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).

Posology
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 (see section 5.1).
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 5-20mg/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.
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 (see section 4.4).
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 5mg 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 (see section 4.5).
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 (see sections 4.5 
and 5.2).
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 (see sections 4.4, 4.8, 5.1 and 5.2).
Method of administration
Olanzapine can be given without regard for meals, as absorption is not affected by foo

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 placebo-treated 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 (see section 4.8), 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.
Patients treated with any antipsychotic medicines, including Olanzapine, should be observed for 
signs and symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia, and weakness) 
and patients with diabetes mellitus or with risk factors for diabetes mellitus should be monitored 
regularly for worsening of glucose control. Weight should be monitored regularly, e.g. at 
baseline, 4, 8 and 12 weeks after starting olanzapine treatment and quarterly thereafter.
Lipid alterations
Undesirable alterations in lipids have been observed in olanzapine-treated patients in placebocontrolled clinical trials (see section 4.8). Lipid alterations should be managed as clinically 
appropriate, particularly in dyslipidemic patients and in patients with risk factors for the 
development of lipids disorders. Patients treated with any antipsychotic medicines, including 
Olanzapine, should be monitored regularly for lipids in accordance with utilised antipsychotic 
guidelines, e.g. at baseline, 12 weeks after starting olanzapine treatment and every 5 years 
thereafter.
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 (see section 4.8 and 5.1).
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 non-smokers 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 (see section 4.4).
QTc interval
Caution should be used if olanzapine is being administered concomitantly with medicinal 
products known to increase QTc interval (see section 4.4)

Pregnancy
Teratogenic Effects, 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/m2basis). Gestation was prolonged at 10 mg/kg/day (5 times the maximum recommended human daily oral dose on a mg/m2basis). 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/m2basis). 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.
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.
Non-Teratogenic Effects, Neonates exposed to antipsychotic drugs (including olanzapine), 
during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal 
symptoms following delivery. There have been reports of hypertonia, hypotonia, tremor, 
somnolence, respiratory distress and feeding disorder in these neonates. These complications 
have varied in severity; while in some cases symptoms have been self-limited, in other cases 
neonates have required intensive care unit support and prolonged hospitalization. 
Olanzapine should be used during pregnancy only if the potential benefit justifies the potential 
risk to the fetus.
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 (see section 5.3 for preclinical information).

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 (see section 4.4), glucosuria, increased appetite, 
dizziness, akathisia, parkinsonism, leukopenia, neutropenia (see section 4.4), dyskinesia, 
orthostatic hypotension, anticholinergic effects, transient asymptomatic elevations of hepatic 
aminotransferases (see section 4.4), 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).

¹ clinically 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 can not 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.
⁸In 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.
⁹Adverse event identified from clinical trials in the Olanzapine Integrated Database.
¹⁰As assessed by measured values from clinical trials in the Olanzapine Integrated Database.
11Adverse 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 4-6 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 (see 
section 4.4). 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 short-term 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 and < 1/10)

¹³Following short term treatment (median duration 22 days), weight gain ≥ 7% of the 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.

Olanzapine administered with lithium or valproate resulted in increased levels (10%) of tremor, dry mouth (32% for olanzapine combination vs 9% for placebo), increased appetite (24% vs 8%), increased salivation (6% vs 2%), weight gain (26% vs 7%), dizziness (14% vs 7%), back pain (8% vs 4%), constipation (8% vs 4%). Speech disorder (7% vs 1%) was also reported commonly, amnesia (5% vs 2%), and paresthesia (5% vs 2%).

To report any side effect(s):

• Saudi Arabia:

The National Pharmacovigilance Center (NPC):

Fax: +966-11-205-7662

SFDA Call Center: 19999

E-mail: npc.drug@sfda.gov.sa

Website: https://ade.sfda.gov.sa

• 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 beta-agonist 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.

Pharmacotherapeutic group: Psycholeptics; diazepines, oxazepines, thiazepines and 
oxepines.
ATC code: N05A H03.
Pharmacodynamic effects
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 antipsychotic- and 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-
acidglycoprotein.
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 Ndesmethyl 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 nonelderly. In 44 patients with schizophrenia >65 years of age, dosing from 5 to 20mg/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 (5-20mg) 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.
Pediatric 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 leucocytes in mice and non-specific reductions of circulating

leucocytes 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 [AUC] 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.

Not applicable.

Store below 30°C.

Do not use beyond the expiry date or if the product shows any sign of deterioration.

Two Aluminum- Aluminum blisters of 14 Tablets each, packed in a printed carton with folded leaflet.

No special requirements.