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OLANZAPINE RANBAXY 2.5 MG TABLETS

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Olanzapine Ranbaxy 2.5mg tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 2.5mg olanzapine.
Excipient with known effect: Each tablet also contains 65.5mg lactose
For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Tablet
Olanzapine Ranbaxy 2.5 mg tablets: Light yellow to yellow coloured, slightly
mottled, round, biconvex tablets, debossed with ‘O4’ on one side and plain on the
other side.

4

CLINICAL PARTICULARS

4.1

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

4.2.

Posology and method of administration
Adults
Schizophrenia: The recommended starting dose for olanzapine is 10mg/day.
Manic episode: The starting dose is 15mg as a single daily dose in monotherapy or
10mg daily in combination therapy (see section 5.1).
Preventing recurrence in bipolar disorder: The recommended starting dose is
10mg/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 5-20mg/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 regard for meals, as absorption is not affected by
food. Gradual tapering of the dose should be considered when discontinuing
olanzapine
Paediatric population
Olanzapine is not recommended for use in children and adolescents below 18 years of
age due to 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 patients
A lower starting dose (5mg/day) is not routinely indicated but should be considered
for those 65 and over when clinical factors warrant (see also section 4.4).
Patients with renal and/or hepatic impairment
A lower starting dose (5mg) should be considered for such patients. In cases of
moderate hepatic insufficiency (cirrhosis, Child-Pugh class A or B), the starting dose
should be 5mg 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.
(See also section 4.5 and section 5.2.).

4.3

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

4.4.

Special warnings and precautions for use
During antipsychotic treatment, improvement in the patient's clinical condition may
take several days to some weeks. Patients should be closely monitored during this
period.
Dementia-related psychosis and/or behavioural disturbances
Olanzapine is not approved for the treatment of dementia-related psychosis and/or
behavioural disturbances and is not recommended for use in this particular group of
patients because of an increase in mortality and the risk of cerebrovascular accident.
In placebo-controlled clinical trials (6-12 weeks duration) of elderly patients (mean
age 78 years) with dementia-related psychosis and/or disturbed behaviours, there was
a 2-fold increase in the incidence of death in olanzapine -treated patients compared to
patients treated with placebo (3.5% vs. 1.5%, respectively). The higher incidence of
death was not associated with olanzapine dose (mean daily dose 4.4 mg) or duration
of treatment. Risk factors that may predispose this patient population to increased
mortality include age> 65 years, dysphagia, sedation, malnutrition and dehydration,
pulmonary conditions (e.g., pneumonia, with or without aspiration), or concomitant
use of benzodiazepines. However, the incidence of death was higher in olanzapinetreated than in placebo-treated patients independent of these risk factors.
In the same clinical trials, cerebrovascular adverse events (CVAE e.g., stroke,
transient ischaemic attack), including fatalities, were reported. There was a 3-fold
increase in CVAE in patients treated with olanzapine compared to patients treated
with placebo (1.3% vs. 0.4%, respectively). All olanzapine- and placebo-treated
patients who experienced a cerebrovascular event had pre-existing risk factors. Age>
75 years and vascular/mixed type dementia were identified as risk factors for CVAE
in association with olanzapine treatment. The efficacy of olanzapine was not
established in these trials.
Parkinson's disease
The use of olanzapine in the treatment of dopamine agonist associated psychosis in
patients with Parkinson's disease is not recommended. In clinical trials, worsening of
Parkinsonian symptomatology and hallucinations were reported very commonly and
more frequently than with placebo (see section 4.8), and olanzapine was not more
effective than placebo in the treatment of psychotic symptoms. In these trials, patients
were initially required to be stable on the lowest effective dose of anti-Parkinsonian
medicinal products (dopamine agonist) and to remain on the same anti-Parkinsonian

medicinal products and dosages throughout the study. Olanzapine was started at 2.5
mg/day and titrated to a maximum of 15 mg/day based on investigator judgement.
Neuroleptic Malignant Syndrome (NMS)
NMS is a potentially life-threatening condition associated with antipsychotic
medicinal product. Rare cases reported as NMS have also been received in
association with olanzapine. Clinical manifestations of NMS are hyperpyrexia,
muscle rigidity, altered mental status, and evidence of autonomic instability (irregular
pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia).
Additional signs may include elevated creatinine phosphokinase, myoglobinuria
(rhabdomyolysis), and acute renal failure. If a patient develops signs and symptoms
indicative of NMS, or presents with unexplained high fever without additional clinical
manifestations of NMS, all antipsychotic medicines, including olanzapine must be
discontinued.
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 e.g. measuring of blood
glucose at baseline, 12 weeks after starting olanzapine treatment and annually
thereafter. Patients treated with any antipsychotic agents, including Olanzapine,
should be observed for signs and symptoms of hyperglycaemia (such as polydipsia,
polyuria, polyphagia, and weakness) and patients with diabetes mellitus or with risk
factors for diabetes mellitus should be monitored regularly for worsening of glucose
control. Weight should be monitored regularly e.g. at baseline, 4, 8 and 12 weeks
after starting olanzapine treatment and quarterly thereafter.
Lipid alterations
Undesirable alterations in lipids have been observed in olanzapine-treated patients in
placebo-controlled clinical trials (see section 4.8). Lipid alterations should be
managed as clinically appropriate, particularly in dyslipidemic patients and in patients
with risk factors for the development of lipids disorders. Patients treated with any
antipsychotic agents, including Olanzapine, should be monitored regularly for lipids
in accordance with utilised antipsychotic guidelines e.g. at baseline, 12 weeks after
starting olanzapine treatment and every 5 years thereafter.
Anticholinergic activity
While olanzapine demonstrated anticholinergic activity in vitro, experience during the
clinical trials revealed a low incidence of related events. However, as clinical
experience with olanzapine in patients with concomitant illness is limited, caution is
advised when prescribing for patients with prostatic hypertrophy, or paralytic ileus
and related conditions.
Hepatic function
Transient, asymptomatic elevations of hepatic transaminases, alanine
aminotransferase (ALT), aspartate aminotransferase (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 leucocyte 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 (VTE)
Temporal association of olanzapine treatment and venous thromboembolism has been
reported uncommonly ( 0.1% and < 1%). A causal relationship between the
occurrence of venous thromboembolism and treatment with olanzapine has not been
established. However, since patients with schizophrenia often present with acquired
risk factors for VTE, all possible risk factors of VTE e.g., immobilization of patients,
should be identified before and during treatment with Olanzapine Ranbaxy and
preventive measures undertaken.



General CNS activity
Given the primary CNS effects of olanzapine, caution should be used when it is taken
in combination with other centrally acting medicines and alcohol. As it exhibits in
vitro dopamine antagonism, olanzapine may antagonise 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. Longterm outcomes associated with these events have not been studied and remain
unknown (see sections 4.8 and 5.1).
Lactose
Olanzapine Ranbaxy tablets contain lactose. Patients with rare hereditary problems of
galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption
should not take this medicine.

4.5

Interaction with other medicinal products and other forms of interaction
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).
Inhibition of CYP1A2: Fluvoxamine, a specific CYP1A2 inhibitor, has been
shown to significantly inhibit the metabolism of olanzapine. The mean
increase in olanzapine Cmax following fluvoxamine was 54% in female nonsmokers and 77% in male smokers. The mean increase in olanzapine AUC
was 52% and 108%, respectively. A lower starting dose of olanzapine should
be considered in patients who are using fluvoxamine or any other CYP1A2
inhibitors, such as ciprofloxacin. A decrease in the dose of olanzapine should
be considered if treatment with an inhibitor of CYP1A2 is initiated.

Decreased bioavailability: Activated charcoal reduces the bioavailability of
oral olanzapine by 50 to 60% and should be taken at least 2 hours before or
after olanzapine.
Fluoxetine (a CYP2D6 inhibitor), single doses of antacid (aluminium,
magnesium) or cimetidine have not been found to significantly affect the
pharmacokinetics of olanzapine.
Potential for Olanzapine to Affect Other Medicinal Products: Olanzapine may
antagonise the effects of direct and indirect dopamine agonists.
Olanzapine does not inhibit the main CYP450 isoenzymes in vitro (e.g. 1A2,
2D6, 2C9, 2C19, 3A4). Thus, no particular interaction is expected, as verified
through in vivo studies, where no inhibition of metabolism of the following
active substances was found: tricyclic antidepressant (representing mostly
CYP2D6 pathway), warfarin (CYP2C9), theophylline (CYP1A2), or diazepam
(CYP3A4 and 2C19).
Olanzapine showed no interaction when co-administered with lithium or
biperiden.
Therapeutic monitoring of valproate plasma levels did not indicate that
valproate dosage adjustment is required after the introduction of concomitant
olanzapine.
General CNS activity
Caution should be exercised in patients who consume alcohol or receive
medicinal products that can cause central nervous system depression.
The concomitant use of olanzapine with anti-Parkinsonian medicinal products
in patients with Parkinson's disease and dementia is not recommended (see
section 4.4).

QTc interval
Caution should be used if olanzapine is being administered concomitantly with
medicinal products known to increase QTc interval (see section 4.4).

4.6.

Fertility, pregnancy and lactation
Pregnancy
There are no adequate and well-controlled studies in pregnant women. Patients should
be advised to notify their physician if they become pregnant or intend to become
pregnant during treatment with olanzapine. Nevertheless, because human experience

is limited, olanzapine should be used in pregnancy only if the potential benefit
justifies the potential risk to the foetus.
Neonates exposed to antipsychotics (including Olanzapine Ranbaxy) during the third
trimester of pregnancy are at risk of adverse reactions including extrapyramidal
and/or withdrawal symptoms that may vary in severity and duration following
delivery. There have been reports of agitation, hypertonia, hypotonia, tremor,
somnolence, respiratory distress or feeding disorder. Consequently, newborns should
be monitored carefully.
Breast-feeding
In a study in breast-feeding, healthy women, olanzapine was excreted in breast milk.
Mean infant exposure (mg/kg) at steady-state was estimated to be 1.8% of the
maternal olanzapine dose (mg/kg). Patients should be advised not to breast-feed an
infant if they are taking olanzapine.

4.7

Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been
performed. Because olanzapine may cause somnolence and dizziness, patients
should be cautioned about operating machinery, including motor vehicles.

Undesirable effects
Adults
The most frequently (seen in 1% of patients) reported adverse reactions associated
with the use of olanzapine in clinical trials were somnolence, weight gain,
eosinophilia, elevated prolactin, cholesterol, glucose and triglyceride levels (see
section 4.4), glucosuria, increased appetite, dizziness, akathisia, parkinsonism (see
section 4.4), dyskinesia, orthostatic hypotension, anticholinergic effects, transient
asymptomatic elevations of hepatic transaminases (see section 4.4), rash, asthenia,
fatigue and oedema.



Tabulated list of adverse reactions
The following table lists the adverse reactions and laboratory investigations observed
from spontaneous reporting and in clinical trials. Within each frequency grouping,
adverse reactions are presented in order of decreasing seriousness. The frequency
terms listed are defined as follows: Very common ( 1/10), common ( 1/100 and <
1/10), uncommon ( 1/1,000 and < 1/100), rare ( 1/10,000 and < 1/1,000), very rare
(< 1/10,000), not known (cannot be estimated from the data available).





Common

Uncommon



Very
common



4.8.

Not known

Blood and the lymphatic system disorders
Eosinophilia

Leucopenia
Neutropenia

Thrombocytopenia

Immune system disorders
Allergic reaction
Metabolism and nutrition disorders
Weight gain1 Elevated
cholesterol levels2,3
Elevated glucose
levels4
Elevated
triglyceride levels2,5
Glucosuria
Increased appetite

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

Nervous system disorders
Somnolence

Seizures where in most
cases a history of
seizures or risk factors
for seizures were
reported

Dizziness
Akathisia6
Parkinsonism6
Dyskinesia6

Neuroleptic malignant
syndrome (see section
4.4)
Dystonia (including
oculogyration)
Tardive dyskinesia
Discontinuation
symptoms7
Cardiac disorders
Bradycardia
QTc prolongation
(see section 4.4)

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

Vascular disorders
Orthostatic
hypotension

Thromboembolism
(including pulmonary
embolism and deep
vein thrombosis)

Gastrointestinal disorders
Mild, transient
anticholinergic

Pancreatitis

effects including
constipation and
dry mouth
Hepato-biliary disorders
Transient,
asymptomatic
elevations of
hepatic
transaminases
(ALT, AST),
especially in early
treatment (see
section 4.4)

Hepatitis (including
hepatocellular,
cholestatic or mixed
liver injury)

Skin and subcutaneous tissue disorders
Rash

Photosensitivity
reaction
Alopecia

Musculoskeletal and connective tissue disorders
Rhabdomyolysis
Renal and urinary disorders
Urinary incontinence Urinary hesitation
Urinary retention
Pregnancy, puerperium and perinatal conditions
Drug withdrawal
syndrome neonatal (see
4.6)
Reproductive system and breast disorders
Erectile
dysfunction in
males
Decreased libido in
males and females

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

General disorders and administration site conditions
Asthenia
Fatigue
Oedema
Investigations
Elevated

High creatine

Increased alkaline

phosphokinase
Increased total
bilirubin

plasma
prolactin
levels8

phosphatase

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.
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 also section 4.4). Very common adverse reactions
associated with the use of olanzapine in this patient group were abnormal gait and

falls. Pneumonia, increased body temperature, lethargy, erythema, visual
hallucinations and urinary incontinence were observed commonly.
In clinical trials in patients with drug-induced (dopamine agonist) psychosis
associated with Parkinson's disease, worsening of Parkinsonian symptomatology and
hallucinations were reported very commonly and more frequently than with placebo.
In one clinical trial in patients with bipolar mania, valproate combination therapy with
olanzapine resulted in an incidence of neutropenia of 4.1%; a potential contributing
factor could be high plasma valproate levels. Olanzapine administered with lithium or
valproate resulted in increased levels ( 10%) of tremor, dry mouth, increased
appetite, and weight gain. Speech disorder was also reported commonly. During
treatment with olanzapine in combination with lithium or divalproex, an increase of
7% from baseline body weight occurred in 17.4% of patients during acute treatment
(up to 6 weeks). Long-term olanzapine treatment (up to 12 months) for recurrence
prevention in patients with bipolar disorder was associated with an increase of 7%
from baseline body weight in 39.9% of patients.







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 shortterm exposure.



Within each frequency grouping, adverse reactions are presented in order of
decreasing seriousness. The frequency terms listed are defined as follows: Very
common ( 1/10), common ( 1/100 and < 1/10).





Metabolism and nutrition disorders
Very common: Weight gain9, elevated triglyceride levels10 , increased appetite.
Common: Elevated cholesterol levels11.
Nervous system disorders
Very common: Sedation (including: hypersomnia, lethargy, somnolence).
Gastrointestinal disorders
Common: Dry mouth.
Hepato-biliary disorders
Very common: Elevations of hepatic transaminases (ALT/AST; see section 4.4).
Investigations
Very common: Decreased total bilirubin, increased GGT, elevated plasma prolactin
levels12.
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.

4.9

Overdose
Signs and Symptoms
Very common symptoms in overdose ( >10% incidence) include tachycardia,
agitation/aggressiveness, dysarthria, various extrapyramidal symptoms, and
reduced level of consciousness ranging from sedation to coma.
Other medically significant sequelae of overdose include delirium, convulsion,
coma, possible neuroleptic malignant syndrome, respiratory depression,
aspiration, hypertension or hypotension, cardiac arrhythmias (<2% of
overdose cases), and cardiopulmonary arrest. Fatal outcomes have been
reported for acute overdoses as low as 450mg, 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. 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.

PHARMACOLOGICAL PROPERTIES

5.1.

Pharmacodynamic properties
Pharmacotherapeutic group: Antipsychotic. Diazepines, oxazepines and thiazepines
ATC code: N05A H03.
Pharmacodynamic effects
Olanzapine is an antipsychotic, antimanic, and mood stabilising agent that
demonstrates a broad pharmacologic profile across a number of receptor systems.
In preclinical studies, olanzapine exhibited a range of receptor affinities (Ki;
<100nM) for serotonin 5HT2A/2C, 5HT3, 5HT6; dopamine D1, D2, D3, D4, D5;
cholinergic muscarinic receptors M1-M5; alpha1 adrenergic; and histamine H1
receptors. Animal behavioural studies with olanzapine indicated 5HT, dopamine, and
cholinergic antagonism, consistent with the receptor-binding profile. Olanzapine
demonstrated a greater in vitro affinity for serotonin 5HT2 than dopamine D2
receptors and greater 5HT2 than D2 activity in 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 (10mg) Positron Emission Tomography (PET) study in healthy
volunteers, olanzapine produced a higher 5HT2A than dopamine D2 receptor
occupancy. In addition, a Single Photon Emission Computed Tomography (SPECT)
imaging study in schizophrenic patients revealed that olanzapine-responsive patients
had lower striatal D2 occupancy than some other antipsychotic- and risperidoneresponsive patients, while being comparable to clozapine-responsive patients.
Clinical efficacy
In two of two placebo- and two of three comparator-controlled trials with over 2,900
schizophrenic patients presenting with both positive and negative symptoms,
olanzapine was associated with statistically significantly greater improvements in
negative as well as positive symptoms.
In a multinational, double-blind, comparative study of schizophrenia, schizoaffective
and related disorders, which included 1,481 patients with varying degrees of
associated depressive symptoms (baseline mean of 16.6 on the Montgomery-Asberg
Depression Rating Scale), a prospective secondary analysis of baseline to endpoint
mood score change demonstrated a statistically significant improvement (P = 0.001)
favouring olanzapine (-6.0) versus haloperidol (-3.1).
In patients with a manic or mixed episode of bipolar disorder, olanzapine
demonstrated superior efficacy to placebo and valproate semisodium (divalproex) in
reduction of manic symptoms over 3 weeks. Olanzapine also demonstrated
comparable efficacy results to haloperidol in terms of the proportion of patients in
symptomatic remission from mania and depression at 6 and 12 weeks. In a co-therapy
study of patients treated with lithium or valproate for a minimum of 2 weeks, the
addition of olanzapine 10mg (co-therapy with lithium or valproate) resulted in a

greater reduction in symptoms of mania than lithium or valproate monotherapy after 6
weeks.
In a 12-month recurrence prevention study in manic episode patients who achieved
remission on olanzapine and were then randomised to olanzapine or placebo,
olanzapine demonstrated statistically significant superiority over placebo on the
primary endpoint of bipolar recurrence. Olanzapine also showed a statistically
significant advantage over placebo in terms of preventing either recurrence into mania
or recurrence into depression.
In a second 12-month recurrence prevention study in manic episode patients who
achieved remission with a combination of olanzapine and lithium and were then
randomised to olanzapine or lithium alone, olanzapine was statistically non-inferior to
lithium on the primary endpoint of bipolar recurrence (olanzapine 30.0%, lithium
38.3%; P = 0.055).
In an 18-month co-therapy study in manic or mixed episode patients stabilised with
olanzapine plus a mood stabiliser (lithium or valproate), long-term olanzapine cotherapy with lithium or valproate was not statistically significantly superior to lithium
or valproate alone in delaying bipolar recurrence, defined according to syndromic
(diagnostic) criteria.
Paediatric population
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).

Pharmacokinetic properties
Absorption
Olanzapine is well absorbed after oral administration, reaching peak plasma
concentrations within 5 to 8 hours. The absorption is not affected by food. Absolute
oral bioavailability relative to intravenous administration has not been determined.
Distribution
The plasma protein binding of olanzapine was about 93 % over the concentration
range of about 7 to about 1000 ng/ml. Olanzapine is bound predominantly to albumin
and 1-acid-glycoprotein.

α

5.2.

Biotransformation
Olanzapine is metabolised in the liver by conjugative and oxidative pathways. The
major circulating metabolite is the 10-N-glucuronide, which does not pass the blood
brain barrier. Cytochromes P450-CYP1A2 and P450-CYP2D6 contribute to the
formation of the N-desmethyl and 2-hydroxymethyl metabolites; both exhibited
significantly less in vivo pharmacological activity than olanzapine in animal studies.
The predominant pharmacologic activity is from the parent, olanzapine.

Elimination
After oral administration, the mean terminal elimination half-life of olanzapine in
healthy subjects varied on the basis of age and gender.
In healthy elderly (65 and over) versus non-elderly subjects, the mean elimination
half-life was prolonged (51.8 versus 33.8 hours) 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 20mg/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 hours) and the clearance was reduced (18.9 versus 27.3
l/hr). However, olanzapine (5-20mg) demonstrated a comparable safety profile in
female (n = 467) as in male patients (n = 869).
Renal impairment
In renally impaired patients (creatinine clearance <10ml/min) versus healthy subjects,
there was no significant difference in mean elimination half-life (37.7 versus 32.4
hours) or clearance (21.2 versus 25.0 l/hr). A mass balance study showed that
approximately 57% of radiolabelled olanzapine appeared in urine, principally as
metabolites.
Smokers
In smoking subjects with mild hepatic dysfunction, mean elimination half-life (39.3
hours) was prolonged and clearance (18.0 l/hr) was reduced analogous to nonsmoking healthy subjects (48.8 hours 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 hours) and the clearance was reduced (18.6
versus 27.7 l/hr).
The plasma clearance of olanzapine is lower in elderly versus young subjects, in
females versus males, and in non-smokers versus smokers. However, the magnitude
of the impact of age, gender, or smoking on olanzapine clearance and half-life is
small in comparison to the overall variability between individuals.
In a study of Caucasians, Japanese, and Chinese subjects, there were no differences in
the pharmacokinetic parameters among the three populations.
Paediatric population
Adolescents (ages 13 to 17 years): The pharmacokinetics of olanzapine are similar
between adolescents and adults. In clinical studies, the average olanzapine exposure
was approximately 27% higher in adolescents. Demographic differences between the
adolescents and adults include a lower average body weight and fewer adolescents
were smokers. Such factors possibly contribute to the higher average exposure
observed in adolescents.

5.3

Preclinical safety data
Acute (single-dose) toxicity

Signs of oral toxicity in rodents were characteristic of potent neuroleptic
compounds: hypoactivity, coma, tremors, clonic convulsions, salivation, and
depressed weight gain. The median lethal doses were approximately 210mg/kg
(mice) and 175mg/kg (rats). Dogs tolerated single oral doses up to 100mg/kg
without mortality. Clinical signs included sedation, ataxia, tremors, increased
heart rate, laboured respiration, miosis, and anorexia. In monkeys, single oral
doses up to 100mg/kg resulted in prostration and, at higher doses, semiconsciousness.
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 leucocytes in mice and non-specific
reductions of circulating leucocytes in rats; however, no evidence of bone
marrow cytotoxicity was found. Reversible neutropenia, thrombocytopenia, or
anaemia developed in a few dogs treated with 8 or 10mg/kg/day (total
olanzapine exposure [area under the curve - AUC] is 12- to 15-fold greater
than that of a man given a 12mg dose). In cytopenic dogs, there were no
adverse effects on progenitor and proliferating cells in the bone marrow.
Reproductive toxicity
Olanzapine had no teratogenic effects. Sedation affected mating performance
of male rats. Oestrous cycles were affected at doses of 1.1mg/kg (3-times the
maximum human dose) and reproduction parameters were influenced in rats
given 3mg/kg (9-times the maximum human dose). In the offspring of rats
given olanzapine, delays in foetal development and transient decreases in
offspring activity levels were seen.
Mutagenicity
Olanzapine was not mutagenic or clastogenic in a full range of standard tests,
which included bacterial mutation tests and in vitro and in vivo mammalian
tests.
Carcinogenicity
Based on the results of studies in mice and rats, it was concluded that
olanzapine is not carcinogenic.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Lactose anhydrous
Microcrystalline cellulose
Low substituted hydroxypropyl cellulose
Magnesium stearate

6.2

Incompatibilities
Not applicable

6.3

Shelf life
3 years

6.4

Special precautions for storage
This medicinal product does not require any special storage conditions.

6.5

Nature and contents of container
Cold form blister packs of oPA-Al-PVC/Al
Pack size:
2.5mg: 7, 10, 14, 28, 35, 56 and 70 tablet packs.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
No special requirements

7.

MARKETING AUTHORISATION HOLDER
Ranbaxy (UK) Ltd
Building 4, Chiswick Park
566 Chiswick High Road
London W4 5YE
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 14894/0700

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
14/09/2011

10

DATE OF REVISION OF THE TEXT
23/12/2012

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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