ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Olanzapine Glenmark Europe 5 mg orodispersible tablets
2.
Each orodispersible tablet contains 5 mg olanzapine.
Excipient: Each orodispersible tablet contains 0.23 mg of aspartame
For a full list of excipients, see section 6.1
3.
Orodispersible tablet
Yellow coloured circular flat bevelled edge tablets with ‘2’ debossed on one side.
4.
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).
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.
2
Olanzapine Glenmark Europe orodispersible tablets should be placed in the mouth, where it will
rapidlydisperse in saliva, so it can be easily swallowed. Alternatively, it may be dispersed in a full
glass of water or other suitable beverage (orange juice, apple juice, milk or coffee) immediately
before the administration.
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).
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.
Gender
The starting dose and dose range need not be routinely altered for female patients relative to male
patients.
Smokers
The starting dose and dose range need not be routinely altered for non-smokers relative to smokers.
When more than one factor is present which might result in slower metabolism (female gender,
geriatric age, non-smoking status), consideration should be given to decreasing the starting dose. Dose
escalation, when indicated, should be conservative in such patients.
In cases where dose increments of 2.5 mg are considered necessary, Olanzapine Glenmark tablets
should be used.
(See sections 4.5 and 5.2.)
Hypersensitivity to the active substance or to any of the excipients. Patients with known risk of
narrow-angle glaucoma.
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 % verses 1.5 %,
3
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 % verses 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 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 rarely, 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.
Patients treated with any antipsychotic agents, 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.
Lipid alterations
Undesirable alterations in lipids have been observed in olanzapine-treated patients in placebo-
4
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 agents, including olanzapine, should be
monitored regularly for lipids in accordance with utilised antipsychotic guidelines.
Anticholinergic activity
While olanzapine demonstrated anticholinergic activity
in vitro
, experience during the clinical trials
revealed a low incidence of related events. However, as clinical experience with olanzapine in
patients with concomitant illness is limited, caution is advised when prescribing for patients with
prostatic hypertrophy, or paralytic ileus and related conditions.
Hepatic function
Transient, asymptomatic elevations of hepatic aminotransferases, alanine transferase (ALT), aspartate
transferase (AST) have been seen commonly, especially in early treatment.
Caution should be exercised and follow-up organised in patients with elevated ALT and/or AST, in
patients with signs and symptoms of hepatic impairment, in patients with pre-existing conditions
associated with limited hepatic functional reserve, and in patients who are being treated with
potentially hepatotoxic medicines.
In cases where hepatitis (including hepatocellular, cholestatic or mixed liver injury) has been
diagnosed, olanzapine treatment should be discontinued.
Neutropenia
Caution should be exercised in patients with low leukocyte and/or neutrophil counts for any reason, in
patients receiving medicines known to cause neutropenia, in patients with a history of drug-induced
bone marrow depression/toxicity, in patients with bone marrow depression caused by concomitant
illness, radiation therapy or chemotherapy and in patients with hypereosinophilic conditions or with
myeloproliferative disease.
Neutropenia has been reported commonly when olanzapine and valproate are used concomitantly (see
section 4.8).
Discontinuation of treatment
Acute symptoms such as sweating, insomnia, tremor, anxiety, nausea, or vomiting have been reported
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
5
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 rarely 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. As with
other antipsychotics, 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
Olanzapine Glenmark Europe orodispersible tablet contains aspartame, which is a source of
phenylalanine. May be harmful for people with phenylketonuria.
Paediatric population
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).
6
Inhibition of CYP1A2
Fluvoxamine, a specific CYP1A2 inhibitor, has been shown to significantly inhibit the metabolism of
olanzapine.
The mean increase in olanzapine C
max
following fluvoxamine was 54 % in female nonsmokers and
77 % 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, p
regnancy 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.
Spontaneous reports have been very rarely received on tremor, hypertonia, lethargy and sleepiness, in
7
infants born to mothers who had used olanzapine during the 3rd trimester.
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.
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.
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 aminotransferases (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).
Very common
Common
Uncommon
Not known
Blood and the
lymphatic
system
disorders
Eosinophilia
Leukopenia
Thrombocytopenia
Neutropenia
Immune system
disorders
Allergic reaction
Metabolism
and nutrition
disorders
Weight gain
1
Elevated
cholesterol
levels
Development or
exacerbation of
diabetes
occasionally
associated with
ketoacidosis or
coma,
including some
fatal
2,3
Elevated glucose
levels
Elevated
triglyceride
levels
2,5
cases (see section
4.4)
Glucosuria
Hypothermia
Increased appetite
8
4
Nervous system
disorders
Somnolence
Dizziness
Seizures where in
most cases a
history of seizures
or risk factors for
seizures were
reported
Akathisia
6
Parkinsonism
6
Dyskinesia
6
Neuroleptic
malignant
syndrome (see
section
4.4)
Dystonia (including
oculogyration)
Tardive dyskinesia
Discontinuation
Cardiac
disorders
Bradycardia
Ventricular
tachycardia/fibrilla
tion
QTc
prolongation
(see
sudden death (see
section 4.4)
section 4.4)
Vascular
disorders
Orthostatic
hypotension
Thromboembolism
(including
pulmonary
embolism and deep
vein thrombosis)
Gastrointestina
l disorders
Mild, transient
Pancreatitis
anticholinergic
effects including
constipation and
dry mouth
Hepato-biliary
disorders
Transient,
asymptomatic
elevations of
hepatic
aminotransferases
(ALT, AST),
especially in
Hepatitis
(including
hepatocellular,
cholestatic or
mixed
liver injury)
early treatment
(see
section 4.4)
Skin and
subcutaneous
tissue disorders
Rash
Photosensitivity
reaction
Alopecia
Musculoskeleta
l and
connective
tissue disorders
Rhabdomyolysis
Renal and
Urinary
Urinary hesitation
9
Symptoms
7
urinary
disorders
incontinence
Reproductive
system and
breast
disorders
Priapism
General
disorders and
administration
site conditions
Asthenia
Fatigue
Oedema
Investigations
Elevated plasma
High creatine
Increased alkaline
prolactin levels
8
phosphokinase
phosphatase
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. Generally in olanzapine-treated patients potentially associated
breast- and menstrual related clinical manifestations (e.g. amenorrhoea, breast enlargement,
galactorrhea in females, and gynaecomastia/breast enlargement in males) were uncommon. Potentially
associated sexual function-related adverse reactions (e.g. erectile dysfunction in males and decreased
libido in both genders) were commonly observed.
10
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 (≥ 10 %), common (≥ 1 % and
< 10 %).
11
Metabolism and nutrition disorders
Very common:
Weight gain
9
, elevated triglyceride levels
10
Common:
Elevated cholesterol levels
11
, increased appetite.
Nervous system disorders
Very common:
Sedation (including: hypersomnia, lethargy, somnolence).
Gastrointestinal disorders
Common:
Dry mouth
Hepato-biliary disorders
Very common:
Elevations of hepatic
aminotransferases
(ALT/AST; see section 4.4).
Investigations
Very common:
Decreased total bilirubin, increased GGT, elevated plasma prolactin levels
12
9
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.
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.
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 of overdose
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.
12
Do not use epinephrine, dopamine, or other sympathomimetic agents with betaagonist 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.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: diazepines, oxazepines and thiazepines, ATC code: N05A H03
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 (K
i
< 100 nM) for serotonin
5HT
2A/2C
, 5HT
3
, 5HT
6
; dopamine D
1
, D
2
, D
3
, D
4
, D
5
; cholinergic muscarinic receptors M
1
-M
5
;
α
1
adrenergic; and histamine H
1
receptors.
Animal behavioral studies with olanzapine indicated 5HT, dopamine, and cholinergic antagonism,
consistent with the receptor-binding profile. Olanzapine demonstrated a greater
in vitro
affinity for
serotonin 5HT
2
than dopamine D
2
receptors and greater 5HT
2
than D
2
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 5HT
2A
than dopamine D
2
receptor occupancy. In addition, a Single
Photon Emission Computed Tomography (SPECT) imaging study in schizophrenic patients revealed
that olanzapine-responsive patients had lower striatal D
2
occupancy than some other antipsychotic and
risperidone-responsive patients, while being comparable to clozapine-responsive patients.
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.
13
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
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
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.
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.
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).
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.
14
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.
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.
Paediatric population
Adolescents (ages 13 to 17 years): The pharmacokinetics of olanzapine are similar between
adolescents and adults. In clinical studies, the average olanzapine exposure was approximately 27 %
higher in adolescents. Demographic differences between the adolescents and adults include a lower
average body weight and fewer adolescents were smokers. Such factors possibly contribute to the
higher average exposure observed in adolescents.
5.3 Preclinical safety data
Acute (single-dose) toxicity
Signs of oral toxicity in rodents were characteristic of potent neuroleptic compounds: hypoactivity,
coma, tremors, clonic convulsions, salivation, and depressed weight gain. The median lethal doses
were approximately 210 mg/kg (mice) and 175 mg/kg (rats). Dogs tolerated single oral doses up to
100 mg/kg without mortality. Clinical signs included sedation, ataxia, tremors, increased heart rate,
labored respiration, miosis, and anorexia. In monkeys, single oral doses up to 100 mg/kg resulted in
prostration and, at higher doses, semi-consciousness.
Repeated-dose toxicity
In studies up to 3 months duration in mice and up to 1 year in rats and dogs, the predominant effects
were CNS depression, anticholinergic effects, and peripheral haematological disorders. Tolerance
developed to the CNS depression. Growth parameters were decreased at high doses. Reversible
effects consistent with elevated prolactin in rats included decreased weights of ovaries and uterus and
morphologic changes in vaginal epithelium and in mammary gland.
Haematologic toxicity:
Effects on haematology parameters were found in each species, including dose-related reductions in
circulating leukocytes in mice and non-specific reductions of circulating leukocytes in rats; however,
no evidence of bone marrow cytotoxicity was found. Reversible neutropenia, thrombocytopenia, or
anemia 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.
15
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 fetal 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.
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
21 months.
6.4 Special precautions for storage
Store below 30°C.
6.5
Nature and contents of container
5mg tablets
Aluminium/aluminium blisters in cartons of 28, 56, 70 tablets per carton.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
16
7.
Glenmark Generics (Europe) Limited
Laxmi House
2-B Draycott Avenue
Kenton
Harrow
Middlesex
HA3 OBU.
United Kingdom
8.
EU/1/09/588/001
EU/1/09/588/002
EU/1/09/588/003
9.
03.12.2009
Detailed information on this product is available on the website of the European Medicines Agency
(EMA)
http://www.ema.europa.eu
17
1.
Olanzapine Glenmark Europe 10 mg orodispersible tablets
2.
Each orodispersible tablet contains 10 mg olanzapine
Excipient: Each orodispersible tablet contains 0.46 mg of aspartame
For a full list of excipients, see section 6.1
3.
Orodispersible tablet
Yellow coloured circular flat bevelled edge tablets with ‘OL’debossed on one side and ‘4’ debossed
on one side.
4.
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).
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
18
tapering of the dose should be considered when discontinuing olanzapine.
Olanzapine Glenmark Europe orodispersible tablets should be placed in the mouth, where it will
rapidlydisperse in saliva, so it can be easily swallowed. Alternatively, it may be dispersed in a full
glass of water or other suitable beverage (orange juice, apple juice, milk or coffee) immediately
before the administration.
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).
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.
Gender
The starting dose and dose range need not be routinely altered for female patients relative to male
patients.
Smokers
The starting dose and dose range need not be routinely altered for non-smokers relative to smokers.
When more than one factor is present which might result in slower metabolism (female gender,
geriatric age, non-smoking status), consideration should be given to decreasing the starting dose. Dose
escalation, when indicated, should be conservative in such patients.
In cases where dose increments of 2.5 mg are considered necessary, Olanzapine Glenmark tablets
should be used.
(See sections 4.5 and 5.2.)
Hypersensitivity to the active substance or to any of the excipients. Patients with known risk of
narrow-angle glaucoma.
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.
19
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 % verses 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 % verses 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 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 rarely, 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.
Patients treated with any antipsychotic agents, 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.
20
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 agents, including olanzapine, should be
monitored regularly for lipids in accordance with utilised antipsychotic guidelines.
Anticholinergic activity
While olanzapine demonstrated anticholinergic activity
in vitro
, experience during the clinical trials
revealed a low incidence of related events. However, as clinical experience with olanzapine in
patients with concomitant illness is limited, caution is advised when prescribing for patients with
prostatic hypertrophy, or paralytic ileus and related conditions.
Hepatic function
Transient, asymptomatic elevations of hepatic aminotransferases, alanine transferase (ALT), aspartate
transferase (AST) have been seen commonly, especially in early treatment.
Caution should be exercised and follow-up organised in patients with elevated ALT and/or AST, in
patients with signs and symptoms of hepatic impairment, in patients with pre-existing conditions
associated with limited hepatic functional reserve, and in patients who are being treated with
potentially hepatotoxic medicines.
In cases where hepatitis (including hepatocellular, cholestatic or mixed liver injury) has been
diagnosed, olanzapine treatment should be discontinued.
Neutropenia
Caution should be exercised in patients with low leukocyte and/or neutrophil counts for any reason, in
patients receiving medicines known to cause neutropenia, in patients with a history of drug-induced
bone marrow depression/toxicity, in patients with bone marrow depression caused by concomitant
illness, radiation therapy or chemotherapy and in patients with hypereosinophilic conditions or with
myeloproliferative disease.
Neutropenia has been reported commonly when olanzapine and valproate are used concomitantly (see
section 4.8).
Discontinuation of treatment
Acute symptoms such as sweating, insomnia, tremor, anxiety, nausea, or vomiting have been reported
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.
21
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 rarely 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. As with
other antipsychotics, 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
Olanzapine Glenmark Europe orodispersible tablet contains aspartame, which is a source of
phenylalanine. May be harmful for people with phenylketonuria.
Paediatric population
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.
22
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 C
max
following fluvoxamine was 54 % in female nonsmokers and
77 % 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, p
regnancy 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
23
pregnancy only if the potential benefit justifies the potential risk to the foetus.
Spontaneous reports have been very rarely received on tremor, hypertonia, lethargy and sleepiness, in
infants born to mothers who had used olanzapine during the 3rd trimester.
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.
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.
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 aminotransferases (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).
Very common
Common
Uncommon
Not known
Blood and the
lymphatic
system
disorders
Eosinophilia
Leukopenia
Thrombocytopenia
Neutropenia
Immune system
disorders
Allergic reaction
Metabolism
and nutrition
disorders
Weight gain
1
Elevated
cholesterol
levels
Development or
exacerbation of
diabetes
occasionally
associated with
ketoacidosis or
coma,
including some
fatal
2,3
Elevated glucose
levels
Elevated
triglyceride
levels
2,5
cases (see section
4.4)
Glucosuria
Hypothermia
Increased appetite
24
4
Nervous system
disorders
Somnolence
Dizziness
Seizures where in
most cases a
history of seizures
or risk factors for
seizures were
reported
Akathisia
6
Parkinsonism
6
Dyskinesia
6
Neuroleptic
malignant
syndrome (see
section
4.4)
Dystonia (including
oculogyration)
Tardive dyskinesia
Discontinuation
Cardiac
disorders
Bradycardia
Ventricular
tachycardia/fibrilla
tion
QTc
prolongation
(see
sudden death (see
section 4.4)
section 4.4)
Vascular
disorders
Orthostatic
hypotension
Thromboembolism
(including
pulmonary
embolism and deep
vein thrombosis)
Gastrointestina
l disorders
Mild, transient
Pancreatitis
anticholinergic
effects including
constipation and
dry mouth
Hepato-biliary
disorders
Transient,
asymptomatic
elevations of
hepatic
aminotransferases
(ALT, AST),
especially in
Hepatitis
(including
hepatocellular,
cholestatic or
mixed
liver injury)
early treatment
(see
section 4.4)
Skin and
subcutaneous
tissue disorders
Rash
Photosensitivity
reaction
Alopecia
Musculoskeleta
l and
connective
tissue disorders
Rhabdomyolysis
Renal and
Urinary
Urinary hesitation
25
Symptoms
7
urinary
disorders
incontinence
Reproductive
system and
breast
disorders
Priapism
General
disorders and
administration
site conditions
Asthenia
Fatigue
Oedema
Investigations
Elevated plasma
High creatine
Increased alkaline
prolactin levels
8
phosphokinase
phosphatase
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. Generally in olanzapine-treated patients potentially associated
breast- and menstrual related clinical manifestations (e.g. amenorrhoea, breast enlargement,
galactorrhea in females, and gynaecomastia/breast enlargement in males) were uncommon. Potentially
associated sexual function-related adverse reactions (e.g. erectile dysfunction in males and decreased
libido in both genders) were commonly observed.
26
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 (≥ 10 %), common (≥ 1 % and
< 10 %).
27
Metabolism and nutrition disorders
Very common:
Weight gain
9
, elevated triglyceride levels
10
Common:
Elevated cholesterol levels
11
, increased appetite.
Nervous system disorders
Very common:
Sedation (including: hypersomnia, lethargy, somnolence).
Gastrointestinal disorders
Common:
Dry mouth
Hepato-biliary disorders
Very common:
Elevations of hepatic
aminotransferases
(ALT/AST; see section 4.4).
Investigations
Very common:
Decreased total bilirubin, increased GGT, elevated plasma prolactin levels
12
9
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.
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.
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 of overdose
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.
28
Do not use epinephrine, dopamine, or other sympathomimetic agents with betaagonist 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.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: diazepines, oxazepines and thiazepines, ATC code: N05A H03
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 (K
i
< 100 nM) for serotonin
5HT
2A/2C
, 5HT
3
, 5HT
6
; dopamine D
1
, D
2
, D
3
, D
4
, D
5
; cholinergic muscarinic receptors M
1
-M
5
;
α
1
adrenergic; and histamine H
1
receptors.
Animal behavioral studies with olanzapine indicated 5HT, dopamine, and cholinergic antagonism,
consistent with the receptor-binding profile. Olanzapine demonstrated a greater
in vitro
affinity for
serotonin 5HT
2
than dopamine D
2
receptors and greater 5HT
2
than D
2
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 5HT
2A
than dopamine D
2
receptor occupancy. In addition, a Single
Photon Emission Computed Tomography (SPECT) imaging study in schizophrenic patients revealed
that olanzapine-responsive patients had lower striatal D
2
occupancy than some other antipsychotic and
risperidone-responsive patients, while being comparable to clozapine-responsive patients.
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
29
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
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
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.
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.
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).
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.
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
30
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.
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.
Paediatric population
Adolescents (ages 13 to 17 years): The pharmacokinetics of olanzapine are similar between
adolescents and adults. In clinical studies, the average olanzapine exposure was approximately 27 %
higher in adolescents. Demographic differences between the adolescents and adults include a lower
average body weight and fewer adolescents were smokers. Such factors possibly contribute to the
higher average exposure observed in adolescents.
5.3 Preclinical safety data
Acute (single-dose) toxicity
Signs of oral toxicity in rodents were characteristic of potent neuroleptic compounds: hypoactivity,
coma, tremors, clonic convulsions, salivation, and depressed weight gain. The median lethal doses
were approximately 210 mg/kg (mice) and 175 mg/kg (rats). Dogs tolerated single oral doses up to
100 mg/kg without mortality. Clinical signs included sedation, ataxia, tremors, increased heart rate,
labored respiration, miosis, and anorexia. In monkeys, single oral doses up to 100 mg/kg resulted in
prostration and, at higher doses, semi-consciousness.
Repeated-dose toxicity
In studies up to 3 months duration in mice and up to 1 year in rats and dogs, the predominant effects
were CNS depression, anticholinergic effects, and peripheral haematological disorders. Tolerance
developed to the CNS depression. Growth parameters were decreased at high doses. Reversible
effects consistent with elevated prolactin in rats included decreased weights of ovaries and uterus and
morphologic changes in vaginal epithelium and in mammary gland.
Haematologic toxicity:
Effects on haematology parameters were found in each species, including dose-related reductions in
circulating leukocytes in mice and non-specific reductions of circulating leukocytes in rats; however,
no evidence of bone marrow cytotoxicity was found. Reversible neutropenia, thrombocytopenia, or
anemia 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).
31
In the offspring of rats given olanzapine, delays in fetal 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.
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
21 months.
6.4 Special precautions for storage
Store below 30°C.
6.5 Nature and contents of container
Aluminium/aluminium blisters in cartons of 28, 56, 70 tablets per carton.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Glenmark Generics (Europe) Limited
Laxmi House
2-B Draycott Avenue
Kenton
Harrow
Middlesex
HA3 OBU.
United Kingdom
32
8.
EU/1/09/588/004
EU/1/09/588/005
EU/1/09/588/006
9.
03.12.2009
Detailed information on this product is available on the website of the European Medicines Agency
(EMA)
http://www.ema.europa.eu
33
1.
Olanzapine Glenmark Europe 15 mg orodispersible tablets
2.
Each orodispersible tablet contains 15 mg Olanzapine
Excipient: Each orodispersible tablet contains 0.69 mg of aspartame
For a full list of excipients, see section 6.1
3.
Orodispersible tablet
Yellow coloured circular flat bevelled edge tablets with ‘OL’ debossed on one side and ‘5’ debossed
on other side.
4.
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).
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.
34
Olanzapine Glenmark Europe orodispersible tablets should be placed in the mouth, where it will
rapidlydisperse in saliva, so it can be easily swallowed. Alternatively, it may be dispersed in a full
glass of water or other suitable beverage (orange juice, apple juice, milk or coffee) immediately
before the administration.
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).
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.
Gender
The starting dose and dose range need not be routinely altered for female patients relative to male
patients.
Smokers
The starting dose and dose range need not be routinely altered for non-smokers relative to smokers.
When more than one factor is present which might result in slower metabolism (female gender,
geriatric age, non-smoking status), consideration should be given to decreasing the starting dose. Dose
escalation, when indicated, should be conservative in such patients.
In cases where dose increments of 2.5 mg are considered necessary, Olanzapine Glenmark tablets
should be used.
(See sections 4.5 and 5.2.)
Hypersensitivity to the active substance or to any of the excipients. Patients with known risk of
narrow-angle glaucoma.
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
35
of death in olanzapine-treated patients compared to patients treated with placebo (3.5 % verses 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 % verses 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 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 rarely, 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.
Patients treated with any antipsychotic agents, 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.
Lipid alterations
36
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 agents, including olanzapine, should be
monitored regularly for lipids in accordance with utilised antipsychotic guidelines.
Anticholinergic activity
While olanzapine demonstrated anticholinergic activity
in vitro
, experience during the clinical trials
revealed a low incidence of related events. However, as clinical experience with olanzapine in
patients with concomitant illness is limited, caution is advised when prescribing for patients with
prostatic hypertrophy, or paralytic ileus and related conditions.
Hepatic function
Transient, asymptomatic elevations of hepatic aminotransferases, alanine transferase (ALT), aspartate
transferase (AST) have been seen commonly, especially in early treatment.
Caution should be exercised and follow-up organised in patients with elevated ALT and/or AST, in
patients with signs and symptoms of hepatic impairment, in patients with pre-existing conditions
associated with limited hepatic functional reserve, and in patients who are being treated with
potentially hepatotoxic medicines.
In cases where hepatitis (including hepatocellular, cholestatic or mixed liver injury) has been
diagnosed, olanzapine treatment should be discontinued.
Neutropenia
Caution should be exercised in patients with low leukocyte and/or neutrophil counts for any reason, in
patients receiving medicines known to cause neutropenia, in patients with a history of drug-induced
bone marrow depression/toxicity, in patients with bone marrow depression caused by concomitant
illness, radiation therapy or chemotherapy and in patients with hypereosinophilic conditions or with
myeloproliferative disease.
Neutropenia has been reported commonly when olanzapine and valproate are used concomitantly (see
section 4.8).
Discontinuation of treatment
Acute symptoms such as sweating, insomnia, tremor, anxiety, nausea, or vomiting have been reported
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
37
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 rarely 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. As with
other antipsychotics, 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
Olanzapine Glenmark Europe orodispersible tablet contains aspartame, which is a source of
phenylalanine. May be harmful for people with phenylketonuria.
Paediatric population
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
38
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 C
max
following fluvoxamine was 54 % in female nonsmokers and
77 % 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, p
regnancy 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.
39
Spontaneous reports have been very rarely received on tremor, hypertonia, lethargy and sleepiness, in
infants born to mothers who had used olanzapine during the 3rd trimester.
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.
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.
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 aminotransferases (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).
Very common
Common
Uncommon
Not known
Blood and the
lymphatic
system
disorders
Eosinophilia
Leukopenia
Thrombocytopenia
Neutropenia
Immune system
disorders
Allergic reaction
Metabolism
and nutrition
disorders
Weight gain
1
Elevated
cholesterol
levels
Development or
exacerbation of
diabetes
occasionally
associated with
ketoacidosis or
coma,
including some
fatal
2,3
Elevated glucose
levels
Elevated
triglyceride
levels
2,5
cases (see section
4.4)
Glucosuria
Hypothermia
Increased appetite
Nervous system
Somnolence
Dizziness
Seizures where in
40
4
disorders
Akathisia
6
most cases a
history of seizures
or risk factors for
seizures were
reported
Parkinsonism
6
Dyskinesia
6
Neuroleptic
malignant
syndrome (see
section
4.4)
Dystonia (including
oculogyration)
Tardive dyskinesia
Discontinuation
Cardiac
disorders
Bradycardia
Ventricular
tachycardia/fibrilla
tion
QTc
prolongation
(see
sudden death (see
section 4.4)
section 4.4)
Vascular
disorders
Orthostatic
hypotension
Thromboembolism
(including
pulmonary
embolism and deep
vein thrombosis)
Gastrointestina
l disorders
Mild, transient
Pancreatitis
anticholinergic
effects including
constipation and
dry mouth
Hepato-biliary
disorders
Transient,
asymptomatic
elevations of
hepatic
aminotransferases
(ALT, AST),
especially in
Hepatitis
(including
hepatocellular,
cholestatic or
mixed
liver injury)
early treatment
(see
section 4.4)
Skin and
subcutaneous
tissue disorders
Rash
Photosensitivity
reaction
Alopecia
Musculoskeleta
l and
connective
tissue disorders
Rhabdomyolysis
Renal and
urinary
Urinary
incontinence
Urinary hesitation
41
Symptoms
7
disorders
Reproductive
system and
breast
disorders
Priapism
General
disorders and
administration
site conditions
Asthenia
Fatigue
Oedema
Investigations
Elevated plasma
High creatine
Increased alkaline
prolactin levels
8
phosphokinase
phosphatase
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
42
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. Generally in olanzapine-treated patients potentially associated
breast- and menstrual related clinical manifestations (e.g. amenorrhoea, breast enlargement,
galactorrhea in females, and gynaecomastia/breast enlargement in males) were uncommon. Potentially
associated sexual function-related adverse reactions (e.g. erectile dysfunction in males and decreased
libido in both genders) were commonly observed.
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 (≥ 10 %), common (≥ 1 % and
< 10 %).
43
Metabolism and nutrition disorders
Very common:
Weight gain
9
, elevated triglyceride levels
10
Common:
Elevated cholesterol levels
11
, increased appetite.
Nervous system disorders
Very common:
Sedation (including: hypersomnia, lethargy, somnolence).
Gastrointestinal disorders
Common:
Dry mouth
Hepato-biliary disorders
Very common:
Elevations of hepatic
aminotransferases
(ALT/AST; see section 4.4).
Investigations
Very common:
Decreased total bilirubin, increased GGT, elevated plasma prolactin levels
12
9
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.
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.
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 of overdose
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.
44
Do not use epinephrine, dopamine, or other sympathomimetic agents with betaagonist 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.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: diazepines, oxazepines and thiazepines, ATC code: N05A H03
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 (K
i
< 100 nM) for serotonin
5HT
2A/2C
, 5HT
3
, 5HT
6
; dopamine D
1
, D
2
, D
3
, D
4
, D
5
; cholinergic muscarinic receptors M
1
-M
5
;
α
1
adrenergic; and histamine H
1
receptors.
Animal behavioral studies with olanzapine indicated 5HT, dopamine, and cholinergic antagonism,
consistent with the receptor-binding profile. Olanzapine demonstrated a greater
in vitro
affinity for
serotonin 5HT
2
than dopamine D
2
receptors and greater 5HT
2
than D
2
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 5HT
2A
than dopamine D
2
receptor occupancy. In addition, a Single
Photon Emission Computed Tomography (SPECT) imaging study in schizophrenic patients revealed
that olanzapine-responsive patients had lower striatal D
2
occupancy than some other antipsychotic and
risperidone-responsive patients, while being comparable to clozapine-responsive patients.
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.
45
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
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
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.
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.
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).
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.
46
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.
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.
Paediatric population
Adolescents (ages 13 to 17 years): The pharmacokinetics of olanzapine are similar between
adolescents and adults. In clinical studies, the average olanzapine exposure was approximately 27 %
higher in adolescents. Demographic differences between the adolescents and adults include a lower
average body weight and fewer adolescents were smokers. Such factors possibly contribute to the
higher average exposure observed in adolescents.
5.3 Preclinical safety data
Acute (single-dose) toxicity
Signs of oral toxicity in rodents were characteristic of potent neuroleptic compounds: hypoactivity,
coma, tremors, clonic convulsions, salivation, and depressed weight gain. The median lethal doses
were approximately 210 mg/kg (mice) and 175 mg/kg (rats). Dogs tolerated single oral doses up to
100 mg/kg without mortality. Clinical signs included sedation, ataxia, tremors, increased heart rate,
labored respiration, miosis, and anorexia. In monkeys, single oral doses up to 100 mg/kg resulted in
prostration and, at higher doses, semi-consciousness.
Repeated-dose toxicity
In studies up to 3 months duration in mice and up to 1 year in rats and dogs, the predominant effects
were CNS depression, anticholinergic effects, and peripheral haematological disorders. Tolerance
developed to the CNS depression. Growth parameters were decreased at high doses. Reversible
effects consistent with elevated prolactin in rats included decreased weights of ovaries and uterus and
morphologic changes in vaginal epithelium and in mammary gland.
Haematologic toxicity:
Effects on haematology parameters were found in each species, including dose-related reductions in
circulating leukocytes in mice and non-specific reductions of circulating leukocytes in rats; however,
no evidence of bone marrow cytotoxicity was found. Reversible neutropenia, thrombocytopenia, or
anemia 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.
47
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 fetal 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.
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
21 months.
6.4 Special precautions for storage
Store below 30°C.
6.5 Nature and contents of container
Aluminium/aluminium blisters in cartons of 28, 56, 70 tablets per carton.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
48
7.
Glenmark Generics (Europe) Limited
Laxmi House
2-B Draycott Avenue
Kenton
Harrow
Middlesex
HA3 OBU.
United Kingdom
8.
EU/1/09/588/007
EU/1/09/588/008
EU/1/09/588/009
9.
03.12.2009
Detailed information on this product is available on the website of the European Medicines Agency
(EMA)
http://www.ema.europa.eu
49
1.
Olanzapine Glenmark Europe 20 mg orodispersible tablets
2.
Each orodispersible tablet contains 20 mg olanzapine
Excipient:
Each orodispersible tablet contains 0.92 mg of aspartame
For a full list of excipients, see section 6.1
3.
Orodispersible tablet
Yellow coloured circular flat bevelled edge with ‘OL’ debossed on one side and ‘6’ debossed on other
side.
4.
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).
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.
50
Olanzapine can be given without regards for meals as absorption is not affected by food. Gradual
tapering of the dose should be considered when discontinuing olanzapine.
Olanzapine Glenmark Europe orodispersible tablets should be placed in the mouth, where it will
rapidlydisperse in saliva, so it can be easily swallowed. Alternatively, it may be dispersed in a full
glass of water or other suitable beverage (orange juice, apple juice, milk or coffee) immediately
before the administration.
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).
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.
Gender
The starting dose and dose range need not be routinely altered for female patients relative to male
patients.
Smokers
The starting dose and dose range need not be routinely altered for non-smokers relative to smokers.
When more than one factor is present which might result in slower metabolism (female gender,
geriatric age, non-smoking status), consideration should be given to decreasing the starting dose. Dose
escalation, when indicated, should be conservative in such patients.
In cases where dose increments of 2.5 mg are considered necessary, Olanzapine Glenmark tablets
should be used.
(See sections 4.5 and 5.2.)
Hypersensitivity to the active substance or to any of the excipients. Patients with known risk of
narrow-angle glaucoma.
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.
51
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 % verses 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 % verses 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 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 rarely, 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.
Patients treated with any antipsychotic agents, 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.
52
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 agents, including olanzapine, should be
monitored regularly for lipids in accordance with utilised antipsychotic guidelines.
Anticholinergic activity
While olanzapine demonstrated anticholinergic activity
in vitro
, experience during the clinical trials
revealed a low incidence of related events. However, as clinical experience with olanzapine in
patients with concomitant illness is limited, caution is advised when prescribing for patients with
prostatic hypertrophy, or paralytic ileus and related conditions.
Hepatic function
Transient, asymptomatic elevations of hepatic aminotransferases, alanine transferase (ALT), aspartate
transferase (AST) have been seen commonly, especially in early treatment.
Caution should be exercised and follow-up organised in patients with elevated ALT and/or AST, in
patients with signs and symptoms of hepatic impairment, in patients with pre-existing conditions
associated with limited hepatic functional reserve, and in patients who are being treated with
potentially hepatotoxic medicines.
In cases where hepatitis (including hepatocellular, cholestatic or mixed liver injury) has been
diagnosed, olanzapine treatment should be discontinued.
Neutropenia
Caution should be exercised in patients with low leukocyte and/or neutrophil counts for any reason, in
patients receiving medicines known to cause neutropenia, in patients with a history of drug-induced
bone marrow depression/toxicity, in patients with bone marrow depression caused by concomitant
illness, radiation therapy or chemotherapy and in patients with hypereosinophilic conditions or with
myeloproliferative disease.
Neutropenia has been reported commonly when olanzapine and valproate are used concomitantly (see
section 4.8).
Discontinuation of treatment
Acute symptoms such as sweating, insomnia, tremor, anxiety, nausea, or vomiting have been reported
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.
53
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 rarely 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. As with
other antipsychotics, 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
Olanzapine Glenmark Europe orodispersible tablet contains aspartame, which is a source of
phenylalanine. May be harmful for people with phenylketonuria.
Paediatric population
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.
54
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 C
max
following fluvoxamine was 54 % in female nonsmokers and
77 % 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, p
regnancy 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
55
pregnancy only if the potential benefit justifies the potential risk to the foetus.
Spontaneous reports have been very rarely received on tremor, hypertonia, lethargy and sleepiness, in
infants born to mothers who had used olanzapine during the 3rd trimester.
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.
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.
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 aminotransferases (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).
Very common
Common
Uncommon
Not known
Blood and the
lymphatic
system
disorders
Eosinophilia
Leukopenia
Thrombocytopenia
Neutropenia
Immune system
disorders
Allergic reaction
Metabolism
and nutrition
disorders
Weight gain
1
Elevated
cholesterol
levels
Development or
exacerbation of
diabetes
occasionally
associated with
ketoacidosis or
coma,
including some
fatal
2,3
Elevated glucose
levels
Elevated
triglyceride
levels
2,5
cases (see section
4.4)
Glucosuria
Hypothermia
Increased appetite
56
4
Nervous system
disorders
Somnolence
Dizziness
Seizures where in
most cases a
history of seizures
or risk factors for
seizures were
reported
Akathisia
6
Parkinsonism
6
Dyskinesia
6
Neuroleptic
malignant
syndrome (see
section
4.4)
Dystonia (including
oculogyration)
Tardive dyskinesia
Discontinuation
Cardiac
disorders
Bradycardia
Ventricular
tachycardia/fibrilla
tion
QTc
prolongation
(see
sudden death (see
section 4.4)
section 4.4)
Vascular
disorders
Orthostatic
hypotension
Thromboembolism
(including
pulmonary
embolism and deep
vein thrombosis)
Gastrointestina
l disorders
Mild, transient
Pancreatitis
anticholinergic
effects including
constipation and
dry mouth
Hepato-biliary
disorders
Transient,
asymptomatic
elevations of
hepatic
aminotransferases
(ALT, AST),
especially in
Hepatitis
(including
hepatocellular,
cholestatic or
mixed
liver injury)
early treatment
(see
section 4.4)
Skin and
subcutaneous
tissue disorders
Rash
Photosensitivity
reaction
Alopecia
Musculoskeleta
l and
connective
tissue disorders
Rhabdomyolysis
Renal and
Urinary
Urinary hesitation
57
Symptoms
7
urinary
disorders
incontinence
Reproductive
system and
breast
disorders
Priapism
General
disorders and
administration
site conditions
Asthenia
Fatigue
Oedema
Investigations
Elevated plasma
High creatine
Increased alkaline
prolactin levels
8
phosphokinase
phosphatase
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. Generally in olanzapine-treated patients potentially associated
breast- and menstrual related clinical manifestations (e.g. amenorrhoea, breast enlargement,
galactorrhea in females, and gynaecomastia/breast enlargement in males) were uncommon. Potentially
associated sexual function-related adverse reactions (e.g. erectile dysfunction in males and decreased
libido in both genders) were commonly observed.
58
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 (≥ 10 %), common (≥ 1 % and
< 10 %).
59
Metabolism and nutrition disorders
Very common:
Weight gain
9
, elevated triglyceride levels
10
Common:
Elevated cholesterol levels
11
, increased appetite.
Nervous system disorders
Very common:
Sedation (including: hypersomnia, lethargy, somnolence).
Gastrointestinal disorders
Common:
Dry mouth
Hepato-biliary disorders
Very common:
Elevations of hepatic
aminotransferases
(ALT/AST; see section 4.4).
Investigations
Very common:
Decreased total bilirubin, increased GGT, elevated plasma prolactin levels
12
9
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.
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.
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 of overdose
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.
60
Do not use epinephrine, dopamine, or other sympathomimetic agents with betaagonist 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.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: diazepines, oxazepines and thiazepines, ATC code: N05A H03
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 (K
i
< 100 nM) for serotonin
5HT
2A/2C
, 5HT
3
, 5HT
6
; dopamine D
1
, D
2
, D
3
, D
4
, D
5
; cholinergic muscarinic receptors M
1
-M
5
;
α
1
adrenergic; and histamine H
1
receptors.
Animal behavioral studies with olanzapine indicated 5HT, dopamine, and cholinergic antagonism,
consistent with the receptor-binding profile. Olanzapine demonstrated a greater
in vitro
affinity for
serotonin 5HT
2
than dopamine D
2
receptors and greater 5HT
2
than D
2
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 5HT
2A
than dopamine D
2
receptor occupancy. In addition, a Single
Photon Emission Computed Tomography (SPECT) imaging study in schizophrenic patients revealed
that olanzapine-responsive patients had lower striatal D
2
occupancy than some other antipsychotic and
risperidone-responsive patients, while being comparable to clozapine-responsive patients.
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.
61
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
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
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.
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.
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).
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.
62
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.
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.
Paediatric population
Adolescents (ages 13 to 17 years): The pharmacokinetics of olanzapine are similar between
adolescents and adults. In clinical studies, the average olanzapine exposure was approximately 27 %
higher in adolescents. Demographic differences between the adolescents and adults include a lower
average body weight and fewer adolescents were smokers. Such factors possibly contribute to the
higher average exposure observed in adolescents.
5.3 Preclinical safety data
Acute (single-dose) toxicity
Signs of oral toxicity in rodents were characteristic of potent neuroleptic compounds: hypoactivity,
coma, tremors, clonic convulsions, salivation, and depressed weight gain. The median lethal doses
were approximately 210 mg/kg (mice) and 175 mg/kg (rats). Dogs tolerated single oral doses up to
100 mg/kg without mortality. Clinical signs included sedation, ataxia, tremors, increased heart rate,
labored respiration, miosis, and anorexia. In monkeys, single oral doses up to 100 mg/kg resulted in
prostration and, at higher doses, semi-consciousness.
Repeated-dose toxicity
In studies up to 3 months duration in mice and up to 1 year in rats and dogs, the predominant effects
were CNS depression, anticholinergic effects, and peripheral haematological disorders. Tolerance
developed to the CNS depression. Growth parameters were decreased at high doses. Reversible
effects consistent with elevated prolactin in rats included decreased weights of ovaries and uterus and
morphologic changes in vaginal epithelium and in mammary gland.
Haematologic toxicity:
Effects on haematology parameters were found in each species, including dose-related reductions in
circulating leukocytes in mice and non-specific reductions of circulating leukocytes in rats; however,
no evidence of bone marrow cytotoxicity was found. Reversible neutropenia, thrombocytopenia, or
anemia 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.
63
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 fetal 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.
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
21 months.
6.4 Special precautions for storage
Store below 30°C.
6.5 Nature and contents of container
Aluminium/aluminium blisters in cartons of 28, 56, 70 tablets per carton.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Glenmark Generics (Europe) Limited
Laxmi House
2-B Draycott Avenue
Kenton
Harrow
Middlesex
HA3 OBU.
64
United Kingdom
8.
EU/1/09/588/010
EU/1/09/588/011
EU/1/09/588/012
9.
03.12.2009
Detailed information on this product is available on the website of the European Medicines Agency
(EMA)
http://www.ema.europa.eu
65
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
66
A. MANUFACTURING AUTHORISATION HOLDER 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 OF THE MARKETING AUTHORISATION
•
Medicinal product subject to medical prescription.
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 7, October 2008
presented in Module 1.8.1. of the Marketing Authorisation Application, is in place and functioning
before and whilst the product is on the market.
PSURs
The PSUR submission schedule for Olanzapine Glenmark Europe should follow the PSURs
submission schedule for the reference medicinal product.
67
ANNEX III
LABELLING AND PACKAGE LEAFLET
68
A. LABELLING
69
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON
1.
Olanzapine Glenmark Europe 5 mg orodispersible tablets
Olanzapine
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each orodispersible tablet contains 5 mg olanzapine.
3.
LIST OF EXCIPIENTS
Contains aspartame.
See package leaflet for further information
4.
Orodispersible tablet
28 orodispersible tablets
56 orodispersible tablets
70 orodispersible tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
The tablet should be dissolved in the mouth or in a drink. Read the package leaflet before use.
Oral use
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
70
9.
SPECIAL STORAGE CONDITIONS
Store below 30°C
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Glenmark Generics (Europe) Limited
Laxmi House
2-B Draycott Avenue
Kenton
Harrow
Middlesex
HA3 OBU.
United Kingdom
EU/1/09/588/001
EU/1/09/588/002
EU/1/09/588/003
13. BATCH NUMBER
BN
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Olanzapine Glenmark Europe 5 mg orodispersible tablets
71
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
ALUMINIUM BLISTERS
1.
Olanzapine Glenmark Europe 5 mg orodispersible tablets
Olanzapine
2.
Glenmark Generics (Europe) Limited
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
BN
5.
OTHER
72
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON
1.
Olanzapine Glenmark Europe 10 mg orodispersible tablets
Olanzapine
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each orodispersible tablet contains 10 mg olanzapine.
3.
LIST OF EXCIPIENTS
Contains aspartame.
See package leaflet for further information
4.
Orodispersible tablet
28 orodispersible tablets
56 orodispersible tablets
70 orodispersible tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
The tablet should be dissolved in the mouth or in a drink. Read the package leaflet before use.
Oral use
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
73
9.
SPECIAL STORAGE CONDITIONS
Store below 30°C
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Glenmark Generics (Europe) Limited
Laxmi House
2-B Draycott Avenue
Kenton
Harrow
Middlesex
HA3 OBU.
United Kingdom
EU/1/09/588/004
EU/1/09/588/005
EU/1/09/588/006
13. BATCH NUMBER
BN
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Olanzapine Glenmark Europe 10 mg orodispersible tablets
74
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
ALUMINIUM BLISTERS
1.
Olanzapine Glenmark Europe 10 mg orodispersible tablets
Olanzapine
2.
Glenmark Generics (Europe) Limited
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
BN
5.
OTHER
75
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON
1.
Olanzapine Glenmark Europe 15 mg orodispersible tablets
Olanzapine
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each orodispersible tablet contains 15 mg olanzapine.
3.
LIST OF EXCIPIENTS
Contains aspartame.
See package leaflet for further information
4.
Orodispersible tablet
28 orodispersible tablets
56 orodispersible tablets
70 orodispersible tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
The tablet should be dissolved in the mouth or in a drink. Read the package leaflet before use.
Oral use
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
76
9.
SPECIAL STORAGE CONDITIONS
Store below 30°C
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Glenmark Generics (Europe) Limited
Laxmi House
2-B Draycott Avenue
Kenton
Harrow
Middlesex
HA3 OBU.
United Kingdom
EU/1/09/588/007
EU/1/09/588/008
EU/1/09/588/009
13. BATCH NUMBER
BN
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Olanzapine Glenmark Europe 15 mg orodispersible tablets
77
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
ALUMINIUM BLISTERS
1.
Olanzapine Glenmark Europe 15 mg orodispersible tablets
Olanzapine
2.
Glenmark Generics (Europe) Limited
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
BN
5.
OTHER
78
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON
1.
Olanzapine Glenmark Europe 20 mg orodispersible tablets
Olanzapine
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each orodispersible tablet contains 20 mg olanzapine
3.
LIST OF EXCIPIENTS
Contains aspartame.
See package leaflet for further information
4.
Orodispersible tablet
28 orodispersible tablets
56 orodispersible tablets
70 orodispersible tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
The tablet should be dissolved in the mouth or in a drink. Read the package leaflet before use.
Oral use
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
79
9.
SPECIAL STORAGE CONDITIONS
Store below 30°C
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Glenmark Generics (Europe) Limited
Laxmi House
2-B Draycott Avenue
Kenton
Harrow
Middlesex
HA3 OBU.
United Kingdom
EU/1/09/588/010
EU/1/09/588/011
EU/1/09/588/012
13. BATCH NUMBER
BN
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Olanzapine Glenmark Europe 20 mg orodispersible tablets
80
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
ALUMINIUM BLISTERS
1.
Olanzapine Glenmark Europe 20 mg orodispersible tablets
Olanzapine
2.
Glenmark Generics (Europe) Limited
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
BN
5.
OTHER
81
B. PACKAGE LEAFLET
82
PACKAGE LEAFLET: INFORMATION FOR THE USER
Olanzapine Glenmark Europe 5 mg orodispersible tablets
Olanzapine Glenmark Europe 10 mg orodispersible tablets
Olanzapine Glenmark Europe 15 mg orodispersible tablets
Olanzapine Glenmark Europe 20 mg orodispersible tablets
Olanzapine
Read all of this leaflet carefully before you start taking this medicine.
-
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. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist
In this leaflet
:
1. What Olanzapine Glenmark Europe is and what it is used for
2. Before you take Olanzapine Glenmark Europe
3. How to take Olanzapine Glenmark Europe
4. Possible side effects
5.
How to store Olanzapine Glenmark Europe
6.
Further information
1.
WHAT OLANZAPINE GLENMARK EUROPE IS AND WHAT IT IS USED FOR
Olanzapine Glenmark Europe belongs to a group of medicines called antipsychotics.
Olanzapine Glenmark Europe is used to treat 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.
Olanzapine Glenmark Europe is used to treat a condition with symptoms such as feeling "high",
having excessive amounts of energy, needing much less sleep than usual, talking very quickly with
racing ideas and sometimes severe irritability. It is also a mood stabiliser that prevents further
occurrences of the disabling high and low (depressed) extremes of mood associated with this
condition.
2.
BEFORE YOU TAKE OLANZAPINE GLENMARK EUROPE
Do not take Olanzapine Glenmark Europe
-
if you are allergic (hypersensitive) to olanzapine or any of the other ingredients of Olanzapine
Glenmark Europe
.
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).
Take special care with Olanzapine Glenmark Europe
-
Medicines of this type may cause unusual movements mainly of the face or tongue. If this
happens after you have been given Olanzapine Glenmark Europe, 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.
83
-
The use of Olanzapine Glenmark Europe in elderly patients with dementia is not recommended
as it may have serious side effects.
If you suffer from any of the following illnesses tell your doctor as soon as possible:
•
Diabetes
•
Heart disease
•
Liver or kidney disease
•
Parkinson’s disease
•
Epilepsy
•
Prostate problems
•
A blocked intestine (Paralytic ileus)
•
Blood disorders
•
Stroke or “mini” stroke (temporary symptoms of stroke)
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.
Olanzapine Glenmark Europe is not for patients who are under 18 years..
Taking other medicines
Only take other medicines while you are on Olanzapine Glenmark Europe if your doctor tells you that
you can. You might feel drowsy if Olanzapine Glenmark Europe is taken in combination with
antidepressants or medicines taken for anxiety or to help you sleep (tranquillisers).
You should tell your doctor if you are taking fluvoxamine (an antidepressant), or ciprofloxacin (an
antibiotic), as it may be necessary to change your Olanzapine Glenmark Europe dose.
Please tell your doctor if you are taking or have recently taken any other medicines, including
medicines obtained without a prescription. Especially tell your doctor if you are taking medicines for
Parkinson’s disease.
Taking Olanzapine Glenmark Europe
with food and drink
Do not drink any alcohol if you have been given Olanzapine Glenmark Europe as Olanzapine
Glenmark Europe and alcohol together may make you feel drowsy.
Pregnancy and breast-feeding
Tell your doctor as soon as possible if you are pregnant or think you may be pregnant. You should not
take this medicine when pregnant, unless you have discussed this with your doctor. You should not be
given this medicine when breast-feeding, as small amounts of Olanzapine Glenmark Europe can pass
into breast milk.
Driving and using machines
There is a risk of feeling drowsy when you are given Olanzapine Glenmark Europe. If this happens do
not drive or use any tools or machines. Tell your doctor.
Important information about some of the ingredients of Olanzapine Glenmark Europe
Olanzapine Glenmark Europe contains a source of phenylalanine. This may be harmful for people
with phenylketonuria.
84
3.
HOW TO TAKE OLANZAPINE GLENMARK EUROPE
Always take Olanzapine Glenmark Europe exactly as your doctor has told you. You should check
with your doctor or pharmacist if you are not sure.
doctor will tell you how many Olanzapine Glenmark Europe orodispersible tablets to take and
how long you should continue to take them. The daily dose of Olanzapine Glenmark Europe is
between 5 and 20 mg. Consult your doctor if your symptoms return but do not stop taking
Olanzapine Glenmark Europe
unless your doctor tells you to.
orodispersible tablets
are for oral use. Put the tablet in your mouth. It will dissolve directly in your mouth, so that it can
be easily swallowed. You can also place the tablet in a full glass or cup of water or other suitable
beverage (orange juice, apple juice, milk or coffee) and stir. Drink it straightaway.
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. Show the doctor your pack of tablets.
If you forget to take Olanzapine Glenmark Europe
Take your tablets as soon as you remember. Do not take two doses in one day.
If you stop taking Olanzapine Glenmark Europe
Do not stop taking your tablets just because you feel better. It is important that you carry on taking
Olanzapine Glenmark Europe for as long as your doctor tells you.
If you suddenly stop taking Olanzapine Glenmark Europe, 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 product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Olanzapine Glenmark Europe can cause side effects, although not everybody gets
them.
Very common side effects: affect 1 user in 10
•
•
Weight gain
Sleepiness
•
Increases in the levels of prolactin in the blood.
Common side effects: affect 1 to 10 users in 100
•
Changes in the levels of some blood cells and circulating fats.
•
Increases in the level of sugars in the blood and urine.
•
Feeling more hungry.
•
Dizziness.
85
You should take your Olanzapine Glenmark Europe orodispersible tablets once a day following
the advice of your doctor. Try to take your tablets at the same time each day. It does not matter
whether you take them with or without food. Olanzapine Glenmark Europe
If you take more Olanzapine Glenmark Europe
than you should
Patients who have taken more Olanzapine Glenmark Europe
•
•
Restlessness.
Tremor.
•
Muscle stiffness or spasm (including eye movements).
•
Problems with speech.
•
Unusual movement (especially of the face and tongue).
•
Constipation.
•
Dry mouth.
•
Rash.
•
Loss of strength.
•
Extreme tiredness.
•
Water retention leading to swelling of the hands, ankles or feet.
•
In 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.
•
Sexual dysfunctions such as decreased libido in males and females or erectile
dysfunction in males.
Uncommon side effects: affect 1 to 10 users in 1,000
•
Slow heart rate.
•
Make you sensitive to sunlight.
•
Urinary incontinence.
•
•
Absence or decrease in menstrual periods.
Hair loss.
•
Changes in breasts in males and females such as an abnormal production of breast milk or
abnormal growth.
Other possible side effects: frequency cannot be estimated from the available data.
•
Allergic reaction (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.
•
Lowering of normal body temperature.
•
Seizures, usually associated with a history of seizures (epilepsy).
•
Combination of fever, faster breathing, sweating, muscle stiffness and drowsiness or
sleepiness.
•
Spasms of the muscle of the eye causing rolling movement of the eye.
•
Abnormal rhythms of the heart.
•
Sudden unexplained death.
•
Blood clots such as deep venous thrombosis of the leg or blood clot on the lung.
•
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.
•
Difficulty in passing urine.
•
Prolonged and/or painful erection.
While taking olanzapine, elderly patients with dementia may suffer from stroke, pneumonia, urinary
incontinence, falls, extreme tiredness, visual hallucinations, a rise in body temperature, redness of the
skin and have trouble walking. Some fatal cases have been reported in this particular group of
patients.
In patients with Parkinson’s disease Olanzapine Glenmark Europe
may worsen the symptoms
Rarely women taking medicines of this type for a long time have started to secrete milk and have
missed periods or had irregular periods. If this persists tell your doctor. Very rarely babies born to
86
mothers who have taken olanzapine in the last stage of pregnancy (3rd trimester) may have tremors,
be sleepy or drowsy.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor.
5.
HOW TO STORE OLANZAPINE GLENMARK EUROPE
Keep out of the reach and sight of children
Do not use Olanzapine Glenmark Europe 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.
Please return left over medicine to your pharmacist. Medicines should not be disposed of via
wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required.
These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Olanzapine Glenmark Europe
contains
-
The active substance is olanzapine
-
Each Olanzapine Glenmark Europe orodispersible tablet contains, 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 Olanzapine Glenmark Europe
looks like and contents of the pack
Olanzapine Glenmark Europe 5mg is supplied as :
yellow coloured circular flat bevelled edge orodispersible tablets with ‘2’ debossed on one side.
Olanzapine Glenmark Europe 10 mg:
yellow coloured circular flat bevelled edge orodispersible tablets with ‘OL’ debossed on one side and
‘4’ debossed on other side.
Olanzapine Glenmark Europe 15 mg:
yellow coloured circular flat bevelled edge orodispersible tablets with ‘OL’ debossed on one side and
‘5’ debossed on other side.
Olanzapine Glenmark Europe 20 mg:
yellow coloured circular flat bevelled edge orodispersible tablets with ‘OL’ debossed on one side and
‘6’ debossed on other side.
Olanzapine Glenmark Europe 5 mg, 10 mg, 15 mg and 20 mg are available in aluminium foil blisters
of 28, 56, and 70 orodispersible tablets
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Glenmark Generics (Europe) Limited
Laxmi House
2-B Draycott Avenue
Kenton
87
Harrow
Middlesex
HA3 OBU.
United Kingdom
Manufacturer
Glenmark Pharmaceuticals s.r.o.
City Tower, Hvězdova 1716/2b, 140 78 Praha 4
Czech Republic
This leaflet was last approved in
{MM/YYYY}.
Detailed information on this medicine is available on the European Medicines Agency (EMA)
website
:
http://www.ema.europa.eu
88
Source: European Medicines Agency
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