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OLANZAPINE SUN 15 MG TABLETS

Active substance(s): OLANZAPINE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Olanzapine SUN 15 mg tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Olanzapine 15 mg tablets:
Each tablet contains 15 mg olanzapine.
Excipient with known effect:
Each tablet contains 123.0 mg lactose.

3

PHARMACEUTICAL FORM
Tablet
Olanzapine 15 mg tablets:
Oval, yellow, uncoated tablet embossed with ’15’ on one side and plain on the other
side.

4

CLINICAL PARTICULARS

4.1

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

4.2

Posology and method of administration

Posology
Adults
Schizophrenia: The recommended starting dose for olanzapine is 10 mg/day.
Manic episode: The starting dose is 15 mg as a single daily dose in monotherapy or 10
mg daily in combination therapy (see section 5.1).
Preventing recurrence in bipolar disorder: The recommended starting dose is 10
mg/day. For patients who have been receiving olanzapine for treatment of manic
episode, continue therapy for preventing recurrence at the same dose. If a new manic,
mixed, or depressive episode occurs, olanzapine treatment should be continued (with
dose optimisation as needed), with supplementary therapy to treat mood symptoms, as
clinically indicated.
During treatment for schizophrenia, manic episode and recurrence prevention in
bipolar disorder, daily dosage may subsequently be adjusted on the basis of individual
clinical status within the range 5-20 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.
Special populations
Elderly patients
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).
Patients with 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).
Method of administration
For oral use.
4.3

Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section
6.1.
Patients with known risk of narrow-angle glaucoma.

4.4

Special warnings and precautions for use

During antipsychotic treatment, improvement in the patient's clinical condition may
take several days to some weeks. Patients should be closely monitored during this
period.
Dementia-related psychosis and/or behavioural disturbances
Olanzapine is not recommended for use in patients with dementia-related psychosis
and/or behavioural disturbances because of an increase in mortality and the risk of
cerebrovascular accident. In placebo-controlled clinical trials (6-12 weeks duration) of
elderly patients (mean age 78 years) with dementia-related psychosis and/or disturbed
behaviours, there was a 2-fold increase in the incidence of death in olanzapine-treated
patients compared to patients treated with placebo (3.5% vs. 1.5%, respectively). The
higher incidence of death was not associated with olanzapine dose (mean daily dose
4.4 mg) or duration of treatment. Risk factors that may predispose this patient
population to increased mortality include age > 65 years, dysphagia, sedation,
malnutrition and dehydration, pulmonary conditions (e.g., pneumonia, with or without
aspiration), or concomitant use of benzodiazepines. However, the incidence of death
was higher in olanzapine-treated than in placebo-treated patients independent of these
risk factors.
In the same clinical trials, cerebrovascular adverse events (CVAE e.g., stroke,
transient ischemic attack), including fatalities, were reported. There was a 3-fold
increase in CVAE in patients treated with olanzapine compared to patients treated
with placebo (1.3% vs. 0.4%, respectively). All olanzapine- and placebo-treated
patients who experienced a cerebrovascular event had pre-existing risk factors. Age
>75 years and vascular/mixed type dementia were identified as risk factors for CVAE
in association with olanzapine treatment. The efficacy of olanzapine was not
established in these trials.

Parkinson’s disease
The use of olanzapine in the treatment of dopamine agonist associated psychosis in
patients with Parkinson's disease is not recommended. In clinical trials, worsening of
Parkinsonian symptomatology and hallucinations were reported very commonly and
more frequently than with placebo (see section 4.8), and olanzapine was not more
effective than placebo in the treatment of psychotic symptoms. In these trials, patients
were initially required to be stable on the lowest effective dose of anti-Parkinsonian
medicinal products (dopamine agonist) and to remain on the same anti-Parkinsonian
medicinal products and dosages throughout the study. Olanzapine was started at 2.5
mg/day and titrated to a maximum of 15 mg/day based on investigator judgement.
Neuroleptic Malignant Syndrome (NMS)
NMS is a potentially life-threatening condition associated with antipsychotic
medicinal products. Rare cases reported as NMS have also been received in
association with olanzapine. Clinical manifestations of NMS are hyperpyrexia, muscle
rigidity, altered mental status, and evidence of autonomic instability (irregular pulse
or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional
signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis),
and acute renal failure. If a patient develops signs and symptoms indicative of NMS,
or presents with unexplained high fever without additional clinical manifestations of
NMS, all antipsychotic medicines, including olanzapine must be discontinued.
Hyperglycaemia and diabetes
Hyperglycaemia and/or development or exacerbation of diabetes occasionally
associated with ketoacidosis or coma has been reported uncommonly, including some
fatal cases (see section 4.8). In some cases, a prior increase in body weight has been
reported which may be a predisposing factor. Appropriate clinical monitoring is
advisable in accordance with utilised antipsychotic guidelines, e.g. measuring of
blood glucose at baseline, 12 weeks after starting olanzapine treatment and annually
thereafter. Patients treated with any antipsychotic agents, including Olanzapine SUN,
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 SUN, should be monitored regularly
for lipids in accordance with utilised antipsychotic guidelines, e.g. at baseline,
12 weeks after starting olanzapine treatment and every 5 years thereafter.
Anticholinergic activity
While olanzapine demonstrated anticholinergic activity in vitro, experience during the
clinical trials revealed a low incidence of related events. However, as clinical
experience with olanzapine in patients with concomitant illness is limited, caution is

advised when prescribing for patients with prostatic hypertrophy, or paralytic ileus
and related conditions.
Hepatic function
Transient, asymptomatic elevations of hepatic aminotransferases, ALT, AST have
been seen commonly, especially in early treatment. Caution should be exercised and
follow-up organised in patients with elevated ALT and/or AST, in patients with signs
and symptoms of hepatic impairment, in patients with pre-existing conditions
associated with limited hepatic functional reserve, and in patients who are being
treated with potentially hepatotoxic medicines. In cases where hepatitis (including
hepatocellular, cholestatic or mixed liver injury) has been diagnosed, olanzapine
treatment should be discontinued.
Neutropenia
Caution should be exercised in patients with low leukocyte and/or neutrophil counts
for any reason, in patients receiving medicines known to cause neutropenia, in
patients with a history of drug-induced bone marrow depression/toxicity, in patients
with bone marrow depression caused by concomitant illness, radiation therapy or
chemotherapy and in patients with hypereosinophilic conditions or with
myeloproliferative disease. Neutropenia has been reported commonly when
olanzapine and valproate are used concomitantly (see section 4.8).
Discontinuation of treatment
Acute symptoms such as sweating, insomnia, tremor, anxiety, nausea, or vomiting
have been reported rarely (≥0.01% and <0.1%) when olanzapine is stopped abruptly.
QT interval
In clinical trials, clinically meaningful QTc prolongations (Fridericia QT correction
[QTcF] ≥ 500 milliseconds [msec] at any time post baseline in patients with baseline
QTcF < 500 msec) were uncommon (0.1% to 1%) in patients treated with olanzapine,
with no significant differences in associated cardiac events compared to placebo.
However, caution should be exercised when olanzapine is prescribed with medicines
known to increase QTc interval, especially in the elderly, in patients with congenital
long QT syndrome, congestive heart failure, heart hypertrophy, hypokalaemia or
hypomagnesaemia.
Thromboembolism
Temporal association of olanzapine treatment and venous thromboembolism has been
reported uncommonly (≥ 0.1% and < 1%). A causal relationship between the
occurrence of venous thromboembolism and treatment with olanzapine has not been
established. However, since patients with schizophrenia often present with acquired
risk factors for venous thromboembolism all possible risk factors of VTE e.g.
immobilisation of patients, should be identified and preventive measures undertaken.
General CNS activity
Given the primary CNS effects of olanzapine, caution should be used when it is taken
in combination with other centrally acting medicines and alcohol. As it exhibits in
vitro dopamine antagonism, olanzapine may antagonize the effects of direct and
indirect dopamine agonists.

Seizures
Olanzapine should be used cautiously in patients who have a history of seizures or are
subject to factors which may lower the seizure threshold. Seizures have been reported
to occur uncommonly in patients when treated with olanzapine. In most of these
cases, a history of seizures or risk factors for seizures were reported.
Tardive Dyskinesia
In comparator studies of one year or less duration, olanzapine was associated with a
statistically significant lower incidence of treatment emergent dyskinesia. However
the risk of tardive dyskinesia increases with long term exposure, and therefore if signs
or symptoms of tardive dyskinesia appear in a patient on olanzapine, a dose reduction
or discontinuation should be considered. These symptoms can temporally deteriorate
or even arise after discontinuation of treatment.
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).
Olanzapine tablets:
Lactose: Olanzapine SUN tablets contain lactose. Patients with rare hereditary
problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose
malabsorption should not take this medicine.

4.5

Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.
Potential interactions affecting olanzapine
Since olanzapine is metabolised by CYP1A2, substances that can specifically induce or
inhibit this isoenzyme may affect the pharmacokinetics of olanzapine.
Induction of CYP1A2
The metabolism of olanzapine may be induced by smoking and carbamazepine, which may
lead to reduced olanzapine concentrations. Only slight to moderate increase in olanzapine

clearance has been observed. The clinical consequences are likely to be limited, but clinical
monitoring is recommended and an increase of olanzapine dose may be considered if
necessary (see section 4.2).
Inhibition of CYP1A2
Fluvoxamine, a specific CYP1A2 inhibitor, has been shown to significantly inhibit the
metabolism of olanzapine. The mean increase in olanzapine Cmax following fluvoxamine
was 54 % in female non-smokers and 77 % in male smokers. The mean increase in olanzapine
AUC was 52 % and 108 % respectively. A lower starting dose of olanzapine should be
considered in patients who are using fluvoxamine or any other CYP1A2 inhibitors, such as
ciprofloxacin. A decrease in the dose of olanzapine should be considered if treatment with an
inhibitor of CYP1A2 is initiated.
Decreased bioavailability
Activated charcoal reduces the bioavailability of oral olanzapine by 50 to 60% and should be
taken at least 2 hours before or after olanzapine.
Fluoxetine (a CYP2D6 inhibitor), single doses of antacid (aluminium, magnesium) or
cimetidine have not been found to significantly affect the pharmacokinetics of olanzapine.
Potential for olanzapine to affect other medicinal products
Olanzapine may antagonise the effects of direct and indirect dopamine agonists.
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
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
Uncommon
common
Blood and lymphatic system disorders
Eosinophilia

Rare

Thrombocytopenia11

Not known

Leukopenia10
Neutropenia10
Immune system disorders
Hypersensitivity11
Metabolism and nutrition disorders
Weight gain1 Elevated cholesterol
levels2,3
Elevated glucose
levels4
Elevated triglyceride
levels2,5
Glucosuria
Increased appetite
Nervous system disorders
Dizziness
Somnolence
Akathisia6
Parkinsonism6
Dyskinesia6

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

Hypothermia12

Seizures where in
most cases a history
of seizures or risk
factors for seizures
were reported11
Dystonia (including
oculogyration)11
Tardive dyskinesia11
Amnesia9
Dysarthria

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

Cardiac disorders
Bradycardia,
Ventricular
QTc prolongation (see tachycardia/fibrillation,
section 4.4)
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
Abdominal
anticholinergic
distension9
effects including
constipation and dry
mouth
Hepatobiliary disorders
Transient,
asymptomatic
elevations of hepatic
aminotransferases
(ALT, AST),
especially in early

Pancreatitis11

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

Formatted:

French (France)

treatment (see section
4.4)
Skin and subcutaneous tissue disorders
Rash
Photosensitivity
reaction
Alopecia
Musculoskeletal and connective tissue disorders
Arthralgia9
Renal and urinary disorders
Urinary incontinence,
urinary retention
Urinary hesitation11
Pregnancy, puerperium and perinatal conditions

Rhabdomyolysis11

Drug withdrawal
syndrome
neonatal (see
section 4.6)
Reproductive system and breast disorders
Erectile dysfunction
Amenorrhea
Priapism12
in males
Breast enlargement
Decreased libido in
Galactorrhea in
males and females
females
Gynaecomastia/breast
enlargement in males
General disorders and administration site conditions
Asthenia
Fatigue
Oedema
Pyrexia10
Investigations
Elevated
Increased
alkaline Increased total
bilirubin
plasma
phosphatase10
High
creatine
prolactin
phosphokinase11
levels8
High Gamma
Glutamyltransferase10
High Uric Acid10

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) to high (≥ 6.2 mmol) 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 olanzapinetreated patients was numerically higher, but not statistically significantly different
from placebo. Olanzapine-treated patients had a lower incidence of Parkinsonism,
akathisia and dystonia compared with titrated doses of haloperidol. In the absence
of detailed information on the pre-existing history of individual acute and tardive
extrapyramidal movement disorders, it cannot be concluded at present that
olanzapine produces less tardive dyskinesia and/or other tardive extrapyramidal
syndromes.

7

Acute symptoms such as sweating, insomnia, tremor, anxiety, nausea and
vomiting have been reported when olanzapine is stopped abruptly.

8

In clinical trials of up to 12 weeks, plasma prolactin concentrations exceeded
the upper limit of normal range in approximately 30% of olanzapine treated patients
with normal baseline prolactin value. In the majority of these patients the
elevations were generally mild, and remained below two times the upper limit of
normal range.
9

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

10

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

11

Adverse event identified from spontaneous post-marketing reporting with
frequency determined utilising the Olanzapine Integrated Database.

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 s e c t i o n 4.4). Very common adverse
reactions associated with the use of olanzapine in this patient group were
abnormal gait and falls. Pneumonia, increased body temperature, lethargy,
erythema, visual hallucinations and urinary incontinence were observed commonly.
In clinical trials in patients with drug-induced (dopamine agonist) psychosis
associated with Parkinson’s disease, worsening of Parkinsonian symptomatology
and hallucinations were reported very commonly and more frequently than with
placebo.
In one clinical trial in patients with bipolar mania, valproate combination therapy
with olanzapine resulted in an incidence of neutropenia of 4.1%; a potential
contributing factor could be high plasma valproate levels. Olanzapine administered
with lithium or valproate resulted in increased levels (≥10%) of tremor, dry
mouth, increased appetite, and weight gain. Speech disorder was also reported
commonly. During treatment with olanzapine in combination with lithium or
divalproex, an increase of ≥7% from baseline body weight occurred in 17.4% of
patients during acute treatment (up to 6 weeks). Long-term olanzapine treatment (up to
12 months) for recurrence prevention in patients with bipolar disorder was associated
with an increase of ≥7% from baseline body weight in 39.9% of patients.
Paediatric population
Olanzapine is not indicated for the treatment of children and adolescent patients
below 18 years. Although no clinical studies designed to compare adolescents
to adults have been conducted, data from the adolescent trials were compared to
those of the adult trials.
The following table summarises the adverse reactions reported with a greater
frequency in adolescent patients (aged 13-17 years) than in adult patients or
adverse reactions only identified during short-term clinical trials in adolescent
patients. Clinically significant weight gain (≥ 7%) appears to occur more
frequently in the adolescent population compared to adults with comparable
exposures. The magnitude of weight gain and the proportion of adolescent patients
who had clinically significant weight gain were greater with long-term exposure (at
least 24 weeks) than with short- term exposure.
Within each frequency grouping, adverse reactions are presented in order of
decreasing seriousness. The frequency terms listed are defined as follows: Very
common (≥ 1/10), common (≥ 1/100 to < 1/10).

Metabolism and nutrition disorders
Very common: Weight gain13, elevated triglyceride levels14, increased appetite
Common: Elevated cholesterol levels15
Nervous system disorders
Very common: Sedation (including: hypersomnia, lethargy, somnolence)
Gastrointestinal disorders
Common: Dry mouth
Hepatobiliary disorders
Very common: Elevations of hepatic aminotransferases (ALT/AST; see section 4.4)
Investigations
Very common: Decreased total bilirubin, increased GGT, elevated plasma prolactin
levels16
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 longterm exposure (at least 24 weeks), 89.4 % gained ≥ 7 %, 55.3 % gained ≥ 15 % and
29.1 % gained ≥ 25% of their baseline body weight.

13

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 Yellow Card Scheme: www.mhra.gov.uk/yellowcard

4.9

Overdose
Signs and symptoms
Very common symptoms in overdose (>10% incidence) include tachycardia,
agitation/aggressiveness, dysarthria, various extrapyramidal symptoms, and reduced
level of consciousness ranging from sedation to coma.

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

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: psycholeptics, diazepines, oxazepines, thiazepines and
oxepines, ATC code: N05A H03.
Pharmacodynamic effects
Olanzapine is an antipsychotic, antimanic and mood stabilising agent that
demonstrates a broad pharmacologic profile across a number of receptor systems.
In preclinical studies, olanzapine exhibited a range of receptor affinities (Ki; < 100
nM) for serotonin 5 HT2A/2C, 5 HT3, 5 HT6; dopamine D1, D2, D3, D4, D5; cholinergic
muscarinic receptors M1-M5; α1 adrenergic; and histamine H1 receptors. Animal
behavioural studies with olanzapine indicated 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 5 HT2A than dopamine D2 receptor
occupancy. In addition, a Single Photon Emission Computed Tomography (SPECT)

imaging study in schizophrenic patients revealed that olanzapine-responsive patients
had lower striatal D2 occupancy than some other antipsychotic- and risperidoneresponsive patients, while being comparable to clozapine-responsive patients.
Clinical efficacy
In two of two placebo and two of three comparator controlled trials with over 2,900
schizophrenic patients presenting with both positive and negative symptoms,
olanzapine was associated with statistically significantly greater improvements in
negative as well as positive symptoms.
In a multinational, double-blind, comparative study of schizophrenia, schizoaffective,
and related disorders which included 1,481 patients with varying degrees of
associated depressive symptoms (baseline mean of 16.6 on the Montgomery-Asberg
Depression Rating Scale), a prospective secondary analysis of baseline to endpoint
mood score change demonstrated a statistically significant improvement (p=0.001)
favouring olanzapine (-6.0) versus haloperidol (-3.1).
In patients with a manic or mixed episode of bipolar disorder, olanzapine
demonstrated superior efficacy to placebo and valproate semisodium (divalproex) in
reduction of manic symptoms over 3 weeks. Olanzapine also demonstrated
comparable efficacy results to haloperidol in terms of the proportion of patients in
symptomatic remission from mania and depression at 6 and 12 weeks. In a co-therapy
study of patients treated with lithium or valproate for a minimum of 2 weeks, the
addition of olanzapine 10 mg (co-therapy with lithium or valproate) resulted in a
greater reduction in symptoms of mania than lithium or valproate monotherapy after 6
weeks.
In a 12-month recurrence prevention study in manic episode patients who achieved
remission on olanzapine and were then randomised to olanzapine or placebo,
olanzapine demonstrated statistically significant superiority over placebo on the
primary endpoint of bipolar recurrence. Olanzapine also showed a statistically
significant advantage over placebo in terms of preventing either recurrence into mania
or recurrence into depression.
In a second 12-month recurrence prevention study in manic episode patients who
achieved remission with a combination of olanzapine and lithium and were then
randomised to olanzapine or lithium alone, olanzapine was statistically non-inferior to
lithium on the primary endpoint of bipolar recurrence (olanzapine 30.0%, lithium
38.3%; p= 0.055).
In an 18-month co-therapy study in manic or mixed episode patients stabilised with
olanzapine plus a mood stabiliser (lithium or valproate), long-term olanzapine cotherapy with lithium or valproate was not statistically significantly superior to lithium
or valproate alone in delaying bipolar recurrence, defined according to syndromic
(diagnostic) criteria.
Paediatric population
Controlled efficacy data in adolescents (ages 13 to 17 years) are limited to short term
studies in schizophrenia (6 weeks) and mania associated with bipolar I disorder (3
weeks), involving less than 200 adolescents. Olanzapine was used as a flexible dose

starting with 2.5 and ranging up to 20 mg/day. During treatment with olanzapine,
adolescents gained significantly more weight compared with adults. The magnitude of
changes in fasting total cholesterol, LDL cholesterol, triglycerides, and prolactin (see
sections 4.4 and 4.8) were greater in adolescents than in adults. There are no
controlled data on maintenance of effect or long term safety (see sections 4.4 and 4.8).
Information on long term safety is primarily limited to open-label, uncontrolled data.
5.2

Pharmacokinetic properties
Absorption
Olanzapine is well absorbed after oral administration, reaching peak plasma
concentrations within 5 to 8 hours. The absorption is not affected by food. Absolute
oral bioavailability relative to intravenous administration has not been determined.
Distribution
The plasma protein binding of olanzapine was about 93 % over the concentration
range of about 7 to about 1000 ng/ml. Olanzapine is bound predominantly to albumin
and α1-acid-glycoprotein.
Biotransformation
Olanzapine is metabolized in the liver by conjugative and oxidative pathways. The
major circulating metabolite is the 10-N-glucuronide, which does not pass the blood
brain barrier. Cytochromes P450- CYP1A2 and P450-CYP2D6 contribute to the
formation of the N-desmethyl and 2-hydroxymethyl metabolites, both exhibited
significantly less in vivo pharmacological activity than olanzapine in animal studies.
The predominant pharmacologic activity is from the parent olanzapine.
Elimination
After oral administration, the mean terminal elimination half-life of olanzapine in
healthy subjects varied on the basis of age and gender.
In healthy elderly (65 and over) versus non-elderly subjects, the mean elimination
half-life was prolonged (51.8 versus 33.8 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 hr) 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.

Smokers
In smoking subjects with mild hepatic dysfunction, mean elimination half-life (39.3
hr) was prolonged and clearance (18.0 l/hr) was reduced analogous to non-smoking
healthy subjects (48.8 hr and 14.1 l/hr, respectively).
In non-smoking versus smoking subjects (males and females) the mean elimination
half-life was prolonged (38.6 versus 30.4 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.
Haematologic toxicity
Effects on haematology parameters were found in each species, including doserelated 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 15fold 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

Olanzapine tablets:
Lactose anhydrous
Microcrystalline cellulose
Crospovidone type A
Low-substituted Hydroxypropylcellulose
Magnesium stearate
Silica, colloidal anhydrous
6.2

Incompatibilities
Not applicable.

6.3

Shelf life
Olanzapine tablets:
3 years

6.4

Special precautions for storage
Do not store above 30°C
6.5

Nature and contents of container

Olanzapine tablets:
Aluminium-aluminium blisters
Pack size of 28, 35, 56 or 70 tablets.
HDPE bottles with a white child-resistant polypropylene-cap
Pack sizes of 30 or 100 tablets.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
No special requirements.

7

MARKETING AUTHORISATION HOLDER
Sun Pharmaceutical Industries Europe B.V.
Polarisavenue 87
2132 JH Hoofddorp
The Netherlands

8

MARKETING AUTHORISATION NUMBER(S)
PL 31750/0021

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
12/06/2014

10

DATE OF REVISION OF THE TEXT
11/11/2015

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Source: Medicines and Healthcare Products Regulatory Agency

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