ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Olanzapine Neopharma 2.5 mg coated tablets
2.
Each coated tablet contains 2.5 mg olanzapine.
Excipient(s): Each coated tablet contains 80.7 mg lactose monohydrate
For a full list of excipients, see section 6.1.
3.
Coated tablet
White, round, biconvex, coated tablets with ‘2.5’ debossing on one side and ‘OLZ’ on the other.
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
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.
(See sections 4.5 and 5.2)
Hypersensitivity to the active substance or to any of the excipients. Patients with known risk for
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% vs. 1.5%, respectively). The higher incidence of death
was not associated with olanzapine dose (mean daily dose 4.4 mg) or duration of treatment. Risk
factors that may predispose this patient population to increased mortality include age > 65 years,
dysphagia, sedation, malnutrition and dehydration, pulmonary conditions (e.g., pneumonia, with or
without aspiration), or concomitant use of benzodiazepines. However, the incidence of death was
higher in olanzapine-treated than in placebo-treated patients independent of these risk factors.
In the same clinical trials, cerebrovascular adverse events (CVAE e.g., stroke, transient ischemic
attack), including fatalities, were reported. There was a 3-fold increase in CVAE in patients treated
with olanzapine compared to patients treated with placebo (1.3% vs. 0.4%, respectively). All
olanzapine- and placebo-treated patients who experienced a cerebrovascular event had pre-existing
risk factors. Age > 75 years and vascular/mixed type dementia were identified as risk factors for
3
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 Neopharma, 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-
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 Neopharma,
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, ALT, AST have been seen
commonly, especially in early treatment. Caution should be exercised and follow-up organised in
patients with elevated ALT and/or AST, in patients with signs and symptoms of hepatic impairment, in
patients with pre-existing conditions associated with limited hepatic functional reserve, and in patients
who are being treated with potentially hepatotoxic medicines. In cases where hepatitis (including
hepatocellular, cholestatic or mixed liver injury) has been diagnosed, olanzapine treatment should be
discontinued.
4
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
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.
5
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).
Lactose
OLANZAPINE NEOPHARMA
tablets contain lactose. Patients with rare hereditary problems of
galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take
this medicine.
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 C
max
following fluvoxamine was 54 % in female non-
smokers and 77 % in male smokers. The mean increase in olanzapine AUC was 52 % and 108 %
respectively. A lower starting dose of olanzapine should be considered in patients who are using
fluvoxamine or any other CYP1A2 inhibitors, such as ciprofloxacin. A decrease in the dose of
olanzapine should be considered if treatment with an inhibitor of CYP1A2 is initiated.
Decreased bioavailability
Activated charcoal reduces the bioavailability of oral
olanzapine by 50 to 60% and should be taken at
least 2 hours before or after olanzapine.
Fluoxetine (a CYP2D6 inhibitor), single doses of antacid (aluminium, magnesium) or cimetidine have
not been found to significantly affect the pharmacokinetics of olanzapine.
Potential for olanzapine to affect other medicinal products
Olanzapine may antagonise the effects of direct and indirect dopamine agonists.
Olanzapine does not inhibit the main CYP450 isoenzymes
in vitro
(e.g. 1A2, 2D6, 2C9, 2C19, 3A4).
Thus no particular interaction is expected as verified through
in vivo
studies where no inhibition of
metabolism of the following active substances was found: tricyclic antidepressant (representing mostly
CYP2D6 pathway), warfarin (CYP2C9), theophylline (CYP1A2) or diazepam (CYP3A4 and 2C19).
Olanzapine showed no interaction when co-administered with lithium or biperiden.
Therapeutic monitoring of valproate plasma levels did not indicate that valproate dosage adjustment is
required after the introduction of concomitant olanzapine.
6
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).
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
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).
7
Very common
Common
Uncommon
Not known
Blood and the lymphatic system disorders
Eosinophilia
Leukopenia
Neutropenia
Thrombocytopenia
Immune system disorders
Allergic reaction
Metabolism and nutrition disorders
Weight gain
1
Elevated cholesterol
levels
2,3
Elevated glucose
levels
4
Elevated triglyceride
levels
2,5
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
Dizziness
Akathisia
6
Parkinsonism
6
Dyskinesia
6
Seizures where in most
cases a history of
seizures or risk factors
for seizures were
reported
Neuroleptic malignant
syndrome (see section
4.4)
Dystonia (including
oculogyration)
Tardive dyskinesia
Discontinuation
symptoms
7
Cardiac disorders
Bradycardia
QT
c
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 effects
including constipation
and dry mouth
Pancreatitis
Hepato-biliary disorders
Transient,
asymptomatic
elevations of hepatic
aminotransferases
(ALT, AST),
especially in early
treatment (see section
4.4)
Hepatitis (including
hepatocellular,
cholestatic or mixed
liver injury)
Skin and subcutaneous tissue disorders
8
Rash
Photosensitivity
reaction
Alopecia
Musculoskeletal and connective tissue disorders
Rhabdomyolysis
Renal and urinary disorders
Urinary incontinence
Urinary hesitation
Reproductive system and breast disorders
Priapism
General disorders and administration site conditions
Asthenia
Fatigue
Oedema
Investigations
Elevated plasma
prolactin levels
8
High creatine
phosphokinase
Increased total
bilirubin
Increased alkaline
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) to high (≥ 6.2 mmol) were very common.
4
Observed for fasting normal levels at baseline (< 5.56 mmol/l) which increased to high (≥ 7 mmol/l).
Changes in fasting glucose from borderline at baseline (≥ 5.56 - < 7 mmol/l) to high (≥ 7 mmol/l) were
very common.
5
Observed for fasting normal levels at baseline (< 1.69 mmol/l) which increased to high
(≥ 2.26 mmol/l). Changes in fasting triglycerides from borderline at baseline (≥ 1.69 mmol/l -
< 2.26 mmol/l) to high (≥ 2.26 mmol/l) were very common.
6
In clinical trials, the incidence of Parkinsonism and dystonia in 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
9
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 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 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%).
10
Metabolism and nutrition disorders
Very common:
Weight gain
9
, elevated triglyceride levels
10
, increased appetite.
Common:
Elevated cholesterol levels
11
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 2g 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
beta-agonist activity since beta stimulation may worsen hypotension. Cardiovascular monitoring is
necessary to detect possible arrhythmias. Close medical supervision and monitoring should continue
until the patient recovers.
11
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 5
HT
2A/2C
, 5 HT
3
, 5 HT
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 5
HT
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 5 HT
2A
than dopamine D
2
receptor occupancy. In addition, a 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
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).
12
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 hr) and the clearance was reduced (18.9 versus 27.3 l/hr). However, olanzapine (5-20 mg)
demonstrated a comparable safety profile in female (n=467) as in male patients (n=869).
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
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.
13
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 α
1
-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 effects on progenitor and proliferating cells in the bone marrow.
Reproductive toxicity
Olanzapine had no teratogenic effects. Sedation affected mating performance of male rats. Estrous
cycles were affected at doses of 1.1 mg/kg (3 times the maximum human dose) and reproduction
parameters were influenced in rats given 3 mg/kg (9 times the maximum human dose). In the offspring
of rats given olanzapine, delays in 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.
14
6.
6.1 List of excipients
Tablet core
Lactose monohydrate,
Maize starch
Hydroxypropyl cellulose
Magnesium stearate
Tablet coat
Opadry II White containing:
Hypromellose (E464)
Titanium dioxide (E171)
Lactose monohydrate
Polyethylene glycol 3000
Glycerol triacetate
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
Store in the original package.
Store below 30°C.
6.5
Nature and contents of container
Cold-formed aluminium blisters in cartons of 28 or 56 tablets per carton.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements.
7.
Neopharma Limited
57 High Street
Odiham
Hampshire
RG29 1LF
UK
15
8.
EU/1/07/426/001 – Olanzapine Neopharma – 2.5 mg – coated tablets – 28 tablets per box
EU/1/07/426/002 – Olanzapine Neopharma – 2.5 mg – coated tablets – 56 tablets per box
9.
Date of first authorisation: 14 November 2007
{MM/YYYY}
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMA) http://www.ema.europa.eu/.
16
1.
Olanzapine Neopharma 5 mg coated tablets
2.
Each coated tablet contains 5 mg olanzapine.
Excipient(s): Each coated tablet contains 161.3 mg lactose monohydrate
For a full list of excipients, see section 6.1.
3.
Coated tablet
White, round, biconvex, coated tablets with ‘OLZ 5’ debossing on one side and ‘NEO’ on the other.
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.
17
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.
(See sections 4.5 and 5.2)
Hypersensitivity to the active substance or to any of the excipients. Patients with known risk for
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% vs. 1.5%, respectively). The higher incidence of death
was not associated with olanzapine dose (mean daily dose 4.4 mg) or duration of treatment. Risk
factors that may predispose this patient population to increased mortality include age > 65 years,
dysphagia, sedation, malnutrition and dehydration, pulmonary conditions (e.g., pneumonia, with or
without aspiration), or concomitant use of benzodiazepines. However, the incidence of death was
higher in olanzapine-treated than in placebo-treated patients independent of these risk factors.
In the same clinical trials, cerebrovascular adverse events (CVAE e.g., stroke, transient ischemic
attack), including fatalities, were reported. There was a 3-fold increase in CVAE in patients treated
with olanzapine compared to patients treated with placebo (1.3% vs. 0.4%, respectively). All
olanzapine- and placebo-treated patients who experienced a cerebrovascular event had pre-existing
risk factors. Age > 75 years and vascular/mixed type dementia were identified as risk factors for
18
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 NEOPHARMA, 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-
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
NEOPHARMA, 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, ALT, AST have been seen
commonly, especially in early treatment. Caution should be exercised and follow-up organised in
patients with elevated ALT and/or AST, in patients with signs and symptoms of hepatic impairment, in
patients with pre-existing conditions associated with limited hepatic functional reserve, and in patients
who are being treated with potentially hepatotoxic medicines. In cases where hepatitis (including
hepatocellular, cholestatic or mixed liver injury) has been diagnosed, olanzapine treatment should be
discontinued.
19
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
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.
20
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).
Lactose
OLANZAPINE NEOPHARMA
tablets contain lactose. Patients with rare hereditary problems of
galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take
this medicine.
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 C
max
following fluvoxamine was 54 % in female non-
smokers and 77 % in male smokers. The mean increase in olanzapine AUC was 52 % and 108 %
respectively. A lower starting dose of olanzapine should be considered in patients who are using
fluvoxamine or any other CYP1A2 inhibitors, such as ciprofloxacin. A decrease in the dose of
olanzapine should be considered if treatment with an inhibitor of CYP1A2 is initiated.
Decreased bioavailability
Activated charcoal reduces the bioavailability of oral
olanzapine by 50 to 60% and should be taken at
least 2 hours before or after olanzapine.
Fluoxetine (a CYP2D6 inhibitor), single doses of antacid (aluminium, magnesium) or cimetidine have
not been found to significantly affect the pharmacokinetics of olanzapine.
Potential for olanzapine to affect other medicinal products
Olanzapine may antagonise the effects of direct and indirect dopamine agonists.
Olanzapine does not inhibit the main CYP450 isoenzymes
in vitro
(e.g. 1A2, 2D6, 2C9, 2C19, 3A4).
Thus no particular interaction is expected as verified through
in vivo
studies where no inhibition of
metabolism of the following active substances was found: tricyclic antidepressant (representing mostly
CYP2D6 pathway), warfarin (CYP2C9), theophylline (CYP1A2) or diazepam (CYP3A4 and 2C19).
Olanzapine showed no interaction when co-administered with lithium or biperiden.
Therapeutic monitoring of valproate plasma levels did not indicate that valproate dosage adjustment is
required after the introduction of concomitant olanzapine.
21
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).
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
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).
22
Very common
Common
Uncommon
Not known
Blood and the lymphatic system disorders
Eosinophilia
Leukopenia
Neutropenia
Thrombocytopenia
Immune system disorders
Allergic reaction
Metabolism and nutrition disorders
Weight gain
1
Elevated cholesterol
levels
2,3
Elevated glucose
levels
4
Elevated triglyceride
levels
2,5
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
Dizziness
Akathisia
6
Parkinsonism
6
Dyskinesia
6
Seizures where in most
cases a history of
seizures or risk factors
for seizures were
reported
Neuroleptic malignant
syndrome (see section
4.4)
Dystonia (including
oculogyration)
Tardive dyskinesia
Discontinuation
symptoms
7
Cardiac disorders
Bradycardia
QT
c
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 effects
including constipation
and dry mouth
Pancreatitis
Hepato-biliary disorders
Transient,
asymptomatic
elevations of hepatic
aminotransferases
(ALT, AST),
especially in early
treatment (see section
4.4)
Hepatitis (including
hepatocellular,
cholestatic or mixed
liver injury)
Skin and subcutaneous tissue disorders
23
Rash
Photosensitivity
reaction
Alopecia
Musculoskeletal and connective tissue disorders
Rhabdomyolysis
Renal and urinary disorders
Urinary incontinence
Urinary hesitation
Reproductive system and breast disorders
Priapism
General disorders and administration site conditions
Asthenia
Fatigue
Oedema
Investigations
Elevated plasma
prolactin levels
8
High creatine
phosphokinase
Increased total
bilirubin
Increased alkaline
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) to high (≥ 6.2 mmol) were very common.
4
Observed for fasting normal levels at baseline (< 5.56 mmol/l) which increased to high (≥ 7 mmol/l).
Changes in fasting glucose from borderline at baseline (≥ 5.56 - < 7 mmol/l) to high (≥ 7 mmol/l) were
very common.
5
Observed for fasting normal levels at baseline (< 1.69 mmol/l) which increased to high
(≥ 2.26 mmol/l). Changes in fasting triglycerides from borderline at baseline (≥ 1.69 mmol/l -
< 2.26 mmol/l) to high (≥ 2.26 mmol/l) were very common.
6
In clinical trials, the incidence of Parkinsonism and dystonia in 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 rangeGenerally 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
24
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 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 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%).
25
Metabolism and nutrition disorders
Very common:
Weight gain
9
, elevated triglyceride levels
10
, increased appetite.
Common:
Elevated cholesterol levels
11
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).
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 2g 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
beta-agonist activity since beta stimulation may worsen hypotension. Cardiovascular monitoring is
necessary to detect possible arrhythmias. Close medical supervision and monitoring should continue
until the patient recovers.
26
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 5
HT
2A/2C
, 5 HT
3
, 5 HT
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 5
HT
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 5 HT
2A
than dopamine D
2
receptor occupancy. In addition, a 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
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
27
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 hr) and the clearance was reduced (18.9 versus 27.3 l/hr). However, olanzapine (5-20 mg)
demonstrated a comparable safety profile in female (n=467) as in male patients (n=869).
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
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.
28
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 α
1
-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 effects on progenitor and proliferating cells in the bone marrow.
Reproductive toxicity
Olanzapine had no teratogenic effects. Sedation affected mating performance of male rats. Estrous
cycles were affected at doses of 1.1 mg/kg (3 times the maximum human dose) and reproduction
parameters were influenced in rats given 3 mg/kg (9 times the maximum human dose). In the offspring
of rats given olanzapine, delays in 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
29
Tablet core
Lactose monohydrate,
Maize starch
Hydroxypropyl cellulose
Magnesium stearate
Tablet coat
Opadry II White containing:
Hypromellose (E464)
Titanium dioxide (E171)
Lactose monohydrate
Polyethylene glycol 3000
Glycerol triacetate
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
Store in the original package.
Store below 30°C.
6.5 Nature and contents of container
Cold-formed aluminium blisters in cartons of 28 or 56 tablets per carton.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements.
7.
Neopharma Limited
57 High Street
Odiham
Hampshire
RG29 1LF
UK
30
8.
EU/1/07/426/003 – Olanzapine Neopharma – 5 mg – coated tablets – 28 tablets per box
EU/1/07/426/004 – Olanzapine Neopharma – 5 mg – coated tablets – 56 tablets per box
9.
Date of first authorisation: 14 November 2007
{MM/YYYY}
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMA) http://www.ema.europa.eu/.
31
1.
Olanzapine Neopharma 7.5 mg coated tablets
2.
Each coated tablet contains 7.5 mg olanzapine.
Excipient(s): Each coated tablet contains 242 mg lactose monohydrate
For a full list of excipients, see section 6.1.
3.
Coated tablet
White, round, biconvex, coated tablets with ‘OLZ 7.5’ debossing on one side and ‘NEO’ on the other.
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.
32
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.
(See sections 4.5 and 5.2)
Hypersensitivity to the active substance or to any of the excipients. Patients with known risk for
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% vs. 1.5%, respectively). The higher incidence of death
was not associated with olanzapine dose (mean daily dose 4.4 mg) or duration of treatment. Risk
factors that may predispose this patient population to increased mortality include age > 65 years,
dysphagia, sedation, malnutrition and dehydration, pulmonary conditions (e.g., pneumonia, with or
without aspiration), or concomitant use of benzodiazepines. However, the incidence of death was
higher in olanzapine-treated than in placebo-treated patients independent of these risk factors.
In the same clinical trials, cerebrovascular adverse events (CVAE e.g., stroke, transient ischemic
attack), including fatalities, were reported. There was a 3-fold increase in CVAE in patients treated
with olanzapine compared to patients treated with placebo (1.3% vs. 0.4%, respectively). All
olanzapine- and placebo-treated patients who experienced a cerebrovascular event had pre-existing
risk factors. Age > 75 years and vascular/mixed type dementia were identified as risk factors for
33
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 NEOPHARMA, 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-
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
NEOPHARMA, 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, ALT, AST have been seen
commonly, especially in early treatment. Caution should be exercised and follow-up organised in
patients with elevated ALT and/or AST, in patients with signs and symptoms of hepatic impairment, in
patients with pre-existing conditions associated with limited hepatic functional reserve, and in patients
who are being treated with potentially hepatotoxic medicines. In cases where hepatitis (including
hepatocellular, cholestatic or mixed liver injury) has been diagnosed, olanzapine treatment should be
discontinued.
34
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
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.
35
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).
Lactose
OLANZAPINE NEOPHARMA tablets contain lactose. Patients with rare hereditary problems of
galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take
this medicine.
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 C
max
following fluvoxamine was 54 % in female non-
smokers and 77 % in male smokers. The mean increase in olanzapine AUC was 52 % and 108 %
respectively. A lower starting dose of olanzapine should be considered in patients who are using
fluvoxamine or any other CYP1A2 inhibitors, such as ciprofloxacin. A decrease in the dose of
olanzapine should be considered if treatment with an inhibitor of CYP1A2 is initiated.
Decreased bioavailability
Activated charcoal reduces the bioavailability of oral
olanzapine by 50 to 60% and should be taken at
least 2 hours before or after olanzapine.
Fluoxetine (a CYP2D6 inhibitor), single doses of antacid (aluminium, magnesium) or cimetidine have
not been found to significantly affect the pharmacokinetics of olanzapine.
Potential for olanzapine to affect other medicinal products
Olanzapine may antagonise the effects of direct and indirect dopamine agonists.
Olanzapine does not inhibit the main CYP450 isoenzymes
in vitro
(e.g. 1A2, 2D6, 2C9, 2C19, 3A4).
Thus no particular interaction is expected as verified through
in vivo
studies where no inhibition of
metabolism of the following active substances was found: tricyclic antidepressant (representing mostly
CYP2D6 pathway), warfarin (CYP2C9), theophylline (CYP1A2) or diazepam (CYP3A4 and 2C19).
Olanzapine showed no interaction when co-administered with lithium or biperiden.
Therapeutic monitoring of valproate plasma levels did not indicate that valproate dosage adjustment is
required after the introduction of concomitant olanzapine.
36
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).
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
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).
37
Very common
Common
Uncommon
Not known
Blood and the lymphatic system disorders
Eosinophilia
Leukopenia
Neutropenia
Thrombocytopenia
Immune system disorders
Allergic reaction
Metabolism and nutrition disorders
Weight gain
1
Elevated cholesterol
levels
2,3
Elevated glucose
levels
4
Elevated triglyceride
levels
2,5
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
Dizziness
Akathisia
6
Parkinsonism
6
Dyskinesia
6
Seizures where in most
cases a history of
seizures or risk factors
for seizures were
reported
Neuroleptic malignant
syndrome (see section
4.4)
Dystonia (including
oculogyration)
Tardive dyskinesia
Discontinuation
symptoms
7
Cardiac disorders
Bradycardia
QT
c
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 effects
including constipation
and dry mouth
Pancreatitis
Hepato-biliary disorders
Transient,
asymptomatic
elevations of hepatic
aminotransferases
(ALT, AST),
especially in early
treatment (see section
4.4)
Hepatitis (including
hepatocellular,
cholestatic or mixed
liver injury)
Skin and subcutaneous tissue disorders
38
Rash
Photosensitivity
reaction
Alopecia
Musculoskeletal and connective tissue disorders
Rhabdomyolysis
Renal and urinary disorders
Urinary incontinence
Urinary hesitation
Reproductive system and breast disorders
Priapism
General disorders and administration site conditions
Asthenia
Fatigue
Oedema
Investigations
Elevated plasma
prolactin levels
8
High creatine
phosphokinase
Increased total
bilirubin
Increased alkaline
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) to high (≥ 6.2 mmol) were very common.
4
Observed for fasting normal levels at baseline (< 5.56 mmol/l) which increased to high (≥ 7 mmol/l).
Changes in fasting glucose from borderline at baseline (≥ 5.56 - < 7 mmol/l) to high (≥ 7 mmol/l) were
very common.
5
Observed for fasting normal levels at baseline (< 1.69 mmol/l) which increased to high
(≥ 2.26 mmol/l). Changes in fasting triglycerides from borderline at baseline (≥ 1.69 mmol/l -
< 2.26 mmol/l) to high (≥ 2.26 mmol/l) were very common.
6
In clinical trials, the incidence of Parkinsonism and dystonia in 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
39
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 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 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%).
40
Metabolism and nutrition disorders
Very common:
Weight gain
9
, elevated triglyceride levels
10
, increased appetite.
Common:
Elevated cholesterol levels
11
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).
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 2g 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
beta-agonist activity since beta stimulation may worsen hypotension. Cardiovascular monitoring is
necessary to detect possible arrhythmias. Close medical supervision and monitoring should continue
until the patient recovers.
41
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 5
HT
2A/2C
, 5 HT
3
, 5 HT
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 5
HT
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 5 HT
2A
than dopamine D
2
receptor occupancy. In addition, a 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
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
42
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 hr) and the clearance was reduced (18.9 versus 27.3 l/hr). However, olanzapine (5-20 mg)
demonstrated a comparable safety profile in female (n=467) as in male patients (n=869).
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
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.
43
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 α
1
-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 effects on progenitor and proliferating cells in the bone marrow.
Reproductive toxicity
Olanzapine had no teratogenic effects. Sedation affected mating performance of male rats. Estrous
cycles were affected at doses of 1.1 mg/kg (3 times the maximum human dose) and reproduction
parameters were influenced in rats given 3 mg/kg (9 times the maximum human dose). In the offspring
of rats given olanzapine, delays in 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
44
Tablet core
Lactose monohydrate,
Maize starch
Hydroxypropyl cellulose
Magnesium stearate
Tablet coat
Opadry II White containing:
Hypromellose (E464)
Titanium dioxide (E171)
Lactose monohydrate
Polyethylene glycol 3000
Glycerol triacetate
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
Store in the original package.
Store below 30°C.
6.5 Nature and contents of container
Cold-formed aluminium blisters in cartons of 28 or 56 tablets per carton.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements.
7.
Neopharma Limited
57 High Street
Odiham
Hampshire
RG29 1LF
UK
8.
EU/1/07/426/005 – Olanzapine Neopharma – 7.5 mg – coated tablets – 28 tablets per box
EU/1/07/426/006 – Olanzapine Neopharma – 7.5 mg – coated tablets – 56 tablets per box
9.
45
Date of first authorisation: 14 November 2007
{MM/YYYY}
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMA) http://www.ema.europa.eu/.
46
1.
FURTHER INFORMATION
What Olanzapine Neopharma
contains
-
The active substance is olanzapine. Each Olanzapine Neopharma coated tablet contains either
2.5 mg, 5 mg, 7.5 mg, 10 mg or 15 mg of the active substance.
-
The other ingredients are:
-
Tablet core: lactose monohydrate (See also end of section 2 – important information about some
of the ingredients of Olanzapine Neopharma), maize starch, hydroxypropyl cellulose,
magnesium stearate.
-
Tablet coat:
-
2.5 mg, 5 mg, 7.5 mg and 10 mg tablets: Opadry white containing hypromellose (E464),
titanium dioxide (E171), lactose monohydrate, polyethylene glycol 3000 and glycerol triacetate
-
15 mg tablets: Opadry Blue containing hypromellose (E464), titanium dioxide (E171),
polyethylene glycol 6000, indigo carmine aluminium lake (E132), brilliant blue FCF aluminium
lake (E133) and iron oxide black (E172)
What OLANZAPINE NEOPHARMA looks like and contents of the pack
Olanzapine Neopharma 2.5 mg coated tablets are white, round, biconvex, coated tablets with ‘2.5’
debossed on one side and ‘OLZ’ on the other.
Olanzapine Neopharma 5 mg coated tablets are white, round, biconvex, coated tablets with ‘OLZ 5’
debossed on one side and ‘NEO’ on the other.
Olanzapine Neopharma 7.5 mg coated tablets are white, round, biconvex, coated tablets with ‘OLZ
7.5’ debossed on one side and ‘NEO’ on the other.
Olanzapine Neopharma 10 mg coated tablets are white, round, biconvex, coated tablets with ‘OLZ 10’
debossed on one side and ‘NEO’ on the other.
Olanzapine Neopharma 15 mg coated tablets are blue, elliptical, convex, coated tablets with ‘NEO’
debossed on one side and plain on the other side.
Olanzapine Neopharma 2.5 mg, 5 mg, 7.5 mg and 15 mg coated tablets are available in 28 and 56
blister packs.
Olanzapine Neopharma 10 mg coated tablets are available in 7, 28 and 56 blister packs.
Not all pack sizes may be marketed.
101
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
Neopharma Limited, 57 High Street, Odiham, Hampshire,
RG29 1LF, UK
Tel: +44 (0)1256 704110
Fax: +44 (0)1256 701144
Manufacturer:
Neolab Limited, 57 High Street, Odiham, Hampshire, RG29 1LF, UK
Tel: +44 (0)1256 704110
Fax: +44 (0)1256 701144
This leaflet was last approved in
{MM/YYYY}.
Detailed information on this medicine is available on the European Medicines Agency (EMA) web
site: http://www.ema.europa.eu/.
102
Source: European Medicines Agency
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