Olazax

1 

  

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX I 

 

SUMMARY OF PRODUCT CHARACTERISTICS 

 



2 

1. NAME OF THE MEDICINAL PRODUCT 

 

Olazax 5 mg tablets 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

Each tablet contains 5 mg olanzapine. 

 

Excipient with known effect: Each tablet contains 0.23 mg aspartame 

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL form 

 

Tablet 

Yellow coloured circular flat bevelled edge tablets with ‘B’ debossed on one 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. 

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. 



3 

 

 

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 % versus 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 % versus 0.4 %, respectively). All 

olanzapine and placebo-treated patients who experienced a cerebrovascular event had pre-existing risk 



4 

factors. Age > 75 years and vascular/mixed type dementia were identified as risk factors for CVAE in 

association with olanzapine treatment. The efficacy of olanzapine was not established in these trials. 

 

Parkinson's disease 

The use of olanzapine in the treatment of dopamine agonist associated psychosis in patients with 

Parkinson's disease is not recommended.  

 

In clinical trials, worsening of Parkinsonian symptomatology and hallucinations were reported very 

commonly and more frequently than with placebo (see section 4.8), and olanzapine was not more 

effective than placebo in the treatment of psychotic symptoms.  

 

In these trials, patients were initially required to be stable on the lowest effective dose of 

anti-Parkinsonian medicinal products (dopamine agonist) and to remain on the same anti-Parkinsonian 

medicinal products and dosages throughout the study. Olanzapine was started at 2.5 mg/day and 

titrated to a maximum of 15 mg/day based on investigator judgement. 

 

Neuroleptic Malignant Syndrome (NMS) 

NMS is a potentially life-threatening condition associated with antipsychotic medicinal products. 

Rare cases reported as NMS have also been received in association with olanzapine.  

 

Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence 

of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac 

dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria 

(rhabdomyolysis), and acute renal failure.  

 

If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever 

without additional clinical manifestations of NMS, all antipsychotic medicines, including olanzapine 

must be discontinued. 

 

Hyperglycaemia and diabetes 

Hyperglycaemia and/or development or exacerbation of diabetes occasionally associated with 

ketoacidosis or coma has been reported uncommonly, including some fatal cases (see section 4.8). In 

some cases, a prior increase in body weight has been reported which may be a predisposing factor. 

Appropriate clinical monitoring is advisable in accordance with utilised antipsychotic guidelines e.g. 

measuring of blood glucose at baseline, 12 weeks after starting olanzapine treatment and annually 

thereafter . Patients treated with any antipsychotic medicines, including olanzapine, should be 

observed for signs and symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia, and 

weakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus should be 

monitored regularly for worsening of glucose control. Weight should be monitored regularly e.g. at 

baseline, 4, 8 and 12 weeks after starting olanzapine treatment and quarterly thereafter. 

 

Lipid alterations 

Undesirable alterations in lipids have been observed in olanzapine-treated patients in 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, 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 



5 

Transient, asymptomatic elevations of hepatic aminotransferases, alanine transferase (ALT), 

aspartatetransferase (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 



6 

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). 

 

Phenylalanine 

Olazax tablet contains aspartame, which is a source of phenylalanine. 

May be harmful for people with phenylketonuria. 

 

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. 



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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. 

 

New born infants exposed to antipsychotics (including olanzapine) during the third trimester of 

pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that 

may vary in severity and duration following delivery. There have been reports of agitation, 

hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, 

newborns should be monitored carefully.  

 

Breastfeeding 

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. 

 



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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, 

akathisia, parkinsonism, leukopenia, neutropenia (see section 4.4), dyskinesia, orthostatic 

hypotension, anticholinergic effects, transient asymptomatic elevations of hepatic aminotransferases 

(see section 4.4), rash, asthenia, fatigue, pyrexia, arthralgia, increased alkaline phosphatase, high 

gamma glutamyltransferase, high uric acid, high creatine phosphokinase and oedema. 

 

Tabulated list of adverse reactions 

The following table lists the adverse reactions and laboratory investigations observed from 

spontaneous reporting and in clinical trials. Within each frequency grouping, adverse reactions are 

presented in order of decreasing seriousness. The frequency terms listed are defined as follows: Very 

common (≥1/10), common (≥1/100 to < 1/10), uncommon (≥1/1,000 to < 1/100), rare (≥1/10,000 to 

< 1/1,000), very rare (<1/10,000), not known (cannot be estimated from the data available). 

 

Very common Common Uncommon  Rare Not 

known 

Blood and the lymphatic system disorders  

 Eosinophilia 

Leukopenia10 

Neutropenia10 

 Thrombocytopeni

a11 

 

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 

Neuroleptic 

malignant 

syndrome (see 

section 4.4) 12 

Discontinuation 

symptoms7, 12 

 

 



9 

Restless legs 

syndrome11 
Cardiac disorders  

  Bradycardia 

QTc prolongation 

(see section 4.4) 

Ventricular 

tachycardia/fibrill

ation, sudden 

death (see section 

4.4)11 

 

Vascular disorders  

Orthostatic 

hypotension10 

 Thromboembolis

m (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  Rhabdomyolysis 
11 

 

Renal and urinary disorders  

  Urinary 

incontinence, 

urinary retention 

Urinary 

hesitation11 

  

Pregnancy, puerperium and perinatal conditions                                         

    Drug 

withdraw

al 

syndrome 



10 

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/br

east enlargement 

in males 

Priapism12  

General disorders and administration site conditions  

 Asthenia 

Fatigue 

Oedema 

Pyrexia10 

   

Investigations  

Elevated plasma 

prolactin levels8 

Increased alkaline 

phosphatase10 

High creatine 

phosphokinase11 

High Gamma 

Glutamyltransferase10 

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. 



11 

 
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. 

 
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.  



12 

 

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. 

 
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. 

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


13 

 

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  

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; α 1 adrenergic; and histamine 

H1 receptors. Animal behavioural studies with olanzapine indicated 5HT, dopamine, and cholinergic 

antagonism, consistent with the receptor-binding profile. Olanzapine demonstrated a greater in vitro 

affinity for serotonin 5HT2 than dopamine D2 receptors and greater 5HT2 than D2 activity in vivo, 

models. Electrophysiological studies demonstrated that olanzapine selectively reduced the firing of 

mesolimbic (A10) dopaminergic neurons, while having little effect on the striatal (A9) pathways 

involved in motor function. Olanzapine reduced a conditioned avoidance response, a test indicative of 

antipsychotic activity, at doses below those producing catalepsy, an effect indicative of motor side-

effects. Unlike some other antipsychotic agents, olanzapine increases responding in an “anxiolytic” 

test. 

 

In a single oral dose (10 mg) Positron Emission Tomography (PET) study in healthy volunteers, 

olanzapine produced a higher 5HT2A than dopamine D2 receptor occupancy. In addition, a Single 

Photon Emission Computed Tomography (SPECT) imaging study in schizophrenic patients revealed 

that olanzapine-responsive patients had lower striatal 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 



14 

manic or mixed episode of bipolar disorder, olanzapine demonstrated superior efficacy to placebo and 

valproate semisodium (divalproex) in reduction of manic symptoms over 3 weeks. Olanzapine also 

demonstrated comparable efficacy results to haloperidol in terms of the proportion of patients in 

symptomatic remission from mania and depression at 6 and 12 weeks.  

 

In a co-therapy study of patients treated with lithium or valproate for a minimum of 2 weeks, the 

addition of olanzapine 10 mg (co-therapy with lithium or valproate) resulted in a greater reduction in 

symptoms of mania than lithium or valproate monotherapy after 6 weeks. 

 

In a 12-month recurrence prevention study in manic episode patients who achieved remission on 

olanzapine and were then randomised to olanzapine or placebo, olanzapine demonstrated statistically 

significant superiority over placebo on the primary endpoint of bipolar recurrence. Olanzapine also 

showed a statistically significant advantage over placebo in terms of preventing either recurrence into 

mania or recurrence into depression. 

 

In a second 12-month recurrence prevention study in manic episode patients who achieved remission 

with a combination of olanzapine and lithium and were then randomised to olanzapine or lithium 

alone, olanzapine was statistically non-inferior to lithium on the primary endpoint of bipolar 

recurrence (olanzapine 30.0 %, lithium 38.3 %; p = 0.055). 

 

In an 18-month co-therapy study in manic or mixed episode patients stabilised with olanzapine plus 

a mood stabiliser (lithium or valproate), long-term olanzapine co-therapy with lithium or valproate 

was not statistically significantly superior to lithium or valproate alone in delaying bipolar recurrence, 

defined according to syndromic (diagnostic) criteria. 

 

Paediatric population 

Controlled efficacy data in adolescents (ages 13 to 17 years) are limited to short term studies in 

schizophrenia (6 weeks) and mania associated with bipolar I disorder (3 weeks), involving less than 

200 adolescents. Olanzapine was used as a flexible dose starting with 2.5 and ranging up to 

20 mg/day. During treatment with olanzapine, adolescents gained significantly more weight compared 

with adults. The magnitude of changes in fasting total cholesterol, LDL cholesterol, triglycerides, and 

prolactin (see sections 4.4 and 4.8) were greater in adolescents than in adults. There are no controlled 

data on maintenance of effect or long term safety (see sections 4.4 and 4.8). Information on long term 

safety is primarily limited to open-label, uncontrolled data. 

 

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 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 



15 

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 hr) 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 hr) 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 

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 %). 

 

SmokingIn non-smoking versus smoking subjects (males and females) the mean elimination half-life 

was prolonged (38.6 versus 30.4 hr) 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. 



16 

 

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 foetall 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. 

 

 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 

 

Mannitol E 421 

Microcrystalline cellulose 

Aspartame E 951 

Crospovidone 

Magnesium stearate 

 

6.2 Incompatibilities 

 

Not applicable. 

 

6.3 Shelf life 

 

30 months  

 

6.4 Special precautions for storage 

 

Store below 30ºC 

 



17 

6.5 Nature and contents of container 

 

Aluminium/aluminium blisters in cartons of 28, 56 tablets per carton. 

 

Not all pack sizes may be marketed 

 

6.6 Special precautions for disposal  

 

No special requirements 

 

 

7. MARKETING AUTHORISATION HOLDER 

 

Glenmark Pharmaceuticals s.r.o. 

Hvězdova 1716/2b, 140 78 Praha 4 

Czech Republic  

 

 

8. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/09/597/001 

EU/1/09/597/006 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 

Date of first authorisation: 11.12.2009 

 

Date of renewal: 22.08.2014 

 

 

10. DATE OF REVISION OF THE TEXT 

 

{MM/YYYY} 

 

 

Detailed information on this medicinal product is available on the website of the European Medicines 

Agency (EMA) http://www.emea.europa.eu 

http://www.emea.europa.eu/


18 

1. NAME OF THE MEDICINAL PRODUCT 

 

Olazax 7.5 mg tablets 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

Each tablet contains 7.5 mg olanzapine. 

 

Excipient with known effect: Each tablet contains 0.35 mg aspartame 

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL form 

 

Tablet 

Yellow coloured circular flat bevelled edge tablets with ‘C’ debossed on one 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. 

 

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. 



19 

 

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 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 % versus 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 % versus 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. 



20 

 

Parkinson's disease 

The use of olanzapine in the treatment of dopamine agonist associated psychosis in patients with 

Parkinson's disease is not recommended.  

 

In clinical trials, worsening of Parkinsonian symptomatology and hallucinations were reported very 

commonly and more frequently than with placebo (see section 4.8), and olanzapine was not more 

effective than placebo in the treatment of psychotic symptoms.  

 

In these trials, patients were initially required to be stable on the lowest effective dose of anti-

Parkinsonian medicinal products (dopamine agonist) and to remain on the same anti-Parkinsonian 

medicinal products and dosages throughout the study. Olanzapine was started at 2.5 mg/day and 

titrated to a maximum of 15 mg/day based on investigator judgement. 

 

Neuroleptic Malignant Syndrome (NMS) 

NMS is a potentially life-threatening condition associated with antipsychotic medicinal products. 

Rare cases reported as NMS have also been received in association with olanzapine.  

 

Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence 

of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac 

dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria 

(rhabdomyolysis), and acute renal failure.  

 

If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever 

without additional clinical manifestations of NMS, all antipsychotic medicines, including olanzapine 

must be discontinued. 

 

Hyperglycaemia and diabetes 

Hyperglycaemia and/or development or exacerbation of diabetes occasionally associated with 

ketoacidosis or coma has been reported uncommonly, including some fatal cases (see section 4.8). In 

some cases, a prior increase in body weight has been reported which may be a predisposing factor. 

Appropriate clinical monitoring is advisable in accordance with utilised antipsychotic guidelines e.g. 

measuring of blood glucose at baseline, 12 weeks after starting olanzapine treatment and annually 

thereafter. Patients treated with any antipsychotic medicines, including olanzapine, should be 

observed for signs and symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia, and 

weakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus should be 

monitored regularly for worsening of glucose control. Weight should be monitored regularly e.g. at 

baseline, 4, 8 and 12 weeks after starting olanzapine treatment and quarterly thereafter. 

 

Lipid alterations 

Undesirable alterations in lipids have been observed in olanzapine-treated patients in 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, 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), 

aspartatetransferase (AST) have been seen commonly, especially in early treatment.  



21 

 

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 



22 

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. Long-term outcomes associated with these events have 

not been studied and remain unknown (see sections 4.8 and 5.1). 

 

Phenylalanine 

Olazax tablet contains aspartame, which is a source of phenylalanine. 

May be harmful for people with phenylketonuria. 

 

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 

nonsmokers and 77 % in male smokers. The mean increase in olanzapine AUC was 52 % and 108 % 

respectively. 

 

A lower starting dose of olanzapine should be considered in patients who are using 

fluvoxamine or any other CYP1A2 inhibitors, such as ciprofloxacin.  

 

A decrease in the dose of olanzapine should be considered if treatment with an inhibitor of CYP1A2 

is initiated. 

 

Decreased bioavailability 

Activated charcoal reduces the bioavailability of oral olanzapine by 50 to 60 % and should be taken at 

least 2 hours before or after olanzapine. 

 

Fluoxetine (a CYP2D6 inhibitor), single doses of antacid (aluminium, magnesium) or cimetidine have 

not been found to significantly affect the pharmacokinetics of olanzapine. 



23 

 

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. 

 

New born infants exposed to antipsychotics (including olanzapine) during the third trimester of 

pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that 

may vary in severity and duration following delivery. There have been reports of agitation, 

hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, 

newborns should be monitored carefully. 

 

Breast-feeding 

In a study in breast-feeding, healthy women, olanzapine was excreted in breast milk. Mean infant 

exposure (mg/kg) at steady state was estimated to be 1.8 % of the maternal olanzapine dose (mg/kg). 

Patients should be advised not to breast-feed an infant if they are taking olanzapine. 

 

Fertility 

Effects on fertility are unknown (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. 

 



24 

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, 

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 (< 01/10,000), not known (cannot be estimated from the data available). 

 

Very common Common Uncommon  Rare Not known 

Blood and the lymphatic system disorders  

 Eosinophilia 

Leukopenia10 

Neutropenia10 

 

 

Thrombocytopeni

a11 

 

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  



25 

QTc prolongation 

(see section 4.4) 

tachycardia/fibrill

ation, 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 

Eosinophilia 

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 

Amenorrhea 

Breast enlargement 

Galactorrhea in 

females 

Priapism12  



26 

males and females Gynaecomastia/breas

t enlargement in 

males 

General disorders and administration site conditions  

 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 can not 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.  

 



27 

9 Adverse event identified from clinical trials in the Olanzapine Integrated Database. 

 
10 As assessed by measured values from clinical trials in the Olanzapine Integrated Database. 

 
11 Adverse event identified from spontaneous post-marketing reporting with frequency determined 

utilising the Olanzapine Integrated Database. 

 
12 Adverse event identified from spontaneous post-marketing reporting with frequency estimated at 

the upper limit of the 95% confidence interval utilising the Olanzapine Integrated Database. 

 

Long-term exposure (at least 48 weeks) 

The proportion of patients who had adverse, clinically significant changes in weight gain, glucose, 

total/LDL/HDL cholesterol or triglycerides increased over time. In adult patients who completed 

9-12 months of therapy, the rate of increase in mean blood glucose slowed after approximately 

6 months. 

 

Additional information on special populations 

In clinical trials in elderly patients with dementia, olanzapine treatment was associated with a higher 

incidence of death and cerebrovascular adverse reactions compared to placebo (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). 



28 

 

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. 

 
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 %. 

 

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


29 

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  

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; α 1 

adrenergic; and histamine H1 receptors. Animal behavioural studies with olanzapine indicated 5HT, 

dopamine, and cholinergic antagonism, consistent with the receptor-binding profile. Olanzapine 

demonstrated a greater in vitro affinity for serotonin 5HT2 than dopamine D2 receptors and greater 

5HT2 than D2 activity in vivo, models. Electrophysiological studies demonstrated that olanzapine 

selectively reduced the firing of mesolimbic (A10) dopaminergic neurons, while having little effect on 

the striatal (A9) pathways involved in motor function. Olanzapine reduced a conditioned avoidance 

response, a test indicative of antipsychotic activity, at doses below those producing catalepsy, an 

effect indicative of motor side-effects. Unlike some other antipsychotic agents, olanzapine increases 

responding in an “anxiolytic” test. 

 

In a single oral dose (10 mg) Positron Emission Tomography (PET) study in healthy volunteers, 

olanzapine produced a higher 5HT2A than dopamine D2 receptor occupancy. In addition, a Single 

Photon Emission Computed Tomography (SPECT) imaging study in schizophrenic patients revealed 

that olanzapine-responsive patients had lower striatal 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.  

 



30 

In a co-therapy study of patients treated with lithium or valproate for a minimum of 2 weeks, the 

addition of olanzapine 10 mg (co-therapy with lithium or valproate) resulted in a greater reduction in 

symptoms of mania than lithium or valproate monotherapy after 6 weeks. 

 

In a 12-month recurrence prevention study in manic episode patients who achieved remission on 

olanzapine and were then randomised to olanzapine or placebo, olanzapine demonstrated statistically 

significant superiority over placebo on the primary endpoint of bipolar recurrence. Olanzapine also 

showed a statistically significant advantage over placebo in terms of preventing either recurrence into 

mania or recurrence into depression. 

 

In a second 12-month recurrence prevention study in manic episode patients who achieved remission 

with a combination of olanzapine and lithium and were then randomised to olanzapine or lithium 

alone, olanzapine was statistically non-inferior to lithium on the primary endpoint of bipolar 

recurrence (olanzapine 30.0 %, lithium 38.3 %; p = 0.055). 

 

In an 18-month co-therapy study in manic or mixed episode patients stabilised with olanzapine plus 

a mood stabiliser (lithium or valproate), long-term olanzapine co-therapy with lithium or valproate 

was not statistically significantly superior to lithium or valproate alone in delaying bipolar recurrence, 

defined according to syndromic (diagnostic) criteria. 

 

Paediatric population 

Controlled efficacy data in adolescents (ages 13 to 17 years) are limited to short term studies in 

schizophrenia (6 weeks) and mania associated with bipolar I disorder (3 weeks), involving less than 

200 adolescents. Olanzapine was used as a flexible dose starting with 2.5 and ranging up to 

20 mg/day. During treatment with olanzapine, adolescents gained significantly more weight compared 

with adults. The magnitude of changes in fasting total cholesterol, LDL cholesterol, triglycerides, and 

prolactin (see sections 4.4 and 4.8) were greater in adolescents than in adults. There are no controlled 

data on maintenance of effect or long term safety (see sections 4.4 and 4.8). Information on long term 

safety is primarily limited to open-label, uncontrolled data. 

 

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 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 hr) 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 



31 

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 hr) 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 

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 hr) 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 



32 

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. 

 

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 E 421 

Microcrystalline cellulose 

Aspartame E 951 

Crospovidone 

Magnesium stearate 

 

6.2 Incompatibilities 

 

Not applicable. 

 

6.3 Shelf life 

 

30 months  

 

6.4 Special precautions for storage 

 

Store below 30ºC 

 

6.5 Nature and contents of container 

 

Aluminium/aluminium blisters in cartons of 28, 56 tablets per carton 

 

Not all pack sizes may be marketed 



33 

 

6.6 Special precautions for disposal  

 

No special requirements 

 

 

7. MARKETING AUTHORISATION HOLDER 

 

Glenmark Pharmaceuticals s.r.o. 

Hvězdova 1716/2b, 140 78 Praha 4 

Czech Republic  

 

 

8. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/09/597/002 

EU/1/09/597/007 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 

Date of first authorisation: 11.12.2009 

Date of renewal: 22.08.2014 

 

 

10. DATE OF REVISION OF THE TEXT 

 

{MM/YYYY} 

 

 

Detailed information on this medicinal product is available on the website of the European Medicines 

Agency (EMA) http://www.emea.europa.eu 

http://www.emea.europa.eu/


34 

1. NAME OF THE MEDICINAL PRODUCT 

 

Olazax 10 mg tablets 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

Each tablet contains 10 mg olanzapine. 

 

Excipient with known effect: Each tablet contains 0.46 mg aspartame 

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL form 

 

Tablet 

Yellow coloured circular flat bevelled edge tablets with ‘OL’ debossed on one side and ‘D’ debossed 

on 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. 

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. 



35 

 

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 % versus 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 % versus 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. 



36 

 

Parkinson's disease 

The use of olanzapine in the treatment of dopamine agonist associated psychosis in patients with 

Parkinson's disease is not recommended.  

 

In clinical trials, worsening of Parkinsonian symptomatology and hallucinations were reported very 

commonly and more frequently than with placebo (see section 4.8), and olanzapine was not more 

effective than placebo in the treatment of psychotic symptoms.  

 

In these trials, patients were initially required to be stable on the lowest effective dose of anti 

Parkinsonian medicinal products (dopamine agonist) and to remain on the same anti-Parkinsonian 

medicinal products and dosages throughout the study. Olanzapine was started at 2.5 mg/day and 

titrated to a maximum of 15 mg/day based on investigator judgement. 

 

Neuroleptic Malignant Syndrome (NMS) 

NMS is a potentially life-threatening condition associated with antipsychotic medicinal products. 

Rare cases reported as NMS have also been received in association with olanzapine.  

 

Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence 

of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac 

dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria 

(rhabdomyolysis), and acute renal failure.  

 

If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever 

without additional clinical manifestations of NMS, all antipsychotic medicines, including olanzapine 

must be discontinued. 

 

Hyperglycaemia and diabetes 

Hyperglycaemia and/or development or exacerbation of diabetes occasionally associated with 

ketoacidosis or coma has been reported uncommonly, including some fatal cases (see section 4.8). In 

some cases, a prior increase in body weight has been reported which may be a predisposing factor. 

Appropriate clinical monitoring is advisable in accordance with utilised antipsychotic guidelines e.g. 

measuring of blood glucose at baseline, 12 weeks after starting olanzapine treatment and annually 

thereafter Patients treated with any antipsychotic medicines, including olanzapine, should be observed 

for signs and symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia, and weakness) 

and patients with diabetes mellitus or with risk factors for diabetes mellitus should be monitored 

regularly for worsening of glucose control. Weight should be monitored regularly e.g. at baseline, 4, 8 

and 12 weeks after starting olanzapine treatment and quarterly thereafter. 

 

Lipid alterations 

Undesirable alterations in lipids have been observed in olanzapine-treated patients in 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, 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), 

aspartatetransferase (AST) have been seen commonly, especially in early treatment.  



37 

 

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 



38 

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). 

 

Phenylalanine 

Olazax tablet contains aspartame, which is a source of phenylalanine. 

May be harmful for people with phenylketonuria. 

 

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 

nonsmokers and 77 % in male smokers. The mean increase in olanzapine AUC was 52 % and 108 % 

respectively.  

 

A lower starting dose of olanzapine should be considered in patients who are using fluvoxamine or 

any other CYP1A2 inhibitors, such as ciprofloxacin.  

 

A decrease in the dose of olanzapine should be considered if treatment with an inhibitor of CYP1A2 

is initiated. 

 

Decreased bioavailability 

Activated charcoal reduces the bioavailability of oral olanzapine by 50 to 60 % and should be taken at 

least 2 hours before or after olanzapine. 

 

Fluoxetine (a CYP2D6 inhibitor), single doses of antacid (aluminium, magnesium) or cimetidine have 

not been found to significantly affect the pharmacokinetics of olanzapine. 

 



39 

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. 

 

New born infants exposed to antipsychotics (including olanzapine) during the third trimester of 

pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that 

may vary in severity and duration following delivery. There have been reports of agitation, 

hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, 

newborns should be monitored carefully. 

 

Breast-feeding 

In a study in breast-feeding, healthy women, olanzapine was excreted in breast milk. Mean infant 

exposure (mg/kg) at steady state was estimated to be 1.8 % of the maternal olanzapine dose (mg/kg). 

Patients should be advised not to breast-feed an infant if they are taking olanzapine. 

 

Fertility 

Effects on fertility are unknown (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. 

 



40 

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, 

akathisia, parkinsonism, leukopenia, neutropenia (see section 4.4), dyskinesia, orthostatic 

hypotension, anticholinergic effects, transient asymptomatic elevations of hepatic aminotransferases 

(see section 4.4), rash, asthenia, fatigue, pyrexia, arthralgia, increased alkaline phosphatase, high 

gamma glutamyltransferase, high uric acid, high creatine phosphokinase and oedema. 

 

Tabulated list of adverse reactions 

The following table lists the adverse reactions and laboratory investigations observed from 

spontaneous reporting and in clinical trials. Within each frequency grouping, adverse reactions are 

presented in order of decreasing seriousness. The frequency terms listed are defined as follows: Very 

common (≥1/10), common (≥1/100 to < 1/10), uncommon (≥1/1,000 to < 1/100), rare (≥1/10,000 to 

< 1/1,000), very rare (<1/10,000), not known (cannot be estimated from the data available). 

 

Very common Common Uncommon  Rare Not known 

Blood and the lymphatic system disorders  

 Eosinophilia 

Leukopenia10 

Neutropenia10 

 Thrombocytopeni

a11 

 

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 

reported11 

 

 

 

Dystonia 

(including 

oculogyration)11 

Tardive 

dyskinesia11  

 

Amnesia 9 

 

Neuroleptic 

malignant 

syndrome (see 

section 

4.4)12Discontinuat

ion symptoms7, 12 

 



41 

Dysarthria 

Stuttering11 

Restless legs 

syndrome11 
Cardiac disorders  

  Bradycardia 

QTc prolongation 

(see section 4.4) 

Ventricular 

tachycardia/fibrill

ation, sudden 

death (see section 

4.4)11 

 

Vascular disorders  

Orthostatic 

hypotension10 

 Thromboembolis

m (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 Eosinophilia 

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 



42 

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/br

east enlargement 

in males 

Priapism12  

General disorders and administration site conditions  

 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 can not be concluded at present that olanzapine 

produces less tardive dyskinesia and/or other tardive extrapyramidal syndromes. 

 



43 

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. 

 
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.  

 



44 

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. 

 
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. 

 

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


45 

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  

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; α 1 

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 5HT2 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 5HT2A than dopamine D2 receptor occupancy. In addition, a Single 

Photon Emission Computed Tomography (SPECT) imaging study in schizophrenic patients revealed 

that olanzapine-responsive patients had lower striatal 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 



46 

a manic or mixed episode of bipolar disorder, olanzapine demonstrated superior efficacy to placebo 

and valproate semisodium (divalproex) in reduction of manic symptoms over 3 weeks. Olanzapine 

also demonstrated comparable efficacy results to haloperidol in terms of the proportion of patients in 

symptomatic remission from mania and depression at 6 and 12 weeks.  

 

In a co-therapy study of patients treated with lithium or valproate for a minimum of 2 weeks, the 

addition of olanzapine 10 mg (co-therapy with lithium or valproate) resulted in a greater reduction in 

symptoms of mania than lithium or valproate monotherapy after 6 weeks. 

 

In a 12-month recurrence prevention study in manic episode patients who achieved remission on 

olanzapine and were then randomised to olanzapine or placebo, olanzapine demonstrated statistically 

significant superiority over placebo on the primary endpoint of bipolar recurrence. Olanzapine also 

showed a statistically significant advantage over placebo in terms of preventing either recurrence into 

mania or recurrence into depression. 

 

In a second 12-month recurrence prevention study in manic episode patients who achieved remission 

with a combination of olanzapine and lithium and were then randomised to olanzapine or lithium 

alone, olanzapine was statistically non-inferior to lithium on the primary endpoint of bipolar 

recurrence (olanzapine 30.0 %, lithium 38.3 %; p = 0.055). 

 

In an 18-month co-therapy study in manic or mixed episode patients stabilised with olanzapine plus 

a mood stabiliser (lithium or valproate), long-term olanzapine co-therapy with lithium or valproate 

was not statistically significantly superior to lithium or valproate alone in delaying bipolar recurrence, 

defined according to syndromic (diagnostic) criteria. 

 

Paediatric population 

Controlled efficacy data in adolescents (ages 13 to 17 years) are limited to short term studies in 

schizophrenia (6 weeks) and mania associated with bipolar I disorder (3 weeks), involving less than 

200 adolescents. Olanzapine was used as a flexible dose starting with 2.5 and ranging up to 

20 mg/day. During treatment with olanzapine, adolescents gained significantly more weight compared 

with adults. The magnitude of changes in fasting total cholesterol, LDL cholesterol, triglycerides, and 

prolactin (see sections 4.4 and 4.8) were greater in adolescents than in adults. There are no controlled 

data on maintenance of effect or long term safety (see sections 4.4 and 4.8). Information on long term 

safety is primarily limited to open-label, uncontrolled data. 

 

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 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. 



47 

 

In healthy elderly (65 and over) versus non-elderly subjects, the mean elimination half-life was 

prolonged (51.8 versus 33.8 hr) 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 hr) 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 

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 %). 

 

SmokingIn non-smoking versus smoking subjects (males and females) the mean elimination half-life 

was prolonged (38.6 versus 30.4 hr) 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 



48 

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 events 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. 

 

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 E 421 

Microcrystalline cellulose 

Aspartame E 951 

Crospovidone 

Magnesium stearate 

 

6.2 Incompatibilities 

 

Not applicable. 

 

6.3 Shelf life 

 

30 months 

 

6.4 Special precautions for storage 

 

Store below 30ºC 

 



49 

6.5 Nature and contents of container 

 

Aluminium/aluminium blisters in cartons of 28, 56 tablets per carton 

 

Not all pack sizes may be marketed 

 

6.6 Special precautions for disposal  

 

No special requirements 

 

 

7. MARKETING AUTHORISATION HOLDER 

 

Glenmark Pharmaceuticals s.r.o. 

Hvězdova 1716/2b, 140 78 Praha 4 

Czech Republic  

 

 

8. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/09/597/003 

EU/1/09/597/008 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 

Date of first authorisation: 11.12.2009 

Date of renewal: 22.08.2014 

 

 

10. DATE OF REVISION OF THE TEXT 

 

{MM/YYYY} 

 

 

Detailed information on this medicinal product is available on the website of the European Medicines 

Agency (EMA) http://www.emea.europa.eu 

http://www.emea.europa.eu/


50 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Olazax 15 mg tablets 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

Each tablet contains 15 mg olanzapine. 

 

Excipient with known effect: Each tablet contains 0.69 mg aspartame 

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL form 

 

Yellow coloured circular flat bevelled edge tablets with ‘OL’ debossed on one side and ‘E’ debossed 

on 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 % versus 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 % versus 0.4 %, respectively). All 



52 

olanzapine and placebo-treated patients who experienced a cerebrovascular event had pre-existing risk 

factors. Age > 75 years and vascular/mixed type dementia were identified as risk factors for CVAE in 

association with olanzapine treatment. The efficacy of olanzapine was not established in these trials. 

 

Parkinson's disease 

The use of olanzapine in the treatment of dopamine agonist associated psychosis in patients with 

Parkinson's disease is not recommended.  

 

In clinical trials, worsening of Parkinsonian symptomatology and hallucinations were reported very 

commonly and more frequently than with placebo (see section 4.8), and olanzapine was not more 

effective than placebo in the treatment of psychotic symptoms.  

 

In these trials, patients were initially required to be stable on the lowest effective dose of anti-

Parkinsonian medicinal products (dopamine agonist) and to remain on the same anti-Parkinsonian 

medicinal products and dosages throughout the study. Olanzapine was started at 2.5 mg/day and 

titrated to a maximum of 15 mg/day based on investigator judgement. 

 

Neuroleptic Malignant Syndrome (NMS) 

NMS is a potentially life-threatening condition associated with antipsychotic medicinal products. 

Rare cases reported as NMS have also been received in association with olanzapine.  

 

Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence 

of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac 

dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria 

(rhabdomyolysis), and acute renal failure.  

 

If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever 

without additional clinical manifestations of NMS, all antipsychotic medicines, including olanzapine 

must be discontinued. 

 

Hyperglycaemia and diabetes 

Hyperglycaemia and/or development or exacerbation of diabetes occasionally associated with 

ketoacidosis or coma has been reported  uncommonly, including some fatal cases (see section 4.8). In 

some cases, a prior increase in body weight has been reported which may be a predisposing factor. 

Appropriate clinical monitoring is advisable in accordance with utilised antipsychotic guidelines e.g. 

measuring of blood glucose at baseline, 12 weeks after starting olanzapine treatment and annually 

thereafter. Patients treated with any antipsychotic medicines, including olanzapine, should be 

observed for signs and symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia, and 

weakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus should be 

monitored regularly for worsening of glucose control. Weight should be monitored regularly e.g. at 

baseline, 4, 8 and 12 weeks after starting olanzapine treatment and quarterly thereafter. 

 

Lipid alterations 

Undesirable alterations in lipids have been observed in olanzapine-treated patients in 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, 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, ALTAST 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. 

 



54 

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). 

 

Phenylalanine 

Olazax tablet contains aspartame, which is a source of phenylalanine. May be harmful for people with 

phenylketonuria. 

 

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 

nonsmokers and 77 % in male smokers. The mean increase in olanzapine AUC was 52 % and 108 % 

respectively. 

 

A lower starting dose of olanzapine should be considered in patients who are using fluvoxamine or 

any other CYP1A2 inhibitors, such as ciprofloxacin.  

 

A decrease in the dose of olanzapine should be considered if treatment with an inhibitor of CYP1A2 

is initiated. 

 

Decreased bioavailability 

Activated charcoal reduces the bioavailability of oral olanzapine by 50 to 60 % and should be taken at 

least 2 hours before or after olanzapine. 



55 

 

Fluoxetine (a CYP2D6 inhibitor), single doses of antacid (aluminium, magnesium) or cimetidine have 

not been found to significantly affect the pharmacokinetics of olanzapine. 

 

Potential for olanzapine to affect other medicinal products 

Olanzapine may antagonise the effects of direct and indirect dopamine agonists. 

 

Olanzapine does not inhibit the main CYP450 isoenzymes in vitro (e.g. 1A2, 2D6, 2C9, 2C19, 3A4). 

Thus no particular interaction is expected as verified through in vivo studies where no inhibition of 

metabolism of the following active substances was found: tricyclic antidepressant (representing 

mostly CYP2D6 pathway), warfarin (CYP2C9), theophylline (CYP1A2) or diazepam (CYP3A4 and 

2C19). 

 

Olanzapine showed no interaction when co-administered with lithium or biperiden. 

 

Therapeutic monitoring of valproate plasma levels did not indicate that valproate dosage adjustment is 

required after the introduction of concomitant olanzapine. 

 

General CNS activity 

Caution should be exercised in patients who consume alcohol or receive medicinal products that can 

cause central nervous system depression. 

 

The concomitant use of olanzapine with anti-Parkinsonian medicinal products in patients with 

Parkinson's disease and dementia is not recommended (see section 4.4). 

 

QTc interval 

Caution should be used if olanzapine is being administered concomitantly with medicinal products 

known to increase QTc interval (see section 4.4). 

 

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. 

 

New born infants exposed to antipsychotics (including olanzapine) during the third trimester of 

pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that 

may vary in severity and duration following delivery. There have been reports of agitation, 

hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, 

newborns should be monitored carefully. 

 

Breast-feeding 

In a study in breast-feeding, healthy women, olanzapine was excreted in breast milk. Mean infant 

exposure (mg/kg) at steady state was estimated to be 1.8 % of the maternal olanzapine dose (mg/kg). 

Patients should be advised not to breast-feed an infant if they are taking olanzapine. 

 

Fertility 

Effects on fertility are unknown (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. 



56 

 

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, 

akathisia, parkinsonism, leukopenia, neutropenia (see section 4.4), dyskinesia, orthostatic 

hypotension, anticholinergic effects, transient asymptomatic elevations of hepatic aminotransferases 

(see section 4.4), rash, asthenia, fatigue, pyrexia, arthralgia, increased alkaline phosphatase, high 

gamma glutamyltransferase, high uric acid, high creatine phosphokinase and oedema. 

 

Tabulated list of adverse reactions 

The following table lists the adverse reactions and laboratory investigations observed from 

spontaneous reporting and in clinical trials. Within each frequency grouping, adverse reactions are 

presented in order of decreasing seriousness. The frequency terms listed are defined as follows: Very 

common (≥1/10), common (≥1/100 to < 1/10), uncommon (≥1/1,000 to < 1/100), rare (≥1/10,000 to 

< 1/1,000), very rare (<1/10,000), not known (cannot be estimated from the data available). 

Very common Common Uncommon  Rare Not known 

Blood and the lymphatic system disorders  

 Eosinophilia 

Leukopenia10 

Neutropenia10 

 Thrombocytope

nia11 

 

Immune system disorders  

  Hypersensitivi

ty11 

  

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 

reported11 

 

Dystonia 

(including 

oculogyration)
11 

 

Neuroleptic 

malignant 

syndrome (see 

section 4.4)12  

Discontinuation 

symptoms7, 12 

 



57 

Tardive 

dyskinesia11 

 

Amnesia9 

 

Dysarthria 

Stuttering11 

Restless legs 

syndrome11 
Cardiac disorders  

  Bradycardia 

QTc 
prolongation 

(see section 

4.4) 

Ventricular 

tachycardia/fibri

llation, sudden 

death (see 

section 4.4)11 

 

Vascular disorders  

Orthostatic 

hypotension10 

 Thromboembo

lism (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 

hypersecretion
11 

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 Photosensitivit

y reaction 

Alopecia 

 Drug Reaction 

with 

Eosinophilia 

and Systemic 

Symptoms 

(DRESS) 

Musculoskeletal and connective tissue disorders  

 Arthralgia9  Rhabdomyolysis
11 

 

Renal and urinary disorders  

  Urinary 

incontinence, 

urinary 

retention 

Urinary 

  



58 

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 

Gynaecomasti

a/breast 

enlargement in 

males 

Priapism12  

General disorders and administration site conditions  

 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 



59 

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. 

 
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 

 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. 



60 

 

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. 

 
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. 

 
16Elevated 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. 

 

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


61 

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  

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; 

α 1 adrenergic; and histamine H1 receptors. Animal behavioural studies with olanzapine indicated 

5HT, dopamine, and cholinergic antagonism, consistent with the receptor-binding profile. Olanzapine 

demonstrated a greater in vitro affinity for serotonin 5 HT2 than dopamine D2 receptors and greater 

5HT2 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 5HT2A than dopamine D2 receptor occupancy. In addition, a Single 

Photon Emission Computed Tomography (SPECT) imaging study in schizophrenic patients revealed 

that olanzapine-responsive patients had lower striatal 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. 



62 

 

In a multinational, double-blind, comparative study of schizophrenia, schizoaffective, and related 

disorders which included 1,481 patients with varying degrees of associated depressive symptoms 

(baseline mean of 16.6 on the Montgomery-Asberg Depression Rating Scale), a prospective secondary 

analysis of baseline to endpoint mood score change demonstrated a statistically significant 

improvement (p= 0.001) favouring olanzapine (- 6.0) versus haloperidol (- 3.1). In patients with a 

manic or mixed episode of bipolar disorder, olanzapine demonstrated superior efficacy to placebo and 

valproate semisodium (divalproex) in reduction of manic symptoms over 3 weeks. Olanzapine also 

demonstrated comparable efficacy results to haloperidol in terms of the proportion of patients in 

symptomatic remission from mania and depression at 6 and 12 weeks.  

 

In a co-therapy study of patients treated with lithium or valproate for a minimum of 2 weeks, the 

addition of olanzapine 10 mg (co-therapy with lithium or valproate) resulted in a greater reduction in 

symptoms of mania than lithium or valproate monotherapy after 6 weeks. 

 

In a 12-month recurrence prevention study in manic episode patients who achieved remission on 

olanzapine and were then randomised to olanzapine or placebo, olanzapine demonstrated statistically 

significant superiority over placebo on the primary endpoint of bipolar recurrence. Olanzapine also 

showed a statistically significant advantage over placebo in terms of preventing either recurrence into 

mania or recurrence into depression. 

 

In a second 12-month recurrence prevention study in manic episode patients who achieved remission 

with a combination of olanzapine and lithium and were then randomised to olanzapine or lithium 

alone, olanzapine was statistically non-inferior to lithium on the primary endpoint of bipolar 

recurrence (olanzapine 30.0 %, lithium 38.3 %; p = 0.055). 

 

In an 18-month co-therapy study in manic or mixed episode patients stabilised with olanzapine plus 

a mood stabiliser (lithium or valproate), long-term olanzapine co-therapy with lithium or valproate 

was not statistically significantly superior to lithium or valproate alone in delaying bipolar recurrence, 

defined according to syndromic (diagnostic) criteria. 

 

Paediatric population 

Controlled efficacy data in adolescents (ages 13 to 17 years) are limited to short term studies in 

schizophrenia (6 weeks) and mania associated with bipolar I disorder (3 weeks), involving less than 

200 adolescents. Olanzapine was used as a flexible dose starting with 2.5 and ranging up to 

20 mg/day. During treatment with olanzapine, adolescents gained significantly more weight compared 

with adults. The magnitude of changes in fasting total cholesterol, LDL cholesterol, triglycerides, and 

prolactin (see sections 4.4 and 4.8) were greater in adolescents than in adults. There are no controlled 

data on maintenance of effect or long term safety (see sections 4.4 and 4.8). Information on long term 

safety is primarily limited to open-label, uncontrolled data. 

 

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 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 



63 

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 hr) 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 hr) 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 

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 hr) 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 



64 

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. 

 

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 E 421 

Microcrystalline cellulose 

Aspartame E 951 

Crospovidone 

Magnesium stearate 

 

6.2 Incompatibilities 

 

Not applicable. 

 



65 

6.3 Shelf life 

 

30 months  

 

6.4 Special precautions for storage 

 

Store below 30ºC 

 

6.5 Nature and contents of container 

 

Aluminium/aluminium blisters in cartons of 28, 56 tablets per carton 

 

Not all pack sizes may be marketed 

 

6.6 Special precautions for disposal  

 

No special requirements 

 

 

7. MARKETING AUTHORISATION HOLDER 

 

Glenmark Pharmaceuticals s.r.o. 

Hvězdova 1716/2b, 140 78 Praha 4 

Czech Republic  

 

 

8. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/09/597/004 

EU/1/09/597/009 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 

Date of first authorisation: 11.12.2009 

Date of renewal: 22.08.2014 

 

 

10. DATE OF REVISION OF THE TEXT 

 

{MM/YYYY} 

 

 

Detailed information on this medicinal product is available on the website of the European Medicines 

Agency (EMA) http://www.emea.europa.eu 

http://www.emea.europa.eu/


66 

1. NAME OF THE MEDICINAL PRODUCT 

 

Olazax 20 mg tablets 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

Each tablet contains 20 mg olanzapine 

 

Excipient with known effect: Each tablet contains 0.92 mg aspartame 

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL form 

 

Tablet 

Yellow coloured circular flat bevelled edge with ‘OL’ debossed on one side and ‘F’ debossed on 

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. 

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. 



67 

 

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 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 % versus 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 % versus 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. 



68 

 

Parkinson's disease 

The use of olanzapine in the treatment of dopamine agonist associated psychosis in patients with 

Parkinson's disease is not recommended.  

 

In clinical trials, worsening of Parkinsonian symptomatology and hallucinations were reported very 

commonly and more frequently than with placebo (see section 4.8), and olanzapine was not more 

effective than placebo in the treatment of psychotic symptoms.  

 

In these trials, patients were initially required to be stable on the lowest effective dose of anti-

Parkinsonian medicinal products (dopamine agonist) and to remain on the same anti-Parkinsonian 

medicinal products and dosages throughout the study. Olanzapine was started at 2.5 mg/day and 

titrated to a maximum of 15 mg/day based on investigator judgement. 

 

Neuroleptic Malignant Syndrome (NMS) 

NMS is a potentially life-threatening condition associated with antipsychotic medicinal products. 

Rare cases reported as NMS have also been received in association with olanzapine.  

 

Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence 

of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac 

dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria 

(rhabdomyolysis), and acute renal failure.  

 

If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever 

without additional clinical manifestations of NMS, all antipsychotic medicines, including olanzapine 

must be discontinued. 

 

Hyperglycaemia and diabetes 

Hyperglycaemia and/or development or exacerbation of diabetes occasionally associated with 

ketoacidosis or coma has been reported  uncommonly, including some fatal cases (see section 4.8). In 

some cases, a prior increase in body weight has been reported which may be a predisposing factor. 

Appropriate clinical monitoring is advisable in accordance with utilised antipsychotic guidelines e.g. 

measuring of blood glucose at baseline, 12 weeks after starting olanzapine treatment and annually 

thereafter. Patients treated with any antipsychotic medicines, including olanzapine, should be 

observed for signs and symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia, and 

weakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus should be 

monitored regularly for worsening of glucose control. Weight should be monitored regularly e.g. at 

baseline, 4, 8 and 12 weeks after starting olanzapine treatment and quarterly thereafter. 

 

Lipid alterations 

Undesirable alterations in lipids have been observed in olanzapine-treated patients in 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, should 

be monitored regularly for lipids in accordance with utilised antipsychotic guidelines e.g. at baseline, 

12 weeks after starting olanzapine treatment and every 5 years thereafter. 

 

Anticholinergic activity 

While olanzapine demonstrated anticholinergic activity in vitro, experience during the clinical trials 

revealed a low incidence of related events. However, as clinical experience with olanzapine in 

patients with concomitant illness is limited, caution is advised when prescribing for patients with 

prostatic hypertrophy, or paralytic ileus and related conditions. 

 

Hepatic function 

Transient, asymptomatic elevations of hepatic aminotransferases, ALT, AST have been seen 

commonly, especially in early treatment.  



69 

 

Caution should be exercised and follow-up organized 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 



70 

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). 

 

Phenylalanine 

Olazax tablet contains aspartame, which is a source of phenylalanine. 

May be harmful for people with phenylketonuria. 

 

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 

nonsmokers and 77 % in male smokers. The mean increase in olanzapine AUC was 52 % and 108 % 

respectively.  

 

A lower starting dose of olanzapine should be considered in patients who are using fluvoxamine or 

any other CYP1A2 inhibitors, such as ciprofloxacin.  

 

A decrease in the dose of olanzapine should be considered if treatment with an inhibitor of CYP1A2 

is initiated. 

 

Decreased bioavailability 

Activated charcoal reduces the bioavailability of oral olanzapine by 50 to 60 % and should be taken at 

least 2 hours before or after olanzapine. 

 

Fluoxetine (a CYP2D6 inhibitor), single doses of antacid (aluminium, magnesium) or cimetidine have 

not been found to significantly affect the pharmacokinetics of olanzapine. 

 



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. 

 

New born infants exposed to antipsychotics (including olanzapine) during the third trimester of 

pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that 

may vary in severity and duration following delivery. There have been reports of agitation, 

hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, 

newborns should be monitored carefully. 

 

Breast-feeding 

In a study in breast-feeding, healthy women, olanzapine was excreted in breast milk. Mean infant 

exposure (mg/kg) at steady state was estimated to be 1.8 % of the maternal olanzapine dose (mg/kg). 

Patients should be advised not to breast-feed an infant if they are taking olanzapine. 

 

Fertility 

Effects on fertility are unknown (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 



72 

Adults 

The most frequently (seen in ≥ 1% of patients) reported adverse reactions associated with the use of 

olanzapine in clinical trials were somnolence, weight gain, eosinophilia, elevated prolactin, 

cholesterol, glucose and triglyceride levels (see section 4.4), glucosuria, increased appetite, dizziness, 

akathisia, parkinsonism, leukopenia, neutropenia (see section 4.4), dyskinesia, orthostatic 

hypotension, anticholinergic effects, transient asymptomatic elevations of hepatic aminotransferases 

(see section 4.4), rash, asthenia, fatigue, pyrexia, arthralgia, increased alkaline phosphatase, high 

gamma glutamyltransferase, high uric acid, high creatine phosphokinase and oedema. 

 

Tabulated list of adverse reactions 

The following table lists the adverse reactions and laboratory investigations observed from 

spontaneous reporting and in clinical trials. Within each frequency grouping, adverse reactions are 

presented in order of decreasing seriousness. The frequency terms listed are defined as follows: Very 

common (≥1/10), common (≥1/100 to < 1/10), uncommon (≥1/1,000 to < 1/100), rare (≥1/10,000 to 

< 1/1,000), very rare (<1/10,000), not known (cannot be estimated from the data available). 

Very common Common Uncommon  Rare Not known 

Blood and the lymphatic system disorders  

 Eosinophilia 

Leukopenia10 

Neutropenia10 

 Thrombocytopenia1

1 

 

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 

reported11 

Dystonia 

(including 

oculogyration)11 

Tardive 

dyskinesia11 

 

Amnesia9 

 

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/fibrillat

ion, sudden death 

 



73 

(see section 4.4)11 

Vascular disorders  

Orthostatic 

hypotension10 

 Thromboembolis

m (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 

Eosinophilia 

and Systemic 

Symptoms 

(DRESS) 

Musculoskeletal and connective tissue disorders  

 Arthralgia 9  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/br

Priapism12  



74 

east enlargement 

in males 

General disorders and administration site conditions  

 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. 

 



75 

10 As assessed by measured values from clinical trials in the Olanzapine Integrated Database. 

 
11 Adverse event identified from spontaneous post-marketing reporting with frequency determined 

utilising the Olanzapine Integrated Database. 

 
12 Adverse event identified from spontaneous post-marketing reporting with frequency estimated at 

the upper limit of the 95% confidence interval utilising the Olanzapine Integrated Database. 

 

Long-term exposure (at least 48 weeks) 

The proportion of patients who had adverse, clinically significant changes in weight gain, glucose, 

total/LDL/HDL cholesterol or triglycerides increased over time. In adult patients who completed 

9-12 months of therapy, the rate of increase in mean blood glucose slowed after approximately 

6 months. 

 

Additional information on special populations 

In clinical trials in elderly patients with dementia, olanzapine treatment was associated with a higher 

incidence of death and cerebrovascular adverse reactions compared to placebo (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). 

 



76 

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. 

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

weight (kg) was very common (40.6 %), ≥ 15 % of baseline body weight was common (7.1 %) and ≥ 

25 % was common (2.5 %). With long-term exposure (at least 24 weeks), 89.4 % gained ≥ 7 %, 55.3 

% gained ≥ 15 % and 29.1 % gained ≥ 25 % of their baseline body weight.  

 
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). 

 
15Changes in total fasting cholesterol levels from normal at baseline (< 4.39 mmol/l) to high 

(≥ 5.17 mmol/l) were observed commonly. Changes in total fasting cholesterol levels from borderline 

at baseline (≥ 4.39 - < 5.17 mmol/l) to high (≥ 5.17 mmol/l) were very common. 

 
16Elevated plasma prolactin levels were reported in 47.4% of adolescent patients. 

 

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.  

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


77 

 

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  

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; α 1 

adrenergic; and histamine H1 receptors. Animal behavioural studies with olanzapine indicated 5HT, 

dopamine, and cholinergic antagonism, consistent with the receptor-binding profile. Olanzapine 

demonstrated a greater in vitro affinity for serotonin 5HT2 than dopamine D2 receptors and greater 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 5HT2A than dopamine D2 receptor occupancy. In addition, a Single 

Photon Emission Computed Tomography (SPECT) imaging study in schizophrenic patients revealed 

that olanzapine-responsive patients had lower striatal 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. 

 



78 

In a 12-month recurrence prevention study in manic episode patients who achieved remission on 

olanzapine and were then randomised to olanzapine or placebo, olanzapine demonstrated statistically 

significant superiority over placebo on the primary endpoint of bipolar recurrence. Olanzapine also 

showed a statistically significant advantage over placebo in terms of preventing either recurrence into 

mania or recurrence into depression. 

 

In a second 12-month recurrence prevention study in manic episode patients who achieved remission 

with a combination of olanzapine and lithium and were then randomised to olanzapine or lithium 

alone, olanzapine was statistically non-inferior to lithium on the primary endpoint of bipolar 

recurrence (olanzapine 30.0 %, lithium 38.3 %; p = 0.055). 

 

In an 18-month co-therapy study in manic or mixed episode patients stabilised with olanzapine plus 

a mood stabiliser (lithium or valproate), long-term olanzapine co-therapy with lithium or valproate 

was not statistically significantly superior to lithium or valproate alone in delaying bipolar recurrence, 

defined according to syndromic (diagnostic) criteria. 

 

Paediatric population 

Controlled efficacy data in adolescents (ages 13 to 17 years) are limited to short term studies in 

schizophrenia (6 weeks) and mania associated with bipolar I disorder (3 weeks), involving less than 

200 adolescents. Olanzapine was used as a flexible dose starting with 2.5 and ranging up to 

20 mg/day. During treatment with olanzapine, adolescents gained significantly more weight compared 

with adults. The magnitude of changes in fasting total cholesterol, LDL cholesterol, triglycerides, and 

prolactin (see sections 4.4 and 4.8) were greater in adolescents than in adults. There are no controlled 

data on maintenance of effect or long term safety (see sections 4.4 and 4.8). Information on long term 

safety is primarily limited to open-label, uncontrolled data. 

 

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 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 hr) 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. 

 



79 

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 hr) 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 

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 hr) 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. 

 



80 

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 anaemiaa 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. 

 

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 E 421 

Microcrystalline cellulose 

Aspartame E 951 

Crospovidone 

Magnesium stearate 

 

6.2 Incompatibilities 

 

Not applicable. 

 

6.3 Shelf life 

 

30  months  

 

6.4 Special precautions for storage 

 

Store below 30ºC 

 

6.5 Nature and contents of container 

 

Aluminium/aluminium blisters in cartons of 28, 56 tablets per carton 

 

Not all pack sizes may be marketed 

 



81 

6.6 Special precautions for disposal  

 

No special requirements 

 

 

7. MARKETING AUTHORISATION HOLDER 

 

Glenmark Pharmaceuticals s.r.o. 

Hvězdova 1716/2b, 140 78 Praha 4 

Czech Republic  

 

 

8. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/09/597/005 

EU/1/09/597/010 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 

Date of first authorisation: 11.12.2009 

Date of renewal: 22.08.2014 

 

 

10. DATE OF REVISION OF THE TEXT 

 

{MM/YYYY} 

 

 

Detailed information on this medicinal product is available on the website of the European Medicines 

Agency (EMA) http://www.emea.europa.eu 

http://www.emea.europa.eu/


82 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 ANNEX II 

 

A. MANUFACTURERS 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 



83 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 

 

Name and address of the manufacturer responsible for batch release 

 

Glenmark Pharmaceuticals s.r.o 

Fibíchova 143, 566 17  

Vysoké Mýto 

Czech Republic 

 

 

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)  
 

At the time of granting the marketing authorisation, the submission of PSUR is not required for this 

medicinal product. However, the marketing authorisation holder shall submit periodic safety update 

reports for this medicinal product if the product is included 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. 

 



84 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



85 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 

 

 



86 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Olazax 5 mg tablets 

 

Olanzapine 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each tablet contains 5 mg olanzapine. 

 

 

3. LIST OF EXCIPIENTS 

 

Contains aspartame. See leaflet for further information 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Tablet 

28 tablets 

56 tablets 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use 

 

Oral 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 

 

Store below 30C 



87 

 

 

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 

 

Glenmark Pharmaceuticals s.r.o. 

Hvězdova 1716/2b, 140 78 Praha 4 

Czech Republic  

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/09/507/001 

EU/1/09/597/006 

 

13. BATCH NUMBER 

 

BN 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

Medicinal product subject to medical prescription. 

 

 

15. INSTRUCTIONS ON USE 

 

 

 

16. INFORMATION IN BRAILLE 

 

Olazax 5 mg tablets 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC  

SN  

NN 

 

 

 

 

 

 



88 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

Aluminium blisters 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Olazax 5 mg tablets 

 

Olanzapine 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Glenmark Pharmaceuticals s.r.o. 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

BN 

 

 

5. OTHER 

 



89 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Olazax 7.5 mg tablets 

 

Olanzapine 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

 

Each tablet contains 7.5 mg olanzapine. 

 

 

3. LIST OF EXCIPIENTS 

 

Contains aspartame. See leaflet for further information 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Tablet 

28 tablets 

56 tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use 

 

Oral 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 

 



90 

Store below 30C 

 

 

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 

 

Glenmark Pharmaceuticals s.r.o. 

Hvězdova 1716/2b, 140 78 Praha 4 

Czech Republic  

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/09/597/002 

EU/1/09/597/007 

 

13. BATCH NUMBER 

 

BN 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

Medicinal product subject to medical prescription. 

 

 

15. INSTRUCTIONS ON USE 

 

 

 

16. INFORMATION IN BRAILLE 

 

Olazax 7.5 mg tablets 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC  

SN  

NN 

 

 

 

 

 



91 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

Aluminium blisters 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Olazax 7.5 mg tablets 

 

Olanzapine 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Glenmark Pharmaceuticals s.r.o. 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

BN 

 

 

5. OTHER 

 



92 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Olazax 10 mg tablets 

 

Olanzapine 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each tablet contains 10 mg olanzapine. 

 

 

3. LIST OF EXCIPIENTS 

 

Contains aspartame. See leaflet for further information 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Tablet  

28 tablets 

56 tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use 

 

Oral 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 

 

Store below 30C 



93 

 

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 

 

Glenmark Pharmaceuticals s.r.o. 

Hvězdova 1716/2b, 140 78 Praha 4 

Czech Republic  

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/09/597/003 

EU/1/09/597/008 

 

 

13. BATCH NUMBER 

 

BN 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

Medicinal product subject to medical prescription. 

 

 

15. INSTRUCTIONS ON USE 

 

 

 

16. INFORMATION IN BRAILLE 

 

Olazax 10 mg tablets 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC  

SN  

NN 

 

 

 

 

 

 

 



94 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

Aluminium blisters 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Olazax 10 mg tablets 

 

Olanzapine 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Glenmark Pharmaceuticals s.r.o. 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

BN 

 

 

5. OTHER 

 

 

 



95 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Olazax 15 mg tablets 

 

Olanzapine 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each tablet contains 15 mg olanzapine. 

 

 

3. LIST OF EXCIPIENTS 

 

Contains aspartame. See leaflet for further information 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Tablet 

28 tablets 

56 tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use 

 

Oral 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 

 

Store below 30C 



96 

 

 

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 

 

Glenmark Pharmaceuticals s.r.o. 

Hvězdova 1716/2b, 140 78 Praha 4 

Czech Republic  

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/09/597/004 

EU/1/09/597/009 

 

13. BATCH NUMBER 

 

BN 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

Medicinal product subject to medical prescription. 

 

 

15. INSTRUCTIONS ON USE 

 

 

 

16. INFORMATION IN BRAILLE 

 

Olazax 15 mg tablets 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC  

SN  

NN 

 

 

 

 

 

 



97 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

Aluminium blisters 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Olazax 15 mg tablets 

 

Olanzapine 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Glenmark Pharmaceuticals s.r.o. 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

BN 

 

 

5. OTHER 

 



98 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Olazax 20 mg tablets 

 

Olanzapine 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each tablet contains 20 mg olanzapine 

 

 

3. LIST OF EXCIPIENTS 

 

Contains aspartame. See leaflet for further information 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Tablet 

28 tablets 

56 tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use 

 

Oral 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 

 

Store below 30C 



99 

 

 

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 

 

Glenmark Pharmaceuticals s.r.o. 

Hvězdova 1716/2b, 140 78 Praha 4 

Czech Republic  

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/09/597/005 

EU/1/09/597/020 

 

13. BATCH NUMBER 

 

BN 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

Medicinal product subject to medical prescription. 

 

 

15. INSTRUCTIONS ON USE 

 

 

 

16. INFORMATION IN BRAILLE 

 

Olazax 20 mg tablets 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC  

SN  

NN 

 

 

 

 

 

 

 



100 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

Aluminium blisters 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Olazax 20 mg tablets 

 

Olanzapine 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Glenmark Pharmaceuticals s.r.o. 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

BN 

 

 

5. OTHER 

 



101 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. PACKAGE LEAFLET 

 

 

 

 

 



102 

 

Package leaflet: Information for the user 

 

Olazax 5 mg tablets 

Olazax 7.5 mg tablets 

Olazax 10 mg tablets 

Olazax 15 mg tablets 

Olazax 20 mg tablets 

Olanzapine 

 

Read all of this leaflet carefully before you start taking 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 of the 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 Olazax is and what it is used for 

2. What you need to know before you take Olazax 

3. How to take Olazax 

4. Possible side effects 

5. How to store Olazax 

6. Contents of the pack and other information 

 

 

1. What OLAZAX is and what it is used for 

 

Olazax contains the active substance olanzapine. Olazax 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. 

 

Olazax 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 Olazax 

 

Do not take Olazax 

- 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 you take OLAZAX. 

 The use of OLAZAX in elderly patients with dementia is not recommended as it may have serious 

side effects. 



103 

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

happens after you have been given Olazax, 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 Olazax. 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 Olazax. Your doctor should do blood tests to check blood sugar and certain fat levels 

before you start taking Olazax 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 

Olazax is not for patients who are under 18 years 

 

Other medicines and Olazax 

Only take other medicines while you are on Olazax if your doctor tells you that you can. You might 

feel drowsy if Olazax 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 Olazax dose 

 

Olazax with alcohol 

Do not drink any alcohol if you have been given Olazax as together with alcohol it may make you feel 

drowsy. 

 

Pregnancy and breast-feeding 

If you are pregnant or think you might be 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.  



104 

You should not be given this medicine when breast-feeding, as small amounts of  Olazax can pass into 

breast milk.  

 

The following symptoms may occur in newborn babies, of mothers that have used OLAZAX 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 Olazax. If this happens do not drive or operate 

any tools or machines. Tell your doctor. 

 

Olazax contains aspartame a source of phenylalanine. This may be harmful for people with 

phenylketonuria. 

 

3. How to take Olazax 

 

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 Olazax tablets to take and how long you should continue to 

take them. The daily dose of Olazax is between 5 mg and 20 mg. Consult your doctor if your 

symptoms return but do not stop taking Olazax unless your doctor tells you to. 

 

You should take your Olazax 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. Olazax tablets are for oral use. You should swallow the Olazax X tablets whole, with water. 

 

If you take more Olazax than you should 

Patients who have taken more Olazax 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 Olazax 

Take your tablets as soon as you remember. Do not take two doses in one day. 

 

If you stop taking Olazax 

Do not stop taking your tablets just because you feel better. It is important that you carry on taking 

Olazax for as long as your doctor tells you. 

 

If you suddenly stop taking Olazax, 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:  

 



105 

 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 (may affect up to 1 in 10,000) 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 Olazax may worsen the symptoms 

 

Reporting of side effects 

If you get any side effects, talk to your doctor or pharmacist. 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. 

 

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


106 

 

5. How to store Olazax 

 

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.   

 

Store below 30C. 

 

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 to protect the environment. 

 

 

6. Contents of the pack and other information 

 

What Olazax contains 

- The active substance is olanzapine 

- Each tablet contains 5 mg, 7.5 mg, 10 mg, 15 mg or 20 mg olanzapine 

- The other ingredients are mannitol (E 421), microcrystalline cellulose, aspartame (E 951), 

crospovidone, magnesium stearate 

 

What Olazax looks like and contents of the pack 

 

Olazax 5mg is supplied as a yellow coloured circular flat beveled edge tablet with ‘B’ debossed on 

one side. 

Olazax 7.5 mg: 

yellow coloured circular flat bevelled edge tablets with ‘C’ debossed on one side. 

Olazax 10 mg:  

yellow coloured circular flat bevelled edge tablets with ‘OL’ debossed on one side and  ‘D’ debossed 

on other side. 

Olazax 15 mg:  

yellow coloured circular flat bevelled edge tablets with ‘OL’ debossed on one side and ‘E’ debossed 

on other side. 

Olazax 20 mg:  

yellow coloured circular flat bevelled edge tablets  with ‘OL’ debossed on one side and ‘F’ debossed 

on other side. 

 

Olazax, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg are available in aluminium foil blisters of 28 or 56 tablets  

 

 

Marketing Authorisation Holder and Manufacturer 

Glenmark Pharmaceuticals s.r.o. 

Hvězdova 1716/2b, 140 78 Praha 4 

Czech Republic 

 

Manufacturer 

Glenmark Pharmaceuticals s.r.o. 

Hvězdova 1716/2b, 140 78 Praha 4 

Czech Republic  

 

This leaflet was last revised in {month/YYYY}. 

 

Detailed information on this medicine is available on the European Medicines Agency (EMA) 

website: http://www.emae.europa.eu 

 

http://www.emae.europa.eu/

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) 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
	LABELLING AND PACKAGE LEAFLET