Olanzapine Apotex

1 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



2 

1. NAME OF THE MEDICINAL PRODUCT 
 
Olanzapine Apotex 2.5 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains 2.5 mg olanzapine. 
 
Excipient with known effect: Each film-coated tablet contains 63.17 mg lactose. 
 
For the full list of excipients, see section 6.1 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet 
 
White, round, biconvex film-coated tablets engraved ‘APO’ on one side and ‘OLA’ over ‘2.5’ 
on the other side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
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). 
 
4.2 Posology and method of administration 
 
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 5-20 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. 
 



3 

Olanzapine can be given without regards 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 (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 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 (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). 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
Patients with known risk of narrow-angle glaucoma. 
 
4.4 Special warnings and precautions for use 
 
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. 
 



4 

In the same clinical trials, cerebrovascular adverse events (CVAE e.g., stroke, transient ischemic 
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 Apotex, 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 placebo 
controlled 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 Apotex, 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. 



5 

 
Hepatic function 
Transient, asymptomatic elevations of hepatic aminotransferases, alanine transferase (ALT), 
aspartate transferase (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 antagonize 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. 



6 

 
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 sections 4.8 and 5.1). 
 
Lactose 
Olanzapine Apotex film-coated tablets contain lactose. Patients with rare hereditary problems of 
galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not 
take this medicine. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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. 
 



7 

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). 
 
4.6 Fertility, pregnancy and lactation 
 
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. 
 
Newborn 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, 
hypotonis, 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 (see section 5.3 for preclinical information). 
 
4.7 Effects on ability to drive and use machines 
 
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. 
 
4.8 Undesirable effects 
 
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, 



8 

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 available data). 
 
Very common Common Uncommon Rare Not 

known 
Blood and lymphatic system disorders  
 Eosinophilia 

Leukopenia10 
Neutropenia10 

 Thrombocytopenia11  

Immune system disorders  
  Hypersensitivity11   
Metabolism and nutrition disorders  
Weight gain1 Elevated 

cholesterol 
levels2,3 
Elevated glucose 
levels4 
Elevated 
triglyceride 
levels2,5 
Glucosuria  
Increased appetite 

Development or 
exacerbation of 
diabetes occasionally 
associated with 
ketoacidosis or coma, 
including some fatal 
cases (see section 4.4) 
11 

Hypothermia12  

Nervous system disorders  
Somnolence Dizziness 

Akathisia6 
Parkinsonism6 
Dyskinesia6 

Seizures where in most 
cases a history of 
seizures or risk factors 
for seizures were 
reported 11 
 
 
 
Dystonia (including 
oculogyration) 11 
Tardive dyskinesia11 
 
 
Amnesia 9 
 

Dysarthria 

Stuttering11 
Restless legs 
syndrome11 

Neuroleptic 
malignant syndrome 
(see section 4.4)12 
Discontinuation 
symptoms7, 12 
 

 

Cardiac disorders  
  Bradycardia 

QTc prolongation (see 
section 4.4) 

Ventricular 
tachycardia/fibrillatio
n, sudden death (see 

 



9 

section 4.4)11 
Vascular disorders  
Orthostatic 
hypotension10 

 Thromboembolism 
(including pulmonary 
embolism and deep 
vein thrombosis) (see 
section 4.4) 

  

Respiratory, thoracic and mediastinal disorders  
  Epistaxis9   
Gastrointestinal disorders  
 Mild, transient 

anticholinergic 
effects including 
constipation and 
dry mouth 

Abdominal distension9 
Salivary 
hypersecretion11 

Pancreatitis11  

Hepatobiliary disorders  
 Transient, 

asymptomatic 
elevations of 
hepatic 
aminotransferases 
(ALT, AST), 
especially in early 
treatment (see 
section 4.4) 

 Hepatitis (including 
hepatocellular, 
cholestatic or mixed 
liver injury) 11 

 

Skin and subcutaneous tissue disorders  
 Rash Photosensitivity 

reaction 
Alopecia  
 

 Drug 
Reaction 
with 
Eosinophil
ia and 
Systemic 
Symptoms 
(DRESS) 

Musculoskeletal and connective tissue disorders  
 Arthralgia9  Rhabdomyolysis11  
Renal and urinary disorders  
  Urinary incontinence, 

urinary retention 
Urinary hesitation11 

  

Pregnancy, puerperium and perinatal conditions  
    Drug 

withdrawal 
syndrome 
neonatal (see 
section 4.6) 

Reproductive system and breast disorders  
 Erectile 

dysfunction in 
males 
Decreased libido 
in males and 
females 

Amenorrhea 
Breast enlargement 
Galactorrhea in 
females 
Gynaecomastia/breast 
enlargement in males 

Priapism12  

General disorders and administration site conditions  
 Asthenia 

Fatigue 
   



10 

Oedema 
Pyrexia10 

Investigations  
Elevated plasma 
prolactin levels8 

Increased alkaline 
phosphatase10 
High creatine 
phosphokinase11 
High Gamma 
Glutamyltransfera
se10 
High uric acid 10 
 

Increased total 
bilirubin 

  

 
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). 
 
2 Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were 
greater in patients without evidence of lipid dysregulation at baseline. 
 
3 Observed 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. 
 
4 Observed 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.  
 
5 Observed 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. 
 

6 In 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. 
 
7 Acute 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. 
 



11 

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 (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 to 
< 1/10). 
 
Metabolism and nutrition disorders 
Very common: Weight gain13, elevated triglyceride levels14, increased appetite. 
Common: Elevated cholesterol levels15 
Nervous system disorders 
Very common: Sedation (including: hypersomnia, lethargy, somnolence). 
Gastrointestinal disorders 
Common: Dry mouth 
Hepatobiliary disorders 
Very common: Elevations of hepatic aminotransferases (ALT/AST; see section 4.4). 
Investigations  
Very common: Decreased total bilirubin, increased GGT, elevated plasma prolactin levels16. 



12 

 
13 Following 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. 
 
14  Observed 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). 
 
15 Changes 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. 
 
16 Elevated plasma prolactin levels were reported in 47.4% of adolescent patients. 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
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. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: psycholeptics, diazepines, oxazepines, thiazepines and oxepines, 
ATC code N05A H03. 
 
Pharmacodynamic effects 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


13 

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 < 100 nM) for 
serotonin 5 HT2A/2C, 5 HT3, 5 HT6; dopamine D1, D2, D3, D4, D5; cholinergic muscarinic 
receptors M1-M5; α1 adrenergic; and histamine H1 receptors. Animal behavioural studies with 
olanzapine indicated 5 HT, dopamine, and cholinergic antagonism, consistent with the receptor-
binding profile. Olanzapine demonstrated a greater in vitro affinity for serotonin 5 HT2 than 
dopamine D2 receptors and greater 5 HT2 than D2 activity 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 5 HT2A 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 D2 occupancy 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 



14 

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. 
 
5.2 Pharmacokinetic properties 
 
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 metabolized 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 hrs) 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 hrs) 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 < 10 ml/min) versus healthy subjects, there 
was no significant difference in mean elimination half-life (37.7 versus 32.4 hrs) 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. 
 
Hepatic impairment  
A small study of the effect of impaired liver function in 6 subjects with clinically significant (Childs 
Pugh Classification A (n = 5) and B (n = 1)) cirrhosis revealed little effect on the pharmacokinetics of 
orally administered olanzapine (2.5 – 7.5 mg single dose): Subjects with mild to moderate hepatic 
dysfunction had slightly increased systemic clearance and faster elimination half-time compared to 



15 

subjects with no hepatic dysfunction (n = 3). There were more smokers among subjects with cirrhosis 
(4/6; 67 %) than among subjects with no hepatic dysfunction (0/3; 0 %). 
 
Smoking 
In non-smoking versus smoking subjects (males and females), the mean elimination half-life 
was prolonged (38.6 versus 30.4 hrs) 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. 
 
5.3 Preclinical safety data 
 
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, labored 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 [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. 
Estrous 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 



16 

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. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core 
Lactose monohydrate 
Microcrystalline cellulose 
Maize starch 
Magnesium stearate 
 
Tablet coat 
Hypromellose 
Hydroxypropylcellulose 
Macrogol 8000 
Titanium dioxide (E171) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 years 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
Aluminium/aluminium blister strips in cartons of 28 film-coated tablets per carton. 
 
Not all pack sizes may be marketed. 
  
6.6 Special precautions for disposal 
 
No special requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Apotex Europe B.V.  
Archimedesweg 2,  
2333 CN, Leiden, 
The Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 



17 

EU/1/10/635/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
10.06.2010 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 

http://www.ema.europa.eu/


18 

1. NAME OF THE MEDICINAL PRODUCT 
 
Olanzapine Apotex 5 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains 5 mg olanzapine. 
 
Excipient with known effect: Each film-coated tablet contains 126.34 mg lactose. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet 
 
White, round biconvex film-coated tablets engraved ‘APO’ on one side and ‘OLA’ over ‘5’ on 
the other side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
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). 
 
4.2 Posology and method of administration 
 
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 5-20 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. 
 



19 

Olanzapine can be given without regards 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 (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 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 (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). 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
Patients with known risk of narrow-angle glaucoma. 
 
4.4 Special warnings and precautions for use 
 
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. 
 



20 

In the same clinical trials, cerebrovascular adverse events (CVAE e.g., stroke, transient ischemic 
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 Apotex, 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 placebo 
controlled 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 Apotex, 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. 



21 

 
Hepatic function 
Transient, asymptomatic elevations of hepatic aminotransferases, alanine transferase (ALT), 
aspartate transferase (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 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 antagonize 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. 



22 

 
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 sections 4.8 and 5.1). 
 
Lactose 
Olanzapine Apotex film-coated tablets contain lactose. Patients with rare hereditary problems of 
galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not 
take this medicine. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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. 
 



23 

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). 
 
4.6 Fertility, pregnancy and lactation 
 
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. 
 
Newborn 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, 
hypotonis, 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 (see section 5.3 for preclinical information). 
 
4.7 Effects on ability to drive and use machines 
 
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. 
 
4.8 Undesirable effects 
 
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, 



24 

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 available data). 
 
Very common Common Uncommon Rare Not 

known 
Blood and lymphatic system disorders  
 Eosinophilia 

Leukopenia10 
Neutropenia10 

 Thrombocytopenia11  

Immune system disorders  
  Hypersensitivity11   
Metabolism and nutrition disorders  
Weight gain1 Elevated 

cholesterol 
levels2,3 
Elevated glucose 
levels4 
Elevated 
triglyceride 
levels2,5 
Glucosuria  
Increased appetite 

Development or 
exacerbation of 
diabetes occasionally 
associated with 
ketoacidosis or coma, 
including some fatal 
cases (see section 4.4) 
11 

Hypothermia12  

Nervous system disorders  
Somnolence Dizziness 

Akathisia6 
Parkinsonism6 
Dyskinesia6 

Seizures where in most 
cases a history of 
seizures or risk factors 
for seizures were 
reported 11 
 
 
 
Dystonia (including 
oculogyration) 11 
Tardive dyskinesia11 
 
 
Amnesia 9 
 

Dysarthria 

Stuttering11 
Restless legs 
syndrome11 

Neuroleptic 
malignant syndrome 
(see section 4.4)12 
Discontinuation 
symptoms7, 12 
 

 

Cardiac disorders  
  Bradycardia 

QTc prolongation (see 
section 4.4) 

Ventricular 
tachycardia/fibrillatio
n, sudden death (see 
section 4.4)11 

 



25 

Vascular disorders  
Orthostatic 
hypotension10 

 Thromboembolism 
(including pulmonary 
embolism and deep 
vein thrombosis) (see 
section 4.4) 

  

Respiratory, thoracic and mediastinal disorders  
  Epistaxis9   
Gastrointestinal disorders  
 Mild, transient 

anticholinergic 
effects including 
constipation and 
dry mouth 

Abdominal distension9 
Salivary 
hypersecretion11 

Pancreatitis11  

Hepatobiliary disorders  
 Transient, 

asymptomatic 
elevations of 
hepatic 
aminotransferases 
(ALT, AST), 
especially in early 
treatment (see 
section 4.4) 

 Hepatitis (including 
hepatocellular, 
cholestatic or mixed 
liver injury) 11 

 

Skin and subcutaneous tissue disorders  
 Rash Photosensitivity 

reaction 
Alopecia 
 

 Drug 
Reaction 
with 
Eosinophil
ia and 
Systemic 
Symptoms 
(DRESS) 

Musculoskeletal and connective tissue disorders  
 Arthralgia9  Rhabdomyolysis11  
Renal and urinary disorders  
  Urinary incontinence, 

urinary retention 
Urinary hesitation11 

  

Pregnancy, puerperium and perinatal conditions  
    Drug 

withdrawal 
syndrome 
neonatal (see 
section 4.6) 

Reproductive system and breast disorders  
 Erectile 

dysfunction in 
males 
Decreased libido 
in males and 
females 

Amenorrhea 
Breast enlargement 
Galactorrhea in 
females 
Gynaecomastia/breast 
enlargement in males 

Priapism12  

General disorders and administration site conditions  
 Asthenia 

Fatigue 
Oedema 

   



26 

Pyrexia10 
Investigations  
Elevated plasma 
prolactin levels8 

Increased alkaline 
phosphatase10 
High creatine 
phosphokinase11 
High Gamma 
Glutamyltransfera
se10 
High uric acid 10 
 

Increased total 
bilirubin 

  

 
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). 
 
2 Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were 
greater in patients without evidence of lipid dysregulation at baseline. 
 
3 Observed 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. 
 
4 Observed 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.  
 
5 Observed 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. 
 

6 In 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. 
 
7 Acute 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. 
 



27 

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 (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 to 
< 1/10). 
 
Metabolism and nutrition disorders 
Very common: Weight gain13, elevated triglyceride levels14, increased appetite. 
Common: Elevated cholesterol levels15 
Nervous system disorders 
Very common: Sedation (including: hypersomnia, lethargy, somnolence). 
Gastrointestinal disorders 
Common: Dry mouth 
Hepatobiliary disorders 
Very common: Elevations of hepatic aminotransferases (ALT/AST; see section 4.4). 
Investigations  
Very common: Decreased total bilirubin, increased GGT, elevated plasma prolactin levels16. 



28 

 
13 Following 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. 
 
14  Observed 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). 
 
15 Changes 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. 
 
16 Elevated plasma prolactin levels were reported in 47.4% of adolescent patients. 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
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. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: psycholeptics, diazepines, oxazepines, thiazepines and oxepines, 
ATC code N05A H03. 
 
Pharmacodynamic effects 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


29 

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 < 100 nM) for 
serotonin 5 HT2A/2C, 5 HT3, 5 HT6; dopamine D1, D2, D3, D4, D5; cholinergic muscarinic 
receptors M1-M5; α1 adrenergic; and histamine H1 receptors. Animal behavioural studies with 
olanzapine indicated 5 HT, dopamine, and cholinergic antagonism, consistent with the receptor-
binding profile. Olanzapine demonstrated a greater in vitro affinity for serotonin 5 HT2 than 
dopamine D2 receptors and greater 5 HT2 than D2 activity 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 5 HT2A 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 D2 occupancy 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 



30 

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. 
 
5.2 Pharmacokinetic properties 
 
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 metabolized 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 hrs) 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 hrs) 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 < 10 ml/min) versus healthy subjects, there 
was no significant difference in mean elimination half-life (37.7 versus 32.4 hrs) 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. 
 
Hepatic impairment  
A small study of the effect of impaired liver function in 6 subjects with clinically significant 
(Childs Pugh Classification A (n = 5) and B (n = 1)) cirrhosis revealed little effect on the 
pharmacokinetics of orally administered olanzapine (2.5 – 7.5 mg single dose): Subjects with 
mild to moderate hepatic dysfunction had slightly increased systemic clearance and faster 



31 

elimination half-time compared to subjects with no hepatic dysfunction (n = 3). There were 
more smokers among subjects with cirrhosis (4/6; 67 %) than among subjects with no hepatic 
dysfunction (0/3; 0 %). 
 
Smoking 
In non-smoking versus smoking subjects (males and females), the mean elimination half-life 
was prolonged (38.6 versus 30.4 hrs) 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. 
 
5.3 Preclinical safety data 
 
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, labored 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 [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. 
Estrous 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 



32 

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. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core 
Lactose monohydrate 
Microcrystalline cellulose 
Maize starch 
Magnesium stearate 
 
Tablet coat 
Hypromellose 
Hydroxypropylcellulose 
Macrogol 8000 
Titanium dioxide (E171) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 years 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
Aluminium/aluminium blister strips in cartons of 28, 56 and 98 film-coated tablets per carton. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
No special requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Apotex Europe B.V.  
Archimedesweg 2,  
2333 CN, Leiden, 
The Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 



33 

EU/1/10/635/002-003 
EU/1/10/635/015 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
10.06.2010 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 

http://www.ema.europa.eu/


34 

1. NAME OF THE MEDICINAL PRODUCT 
 
Olanzapine Apotex 7.5 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains 7.5 mg olanzapine. 
 
Excipient with known effect: Each film-coated tablet contains 189.50 mg lactose. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet 
 
White, round biconvex film-coated tablets engraved ‘APO’ on one side and ‘OLA’ over ‘7.5’ on 
the other side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
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). 
 
4.2 Posology and method of administration 
 
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 5-20 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. 
 



35 

Olanzapine can be given without regards 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 (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 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 (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). 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
Patients with known risk of narrow-angle glaucoma. 
 
4.4 Special warnings and precautions for use 
 
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. 
 



36 

In the same clinical trials, cerebrovascular adverse events (CVAE e.g., stroke, transient ischemic 
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 Apotex, 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 placebo 
controlled 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 Apotex, 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. 



37 

 
Hepatic function 
Transient, asymptomatic elevations of hepatic aminotransferases, alanine transferase (ALT), 
aspartate transferase (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 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 antagonize 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. 



38 

 
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 sections 4.8 and 5.1). 
 
Lactose 
Olanzapine Apotex film-coated tablets contain lactose. Patients with rare hereditary problems of 
galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not 
take this medicine. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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. 
 



39 

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). 
 
4.6 Fertility, pregnancy and lactation 
 
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. 
 
Newborn 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, 
hypotonis, 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 (see section 5.3 for preclinical information). 
 
4.7 Effects on ability to drive and use machines 
 
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. 
 
4.8 Undesirable effects 
 
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, 



40 

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 available data). 
 
Very common Common Uncommon Rare Not 

known 
Blood and lymphatic system disorders  
 Eosinophilia 

Leukopenia10 
Neutropenia10 

 Thrombocytopenia11  

Immune system disorders  
  Hypersensitivity11   
Metabolism and nutrition disorders  
Weight gain1 Elevated 

cholesterol 
levels2,3 
Elevated glucose 
levels4 
Elevated 
triglyceride 
levels2,5 
Glucosuria  
Increased appetite 

Development or 
exacerbation of 
diabetes occasionally 
associated with 
ketoacidosis or coma, 
including some fatal 
cases (see section 4.4) 
11 

Hypothermia12  

Nervous system disorders  
Somnolence Dizziness 

Akathisia6 
Parkinsonism6 
Dyskinesia6 

Seizures where in most 
cases a history of 
seizures or risk factors 
for seizures were 
reported 11 
 
 
 
Dystonia (including 
oculogyration) 11 
Tardive dyskinesia11 
 
 
Amnesia 9 
 

Dysarthria 

Stuttering11 
Restless legs 
syndrome11 

Neuroleptic 
malignant syndrome 
(see section 4.4)12 
Discontinuation 
symptoms7, 12 
 

 

Cardiac disorders  
  Bradycardia 

QTc prolongation (see 
section 4.4) 

Ventricular 
tachycardia/fibrillatio
n, sudden death (see 
section 4.4)11 

 



41 

Vascular disorders  
Orthostatic 
hypotension10 

 Thromboembolism 
(including pulmonary 
embolism and deep 
vein thrombosis) (see 
section 4.4) 

  

Respiratory, thoracic and mediastinal disorders  
  Epistaxis9   
Gastrointestinal disorders  
 Mild, transient 

anticholinergic 
effects including 
constipation and 
dry mouth 

Abdominal distension9 
Salivary 
hypersecretion11 

Pancreatitis11  

Hepatobiliary disorders  
 Transient, 

asymptomatic 
elevations of 
hepatic 
aminotransferases 
(ALT, AST), 
especially in early 
treatment (see 
section 4.4) 

 Hepatitis (including 
hepatocellular, 
cholestatic or mixed 
liver injury) 11 

 

Skin and subcutaneous tissue disorders  
 Rash Photosensitivity 

reaction 
Alopecia 
 

 Drug 
Reaction 
with 
Eosinophil
ia and 
Systemic 
Symptoms 
(DRESS) 

Musculoskeletal and connective tissue disorders  
 Arthralgia9  Rhabdomyolysis11  
Renal and urinary disorders  
  Urinary incontinence, 

urinary retention 
Urinary hesitation11 

  

Pregnancy, puerperium and perinatal conditions  
    Drug 

withdrawal 
syndrome 
neonatal (see 
section 4.6) 

Reproductive system and breast disorders  
 Erectile 

dysfunction in 
males 
Decreased libido 
in males and 
females 

Amenorrhea 
Breast enlargement 
Galactorrhea in 
females 
Gynaecomastia/breast 
enlargement in males 

Priapism12  

General disorders and administration site conditions  
 Asthenia 

Fatigue 
Oedema 

   



42 

Pyrexia10 
Investigations  
Elevated plasma 
prolactin levels8 

Increased alkaline 
phosphatase10 
High creatine 
phosphokinase11 
High Gamma 
Glutamyltransfera
se10 
High uric acid 10 
 

Increased total 
bilirubin 

  

 
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). 
 
2 Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were 
greater in patients without evidence of lipid dysregulation at baseline. 
 
3 Observed 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. 
 
4 Observed 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.  
 
5 Observed 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. 
 

6 In 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. 
 
7 Acute 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. 
 



43 

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 (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 to 
< 1/10). 
 
Metabolism and nutrition disorders 
Very common: Weight gain13, elevated triglyceride levels14, increased appetite. 
Common: Elevated cholesterol levels15 
Nervous system disorders 
Very common: Sedation (including: hypersomnia, lethargy, somnolence). 
Gastrointestinal disorders 
Common: Dry mouth 
Hepatobiliary disorders 
Very common: Elevations of hepatic aminotransferases (ALT/AST; see section 4.4). 
Investigations  
Very common: Decreased total bilirubin, increased GGT, elevated plasma prolactin levels16. 



44 

 
13 Following 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. 
 
14  Observed 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). 
 
15 Changes 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. 
 
16 Elevated plasma prolactin levels were reported in 47.4% of adolescent patients. 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
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. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
 
Pharmacotherapeutic group: psycholeptics, diazepines, oxazepines, thiazepines and oxepines, 
ATC code N05A H03. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


45 

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 < 100 nM) for 
serotonin 5 HT2A/2C, 5 HT3, 5 HT6; dopamine D1, D2, D3, D4, D5; cholinergic muscarinic 
receptors M1-M5; α1 adrenergic; and histamine H1 receptors. Animal behavioural studies with 
olanzapine indicated 5 HT, dopamine, and cholinergic antagonism, consistent with the receptor-
binding profile. Olanzapine demonstrated a greater in vitro affinity for serotonin 5 HT2 than 
dopamine D2 receptors and greater 5 HT2 than D2 activity 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 5 HT2A 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 D2 occupancy 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). 
 



46 

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. 
 
5.2 Pharmacokinetic properties 
 
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 metabolized 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 hrs) 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 hrs) 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 < 10 ml/min) versus healthy subjects, there 
was no significant difference in mean elimination half-life (37.7 versus 32.4 hrs) 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. 
 
Hepatic impairment 
A small study of the effect of impaired liver function in 6 subjects with clinically significant 
(Childs Pugh Classification A (n = 5) and B (n = 1)) cirrhosis revealed little effect on the 



47 

pharmacokinetics of orally administered olanzapine (2.5 – 7.5 mg single dose): Subjects with 
mild to moderate hepatic dysfunction had slightly increased systemic clearance and faster 
elimination half-time compared to subjects with no hepatic dysfunction (n = 3). There were 
more smokers among subjects with cirrhosis (4/6; 67 %) than among subjects with no hepatic 
dysfunction (0/3; 0 %). 
 
Smoking 
In non-smoking versus smoking subjects (males and females), the mean elimination half-life 
was prolonged (38.6 versus 30.4 hrs) 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. 
 
5.3 Preclinical safety data 
 
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, labored 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 [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. 
Estrous 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. 



48 

 
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. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core 
Lactose monohydrate 
Microcrystalline cellulose 
Maize starch 
Magnesium stearate 
 
Tablet coat 
Hypromellose 
Hydroxypropylcellulose 
Macrogol 8000 
Titanium dioxide (E171) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 years 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
Aluminium/aluminium blister strips in cartons of 28 and 56 film-coated tablets per carton. 
 
Not all pack sizes may be marketed. 
  
6.6 Special precautions for disposal 
 
No special requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Apotex Europe B.V.  
Archimedesweg 2,  
2333 CN, Leiden, 
The Netherlands 
 
 



49 

8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/635/004-005 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
10.06.2010 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 

http://www.ema.europa.eu/


50 

1. NAME OF THE MEDICINAL PRODUCT 
 
Olanzapine Apotex 10 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains 10 mg olanzapine. 
 
Excipient with known effect: Each film-coated tablet contains 252.70 mg lactose. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet 
 
White, round biconvex film-coated tablets engraved ‘APO’ on one side and ‘OLA’ over ‘10’ on 
the other side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
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). 
 
4.2 Posology and method of administration 
 
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 5-20 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. 
 



51 

Olanzapine can be given without regards 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 (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 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 (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). 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
Patients with known risk of narrow-angle glaucoma. 
 
4.4 Special warnings and precautions for use 
 
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. 
 



52 

In the same clinical trials, cerebrovascular adverse events (CVAE e.g., stroke, transient ischemic 
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 Apotex, 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 placebo 
controlled 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 Apotex, 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. 



53 

 
Hepatic function 
Transient, asymptomatic elevations of hepatic aminotransferases, alanine transferase (ALT), 
aspartate transferase (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 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 antagonize 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. 



54 

 
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 sections 4.8 and 5.1). 
 
Lactose 
Olanzapine Apotex film-coated tablets contain lactose. Patients with rare hereditary problems of 
galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not 
take this medicine. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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. 
 



55 

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). 
 
4.6 Fertility, pregnancy and lactation 
 
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. 
 
Newborn 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, 
hypotonis, 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 (see section 5.3 for preclinical information). 
 
4.7 Effects on ability to drive and use machines 
 
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. 
 
4.8 Undesirable effects 
 
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, 



56 

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 available data). 
 
Very common Common Uncommon Rare Not 

known 
Blood and lymphatic system disorders  
 Eosinophilia 

Leukopenia10 
Neutropenia10 

 Thrombocytopenia11  

Immune system disorders  
  Hypersensitivity11   
Metabolism and nutrition disorders  
Weight gain1 Elevated 

cholesterol 
levels2,3 
Elevated glucose 
levels4 
Elevated 
triglyceride 
levels2,5 
Glucosuria  
Increased appetite 

Development or 
exacerbation of 
diabetes occasionally 
associated with 
ketoacidosis or coma, 
including some fatal 
cases (see section 4.4) 
11 

Hypothermia12  

Nervous system disorders  
Somnolence Dizziness 

Akathisia6 
Parkinsonism6 
Dyskinesia6 

Seizures where in most 
cases a history of 
seizures or risk factors 
for seizures were 
reported 11 
 
 
 
Dystonia (including 
oculogyration) 11 
Tardive dyskinesia11 
 
 
Amnesia 9 
 

Dysarthria 

Stuttering11 
Restless legs 
syndrome11 

Neuroleptic 
malignant syndrome 
(see section 4.4)12 
Discontinuation 
symptoms7, 12 
 

 

Cardiac disorders  
  Bradycardia 

QTc prolongation (see 
section 4.4) 

Ventricular 
tachycardia/fibrillatio
n, sudden death (see 
section 4.4)11 

 



57 

Vascular disorders  
Orthostatic 
hypotension10 

 Thromboembolism 
(including pulmonary 
embolism and deep 
vein thrombosis) (see 
section 4.4) 

  

Respiratory, thoracic and mediastinal disorders  
  Epistaxis9   
Gastrointestinal disorders  
 Mild, transient 

anticholinergic 
effects including 
constipation and 
dry mouth 

Abdominal distension9 
Salivary 
hypersecretion11 

Pancreatitis11  

Hepatobiliary disorders  
 Transient, 

asymptomatic 
elevations of 
hepatic 
aminotransferases 
(ALT, AST), 
especially in early 
treatment (see 
section 4.4) 

 Hepatitis (including 
hepatocellular, 
cholestatic or mixed 
liver injury) 11 

 

Skin and subcutaneous tissue disorders  
 Rash Photosensitivity 

reaction 
Alopecia 
 

 Drug 
Reaction 
with 
Eosinophil
ia and 
Systemic 
Symptoms 
(DRESS) 

Musculoskeletal and connective tissue disorders  
 Arthralgia9  Rhabdomyolysis11  
Renal and urinary disorders  
  Urinary incontinence, 

urinary retention 
Urinary hesitation11 

  

Pregnancy, puerperium and perinatal conditions  
    Drug 

withdrawal 
syndrome 
neonatal (see 
section 4.6) 

Reproductive system and breast disorders  
 Erectile 

dysfunction in 
males 
Decreased libido 
in males and 
females 

Amenorrhea 
Breast enlargement 
Galactorrhea in 
females 
Gynaecomastia/breast 
enlargement in males 

Priapism12  

General disorders and administration site conditions  
 Asthenia 

Fatigue 
Oedema 

   



58 

Pyrexia10 
Investigations  
Elevated plasma 
prolactin levels8 

Increased alkaline 
phosphatase10 
High creatine 
phosphokinase11 
High Gamma 
Glutamyltransfera
se10 
High uric acid 10 
 

Increased total 
bilirubin 

  

 
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). 
 
2 Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were 
greater in patients without evidence of lipid dysregulation at baseline. 
 
3 Observed 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. 
 
4 Observed 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.  
 
5 Observed 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. 
 

6 In 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. 
 
7 Acute 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. 
 



59 

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 (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 to 
< 1/10). 
 
Metabolism and nutrition disorders 
Very common: Weight gain13, elevated triglyceride levels14, increased appetite. 
Common: Elevated cholesterol levels15 
Nervous system disorders 
Very common: Sedation (including: hypersomnia, lethargy, somnolence). 
Gastrointestinal disorders 
Common: Dry mouth 
Hepatobiliary disorders 
Very common: Elevations of hepatic aminotransferases (ALT/AST; see section 4.4). 
Investigations  
Very common: Decreased total bilirubin, increased GGT, elevated plasma prolactin levels16. 



60 

 
13 Following 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. 
 
14  Observed 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). 
 
15 Changes 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. 
 
16 Elevated plasma prolactin levels were reported in 47.4% of adolescent patients. 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
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. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: psycholeptics, diazepines, oxazepines, thiazepines and oxepines, 
ATC code N05A H03. 
 
Pharmacodynamic effects 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


61 

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 < 100 nM) for 
serotonin 5 HT2A/2C, 5 HT3, 5 HT6; dopamine D1, D2, D3, D4, D5; cholinergic muscarinic 
receptors M1-M5; α1 adrenergic; and histamine H1 receptors. Animal behavioural studies with 
olanzapine indicated 5 HT, dopamine, and cholinergic antagonism, consistent with the receptor-
binding profile. Olanzapine demonstrated a greater in vitro affinity for serotonin 5 HT2 than 
dopamine D2 receptors and greater 5 HT2 than D2 activity 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 5 HT2A 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 D2 occupancy 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 



62 

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. 
 
5.2 Pharmacokinetic properties 
 
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 metabolized 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 hrs) 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 hrs) 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 < 10 ml/min) versus healthy subjects, there 
was no significant difference in mean elimination half-life (37.7 versus 32.4 hrs) 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. 
 
Hepatic impairment  
A small study of the effect of impaired liver function in 6 subjects with clinically significant 
(Childs Pugh Classification A (n = 5) and B (n = 1)) cirrhosis revealed little effect on the 
pharmacokinetics of orally administered olanzapine (2.5 – 7.5 mg single dose): Subjects with 
mild to moderate hepatic dysfunction had slightly increased systemic clearance and faster 



63 

elimination half-time compared to subjects with no hepatic dysfunction (n = 3). There were 
more smokers among subjects with cirrhosis (4/6; 67 %) than among subjects with no hepatic 
dysfunction (0/3; 0 %). 
 
Smoking 
In non-smoking versus smoking subjects (males and females), the mean elimination half-life 
was prolonged (38.6 versus 30.4 hrs) 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. 
 
5.3 Preclinical safety data 
 
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, labored 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 [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. 
Estrous 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 



64 

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. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core 
Lactose monohydrate 
Microcrystalline cellulose 
Maize starch 
Magnesium stearate 
 
Tablet coat 
Hypromellose 
Hydroxypropylcellulose 
Macrogol 8000 
Titanium dioxide (E171) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 years 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
Aluminium/aluminium blister strips in cartons of 28, 56 and 98 film-coated tablets per carton. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
No special requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Apotex Europe B.V.  
Archimedesweg 2,  
2333 CN, Leiden, 
The Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 



65 

EU/1/10/635/006-007 
EU/1/10/635/016 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
10.06.2010 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 

http://www.ema.europa.eu/


66 

1. NAME OF THE MEDICINAL PRODUCT 
 
Olanzapine Apotex 5 mg orodispersible tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each orodispersible tablet contains 5 mg olanzapine. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Orodispersible tablet 
 
Yellow round flat faced radial edge tablets engraved ‘APO’ on one side and ‘OL’ over ‘5’ on the other 
side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
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). 
 
4.2 Posology and method of administration 
 
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-
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. 
 



67 

Olanzapine can be given without regards for meals as absorption is not affected by food. Gradual 
tapering of the dose should be considered when discontinuing olanzapine. 
 
Olanzapine Apotex orodispersible tablet should be placed in the mouth, where it will rapidly disperse 
in saliva, so it can be easily swallowed. Removal of the intact orodispersible tablet from the mouth is 
difficult. Since the orodispersible tablet is fragile, it should be taken immediately on opening the 
blister. Alternatively, it may be dispersed in a full glass of water or other suitable beverage (orange 
juice, apple juice, milk or coffee) immediately before administration.  
 
 
Olanzapine orodispersible tablet is bioequivalent to olanzapine film-coated tablets, with a similar rate 
and extent of absorption. It has the same dosage and frequency of administration as olanzapine film-
coated tablets. Olanzapine orodispersible tablets may be used as an alternative to olanzapine film-
coated tablets. 
 
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 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 (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.  
 
In cases where dose increments of 2.5  mg are considered necessary, Olanzapine Apotex film-coated 
tablets should be used.  
 
(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). 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
Patients with known risk of narrow-angle glaucoma. 
 
4.4 Special warnings and precautions for use 
 
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. 
 



68 

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 ischemic 
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 Apotex, 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 placebo 
controlled 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 



69 

of lipids disorders. Patients treated with any antipsychotic medicines, including Olanzapine Apotex, 
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, alanine transferase (ALT), aspartate 
transferase (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 antagonize 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 



70 

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 sections 4.8 and 5.1). 
 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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. 
 



71 

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). 
 
4.6 Fertility, pregnancy and lactation 
 
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. 
 
Newborn 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, 
hypotonis, 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 (see section 5.3 for preclinical information). 
 
4.7 Effects on ability to drive and use machines 
 
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. 
 
4.8 Undesirable effects 
 



72 

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 available data). 
 
Very 
common 

Common Uncommon Rare Not known 

Blood and lymphatic system disorders  
 Eosinophilia 

Leukopenia10 
Neutropenia10 

 Thrombocytopenia11  

Immune system disorders  
  Hypersensitivity11   
Metabolism and nutrition disorders  
Weight gain1 Elevated 

cholesterol levels2,3 
Elevated glucose 
levels4 
Elevated 
triglyceride levels2,5 
Glucosuria  
Increased appetite 

Development or 
exacerbation of 
diabetes occasionally 
associated with 
ketoacidosis or coma, 
including some fatal 
cases (see section 4.4) 
11 

Hypothermia12  

Nervous system disorders  
Somnolence Dizziness 

Akathisia6 
Parkinsonism6 
Dyskinesia6 

Seizures where in most 
cases a history of 
seizures or risk factors 
for seizures were 
reported 11 
 
 
 
Dystonia (including 
oculogyration) 11 
Tardive dyskinesia11 
 
 
Amnesia 9 
 

Dysarthria 

Stuttering11 
Restless legs 
syndrome11 

Neuroleptic malignant 
syndrome (see 
section 4.4)12 
 

Discontinuation 
symptoms7, 12 
 

 

Cardiac disorders  
  Bradycardia Ventricular  



73 

QTc prolongation (see 
section 4.4) 

tachycardia/fibrillation, 
sudden death (see 
section 4.4)11 

Vascular disorders  
Orthostatic 
hypotension10 

 Thromboembolism 
(including pulmonary 
embolism and deep 
vein thrombosis) (see 
section 4.4) 

  

Respiratory, thoracic and mediastinal disorders  
  Epistaxis9   
Gastrointestinal disorders  
 Mild, transient 

anticholinergic 
effects including 
constipation and 
dry mouth 

Abdominal distension9 
Salivary 
hypersecretion11 

Pancreatitis11  

Hepatobiliary disorders  
 Transient, 

asymptomatic 
elevations of 
hepatic 
aminotransferases 
(ALT, AST), 
especially in early 
treatment (see 
section 4.4) 

 Hepatitis (including 
hepatocellular, 
cholestatic or mixed 
liver injury) 11 

 

Skin and subcutaneous tissue disorders  
 Rash Photosensitivity 

reaction 
Alopecia 
 

 Drug 
Reaction 
with 
Eosinophili
a and 
Systemic 
Symptoms 
(DRESS) 

Musculoskeletal and connective tissue disorders  
 Arthralgia9  Rhabdomyolysis11  
Renal and urinary disorders  
  Urinary incontinence, 

urinary retention 
Urinary hesitation11 

  

Pregnancy, puerperium and perinatal conditions  
    Drug 

withdrawal 
syndrome 
neonatal 
(see 
section 4.6) 

Reproductive system and breast disorders  
 Erectile 

dysfunction in 
males 
Decreased libido in 
males and females 

Amenorrhea 
Breast enlargement 
Galactorrhea in females 
Gynaecomastia/breast 
enlargement in males 

Priapism12  

General disorders and administration site conditions  



74 

 Asthenia 
Fatigue 
Oedema 
Pyrexia10 

   

Investigations  
Elevated 
plasma 
prolactin 
levels8 

Increased alkaline 
phosphatase10 
High creatine 
phosphokinase11 
High Gamma 
Glutamyltransferase
10 

High uric acid 10 
 

Increased total bilirubin   

 
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). 
 
2 Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were 
greater in patients without evidence of lipid dysregulation at baseline. 
 
3 Observed 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. 
 
4 Observed 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.  
 
5 Observed 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. 
 

6 In 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. 
 
7 Acute 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. 
 



75 

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 (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 to 
< 1/10). 
 
Metabolism and nutrition disorders 
Very common: Weight gain13, elevated triglyceride levels14, increased appetite. 
Common: Elevated cholesterol levels15 
Nervous system disorders 
Very common: Sedation (including: hypersomnia, lethargy, somnolence). 
Gastrointestinal disorders 
Common: Dry mouth 
Hepatobiliary disorders 



76 

Very common: Elevations of hepatic aminotransferases (ALT/AST; see section 4.4). 
Investigations  
Very common: Decreased total bilirubin, increased GGT, elevated plasma prolactin levels16. 
 
13 Following 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. 
 
14  Observed 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). 
 
15 Changes 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. 
 
16 Elevated plasma prolactin levels were reported in 47.4% of adolescent patients. 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
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. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


77 

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 < 100 nM) for serotonin 
5 HT2A/2C, 5 HT3, 5 HT6; dopamine D1, D2, D3, D4, D5; cholinergic muscarinic receptors M1-M5; α1 
adrenergic; and histamine H1 receptors. Animal behavioural studies with olanzapine indicated 5 HT, 
dopamine, and cholinergic antagonism, consistent with the receptor-binding profile. Olanzapine 
demonstrated a greater in vitro affinity for serotonin 5 HT2 than dopamine D2 receptors and greater 5 
HT2 than D2 activity 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 5 HT2A 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 D2 occupancy 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 



78 

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. 
 
5.2 Pharmacokinetic properties 
 
Olanzapine orodispersible tablet is bioequivalent to olanzapine coated tablets, with a similar rate and 
extent of absorption. Olanzapine orodispersible tablets may be used as an alternative to olanzapine 
coated tablets.  
 
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 1-acid-glycoprotein. 
 
Biotransformation 
Olanzapine is metabolized 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 hrs) 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 hrs) 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 <10 ml/min) versus healthy subjects, there was no 
significant difference in mean elimination half-life (37.7 versus 32.4 hrs) 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.  
 
Hepatic impairment 



79 

A small study of the effect of impaired liver function in 6 subjects with clinically significant (Childs 
Pugh Classification A (n = 5) and B (n = 1)) cirrhosis revealed little effect on the pharmacokinetics of 
orally administered olanzapine (2.5 – 7.5 mg single dose): Subjects with mild to moderate hepatic 
dysfunction had slightly increased systemic clearance and faster elimination half-time compared to 
subjects with no hepatic dysfunction (n = 3). There were more smokers among subjects with cirrhosis 
(4/6; 67 %) than among subjects with no hepatic dysfunction (0/3; 0 %). 
  
 
Smoking 
In non-smoking versus smoking subjects (males and females), the mean elimination half-life was 
prolonged (38.6 versus 30.4 hrs) 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. 
 
5.3 Preclinical safety data 
 
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, 
labored 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 [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. Estrous 
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 



80 

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. 



81 

6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Mannitol (E421) 
Microcrystalline cellulose 
Carmellose calcium 
Sucralose 
Magnesium stearate 
Colloidal anhydrous silica 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 years 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
Aluminium/aluminium blister strips in cartons of 28, 56 and 98 orodispersible tablets per carton 
 
Not all pack sizes may be marketed. 
  
6.6 Special precautions for disposal 
 
No special requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Apotex Europe B.V.  
Archimedesweg 2,  
2333 CN, Leiden, 
The Netherlands 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/635/008-009 
EU/1/10/635/017 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
10.06.2010 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 

http://www.ema.europa.eu/


82 

1. NAME OF THE MEDICINAL PRODUCT 
 
Olanzapine Apotex 10 mg orodispersible tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each orodispersible tablet contains 10 mg olanzapine. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Orodispersible tablet 
 
Yellow round flat faced radial edge tablets engraved ‘APO’ on one side and ‘OL’ over ‘10’ on the 
other side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
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). 
 
4.2 Posology and method of administration 
 
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-
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. 
 



83 

Olanzapine can be given without regards for meals as absorption is not affected by food. Gradual 
tapering of the dose should be considered when discontinuing olanzapine. 
 
Olanzapine Apotex orodispersible tablet should be placed in the mouth, where it will rapidly disperse 
in saliva, so it can be easily swallowed. Removal of the intact orodispersible tablet from the mouth is 
difficult. Since the orodispersible tablet is fragile, it should be taken immediately on opening the 
blister. Alternatively, it may be dispersed in a full glass of water or other suitable beverage (orange 
juice, apple juice, milk or coffee) immediately before administration.  
 
 
Olanzapine orodispersible tablet is bioequivalent to olanzapine film-coated tablets, with a similar rate 
and extent of absorption. It has the same dosage and frequency of administration as olanzapine film-
coated tablets. Olanzapine orodispersible tablets may be used as an alternative to olanzapine film-
coated tablets. 
 
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 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 (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.  
 
In cases where dose increments of 2.5 mg are considered necessary, Olanzapine Apotex film-coated 
tablets should be used.  
 
(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). 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
Patients with known risk of narrow-angle glaucoma. 
 
4.4 Special warnings and precautions for use 
 
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. 
 



84 

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 ischemic 
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 Apotex, 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 placebo 
controlled 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 



85 

of lipids disorders. Patients treated with any antipsychotic medicines, including Olanzapine Apotex, 
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, alanine transferase (ALT), aspartate 
transferase (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 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 antagonize 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 



86 

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 sections 4.8 and 5.1). 
 
 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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. 



87 

 
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). 
 
4.6 Fertility, pregnancy and lactation 
 
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. 
 
Newborn 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, 
hypotonis, 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 (see section 5.3 for preclinical information). 
 
4.7 Effects on ability to drive and use machines 
 
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. 
 
4.8 Undesirable effects 
 



88 

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 available data). 
 
Very 
common 

Common Uncommon Rare Not known 

Blood and lymphatic system disorders  
 Eosinophilia 

Leukopenia10 
Neutropenia10 

 Thrombocytopenia11  

Immune system disorders  
  Hypersensitivity11   
Metabolism and nutrition disorders  
Weight gain1 Elevated 

cholesterol levels2,3 
Elevated glucose 
levels4 
Elevated 
triglyceride levels2,5 
Glucosuria  
Increased appetite 

Development or 
exacerbation of 
diabetes occasionally 
associated with 
ketoacidosis or coma, 
including some fatal 
cases (see section 4.4) 
11 

Hypothermia12  

Nervous system disorders  
Somnolence Dizziness 

Akathisia6 
Parkinsonism6 
Dyskinesia6 

Seizures where in most 
cases a history of 
seizures or risk factors 
for seizures were 
reported 11 
 
 
 
Dystonia (including 
oculogyration) 11 
Tardive dyskinesia11 
 
 
Amnesia 9 
 

Dysarthria 

Stuttering11 
Restless legs 
syndrome11 

Neuroleptic malignant 
syndrome (see 
section 4.4)12 
Discontinuation 
symptoms7, 12 
 

 

Cardiac disorders  
  Bradycardia Ventricular  



89 

QTc prolongation (see 
section 4.4) 

tachycardia/fibrillation, 
sudden death (see 
section 4.4)11 

Vascular disorders  
Orthostatic 
hypotension10 

 Thromboembolism 
(including pulmonary 
embolism and deep 
vein thrombosis) (see 
section 4.4) 

  

Respiratory, thoracic and mediastinal disorders  
  Epistaxis9   
Gastrointestinal disorders  
 Mild, transient 

anticholinergic 
effects including 
constipation and 
dry mouth 

Abdominal distension9 
Salivary 
hypersecretion11 

Pancreatitis11  

Hepatobiliary disorders  
 Transient, 

asymptomatic 
elevations of 
hepatic 
aminotransferases 
(ALT, AST), 
especially in early 
treatment (see 
section 4.4) 

 Hepatitis (including 
hepatocellular, 
cholestatic or mixed 
liver injury) 11 

 

Skin and subcutaneous tissue disorders  
 Rash Photosensitivity 

reaction 
Alopecia 

 Drug 
Reaction 
with 
Eosinophili
a and 
Systemic 
Symptoms 
(DRESS) 

Musculoskeletal and connective tissue disorders  
 Arthralgia9  Rhabdomyolysis11  
Renal and urinary disorders  
  Urinary incontinence, 

urinary retention 
Urinary hesitation11 

  

Pregnancy, puerperium and perinatal conditions  
    Drug 

withdrawal 
syndrome 
neonatal 
(see 
section 4.6) 

Reproductive system and breast disorders  
 Erectile 

dysfunction in 
males 
Decreased libido in 
males and females 

Amenorrhea 
Breast enlargement 
Galactorrhea in females 
Gynaecomastia/breast 
enlargement in males 

Priapism12  

General disorders and administration site conditions  



90 

 Asthenia 
Fatigue 
Oedema 
Pyrexia10 

   

Investigations  
Elevated 
plasma 
prolactin 
levels8 

Increased alkaline 
phosphatase10 
High creatine 
phosphokinase11 
High Gamma 
Glutamyltransferase
10 

High uric acid 10 
 

Increased total bilirubin   

 
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). 
 
2 Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were 
greater in patients without evidence of lipid dysregulation at baseline. 
 
3 Observed 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. 
 
4 Observed 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.  
 
5 Observed 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. 
 

6 In 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. 
 
7 Acute 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. 
 



91 

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 (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 to 
< 1/10). 
 
Metabolism and nutrition disorders 
Very common: Weight gain13, elevated triglyceride levels14, increased appetite. 
Common: Elevated cholesterol levels15 
Nervous system disorders 
Very common: Sedation (including: hypersomnia, lethargy, somnolence). 
Gastrointestinal disorders 
Common: Dry mouth 
Hepatobiliary disorders 



92 

Very common: Elevations of hepatic aminotransferases (ALT/AST; see section 4.4). 
Investigations  
Very common: Decreased total bilirubin, increased GGT, elevated plasma prolactin levels16. 
 
13 Following 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. 
 
14  Observed 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). 
 
15 Changes 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. 
 
16 Elevated plasma prolactin levels were reported in 47.4% of adolescent patients. 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
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. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


93 

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 < 100 nM) for serotonin 
5 HT2A/2C, 5 HT3, 5 HT6; dopamine D1, D2, D3, D4, D5; cholinergic muscarinic receptors M1-M5; α1 
adrenergic; and histamine H1 receptors. Animal behavioural studies with olanzapine indicated 5 HT, 
dopamine, and cholinergic antagonism, consistent with the receptor-binding profile. Olanzapine 
demonstrated a greater in vitro affinity for serotonin 5 HT2 than dopamine D2 receptors and greater 5 
HT2 than D2 activity 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 5 HT2A 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 D2 occupancy 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 



94 

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. 
 
5.2 Pharmacokinetic properties 
 
Olanzapine orodispersible tablet is bioequivalent to olanzapine coated tablets, with a similar rate and 
extent of absorption. Olanzapine orodispersible tablets may be used as an alternative to olanzapine 
coated tablets.  
 
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 1-acid-glycoprotein. 
 
Biotransformation 
Olanzapine is metabolized 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 hrs) 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 hrs) 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 <10 ml/min) versus healthy subjects, there was no 
significant difference in mean elimination half-life (37.7 versus 32.4 hrs) 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.  
 
Hepatic impairment 
A small study of the effect of impaired liver function in 6 subjects with clinically significant (Childs 
Pugh Classification A (n = 5) and B (n = 1)) cirrhosis revealed little effect on the pharmacokinetics of 



95 

orally administered olanzapine (2.5 – 7.5 mg single dose): Subjects with mild to moderate hepatic 
dysfunction had slightly increased systemic clearance and faster elimination half-time compared to 
subjects with no hepatic dysfunction (n = 3). There were more smokers among subjects with cirrhosis 
(4/6; 67 %) than among subjects with no hepatic dysfunction (0/3; 0 %). 
  
 
Smoking 
In non-smoking versus smoking subjects (males and females), the mean elimination half-life was 
prolonged (38.6 versus 30.4 hrs) 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. 
 
5.3 Preclinical safety data 
 
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, 
labored 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 [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. Estrous 
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. 
 



96 

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. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Mannitol (E421) 
Microcrystalline cellulose 
Carmellose calcium 
Sucralose 
Magnesium stearate 
Colloidal anhydrous silica 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 years 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
Aluminium/aluminium blister strips in cartons of 28, 56 and 98 orodispersible tablets per carton 
 
Not all pack sizes may be marketed. 
  
6.6 Special precautions for disposal 
 
No special requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Apotex Europe B.V.  
Archimedesweg 2,  
2333 CN, Leiden, 
The Netherlands 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/635/010-011 
EU/1/10/635/018 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 



97 

10.06.2010 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 

http://www.ema.europa.eu/


98 

1. NAME OF THE MEDICINAL PRODUCT 
 
Olanzapine Apotex 15 mg orodispersible tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each orodispersible tablet contains 15 mg olanzapine. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Orodispersible tablet 
 
Yellow round flat faced radial edge tablets engraved ‘APO’ on one side and ‘OL’ over ‘15’ on the 
other side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
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). 
 
4.2 Posology and method of administration 
 
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-
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. 
 



99 

Olanzapine can be given without regards for meals as absorption is not affected by food. Gradual 
tapering of the dose should be considered when discontinuing olanzapine. 
 
Olanzapine Apotex orodispersible tablet should be placed in the mouth, where it will rapidly disperse 
in saliva, so it can be easily swallowed. Removal of the intact orodispersible tablet from the mouth is 
difficult. Since the orodispersible tablet is fragile, it should be taken immediately on opening the 
blister. Alternatively, it may be dispersed in a full glass of water or other suitable beverage (orange 
juice, apple juice, milk or coffee) immediately before administration.  
 
 
Olanzapine orodispersible tablet is bioequivalent to olanzapine film-coated tablets, with a similar rate 
and extent of absorption. It has the same dosage and frequency of administration as olanzapine film-
coated tablets. Olanzapine orodispersible tablets may be used as an alternative to olanzapine film-
coated tablets. 
 
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 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 (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.  
 
In cases where dose increments of 2.5 mg are considered necessary, Olanzapine Apotex film-coated 
tablets should be used.  
 
(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). 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
Patients with known risk of narrow-angle glaucoma. 
 
4.4 Special warnings and precautions for use 
 
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. 
 



100 

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 ischemic 
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 Apotex, 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 placebo 
controlled 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 



101 

of lipids disorders. Patients treated with any antipsychotic medicines, including Olanzapine Apotex, 
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, alanine transferase (ALT), aspartate 
transferase (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 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 antagonize 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 



102 

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 sections 4.8 and 5.1). 
 
 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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. 



103 

 
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). 
 
4.6 Fertility, pregnancy and lactation 
 
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. 
 
Newborn 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, 
hypotonis, 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 (see section 5.3 for preclinical information). 
 
4.7 Effects on ability to drive and use machines 
 
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. 
 
4.8 Undesirable effects 
 



104 

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 available data). 
 
Very 
common 

Common Uncommon Rare Not known 

Blood and lymphatic system disorders  
 Eosinophilia 

Leukopenia10 
Neutropenia10 

 Thrombocytopenia11  

Immune system disorders  
  Hypersensitivity11   
Metabolism and nutrition disorders  
Weight gain1 Elevated 

cholesterol levels2,3 
Elevated glucose 
levels4 
Elevated 
triglyceride levels2,5 
Glucosuria  
Increased appetite 

Development or 
exacerbation of 
diabetes occasionally 
associated with 
ketoacidosis or coma, 
including some fatal 
cases (see section 4.4) 
11 

Hypothermia12  

Nervous system disorders  
Somnolence Dizziness 

Akathisia6 
Parkinsonism6 
Dyskinesia6 

Seizures where in most 
cases a history of 
seizures or risk factors 
for seizures were 
reported 11 
 
 
 
Dystonia (including 
oculogyration) 11 
Tardive dyskinesia11 
 
 
Amnesia 9 
 

Dysarthria 

Stuttering11 
Restless legs 
syndrome11 

Neuroleptic malignant 
syndrome (see 
section 4.4)12 
Discontinuation 
symptoms7, 12 
 

 

Cardiac disorders  
  Bradycardia Ventricular  



105 

QTc prolongation (see 
section 4.4) 

tachycardia/fibrillation, 
sudden death (see 
section 4.4)11 

Vascular disorders  
Orthostatic 
hypotension10 

 Thromboembolism 
(including pulmonary 
embolism and deep 
vein thrombosis) (see 
section 4.4) 

  

Respiratory, thoracic and mediastinal disorders  
  Epistaxis9   
Gastrointestinal disorders  
 Mild, transient 

anticholinergic 
effects including 
constipation and 
dry mouth 

Abdominal distension9 
Salivary 
hypersecretion11 

Pancreatitis11  

Hepatobiliary disorders  
 Transient, 

asymptomatic 
elevations of 
hepatic 
aminotransferases 
(ALT, AST), 
especially in early 
treatment (see 
section 4.4) 

 Hepatitis (including 
hepatocellular, 
cholestatic or mixed 
liver injury) 11 

 

Skin and subcutaneous tissue disorders  
 Rash Photosensitivity 

reaction 
Alopecia 
 

 Drug 
Reaction 
with 
Eosinophili
a and 
Systemic 
Symptoms 
(DRESS) 

Musculoskeletal and connective tissue disorders  
 Arthralgia9  Rhabdomyolysis11  
Renal and urinary disorders  
  Urinary incontinence, 

urinary retention 
Urinary hesitation11 

  

Pregnancy, puerperium and perinatal conditions  
    Drug 

withdrawal 
syndrome 
neonatal 
(see 
section 4.6) 

Reproductive system and breast disorders  
 Erectile 

dysfunction in 
males 
Decreased libido in 
males and females 

Amenorrhea 
Breast enlargement 
Galactorrhea in females 
Gynaecomastia/breast 
enlargement in males 

Priapism12  

General disorders and administration site conditions  



106 

 Asthenia 
Fatigue 
Oedema 
Pyrexia10 

   

Investigations  
Elevated 
plasma 
prolactin 
levels8 

Increased alkaline 
phosphatase10 
High creatine 
phosphokinase11 
High Gamma 
Glutamyltransferase
10 

High uric acid 10 
 

Increased total bilirubin   

 
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). 
 
2 Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were 
greater in patients without evidence of lipid dysregulation at baseline. 
 
3 Observed 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. 
 
4 Observed 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.  
 
5 Observed 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. 
 

6 In 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. 
 
7 Acute 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. 
 



107 

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 (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 to 
< 1/10). 
 
Metabolism and nutrition disorders 
Very common: Weight gain13, elevated triglyceride levels14, increased appetite. 
Common: Elevated cholesterol levels15 
Nervous system disorders 
Very common: Sedation (including: hypersomnia, lethargy, somnolence). 
Gastrointestinal disorders 
Common: Dry mouth 
Hepatobiliary disorders 



108 

Very common: Elevations of hepatic aminotransferases (ALT/AST; see section 4.4). 
Investigations  
Very common: Decreased total bilirubin, increased GGT, elevated plasma prolactin levels16. 
 
13 Following 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. 
 
14  Observed 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). 
 
15 Changes 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. 
 
16 Elevated plasma prolactin levels were reported in 47.4% of adolescent patients. 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
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. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


109 

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 < 100 nM) for serotonin 
5 HT2A/2C, 5 HT3, 5 HT6; dopamine D1, D2, D3, D4, D5; cholinergic muscarinic receptors M1-M5; α1 
adrenergic; and histamine H1 receptors. Animal behavioural studies with olanzapine indicated 5 HT, 
dopamine, and cholinergic antagonism, consistent with the receptor-binding profile. Olanzapine 
demonstrated a greater in vitro affinity for serotonin 5 HT2 than dopamine D2 receptors and greater 5 
HT2 than D2 activity 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 5 HT2A 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 D2 occupancy 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 



110 

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. 
 
5.2 Pharmacokinetic properties 
 
Olanzapine orodispersible tablet is bioequivalent to olanzapine coated tablets, with a similar rate and 
extent of absorption. Olanzapine orodispersible tablets may be used as an alternative to olanzapine 
coated tablets.  
 
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 1-acid-glycoprotein. 
 
Biotransformation 
Olanzapine is metabolized 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 hrs) 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 hrs) 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 <10 ml/min) versus healthy subjects, there was no 
significant difference in mean elimination half-life (37.7 versus 32.4 hrs) 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.  
 
Hepatic impairment 
A small study of the effect of impaired liver function in 6 subjects with clinically significant (Childs 
Pugh Classification A (n = 5) and B (n = 1)) cirrhosis revealed little effect on the pharmacokinetics of 



111 

orally administered olanzapine (2.5 – 7.5 mg single dose): Subjects with mild to moderate hepatic 
dysfunction had slightly increased systemic clearance and faster elimination half-time compared to 
subjects with no hepatic dysfunction (n = 3). There were more smokers among subjects with cirrhosis 
(4/6; 67 %) than among subjects with no hepatic dysfunction (0/3; 0 %). 
 
Smoking 
In non-smoking versus smoking subjects (males and females), the mean elimination half-life was 
prolonged (38.6 versus 30.4 hrs) 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. 
 
5.3 Preclinical safety data 
 
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, 
labored 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 [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. Estrous 
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 



112 

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. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Mannitol (E421) 
Microcrystalline cellulose 
Carmellose calcium 
Sucralose 
Magnesium stearate 
Colloidal anhydrous silica 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 years 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
Aluminium/aluminium blister strips in cartons of 28 orodispersible tablets per carton  
 
Not all pack sizes may be marketed. 
  
6.6 Special precautions for disposal 
 
No special requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Apotex Europe B.V.  
Archimedesweg 2,  
2333 CN, Leiden, 
The Netherlands 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/635/012 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
10.06.2010 
 



113 

 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 

http://www.ema.europa.eu/


114 

1. NAME OF THE MEDICINAL PRODUCT 
 
Olanzapine Apotex 20 mg orodispersible tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each orodispersible tablet contains 20 mg olanzapine. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Orodispersible tablet 
 
Yellow round flat faced radial edge tablets engraved ‘APO’ on one side and ‘OL’ over ‘20’ on the 
other side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
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). 
 
4.2 Posology and method of administration 
 
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-
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. 
 



115 

Olanzapine can be given without regards for meals as absorption is not affected by food. Gradual 
tapering of the dose should be considered when discontinuing olanzapine. 
 
Olanzapine Apotex orodispersible tablet should be placed in the mouth, where it will rapidly disperse 
in saliva, so it can be easily swallowed. Removal of the intact orodispersible tablet from the mouth is 
difficult. Since the orodispersible tablet is fragile, it should be taken immediately on opening the 
blister. Alternatively, it may be dispersed in a full glass of water or other suitable beverage (orange 
juice, apple juice, milk or coffee) immediately before administration.  
 
 
Olanzapine orodispersible tablet is bioequivalent to olanzapine film-coated tablets, with a similar rate 
and extent of absorption. It has the same dosage and frequency of administration as olanzapine film-
coated tablets. Olanzapine orodispersible tablets may be used as an alternative to olanzapine film-
coated tablets. 
 
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 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 (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.  
 
In cases where dose increments of 2.5 mg are considered necessary, Olanzapine Apotex film-coated 
tablets should be used.  
 
(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). 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
Patients with known risk of narrow-angle glaucoma. 
 
4.4 Special warnings and precautions for use 
 
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. 
 



116 

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 ischemic 
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 Apotex, 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 placebo 
controlled 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 



117 

of lipids disorders. Patients treated with any antipsychotic medicines, including Olanzapine Apotex, 
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, alanine transferase (ALT), aspartate 
transferase (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 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 antagonize 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 



118 

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 sections 4.8 and 5.1). 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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 



119 

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). 
 
4.6 Fertility, pregnancy and lactation 
 
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. 
 
Newborn 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, 
hypotonis, 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 (see section 5.3 for preclinical information). 
 
4.7 Effects on ability to drive and use machines 
 
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. 
 
4.8 Undesirable effects 
 
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, 



120 

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 available data). 
 
Very 
common 

Common Uncommon Rare Not known 

Blood and lymphatic system disorders  
 Eosinophilia 

Leukopenia10 
Neutropenia10 

 Thrombocytopenia11  

Immune system disorders  
  Hypersensitivity11   
Metabolism and nutrition disorders  
Weight gain1 Elevated 

cholesterol levels2,3 
Elevated glucose 
levels4 
Elevated 
triglyceride levels2,5 
Glucosuria  
Increased appetite 

Development or 
exacerbation of 
diabetes occasionally 
associated with 
ketoacidosis or coma, 
including some fatal 
cases (see section 4.4) 
11 

Hypothermia12  

Nervous system disorders  
Somnolence Dizziness 

Akathisia6 
Parkinsonism6 
Dyskinesia6 

Seizures where in most 
cases a history of 
seizures or risk factors 
for seizures were 
reported 11 
 
 
 
Dystonia (including 
oculogyration) 11 
Tardive dyskinesia11 
 
 
Amnesia 9 
 

Dysarthria 

Stuttering11 
Restless legs 
syndrome11 

Neuroleptic malignant 
syndrome (see 
section 4.4)12 
Discontinuation 
symptoms7, 12 
 

 

Cardiac disorders  
  Bradycardia 

QTc prolongation (see 
section 4.4) 

Ventricular 
tachycardia/fibrillation, 
sudden death (see 
section 4.4)11 

 

Vascular disorders  



121 

Orthostatic 
hypotension10 

 Thromboembolism 
(including pulmonary 
embolism and deep 
vein thrombosis) (see 
section 4.4) 

  

Respiratory, thoracic and mediastinal disorders  
  Epistaxis9   
Gastrointestinal disorders  
 Mild, transient 

anticholinergic 
effects including 
constipation and 
dry mouth 

Abdominal distension9 
Salivary 
hypersecretion11 

Pancreatitis11  

Hepatobiliary disorders  
 Transient, 

asymptomatic 
elevations of 
hepatic 
aminotransferases 
(ALT, AST), 
especially in early 
treatment (see 
section 4.4) 

 Hepatitis (including 
hepatocellular, 
cholestatic or mixed 
liver injury) 11 

 

Skin and subcutaneous tissue disorders  
 Rash Photosensitivity 

reaction 
Alopecia 
 

 Drug 
Reaction 
with 
Eosinophili
a and 
Systemic 
Symptoms 
(DRESS) 

Musculoskeletal and connective tissue disorders  
 Arthralgia9  Rhabdomyolysis11  
Renal and urinary disorders  
  Urinary incontinence, 

urinary retention 
Urinary hesitation11 

  

Pregnancy, puerperium and perinatal conditions  
    Drug 

withdrawal 
syndrome 
neonatal 
(see 
section 4.6) 

Reproductive system and breast disorders  
 Erectile 

dysfunction in 
males 
Decreased libido in 
males and females 

Amenorrhea 
Breast enlargement 
Galactorrhea in females 
Gynaecomastia/breast 
enlargement in males 

Priapism12  

General disorders and administration site conditions  
 Asthenia 

Fatigue 
Oedema 
Pyrexia10 

   



122 

Investigations  
Elevated 
plasma 
prolactin 
levels8 

Increased alkaline 
phosphatase10 
High creatine 
phosphokinase11 
High Gamma 
Glutamyltransferase
10 

High uric acid 10 
 

Increased total bilirubin   

 
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). 
 
2 Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were 
greater in patients without evidence of lipid dysregulation at baseline. 
 
3 Observed 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. 
 
4 Observed 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.  
 
5 Observed 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. 
 

6 In 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. 
 
7 Acute 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. 
 



123 

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 (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 to 
< 1/10). 
 
Metabolism and nutrition disorders 
Very common: Weight gain13, elevated triglyceride levels14, increased appetite. 
Common: Elevated cholesterol levels15 
Nervous system disorders 
Very common: Sedation (including: hypersomnia, lethargy, somnolence). 
Gastrointestinal disorders 
Common: Dry mouth 
Hepatobiliary disorders 
Very common: Elevations of hepatic aminotransferases (ALT/AST; see section 4.4). 
Investigations  
Very common: Decreased total bilirubin, increased GGT, elevated plasma prolactin levels16. 



124 

 
13 Following 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. 
 
14  Observed 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). 
 
15 Changes 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. 
 
16 Elevated plasma prolactin levels were reported in 47.4% of adolescent patients. 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
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. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: psycholeptics, diazepines, oxazepines, thiazepines and oxepines, ATC 
code N05A H03. 
 
Pharmacodynamic effects 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


125 

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 < 100 nM) for serotonin 
5 HT2A/2C, 5 HT3, 5 HT6; dopamine D1, D2, D3, D4, D5; cholinergic muscarinic receptors M1-M5; α1 
adrenergic; and histamine H1 receptors. Animal behavioural studies with olanzapine indicated 5 HT, 
dopamine, and cholinergic antagonism, consistent with the receptor-binding profile. Olanzapine 
demonstrated a greater in vitro affinity for serotonin 5 HT2 than dopamine D2 receptors and greater 5 
HT2 than D2 activity 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 5 HT2A 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 D2 occupancy 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 



126 

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. 
 
5.2 Pharmacokinetic properties 
 
Olanzapine orodispersible tablet is bioequivalent to olanzapine coated tablets, with a similar rate and 
extent of absorption. Olanzapine orodispersible tablets may be used as an alternative to olanzapine 
coated tablets.  
 
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 1-acid-glycoprotein. 
 
Biotransformation 
Olanzapine is metabolized 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 hrs) 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 hrs) 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 <10 ml/min) versus healthy subjects, there was no 
significant difference in mean elimination half-life (37.7 versus 32.4 hrs) 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.  
 
Hepatic impairment 
A small study of the effect of impaired liver function in 6 subjects with clinically significant (Childs 
Pugh Classification A (n = 5) and B (n = 1)) cirrhosis revealed little effect on the pharmacokinetics of 
orally administered olanzapine (2.5 – 7.5 mg single dose): Subjects with mild to moderate hepatic 
dysfunction had slightly increased systemic clearance and faster elimination half-time compared to 



127 

subjects with no hepatic dysfunction (n = 3). There were more smokers among subjects with cirrhosis 
(4/6; 67 %) than among subjects with no hepatic dysfunction (0/3; 0 %). 
 
Smoking 
In non-smoking versus smoking subjects (males and females), the mean elimination half-life was 
prolonged (38.6 versus 30.4 hrs) 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. 
 
5.3 Preclinical safety data 
 
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, 
labored 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 [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. Estrous 
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. 



128 

 
Carcinogenicity 
Based on the results of studies in mice and rats, it was concluded that olanzapine is not carcinogenic. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Mannitol (E421) 
Microcrystalline cellulose 
Carmellose calcium 
Sucralose 
Magnesium stearate 
Colloidal anhydrous silica 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 years 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
Aluminium/aluminium blister strips in cartons of 28 and 56 orodispersible tablets per carton  
 
Not all pack sizes may be marketed. 
  
6.6 Special precautions for disposal 
 
No special requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Apotex Europe B.V.  
Archimedesweg 2,  
2333 CN, Leiden, 
The Netherlands 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/635/013-014 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
10.06.2010 
 
 
10. DATE OF REVISION OF THE TEXT 



129 

 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 

http://www.ema.europa.eu/


130 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 

 



131 

  
A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer responsible for batch release 
 
Apotex Nederland B.V. 
Archimedesweg 2 
NL-2333 CN Leiden 
Netherlands 
 
APL Swift Services (Malta) Ltd. 
HF26 Hal Far Industrial Estate, 
Hal Far, Birzebbugia, 
BBG 3000, Malta. 
 
Generis Farmacêutica, S.A. 
Rua João de Deus, 19 
2700-487 Amadora 
Portugal 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
 
Medicinal product subject to medical prescription. 
 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION 

 
 Periodic safety update reports (PSURs) 
 
The marketing authorisation holder (MAH) shall submit PSURs for this product in accordance 
with the requirements set out in the list of Union reference dates (EURD list) provided for under 
Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
 Risk management plan (RMP) 
 
Not applicable. 
 
 
 



132 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



133 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
 
 



134 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON BOX 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Olanzapine Apotex 2.5 mg film-coated tablets 
olanzapine 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 2.5 mg olanzapine. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. 
See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
28 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 



135 

 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Apotex Europe B.V.  
Archimedesweg 2,  
2333 CN, Leiden, 
The Netherlands 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/635/001 
 
13. BATCH NUMBER 
 
BN 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Olanzapine Apotex 2.5 mg film-coated tablet 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC 
SN 
NN 
 



136 

 
PARTICULARS TO APPEAR ON IMMEDIATE PACKAGING 
 
BLISTER PACK 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Olanzapine Apotex 2.5 mg film-coated tablets 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Apotex Europe B.V.  
 
3. EXPIRY DATE 
 
EXP 
 
4. BATCH NUMBER 
 
BN 
 
5. OTHER 
 



137 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON BOX 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Olanzapine Apotex 5 mg film-coated tablets 
olanzapine 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 5 mg olanzapine. 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. 
See package leaflet for further information. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
28 film-coated tablets 
56 film-coated tablets 
98 film-coated tablets 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 



138 

 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Apotex Europe B.V.  
Archimedesweg 2,  
2333 CN, Leiden, 
The Netherlands 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/635/002-003 
EU/1/10/635/015 
 
13. BATCH NUMBER 
 
BN 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Olanzapine Apotex 5 mg film-coated tablet 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC 
SN 
NN 
 
 



139 

 
PARTICULARS TO APPEAR ON IMMEDIATE PACKAGING 
 
BLISTER PACK 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Olanzapine Apotex 5 mg film-coated tablets 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Apotex Europe B.V.  
 
3. EXPIRY DATE 
 
EXP 
 
4. BATCH NUMBER 
 
BN 
 
5. OTHER 
 
 
 
 



140 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON BOX 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Olanzapine Apotex 7.5 mg film-coated tablets 
olanzapine 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 7.5 mg olanzapine. 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. 
See package leaflet for further information. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
28 film-coated tablets 
56 film-coated tablets 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 



141 

 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Apotex Europe B.V.  
Archimedesweg 2,  
2333 CN, Leiden, 
The Netherlands 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/635/004-005 
 
13. BATCH NUMBER 
 
BN 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Olanzapine Apotex 7.5 mg film-coated tablet 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC 
SN 
NN 
 
 
 



142 

 
PARTICULARS TO APPEAR ON IMMEDIATE PACKAGING 
 
BLISTER PACK 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Olanzapine Apotex 7.5 mg film-coated tablets 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Apotex Europe B.V.  
 
3. EXPIRY DATE 
 
EXP 
 
4. BATCH NUMBER 
 
BN 
 
5. OTHER 
 
 
 



143 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON BOX 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Olanzapine Apotex 10 mg film-coated tablets 
olanzapine 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 10 mg olanzapine. 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. 
See package leaflet for further information. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
28 film-coated tablets 
56 film-coated tablets 
98 film-coated tablets 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 



144 

 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Apotex Europe B.V.  
Archimedesweg 2,  
2333 CN, Leiden, 
The Netherlands 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/635/006-007 
EU/1/10/635/016 
 
13. BATCH NUMBER 
 
BN 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Olanzapine Apotex 10 mg film-coated tablet 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC 
SN 
NN 
 
 
 



145 

 
PARTICULARS TO APPEAR ON IMMEDIATE PACKAGING 
 
BLISTER PACK 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Olanzapine Apotex 10 mg film-coated tablets 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Apotex Europe B.V.  
 
3. EXPIRY DATE 
 
EXP 
 
4. BATCH NUMBER 
 
BN 
 
5. OTHER 
 
 
 



146 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON BOX 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Olanzapine Apotex 5 mg orodispersible tablets 
olanzapine 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 5 mg olanzapine. 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
28 orodispersible tablets 
56 orodispersible tablets 
98 orodispersible tablets 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use  
Read the package leaflet before use. 
Place the tablet in your mouth. It will quickly dissolve with your saliva and can be swallowed. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Apotex Europe B.V.  
Archimedesweg 2,  



147 

2333 CN, Leiden, 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/635/008-009 
EU/1/10/635/017 
 
13. BATCH NUMBER 
 
BN 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Olanzapine Apotex 5 mg orodispersible tablet  
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC 
SN 
NN 
 
 
 



148 

 
PARTICULARS TO APPEAR ON IMMEDIATE PACKAGING 
 
BLISTER PACK 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Olanzapine Apotex 5 mg orodispersible tablets 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Apotex Europe B.V.  
 
3. EXPIRY DATE 
 
EXP 
 
4. BATCH NUMBER 
 
BN 
 
5. OTHER 
 
 



149 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON BOX 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Olanzapine Apotex 10 mg orodispersible tablets 
olanzapine 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 10 mg olanzapine. 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
28 orodispersible tablets 
56 orodispersible tablets 
98 orodispersible tablets 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use  
Read the package leaflet before use. 
Place the tablet in your mouth. It will quickly dissolve with your saliva and can be swallowed. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Apotex Europe B.V.  
Archimedesweg 2,  
2333 CN, Leiden, 



150 

The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/635/010-011 
EU/1/10/635/018 
 
13. BATCH NUMBER 
 
BN 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Olanzapine Apotex 10 mg orodispersible tablet  
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC 
SN 
NN 
 
 
 



151 

 
PARTICULARS TO APPEAR ON IMMEDIATE PACKAGING 
 
BLISTER PACK 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Olanzapine Apotex 10 mg orodispersible tablets 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Apotex Europe B.V.  
 
3. EXPIRY DATE 
 
EXP 
 
4. BATCH NUMBER 
 
BN 
 
5. OTHER 
 
 
 



152 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON BOX 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Olanzapine Apotex 15 mg orodispersible tablets 
olanzapine 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 15 mg olanzapine. 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
28 orodispersible tablets 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use  
Read the package leaflet before use. 
Place the tablet in your mouth. It will quickly dissolve with your saliva and can be swallowed. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Apotex Europe B.V.  
Archimedesweg 2,  
2333 CN, Leiden, 
The Netherlands 



153 

 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/635/012 
 
13. BATCH NUMBER 
 
BN 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Olanzapine Apotex 15 mg orodispersible tablet  
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC 
SN 
NN 
 
 
 



154 

 
PARTICULARS TO APPEAR ON IMMEDIATE PACKAGING 
 
BLISTER PACK 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Olanzapine Apotex 15 mg orodispersible tablets 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Apotex Europe B.V.  
 
3. EXPIRY DATE 
 
EXP 
 
4. BATCH NUMBER 
 
BN 
 
5. OTHER 
 
 
 



155 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON BOX 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Olanzapine Apotex 20 mg orodispersible tablets 
olanzapine 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 20 mg olanzapine. 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
28 orodispersible tablets 
56 orodispersible tablets 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use  
Read the package leaflet before use. 
Place the tablet in your mouth. It will quickly dissolve with your saliva and can be swallowed. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Apotex Europe B.V.  
Archimedesweg 2,  
2333 CN, Leiden, 
The Netherlands 



156 

 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/635/013-014 
 
13. BATCH NUMBER 
 
BN 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Olanzapine Apotex 20 mg orodispersible tablet  
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC 
SN 
NN 
 
 
 



157 

 
PARTICULARS TO APPEAR ON IMMEDIATE PACKAGING 
 
BLISTER PACK 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Olanzapine Apotex 20 mg orodispersible tablets 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Apotex Europe B.V.  
 
3. EXPIRY DATE 
 
EXP 
 
4. BATCH NUMBER 
 
BN 
 
5. OTHER 
 
 
 



158 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 



159 

Package leaflet: Information for the user 
 

Olanzapine Apotex 2.5 mg film-coated tablets 
Olanzapine Apotex 5 mg film-coated tablets 

Olanzapine Apotex 7.5 mg film-coated tablets 
Olanzapine Apotex 10 mg film-coated tablets 

 
Olanzapine 

 
 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
 Keep this leaflet. You may need to read it again. 
 If you have any further questions, ask your doctor or pharmacist. 
 This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
 If you get any side effects talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
 
What is in this leaflet 
 
1. What Olanzapine Apotex is and what it is used for 
2. What you need to know before you take Olanzapine Apotex 
3. How to take Olanzapine Apotex 
4. Possible side effects 
5. How to store Olanzapine Apotex 
6. Contents of the pack and other information 
 
 
1. What Olanzapine Apotex is and what it is used for 
 
Olanzapine Apotex contains the active substance olanzapine. Olanzapine Apotex belongs to a group of 
medicines called antipsychotics and is used to treat the following conditions:  
 

 Schizophrenia, a disease with symptoms such as hearing, seeing or sensing things which are 
not there, mistaken beliefs, unusual suspiciousness, and becoming withdrawn. People with this 
disease may also feel depressed, anxious or tense. 

 Moderate to severe manic episodes, a condition with symptoms of excitement or euphoria. 
 
Olanzapine Apotex has been shown to prevent recurrence of these symptoms in patients with bipolar 
disorder whose manic episode has responded to olanzapine treatment. 
 
 
2. What you need to know before you take Olanzapine Apotex 
 
Do not take Olanzapine Apotex 
 If you are allergic (hypersensitive) to olanzapine or any of the other ingredients of this medicine 

(listed in section 6). An allergic reaction may be recognised as a rash, itching, a swollen face, 
swollen lips or shortness of breath. If this has happened to you, tell your doctor. 

 If you have been previously diagnosed with eye problems such as certain kinds of glaucoma 
(increased pressure in the eye).  

 
Warnings and precautions 
Talk to your doctor or pharmacist before taking Olanzapine Apotex. 
 The use of Olanzapine Apotex in elderly patients with dementia is not recommended as it may 

have serious side effects. 



160 

 Medicines of this type may cause unusual movements mainly of the face or tongue. If this happens 
after you have been given Olanzapine Apotex tell your doctor. 

 Very rarely, medicines of this type cause a combination of fever, faster breathing, sweating, 
muscle stiffness and drowsiness or sleepiness. If this happens, contact your doctor at once.  

 Weight gain has been seen in patients taking Olanzapine Apotex. You and your doctor should 
check your weight regularly. Consider referral to a dietician or help with a diet plan if necessary. 

 High blood sugar and high levels of fat (triglycerides and cholesterol) have been seen in patients 
taking Olanzapine Apotex. Your doctor should do blood tests to check blood sugar and certain fat 
levels before you start taking Olanzapine Apotex and regularly during treatment. 

 Tell the doctor if you or someone else in your family has a history of blood clots, as medicines 
like these have been associated with the formation of blood clots. 

 
If you suffer from any of the following illnesses tell your doctor as soon as possible: 
 
 Stroke or “mini” stroke (temporary symptoms of stroke) 
 Parkinson’s disease 
 Prostate problems 
 A blocked intestine (Paralytic ileus) 
 Liver or kidney disease 
 Blood disorders 
 Heart disease 
 Diabetes 
 Seizures 
 If you know that you may have salt depletion as a result of prolonged severe diarrhoea and 

vomiting (being sick) or usage of diuretics (water tablets)  
 

 
If you suffer from dementia, you or your carer/relative should tell your doctor if you have ever had a 
stroke or “mini” stroke. 
 
As a routine precaution, if you are over 65 years your blood pressure may be monitored by your 
doctor. 
 
Children and adolescents 
Olanzapine Apotex is not for patients who are under 18 years. 
 
Other medicines and Olanzapine Apotex 
Only take other medicines while you are on Olanzapine Apotex if your doctor tells you that you can. 
You might feel drowsy if Olanzapine Apotex is taken in combination with antidepressants or 
medicines taken for anxiety or to help you sleep (tranquillisers). 
 
Tell your doctor if you are taking, have recently taken or might take any other medicines. 
 
In particular, tell your doctor if you are taking: 
 medicines for Parkinson’s disease. 
 carbamazepine (an anti-epileptic and mood stabiliser), fluvoxamine (an antidepressant) or  

ciprofloxacin (an antibiotic) – it may be necessary to change your Olanzapine Apotex dose. 
 
Olanzapine Apotex with alcohol 
Do not drink any alcohol if you have been given Olanzapine Apotex as together with alcohol it may 
make you feel drowsy. 
 
Pregnancy and breast-feeding 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor for advice before taking this medicine.You should not be given this medicine when breast-
feeding, as small amounts of Olanzapine Apotex can pass into breast milk. 
 



161 

The following symptoms may occur in newborn babies, of mothers that have used Olanzapine Apotex 
in the last trimester (last three months of their pregnancy): shaking, muscle stiffness and/or weakness, 
sleepiness, agitation, breathing problems, and difficulty in feeding. If your baby develops any of these 
symptoms you may need to contact your doctor. 
 
Driving and using machines 
There is a risk of feeling drowsy when you are given Olanzapine Apotex. If this happens do not drive 
or operate any tools or machines. Tell your doctor. 
 
Olanzapine Apotex contains lactose 
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor 
before taking this medicinal product. 
 
 
3. How to take Olanzapine Apotex 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure. 
 
Your doctor will tell you how many Olanzapine Apotex tablets to take and how long you should 
continue to take them. The daily dose of Olanzapine Apotex is between 5 mg and 20 mg. Consult your 
doctor if your symptoms return but do not stop taking Olanzapine Apotex unless your doctor tells you 
to. 
 
You should take your Olanzapine Apotex tablets once a day following the advice of your doctor. Try 
to take your tablets at the same time each day. It does not matter whether you take them with or 
without food. 
Olanzapine Apotex film-coated tablets are for oral use. You should swallow the Olanzapine Apotex 
tablets whole with water. 
 
If you take more Olanzapine Apotex than you should 
Patients who have taken more Olanzapine Apotex than they should have experienced the following 
symptoms: rapid beating of the heart, agitation/aggressiveness, problems with speech, unusual 
movements (especially of the face or tongue) and reduced level of consciousness. Other symptoms 
may be: acute confusion, seizures (epilepsy), coma, a combination of fever, faster breathing, sweating, 
muscle stiffness and drowsiness or sleepiness, slowing of the breathing rate, aspiration, high blood 
pressure or low blood pressure, abnormal rhythms of the heart. Contact your doctor or hospital straight 
away if you experience any of the above symptoms. Show the doctor your pack of tablets. 
 
If you forget to take Olanzapine Apotex 
Take your tablets as soon as you remember. Do not take two doses in one day. 
  
If you stop taking Olanzapine Apotex 
Do not stop taking your tablets just because you feel better. It is important that you carry on taking 
Olanzapine Apotex for as long as your doctor tells you. 
 
If you suddenly stop taking Olanzapine Apotex, symptoms such as sweating, unable to sleep, tremor, 
anxiety or nausea and vomiting might occur. Your doctor may suggest you to reduce the dose 
gradually before stopping treatment. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 



162 

Tell your doctor immediately if you have:  
 unusual movement (a common side effect that may affect up to 1 in 10 people) mainly of the 

face or tongue; 
 blood clots in the veins (an uncommon side effect that may affect up to 1 in 100 people) 

especially in the legs (symptoms include swelling, pain, and redness in the leg), which may travel 
through blood vessels to the lungs causing chest pain and difficulty in breathing. If you notice any 
of these symptoms seek medical advice immediately; 

 a combination of fever, faster breathing, sweating, muscle stiffness and drowsiness or sleepiness 
(the frequency of this side effect cannot be estimated from the available data). 

 

Very common side effects (may affect more than 1 in 10 people) include weight gain; sleepiness; and 
increases in levels of prolactin in the blood. In the early stages of treatment, some people may feel 
dizzy or faint (with a slow heart rate), especially when getting up from a lying or sitting position. This 
will usually pass on its own but if it does not, tell your doctor. 
 

Common side effects (may affect up to 1 in 10 people) include changes in the levels of some blood 
cells, circulating fats and early in treatment, temporary increases in liver enzymes; increases in the level 
of sugars in the blood and urine; increases in levels of uric acid and creatine phosphokinase in the blood; 
feeling more hungry; dizziness; restlessness; tremor; unusual movements(dyskinesias); constipation; dry 
mouth; rash; loss of strength; extreme tiredness; water retention leading to swelling of the hands, ankles 
or feet; fever; joint pain; and sexual dysfunctions such as decreased libido in males and females or 
erectile dysfunction in males.  
 
Uncommon side effects (may affect up to 1 in 100 people) include hypersensitivity (e.g. swelling in the 
mouth and throat, itching, rash); diabetes or the worsening of diabetes, occasionally associated with 
ketoacidosis (ketones in the blood and urine) or coma; seizures, usually associated with a history of 
seizures (epilepsy); muscle stiffness or spasms (including eye movements); restless legs syndrome 
problems with speech; stuttering; slow heart rate; sensitivity to sunlight; bleeding from the nose; 
abdominal distension; drooling; memory loss or forgetfulness; urinary incontinence; lack of ability to 
urinate; hair loss; absence or decrease in menstrual periods; and changes in breasts in males and females 
such as an abnormal production of breast milk or abnormal growth. 
 
Rare side effects (may affect up to 1 in 1000 people) include lowering of normal body temperature; 
abnormal rhythms of the heart; sudden unexplained death; inflammation of the pancreas causing severe 
stomach pain, fever and sickness; liver disease appearing as yellowing of the skin and white parts of the 
eyes; muscle disease presenting as unexplained aches and pains; and prolonged and/or painful erection. 
 
Very rare side effects include serious allergic reactions such as Drug Reaction with Eosinophilia and 
Systemic Symptoms (DRESS). DRESS appears initially as flu-like symptoms with a rash on the face 
and then with an extended rash, high temperature, enlarged lymph nodes, increased levels of liver 
enzymes seen in blood tests and an increase in a type of white blood cell (eosinophilia). 
 
While taking olanzapine, elderly patients with dementia may suffer from stroke, pneumonia, urinary 
incontinence, falls, extreme tiredness, visual hallucinations, a rise in body temperature, redness of the 
skin and have trouble walking. Some fatal cases have been reported in this particular group of patients. 
 
In patients with Parkinson's disease Olanzapine Apotex may worsen the symptoms. 
 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not 
listed in this leaflet. You can also report side effects directly via the national reporting system listed in 
Appendix V. By reporting side effects you can help provide more information on the safety of this 
medicine. 
 
5. How to store Olanzapine Apotex 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


163 

 
Keep this medicine out of sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The 
expiry date refers to the last day of that month. 
 
This medicinal product does not require any special storage conditions. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Olanzapine Apotex contains 
The active substance is olanzapine. 
 Each Olanzapine Apotex 2.5 mg film-coated tablet contains 2.5 mg olanzapine. 
 Each Olanzapine Apotex 5 mg film-coated tablet contains 5 mg olanzapine. 
 Each Olanzapine Apotex 7.5 mg film-coated tablet contains 7.5 mg olanzapine. 
 Each Olanzapine Apotex 10 mg film-coated tablet contains 10 mg olanzapine. 
 
The other ingredients are (tablet core) lactose monohydrate, microcrystalline cellulose, maize 
starch, magnesium stearate, (tablet coat) hypromellose, hydroxypropylcellulose, macrogol 8000, 
titanium dioxide (E171).  
 
What Olanzapine Apotex looks like and contents of the pack 
 Olanzapine Apotex 2.5 mg are white, round, biconvex film-coated tablets engraved ‘APO’ on one 

side and ‘OLA’ over ‘2.5’ on the other side. 
 Olanzapine Apotex 5 mg are white, round biconvex film-coated tablets engraved ‘APO’ on one 

side and ‘OLA’ over ‘5’ on the other side. 
 Olanzapine Apotex 7.5 mg are white, round biconvex film-coated tablets engraved ‘APO’ on one 

side and ‘OLA’ over ‘7.5’ on the other side. 
 Olanzapine Apotex 10 mg are white, round biconvex film-coated tablets engraved ‘APO’ on one 

side and ‘OLA’ over ‘10’ on the other side. 
 
 Olanzapine Apotex 2.5 mg film-coated tablets are available in blisters packs of 28 tablets. 
 Olanzapine Apotex 7.5 mg film-coated tablets are available in blisters packs of 28 and 56 tablets.  
 Olanzapine Apotex 5 mg and 10 mg film- coated tablets are available in blister packs of 28, 56 

and 98 tablets.. 
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
Apotex Europe B.V.  
Archimedesweg 2,  
2333 CN, Leiden, 
The Netherlands 
 
Manufacturer 
Apotex Nederland B.V. 
Archimedesweg 2 
2333 CN Leiden 
The Netherlands 
 
Generis Farmacêutica, S.A. 
Rua João de Deus, 19 
2700-487 Amadora 



164 

Portugal 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
NV Apotex SA 
Tél/Tel:(32) 475.35.40 

Luxembourg/Luxemburg 
NV Apotex SA 
Tél/Tel:(32) 475.35.40 

България 
Apotex Europe B.V. 
тел. (31) 71. 565.77. 77 

Magyarország 
Apotex Europe B.V. 
Tel: (31) 71. 565.77. 77 

Česká republika 
 Aurovitas, spol. s r.o. 
Tel: (420) 234.705.721 

Malta 
Apotex Europe B.V. 
Tel:  (31) 71. 565.77.77 

Danmark 
Apotex Europe B.V. 
Tlf.: (31) 71. 565.77. 77 

Nederland 
Apotex Nederland B.V. 
Tel: (31) 71. 52.43.100 

Deutschland 
Apotex Europe B.V. 
Tel: (31) 71. 565.77. 77 

Norge 
Apotex Europe B.V. 
Tlf.: (31) 71. 565.77. 77 

Eesti 
Apotex Europe B.V. 
Tel: (31) 71. 565.77. 77 

Österreich 
Apotex Europe B.V. 
Tel: (31) 71. 565.77. 77 

Ελλάδα 
Apotex Europe B.V. 
Τηλ: (31) 71. 565.77. 77 

Polska 
 Aurovitas Pharma Polska Sp. z o.o. 
Tel: (048) 22.311.20.00 

España 
 Aurovitas Spain, S.A.U.Tel: (34) 
91.630.86.45 

Portugal 
Apotex Europe B.V. 
Tel: (31) 71. 565.77. 77 

France 
NV Apotex SA 
Tél: (32) 475.35.40 
Hrvatska  
Apotex Europe B.V.. 
Tel:  (31) 71. 565.77.77 

România 
Apotex Europe B.V. 
Tel: (31) 71. 565.77. 77 

Ireland 
Apotex Europe B.V. 
Tel:  (31) 71. 565.77.77 

Slovenija 
Apotex Europe B.V. 
Tel: (31) 71. 565.77. 77 

Ísland 
Apotex Europe B.V. 
Sími: (31) 71. 565.77. 77 

Slovenská republika 
Apotex Europe B.V. 
Tel: (31) 71. 565.77. 77 

Italia 
Apotex Europe B.V. 
Tel: (31) 71. 565.77. 77 

Suomi/Finland 
Apotex Europe B.V. 
Puh/Tel: (31) 71. 565.77. 77 

Κύπρος 
Apotex Europe B.V. 
Τηλ: (31) 71. 565.77. 77 

Sverige 
Apotex Europe B.V. 
Tel: (31) 71. 565.77. 77 

Latvija 
Apotex Europe B.V. 
Tel: (31) 71. 565.77. 77 

United Kingdom 
Apotex Europe B.V. 
Tel:  (31) 71. 565.77.77 



165 

Lietuva 
Apotex Europe B.V. 
Tel. (31) 71. 565.77. 77 

 

 
 
This leaflet was last revised in {month XXXX}. 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 

http://www.ema.europa.eu/


166 

Package leaflet: Information for the user 
 

Olanzapine Apotex 5 mg orodispersible tablets 
Olanzapine Apotex 10 mg orodispersible tablets 
Olanzapine Apotex 15 mg orodispersible tablets 
Olanzapine Apotex 20 mg orodispersible tablets 

 
Olanzapine 

 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 

 Keep this leaflet. You may need to read it again. 
 If you have any further questions, ask your doctor or pharmacist. 
 This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
 If you get any side effects talk to your doctor or pharmacist.This includes any possible side effects 

not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Olanzapine Apotex is and what it is used for 
2. What you need to know before you take Olanzapine Apotex 
3. How to take Olanzapine Apotex 
4. Possible side effects 
5. How to store Olanzapine Apotex 
6. Contents of the pack and other information 
 
 
1. What Olanzapine Apotex is and what it is used for 
 
Olanzapine Apotex contains the active substance olanzapine. Olanzapine Apotex belongs to a group of 
medicines called antipsychotics and is used to treat the following conditions:  

 Schizophrenia, a disease with symptoms such as hearing, seeing or sensing things which are 
not there, mistaken beliefs, unusual suspiciousness, and becoming withdrawn. People with this 
disease may also feel depressed, anxious or tense.  

 Moderate to severe manic episodes, a condition with symptoms of excitement or euphoria. 
 
Olanzapine Apotex has been shown to prevent recurrence of these symptoms in patients with bipolar 
disorder whose manic episode has responded to olanzapine treatment. 
 
 
2. What you need to know before you take Olanzapine Apotex 
 
Do not take Olanzapine Apotex 
 If you are allergic (hypersensitive) to olanzapine or any of the other ingredients of this medicine 

(listed in section 6). An allergic reaction may be recognised as a rash, itching, a swollen face, 
swollen lips or shortness of breath. If this has happened to you, tell your doctor.  

 If you have been previously diagnosed with eye problems such as certain kinds of glaucoma 
(increased pressure in the eye).  

 
Warnings and precautions 
Talk to your doctor or pharmacist before taking Olanzapine Apotex. 
 The use of Olanzapine Apotex in elderly patients with dementia is not recommended as it may have 

serious side effects. 
 Medicines of this type may cause unusual movements mainly of the face or tongue. If this happens 

after you have been given Olanzapine Apotex tell your doctor.  
 Very rarely, medicines of this type cause a combination of fever, faster breathing, sweating, 



167 

muscle stiffness and drowsiness or sleepiness. If this happens, contact your doctor at once.  
 Weight gain has been seen in patients taking Olanzapine Apotex. You and your doctor should 

check your weight regularly. Consider referral to a dietician or help with a diet plan if necessary. 
 High blood sugar and high levels of fat (triglycerides and cholesterol) have been seen in patients 

taking Olanzapine Apotex. Your doctor should do blood tests to check blood sugar and certain fat 
levels before you start taking Olanzapine Apotex and regularly during treatment. 

 Tell the doctor if you or someone else in your family has a history of blood clots, as medicines 
like these have been associated with formation of blood clots.  

 
If you suffer from any of the following illnesses tell your doctor as soon as possible:  
 
 Stroke or “mini” stroke (temporary symptoms of stroke) 
 Parkinson’s disease 
 Prostate problems 
 A blocked intestine (Paralytic ileus) 
 Liver or kidney disease 
 Blood disorders 
 Heart disease 
 Diabetes 
 Seizures 
 If you know that you may have salt depletion as a result of prolonged severe diarrhoea and 

vomiting (being sick) or usage of diuretics (water tablets)  
 

 
If you suffer from dementia, you or your carer/relative should tell your doctor if you have ever had a 
stroke or “mini” stroke.  
 
As a routine precaution, if you are over 65 years your blood pressure may be monitored by your 
doctor.  
 
Children and adolescents 
Olanzapine Apotex is not for patients who are under 18 years.  
 
Other medicines and Olanzapine Apotex 
Only take other medicines while you are on Olanzapine Apotex if your doctor tells you that you can. 
You might feel drowsy if Olanzapine Apotex is taken in combination with antidepressants or 
medicines taken for anxiety or to help you sleep (tranquillisers).  
 
Tell your doctor if you are taking, have recently taken or might take any other medicines. 
 
In particular, tell your doctor if you are taking: 
 medicines for Parkinson’s disease. 
 carbamazepine (an anti-epileptic and mood stabiliser), fluvoxamine (an antidepressant) or 

ciprofloxacin (an antibiotic) – it may be necessary to change your Olanzapine Apotex dose. 
 
Olanzapine Apotex with alcohol 
Do not drink any alcohol if you have been given Olanzapine Apotex as together with alcohol it may 
make you feel drowsy.  
 
Pregnancy and breast-feeding 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor for advice before taking this medicine.  
You should not be given this medicine when breast-feeding, as small amounts of OlanzapineApotex 
can pass into breast milk 
 
The following symptoms may occur in newborn babies, of mothers that have used Olanzapine Apotex 
in the last trimester (last three months of their pregnancy): shaking, muscle stiffness and/or weakness, 



168 

sleepiness, agitation, breathing problems, and difficulty in feeding. If your baby develops any of these 
symptoms you may need to contact your doctor. 
 
Driving and using machines 
There is a risk of feeling drowsy when you are given Olanzapine Apotex. If this happens do not drive 
or operate any tools or machines. Tell your doctor.  
 
 
3. How to take Olanzapine Apotex 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure.  
 
Your doctor will tell you how many Olanzapine Apotex tablets to take and how long you should 
continue to take them. The daily dose of Olanzapine Apotex is between 5 mg and 20 mg. Consult your 
doctor if your symptoms return but do not stop taking Olanzapine Apotex unless your doctor tells you 
to.  
 
You should take your Olanzapine Apotex tablets once a day following the advice of your doctor. Try 
to take your tablets at the same time each day. It does not matter whether you take them with or 
without food. Olanzapine Apotex orodispersible tablets are for oral use.  
 
Olanzapine Apotex tablets break easily, so you should handle the tablets carefully. Do not handle the 
tablets with wet hands as the tablets may break up.  

 
You can also place the tablet in a full glass or cup of water, orange juice, apple juice, milk or or coffee 
and stir.  With some drinks, the mixture may change colour and possibly become cloudy. Drink it 
straight away.  

 
If you take more Olanzapine Apotex than you should 
Patients who have taken more Olanzapine Apotex than they should have experienced the following 
symptoms: rapid beating of the heart, agitation/aggressiveness, problems with speech, unusual 
movements (especially of the face or tongue) and reduced level of consciousness. Other symptoms 
may be: acute confusion, seizures (epilepsy), coma, a combination of fever, faster breathing, sweating, 
muscle stiffness and drowsiness or sleepiness, slowing of the breathing rate, aspiration, high blood 
pressure or low blood pressure, abnormal rhythms of the heart. Contact your doctor or hospital straight 
away if you experience any of the above symptoms. Show the doctor your pack of tablets.  
  
If you forget to take Olanzapine Apotex 
Take your tablets as soon as you remember. Do not take two doses in one day. 
 
If you stop taking Olanzapine Apotex 
Do not stop taking your tablets just because you feel better. It is important that you carry on taking 
Olanzapine Apotex for as long as your doctor tells you.  
 
If you suddenly stop taking Olanzapine Apotex, symptoms such as sweating, unable to sleep, tremor, 
anxiety or nausea and vomiting might occur. Your doctor may suggest you to reduce the dose 
gradually before stopping treatment.  
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Tell your doctor immediately if you have:  



169 

 unusual movement (a common side effect that may affect up to 1 in 10 people) mainly of the 
face or tongue; 

 blood clots in the veins (an uncommon side effect that may affect up to 1 in 100 people) 
especially in the legs (symptoms include swelling, pain, and redness in the leg), which may travel 
through blood vessels to the lungs causing chest pain and difficulty in breathing. If you notice any 
of these symptoms seek medical advice immediately; 

 a combination of fever, faster breathing, sweating, muscle stiffness and drowsiness or sleepiness 
(the frequency of this side effect cannot be estimated from the available data). 

 

Very common side effects (may affect more than 1 in 10 people) include weight gain; sleepiness; and 
increases in levels of prolactin in the blood. In the early stages of treatment, some people may feel 
dizzy or faint (with a slow heart rate), especially when getting up from a lying or sitting position. This 
will usually pass on its own but if it does not, tell your doctor. 
 

Common side effects (may affect up to 1 in 10 people) include changes in the levels of some blood 
cells, circulating fats and early in treatment, temporary increases in liver enzymes; increases in the level 
of sugars in the blood and urine; increases in levels of uric acid and creatine phosphokinase in the blood; 
feeling more hungry; dizziness; restlessness; tremor; unusual movements(dyskinesias); constipation; dry 
mouth; rash; loss of strength; extreme tiredness; water retention leading to swelling of the hands, ankles 
or feet; fever; joint pain; and sexual dysfunctions such as decreased libido in males and females or 
erectile dysfunction in males.  
 
Uncommon side effects (may affect up to 1 in 100 people) include hypersensitivity (e.g. swelling in the 
mouth and throat, itching, rash); diabetes or the worsening of diabetes, occasionally associated with 
ketoacidosis (ketones in the blood and urine) or coma; seizures, usually associated with a history of 
seizures (epilepsy); muscle stiffness or spasms (including eye movements); restless legs syndrome 
problems with speech; stuttering; slow heart rate; sensitivity to sunlight; bleeding from the nose; 
abdominal distension; drooling; memory loss or forgetfulness; urinary incontinence; lack of ability to 
urinate; hair loss; absence or decrease in menstrual periods; and changes in breasts in males and females 
such as an abnormal production of breast milk or abnormal growth. 
 
Rare side effects (may affect up to 1 in 1000 people) include lowering of normal body temperature; 
abnormal rhythms of the heart; sudden unexplained death; inflammation of the pancreas causing severe 
stomach pain, fever and sickness; liver disease appearing as yellowing of the skin and white parts of the 
eyes; muscle disease presenting as unexplained aches and pains; and prolonged and/or painful erection. 
 
Very rare side effects include serious allergic reactions such as Drug Reaction with Eosinophilia and 
Systemic Symptoms (DRESS). DRESS appears initially as flu-like symptoms with a rash on the face 
and then with an extended rash, high temperature, enlarged lymph nodes, increased levels of liver 
enzymes seen in blood tests and an increase in a type of white blood cell (eosinophilia). 
 
While taking olanzapine, elderly patients with dementia may suffer from stroke, pneumonia, urinary 
incontinence, falls, extreme tiredness, visual hallucinations, a rise in body temperature, redness of the 
skin and have trouble walking. Some fatal cases have been reported in this particular group of patients. 
 
In patients with Parkinson's disease Olanzapine Apotex may worsen the symptoms. 
 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not 
listed in this leaflet. You can also report side effects directly via the national reporting system listed in 
Appendix V. By reporting side effects you can help provide more information on the safety of this 
medicine. 
 
5. How to store Olanzapine Apotex 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


170 

Keep this medicine out of sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The expiry date 
refers to the last day of that month. 
 
This medicinal product does not require any special storage conditions. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Olanzapine Apotex contains 
The active substance is olanzapine. 
 Each Olanzapine Apotex 5 mg orodispersible tablet contains 5 mg olanzapine. 
 Each Olanzapine Apotex 10 mg orodispersible tablet contains 10 mg olanzapine. 
 Each Olanzapine Apotex 15 mg orodispersible tablet contains 15 mg olanzapine. 
 Each Olanzapine Apotex 20 mg orodispersible tablet contains 20 mg olanzapine. 
 
The other ingredients are mannitol (E421), microcrystalline cellulose, carmellose calcium, sucralose, 
magnesium stearate and colloidal anhydrous silica. 
 
What Olanzapine Apotex looks like and contents of the pack 
Orodispersible tablet is the technical name for a tablet which dissolves directly in your mouth, so that 
it can be easily swallowed. 
 
 Olanzapine Apotex 5 mg orodispersible tablets are yellow round flat faced radial edge tablets 

engraved  ‘APO’ on one side and ‘OL’ over ‘5’ on the other side. 
 Olanzapine Apotex 10 mg orodispersible tablets are yellow round flat faced radial edge tablets 

engraved  ‘APO’ on one side and ‘OL’ over ‘10’ on the other side.   
 Olanzapine Apotex 15 mg orodispersible tablets are yellow round flat faced radial edge tablets 

engraved  ‘APO’ on one side and ‘OL’ over ‘15’ on the other side 
 Olanzapine Apotex 20 mg orodispersible tablets are yellow round flat faced  radial edge tablets 

engraved  ‘APO’ on one side and ‘OL’ over ‘20’ on the other side. 
 
 Olanzapine Apotex 5 mg and 10 mg orodispersible tablets are available in blisters packs of 28 , 56 

and 98 tablets. 
 Olanzapine Apotex 20 mg orodispersible tablets are available in blister packs of 28 and 56 tablets. 
 Olanzapine Apotex 15 mg orodispersible tablets are available in blisters packs of 28 tablets. 
 
Not all pack sizes may be marketed. 
 
 
Marketing Authorisation Holder 
 
Apotex Europe B.V.  
Archimedesweg 2,  
2333 CN, Leiden, 
The Netherlands 
 
Manufacturer 
Apotex Nederland B.V. 
Archimedesweg 2  
2333 CN Leiden 
The Netherlands 
 



171 

APL Swift Services (Malta) Ltd. 
HF26 Hal Far Industrial Estate, 
Hal Far, Birzebbugia, 
BBG 3000, Malta. 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
NV Apotex SA 
Tél/Tel:(32) 475.35.40 

Luxembourg/Luxemburg 
NV Apotex SA 
Tél/Tel:(32) 475.35.40 

България 
Apotex Europe B.V. 
тел. (31) 71. 565.77. 77 

Magyarország 
Apotex Europe B.V. 
Tel: (31) 71. 565.77. 77 

Česká republika 
 Aurovitas, spol. s r.o.Tel: (420) 234.705.721 

Malta 
Apotex Europe B.V. 
Tel:  (31) 71. 565.77.77 

Danmark 
Apotex Europe B.V. 
Tlf.: (31) 71. 565.77. 77 

Nederland 
Apotex Nederland B.V. 
Tel: (31) 71. 52.43.100 

Deutschland 
Apotex Europe B.V. 
Tel: (31) 71. 565.77. 77 

Norge 
Apotex Europe B.V. 
Tlf.: (31) 71. 565.77. 77 

Eesti 
Apotex Europe B.V. 
Tel: (31) 71. 565.77. 77 

Österreich 
Apotex Europe B.V. 
Tel: (31) 71. 565.77. 77 

Ελλάδα 
Apotex Europe B.V. 
Τηλ: (31) 71. 565.77. 77 

Polska 
 Aurovitas Pharma Polska Sp. z o.o. 
Tel: (048) 22.311.20.00  

España 
 Aurovitas Spain, S.A.U.Tel: (34) 
91.630.86.45 

Portugal 
Apotex Europe B.V. 
Tel: (31) 71. 565.77. 77 

France 
NV Apotex SA 
Tél: (32) 475.35.40 
Hrvatska  
Apotex Europe B.V.. 
Tel:  (31) 71. 565.77.77 

România 
Apotex Europe B.V. 
Tel: (31) 71. 565.77. 77 

Ireland 
Apotex Europe B.V. 
Tel:  (31) 71. 565.77.77 

Slovenija 
Apotex Europe B.V. 
Tel: (31) 71. 565.77. 77 

Ísland 
Apotex Europe B.V. 
Sími: (31) 71. 565.77. 77 

Slovenská republika 
Apotex Europe B.V. 
Tel: (31) 71. 565.77. 77 

Italia 
Apotex Europe B.V. 
Tel: (31) 71. 565.77. 77 

Suomi/Finland 
Apotex Europe B.V. 
Puh/Tel: (31) 71. 565.77. 77 



172 

 
Κύπρος 
Apotex Europe B.V. 
Τηλ: (31) 71. 565.77. 77 

Sverige 
Apotex Europe B.V. 
Tel: (31) 71. 565.77. 77 

Latvija 
Apotex Europe B.V. 
Tel: (31) 71. 565.77. 77 

United Kingdom 
Apotex Europe B.V. 
Tel:  (31) 71. 565.77.77 

Lietuva 
Apotex Europe B.V. 
Tel. (31) 71. 565.77. 77 

 

 
This leaflet was last revised in {month XXXX}. 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 

http://www.ema.europa.eu/

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET