Zyprexa: Olanzapine Tablets

1
PV 5198 AMP
®
ZYPREXA
Olanzapine Tablets
ZYPREXA® ZYDIS®
Olanzapine Orally Disintegrating Tablets
ZYPREXA® IntraMuscular
Olanzapine for Injection
WARNING
Increased Mortality in Elderly Patients with Dementia-Related Psychosis — Elderly
patients with dementia-related psychosis treated with atypical antipsychotic drugs are at
an increased risk of death compared to placebo. Analyses of seventeen placebo-controlled
trials (modal duration of 10 weeks) in these patients revealed a risk of death in the
drug-treated patients of between 1.6 to 1.7 times that seen in placebo-treated patients. Over
the course of a typical 10-week controlled trial, the rate of death in drug-treated patients
was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the
causes of death were varied, most of the deaths appeared to be either cardiovascular
(e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.
ZYPREXA (olanzapine) is not approved for the treatment of patients with
dementia-related psychosis (see WARNINGS).
DESCRIPTION
ZYPREXA (olanzapine) is a psychotropic agent that belongs to the thienobenzodiazepine
class. The chemical designation is 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b]
[1,5]benzodiazepine. The molecular formula is C17H20N4S, which corresponds to a molecular
weight of 312.44. The chemical structure is:
Olanzapine is a yellow crystalline solid, which is practically insoluble in water.

ZYPREXA tablets are intended for oral administration only.
Each tablet contains olanzapine equivalent to 2.5 mg (8 µmol), 5 mg (16 µmol), 7.5 mg
(24 µmol), 10 mg (32 µmol), 15 mg (48 µmol), or 20 mg (64 µmol). Inactive ingredients are
carnauba wax, crospovidone, hydroxypropyl cellulose, hypromellose, lactose, magnesium
stearate, microcrystalline cellulose, and other inactive ingredients. The color coating contains
Titanium Dioxide (all strengths), FD&C Blue No. 2 Aluminum Lake (15 mg), or Synthetic Red
Iron Oxide (20 mg). The 2.5, 5, 7.5, and 10 mg tablets are imprinted with edible ink which
contains FD&C Blue No. 2 Aluminum Lake.
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ZYPREXA ZYDIS (olanzapine orally disintegrating tablets) is intended for oral administration
only.
Each orally disintegrating tablet contains olanzapine equivalent to 5 mg (16 µmol), 10 mg
(32 µmol), 15 mg (48 µmol) or 20 mg (64 µmol). It begins disintegrating in the mouth within
seconds, allowing its contents to be subsequently swallowed with or without liquid.
ZYPREXA ZYDIS (olanzapine orally disintegrating tablets) also contains the following inactive
ingredients: gelatin, mannitol, aspartame, sodium methyl paraben and sodium propyl paraben.
ZYPREXA IntraMuscular (olanzapine for injection) is intended for intramuscular use only.
Each vial provides for the administration of 10 mg (32 µmol) olanzapine with inactive
ingredients 50 mg lactose monohydrate and 3.5 mg tartaric acid. Hydrochloric acid and/or
sodium hydroxide may have been added during manufacturing to adjust pH.
CLINICAL PHARMACOLOGY
Pharmacodynamics
Olanzapine is a selective monoaminergic antagonist with high affinity binding to the following
receptors: serotonin 5HT2A/2C, 5HT6, (Ki=4, 11, and 5 nM, respectively), dopamine D1-4
(Ki=11-31 nM), histamine H1 (Ki=7 nM), and adrenergic α1 receptors (Ki=19 nM). Olanzapine is
an antagonist with moderate affinity binding for serotonin 5HT3 (Ki=57 nM) and muscarinic M1-5
(Ki=73, 96, 132, 32, and 48 nM, respectively). Olanzapine binds weakly to GABAA, BZD, and
β adrenergic receptors (Ki>10 µM).
The mechanism of action of olanzapine, as with other drugs having efficacy in schizophrenia,
is unknown. However, it has been proposed that this drug’s efficacy in schizophrenia is mediated
through a combination of dopamine and serotonin type 2 (5HT2) antagonism. The mechanism of
action of olanzapine in the treatment of acute manic episodes associated with Bipolar I Disorder
is unknown.
Antagonism at receptors other than dopamine and 5HT2 may explain some of the other
therapeutic and side effects of olanzapine. Olanzapine’s antagonism of muscarinic M1-5 receptors
may explain its anticholinergic-like effects. Olanzapine’s antagonism of histamine H1 receptors
may explain the somnolence observed with this drug. Olanzapine’s antagonism of adrenergic α1
receptors may explain the orthostatic hypotension observed with this drug.
Pharmacokinetics
Oral Administration
Olanzapine is well absorbed and reaches peak concentrations in approximately 6 hours
following an oral dose. It is eliminated extensively by first pass metabolism, with approximately
40% of the dose metabolized before reaching the systemic circulation. Food does not affect the
rate or extent of olanzapine absorption. Pharmacokinetic studies showed that ZYPREXA tablets
and ZYPREXA ZYDIS (olanzapine orally disintegrating tablets) dosage forms of olanzapine are
bioequivalent.
Olanzapine displays linear kinetics over the clinical dosing range. Its half-life ranges from
21 to 54 hours (5th to 95th percentile; mean of 30 hr), and apparent plasma clearance ranges
from 12 to 47 L/hr (5th to 95th percentile; mean of 25 L/hr).
Administration of olanzapine once daily leads to steady-state concentrations in about one week
that are approximately twice the concentrations after single doses. Plasma concentrations,
half-life, and clearance of olanzapine may vary between individuals on the basis of smoking
status, gender, and age (see Special Populations).
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Olanzapine is extensively distributed throughout the body, with a volume of distribution of

approximately 1000 L. It is 93% bound to plasma proteins over the concentration range of 7 to
1100 ng/mL, binding primarily to albumin and α1-acid glycoprotein.
Metabolism and Elimination — Following a single oral dose of 14C labeled olanzapine, 7% of
the dose of olanzapine was recovered in the urine as unchanged drug, indicating that olanzapine
is highly metabolized. Approximately 57% and 30% of the dose was recovered in the urine and
feces, respectively. In the plasma, olanzapine accounted for only 12% of the AUC for total
radioactivity, indicating significant exposure to metabolites. After multiple dosing, the major
circulating metabolites were the 10-N-glucuronide, present at steady state at 44% of the
concentration of olanzapine, and 4´-N-desmethyl olanzapine, present at steady state at 31% of
the concentration of olanzapine. Both metabolites lack pharmacological activity at the
concentrations observed.
Direct glucuronidation and cytochrome P450 (CYP) mediated oxidation are the primary
metabolic pathways for olanzapine. In vitro studies suggest that CYPs 1A2 and 2D6, and the
flavin-containing monooxygenase system are involved in olanzapine oxidation.
CYP2D6 mediated oxidation appears to be a minor metabolic pathway in vivo, because the
clearance of olanzapine is not reduced in subjects who are deficient in this enzyme.
Intramuscular Administration
ZYPREXA IntraMuscular results in rapid absorption with peak plasma concentrations
occurring within 15 to 45 minutes. Based upon a pharmacokinetic study in healthy volunteers, a
5 mg dose of intramuscular olanzapine for injection produces, on average, a maximum plasma
concentration approximately 5 times higher than the maximum plasma concentration produced
by a 5 mg dose of oral olanzapine. Area under the curve achieved after an intramuscular dose is
similar to that achieved after oral administration of the same dose. The half-life observed after
intramuscular administration is similar to that observed after oral dosing. The pharmacokinetics
are linear over the clinical dosing range. Metabolic profiles after intramuscular administration
are qualitatively similar to metabolic profiles after oral administration.
Special Populations
Renal Impairment — Because olanzapine is highly metabolized before excretion and only
7% of the drug is excreted unchanged, renal dysfunction alone is unlikely to have a major impact
on the pharmacokinetics of olanzapine. The pharmacokinetic characteristics of olanzapine were
similar in patients with severe renal impairment and normal subjects, indicating that dosage
adjustment based upon the degree of renal impairment is not required. In addition, olanzapine is
not removed by dialysis. The effect of renal impairment on metabolite elimination has not been
studied.
Hepatic Impairment — Although the presence of hepatic impairment may be expected to
reduce the clearance of olanzapine, a study of the effect of impaired liver function in
subjects (n=6) with clinically significant (Childs Pugh Classification A and B) cirrhosis revealed
little effect on the pharmacokinetics of olanzapine.
Age — In a study involving 24 healthy subjects, the mean elimination half-life of olanzapine
was about 1.5 times greater in elderly (>65 years) than in non-elderly subjects (≤65 years).
Caution should be used in dosing the elderly, especially if there are other factors that might
additively influence drug metabolism and/or pharmacodynamic sensitivity (see DOSAGE AND
ADMINISTRATION).
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Gender — Clearance of olanzapine is approximately 30% lower in women than in men. There
were, however, no apparent differences between men and women in effectiveness or adverse
effects. Dosage modifications based on gender should not be needed.
Smoking Status — Olanzapine clearance is about 40% higher in smokers than in nonsmokers,
although dosage modifications are not routinely recommended.
Race — In vivo studies have shown that exposures are similar among Japanese, Chinese and
Caucasians, especially after normalization for body weight differences. Dosage modifications for
race are, therefore, not recommended.
Combined Effects — The combined effects of age, smoking, and gender could lead to
substantial pharmacokinetic differences in populations. The clearance in young smoking males,
for example, may be 3 times higher than that in elderly nonsmoking females. Dosing
modification may be necessary in patients who exhibit a combination of factors that may result
in slower metabolism of olanzapine (see DOSAGE AND ADMINISTRATION).
For specific information about the pharmacology of lithium or valproate, refer to the
CLINICAL PHARMACOLOGY section of the package inserts for these other products.
CLINICAL EFFICACY DATA
Schizophrenia
The efficacy of oral olanzapine in the treatment of schizophrenia was established in
2 short-term (6-week) controlled trials of inpatients who met DSM III-R criteria for
schizophrenia. A single haloperidol arm was included as a comparative treatment in one of the
two trials, but this trial did not compare these two 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,
two 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 two 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
two 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.
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Examination of population subsets (race and gender) did not reveal any differential
responsiveness on the basis of these subgroupings.
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.
Bipolar Disorder
Monotherapy — The efficacy of oral olanzapine in the treatment of acute manic or mixed
episodes was established in 2 short-term (one 3-week and one 4-week) placebo-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 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 disorder who had responded during an initial open-label treatment phase for about two
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.
Combination Therapy — The efficacy of oral olanzapine with concomitant lithium or valproate
in the treatment of acute manic episodes was established in two controlled trials in patients who
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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.
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
inpatients from two 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 mania study).
Patients enrolled in the trials needed to be: (1) judged by the clinical investigators as clinically
agitated and clinically appropriate candidates for treatment with intramuscular medication, and
(2) exhibiting a level of agitation that met or exceeded a threshold score of ≥14 on the five 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 ≥4 using a 1-7 scoring system (1=absent, 4=moderate, 7=extreme). In
the studies, the mean baseline PANSS Excited Component score was 18.4, with scores ranging
from 13 to 32 (out of a maximum score of 35), thus suggesting predominantly moderate levels of
agitation with some patients experiencing mild or severe levels of agitation. 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
three 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:
(1) In a placebo-controlled trial in agitated inpatients meeting DSM-IV criteria for
schizophrenia (n=270), four 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 three highest doses. There were no significant pairwise differences for the 7.5 and 10 mg
doses over the 5 mg dose.
(2) In a second placebo-controlled trial in agitated inpatients meeting DSM-IV criteria for
schizophrenia (n=311), one 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.
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(3) 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), one 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.
Examination of population subsets (age, race, and gender) did not reveal any differential
responsiveness on the basis of these subgroupings.
INDICATIONS AND USAGE
Schizophrenia
Oral ZYPREXA is indicated for the treatment of schizophrenia.
The efficacy of ZYPREXA was established in short-term (6-week) controlled trials of
schizophrenic inpatients (see CLINICAL EFFICACY DATA).
The effectiveness of oral ZYPREXA at maintaining a treatment response in schizophrenic
patients who had been stable on ZYPREXA for approximately 8 weeks and were then followed
for a period of up to 8 months has been demonstrated in a placebo-controlled trial (see
CLINICAL EFFICACY DATA). Nevertheless, the physician who elects to use ZYPREXA for
extended periods should periodically re-evaluate the long-term usefulness of the drug for the
individual patient (see DOSAGE AND ADMINISTRATION).
Bipolar Disorder
Acute Monotherapy — Oral ZYPREXA is indicated for the treatment of acute mixed or manic
episodes associated with Bipolar I Disorder.
The efficacy of ZYPREXA was established in two placebo-controlled trials (one 3-week and
one 4-week) with patients meeting DSM-IV criteria for Bipolar I Disorder who currently
displayed an acute manic or mixed episode with or without psychotic features (see CLINICAL
EFFICACY DATA).
Maintenance Monotherapy — The benefit of maintaining bipolar patients on monotherapy
with oral ZYPREXA after achieving a responder status for an average duration of two weeks
was demonstrated in a controlled trial (see CLINICAL EFFICACY DATA). The physician who
elects to use ZYPREXA for extended periods should periodically re-evaluate the long-term
usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
Combination Therapy — The combination of oral ZYPREXA with lithium or valproate is
indicated for the short-term treatment of acute mixed or manic episodes associated with Bipolar I
Disorder.
The efficacy of ZYPREXA in combination with lithium or valproate was established in
two placebo-controlled (6-week) trials with patients meeting DSM-IV criteria for Bipolar I
Disorder who currently displayed an acute manic or mixed episode with or without psychotic
features (see CLINICAL EFFICACY DATA).
ZYPREXA IntraMuscular is indicated for the treatment of agitation associated with
schizophrenia and bipolar I mania. “Psychomotor agitation” is defined in DSM-IV as “excessive
motor activity associated with a feeling of inner tension.” Patients experiencing agitation often
manifest behaviors that interfere with their diagnosis and care, e.g., threatening behaviors,
escalating or urgently distressing behavior, or self-exhausting behavior, leading clinicians to the
use of intramuscular antipsychotic medications to achieve immediate control of the agitation.
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The efficacy of ZYPREXA IntraMuscular for the treatment of agitation associated with
schizophrenia and bipolar I mania was established in 3 short-term (24 hours) placebo-controlled
trials in agitated inpatients with schizophrenia or Bipolar I Disorder (manic or mixed episodes)
(see CLINICAL EFFICACY DATA).
CONTRAINDICATIONS
ZYPREXA is contraindicated in patients with a known hypersensitivity to the product.
For specific information about the contraindications of lithium or valproate, refer to the
CONTRAINDICATIONS section of the package inserts for these other products.
WARNINGS
Increased Mortality in Elderly Patients with Dementia-Related Psychosis — Elderly
patients with dementia-related psychosis treated with atypical antipsychotic drugs are at
an increased risk of death compared to placebo. ZYPREXA is not approved for the
treatment of patients with dementia-related psychosis (see BOX WARNING).
In placebo-controlled clinical trials of elderly patients with dementia-related psychosis, the
incidence of death in olanzapine-treated patients was significantly greater than placebo-treated
patients (3.5% vs 1.5%, respectively).
Cerebrovascular Adverse Events, Including Stroke, in Elderly Patients with Dementia-Related
Psychosis — Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including
fatalities, were reported in patients in trials of olanzapine in elderly patients with
dementia-related psychosis. In placebo-controlled trials, there was a significantly higher
incidence of cerebrovascular adverse events in patients treated with olanzapine compared to
patients treated with placebo. Olanzapine is not approved for the treatment of patients with
dementia-related psychosis.
Hyperglycemia and Diabetes Mellitus — Hyperglycemia, in some cases extreme and
associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated
with atypical antipsychotics including olanzapine. Assessment of the relationship between
atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an
increased background risk of diabetes mellitus in patients with schizophrenia and the increasing
incidence of diabetes mellitus in the general population. Given these confounders, the
relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not
completely understood. However, epidemiological studies suggest an increased risk of
treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical
antipsychotics. Precise risk estimates for hyperglycemia-related adverse events in patients treated
with atypical antipsychotics are not available.
Patients with an established diagnosis of diabetes mellitus who are started on atypical
antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk
factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment
with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of
treatment and periodically during treatment. Any patient treated with atypical antipsychotics
should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia,
and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical
antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has
resolved when the atypical antipsychotic was discontinued; however, some patients required
continuation of anti-diabetic treatment despite discontinuation of the suspect drug.
Neuroleptic Malignant Syndrome (NMS) — A potentially fatal symptom complex sometimes
referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with
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administration of antipsychotic drugs, including olanzapine. Clinical manifestations of NMS are

hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability
(irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional
signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and
acute renal failure.
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a
diagnosis, it is important to exclude cases where the clinical presentation includes both serious
medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated
extrapyramidal signs and symptoms (EPS). Other important considerations in the differential
diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central
nervous system pathology.
The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs
and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and
medical monitoring; and 3) treatment of any concomitant serious medical problems for which
specific treatments are available. There is no general agreement about specific pharmacological
treatment regimens for NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the potential
reintroduction of drug therapy should be carefully considered. The patient should be carefully
monitored, since recurrences of NMS have been reported.
Tardive Dyskinesia — A syndrome of potentially irreversible, involuntary, dyskinetic
movements may develop in patients treated with antipsychotic drugs. Although the prevalence of
the syndrome appears to be highest among the elderly, especially elderly women, it is impossible
to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which
patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their
potential to cause tardive dyskinesia is unknown.
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, after relatively brief treatment periods at low doses.
There is no known treatment for established cases of tardive dyskinesia, although the syndrome
may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic
treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the
syndrome and thereby may possibly mask the underlying process. The effect that symptomatic
suppression has upon the long-term course of the syndrome is unknown.
Given these considerations, olanzapine should be prescribed in a manner that is most likely to
minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally
be reserved for patients (1) who suffer from a chronic illness that is known to respond to
antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful
treatments are not available or appropriate. In patients who do require chronic treatment, the
smallest dose and the shortest duration of treatment producing a satisfactory clinical response
should be sought. The need for continued treatment should be reassessed periodically.
If signs and symptoms of tardive dyskinesia appear in a patient on olanzapine, drug
discontinuation should be considered. However, some patients may require treatment with
olanzapine despite the presence of the syndrome.
For specific information about the warnings of lithium or valproate, refer to the WARNINGS
section of the package inserts for these other products.
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PRECAUTIONS
General
Hemodynamic Effects — Olanzapine may induce orthostatic hypotension associated with
dizziness, tachycardia, and in some patients, syncope, especially during the initial dose-titration
period, probably reflecting its α1-adrenergic antagonistic properties. Hypotension, bradycardia
with or without hypotension, tachycardia, and syncope were also reported during the clinical
trials with intramuscular olanzapine for injection. In an open-label clinical pharmacology study
in non-agitated patients with schizophrenia in which the safety and tolerability of intramuscular
olanzapine were evaluated under a maximal dosing regimen (three 10 mg doses administered
4 hours apart), approximately one-third of these patients experienced a significant orthostatic
decrease in systolic blood pressure (i.e., decrease ≥30 mmHg) (see DOSAGE AND
ADMINISTRATION). Syncope was reported in 0.6% (15/2500) of olanzapine-treated patients in
phase 2-3 oral olanzapine studies and in 0.3% (2/722) of olanzapine-treated patients with
agitation in the intramuscular olanzapine for injection studies. Three normal volunteers in
phase 1 studies with intramuscular olanzapine experienced hypotension, bradycardia, and sinus
pauses of up to 6 seconds that spontaneously resolved (in 2 cases the events occurred on
intramuscular olanzapine, and in 1 case, on oral olanzapine). The risk for this sequence of
hypotension, bradycardia, and sinus pause may be greater in nonpsychiatric patients compared to
psychiatric patients who are possibly more adapted to certain effects of psychotropic drugs.
For oral olanzapine therapy, the risk of orthostatic hypotension and syncope may be minimized
by initiating therapy with 5 mg QD (see DOSAGE AND ADMINISTRATION). A more gradual
titration to the target dose should be considered if hypotension occurs.
For intramuscular olanzapine for injection therapy, patients should remain recumbent if drowsy
or dizzy after injection until examination has indicated that they are not experiencing postural
hypotension, bradycardia, and/or hypoventilation.
Olanzapine should be used with particular caution in patients with known cardiovascular
disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities),
cerebrovascular disease, and conditions which would predispose patients to hypotension
(dehydration, hypovolemia, and treatment with antihypertensive medications) where the
occurrence of syncope, or hypotension and/or bradycardia might put the patient at increased
medical risk.
Caution is necessary in patients who receive treatment with other drugs having effects that can
induce hypotension, bradycardia, respiratory or central nervous system depression (see Drug
Interactions). Concomitant administration of intramuscular olanzapine and parenteral
benzodiazepine has not been studied and is therefore not recommended. If use of intramuscular
olanzapine in combination with parenteral benzodiazepines is considered, careful evaluation of
clinical status for excessive sedation and cardiorespiratory depression is recommended.
Seizures — During premarketing testing, seizures occurred in 0.9% (22/2500) of
olanzapine-treated patients. There were confounding factors that may have contributed to the
occurrence of seizures in many of these cases. Olanzapine should be used cautiously in patients
with a history of seizures or with conditions that potentially lower the seizure threshold,
e.g., Alzheimer’s dementia. Conditions that lower the seizure threshold may be more prevalent in
a population of 65 years or older.
Hyperprolactinemia — As with other drugs that antagonize dopamine D2 receptors, olanzapine
elevates prolactin levels, and a modest elevation persists during chronic administration. Tissue
culture experiments indicate that approximately one-third of human breast cancers are prolactin
11
dependent in vitro, a factor of potential importance if the prescription of these drugs is

contemplated in a patient with previously detected breast cancer of this type. Although
disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported
with prolactin-elevating compounds, the clinical significance of elevated serum prolactin levels
is unknown for most patients. As is common with compounds which increase prolactin release,
an increase in mammary gland neoplasia was observed in the olanzapine carcinogenicity studies
conducted in mice and rats (see Carcinogenesis). However, neither clinical studies nor
epidemiologic studies have shown an association between chronic administration of this class of
drugs and tumorigenesis in humans; the available evidence is considered too limited to be
conclusive.
Transaminase Elevations — In placebo-controlled studies, clinically significant ALT (SGPT)
elevations (≥3 times the upper limit of the normal range) were observed in 2% (6/243) of patients
exposed to olanzapine compared to none (0/115) of the placebo patients. None of these patients
experienced jaundice. In two of these patients, liver enzymes decreased toward normal despite
continued treatment and in two others, enzymes decreased upon discontinuation of olanzapine. In
the remaining two patients, one, seropositive for hepatitis C, had persistent enzyme elevation for
four months after discontinuation, and the other had insufficient follow-up to determine if
enzymes normalized.
Within the larger premarketing database of about 2400 patients with baseline SGPT ≤90 IU/L,
the incidence of SGPT elevation to >200 IU/L was 2% (50/2381). Again, none of these patients
experienced jaundice or other symptoms attributable to liver impairment and most had transient
changes that tended to normalize while olanzapine treatment was continued.
Among 2500 patients in oral olanzapine clinical trials, about 1% (23/2500) discontinued
treatment due to transaminase increases.
Rare postmarketing reports of hepatitis have been received. Very rare cases of cholestatic or
mixed liver injury have also been reported in the postmarketing period.
Caution should be exercised in patients with signs and symptoms of hepatic impairment, in
patients with pre-existing conditions associated with limited hepatic functional reserve, and in
patients who are being treated with potentially hepatotoxic drugs. Periodic assessment of
transaminases is recommended in patients with significant hepatic disease (see Laboratory
Tests).
Potential for Cognitive and Motor Impairment — Somnolence was a commonly reported
adverse event associated with olanzapine treatment, occurring at an incidence of 26% in
olanzapine patients compared to 15% in placebo patients. This adverse event was also dose
related. Somnolence led to discontinuation in 0.4% (9/2500) of patients in the premarketing
database.
Since olanzapine has the potential to impair judgment, thinking, or motor skills, patients should
be cautioned about operating hazardous machinery, including automobiles, until they are
reasonably certain that olanzapine therapy does not affect them adversely.
Body Temperature Regulation — Disruption of the body’s ability to reduce core body
temperature has been attributed to antipsychotic agents. Appropriate care is advised when
prescribing olanzapine for patients who will be experiencing conditions which may contribute to
an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat,
receiving concomitant medication with anticholinergic activity, or being subject to dehydration.
Dysphagia — Esophageal dysmotility and aspiration have been associated with antipsychotic
drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with
12
advanced Alzheimer’s disease. Olanzapine and other antipsychotic drugs should be used
cautiously in patients at risk for aspiration pneumonia.
Suicide — The possibility of a suicide attempt is inherent in schizophrenia and in bipolar
disorder, and close supervision of high-risk patients should accompany drug therapy.
Prescriptions for olanzapine should be written for the smallest quantity of tablets consistent with
good patient management, in order to reduce the risk of overdose.
Use in Patients with Concomitant Illness — Clinical experience with olanzapine in patients
with certain concomitant systemic illnesses (see Renal Impairment and Hepatic Impairment
under CLINICAL PHARMACOLOGY, Special Populations) is limited.
Olanzapine exhibits in vitro muscarinic receptor affinity. In premarketing clinical trials with
olanzapine, olanzapine was associated with constipation, dry mouth, and tachycardia, all adverse
events possibly related to cholinergic antagonism. Such adverse events were not often the basis
for discontinuations from olanzapine, but olanzapine should be used with caution in patients with
clinically significant prostatic hypertrophy, narrow angle glaucoma, or a history of paralytic
ileus.
In five placebo-controlled studies of olanzapine in elderly patients with dementia-related
psychosis (n=1184), the following treatment-emergent adverse events were reported in
olanzapine-treated patients at an incidence of at least 2% and significantly greater than
placebo-treated patients: falls, somnolence, peripheral edema, abnormal gait, urinary
incontinence, lethargy, increased weight, asthenia, pyrexia, pneumonia, dry mouth and visual
hallucinations. The rate of discontinuation due to adverse events was significantly greater with
olanzapine than placebo (13% vs 7%). Elderly patients with dementia-related psychosis treated
with olanzapine are at an increased risk of death compared to placebo. Olanzapine is not
approved for the treatment of patients with dementia-related psychosis. If the prescriber elects to
treat elderly patients with dementia-related psychosis, vigilance should be exercised (see BOX
WARNING and WARNINGS).
Olanzapine has not been evaluated or used to any appreciable extent in patients with a recent
history of myocardial infarction or unstable heart disease. Patients with these diagnoses were
excluded from premarketing clinical studies. Because of the risk of orthostatic hypotension with
olanzapine, caution should be observed in cardiac patients (see Hemodynamic Effects).
For specific information about the precautions of lithium or valproate, refer to the
PRECAUTIONS section of the package inserts for these other products.
Information for Patients
Physicians are advised to discuss the following issues with patients for whom they prescribe
olanzapine:
Orthostatic Hypotension — Patients should be advised of the risk of orthostatic hypotension,
especially during the period of initial dose titration and in association with the use of
concomitant drugs that may potentiate the orthostatic effect of olanzapine, e.g., diazepam or
alcohol (see Drug Interactions).
Interference with Cognitive and Motor Performance — Because olanzapine has the potential to
impair judgment, thinking, or motor skills, patients should be cautioned about operating
hazardous machinery, including automobiles, until they are reasonably certain that olanzapine
therapy does not affect them adversely.
Pregnancy — Patients should be advised to notify their physician if they become pregnant or
intend to become pregnant during therapy with olanzapine.
Nursing — Patients should be advised not to breast-feed an infant if they are taking olanzapine.
13
Concomitant Medication — Patients should be advised to inform their physicians if they are
taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for
interactions.
Alcohol — Patients should be advised to avoid alcohol while taking olanzapine.
Heat Exposure and Dehydration — Patients should be advised regarding appropriate care in
avoiding overheating and dehydration.
Phenylketonurics — ZYPREXA ZYDIS (olanzapine orally disintegrating tablets) contains
phenylalanine (0.34, 0.45, 0.67, or 0.90 mg per 5, 10, 15, or 20 mg tablet, respectively).
Laboratory Tests
Periodic assessment of transaminases is recommended in patients with significant hepatic
disease (see Transaminase Elevations).
Drug Interactions
The risks of using olanzapine in combination with other drugs have not been extensively
evaluated in systematic studies. Given the primary CNS effects of olanzapine, caution should be
used when olanzapine is taken in combination with other centrally acting drugs and alcohol.
Because of its potential for inducing hypotension, olanzapine may enhance the effects of
certain antihypertensive agents.
Olanzapine may antagonize the effects of levodopa and dopamine agonists.
The Effect of Other Drugs on Olanzapine — Agents that induce CYP1A2 or glucuronyl
transferase enzymes, such as omeprazole and rifampin, may cause an increase in olanzapine
clearance. Inhibitors of CYP1A2 could potentially inhibit olanzapine clearance. Although
olanzapine is metabolized by multiple enzyme systems, induction or inhibition of a
single enzyme may appreciably alter olanzapine clearance. Therefore, a dosage increase (for
induction) or a dosage decrease (for inhibition) may need to be considered with specific drugs.
Charcoal — The administration of activated charcoal (1 g) reduced the Cmax and AUC of oral
olanzapine by about 60%. As peak olanzapine levels are not typically obtained until about
6 hours after dosing, charcoal may be a useful treatment for olanzapine overdose.
Cimetidine and Antacids — Single doses of cimetidine (800 mg) or aluminum- and
magnesium-containing antacids did not affect the oral bioavailability of olanzapine.
Carbamazepine — Carbamazepine therapy (200 mg bid) causes an approximately
50% increase in the clearance of olanzapine. This increase is likely due to the fact that
carbamazepine is a potent inducer of CYP1A2 activity. Higher daily doses of carbamazepine
may cause an even greater increase in olanzapine clearance.
Ethanol — Ethanol (45 mg/70 kg single dose) did not have an effect on olanzapine
pharmacokinetics.
Fluoxetine — Fluoxetine (60 mg single dose or 60 mg daily for 8 days) causes a small (mean
16%) increase in the maximum concentration of olanzapine and a small (mean 16%) decrease in
olanzapine clearance. The magnitude of the impact of this factor is small in comparison to the
overall variability between individuals, and therefore dose modification is not routinely
recommended.
Fluvoxamine — Fluvoxamine, a CYP1A2 inhibitor, decreases the clearance of olanzapine.
This results in a mean increase in olanzapine Cmax following fluvoxamine of 54% in female
nonsmokers and 77% in male smokers. The mean increase in olanzapine AUC is 52% and 108%,
respectively. Lower doses of olanzapine should be considered in patients receiving concomitant
treatment with fluvoxamine.
Warfarin — Warfarin (20 mg single dose) did not affect olanzapine pharmacokinetics.
14
Effect of Olanzapine on Other Drugs — In vitro studies utilizing human liver microsomes
suggest that olanzapine has little potential to inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6,
and CYP3A. Thus, olanzapine is unlikely to cause clinically important drug interactions
mediated by these enzymes.
Lithium — Multiple doses of olanzapine (10 mg for 8 days) did not influence the kinetics of
lithium. Therefore, concomitant olanzapine administration does not require dosage adjustment of
lithium.
Valproate — Studies in vitro using human liver microsomes determined that olanzapine has
little potential to inhibit the major metabolic pathway, glucuronidation, of valproate. Further,
valproate has little effect on the metabolism of olanzapine in vitro. In vivo administration of
olanzapine (10 mg daily for 2 weeks) did not affect the steady state plasma concentrations of
valproate. Therefore, concomitant olanzapine administration does not require dosage adjustment
of valproate.
Single doses of olanzapine did not affect the pharmacokinetics of imipramine or its active
metabolite desipramine, and warfarin. Multiple doses of olanzapine did not influence the kinetics
of diazepam and its active metabolite N-desmethyldiazepam, ethanol, or biperiden. However, the
co-administration of either diazepam or ethanol with olanzapine potentiated the orthostatic
hypotension observed with olanzapine. Multiple doses of olanzapine did not affect the
pharmacokinetics of theophylline or its metabolites.
Lorazepam — Administration of intramuscular lorazepam (2 mg) 1 hour after intramuscular
olanzapine for injection (5 mg) did not significantly affect the pharmacokinetics of olanzapine,
unconjugated lorazepam, or total lorazepam. However, this co-administration of intramuscular
lorazepam and intramuscular olanzapine for injection added to the somnolence observed with
either drug alone (see Hemodynamic Effects).
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis — Oral carcinogenicity studies were conducted in mice and rats. Olanzapine
was administered to mice in two 78-week studies at doses of 3, 10, 30/20 mg/kg/day (equivalent
to 0.8-5 times the maximum recommended human daily oral dose on a mg/m2 basis) and 0.25, 2,
8 mg/kg/day (equivalent to 0.06-2 times the maximum recommended human daily oral dose on a
mg/m2 basis). Rats were dosed for 2 years at doses of 0.25, 1, 2.5, 4 mg/kg/day (males) and 0.25,
1, 4, 8 mg/kg/day (females) (equivalent to 0.13-2 and 0.13-4 times the maximum recommended
human daily oral dose on a mg/m2 basis, respectively). The incidence of liver hemangiomas and
hemangiosarcomas was significantly increased in one mouse study in female mice dosed at
8 mg/kg/day (2 times the maximum recommended human daily oral dose on a mg/m2 basis).
These tumors were not increased in another mouse study in females dosed at 10 or
30/20 mg/kg/day (2-5 times the maximum recommended human daily oral dose on a mg/m2
basis); in this study, there was a high incidence of early mortalities in males of the
30/20 mg/kg/day group. The incidence of mammary gland adenomas and adenocarcinomas was
significantly increased in female mice dosed at ≥2 mg/kg/day and in female rats dosed at
≥4 mg/kg/day (0.5 and 2 times the maximum recommended human daily oral dose on a mg/m2
basis, respectively). Antipsychotic drugs have been shown to chronically elevate prolactin levels
in rodents. Serum prolactin levels were not measured during the olanzapine carcinogenicity
studies; however, measurements during subchronic toxicity studies showed that olanzapine
elevated serum prolactin levels up to 4-fold in rats at the same doses used in the carcinogenicity
study. An increase in mammary gland neoplasms has been found in rodents after chronic
administration of other antipsychotic drugs and is considered to be prolactin mediated. The
15
relevance for human risk of the finding of prolactin mediated endocrine tumors in rodents is
unknown (see Hyperprolactinemia under PRECAUTIONS, General).
Mutagenesis — No evidence of mutagenic potential for olanzapine was found in the Ames
reverse mutation test, in vivo micronucleus test in mice, the chromosomal aberration test in
Chinese hamster ovary cells, unscheduled DNA synthesis test in rat hepatocytes, induction of
forward mutation test in mouse lymphoma cells, or in vivo sister chromatid exchange test in
bone marrow of Chinese hamsters.
Impairment of Fertility — In an oral fertility and reproductive performance study in rats, male
mating performance, but not fertility, was impaired at a dose of 22.4 mg/kg/day and female
fertility was decreased at a dose of 3 mg/kg/day (11 and 1.5 times the maximum recommended
human daily oral dose on a mg/m2 basis, respectively). Discontinuance of olanzapine treatment
reversed the effects on male mating performance. In female rats, the precoital period was
increased and the mating index reduced at 5 mg/kg/day (2.5 times the maximum recommended
human daily oral dose on a mg/m2 basis). Diestrous was prolonged and estrous delayed at
1.1 mg/kg/day (0.6 times the maximum recommended human daily oral dose on a mg/m2 basis);
therefore olanzapine may produce a delay in ovulation.
Pregnancy
Pregnancy Category C — In oral reproduction studies in rats at doses up to 18 mg/kg/day and
in rabbits at doses up to 30 mg/kg/day (9 and 30 times the maximum recommended human daily
oral dose on a mg/m2 basis, respectively) no evidence of teratogenicity was observed. In an oral
rat teratology study, early resorptions and increased numbers of nonviable fetuses were observed
at a dose of 18 mg/kg/day (9 times the maximum recommended human daily oral dose on a
mg/m2 basis). Gestation was prolonged at 10 mg/kg/day (5 times the maximum recommended
human daily oral dose on a mg/m2 basis). In an oral rabbit teratology study, fetal toxicity
(manifested as increased resorptions and decreased fetal weight) occurred at a maternally toxic
dose of 30 mg/kg/day (30 times the maximum recommended human daily oral dose on a mg/m2
basis).
Placental transfer of olanzapine occurs in rat pups.
There are no adequate and well-controlled trials with olanzapine in pregnant females.
Seven pregnancies were observed during clinical trials with olanzapine, including 2 resulting in
normal births, 1 resulting in neonatal death due to a cardiovascular defect, 3 therapeutic
abortions, and 1 spontaneous abortion. Because animal reproduction studies are not always
predictive of human response, this drug should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus.
Labor and Delivery
Parturition in rats was not affected by olanzapine. The effect of olanzapine on labor and
delivery in humans is unknown.
Nursing Mothers
In a study in lactating, healthy women, olanzapine was excreted in breast milk. Mean infant
dose at steady state was estimated to be 1.8% of the maternal olanzapine dose. It is
recommended that women receiving olanzapine should not breast-feed.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
16
Geriatric Use
Of the 2500 patients in premarketing clinical studies with oral olanzapine, 11% (263) were
65 years of age or over. In patients with schizophrenia, there was no indication of any different
tolerability of olanzapine in the elderly compared to younger patients. Studies in elderly patients
with dementia-related psychosis have suggested that there may be a different tolerability profile
in this population compared to younger patients with schizophrenia. Elderly patients with
dementia-related psychosis treated with olanzapine are at an increased risk of death compared to
placebo. Olanzapine is not approved for the treatment of patients with dementia-related
psychosis. If the prescriber elects to treat elderly patients with dementia-related psychosis,
vigilance should be exercised. Also, the presence of factors that might decrease pharmacokinetic
clearance or increase the pharmacodynamic response to olanzapine should lead to consideration
of a lower starting dose for any geriatric patient (see BOX WARNING, WARNINGS,
PRECAUTIONS, and DOSAGE AND ADMINISTRATION).
ADVERSE REACTIONS
The information below is derived from a clinical trial database for olanzapine consisting of
8661 patients with approximately 4165 patient-years of exposure to oral olanzapine and
722 patients with exposure to intramuscular olanzapine for injection. This database includes:
(1) 2500 patients who participated in multiple-dose oral olanzapine premarketing trials in
schizophrenia and Alzheimer’s disease representing approximately 1122 patient-years of
exposure as of February 14, 1995; (2) 182 patients who participated in oral olanzapine
premarketing bipolar mania trials representing approximately 66 patient-years of exposure;
(3) 191 patients who participated in an oral olanzapine trial of patients having various psychiatric
symptoms in association with Alzheimer’s disease representing approximately 29 patient-years
of exposure; (4) 5788 patients from 88 additional oral olanzapine clinical trials as of
December 31, 2001; and (5) 722 patients who participated in intramuscular olanzapine for
injection premarketing trials in agitated patients with schizophrenia, Bipolar I Disorder (manic or
mixed episodes), or dementia. In addition, information from the premarketing 6-week clinical
study database for olanzapine in combination with lithium or valproate, consisting of
224 patients who participated in bipolar mania trials with approximately 22 patient-years of
exposure, is included below.
The conditions and duration of treatment with olanzapine varied greatly and included (in
overlapping categories) open-label and double-blind phases of studies, inpatients and outpatients,
fixed-dose and dose-titration studies, and short-term or longer-term exposure. Adverse reactions
were assessed by collecting adverse events, results of physical examinations, vital signs, weights,
laboratory analytes, ECGs, chest x-rays, and results of ophthalmologic examinations.
Certain portions of the discussion below relating to objective or numeric safety parameters,
namely, dose-dependent adverse events, vital sign changes, weight gain, laboratory changes, and
ECG changes are derived from studies in patients with schizophrenia and have not been
duplicated for bipolar mania or agitation. However, this information is also generally applicable
to bipolar mania and agitation.
Adverse events during exposure were obtained by spontaneous report and recorded by clinical
investigators using terminology of their own choosing. Consequently, it is not possible to
provide a meaningful estimate of the proportion of individuals experiencing adverse events
without first grouping similar types of events into a smaller number of standardized event
categories. In the tables and tabulations that follow, standard COSTART dictionary terminology
has been used initially to classify reported adverse events.
17
The stated frequencies of adverse events represent the proportion of individuals who
experienced, at least once, a treatment-emergent adverse event of the type listed. An event was
considered treatment emergent if it occurred for the first time or worsened while receiving
therapy following baseline evaluation. The reported events do not include those event terms that
were so general as to be uninformative. Events listed elsewhere in labeling may not be repeated
below. It is important to emphasize that, although the events occurred during treatment with
olanzapine, they were not necessarily caused by it. The entire label should be read to gain a
complete understanding of the safety profile of olanzapine.
The prescriber should be aware that the figures in the tables and tabulations cannot be used to
predict the incidence of side effects in the course of usual medical practice where patient
characteristics and other factors differ from those that prevailed in the clinical trials. Similarly,
the cited frequencies cannot be compared with figures obtained from other clinical investigations
involving different treatments, uses, and investigators. The cited figures, however, do provide the
prescribing physician with some basis for estimating the relative contribution of drug and
nondrug factors to the adverse event incidence in the population studied.
Incidence of Adverse Events in Short-Term, Placebo-Controlled and Combination
Trials
The following findings are based on premarketing trials of (1) oral olanzapine for
schizophrenia, bipolar mania, a subsequent trial of patients having various psychiatric symptoms
in association with Alzheimer’s disease, and premarketing combination trials, and
(2) intramuscular olanzapine for injection in agitated patients with schizophrenia or bipolar
mania.
Adverse Events Associated with Discontinuation of Treatment in Short-Term, Placebo-
Controlled Trials
Schizophrenia — Overall, there was no difference in the incidence of discontinuation due to
adverse events (5% for oral olanzapine vs 6% for placebo). However, discontinuations due to
increases in SGPT were considered to be drug related (2% for oral olanzapine vs 0% for placebo)
(see PRECAUTIONS).
Bipolar Mania Monotherapy — Overall, there was no difference in the incidence of
discontinuation due to adverse events (2% for oral olanzapine vs 2% for placebo).
Agitation — Overall, there was no difference in the incidence of discontinuation due to
adverse events (0.4% for intramuscular olanzapine for injection vs 0% for placebo).
Adverse Events Associated with Discontinuation of Treatment in Short-Term
Combination Trials
Bipolar Mania Combination Therapy — In a study of patients who were already tolerating
either lithium or valproate as monotherapy, discontinuation rates due to adverse events were
11% for the combination of oral olanzapine with lithium or valproate compared to 2% for
patients who remained on lithium or valproate monotherapy. Discontinuations with the
combination of oral olanzapine and lithium or valproate that occurred in more than 1 patient
were: somnolence (3%), weight gain (1%), and peripheral edema (1%).
Commonly Observed Adverse Events in Short-Term, Placebo-Controlled Trials
The most commonly observed adverse events associated with the use of oral olanzapine
(incidence of 5% or greater) and not observed at an equivalent incidence among placebo-treated
patients (olanzapine incidence at least twice that for placebo) were:
18
Common Treatment-Emergent Adverse Events Associated with the

Use of Oral Olanzapine in 6-Week Trials — SCHIZOPHRENIA
Percentage of Patients Reporting Event
Adverse Event Olanzapine Placebo
(N=248) (N=118)
Postural hypotension 5 2
Constipation 9 3
Weight gain 6 1
Dizziness 11 4
Personality disorder1 8 4
Akathisia 5 1
1
Personality disorder is the COSTART term for designating non-aggressive objectionable behavior.

Use of Oral Olanzapine in 3-Week and 4-Week Trials — BIPOLAR MANIA
Adverse Event Olanzapine Placebo
(N=125) (N=129)
Asthenia 15 6
Dry mouth 22 7
Constipation 11 5
Dyspepsia 11 5
Increased appetite 6 3
Somnolence 35 13
Dizziness 18 6
Tremor 6 3
There was one adverse event (somnolence) observed at an incidence of 5% or greater among
intramuscular olanzapine for injection-treated patients and not observed at an equivalent
incidence among placebo-treated patients (olanzapine incidence at least twice that for placebo)
during the placebo-controlled premarketing studies. The incidence of somnolence during the
24 hour IM treatment period in clinical trials in agitated patients with schizophrenia or bipolar
mania was 6% for intramuscular olanzapine for injection and 3% for placebo.
Adverse Events Occurring at an Incidence of 2% or More Among Oral Olanzapine-
Treated Patients in Short-Term, Placebo-Controlled Trials
Table 1 enumerates the incidence, rounded to the nearest percent, of treatment-emergent
adverse events that occurred in 2% or more of patients treated with oral olanzapine (doses
≥2.5 mg/day) and with incidence greater than placebo who participated in the acute phase of
placebo-controlled trials.
Table 1
Treatment-Emergent Adverse Events:
Incidence in Short-Term, Placebo-Controlled Clinical Trials1
with Oral Olanzapine
Olanzapine Placebo
Body System/Adverse Event (N=532) (N=294)
Body as a Whole
Accidental injury 12 8
19
Asthenia 10 9
Fever 6 2
Back pain 5 2
Chest pain 3 1
Cardiovascular System
Tachycardia 3 1
Hypertension 2 1
Digestive System
Dry mouth 9 5
Constipation 9 4
Dyspepsia 7 5
Vomiting 4 3
Hemic and Lymphatic System
Ecchymosis 5 3
Metabolic and Nutritional Disorders
Weight gain 5 3
Peripheral edema 3 1
Musculoskeletal System
Extremity pain (other than joint) 5 3
Joint pain 5 3
Nervous System
Somnolence 29 13
Insomnia 12 11
Dizziness 11 4
Abnormal gait 6 1
Tremor 4 3
Akathisia 3 2
Hypertonia 3 2
Articulation impairment 2 1
Respiratory System
Rhinitis 7 6
Cough increased 6 3
Pharyngitis 4 3
Special Senses
Amblyopia 3 2
Urogenital System
Urinary incontinence 2 1
Urinary tract infection 2 1
1
Events reported by at least 2% of patients treated with olanzapine, except the following events which had an
incidence equal to or less than placebo: abdominal pain, agitation, anorexia, anxiety, apathy, confusion,
depression, diarrhea, dysmenorrhea (denominator used was for females only [olanzapine, N=201;
placebo, N=114]), hallucinations, headache, hostility, hyperkinesia, myalgia, nausea, nervousness, paranoid
reaction, personality disorder (COSTART term for designating non-aggressive objectionable behavior), rash,
thinking abnormal, weight loss.
Commonly Observed Adverse Events in Short-Term Combination Trials

In the bipolar mania combination placebo-controlled trials, the most commonly observed
adverse events associated with the combination of olanzapine and lithium or valproate (incidence
of ≥5% and at least twice placebo) were:
20

Use of Oral Olanzapine in 6-Week Combination Trials — BIPOLAR MANIA
Adverse Event Olanzapine with Placebo with
lithium or valproate lithium or valproate
(N=229) (N=115)
Dry mouth 32 9
Weight gain 26 7
Dizziness 14 7
Back pain 8 4
Constipation 8 4
Speech disorder 7 1
Increased salivation 6 2
Amnesia 5 2
Paresthesia 5 2
Adverse Events Occurring at an Incidence of 2% or More Among Oral Olanzapine-

Treated Patients in Short-Term Combination Trials
adverse events that occurred in 2% or more of patients treated with the combination of
olanzapine (doses ≥5 mg/day) and lithium or valproate and with incidence greater than lithium or
valproate alone who participated in the acute phase of placebo-controlled combination trials.
Table 2
Incidence in Short-Term, Placebo-Controlled Combination Clinical Trials1
with Oral Olanzapine
Olanzapine with Placebo with
lithium or valproate lithium or valproate
Body as a Whole
Asthenia 18 13
Back pain 8 4
Accidental injury 4 2
Chest pain 3 2
Hypertension 2 1
Digestive System
Dry mouth 32 9
Thirst 10 6
Constipation 8 4
Increased salivation 6 2
Metabolic and Nutritional Disorders
Weight gain 26 7
Peripheral edema 6 4
Edema 2 1
Nervous System
21
Somnolence 52 27
Tremor 23 13
Depression 18 17
Dizziness 14 7
Speech disorder 7 1
Amnesia 5 2
Paresthesia 5 2
Apathy 4 3
Confusion 4 1
Euphoria 3 2
Incoordination 2 0
Respiratory System
Pharyngitis 4 1
Dyspnea 3 1
Skin and Appendages
Sweating 3 1
Acne 2 0
Dry skin 2 0
Special Senses
Amblyopia 9 5
Abnormal vision 2 0
Urogenital System
Dysmenorrhea2 2 0
Vaginitis2 2 0
1
Events reported by at least 2% of patients treated with olanzapine, except the following events which had an
incidence equal to or less than placebo: abdominal pain, abnormal dreams, abnormal ejaculation, agitation,
akathisia, anorexia, anxiety, arthralgia, cough increased, diarrhea, dyspepsia, emotional lability, fever, flatulence,
flu syndrome, headache, hostility, insomnia, libido decreased, libido increased, menstrual disorder (denominator
used was for females only [olanzapine, N=128; placebo, N=51]), myalgia, nausea, nervousness, pain, paranoid
reaction, personality disorder, rash, rhinitis, sleep disorder, thinking abnormal, vomiting.
2
Denominator used was for females only (olanzapine, N=128; placebo, N=51).
For specific information about the adverse reactions observed with lithium or valproate, refer
to the ADVERSE REACTIONS section of the package inserts for these other products.
Adverse Events Occurring at an Incidence of 1% or More Among Intramuscular
Olanzapine for Injection-Treated Patients in Short-Term, Placebo-Controlled Trials
adverse events that occurred in 1% or more of patients treated with intramuscular olanzapine for
injection (dose range of 2.5-10 mg/injection) and with incidence greater than placebo who
participated in the short-term, placebo-controlled trials in agitated patients with schizophrenia or
bipolar mania.
Table 3
Incidence in Short-Term (24 Hour), Placebo-Controlled Clinical Trials
with Intramuscular Olanzapine for Injection
in Agitated Patients with Schizophrenia or Bipolar Mania1
Olanzapine Placebo
Body as a Whole
Asthenia 2 1
22
Hypotension 2 0
Nervous System
Somnolence 6 3
Dizziness 4 2
Tremor 1 0
1
Events reported by at least 1% of patients treated with olanzapine for injection, except the following events which
had an incidence equal to or less than placebo: agitation, anxiety, dry mouth, headache, hypertension, insomnia,
nervousness.
Dose Dependency of Adverse Events in Short-Term, Placebo-Controlled Trials

Extrapyramidal Symptoms — The following table enumerates the percentage of patients with
treatment-emergent extrapyramidal symptoms as assessed by categorical analyses of formal
rating scales during acute therapy in a controlled clinical trial comparing oral olanzapine at
3 fixed doses with placebo in the treatment of schizophrenia.
Treatment-Emergent Extrapyramidal Symptoms Assessed by Rating Scales Incidence

in a Fixed Dosage Range, Placebo-Controlled Clinical Trial
of Oral Olanzapine in Schizophrenia — Acute Phase*
Olanzapine Olanzapine Olanzapine
Placebo 5 ± 2.5 mg/day 10 ± 2.5 mg/day 15 ± 2.5 mg/day
Parkinsonism1 15 14 12 14
Akathisia2 23 16 19 27
* No statistically significant differences.
1
Percentage of patients with a Simpson-Angus Scale total score >3.
2
Percentage of patients with a Barnes Akathisia Scale global score ≥2.
The following table enumerates the percentage of patients with treatment-emergent

extrapyramidal symptoms as assessed by spontaneously reported adverse events during acute
therapy in the same controlled clinical trial comparing olanzapine at 3 fixed doses with placebo
in the treatment of schizophrenia.
Treatment-Emergent Extrapyramidal Symptoms Assessed by Adverse Events Incidence

in a Fixed Dosage Range, Placebo-Controlled Clinical Trial
of Oral Olanzapine in Schizophrenia — Acute Phase
Placebo 5 ± 2.5 mg/day 10 ± 2.5 mg/day 15 ± 2.5 mg/day
(N=68) (N=65) (N=64) (N=69)
Dystonic events1 1 3 2 3
Parkinsonism events2 10 8 14 20
Akathisia events3 1 5 11* 10*
Dyskinetic events4 4 0 2 1
Residual events5 1 2 5 1
Any extrapyramidal event 16 15 25 32*
23
* Statistically significantly different from placebo.

1
Patients with the following COSTART terms were counted in this category: dystonia, generalized spasm, neck
rigidity, oculogyric crisis, opisthotonos, torticollis.
2
Patients with the following COSTART terms were counted in this category: akinesia, cogwheel rigidity,
extrapyramidal syndrome, hypertonia, hypokinesia, masked facies, tremor.
3
Patients with the following COSTART terms were counted in this category: akathisia, hyperkinesia.
4
Patients with the following COSTART terms were counted in this category: buccoglossal syndrome,
choreoathetosis, dyskinesia, tardive dyskinesia.
5
Patients with the following COSTART terms were counted in this category: movement disorder, myoclonus,
twitching.

extrapyramidal symptoms as assessed by categorical analyses of formal rating scales during
controlled clinical trials comparing fixed doses of intramuscular olanzapine for injection with
placebo in agitation. Patients in each dose group could receive up to three injections during the
trials (see CLINICAL EFFICACY DATA). Patient assessments were conducted during the
24 hours following the initial dose of intramuscular olanzapine for injection. There were no
statistically significant differences from placebo.
Treatment-Emergent Extrapyramidal Symptoms Assessed by Rating Scales Incidence

in a Fixed Dose, Placebo-Controlled Clinical Trial
of Intramuscular Olanzapine for Injection
in Agitated Patients with Schizophrenia*
Olanzapine Olanzapine Olanzapine Olanzapine
IM IM IM IM
Placebo 2.5 mg 5 mg 7.5 mg 10 mg
Parkinsonism1 0 0 0 0 3
Akathisia2 0 0 5 0 0
1
Percentage of patients with a Simpson-Angus total score >3.
2
Percentage of patients with a Barnes Akathisia Scale global score ≥2.

extrapyramidal symptoms as assessed by spontaneously reported adverse events in the same
controlled clinical trial comparing fixed doses of intramuscular olanzapine for injection with
placebo in agitated patients with schizophrenia. There were no statistically significant differences
from placebo.
Treatment-Emergent Extrapyramidal Symptoms Assessed by Adverse Events Incidence

in a Fixed Dose, Placebo-Controlled Clinical Trial
of Intramuscular Olanzapine for Injection
in Agitated Patients with Schizophrenia*
Olanzapine Olanzapine Olanzapine Olanzapine
IM IM IM IM
Placebo 2.5 mg 5 mg 7.5 mg 10 mg
(N=45) (N=48) (N=45) (N=46) (N=46)
Dystonic events1 0 0 0 0 0
Parkinsonism events2 0 4 2 0 0
Akathisia events3 0 2 0 0 0
24
Dyskinetic events4 0 0 0 0 0
Residual events5 0 0 0 0 0
Any extrapyramidal event 0 4 2 0 0
1
Patients with the following COSTART terms were counted in this category: dystonia, generalized spasm, neck
rigidity, oculogyric crisis, opisthotonos, torticollis.
2
Patients with the following COSTART terms were counted in this category: akinesia, cogwheel rigidity,
extrapyramidal syndrome, hypertonia, hypokinesia, masked facies, tremor.
3
Patients with the following COSTART terms were counted in this category: akathisia, hyperkinesia.
4
Patients with the following COSTART terms were counted in this category: buccoglossal syndrome,
choreoathetosis, dyskinesia, tardive dyskinesia.
5
Patients with the following COSTART terms were counted in this category: movement disorder, myoclonus,
twitching.
Other Adverse Events — The following table addresses dose relatedness for other adverse
events using data from a schizophrenia trial involving fixed dosage ranges of oral olanzapine. It
enumerates the percentage of patients with treatment-emergent adverse events for the
three fixed-dose range groups and placebo. The data were analyzed using the Cochran-Armitage
test, excluding the placebo group, and the table includes only those adverse events for which
there was a statistically significant trend.

Adverse Event Placebo 5 ± 2.5 mg/day 10 ± 2.5 mg/day 15 ± 2.5 mg/day
(N=68) (N=65) (N=64) (N=69)
Asthenia 15 8 9 20
Dry mouth 4 3 5 13
Nausea 9 0 2 9
Somnolence 16 20 30 39
Tremor 3 0 5 7
Additional Findings
In a single 8-week randomized, double-blind, fixed-dose study comparing 10 (N=199),
20 (N=200) and 40 (N=200) mg/day of olanzapine in patients with schizophrenia or
schizoaffective disorder, statistically significant differences among 3 dose groups were observed
for the following safety outcomes: weight gain, prolactin elevation, fatigue and dizziness. Mean
baseline to endpoint increase in weight (10 mg/day: 1.9 kg; 20 mg/day: 2.3 kg; 40 mg/day: 3 kg)
was observed with significant differences between 10 vs 40 mg/day. Incidence of
treatment-emergent prolactin elevation >24.2 ng/mL (female) or >18.77 ng/mL (male) at any
time during the trial (10 mg/day: 31.2%; 20 mg/day: 42.7%; 40 mg/day: 61.1%) with significant
differences between 10 vs 40 mg/day and 20 vs 40 mg/day; fatigue (10 mg/day: 1.5%;
20 mg/day: 2.1%; 40 mg/day: 6.6%) with significant differences between 10 vs 40 and 20 vs
40 mg/day; and dizziness (10 mg/day: 2.6%; 20 mg/day: 1.6%; 40 mg/day: 6.6%) with
significant differences between 20 vs 40 mg, was observed.
Additional Findings Observed in Clinical Trials
The following findings are based on clinical trials.
Vital Sign Changes — Oral olanzapine was associated with orthostatic hypotension and
tachycardia in clinical trials. Intramuscular olanzapine for injection was associated with
bradycardia, hypotension, and tachycardia in clinical trials (see PRECAUTIONS).
25
Weight Gain — In placebo-controlled, 6-week studies, weight gain was reported in 5.6% of
olanzapine patients compared to 0.8% of placebo patients. Olanzapine patients gained an average
of 2.8 kg, compared to an average 0.4 kg weight loss in placebo patients; 29% of olanzapine
patients gained greater than 7% of their baseline weight, compared to 3% of placebo patients. A
categorization of patients at baseline on the basis of body mass index (BMI) revealed a
significantly greater effect in patients with low BMI compared to normal or overweight patients;
nevertheless, weight gain was greater in all 3 olanzapine groups compared to the placebo group.
During long-term continuation therapy with olanzapine (238 median days of exposure), 56% of
olanzapine patients met the criterion for having gained greater than 7% of their baseline weight.
Average weight gain during long-term therapy was 5.4 kg.
Laboratory Changes — An assessment of the premarketing experience for olanzapine revealed
an association with asymptomatic increases in SGPT, SGOT, and GGT (see PRECAUTIONS).
Olanzapine administration was also associated with increases in serum prolactin (see
PRECAUTIONS), with an asymptomatic elevation of the eosinophil count in 0.3% of patients,
and with an increase in CPK.
Given the concern about neutropenia associated with other psychotropic compounds and the
finding of leukopenia associated with the administration of olanzapine in several animal models
(see ANIMAL TOXICOLOGY), careful attention was given to examination of hematologic
parameters in premarketing studies with olanzapine. There was no indication of a risk of
clinically significant neutropenia associated with olanzapine treatment in the premarketing
database for this drug.
In clinical trials among olanzapine-treated patients with random triglyceride levels of
<150 mg/dL at baseline (N=659), 0.5% of patients experienced triglyceride levels of
≥500 mg/dL anytime during the trials. In these same trials, olanzapine-treated patients (N=1185)
had a mean increase of 20 mg/dL in triglycerides from a mean baseline value of 175 mg/dL.
In placebo-controlled trials, olanzapine-treated patients with random cholesterol levels of
<200 mg/dL at baseline (N=1034) experienced cholesterol levels of ≥240 mg/dL anytime during
the trials more often than placebo-treated patients (N=602) (3.6% vs 2.2%, respectively). In these
same trials, olanzapine-treated patients (N=2528) had a mean increase of 0.4 mg/dL in
cholesterol from a mean baseline value of 203 mg/dL, which was significantly different
compared to placebo-treated patients (N=1415) with a mean decrease of 4.6 mg/dL from a mean
baseline value of 203 mg/dL.
ECG Changes — Between-group comparisons for pooled placebo-controlled trials revealed no
statistically significant olanzapine/placebo differences in the proportions of patients experiencing
potentially important changes in ECG parameters, including QT, QTc, and PR intervals.
Olanzapine use was associated with a mean increase in heart rate of 2.4 beats per minute
compared to no change among placebo patients. This slight tendency to tachycardia may be
related to olanzapine’s potential for inducing orthostatic changes (see PRECAUTIONS).
Other Adverse Events Observed During the Clinical Trial Evaluation of
Olanzapine
Following is a list of terms that reflect treatment-emergent adverse events reported by patients
treated with oral olanzapine (at multiple doses ≥1 mg/day) in clinical trials (8661 patients,
4165 patient-years of exposure). This listing may not include those events already listed in
previous tables or elsewhere in labeling, those events for which a drug cause was remote, those
event terms which were so general as to be uninformative, and those events reported only once
or twice which did not have a substantial probability of being acutely life-threatening.
26
Events are further categorized by body system and listed in order of decreasing frequency
according to the following definitions: frequent adverse events are those occurring in at least
1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials
appear in this listing); infrequent adverse events are those occurring in 1/100 to 1/1000 patients;
rare events are those occurring in fewer than 1/1000 patients.
Body as a Whole — Frequent: dental pain and flu syndrome; Infrequent: abdomen enlarged,
chills, face edema, intentional injury, malaise, moniliasis, neck pain, neck rigidity, pelvic pain,
photosensitivity reaction, and suicide attempt; Rare: chills and fever, hangover effect, and
sudden death.
Cardiovascular System — Frequent: hypotension; Infrequent: atrial fibrillation, bradycardia,
cerebrovascular accident, congestive heart failure, heart arrest, hemorrhage, migraine, pallor,
palpitation, vasodilatation, and ventricular extrasystoles; Rare: arteritis, heart failure, and
pulmonary embolus.
Digestive System — Frequent: flatulence, increased salivation, and thirst;
Infrequent: dysphagia, esophagitis, fecal impaction, fecal incontinence, gastritis, gastroenteritis,
gingivitis, hepatitis, melena, mouth ulceration, nausea and vomiting, oral moniliasis, periodontal
abscess, rectal hemorrhage, stomatitis, tongue edema, and tooth caries; Rare: aphthous
stomatitis, enteritis, eructation, esophageal ulcer, glossitis, ileus, intestinal obstruction, liver fatty
deposit, and tongue discoloration.
Endocrine System — Infrequent: diabetes mellitus; Rare: diabetic acidosis and goiter.
Hemic and Lymphatic System — Infrequent: anemia, cyanosis, leukocytosis, leukopenia,
lymphadenopathy, and thrombocytopenia; Rare: normocytic anemia and thrombocythemia.
Metabolic and Nutritional Disorders — Infrequent: acidosis, alkaline phosphatase increased,
bilirubinemia, dehydration, hypercholesteremia, hyperglycemia, hyperlipemia, hyperuricemia,
hypoglycemia, hypokalemia, hyponatremia, lower extremity edema, and upper extremity edema;
Rare: gout, hyperkalemia, hypernatremia, hypoproteinemia, ketosis, and water intoxication.
Musculoskeletal System — Frequent: joint stiffness and twitching; Infrequent: arthritis,
arthrosis, leg cramps, and myasthenia; Rare: bone pain, bursitis, myopathy, osteoporosis, and
rheumatoid arthritis.
Nervous System — Frequent: abnormal dreams, amnesia, delusions, emotional lability,
euphoria, manic reaction, paresthesia, and schizophrenic reaction; Infrequent: akinesia, alcohol
misuse, antisocial reaction, ataxia, CNS stimulation, cogwheel rigidity, delirium, dementia,
depersonalization, dysarthria, facial paralysis, hypesthesia, hypokinesia, hypotonia,
incoordination, libido decreased, libido increased, obsessive compulsive symptoms, phobias,
somatization, stimulant misuse, stupor, stuttering, tardive dyskinesia, vertigo, and withdrawal
syndrome; Rare: circumoral paresthesia, coma, encephalopathy, neuralgia, neuropathy,
nystagmus, paralysis, subarachnoid hemorrhage, and tobacco misuse.
Respiratory System — Frequent: dyspnea; Infrequent: apnea, asthma, epistaxis, hemoptysis,
hyperventilation, hypoxia, laryngitis, and voice alteration; Rare: atelectasis, hiccup,
hypoventilation, lung edema, and stridor.
Skin and Appendages — Frequent: sweating; Infrequent: alopecia, contact dermatitis, dry
skin, eczema, maculopapular rash, pruritus, seborrhea, skin discoloration, skin ulcer, urticaria,
and vesiculobullous rash; Rare: hirsutism and pustular rash.
Special Senses — Frequent: conjunctivitis; Infrequent: abnormality of accommodation,
blepharitis, cataract, deafness, diplopia, dry eyes, ear pain, eye hemorrhage, eye inflammation,
eye pain, ocular muscle abnormality, taste perversion, and tinnitus; Rare: corneal lesion,
27
glaucoma, keratoconjunctivitis, macular hypopigmentation, miosis, mydriasis, and pigment

deposits lens.
Urogenital System — Frequent: vaginitis*; Infrequent: abnormal ejaculation*, amenorrhea*,
breast pain, cystitis, decreased menstruation*, dysuria, female lactation*, glycosuria,
gynecomastia, hematuria, impotence*, increased menstruation*, menorrhagia*, metrorrhagia*,
polyuria, premenstrual syndrome*, pyuria, urinary frequency, urinary retention, urinary urgency,
urination impaired, uterine fibroids enlarged*, and vaginal hemorrhage*; Rare: albuminuria,
breast enlargement, mastitis, and oliguria.
* Adjusted for gender.
Following is a list of terms that reflect treatment-emergent adverse events reported by patients
treated with intramuscular olanzapine for injection (at one or more doses ≥2.5 mg/injection) in
clinical trials (722 patients). This listing may not include those events already listed in previous
tables or elsewhere in labeling, those events for which a drug cause was remote, those event
terms which were so general as to be uninformative, and those events reported only once which
did not have a substantial probability of being acutely life-threatening.
Events are further categorized by body system and listed in order of decreasing frequency
according to the following definitions: frequent adverse events are those occurring in at least
1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials
appear in this listing); infrequent adverse events are those occurring in 1/100 to 1/1000 patients.
Body as a Whole — Frequent: injection site pain; Infrequent: abdominal pain and fever.
Cardiovascular System — Infrequent: AV block, heart block, and syncope.
Digestive System — Infrequent: diarrhea and nausea.
Hemic and Lymphatic System — Infrequent: anemia.
Metabolic and Nutritional Disorders — Infrequent: creatine phosphokinase increased,
dehydration, and hyperkalemia.
Musculoskeletal System — Infrequent: twitching.
Nervous System — Infrequent: abnormal gait, akathisia, articulation impairment, confusion,
and emotional lability.
Skin and Appendages — Infrequent: sweating.
Postintroduction Reports
Adverse events reported since market introduction that were temporally (but not necessarily
causally) related to ZYPREXA therapy include the following: allergic reaction
(e.g., anaphylactoid reaction, angioedema, pruritus or urticaria), diabetic coma, jaundice,
neutropenia, pancreatitis, priapism, rhabdomyolysis, and venous thromboembolic events
(including pulmonary embolism and deep venous thrombosis). Random cholesterol levels of
≥240 mg/dL and random triglyceride levels of ≥1000 mg/dL have been reported.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class
Olanzapine is not a controlled substance.
Physical and Psychological Dependence
In studies prospectively designed to assess abuse and dependence potential, olanzapine was
shown to have acute depressive CNS effects but little or no potential of abuse or physical
dependence in rats administered oral doses up to 15 times the maximum recommended human
28
daily oral dose (20 mg) and rhesus monkeys administered oral doses up to 8 times the maximum
recommended human daily oral dose on a mg/m2 basis.
Olanzapine has not been systematically studied in humans for its potential for abuse, tolerance,
or physical dependence. While the clinical trials did not reveal any tendency for any
drug-seeking behavior, these observations were not systematic, and it is not possible to predict
on the basis of this limited experience the extent to which a CNS-active drug will be misused,
diverted, and/or abused once marketed. Consequently, patients should be evaluated carefully for
a history of drug abuse, and such patients should be observed closely for signs of misuse or
abuse of olanzapine (e.g., development of tolerance, increases in dose, drug-seeking behavior).
OVERDOSAGE
Human Experience
In premarketing trials involving more than 3100 patients and/or normal subjects, accidental or
intentional acute overdosage of olanzapine was identified in 67 patients. In the patient taking the
largest identified amount, 300 mg, the only symptoms reported were drowsiness and slurred
speech. In the limited number of patients who were evaluated in hospitals, including the patient
taking 300 mg, there were no observations indicating an adverse change in laboratory analytes or
ECG. Vital signs were usually within normal limits following overdoses.
In postmarketing reports of overdose with olanzapine alone, symptoms have been reported in
the majority of cases. In symptomatic patients, symptoms with ≥10% incidence included
agitation/aggressiveness, dysarthria, tachycardia, various extrapyramidal symptoms, and reduced
level of consciousness ranging from sedation to coma. Among less commonly reported
symptoms were the following potentially medically serious events: aspiration, cardiopulmonary
arrest, cardiac arrhythmias (such as supraventricular tachycardia and one patient experiencing
sinus pause with spontaneous resumption of normal rhythm), delirium, possible neuroleptic
malignant syndrome, respiratory depression/arrest, convulsion, hypertension, and hypotension.
Eli Lilly and Company has received reports of fatality in association with overdose of olanzapine
alone. In one case of death, the amount of acutely ingested olanzapine was reported to be
possibly as low as 450 mg; however, in another case, a patient was reported to survive an acute
olanzapine ingestion of 1500 mg.
Overdosage Management
The possibility of multiple drug involvement should be considered. In case of acute
overdosage, establish and maintain an airway and ensure adequate oxygenation and ventilation,
which may include intubation. Gastric lavage (after intubation, if patient is unconscious) and
administration of activated charcoal together with a laxative should be considered. The
possibility of obtundation, seizures, or dystonic reaction of the head and neck following overdose
may create a risk of aspiration with induced emesis. Cardiovascular monitoring should
commence immediately and should include continuous electrocardiographic monitoring to detect
possible arrhythmias.
There is no specific antidote to olanzapine. Therefore, appropriate supportive measures should
be initiated. Hypotension and circulatory collapse should be treated with appropriate measures
such as intravenous fluids and/or sympathomimetic agents. (Do not use epinephrine, dopamine,
or other sympathomimetics with beta-agonist activity, since beta stimulation may worsen
hypotension in the setting of olanzapine-induced alpha blockade.) Close medical supervision and
monitoring should continue until the patient recovers.
29
DOSAGE AND ADMINISTRATION

Schizophrenia
Usual Dose — 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. The safety of doses above
20 mg/day has not been evaluated in clinical trials.
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 CLINICAL PHARMACOLOGY; also see Use in Patients with Concomitant
Illness and Drug Interactions under PRECAUTIONS). When indicated, dose escalation should
be performed with caution in these patients.
Maintenance Treatment — While there is no body of evidence available to answer the question
of how long the patient treated with olanzapine should remain on it, the effectiveness of oral
olanzapine, 10 mg/day to 20 mg/day, in maintaining treatment response in schizophrenic patients
who had been stable on ZYPREXA for approximately 8 weeks and were then followed for a
period of up to 8 months has been demonstrated in a placebo-controlled trial (see CLINICAL
EFFICACY DATA). Patients should be periodically reassessed to determine the need for
maintenance treatment with appropriate dose.
Bipolar Disorder
Usual Monotherapy Dose — Oral olanzapine should be administered on a once-a-day schedule
without regard to meals, generally beginning with 10 or 15 mg. Dosage adjustments, if indicated,
should generally occur at intervals of not less than 24 hours, reflecting the procedures in the
placebo-controlled trials. When dosage adjustments are necessary, dose increments/decrements
of 5 mg QD are recommended.
Short-term (3-4 weeks) antimanic efficacy was demonstrated in a dose range of 5 mg to
20 mg/day in clinical trials. The safety of doses above 20 mg/day has not been evaluated in
clinical trials.
Maintenance Monotherapy — The benefit of maintaining bipolar patients on monotherapy
with oral ZYPREXA at a dose of 5 to 20 mg/day, after achieving a responder status for an
average duration of two weeks, was demonstrated in a controlled trial (see CLINICAL
EFFICACY DATA). The physician who elects to use ZYPREXA for extended periods should
periodically re-evaluate the long-term usefulness of the drug for the individual patient.
Bipolar Mania Usual Dose in Combination with Lithium or Valproate — When administered
in combination with lithium or valproate, oral olanzapine dosing should generally begin with
10 mg once-a-day without regard to meals.
30
Short-term (6 weeks) antimanic efficacy was demonstrated in a dose range of 5 mg to

20 mg/day in clinical trials. The safety of doses above 20 mg/day has not been evaluated in
clinical trials.
Dosing in Special Populations — See Dosing in Special Populations under DOSAGE AND
ADMINISTRATION, Schizophrenia.
Administration of ZYPREXA ZYDIS (olanzapine orally disintegrating tablets)
After opening sachet, peel back foil on blister. Do not push tablet through foil. Immediately
upon opening the blister, using dry hands, remove tablet and place entire ZYPREXA ZYDIS in
the mouth. Tablet disintegration occurs rapidly in saliva so it can be easily swallowed with or
without liquid.
Usual Dose for Agitated Patients with Schizophrenia or Bipolar Mania — The efficacy of
intramuscular olanzapine for injection in controlling agitation in these disorders was
demonstrated in a dose range of 2.5 mg to 10 mg. The recommended dose in these patients is
10 mg. A lower dose of 5 or 7.5 mg may be considered when clinical factors warrant (see
CLINICAL EFFICACY DATA). If agitation warranting additional intramuscular doses persists
following the initial dose, subsequent doses up to 10 mg may be given. However, the efficacy of
repeated doses of intramuscular olanzapine for injection in agitated patients has not been
systematically evaluated in controlled clinical trials. Also, the safety of total daily doses greater
than 30 mg, or 10 mg injections given more frequently than 2 hours after the initial dose, and
4 hours after the second dose have not been evaluated in clinical trials. Maximal dosing of
intramuscular olanzapine (e.g., three doses of 10 mg administered 2-4 hours apart) may be
associated with a substantial occurrence of significant orthostatic hypotension (see
PRECAUTIONS, Hemodynamic Effects). Thus, it is recommended that patients requiring
subsequent intramuscular injections be assessed for orthostatic hypotension prior to the
administration of any subsequent doses of intramuscular olanzapine for injection. The
administration of an additional dose to a patient with a clinically significant postural change in
systolic blood pressure is not recommended.
If ongoing olanzapine therapy is clinically indicated, oral olanzapine may be initiated in a
range of 5-20 mg/day as soon as clinically appropriate (see Schizophrenia or Bipolar Disorder
under DOSAGE AND ADMINISTRATION).
Intramuscular Dosing in Special Populations — A dose of 5 mg per injection should be
considered for geriatric patients or when other clinical factors warrant. A lower dose of 2.5 mg
per injection should be considered for patients who otherwise might be debilitated, be
predisposed to hypotensive reactions, or be more pharmacodynamically sensitive to olanzapine
(see CLINICAL PHARMACOLOGY; also see Use in Patients with Concomitant Illness and
Drug Interactions under PRECAUTIONS).
Administration of ZYPREXA IntraMuscular
ZYPREXA IntraMuscular is intended for intramuscular use only. Do not administer
intravenously or subcutaneously. Inject slowly, deep into the muscle mass.
Parenteral drug products should be inspected visually for particulate matter and discoloration
prior to administration, whenever solution and container permit.
Directions for preparation of ZYPREXA IntraMuscular with Sterile Water for Injection
Dissolve the contents of the vial using 2.1 mL of Sterile Water for Injection to provide a
solution containing approximately 5 mg/mL of olanzapine. The resulting solution should appear
31
clear and yellow. ZYPREXA IntraMuscular reconstituted with Sterile Water for Injection should
be used immediately (within 1 hour) after reconstitution. Discard any unused portion.
The following table provides injection volumes for delivering various doses of intramuscular
olanzapine for injection reconstituted with Sterile Water for Injection.
Dose, mg Olanzapine Volume of Injection, mL

10 Withdraw total contents of vial
7.5 1.5
5 1
2.5 0.5
Physical Incompatibility Information

ZYPREXA IntraMuscular should be reconstituted only with Sterile Water for Injection.
ZYPREXA IntraMuscular should not be combined in a syringe with diazepam injection because
precipitation occurs when these products are mixed. Lorazepam injection should not be used to
reconstitute ZYPREXA IntraMuscular as this combination results in a delayed reconstitution
time. ZYPREXA IntraMuscular should not be combined in a syringe with haloperidol injection
because the resulting low pH has been shown to degrade olanzapine over time.
HOW SUPPLIED
The ZYPREXA 2.5 mg, 5 mg, 7.5 mg, and 10 mg tablets are white, round, and imprinted in
blue ink with LILLY and tablet number. The 15 mg tablets are elliptical, blue, and debossed with
LILLY and tablet number. The 20 mg tablets are elliptical, pink, and debossed with LILLY and
tablet number. The tablets are available as follows:
TABLET STRENGTH
2.5 mg 5 mg 7.5 mg 10 mg 15 mg 20 mg
Tablet No. 4112 4115 4116 4117 4415 4420
Identification LILLY LILLY LILLY LILLY LILLY LILLY
4112 4115 4116 4117 4415 4420
NDC Codes:
Bottles 30 NDC 0002- NDC 0002- NDC 0002- NDC 0002- NDC 0002- NDC 0002-
4112-30 4115-30 4116-30 4117-30 4415-30 4420-30
Blisters - ID* 100 NDC 0002- NDC 0002- NDC 0002- NDC 0002- NDC 0002- NDC 0002-
4112-33 4115-33 4116-33 4117-33 4415-33 4420-33
Bottles 1000 NDC 0002- NDC 0002- NDC 0002- NDC 0002- NDC 0002- NDC 0002-
4112-04 4115-04 4116-04 4117-04 4415-04 4420-04
* Identi-Dose® (unit dose medication, Lilly).
ZYPREXA ZYDIS (olanzapine orally disintegrating tablets) are yellow, round, and debossed
with the tablet strength. The tablets are available as follows:
ZYPREXA ZYDIS TABLET STRENGTH

Tablets 5 mg 10 mg 15 mg 20 mg
Tablet No. 4453 4454 4455 4456
Debossed 5 10 15 20
NDC Codes:
Dose Pack 30 NDC 0002- NDC 0002- NDC 0002- NDC 0002-
(Child-Resistant) 4453-85 4454-85 4455-85 4456-85
32
ZYPREXA is a registered trademark of Eli Lilly and Company.

ZYDIS is a registered trademark of Catalent Pharma Solutions.
ZYPREXA ZYDIS (olanzapine orally disintegrating tablets) is manufactured for Eli Lilly and
Company by Catalent Pharma Solutions, United Kingdom, SN5 8RU.
ZYPREXA IntraMuscular is available in:

NDC 0002-7597-01 (No. VL7597) - 10 mg vial (1s)
Store ZYPREXA tablets, ZYPREXA ZYDIS, and ZYPREXA IntraMuscular vials (before
reconstitution) at controlled room temperature, 20° to 25°C (68° to 77°F) [see USP].
Reconstituted ZYPREXA IntraMuscular may be stored at controlled room temperature,
20° to 25°C (68° to 77°F) [see USP] for up to 1 hour if necessary. Discard any unused portion
of reconstituted ZYPREXA IntraMuscular. The USP defines controlled room temperature as
a temperature maintained thermostatically that encompasses the usual and customary working
environment of 20° to 25°C (68° to 77°F); that results in a mean kinetic temperature calculated
to be not more than 25°C; and that allows for excursions between 15° and 30°C (59° and 86°F)
that are experienced in pharmacies, hospitals, and warehouses.
Protect ZYPREXA tablets and ZYPREXA ZYDIS from light and moisture. Protect
ZYPREXA IntraMuscular from light, do not freeze.
ANIMAL TOXICOLOGY
In animal studies with olanzapine, the principal hematologic findings were reversible
peripheral cytopenias in individual dogs dosed at 10 mg/kg (17 times the maximum
recommended human daily oral dose on a mg/m2 basis), dose-related decreases in lymphocytes
and neutrophils in mice, and lymphopenia in rats. A few dogs treated with 10 mg/kg developed
reversible neutropenia and/or reversible hemolytic anemia between 1 and 10 months of
treatment. Dose-related decreases in lymphocytes and neutrophils were seen in mice given doses
of 10 mg/kg (equal to 2 times the maximum recommended human daily oral dose on a mg/m2
basis) in studies of 3 months’ duration. Nonspecific lymphopenia, consistent with decreased
body weight gain, occurred in rats receiving 22.5 mg/kg (11 times the maximum recommended
human daily oral dose on a mg/m2 basis) for 3 months or 16 mg/kg (8 times the maximum
recommended human daily oral dose on a mg/m2 basis) for 6 or 12 months. No evidence of bone
marrow cytotoxicity was found in any of the species examined. Bone marrows were
normocellular or hypercellular, indicating that the reductions in circulating blood cells were
probably due to peripheral (non-marrow) factors.
Literature revised August 9, 2007
Eli Lilly and Company
Indianapolis, IN 46285, USA
www.ZYPREXA.com
Copyright © 1997, 2007, Eli Lilly and Company. All rights reserved.
PV 5198 AMP PRINTED IN USA

Zyprexa: Olanzapine Tablets

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1

Olanzapine is a yellow crystalline solid, which is practically insoluble in water.

Olanzapine is extensively distributed throughout the body, with a volume of distribution of

administration of antipsychotic drugs, including olanzapine. Clinical manifestations of NMS are

dependent in vitro, a factor of potential importance if the prescription of these drugs is

Common Treatment-Emergent Adverse Events Associated with the

Common Treatment-Emergent Adverse Events Associated with the

Commonly Observed Adverse Events in Short-Term Combination Trials

Common Treatment-Emergent Adverse Events Associated with the

Adverse Events Occurring at an Incidence of 2% or More Among Oral Olanzapine-

Dose Dependency of Adverse Events in Short-Term, Placebo-Controlled Trials

Treatment-Emergent Extrapyramidal Symptoms Assessed by Rating Scales Incidence

The following table enumerates the percentage of patients with treatment-emergent

Treatment-Emergent Extrapyramidal Symptoms Assessed by Adverse Events Incidence

* Statistically significantly different from placebo.

The following table enumerates the percentage of patients with treatment-emergent

Treatment-Emergent Extrapyramidal Symptoms Assessed by Rating Scales Incidence

The following table enumerates the percentage of patients with treatment-emergent

Treatment-Emergent Extrapyramidal Symptoms Assessed by Adverse Events Incidence

Percentage of Patients Reporting Event

glaucoma, keratoconjunctivitis, macular hypopigmentation, miosis, mydriasis, and pigment

DOSAGE AND ADMINISTRATION

Short-term (6 weeks) antimanic efficacy was demonstrated in a dose range of 5 mg to

Dose, mg Olanzapine Volume of Injection, mL

Physical Incompatibility Information

ZYPREXA ZYDIS TABLET STRENGTH

ZYPREXA is a registered trademark of Eli Lilly and Company.

ZYPREXA IntraMuscular is available in:

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