Olanzapine Mylan

1. NAME OF THE MEDICINAL PRODUCT

Olanzapine Mylan 2.5 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 2.5 mg olanzapine.

Excipient

For the 2.5 mg: Each film-coated tablet contains 76 mg lactose anhydrous.

Excipient

The film-coating of each 2.5 mg tablet contains 0.06 mg soya lecithin

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet (tablet).

7.0 mm, round, normal convex, white film-coated tablets debossed “OZ 2.5” on one side and “G” on

the other side.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Adults

Olanzapine is indicated for the treatment of schizophrenia.

Olanzapine is effective in maintaining the clinical improvement during continuation therapy in

patients who have shown an initial treatment response.

Olanzapine is indicated for the treatment of moderate to severe manic episode.

In patients whose manic episode has responded to olanzapine treatment, olanzapine is indicated for the

prevention of recurrence in patients with bipolar disorder (see section 5.1).

4.2 Posology and method of administration

Adults

Schizophrenia: The recommended starting dose for olanzapine is 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.

2

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.

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.)

4.3 Contraindications

Hypersensitivity to the active substance, peanut or soya or to any of the excipients.

Patients with known risk for narrow-angle glaucoma.

4.4 Special warnings and precautions for use

During antipsychotic treatment, improvement in the patient's clinical condition may take several days

to some weeks. Patients should be closely monitored during this period.

Dementia-related psychosis and/or behavioural disturbances

Olanzapine is not approved for the treatment of dementia-related psychosis and/or behavioural

disturbances and is not recommended for use in this particular group of patients because of an increase

in mortality and the risk of cerebrovascular accident. In placebo-controlled clinical trials (6-12 weeks

duration) of elderly patients (mean age 78 years) with dementia-related psychosis and/or disturbed

behaviours, there was a 2-fold increase in the incidence of death in olanzapine-treated patients

compared to patients treated with placebo (3.5 % vs. 1.5 % , respectively). The higher incidence of

death was not associated with olanzapine dose (mean daily dose 4.4 mg) or duration of treatment. Risk

factors that may predispose this patient population to increased mortality include age >65 years,

dysphagia, sedation, malnutrition and dehydration, pulmonary conditions (e.g., pneumonia, with or

without aspiration), or concomitant use of benzodiazepines. However, the incidence of death was

higher in olanzapine-treated than in placebo-treated patients independent of these risk factors.

3

In the same clinical trials, cerebrovascular adverse events (CVAE e.g., stroke, transient ischemic

attack), including fatalities, were reported. There was a 3-fold increase in CVAE in patients treated

with olanzapine compared to patients treated with placebo (1.3 % vs. 0.4 %, respectively). All

olanzapine- and placebo-treated patients who experienced a cerebrovascular event had pre-existing

risk factors. Age >75 years and vascular/mixed type dementia were identified as risk factors for CVAE

in association with olanzapine treatment. The efficacy of olanzapine was not established in these trials.

Parkinson's disease

The use of olanzapine in the treatment of dopamine agonist associated psychosis in patients with

Parkinson's disease is not recommended. In clinical trials, worsening of Parkinsonian symptomatology

and hallucinations were reported very commonly and more frequently than with placebo (see section

4.8), and olanzapine was not more effective than placebo in the treatment of psychotic symptoms. In

these trials, patients were initially required to be stable on the lowest effective dose of anti-

Parkinsonian medicinal products (dopamine agonist) and to remain on the same anti-Parkinsonian

medicinal products and dosages throughout the study. Olanzapine was started at 2.5 mg/day and

titrated to a maximum of 15 mg/day based on investigator judgment.

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 medicinal products,

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 very rarely, including some fatal cases (see section 4.8). In

some cases, a prior increase in body weight has been reported which may be a predisposing factor.

Appropriate clinical monitoring is advisable in accordance with utilised antipsychotic guidelines.

Patients treated with any antipsychotic agents, including olanzapine, should be observed for signs and

symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia, and weakness) and patients

with diabetes mellitus or with risk factors for diabetes mellitus should be monitored regularly for

worsening of glucose control. Weight should be monitored regularly.

Lipid alterations

Undesirable alterations in lipids have been observed in olanzapine-treated patients in placebo-

controlled clinical trials (see section 4.8). Lipid alterations should be managed as clinically

appropriate, particularly in dyslipidemic patients and in patients with risk factors for the development

of lipids disorders. Patients treated with any antipsychotic agents, including olanzapine, should be

monitored regularly for lipids in accordance with utilised antipsychotic guidelines.

Anticholinergic activity

While olanzapine demonstrated anticholinergic activity in vitro , experience during the clinical trials

revealed a low incidence of related events. However, as clinical experience with olanzapine in patients

with concomitant illness is limited, caution is advised when prescribing for patients with prostatic

hypertrophy, or paralytic ileus and related conditions.

Hepatic function

Transient, asymptomatic elevations of hepatic aminotransferases, 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 medicinal products. In cases where

4

hepatitis (including hepatocellular, cholestatic or mixed liver injury) has been diagnosed, olanzapine

treatment should be discontinued.

Neutropenia

Caution should be exercised in patients with low leukocyte and/or neutrophil counts for any reason, in

patients receiving medicines known to cause neutropenia, in patients with a history of drug-induced

bone marrow depression/toxicity, in patients with bone marrow depression caused by concomitant

illness, radiation therapy or chemotherapy and in patients with hypereosinophilic conditions or with

myeloproliferative disease. Neutropenia has been reported commonly when olanzapine and valproate

are used concomitantly (see section 4.8).

Discontinuation of treatment

Acute symptoms such as sweating, insomnia, tremor, anxiety, nausea, or vomiting have been reported

very rarely (<0.01 %) when olanzapine is stopped abruptly.

QT interval

In clinical trials, clinically meaningful QTc prolongations (Fridericia QT correction [QTcF]

≥ 500 milliseconds [msec] at any time post baseline in patients with baseline QTcF< 500 msec) were

uncommon (0.1 % to 1 %) in patients treated with olanzapine, with no significant differences in

associated cardiac events compared to placebo. However, as with other antipsychotics, caution should

be exercised when olanzapine is prescribed with medicinal products 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 medicinal products 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

5

cardiac death in patients treated with olanzapine was approximately twice the risk in patients not using

antipsychotics. In the study, the risk of olanzapine was comparable to the risk of atypical

antipsychotics included in a pooled analysis.

Paediatric population

Olanzapine is not indicated for use in the treatment of children and adolescents. Studies in patients

aged 13-17 years showed various adverse reactions, including weight gain, changes in metabolic

parameters and increases in prolactin levels. Long-term outcomes associated with these events have

not been studied and remain unknown (see sections 4.8 and 5.1).

Lactose

Olanzapine tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose

intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this

medicine. The film-coating contains soya lecithin. Patients who are allergic to peanut or soya must not

take these tablets.

4.5 Interaction with other medicinal products and other forms of interaction

Paediatric population:

Interaction studies have only been performed in adults.

Potential interactions affecting olanzapine : Since olanzapine is metabolised by CYP1A2, substances

that can specifically induce or inhibit this isoenzyme may affect the pharmacokinetics of olanzapine.

Induction of CYP1A2 : The metabolism of olanzapine may be induced by smoking and carbamazepine,

which may lead to reduced olanzapine concentrations. Only slight to moderate increase in olanzapine

clearance has been observed. The clinical consequences are likely to be limited, but clinical

monitoring is recommended and an increase of olanzapine dose may be considered if necessary (see

section 4.2).

Inhibition of CYP1A2 : Fluvoxamine, a specific CYP1A2 inhibitor, has been shown to significantly

inhibit the metabolism of olanzapine. The mean increase in olanzapine C max following fluvoxamine

was 54 % in female nonsmokers and 77 % male smokers. The mean increase in olanzapine AUC was

52 % and 108 % respectively. A lower starting dose of olanzapine should be considered in patients

who are using fluvoxamine or any other CYP1A2 inhibitors, such as ciprofloxacin. A decrease in the

dose of olanzapine should be considered if treatment with an inhibitor of CYP1A2 is initiated.

Decreased bioavailability : Activated charcoal reduces the bioavailability of oral olanzapine by 50 %

to

60 % and should be taken at least 2 hours before or after olanzapine.

Fluoxetine (a CYP2D6 inhibitor), single doses of antacid (aluminium, magnesium) or cimetidine have

not been found to significantly affect the pharmacokinetics of olanzapine.

Potential for olanzapine to affect other medicinal products : Olanzapine may antagonise the effects of

direct and indirect dopamine agonists.

Olanzapine does not inhibit the main CYP450 isoenzymes in vitro (e.g. 1A2, 2D6, 2C9, 2C19, 3A4).

Thus no particular interaction is expected as verified through in vivo studies where no inhibition of

metabolism of the following active substances was found: tricyclic antidepressant (representing mostly

CYP2D6 pathway), warfarin (CYP2C9), theophylline (CYP1A2) or diazepam (CYP3A4 and 2C19).

Olanzapine showed no interaction when co-administered with lithium or biperiden.

Therapeutic monitoring of valproate plasma levels did not indicate that valproate dosage adjustment is

required after the introduction of concomitant olanzapine.

General CNS activity

6

Caution should be exercised in patients who consume alcohol or receive medicinal products that can

cause central nervous system depression.

The concomitant use of olanzapine with anti-Parkinsonian medicinal products in patients with

Parkinson's disease and dementia is not recommended (see section 4.4).

QTc interval

Caution should be used if olanzapine is being administered concomitantly with medicinal products

known to increase QTc interval (see section 4.4).

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no adequate and well-controlled studies in pregnant women. Patients should be advised to

notify their physician if they become pregnant or intend to become pregnant during treatment with

olanzapine. Nevertheless, because human experience is limited, olanzapine should be used in

pregnancy only if the potential benefit justifies the potential risk to the foetus.

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.

4.7 Effects on ability to drive and use machines

Because olanzapine may cause somnolence and dizziness, patients should be cautioned about

operating machinery, including motor vehicles.

4.8 Undesirable effects

Adults

The most frequently (seen in ≥ 1 % of patients ) reported adverse reactions associated with the use of

olanzapine in clinical trials were somnolence, weight gain, eosinophilia, elevated prolactin,

cholesterol, glucose and triglyceride levels (see section 4.4), glucosuria, increased appetite, dizziness,

akathisia, parkinsonism (see section 4.4), dyskinesia, orthostatic hypotension, anticholinergic effects,

transient asymptomatic elevations of hepatic aminotransferases (see section 4.4), rash, asthenia,

fatigue and oedema.

The following table lists the adverse reactions and laboratory investigations observed from

spontaneous reporting and in clinical trials. Within each frequency grouping, adverse reactions are

presented in order of decreasing seriousness. The frequency terms listed are defined as follows: Very

common (≥10 %), common (≥ 1% and < 10%), uncommon (≥ 0.1% and < 1%), rare (≥ 0.01% and

< 0.1%), very rare (< 0.01%), not known (cannot be estimated from the data available).

Very common

Common

Uncommon

Not known

Blood and the lymphatic system disorders

Eosinophilia

Leucopenia

Neutropenia

Thrombocytopenia

Immune system disorders

Allergic reaction

Metabolism and nutrition disorders

Weight gain 1

Elevated cholesterol

levels 2,3

Development or

exacerbation of diabetes

7

Elevated glucose

levels 4

Elevated triglyceride

levels 2,5

Glucosuria

Increased appetite

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

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

8

Fatigue

Oedema

Investigations

Elevated plasma

prolactin levels 8

High creatine

phosphokinase

Increased total

bilirubin

Increased alkaine

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

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/HCL 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 4-6 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

9

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 propotion 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 %).

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.

10

12 Elevated plasma prolactin levels were reported in 47.4 % of adolescent patients.

4.9 Overdose

Signs and symptoms

Very common symptoms in overdose (>10 % incidence) include tachycardia, agitation/aggressiveness,

dysarthria, various extrapyramidal symptoms, and reduced level of consciousness ranging from

sedation to coma.

Other medically significant sequelae of overdose include delirium, convulsion, coma, possible

neuroleptic malignant syndrome, respiratory depression, aspiration, hypertension or hypotension,

cardiac arrhythmias (< 2 % of overdose cases) and cardiopulmonary arrest. Fatal outcomes have been

reported for acute overdoses as low as 450mg but survival has also been reported following acute

overdose of approximately 2 g of oral olanzapine .

Management of overdose

There is no specific antidote for olanzapine. Induction of emesis is not recommended. Standard

procedures for management of overdose may be indicated (i.e. gastric lavage, administration of

activated charcoal). The concomitant administration of activated charcoal was shown to reduce the

oral bioavailability of olanzapine by 50 to 60 %.

Symptomatic treatment and monitoring of vital organ function should be instituted according to

clinical presentation, including treatment of hypotension and circulatory collapse and support of

respiratory function. Do not use epinephrine, dopamine, or other sympathomimetic agents with beta

agonist activity since beta stimulation may worsen hypotension. Cardiovascular monitoring is

necessary to detect possible arrhythmias. Close medical supervision and monitoring should continue

until the patient recovers.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Diazepines, oxazepines and thiazepines, ATC code: N05AH03.

Olanzapine is an antipsychotic, antimanic and mood stabilising agent that demonstrates a broad

pharmacologic profile across a number of receptor systems.

In preclinical studies, olanzapine exhibited a range of receptor affinities (Ki; < 100 nM) for serotonin

5 HT2A/2C, 5 HT3, 5 HT6; dopamine D1, D2, D3, D4, D5; cholinergic muscarinic receptors m1-m5;

α1 adrenergic; and histamine H1 receptors. Animal 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 5HT2 than dopamine D2 receptors and greater 5

HT2 than D2 activity in vivo , models. Electrophysiological studies demonstrated that olanzapine

selectively reduced the firing of mesolimbic (A10) dopaminergic neurons, while having little effect on

the striatal (A9) pathways involved in motor function. Olanzapine reduced a conditioned avoidance

response, a test indicative of antipsychotic activity, at doses below those producing catalepsy, an effect

indicative of motor undesirable-effects. Unlike some other antipsychotic agents, olanzapine increases

responding in an “anxiolytic” test.

In a single oral dose (10 mg) Positron Emission tomography (PET) study in healthy volunteers,

olanzapine produced a higher 5 HT2A than dopamine D2 receptor occupancy. In addition, a SPECT

imaging study in schizophrenic patients revealed that olanzapine-responsive patients had lower striatal

D2 occupancy than some other antipsychotic- and risperidone-responsive patients, while being

comparable to clozapine-responsive patients.

11

In two of two placebo and two of three comparator controlled trials with over 2,900 schizophrenic

patients presenting with both positive and negative symptoms, olanzapine was associated with

statistically significantly greater improvements in negative as well as positive symptoms.

In a multinational, double-blind, comparative study of schizophrenia, schizoaffective, and related

disorders which included 1,481 patients with varying degrees of associated depressive symptoms

(baseline mean of 16.6 on the Montgomery-Asberg Depression Rating Scale), a prospective secondary

analysis of baseline to endpoint mood score change demonstrated a statistically significant

improvement (p=0.001) favouring olanzapine (-6.0) versus haloperidol (-3.1).

In patients with a manic or mixed episode of bipolar disorder, olanzapine demonstrated superior

efficacy to placebo and valproate semisodium (divalproex) in reduction of manic symptoms over 3

weeks. Olanzapine also demonstrated comparable efficacy results to haloperidol in terms of the

proportion of patients in symptomatic remission from mania and depression at 6 and 12 weeks. In a

co-therapy study of patients treated with lithium or valproate for a minimum of 2 weeks, the addition

of olanzapine 10 mg (co-therapy with lithium or valproate) resulted in a greater reduction in symptoms

of mania than lithium or valproate monotherapy after 6 weeks.

In a 12-month recurrence prevention study in manic episode patients who achieved remission on

olanzapine and were then randomised to olanzapine or placebo, olanzapine demonstrated statistically

significant superiority over placebo on the primary endpoint of bipolar recurrence. Olanzapine also

showed a statistically significant advantage over placebo in terms of preventing either recurrence into

mania or recurrence into depression.

In a second 12 month recurrence prevention study in manic episode patients who achieved remission

with a combination of olanzapine and lithium and were then randomised to olanzapine or lithium

alone, olanzapine was statistically non-inferior to lithium on the primary endpoint of bipolar

recurrence (olanzapine 30.0 %, lithium 38.3 %; p = 0.055).

In an 18-month co-therapy study in manic or mixed episode patients stabilised with olanzapine plus a

mood stabiliser (lithium or valproate), long-term olanzapine 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.

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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.

The plasma protein binding of olanzapine was about 93 % over the concentration range of about 7 to

about 1000 ng/ml. Olanzapine is bound predominantly to albumin and α1-acid-glycoprotein.

Paediatric population

Adolescents (ages 13 to 17 years): The pharmacokinetics of olanzapine are similar between

adolescents and adults. In clinical studies, the average olanzapine exposure was approximately 27 %

higher in adolescents. Demographic differences between the adolescents and adults include a lower

average body weight and fewer adolescents were smokers. Such factors possibly contribute to the

higher average exposure observed in adolescents.

5.3 Preclinical safety data

Acute (single-dose) toxicity

Signs of oral toxicity in rodents were characteristic of potent neuroleptic compounds: hypoactivity,

coma, tremors, clonic convulsions, salivation, and depressed weight gain. The median lethal doses

were approximately 210 mg/kg (mice) and 175 mg/kg (rats). Dogs tolerated single oral doses up to

100 mg/kg without mortality. Clinical signs included sedation, ataxia, tremors, increased heart rate,

labored respiration, miosis, and anorexia. In monkeys, single oral doses up to 100 mg/kg resulted in

prostration and, at higher doses, semi-consciousness.

Repeated-dose toxicity

In studies up to 3 months duration in mice and up to 1 year in rats and dogs, the predominant effects

were CNS depression, anticholinergic effects, and peripheral haematological disorders. Tolerance

developed to the CNS depression. Growth parameters were decreased at high doses. Reversible effects

consistent with elevated prolactin in rats included decreased weights of ovaries and uterus and

morphologic changes in vaginal epithelium and in mammary gland.

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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. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core

Lactose monohydrate

Maize starch

Pregelatinised maize starch

Crospovidone type A

Magnesium stearate

Tablet coat

Opadry White OY-B-28920 containing:

Polyvinyl alcohol

Titanium dioxide E171

Talc E553b

Lecithin soya E322

Xanthan gum E415

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

Blister 2.5 mg

18 months

Tablet containers 2.5 mg 18 months

6.4 Special precautions for storage

Do not store above 25 °C.

6.5 Nature and contents of container

14

Olanzapine Mylan 2.5 mg film-coated tablets:

Cold-formed aluminium/aluminium blister in cartons of 28, 35, 56 & 70 film-coated tablets per carton.

Polypropylene tablet containers with tamper evident polyethylene closure containing 250 & 500 film-

coated tablets per tablet container.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7. MARKETING AUTHORISATION HOLDER

Generics [UK] Limited

Station Close

Potters Bar

Hertfordshire

EN6 1TL

UK.

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/08/475/001

EU/1/08/475/002

EU/1/08/475/003

EU/1/08/475/004

EU/1/08/475/005

EU/1/08/475/006

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

07/10/2008

10. DATE OF REVISION OF THE TEXT

Detailed information on this product is available on the website of the European Medicines Agency

http://www.ema.europa.eu .

15

1. NAME OF THE MEDICINAL PRODUCT

Olanzapine Mylan 5 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 5 mg olanzapine.

Excipient

For the 5 mg: 152 mg lactose anhydrous per tablet.

Excipient

The film-coating of each 5 mg tablet contains 0.12 mg soya lecithin

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet (tablet).

8.0 mm, round, normal convex, white film-coated tablets debossed “OZ 5” on one side and “G” on the

other side.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Adults

Olanzapine is indicated for the treatment of schizophrenia.

Olanzapine is effective in maintaining the clinical improvement during continuation therapy in

patients who have shown an initial treatment response.

Olanzapine is indicated for the treatment of moderate to severe manic episode.

In patients whose manic episode has responded to olanzapine treatment, olanzapine is indicated for the

prevention of recurrence in patients with bipolar disorder (see section 5.1).

4.2 Posology and method of administration

Adults

Schizophrenia: The recommended starting dose for olanzapine is 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.

16