Adults
Olanzapine is indicated for the treatment of schizophrenia.
Olanzapine is effective in maintaining the clinical improvement during continuation therapy in patients
who have shown an initial treatment response.
Olanzapine is indicated for the treatment of moderate to severe manic episode.
In patients whose manic episode has responded to olanzapine treatment, olanzapine is indicated for the
prevention of recurrence in patients with bipolar disorder (see section 5.1).

Adults
Schizophrenia: The recommended starting dose for olanzapine is 10 mg/day.

Manic episode: The starting dose is 15 mg as a single daily dose in monotherapy or 10 mg daily in
combination therapy.
Preventing recurrence in bipolar disorder: The recommended starting dose is 10 mg/day. For patients
who have been receiving olanzapine for treatment of manic episode, continue therapy for preventing
recurrence at the same dose. If a new manic, mixed, or depressive episode occurs, olanzapine
treatment should be continued (with dose optimisation as needed), with supplementary therapy to
treat mood symptoms, as clinically indicated.
During treatment for schizophrenia, manic episode, and recurrence prevention in bipolar disorder,
daily dosage may subsequently be adjusted on the basis of individual clinical status within the range
5-20 mg/day. An increase to a dose greater than the recommended starting dose is advised only after
appropriate clinical reassessment and should generally occur at intervals of not less than 24 hours.
Olanzapine can be given without regard for meals, as absorption is not affected by food. Gradual
tapering of the dose should be considered when discontinuing olanzapine.

Special populations
Elderly
A lower starting dose (5 mg/day) is not routinely indicated but should be considered for those 65 and
over when clinical factors warrant.
Renal and/or hepatic impairment
A lower starting dose (5 mg) should be considered for such patients. In cases of moderate hepatic
insufficiency (cirrhosis, Child-Pugh class A or B), the starting dose should be 5 mg and only
increased with caution.

Smokers
The starting dose and dose range need not be routinely altered for non-smokers relative to smokers.
The metabolism of olanzapine may be induced by smoking. Clinical monitoring is recommended and
an increase of olanzapine dose may be considered if necessary.
When more than one factor is present which might result in slower metabolism (female gender,
geriatric age, non-smoking status), consideration should be given to decreasing the starting dose.
Dose escalation, when indicated, should be conservative in such patients.

In cases where dose increments of 2.5 mg are considered necessary, Olanzapine coated tablets should
be used.
Paediatric population
Olanzapine is not recommended for use in children and adolescents below 18 years of age due to a
lack of data on safety and efficacy. A greater magnitude of weight gain, lipid and prolactin alterations
has been reported in short-term studies of adolescent patients than in studies of adult patients.

During antipsychotic treatment, improvement in the patient's clinical condition may take several days
to some weeks. Patients should be closely monitored during this period.
Dementia-related psychosis and/or behavioural disturbances
Olanzapine is not recommended for use in patients with dementia-related psychosis and/or
behavioural disturbances because of an increase in mortality and the risk of cerebrovascular accident.
In placebo-controlled clinical trials (6-12 weeks duration) of elderly patients (mean age 78 years) with
dementia-related psychosis and/or disturbed behaviours, there was a 2-fold increase in the incidence
of death in olanzapine-treated patients compared to patients treated with placebo (3.5% vs. 1.5%,
respectively). The higher incidence of death was not associated with olanzapine dose (mean daily
dose 4.4 mg) or duration of treatment. Risk factors that may predispose this patient population to
increased mortality include age > 65 years, dysphagia, sedation, malnutrition and dehydration,
pulmonary conditions (e.g., pneumonia, with or without aspiration), or concomitant use of
benzodiazepines. However, the incidence of death was higher in olanzapine-treated than in placebotreated
patients independent of these risk factors.
In the same clinical trials, cerebrovascular adverse events (CVAE e.g., stroke, transient ischaemic
attack), including fatalities, were reported. There was a 3-fold increase in CVAE in patients treated
with olanzapine compared to patients treated with placebo (1.3% vs. 0.4%, respectively). All

olanzapine- and placebo-treated patients who experienced a cerebrovascular event had pre-existing
risk factors. Age > 75 years and vascular/mixed type dementia were identified as risk factors for
CVAE in association with olanzapine treatment. The efficacy of olanzapine was not established in
these trials.
Parkinson's disease
The use of olanzapine in the treatment of dopamine agonist associated psychosis in patients with
Parkinson's disease is not recommended. In clinical trials, worsening of Parkinsonian
symptomatology and hallucinations were reported very commonly and more frequently than with
placebo and olanzapine was not more effective than placebo in the treatment of psychotic symptoms.
In these trials, patients were initially required to be stable on the lowest effective dose of anti-
Parkinsonian medicinal products (dopamine agonist) and to remain on the same anti-Parkinsonian
medicinal products and dosages throughout the study. Olanzapine was started at 2.5 mg/day and
titrated to a maximum of 15 mg/day based on investigator judgement.

Neuroleptic Malignant Syndrome (NMS)
NMS is a potentially life-threatening condition associated with antipsychotic medicinal products.
Rare cases reported as NMS have also been received in association with 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 creatine phosphokinase, myoglobinuria
(rhabdomyolysis), and acute renal failure. If a patient develops signs and symptoms indicative of
NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, all
antipsychotic medicines, including olanzapine must be discontinued.
Hyperglycaemia and diabetes
Hyperglycaemia and/or development or exacerbation of diabetes, occasionally associated with
ketoacidosis or coma, has been reported uncommonly, including some fatal cases (see section 4.8). In
some cases, a prior increase in body weight has been reported, which may be a predisposing factor.
Appropriate clinical monitoring is advisable in accordance with utilised antipsychotic guidelines, e.g.

measuring of blood glucose at baseline, 12 weeks after starting olanzapine treatment and annually
thereafter.
Lipid alterations
Undesirable alterations in lipids have been observed in olanzapine-treated patients in placebocontrolled
clinical trials. Lipid alterations should be managed as clinically appropriate, particularly in
dyslipidemic patients and in patients with risk factors for the development of lipids disorders.
Anticholinergic activity
While olanzapine demonstrated anticholinergic activity in vitro, experience during the clinical trials
revealed a low incidence of related events. However, as clinical experience with olanzapine in
patients with concomitant illness is limited, caution is advised when prescribing for patients with
prostatic hypertrophy, or paralytic ileus and related conditions.

Hepatic function
Transient, asymptomatic elevations of hepatic aminotransferases, ALT, AST have been seen
commonly, especially in early treatment. Caution should be exercised and follow-up organised in
patients with elevated ALT and/or AST, 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 medicines. In cases where hepatitis
(including hepatocellular, cholestatic or mixed liver injury) has been diagnosed, olanzapine treatment
should be discontinued.
Neutropenia
Caution should be exercised in patients with low leukocyte and/or neutrophil counts for any reason, in
patients receiving medicines known to cause neutropenia, in patients with a history of drug-induced
bone marrow depression/toxicity, in patients with bone marrow depression caused by concomitant
illness, radiation therapy or chemotherapy and in patients with hypereosinophilic conditions or with
myeloproliferative disease. Neutropenia has been reported commonly when olanzapine and valproate
are used concomitantly (see section 4.8).

Discontinuation of treatment
Acute symptoms such as sweating, insomnia, tremor, anxiety, nausea, or vomiting have been reported
rarely (≥ 0.01% and < 0.1%) when olanzapine is stopped abruptly.
QT interval
In clinical trials, clinically meaningful QTc prolongations (Fridericia QT correction [QTcF] ≥ 500
milliseconds [msec] at any time post-baseline in patients with baseline QTcF < 500 msec) were
uncommon (0.1% to 1%) in patients treated with olanzapine, with no significant differences in
associated cardiac events compared to placebo. However, caution should be exercised when
olanzapine is prescribed with medicines known to increase QTc interval, especially in the elderly, in
patients with congenital long QT syndrome, congestive heart failure, heart hypertrophy, hypokalaemia
or hypomagnesaemia.
Thromboembolism
Temporal association of olanzapine treatment and venous thromboembolism has been reported
uncommonly (≥ 0.1% and < 1%). A causal relationship between the occurrence of venous
thromboembolism and treatment with olanzapine has not been established. However, since patients
with schizophrenia often present with acquired risk factors for venous thromboembolism, all possible
risk factors of VTE e.g., immobilisation of patients, should be identified and preventive measures
undertaken.

General CNS activity
Given the primary CNS effects of olanzapine, caution should be used when it is taken in combination
with other centrally acting medicines and alcohol. As it exhibits in vitro dopamine antagonism,
olanzapine may antagonise the effects of direct and indirect dopamine agonists.
Seizures
Olanzapine should be used cautiously in patients who have a history of seizures or are subject to
factors which may lower the seizure threshold. Seizures have been reported to occur uncommonly in
patients when treated with olanzapine. In most of these cases, a history of seizures or risk factors for
seizures were reported.

Tardive dyskinesia
In comparator studies of one year or less duration, olanzapine was associated with a statistically
significant lower incidence of treatment-emergent dyskinesia. However, the risk of tardive dyskinesia
increases with long-term exposure, and therefore if signs or symptoms of tardive dyskinesia appear in
a patient on olanzapine, a dose reduction or discontinuation should be considered. These symptoms
can temporally deteriorate or even arise after discontinuation of treatment.
Postural hypotension
Postural hypotension was infrequently observed in the elderly in olanzapine clinical trials. It is
recommended that blood pressure is measured periodically in patients over 65 years.
Sudden cardiac death
In postmarketing reports with olanzapine, the event of sudden cardiac death has been reported in
patients with olanzapine. In a retrospective observational cohort study, the risk of presumed sudden
cardiac death in patients treated with olanzapine was approximately twice the risk in patients not
using antipsychotics. In the study, the risk of olanzapine was comparable to the risk of atypical
antipsychotics included in a pooled analysis.

Paediatric population
Olanzapine is not indicated for use in the treatment of children and adolescents. Studies in patients
aged 13-17 years showed various adverse reactions, including weight gain, changes in metabolic
parameters and increases in prolactin levels.
Lactose
Olanzapine tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the
Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Interaction studies have only been performed in adults.
Potential interactions affecting olanzapine
Since olanzapine is metabolised by CYP1A2, substances that can specifically induce or inhibit this
isoenzyme may affect the pharmacokinetics of olanzapine.
Induction of CYP1A2
The metabolism of olanzapine may be induced by smoking and carbamazepine, which may lead to
reduced olanzapine concentrations. Only slight to moderate increase in olanzapine clearance has been
observed. The clinical consequences are likely to be limited, but clinical monitoring is recommended
and an increase of olanzapine dose may be considered if necessary (see section 4.2).
Inhibition of CYP1A2
Fluvoxamine, a specific CYP1A2 inhibitor, has been shown to significantly inhibit the metabolism of
olanzapine. The mean increase in olanzapine Cmax following fluvoxamine was 54% in female nonsmokers
and 77% in male smokers. The mean increase in olanzapine AUC was 52% and 108%,
respectively. A lower starting dose of olanzapine should be considered in patients who are using
fluvoxamine or any other CYP1A2 inhibitors, such as ciprofloxacin. A decrease in the dose of
olanzapine should be considered if treatment with an inhibitor of CYP1A2 is initiated.
Decreased bioavailability
Activated charcoal reduces the bioavailability of oral olanzapine by 50 to 60% and should be taken at
least 2 hours before or after olanzapine.
Fluoxetine (a CYP2D6 inhibitor), single doses of antacid (aluminium, magnesium) or cimetidine have
not been found to significantly affect the pharmacokinetics of olanzapine.

Potential for olanzapine to affect other medicinal products
Olanzapine may antagonise the effects of direct and indirect dopamine agonists.
Olanzapine does not inhibit the main CYP450 isoenzymes in vitro (e.g., 1A2, 2D6, 2C9, 2C19, 3A4).
Thus, no particular interaction is expected, as verified through in vivo studies, where no inhibition of
metabolism of the following active substances was found: tricyclic antidepressant (representing
mostly CYP2D6 pathway), warfarin (CYP2C9), theophylline (CYP1A2), or diazepam (CYP3A4 and
2C19).
Olanzapine showed no interaction when co-administered with lithium or biperiden.
Therapeutic monitoring of valproate plasma levels did not indicate that valproate dosage adjustment is
required after the introduction of concomitant olanzapine.
General CNS activity
Caution should be exercised in patients who consume alcohol or receive medicinal products that can
cause central nervous system depression.
The concomitant use of olanzapine with anti-Parkinsonian medicinal products in patients with
Parkinson's disease and dementia is not recommended.
QTc interval
Caution should be used if olanzapine is being administered concomitantly with medicinal products
known to increase QTc interval.

Pregnancy Category C
Pregnancy
There are no adequate and well-controlled studies in pregnant women. Patients should be advised to
notify their physician if they become pregnant or intend to become pregnant during treatment with
olanzapine. Nevertheless, because human experience is limited, olanzapine should be used in
pregnancy only if the potential benefit justifies the potential risk to the foetus.

New born infants exposed to antipsychotics (including olanzapine) during the third trimester of
pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that
may vary in severity and duration following delivery. There have been reports of agitation,
hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently,
newborns should be monitored carefully.
Breast-feeding
In a study in breast-feeding, healthy women, olanzapine was excreted in breast milk. Mean infant
exposure (mg/kg) at steady-state was estimated to be 1.8% of the maternal olanzapine dose (mg/kg).
Patients should be advised not to breast-feed an infant if they are taking olanzapine.
Fertility
Effects on fertility are unknown.

No studies on the effects on the ability to drive and use machines have been performed. Because
olanzapine may cause somnolence and dizziness, patients should be cautioned about operating
machinery, including motor vehicles.

Summary of the safety profile
Adults
The most frequently (seen in ≥ 1% of patients) reported adverse reactions associated with the use of
olanzapine in clinical trials were somnolence, weight gain, eosinophilia, elevated prolactin,
cholesterol, glucose and triglyceride levels. glucosuria, increased appetite, dizziness, akathisia,
parkinsonism, leukopenia, neutropenia, dyskinesia, orthostatic hypotension, anticholinergic effects,
transient asymptomatic elevations of hepatic aminotransferases, rash, asthenia, fatigue, pyrexia,
arthralgia, increased alkaline phosphatase, high gamma glutamyltransferase, high uric acid, high
creatine phosphokinase and oedema.

Tabulated list of adverse reactions
The following table lists the adverse reactions and laboratory investigations observed from
spontaneous reporting and in clinical trials. Within each frequency grouping, adverse reactions are
presented in order of decreasing seriousness. The frequency terms listed are defined as follows: Very
common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to
< 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the data available).

1Clinically significant weight gain was observed across all baseline Body Mass Index (BMI)
categories. Following short-term treatment (median duration 47 days), weight gain ≥ 7% of baseline
body weight was very common (22.2%); ≥ 15% was common (4.2%); and ≥ 25% was uncommon
(0.8%). Patients gaining ≥ 7%, ≥ 15% and ≥ 25% of their baseline body weight with long-term
exposure (at least 48 weeks) were very common (64.4%, 31.7% and 12.3% respectively).
2Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were
greater in patients without evidence of lipid dysregulation at baseline.
3Observed for fasting normal levels at baseline (< 5.17 mmol/l) which increased to high (≥ 6.2
mmol/l). Changes in total fasting cholesterol levels from borderline at baseline (≥ 5.17 - < 6.2 mmol/l)
to high (≥ 6.2 mmol/l) were very common.
4Observed for fasting normal levels at baseline (< 5.56 mmol/l) which increased to high (≥ 7 mmol/l).
Changes in fasting glucose from borderline at baseline (≥ 5.56 - < 7 mmol/l) to high (≥ 7 mmol/l)
were very common.
5Observed for fasting normal levels at baseline (< 1.69 mmol/l) which increased to high (≥ 2.26
mmol/l). Changes in fasting triglycerides from borderline at baseline (≥ 1.69 mmol/l - < 2.26 mmol/l)
to high (≥ 2.26 mmol/l) were very common.
6In clinical trials, the incidence of Parkinsonism and dystonia in olanzapine-treated patients was
numerically higher, but not statistically significantly different from placebo. Olanzapine-treated
patients had a lower incidence of Parkinsonism, akathisia and dystonia compared with titrated doses
of haloperidol. In the absence of detailed information on the pre-existing history of individual acute

and tardive extrapyramidal movement disorders, it cannot be concluded at present that olanzapine
produces less tardive dyskinesia and/or other tardive extrapyramidal syndromes.
7Acute symptoms such as sweating, insomnia, tremor, anxiety, nausea and vomiting have been
reported when olanzapine is stopped abruptly.
8 In clinical trials of up to 12 weeks, plasma prolactin concentrations exceeded the upper limit of
normal range in approximately 30% of olanzapine-treated patients with normal baseline prolactin
value. In the majority of these patients the elevations were generally mild, and remained below two
times the upper limit of normal range.
9 Adverse event identified from clinical trials in the Olanzapine Integrated Database.
10 As assessed by measured values from clinical trials in the Olanzapine Integrated Database.
11 Adverse event identified from spontaneous post-marketing reporting with frequency determined
utilising the Olanzapine Integrated Database.
12 Adverse event identified from spontaneous post-marketing reporting with frequency estimated at
the upper limit of the 95% confidence interval utilising the Olanzapine Integrated Database.
Long-term exposure (at least 48 weeks)
The proportion of patients who had adverse, clinically significant changes in weight gain, glucose,
total/LDL/HDL cholesterol or triglycerides increased over time. In adult patients who completed 9-12
months of therapy, the rate of increase in mean blood glucose slowed after approximately 6 months.
Additional information on special populations
In clinical trials in elderly patients with dementia, olanzapine treatment was associated with a higher
incidence of death and cerebrovascular adverse reactions compared to placebo. Very common adverse
reactions associated with the use of olanzapine in this patient group were abnormal gait and falls.
Pneumonia, increased body temperature, lethargy, erythema, visual hallucinations and urinary
incontinence were observed commonly.
In clinical trials in patients with drug-induced (dopamine agonist) psychosis associated with
Parkinson's disease, worsening of Parkinsonian symptomatology and hallucinations were reported
very commonly and more frequently than with placebo.
In one clinical trial in patients with bipolar mania, valproate combination therapy with olanzapine
resulted in an incidence of neutropenia of 4.1%; a potential contributing factor could be high plasma

valproate levels. Olanzapine administered with lithium or valproate resulted in increased levels
(≥10%) of tremor, dry mouth, increased appetite, and weight gain. Speech disorder was also reported
commonly. During treatment with olanzapine in combination with lithium or divalproex, an increase
of ≥ 7% from baseline body weight occurred in 17.4% of patients during acute treatment (up to 6
weeks). Long-term olanzapine treatment (up to 12 months) for recurrence prevention in patients with
bipolar disorder was associated with an increase of ≥7% from baseline body weight in 39.9% of
patients.
Paediatric population
Olanzapine is not indicated for the treatment of children and adolescent patients below 18 years.
Although no clinical studies designed to compare adolescents to adults have been conducted, data
from the adolescent trials were compared to those of the adult trials.
The following table summarises the adverse reactions reported with a greater frequency in adolescent
patients (aged 13-17 years) than in adult patients or adverse reactions only identified during shortterm
clinical trials in adolescent patients. Clinically significant weight gain (≥ 7%) appears to occur
more frequently in the adolescent population compared to adults with comparable exposures. The
magnitude of weight gain and the proportion of adolescent patients who had clinically significant
weight gain were greater with long-term exposure (at least 24 weeks) than with short-term exposure.
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
The frequency terms listed are defined as follows: Very common (≥ 1/10), common (≥ 1/100 to <
1/10).

13Following short-term treatment (median duration 22 days), weight gain ≥ 7% of baseline body
weight (kg) was very common (40.6%); ≥ 15% of baseline body weight was common (7.1%) and ≥
25% was common (2.5%). With long-term exposure (at least 24 weeks), 89.4% gained ≥ 7%, 55.3%
gained ≥ 15% and 29.1% gained ≥ 25% of their baseline body weight.
14Observed for fasting normal levels at baseline (< 1.016 mmol/l) which increased to high (≥ 1.467
mmol/l) and changes in fasting triglycerides from borderline at baseline (≥ 1.016 mmol/l - < 1.467
mmol/l) to high (≥ 1.467 mmol/l).
15Changes in total fasting cholesterol levels from normal at baseline (< 4.39 mmol/l) to high (≥ 5.17
mmol/l) were observed commonly. Changes in total fasting cholesterol levels from borderline at
baseline (≥ 4.39 - < 5.17 mmol/l) to high (≥ 5.17 mmol/l) were very common.
16Elevated plasma prolactin levels were reported in 47.4% of adolescent patients.
To report any side effect(s):
• Saudi Arabia:
The National Pharmacovigilance and Drug Safety Centre (NPC)
Fax: +966-11-205-7662
Call NPC at +966-11-2038222,
Exts: 2317-2356-2353-2354-2334-2340.
Toll free phone: 8002490000
E-mail: npc.drug@sfda.gov.sa
Website: www.sfda.gov.sa/npc
• Other GCC States:
− Please contact the relevant competent authority

Signs and symptoms
Very common symptoms in overdose (> 10% incidence) include tachycardia,
agitation/aggressiveness, dysarthria, various extrapyramidal symptoms, and reduced level of
consciousness ranging from sedation to coma.
Other medically significant sequelae of overdose include delirium, convulsion, coma, possible
neuroleptic malignant syndrome, respiratory depression, aspiration, hypertension or hypotension,
cardiac arrhythmias (<2% of overdose cases), and cardiopulmonary arrest. Fatal outcomes have been
reported for acute overdoses as low as 450 mg, but survival has also been reported following acute
overdose of approximately 2 g of oral olanzapine.
Management
There is no specific antidote for olanzapine. Induction of emesis is not recommended. Standard
procedures for management of overdose may be indicated (i.e., gastric lavage, administration of
activated charcoal). The concomitant administration of activated charcoal was shown to reduce the
oral bioavailability of olanzapine by 50 to 60%.
Symptomatic treatment and monitoring of vital organ function should be instituted according to
clinical presentation, including treatment of hypotension and circulatory collapse and support of
respiratory function. Do not use epinephrine, dopamine, or other sympathomimetic agents with betaagonist
activity, since beta stimulation may worsen hypotension. Cardiovascular monitoring is
necessary to detect possible arrhythmias. Close medical supervision and monitoring should continue
until the patient recovers.

psycholeptics, diazepines, oxazepines, thiazepines and oxepines,
ATC code N05A H03
Olanzapine is an antipsychotic, antimanic, and mood stabilising agent that demonstrates a broad
pharmacologic profile across a number of receptor systems.
In preclinical studies, olanzapine exhibited a range of receptor affinities (Ki <100nM) for serotonin
5HT2A/2C, 5HT3, 5HT6; dopamine D1, D2, D3, D4, D5; cholinergic muscarinic receptors M1-M5;
α1 adrenergic; and histamine H1 receptors. Animal behavioural studies with olanzapine indicated
5HT, dopamine, and cholinergic antagonism, consistent with the receptor-binding profile. Olanzapine
demonstrated a greater in vitro affinity for serotonin 5HT2 than dopamine D2 receptors and greater
5HT2 than D2 activity in in vivo models. Electrophysiological studies demonstrated that olanzapine
selectively reduced the firing of mesolimbic (A10) dopaminergic neurons, while having little effect on
the striatal (A9) pathways involved in motor function. Olanzapine reduced a conditioned avoidance
response, a test indicative of antipsychotic activity, at doses below those producing catalepsy, an
effect indicative of motor side-effects. Unlike some other antipsychotic agents, olanzapine increases
responding in an 'anxiolytic' test.
In a single oral dose (10 mg) Positron Emission Tomography (PET) study in healthy volunteers,
olanzapine produced a higher 5HT2A than dopamine D2 receptor occupancy. In addition, a Single
Photon Emission Computed Tomography (SPECT) imaging study in schizophrenic patients revealed
that olanzapine-responsive patients had lower striatal D2occupancy than some other antipsychoticand
risperidone-responsive patients, while being comparable to clozapine-responsive patients.
Clinical efficacy
In two of two placebo- and two of three comparator-controlled trials with over 2,900 schizophrenic
patients presenting with both positive and negative symptoms, olanzapine was associated with
statistically significantly greater improvements in negative as well as positive symptoms.
In a multinational, double-blind, comparative study of schizophrenia, schizoaffective and related
disorders, which included 1,481 patients with varying degrees of associated depressive symptoms
(baseline mean of 16.6 on the Montgomery-Asberg Depression Rating Scale), a prospective

secondary analysis of baseline to endpoint mood score change demonstrated a statistically significant
improvement (P = 0.001) favouring olanzapine (-6.0) versus haloperidol (-3.1).
In patients with a manic or mixed episode of bipolar disorder, olanzapine demonstrated superior
efficacy to placebo and valproate semisodium (divalproex) in reduction of manic symptoms over 3
weeks. Olanzapine also demonstrated comparable efficacy results to haloperidol in terms of the
proportion of patients in symptomatic remission from mania and depression at 6 and 12 weeks. In a
co-therapy study of patients treated with lithium or valproate for a minimum of 2 weeks, the addition
of olanzapine 10 mg (co-therapy with lithium or valproate) resulted in a greater reduction in
symptoms of mania than lithium or valproate monotherapy after 6 weeks.
In a 12 month recurrence prevention study in manic episode patients who achieved remission on
olanzapine and were then randomised to olanzapine or placebo, olanzapine demonstrated statistically
significant superiority over placebo on the primary endpoint of bipolar recurrence. Olanzapine also
showed a statistically significant advantage over placebo in terms of preventing either recurrence into
mania or recurrence into depression.
In a second 12 month recurrence prevention study in manic episode patients who achieved remission
with a combination of olanzapine and lithium and were then randomised to olanzapine or lithium
alone, olanzapine was statistically non-inferior to lithium on the primary endpoint of bipolar
recurrence (olanzapine 30.0%, lithium 38.3%; P = 0.055).
In an 18 month co-therapy study in manic or mixed episode patients stabilised with olanzapine plus a
mood stabiliser (lithium or valproate), long-term olanzapine co-therapy with lithium or valproate was
not statistically significantly superior to lithium or valproate alone in delaying bipolar recurrence,
defined according to syndromic (diagnostic) criteria.
Paediatric population
Controlled efficacy data in adolescents (ages 13 to 17 years) are limited to short term studies in
schizophrenia (6 weeks) and mania associated with bipolar I disorder (3 weeks), involving less than
200 adolescents. Olanzapine was used as a flexible dose starting with 2.5 and ranging up to 20
mg/day. During treatment with olanzapine, adolescents gained significantly more weight compared
with adults. The magnitude of changes in fasting total cholesterol, LDL cholesterol, triglycerides, and
prolactin (see sections 4.4 and 4.8) were greater in adolescents than in adults. There are no controlled
data on maintenance of effect or long term safety (see sections 4.4 and 4.8). Information on long term
safety is primarily limited to open-label, uncontrolled data.

Absorption
Olanzapine is well absorbed after oral administration, reaching peak plasma concentrations within 5
to 8 hours. The absorption is not affected by food. Absolute oral bioavailability relative to intravenous
administration has not been determined.
Distribution
The plasma protein binding of olanzapine was about 93% over the concentration range of about 7 to
about 1000 ng/ml. Olanzapine is bound predominantly to albumin and α1-acid-glycoprotein.
Biotransformation
Olanzapine is metabolised in the liver by conjugative and oxidative pathways. The major circulating
metabolite is the 10-N-glucuronide, which does not pass the blood brain barrier. Cytochromes P450-
CYP1A2 and P450-CYP2D6 contribute to the formation of the N-desmethyl and 2-hydroxymethyl
metabolites; both exhibited significantly less in vivo pharmacological activity than olanzapine in
animal studies. The predominant pharmacologic activity is from the parent, olanzapine.
Elimination
After oral administration, the mean terminal elimination half-life of olanzapine in healthy subjects
varied on the basis of age and gender.
In healthy elderly (65 and over) versus non-elderly subjects, the mean elimination half-life was
prolonged (51.8 versus 33.8 hours) and the clearance was reduced (17.5 versus 18.2 l/hr). The
pharmacokinetic variability observed in the elderly is within the range for the non-elderly. In 44
patients with schizophrenia >65 years of age, dosing from 5 to 20 mg/day was not associated with any
distinguishing profile of adverse events.
In female versus male subjects, the mean elimination half-life was somewhat prolonged (36.7 versus
32.3 hours) and the clearance was reduced (18.9 versus 27.3 l/hr). However, olanzapine (5-20 mg)
demonstrated a comparable safety profile in female (n = 467) as in male patients (n = 869).
Renal impairment
In renally impaired patients (creatinine clearance <10ml/min) versus healthy subjects, there was no
significant difference in mean elimination half-life (37.7 versus 32.4 hours) or clearance (21.2 versus
25.0 l/hr). A mass balance study showed that approximately 57% of radiolabelled olanzapine
appeared in urine, principally as metabolites.

Smokers
In smoking subjects with mild hepatic dysfunction, mean elimination half-life (39.3 hours) was
prolonged and clearance (18.0 l/hr) was reduced analogous to non-smoking healthy subjects (48.8
hours and 14.1 l/hr, respectively).
In non-smoking versus smoking subjects (males and females), the mean elimination half-life was
prolonged (38.6 versus 30.4 hours) and the clearance was reduced (18.6 versus 27.7 l/hr).
The plasma clearance of olanzapine is lower in elderly versus young subjects, in females versus
males, and in non-smokers versus smokers. However, the magnitude of the impact of age, gender, or
smoking on olanzapine clearance and half-life is small in comparison to the overall variability
between individuals.
In a study of Caucasians, Japanese, and Chinese subjects, there were no differences in the
pharmacokinetic parameters among the three populations.
Paediatric population
Adolescents (ages 13 to 17 years): The pharmacokinetics of olanzapine are similar between
adolescents and adults. In clinical studies, the average olanzapine exposure was approximately 27%
higher in adolescents. Demographic differences between the adolescents and adults include a lower
average body weight and fewer adolescents were smokers. Such factors possibly contribute to the
higher average exposure observed in adolescents.

Acute (single-dose) toxicity
Signs of oral toxicity in rodents were characteristic of potent neuroleptic compounds: hypoactivity,
coma, tremors, clonic convulsions, salivation, and depressed weight gain. The median lethal doses
were approximately 210 mg/kg (mice) and 175 mg/kg (rats). Dogs tolerated single oral doses up to
100 mg/kg without mortality. Clinical signs included sedation, ataxia, tremors, increased heart rate,
laboured respiration, miosis, and anorexia. In monkeys, single oral doses up to 100 mg/kg resulted in
prostration and, at higher doses, semi-consciousness.

Repeated-dose toxicity
In studies up to 3 months duration in mice and up to 1 year in rats and dogs, the predominant effects
were CNS depression, anticholinergic effects, and peripheral haematological disorders. Tolerance
developed to the CNS depression. Growth parameters were decreased at high doses. Reversible
effects consistent with elevated prolactin in rats included decreased weights of ovaries and uterus and
morphologic changes in vaginal epithelium and in mammary gland.
Haematologic toxicity
Effects on haematology parameters were found in each species, including dose-related reductions in
circulating leukocytes in mice and non-specific reductions of circulating leukocytes in rats; however,
no evidence of bone marrow cytotoxicity was found. Reversible neutropenia, thrombocytopenia, or
anaemia developed in a few dogs treated with 8 or 10 mg/kg/day (total olanzapine exposure [area
under the curve] is 12- to 15-fold greater than that of a man given a 12 mg dose). In cytopenic dogs,
there were no adverse effects on progenitor and proliferating cells in the bone marrow.
Reproductive toxicity
Olanzapine had no teratogenic effects. Sedation affected mating performance of male rats. Oestrous
cycles were affected at doses of 1.1 mg/kg (3-times the maximum human dose) and reproduction
parameters were influenced in rats given 3 mg/kg (9-times the maximum human dose). In the
offspring of rats given olanzapine, delays in foetal development and transient decreases in offspring
activity levels were seen.
Mutagenicity
Olanzapine was not mutagenic or clastogenic in a full range of standard tests, which included
bacterial mutation tests and in vitro and in vivo mammalian tests.
Carcinogenicity
Based on the results of studies in mice and rats, it was concluded that olanzapine is not carcinogenic

Lactose Monohydrate
Lactose Monohydrate (Super tab 11 SD)
Microcrystalline Cellulose (Avicel PH112)
Crospovidone (Polyplasdone XL-10)
Magnesium Stearate
Opadry -OY-B-28920
Purified Water

Not applicable.

Do not store above 30°C.

Alu-Alu blister pack
Pack sizes: 3 X 10’s Blister Pack

Any unused product should be disposed of in accordance with local requirements.