target: 10 mg/day
• Adjunctive Therapy to Lithium or Valproate
  • Oral Zyprexa is indicated for the treatment of manic or mixed episodes associated with bipolar I disorder as an adjunct to lithium or valproate.
    • Adults Only: Start at 10 mg once daily

Agitation Associated with Schizophrenia and Bipolar I Mania

Zyprexa IntraMuscular is indicated for the treatment of acute agitation associated with schizophrenia and bipolar I mania.

• Adults: 10 mg (5 mg or 7.5 mg when clinically warranted) Assess for orthostatic hypotension prior to subsequent dosing (max. 3 doses 2-4 hrs apart)

Depressive Episodes Associated with Bipolar I Disorder

Oral Zyprexa and fluoxetine in combination is indicated for the treatment of depressive episodes associated with bipolar I disorder

• Adults: Start at 5 mg of oral olanzapine and 20 mg of fluoxetine once daily
• Pediatrics: Start at 2.5 mg of oral olanzapine and 20 mg of fluoxetine once daily

Treatment Resistant Depression

Oral Zyprexa 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

• Adults: Start at 5 mg of oral olanzapine and 20 mg of fluoxetine once daily

Mechanism of Action

Zyprexa (olanzapine) is an atypical antipsychotic. The mechanism of action of olanzapine, in the listed indications is unclear. However, the efficacy of olanzapine in schizophrenia could be mediated through a combination of dopamine and serotonin type 2 (5HT2) antagonism.

Side Effects

Adverse effects may include, but are not limited to, the following:

Oral Olanzapine Monotherapy:

• Schizophrenia (Adults) – postural hypotension, constipation, weight gain, dizziness, personality disorder, akathisia.
•  Schizophrenia (Adolescents) – sedation, weight increased, headache, increased appetite, dizziness, abdominal pain, pain in extremity, fatigue, dry mouth.
• Manic or Mixed Episodes, Bipolar I Disorder (Adults) – asthenia, dry mouth, constipation, increased appetite, somnolence, dizziness, tremor.
• Manic or Mixed Episodes, Bipolar I Disorder (Adolescents) – sedation, weight increased, increased appetite, headache, fatigue, dizziness, dry mouth, abdominal pain, pain in extremity.

Combination of Zyprexa and Lithium or Valproate:

Manic or Mixed Episodes, Bipolar I Disorder (Adults) - dry mouth, weight gain, increased appetite, dizziness, back pain, constipation, speech disorder, increased salivation, amnesia, paresthesia.

Zyprexa and Fluoxetine in Combination:

Also refer to the Adverse Reactions section of the package insert for Symbyax.

Zyprexa IntraMuscular for Injection:

Agitation with Schizophrenia and Bipolar I Mania (Adults) – somnolence

The Zyprexa drug label comes with the following Black Box Warning: Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Zyprexa is not approved for the treatment of patients with dementia-related psychosis. When using Zyprexa and fluoxetine in combination, also refer to the Boxed Warning section of the package insert for Symbyax.

Clinical Trial Results

Schizophrenia

Lilly submitted data from extensive clinical trials involving more than 3,100 people in 22 countries. According to data gathered from these studies, subjects treated with Zyprexa reported statistically significant differences across several key test instruments measuring symptoms of schizophrenia when compared with placebo.

 In clinical trials, Zyprexa was superior to placebo in treating the symptoms of schizophrenia. The efficacy of Zyprexa in the management of the symptoms of psychotic disorders was established in two six-week placebo controlled trials of schizophrenic inpatients. Subjects were assessed using several test instruments, including the Brief Psychiatric Rating Scale (BPRS), an 18-item inventory of symptoms traditionally used to evaluate the effects of drug treatment in psychosis. The BPRS score was extracted from the Positive and Negative Syndrome scale (PANSS), a 30-item rating instrument that evaluates each symptom item on a scale of 1 (absent) to 7 (extreme). The BPRS psychosis cluster assessed psychotic symptoms, such as conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content. A second assessment, the Clinical Global Impression (CGI), measures the overall severity of the illness. In addition, subjects were evaluated on the PANSS and the Scale for Assessing Negative Symptoms (SANS). In a six-week, placebo-controlled trial involving 149 subjects, subjects received either placebo or a fixed dose of Zyprexa at 1 and 10 mg/day. In this trial, Zyprexa at 10 mg/day (but not 1 mg/day) was superior to placebo on the PANSS total score, the BPRS total, the BPRS psychosis cluster, the PANSS negative symptom sub-scale, and on CGI severity. In a six-week, placebo-controlled trial involving 253 subjects, subjects received placebo or one of three fixed dose ranges of Zyprexa (5 +/- 2.5 mg/day, 10 +/- 2.5 mg/day, 15 +/- 2.5 mg/day). The two highest Zyprexa doses (but not the lowest) were superior to placebo on the BPRS total score, BPRS psychosis cluster, and CGI severity score. The highest Zyprexa dose was statistically superior to placebo on the SANS.

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:

• 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.
• 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.
• 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:

• 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.
• 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.

Agitation Associated with Schizophrenia and Bipolar I Mania

The efficacy of intramuscular olanzapine for injection for the treatment of agitation was established in 3 short-term (24 hours of IM treatment) placebo-controlled trials in agitated adult inpatients from 2 diagnostic groups: schizophrenia and bipolar I disorder (manic or mixed episodes). Each of the trials included a single active comparator treatment arm of either haloperidol injection (schizophrenia studies) or lorazepam injection (bipolar I mania study). The primary efficacy measure used for assessing agitation signs and symptoms 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 during the 24 hour IM treatment periods; however, patients could not receive the second injection until after the initial 2 hour period when the primary efficacy measure was assessed. The results of the trials follow:

• In a placebo-controlled trial in agitated inpatients meeting DSM-IV criteria for schizophrenia (n=270), 4 fixed intramuscular olanzapine for injection doses of 2.5 mg, 5 mg, 7.5 mg and 10 mg were evaluated. All doses were statistically superior to placebo on the PANSS Excited Component at 2 hours post-injection. However, the effect was larger and more consistent for the 3 highest doses. There were no significant pairwise differences for the 7.5 and 10 mg doses over the 5 mg dose.
• In a second placebo-controlled trial in agitated inpatients meeting DSM-IV criteria for schizophrenia (n=311), 1 fixed intramuscular olanzapine for injection dose of 10 mg was evaluated. Olanzapine for injection was statistically superior to placebo on the PANSS Excited Component at 2 hours post-injection.
• In a placebo-controlled trial in agitated inpatients meeting DSM-IV criteria for bipolar I disorder (and currently displaying an acute manic or mixed episode with or without psychotic features) (n=201), 1 fixed intramuscular olanzapine for injection dose of 10 mg was evaluated. Olanzapine for injection was statistically superior to placebo on the PANSS Excited Component at 2 hours post-injection.