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Please Note: This SPC has been Re-formatted in its entirety
4. CLINICAL PARTICULARS
4.2 Posology and method of administration
Added:
Children and adolescents
Olanzapine is not recommended for use in children and adolescents below 18 years of age due to a lack
of data on long term 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).
4.4 Special warnings and precautions for use
Added:
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 approved for the treatment of dementia-related psychosis and/or behavioural
disturbances and is not recommended for use in this particular group of patients 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 product. 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 creatinine 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.
Lipid alterations
Deleted:
Acute symptoms such as sweating, insomnia, tremor, anxiety, nausea, or vomiting have been reported
very rarely (<0.01%) when olanzapine is stopped abruptly. Gradual dose reduction should be
considered when discontinuing olanzapine.
Anticholinergic activity
Deleted:
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 also 4.8
Undesirable effects), 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 medications (dopamine agonist) and to remain on the same anti-Parkinsonian
medications 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.
Olanzapine is not approved for the treatment of dementia-related psychosis and/or behavioural
disturbances and is not recommended for use in this particular group of patients 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.
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.
Added:
Discontinuation of treatment
Acute symptoms such as sweating, insomnia, tremor, anxiety, nausea, or vomiting have been reported
very rarely (<0.01%) 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, as with other antipsychotics, 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 very rarely (< 0.01%)
been reported. . 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.
Deleted:
There are limited data on co-medication with lithium and valproate (see section 5.1). There are no
clinical data available on olanzapine and carbamazepine co-therapy, however a pharmacokinetic study
has been conducted (see section 4.5).
Neuroleptic Malignant Syndrome (NMS): NMS is a potentially life-threatening condition associated
with antipsychotic medication. 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 creatinine 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.
Tardive Dyskinesia
Deleted:
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.
Postural hypotension
Deleted:
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, as with other antipsychotics, 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.
Temporal association of olanzapine treatment and venous thromboembolism has very rarely (<0.01%)
been reported. . 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.
Added:
Use in children and adolescents under 18 years of age
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).
4.5 Interaction with other medicinal products and other forms of interaction
Added:
Interaction studies have only been performed in adults.
CNS medicinal products
Caution should be exercised in patients who 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).
4.8 Undesirable effects
Changed in its entirety:
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 (see section 4.4), dyskinesia, orthostatic hypotension, anticholinergic effects, transient
asymptomatic elevations of hepatic transaminases (see section 4.4), rash, asthenia, fatigue and oedema.
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 ( ≥10%), common (≥ 1% and < 10%), uncommon (≥ 0.1% and < 1%), rare (≥ 0.01% and
< 0.1%), very rare (< 0.01%), not known (cannot be estimated from the data available).
TABLE
1 Clinically significant weight gain was observed across all baseline Body Mass Index (BMI) categories.
Weight gain ≥ 7% of baseline body weight was very common and ≥ 15% of baseline body weight was
common.
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 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 Associated clinical manifestations (e.g., gynaecomastia, galactorrhoea, and breast enlargement) were
rare. In most patients, levels returned to normal ranges without cessation of treatment.
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 also 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.
Children and adolescents
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 clinical
trials in adolescent patients. Clinically significant weight gain ( ≥ 7%) appears to occur more frequently
in the adolescent population.
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
The frequency terms listed are defined as follows: Very common ( ≥ 10%), common (≥ 1% and < 10%).
TABLE
9 Weight gain > 7% of baseline body weight (kg) was very common and ≥ 15% of baseline body weight
was common.
10 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).
11 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.
12 Elevated plasma prolactin levels were reported in 47.4% of adolescent patients.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Added:
Paediatric population
The experience in adolescents (ages 13 to 17 years) is limited to short term efficacy data 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 data on maintenance of
effect and limited data on long term safety (see sections 4.4 and 4.8).
5.2 Pharmacokinetic properties
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.
6. PHARMACEUTICAL PARTICULARS
6.4 Special precautions for storage
Changed:
ZYPREXA tablets: Store in the original package in order to protect from light and moisture.
10. DATE OF REVISION OF THE TEXT
New date:
22 April 2008
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