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Olanzapine Cipla (Olanzapine Neopharma) (olanzapine) – Summary of product characteristics - N05AH03

Updated on site: 08-Oct-2017

Medication nameOlanzapine Cipla (Olanzapine Neopharma)
ATC CodeN05AH03
Substanceolanzapine
ManufacturerCipla (EU) Limited
Coated tablet

3. PHARMACEUTICAL FORM

1. NAME OF THE MEDICINAL PRODUCT

Olanzapine Cipla 2.5 mg coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each coated tablet contains 2.5 mg olanzapine.
Excipient with known effect: Each coated tablet contains 80.7 mg lactose monohydrate For the full list of excipients, see section 6.1.

White, round, biconvex, coated tablets with ‘2.5’ debossing on one sideauthorisedand ‘OLZ’ on the other.

4.CLINICAL PARTICULARS

4.1 Therapeutic indications

Adults

 

 

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Olanzapine is indicated for the treatment of schizophrenia.

 

 

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

patients who have shown an initial treatment response.

 

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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 PosologyMedicinaland 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.

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 patients

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).

Patients with 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

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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)

 

no

longer

4.3

Contraindications

 

 

 

 

 

 

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Patients with known risk for narrow-angle glaucoma.

 

4.4

Special warnings and precautions for use

 

 

 

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During antipsychoticMedicinaltreatment, improvement in the patient's clinical condition may take several days to some weeks. Patients should be closely monitored during this period.

Dementia-related psychosis and/or behavioural disturbances

Olanzapine is not approved for the treatment of dementia-related psychosis and/or behavioural disturbances and is not recommended for use in this particular group of patients because of an increase in mortality and the risk of cerebrovascular accident. In placebo-controlled clinical trials (6- 12 weeks duration) of elderly patients (mean age 78 years) with dementia-related psychosis and/or disturbed behaviours, there was a 2-fold increase in the incidence of death in olanzapine-treated patients compared to patients treated with placebo (3.5% vs. 1.5%, respectively). The higher incidence of death was not associated with olanzapine dose (mean daily dose 4.4 mg) or duration of treatment. Risk factors that may predispose this patient population to increased mortality include age > 65 years, dysphagia, sedation, malnutrition and dehydration, pulmonary conditions (e.g., pneumonia, with or without aspiration), or concomitant use of benzodiazepines. However, the incidence of death was higher in olanzapine-treated than in placebo-treated patients independent of these risk factors.

In the same clinical trials, cerebrovascular adverse events (CVAE e.g., stroke, transient ischemic attack), including fatalities, were reported. There was a 3-fold increase in CVAE in patients treated with olanzapine compared to patients treated with placebo (1.3% vs. 0.4%, respectively). All

olanzapine- and placebo-treated patients who experienced a cerebrovascular event had pre-existing risk factors. Age > 75 years and vascular/mixed type dementia were identified as risk factors for CVAE in association with olanzapine treatment. The efficacy of olanzapine was not established in these trials.

Parkinson's disease

The use of olanzapine in the treatment of dopamine agonist associated psychosis in patients with Parkinson's disease is not recommended. In clinical trials, worsening of Parkinsonian symptomatology and hallucinations were reported very commonly and more frequently than with placebo (see section 4.8), and olanzapine was not more effective than placebo in the treatment of psychotic symptoms. In these trials, patients were initially required to be stable on the lowest effective dose of anti- Parkinsonian medicinal products (dopamine agonist) and to remain on the same anti-Parkinsonian medicinal products and dosages throughout the study. Olanzapine was started at 2.5 mg/day and titrated to a maximum of 15 mg/day based on investigator judgement.

Neuroleptic Malignant Syndrome (NMS)

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NMS is a potentially life-threatening condition associated with antipsychotic medicinal products. 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 belongerdiscontinued.

Hyperglycaemia and diabetes

Hyperglycaemia and/or development or exacerbation of diabetes occasionally associated with ketoacidosis or coma has been reported uncommonly,no including some fatal cases (see section 4.8). In some cases, a prior increase in body weight has been reported which may be a predisposing factor. Appropriate clinical monitoring is advisable in accordance with utilised antipsychotic guidelines, e.g. measuring of blood glucose at baseline, 12 weeks after starting olanzapine treatment and annually thereafter. Patients treated with any antipsychotic agents, including Olanzapine Cipla, should be observed for signs and symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia, and weakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus should be

monitored regularly for worsening of glucose control. Weight should be monitored regularly, e.g. at

 

 

product

baseline, 4, 8 and 12 weeks after starting olanzapine treatment and quarterly thereafter.

Lipid alterations

 

 

Undesirable alterations

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

dyslipidemic patients and in patients with risk factors for the development

Medicinal

 

of lipids disorders. Patients treated with any antipsychotic agents, including Olanzapine Cipla, should be monitored regularly for lipids in accordance with utilised antipsychotic guidelines, e.g. at baseline, 12 weeks after starting olanzapine treatment and every 5 years thereafter.

Anticholinergic activity

While olanzapine demonstrated anticholinergic activity in vitro, experience during the clinical trials revealed a low incidence of related events. However, as clinical experience with olanzapine in patients with concomitant illness is limited, caution is advised when prescribing for patients with prostatic hypertrophy, or paralytic ileus and related conditions.

Hepatic function

Transient, asymptomatic elevations of hepatic 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.

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).

QT interval

authorised

Discontinuation of treatment

 

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

rarely ( ≥ 0.01% and < 0.1%) when olanzapine is stopped abruptly.

 

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. longer

Thromboembolism

Temporal association of olanzapine treatment and venous thromboembolism has been reported uncommonly (≥ 0.1% and < 1%). A causal relationship between the occurrence of venous thromboembolism and treatment with olanzapine has not been established. However, since patients

General CNS activity

with schizophrenia often present with acquired risk factors for venous thromboembolism all possible

 

 

no

risk factors of VTE e.g. immobilisation of patients, should be identified and preventive measures

undertaken.

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Given the primary CNS effects of olanzapine, caution should be used when it is taken in combination with other centrallyMedicinalacting 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 uncommonly in patients when treated with olanzapine. In most of these cases, a history of seizures or risk factors for seizures were reported.

Tardive Dyskinesia

In comparator studies of one year or less duration, olanzapine was associated with a statistically significant lower incidence of treatment emergent dyskinesia. However the risk of tardive dyskinesia increases with long term exposure, and therefore if signs or symptoms of tardive dyskinesia appear in a patient on olanzapine, a dose reduction or discontinuation should be considered. These symptoms can temporally deteriorate or even arise after discontinuation of treatment.

Postural hypotension

Postural hypotension was infrequently observed in the elderly in olanzapine clinical trials. As with other antipsychotics, it is recommended that blood pressure is measured periodically in patients over 65 years.

Sudden cardiac death

In postmarketing reports with olanzapine, the event of sudden cardiac death has been reported in patients with olanzapine. In a retrospective observational cohort study, the risk of presumed sudden cardiac death in patients treated with olanzapine was approximately twice the risk in patients not using antipsychotics. In the study, the risk of olanzapine was comparable to the risk of atypical antipsychotics included in a pooled analysis.

Paediatric population

Olanzapine is not indicated for use in the treatment of children and adolescents. Studies in patients aged 13-17 years showed various adverse reactions, including weight gain, changes in metabolic parameters and increases in prolactin levels. Long-term outcomes associated with these events have not been studied and remain unknown (see sections 4.8 and 5.1).

Lactose

OLANZAPINE CIPLA tablets contain lactose. Patients with rare hereditary problems of galactose authorised

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

4.5 Interaction with other medicinal products and other forms of interaction

Paediatric population

Interaction studies have only been performed in adults.

Potential interactions affecting olanzapine

Since olanzapine is metabolised by CYP1A2, substances that can specifically induce or inhibit this

isoenzyme may affect the pharmacokinetics of olanzapine.

Induction of CYP1A2

longer

The metabolism of olanzapine may be induced bynosmoking 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).

Fluvoxamine, a specific CYP1A2productinhibitor, has been shown to significantly inhibit the metabolism of olanzapine. The mean increase in olanzapine Cmax following fluvoxamine was 54 % in female non-

Inhibition of CYP1A2

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.

smokers andMedicinal77 % 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

Decreased bioavailability

Activated charcoal reduces the bioavailability of oral olanzapine by 50 to 60% and should be taken at least 2 hours before or after olanzapine.

Fluoxetine (a CYP2D6 inhibitor), single doses of antacid (aluminium, magnesium) or cimetidine have not been found to significantly affect the pharmacokinetics of olanzapine.

Potential for olanzapine to affect other medicinal products

Olanzapine may antagonise the effects of direct and indirect dopamine agonists.

Olanzapine does not inhibit the main CYP450 isoenzymes in vitro (e.g. 1A2, 2D6, 2C9, 2C19, 3A4). Thus no particular interaction is expected as verified through in vivo studies where no inhibition of metabolism of the following active substances was found: tricyclic antidepressant (representing mostly CYP2D6 pathway), warfarin (CYP2C9), theophylline (CYP1A2) or diazepam (CYP3A4 and 2C19).

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

Therapeutic monitoring of valproate plasma levels did not indicate that valproate dosage adjustment is required after the introduction of concomitant olanzapine.

General CNS activity

Caution should be exercised in patients who consume alcohol or receive medicinal products that can cause central nervous system depression.

The concomitant use of olanzapine with anti-Parkinsonian medicinal products in patients with Parkinson's disease and dementia is not recommended (see section 4.4).

QTc interval

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

4.6 Fertility, pregnancy and lactation

Pregnancy

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There are no adequate and well-controlled studies in pregnant women. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during treatment with olanzapine. Nevertheless, because human experience is limited, olanzapine should be used in pregnancy only if the potential benefit justifies the potential risk to the foetus.

Neonates exposed to antipsychotics (including olanzapine) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in

 

 

no

severity and duration following delivery. There have beenlongerreports of agitation, hypertonia, hypotonis,

tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be

monitored carefully.

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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 EffectsMedicinalon ability to drive and use machines

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

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, leukopenia, neutropenia (see section 4.4), dyskinesia, orthostatic hypotension, anticholinergic effects, transient asymptomatic elevations of hepatic aminotransferases (see section 4.4), rash, asthenia, fatigue, pyrexia, arthralgia, increased alkaline phosphatase, high gamma glutamyltransferase, high uric acid, high creatine phosphokinase and oedema.

Tabulated list of adverse reactions

The following table lists the adverse reactions and laboratory investigations observed from spontaneous reporting and in clinical trials. Within each frequency grouping, adverse reactions are

presented in order of decreasing seriousness. The frequency terms listed are defined as follows: Very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the data available).

 

 

 

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Very common

Common

 

 

Uncommon

 

Rare

Blood and the lymphatic system disorders

 

 

 

 

 

 

Eosinophilia

 

 

 

 

Thrombocytopenia11

 

Leukopenia10

 

 

 

 

 

 

Neutropenia10

 

 

 

 

 

Immune system disorders

 

 

 

 

 

 

 

 

 

Hypersensitivity11

 

 

Metabolism and nutrition disorders

 

 

 

 

 

Weight gain1

Elevated cholesterol

 

 

Development or

 

Hypothermia12

 

levels2,3

 

 

exacerbation of

 

 

 

Elevated glucose

 

 

diabetes occasionally

 

 

levels4

 

 

associated with

 

 

 

Elevated triglyceride

 

 

ketoacidosis or coma,

 

 

levels2,5

 

 

including some fatal

 

 

Dyskinesia6

 

 

for seizures wereauthorised

 

Glucosuria

 

 

cases (see section 4.4)

 

 

Increased appetite

 

 

 

 

Nervous system disorders

 

 

 

 

 

Somnolence

Dizziness

 

 

Seizures where in most

Neuroleptic malignant

 

Akathisia6

 

 

cases a history of

 

syndrome (see section

 

Parkinsonism6

 

 

seizures or risk factors

4.4)12

 

 

 

 

longer

Discontinuation

 

 

 

 

reported 11

 

 

 

 

 

Dystonia (including

symptoms7, 12

 

 

 

 

 

 

 

 

 

oculogyration) 11

 

 

 

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Tardive dyskinesia

 

 

 

noAmnesia 9

 

 

 

 

 

 

 

 

 

 

Dysarthria

 

 

 

 

 

 

 

Respiratory, thoracic and mediastinal disorders

 

 

 

 

 

 

 

Epistaxis9

 

 

Cardiac disorders

 

 

 

 

 

 

 

 

 

 

Bradycardia

 

Ventricular

 

 

 

 

QTc prolongation (see

tachycardia/fibrillation

 

 

 

 

section 4.4)

 

, sudden death (see

 

 

 

 

 

 

section 4.4)11

Vascular disorders

 

 

 

 

 

 

Medicinal

 

 

 

 

Orthostatic 10

 

 

 

Thromboembolism

 

hypotension

 

 

 

(including pulmonary

 

 

 

 

 

embolism and deep

 

 

 

 

 

vein thrombosis) (see

 

 

 

 

 

section 4.4)

 

 

Gastrointestinal disorders

 

 

 

 

 

 

Mild, transient

 

 

Abdominal distension9

Pancreatitis11

 

anticholinergic effects

 

 

 

 

 

including constipation

 

 

 

 

 

and dry mouth

 

 

 

 

 

Hepato-biliary disorders

 

 

 

 

 

 

Transient,

 

 

 

 

Hepatitis (including

 

asymptomatic

 

 

 

 

hepatocellular,

 

elevations of hepatic

 

 

 

 

cholestatic or mixed

 

aminotransferases

 

 

 

 

liver injury)11

 

 

 

 

 

(ALT, AST), especially in early treatment (see section 4.4)

Skin and subcutaneous tissue disorders

 

Rash

 

 

 

Photosensitivity

 

 

 

 

 

 

reaction

 

 

 

 

 

 

Alopecia

 

Musculoskeletal and connective tissue disorders

 

 

 

 

Arthralgia9

 

 

 

 

 

Rhabdomyolysis11

Renal and urinary disorders

 

 

 

 

 

 

 

 

 

 

 

Urinary incontinence,

 

 

 

 

 

 

urinary retention

 

 

 

 

 

 

Urinary hesitation11

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Reproductive system and breast disorders

 

 

enlargement in malesauthorised

 

 

 

 

 

 

Erectile dysfunction in

 

Amenorrhea

Priapism12

 

males

 

 

 

Breast enlargement

 

 

Decreased libido in

 

 

Galactorrhea in

 

 

males and females

 

 

females

 

 

 

 

 

 

Gynaecomastia/breast

 

 

 

 

 

 

 

 

 

 

Pyrexia10

 

 

 

 

longer

 

General disorders and administration site conditions

 

 

Asthenia

 

 

 

 

 

 

 

Fatigue

 

 

 

 

 

 

 

Oedema

 

no

 

 

Investigations

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Elevated plasma

Increased alkaline

 

 

 

Increased total

 

prolactin levels8

phosphatase10

 

 

 

bilirubin

 

 

High creatine

 

 

 

 

 

 

 

phosphokinase11

 

 

 

 

 

 

 

High Gamma

 

 

 

 

 

 

Medicinal

 

 

 

 

 

 

 

Glutamyltransferaseproduct

 

 

 

 

 

 

 

 

 

 

 

 

 

High Uric Acid 10

 

 

 

 

 

 

 

 

 

 

 

 

 

Not known

Pregnancy, puerperium and perinatal conditions

 

 

 

 

 

 

 

 

 

Drug withdrawal

 

 

 

 

 

 

 

syndrome neonatal

 

 

 

 

 

 

 

(see section 4.6)

1 Clinically significant weight gain was observed across all baseline Body Mass Index (BMI) categories. Following short term treatment (median duration 47 days), weight gain ≥ 7% of baseline body weight was very common (22.2 %), ≥ 15 % was common (4.2 %) and ≥ 25 % was uncommon (0.8 %). Patients gaining ≥ 7 %, ≥ 15 % and ≥ 25 % of their baseline body weight with long-term exposure (at least 48 weeks) were very common (64.4 %, 31.7 % and 12.3 % respectively).

2 Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were greater in patients without evidence of lipid dysregulation at baseline.

3 Observed for fasting normal levels at baseline (< 5.17 mmol/l) which increased to high

(≥ 6.2 mmol/l). Changes in total fasting cholesterol levels from borderline at baseline (≥ 5.17 - < 6.2 mmol/l) to high (≥ 6.2 mmol/l) were very common.

4 Observed for fasting normal levels at baseline (< 5.56 mmol/l) which increased to high (≥ 7 mmol/l). Changes in fasting glucose from borderline at baseline (≥ 5.56 - < 7 mmol/l) to high (≥ 7 mmol/l) were very common.

5 Observed for fasting normal levels at baseline (< 1.69 mmol/l) which increased to high

(≥ 2.26 mmol/l). Changes in fasting triglycerides from borderline at baseline (≥ 1.69 mmol/l - < 2.26 mmol/l) to high (≥ 2.26 mmol/l) were very common.

6 In clinical trials, the incidence of Parkinsonism and dystonia in olanzapine-treated patients was numerically higher, but not statistically significantly different from placebo. Olanzapine-treated patients had a lower incidence of Parkinsonism, akathisia and dystonia compared with titrated doses of haloperidol. In the absence of detailed information on the pre-existing history of individual acute and tardive extrapyramidal movement disorders, it cannot 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.

authorised

9 Adverse event identified from clinical trials in the Olanzapine Integrated Database.

10 As assessed by measured values from clinical trials in the Olanzapine Integrated Database.

 

 

no

Adverse event identified from spontaneous post-marketinglongerreporting with frequency determined

utilising the Olanzapine Integrated Database.

 

 

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Adverse event identified from spontaneous post-marketing reporting with frequency estimated at

the upper limit of the 95% confidence interval utilising the Olanzapine Integrated Database.

Long-term exposure (at least 48 weeks)

Additional information on special populations

The proportion of patients who had adverse, clinically significant changes in weight gain, glucose, total/LDL/HDLMedicinalcholesterol 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.

In clinical trials 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

Common: Dry mouth
Gastrointestinal disorders

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 orderauthorisedof decreasing seriousness.

The frequency terms listed are defined as follows: Very common (≥ 1/10), common (≥ 1/100 to < 1/10).

Metabolism and nutrition disorders

Very common: Weight gain13, elevated triglyceride levels14, increased appetite. Common: Elevated cholesterol levels15

Nervous system disorders

Very common: Sedation (including: hypersomnia, lethargy,longersomnolence).

Hepato-biliary disorders

Investigationsno

Very common: Elevations of hepatic aminotransferases (ALT/AST; see section 4.4).

Very common: Decreased total bilirubin,productincreased GGT, elevated plasma prolactin levels16.

13 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.

14 ObservedMedicinalfor 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).

15 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.

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

4.9Overdose

Signs and symptoms

Very common symptoms in overdose (> 10% incidence) include tachycardia, agitation/aggressiveness, dysarthria, various extrapyramidal symptoms, and reduced level of consciousness ranging from sedation to coma.

Other medically significant sequelae of overdose include delirium, convulsion, coma, possible neuroleptic malignant syndrome, respiratory depression, aspiration, hypertension or hypotension,

cardiac arrhythmias (< 2% of overdose cases) and cardiopulmonary arrest. Fatal outcomes have been reported for acute overdoses as low as 450 mg but survival has also been reported following acute overdose of approximately 2 g of oral olanzapine.

Management

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

 

 

authorised

Pharmacotherapeutic group: diazepines, oxazepines and thiazepines., ATC code: N05A H03.

Pharmacodynamic effects

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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 rangenoof receptor affinities (Ki < 100 nM) for serotonin 5

HT , 5 HT , 5 HT ; dopamine D , D , D , D , D ; cholinergic muscarinic receptors M -M ;

adrenergic; and histamine H1 receptors. Animal behavioural studies with olanzapine indicated 5HT, dopamine, and cholinergic antagonism, consistent with the receptor-binding profile. Olanzapine

demonstrated a greater in vitro affinity for serotonin 5HT2 than dopamine D2 receptors and greater 5 HT2 than D2 activity in vivo models. Electrophysiological studies demonstrated that olanzapine

2A/2C 3 6product1 2 3 4 51 5 1

effect indicative of motor side-effects. Unlike some other antipsychotic agents, olanzapine increases responding an “anxiolytic” test.

selectively reduced the firing of mesolimbic (A10) dopaminergic neurons, while having little effect on the striatal (A9)Medicinalpathways involved in motor function. Olanzapine reduced a conditioned avoidance response, a test indicative of antipsychotic activity, at doses below those producing catalepsy, an

In a single oral dose (10 mg) Positron Emission Tomography (PET) study in healthy volunteers, olanzapine produced higher 5 HT2A than dopamine D2 receptor occupancy. In addition, a Single Photon Emission Computed Tomography (SPECT) imaging study in schizophrenic patients revealed that olanzapine-responsive patients had lower striatal D2 occupancy than some other antipsychotic- and risperidone-responsive patients, while being comparable to clozapine-responsive patients.

Clinical efficacy

In two of two placebo and two of three comparator controlled trials with over 2,900 schizophrenic patients presenting with both positive and negative symptoms, olanzapine was associated with statistically significantly greater improvements in negative as well as positive symptoms.

In a multinational, double-blind, comparative study of schizophrenia, schizoaffective, and related disorders which included 1,481 patients with varying degrees of associated depressive symptoms (baseline mean of 16.6 on the Montgomery-Asberg Depression Rating Scale), a prospective secondary analysis of baseline to endpoint mood score change demonstrated a statistically significant improvement (p= 0.001) favouring olanzapine (-6.0) versus haloperidol (-3.1).

In patients with a manic or mixed episode of bipolar disorder, olanzapine demonstrated superior efficacy to placebo and valproate semisodium (divalproex) in reduction of manic symptoms over 3 weeks. Olanzapine also demonstrated comparable efficacy results to haloperidol in terms of the proportion of patients in symptomatic remission from mania and depression at 6 and 12 weeks. In a co-therapy study of patients treated with lithium or valproate for a minimum of 2 weeks, the addition of olanzapine 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.

 

authorised

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 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 valproate was

not statistically significantly superior to lithium or valproate alone in delaying bipolar recurrence, defined according to syndromic (diagnostic) criteria. longer

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, adolescentsno gained significantly more weight compared with adults. The magnitude of changes in fasting total cholesterol, LDL cholesterol, triglycerides, and

5.2 Pharmacokinetic properties

prolactin (see sections 4.4 and 4.8)productwere 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).

Absorption

Olanzapine Medicinalis well absorbed after oral administration, reaching peak plasma concentrations within 5 to 8 hours. The absorption is not affected by food. Absolute oral bioavailability relative to intravenous

administration has not been determined

Distribution

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

about 1000 ng/ml. Olanzapine is bound predominantly to albumin and 1-acid-glycoprotein.

Biotransformation

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.

Elimination

After oral administration, the mean terminal elimination half-life of olanzapine in healthy subjects varied on the basis of age and gender.

In healthy elderly (65 and over) versus non-elderly subjects, the mean elimination half-life was prolonged (51.8 versus 33.8 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).

Renal impairment

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.

Smokers

authorised

 

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.

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In a study of Caucasians, Japanese, and Chinesenosubjects, there were no differences in the

 

product

pharmacokinetic parameters among the three populations.

Paediatric population

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

higher average exposure observed in adolescents.

adolescents and adults. In clinical studies, the average olanzapine exposure was approximately 27% higher in adolescents.MedicinalDemographic differences between the adolescents and adults include a lower average body weight and fewer adolescents were smokers. Such factors possibly contribute to the

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 anaemia 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 foetal development and transient decreases in offspring activity levels were seen.

Mutagenicity

authorised

 

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 not carcinogenic.

Tablet core

 

 

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6.

PHARMACEUTICAL PARTICULARS

 

6.1

List of excipients

 

no

 

Lactose monohydrate,

 

 

 

 

 

Maize starch

product

 

 

Hydroxypropyl cellulose

 

 

 

 

 

Magnesium stearate

 

 

 

Tablet coat

 

 

 

Opadry II White containing:

 

 

 

 

Medicinal

 

 

 

Hypromellose (E464)

 

 

 

Titanium dioxide (E171)

 

 

 

Lactose monohydrate

 

 

 

Polyethylene glycol 3000

 

 

 

Glycerol triacetate

 

 

 

6.2

Incompatibilities

 

 

 

Not applicable.

 

 

 

6.3Shelf life

3 years

6.4Special precautions for storage

Store in the original package.

Store below 30°C.

6.5Nature and contents of container

Cold-formed aluminium blisters in cartons of 28 or 56 tablets per carton.

Not all pack sizes may be marketed.

6.6Special precautions for disposal and other handling

No special requirements.

7.MARKETING AUTHORISATION HOLDER

Cipla (EU) Limited

 

 

 

 

Hillbrow House

 

 

 

 

Hillbrow Road

 

 

 

authorised

Esher

 

 

 

 

 

 

 

 

 

Surrey

 

 

 

 

KT10 9NW

 

 

 

 

UK

 

 

 

 

 

8.

MARKETING AUTHORISATION NUMBER(S)

 

 

 

 

 

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EU/1/07/426/001 – Olanzapine Cipla – 2.5 mg – coated tablets – 28 tablets per box

EU/1/07/426/002 – Olanzapine Cipla – 2.5 mg – coated tablets – 56 tablets per box

 

 

 

no

 

 

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

 

 

product

 

 

 

Date of first authorisation: 14 November 2007

 

 

 

Date of latest renewal: 01 October 2012

 

 

 

 

Medicinal

 

 

 

 

10.

DATE OF REVISION OF THE TEXT

 

 

 

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMA) http://www.ema.europa.eu/.

1. NAME OF THE MEDICINAL PRODUCT
Olanzapine Cipla 5 mg coated tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each coated tablet contains 5 mg olanzapine.
Excipient with known effect: Each coated tablet contains 161.3 mg lactose monohydrate For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM

Coated tablet

White, round, biconvex, coated tablets with ‘OLZ 5’ debossing on one side and ‘NEO’ on the other.

4.

CLINICAL PARTICULARS

 

 

authorised

4.1

Therapeutic indications

 

 

 

 

 

Adults

 

 

 

 

Olanzapine is indicated for the treatment of schizophrenia.

 

 

 

 

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

patients who have shown an initial treatment response.

 

 

 

no

 

 

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

 

product

 

 

 

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 PosologyMedicinaland 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.

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 patients

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).

Patients with 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

authorised

 

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)

 

no

longer

4.3

Contraindications

 

 

 

 

 

 

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Patients with known risk for narrow-angle glaucoma.

 

4.4

Special warnings and precautions for use

 

 

 

product

 

 

During antipsychoticMedicinaltreatment, improvement in the patient's clinical condition may take several days to some weeks. Patients should be closely monitored during this period.

Dementia-related psychosis and/or behavioural disturbances

Olanzapine is not approved for the treatment of dementia-related psychosis and/or behavioural disturbances and is not recommended for use in this particular group of patients because of an increase in mortality and the risk of cerebrovascular accident. In placebo-controlled clinical trials (6- 12 weeks duration) of elderly patients (mean age 78 years) with dementia-related psychosis and/or disturbed behaviours, there was a 2-fold increase in the incidence of death in olanzapine-treated patients compared to patients treated with placebo (3.5% vs. 1.5%, respectively). The higher incidence of death was not associated with olanzapine dose (mean daily dose 4.4 mg) or duration of treatment. Risk factors that may predispose this patient population to increased mortality include age > 65 years, dysphagia, sedation, malnutrition and dehydration, pulmonary conditions (e.g., pneumonia, with or without aspiration), or concomitant use of benzodiazepines. However, the incidence of death was higher in olanzapine-treated than in placebo-treated patients independent of these risk factors.

In the same clinical trials, cerebrovascular adverse events (CVAE e.g., stroke, transient ischemic attack), including fatalities, were reported. There was a 3-fold increase in CVAE in patients treated with olanzapine compared to patients treated with placebo (1.3% vs. 0.4%, respectively). All

olanzapine- and placebo-treated patients who experienced a cerebrovascular event had pre-existing risk factors. Age > 75 years and vascular/mixed type dementia were identified as risk factors for CVAE in association with olanzapine treatment. The efficacy of olanzapine was not established in these trials.

Parkinson's disease

The use of olanzapine in the treatment of dopamine agonist associated psychosis in patients with Parkinson's disease is not recommended. In clinical trials, worsening of Parkinsonian symptomatology and hallucinations were reported very commonly and more frequently than with placebo (see section 4.8), and olanzapine was not more effective than placebo in the treatment of psychotic symptoms. In these trials, patients were initially required to be stable on the lowest effective dose of anti- Parkinsonian medicinal products (dopamine agonist) and to remain on the same anti-Parkinsonian medicinal products and dosages throughout the study. Olanzapine was started at 2.5 mg/day and titrated to a maximum of 15 mg/day based on investigator judgement.

Neuroleptic Malignant Syndrome (NMS)

authorised

 

NMS is a potentially life-threatening condition associated with antipsychotic medicinal products. 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 belongerdiscontinued.

Hyperglycaemia and diabetes

Hyperglycaemia and/or development or exacerbation of diabetes occasionally associated with ketoacidosis or coma has been reported uncommonly,no including some fatal cases (see section 4.8). In some cases, a prior increase in body weight has been reported which may be a predisposing factor. Appropriate clinical monitoring is advisable in accordance with utilised antipsychotic guidelines, e.g. measuring of blood glucose at baseline, 12 weeks after starting olanzapine treatment and annually thereafter. Patients treated with any antipsychotic agents, including Olanzapine Cipla, should be observed for signs and symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia, and weakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus should be

monitored regularly for worsening of glucose control. Weight should be monitored regularly, e.g. at

 

 

product

baseline, 4, 8 and 12 weeks after starting olanzapine treatment and quarterly thereafter.

Lipid alterations

 

 

Undesirable alterations

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

dyslipidemic patients and in patients with risk factors for the development

Medicinal

 

of lipids disorders. Patients treated with any antipsychotic agents, including Olanzapine Cipla, should be monitored regularly for lipids in accordance with utilised antipsychotic guidelines, e.g. at baseline, 12 weeks after starting olanzapine treatment and every 5 years thereafter.

Anticholinergic activity

While olanzapine demonstrated anticholinergic activity in vitro, experience during the clinical trials revealed a low incidence of related events. However, as clinical experience with olanzapine in patients with concomitant illness is limited, caution is advised when prescribing for patients with prostatic hypertrophy, or paralytic ileus and related conditions.

Hepatic function

Transient, asymptomatic elevations of hepatic 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.

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).

QT interval

authorised

Discontinuation of treatment

 

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

rarely ( ≥ 0.01% and < 0.1%) when olanzapine is stopped abruptly.

 

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. longer

Thromboembolism

Temporal association of olanzapine treatment and venous thromboembolism has been reported uncommonly (≥ 0.1% and < 1%). A causal relationship between the occurrence of venous thromboembolism and treatment with olanzapine has not been established. However, since patients

General CNS activity

with schizophrenia often present with acquired risk factors for venous thromboembolism all possible

 

 

no

risk factors of VTE e.g. immobilisation of patients, should be identified and preventive measures

undertaken.

product

 

 

 

Given the primary CNS effects of olanzapine, caution should be used when it is taken in combination with other centrallyMedicinalacting 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 uncommonly in patients when treated with olanzapine. In most of these cases, a history of seizures or risk factors for seizures were reported.

Tardive Dyskinesia

In comparator studies of one year or less duration, olanzapine was associated with a statistically significant lower incidence of treatment emergent dyskinesia. However the risk of tardive dyskinesia increases with long term exposure, and therefore if signs or symptoms of tardive dyskinesia appear in a patient on olanzapine, a dose reduction or discontinuation should be considered. These symptoms can temporally deteriorate or even arise after discontinuation of treatment.

Postural hypotension

Postural hypotension was infrequently observed in the elderly in olanzapine clinical trials. As with other antipsychotics, it is recommended that blood pressure is measured periodically in patients over 65 years.

Sudden cardiac death

In postmarketing reports with olanzapine, the event of sudden cardiac death has been reported in patients with olanzapine. In a retrospective observational cohort study, the risk of presumed sudden cardiac death in patients treated with olanzapine was approximately twice the risk in patients not using antipsychotics. In the study, the risk of olanzapine was comparable to the risk of atypical antipsychotics included in a pooled analysis.

Paediatric population

Olanzapine is not indicated for use in the treatment of children and adolescents. Studies in patients aged 13-17 years showed various adverse reactions, including weight gain, changes in metabolic parameters and increases in prolactin levels. Long-term outcomes associated with these events have not been studied and remain unknown (see sections 4.8 and 5.1).

Lactose

OLANZAPINE CIPLA tablets contain lactose. Patients with rare hereditary problems of galactose authorised

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

4.5 Interaction with other medicinal products and other forms of interaction

Paediatric population

Interaction studies have only been performed in adults.

Potential interactions affecting olanzapine

Since olanzapine is metabolised by CYP1A2, substances that can specifically induce or inhibit this

isoenzyme may affect the pharmacokinetics of olanzapine.

Induction of CYP1A2

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The metabolism of olanzapine may be induced bynosmoking 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).

Fluvoxamine, a specific CYP1A2productinhibitor, has been shown to significantly inhibit the metabolism of olanzapine. The mean increase in olanzapine Cmax following fluvoxamine was 54 % in female non-

Inhibition of CYP1A2

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.

smokers andMedicinal77 % 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

Decreased bioavailability

Activated charcoal reduces the bioavailability of oral olanzapine by 50 to 60% and should be taken at least 2 hours before or after olanzapine.

Fluoxetine (a CYP2D6 inhibitor), single doses of antacid (aluminium, magnesium) or cimetidine have not been found to significantly affect the pharmacokinetics of olanzapine.

Potential for olanzapine to affect other medicinal products

Olanzapine may antagonise the effects of direct and indirect dopamine agonists.

Olanzapine does not inhibit the main CYP450 isoenzymes in vitro (e.g. 1A2, 2D6, 2C9, 2C19, 3A4). Thus no particular interaction is expected as verified through in vivo studies where no inhibition of metabolism of the following active substances was found: tricyclic antidepressant (representing mostly CYP2D6 pathway), warfarin (CYP2C9), theophylline (CYP1A2) or diazepam (CYP3A4 and 2C19).

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

Therapeutic monitoring of valproate plasma levels did not indicate that valproate dosage adjustment is required after the introduction of concomitant olanzapine.

General CNS activity

Caution should be exercised in patients who consume alcohol or receive medicinal products that can cause central nervous system depression.

The concomitant use of olanzapine with anti-Parkinsonian medicinal products in patients with Parkinson's disease and dementia is not recommended (see section 4.4).

QTc interval

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

4.6 Fertility, pregnancy and lactation

Pregnancy

authorised

 

There are no adequate and well-controlled studies in pregnant women. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during treatment with olanzapine. Nevertheless, because human experience is limited, olanzapine should be used in pregnancy only if the potential benefit justifies the potential risk to the foetus.

Neonates exposed to antipsychotics (including olanzapine) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in

 

 

no

severity and duration following delivery. There have beenlongerreports of agitation, hypertonia, hypotonis,

tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be

monitored carefully.

product

 

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 EffectsMedicinalon ability to drive and use machines

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

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, leukopenia, neutropenia (see section 4.4), dyskinesia, orthostatic hypotension, anticholinergic effects, transient asymptomatic elevations of hepatic aminotransferases (see section 4.4), rash, asthenia, fatigue, pyrexia, arthralgia, increased alkaline phosphatase, high gamma glutamyltransferase, high uric acid, high creatine phosphokinase and oedema.

Tabulated list of adverse reactions

The following table lists the adverse reactions and laboratory investigations observed from spontaneous reporting and in clinical trials. Within each frequency grouping, adverse reactions are

presented in order of decreasing seriousness. The frequency terms listed are defined as follows: Very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the data available).

 

 

 

longer

authorised

 

 

no

 

 

product

 

 

Medicinal

 

 

 

 

 

 

 

Very common

Common

 

 

Uncommon

Rare

Blood and the lymphatic system disorders

 

 

 

 

 

Eosinophilia

 

 

 

Thrombocytopenia11

 

Leukopenia10

 

 

 

 

 

Neutropenia10

 

 

 

 

Immune system disorders

 

 

 

 

 

 

 

 

 

 

Hypersensitivity11

 

Metabolism and nutrition disorders

 

 

 

 

Weight gain1

Elevated cholesterol

 

 

Development or

Development or

 

levels2,3

 

 

exacerbation of

exacerbation of

 

Elevated glucose

 

 

diabetes occasionally

diabetes occasionally

 

levels4

 

 

associated with

associated with

 

Elevated triglyceride

 

 

ketoacidosis or coma,

ketoacidosis or coma,

 

levels2,5

 

 

including some fatal

including some fatal

 

Dyskinesia6

 

 

for seizures wereauthorised

 

Glucosuria

 

 

cases (see section 4.4)

cases (see section 4.4)

 

Increased appetite

 

 

Hypothermia12

Nervous system disorders

 

 

 

 

 

Somnolence

Dizziness

 

 

Seizures where in most

Neuroleptic malignant

 

Akathisia6

 

 

cases a history of

syndrome (see section

 

Parkinsonism6

 

 

seizures or risk factors

4.4)12

 

 

 

 

 

longer

Discontinuation

 

 

 

 

 

reported 11Dystonia

 

 

 

 

 

(including

symptoms7, 12

 

 

 

 

 

oculogyration)11

 

 

 

product

 

 

Tardive dyskinesia11

 

 

 

noAmnesia 9

 

 

 

 

 

 

 

 

 

 

Dysarthria

 

Respiratory, thoracic and mediastinal disorders

 

 

 

 

 

 

 

Epistaxis9

 

Cardiac disorders

 

 

 

 

 

 

 

 

 

 

 

Bradycardia

Ventricular

 

 

 

 

 

QTc prolongation (see

tachycardia/fibrillation

 

 

 

 

 

section 4.4)

, sudden death (see

 

 

 

 

 

 

section 4.4)11

Vascular disorders

 

 

 

 

 

 

Orthostatic

 

 

 

 

Thromboembolism

 

hypotensionMedicinal

 

 

 

(including pulmonary

 

 

 

 

 

 

 

 

 

 

 

 

embolism and deep

 

 

 

 

 

 

vein thrombosis) (see

 

 

 

 

 

 

section 4.4)

 

Gastrointestinal disorders

 

 

 

 

 

 

Mild, transient

 

 

Abdominal distension9

Pancreatitis11

 

anticholinergic effects

 

 

 

 

including constipation

 

 

 

 

and dry mouth

 

 

 

 

Hepato-biliary disorders

 

 

 

 

 

 

Transient,

 

 

 

Hepatitis (including

 

asymptomatic

 

 

 

hepatocellular,

 

elevations of hepatic

 

 

 

cholestatic or mixed

 

aminotransferases

 

 

 

liver injury)11

 

 

 

 

 

(ALT, AST), especially in early treatment (see section 4.4)

Skin and subcutaneous tissue disorders

 

Rash

 

 

Photosensitivity

 

 

 

 

 

reaction

 

 

 

 

 

Alopecia

 

Musculoskeletal and connective tissue disorders

 

 

 

 

Arthralgia9

 

 

 

 

Rhabdomyolysis

Renal and urinary disorders

 

 

 

 

 

 

 

 

 

Urinary incontinence,

 

 

 

 

 

urinary retention

 

 

 

 

 

Urinary hesitation11

 

 

 

 

 

 

 

 

 

 

 

 

Reproductive system and breast disorders

 

 

enlargement in malesauthorised

 

 

 

 

 

 

Erectile dysfunction in

 

Amenorrhea

Priapism12

 

males

 

 

Breast enlargement

 

 

Decreased libido in

 

 

Galactorrhea in

 

 

males and females

 

 

females

 

 

 

 

 

Gynaecomastia/breast

 

 

 

 

 

 

 

 

 

Pyrexia10

 

 

 

longer

 

General disorders and administration site conditions

 

 

Asthenia

 

 

 

 

 

 

Fatigue

 

 

 

 

 

 

Oedema

no

 

 

Investigations

 

 

 

 

 

 

 

 

 

 

 

 

Elevated plasma

Increased alkaline

 

 

Increased total

 

prolactin levels8

phosphatase10

 

 

bilirubin

 

 

High creatine

 

 

 

 

 

 

phosphokinase11

 

 

 

 

 

 

High Gamma

 

 

 

 

 

 

Glutamyltransferaseproduct10

 

 

 

 

Medicinal

 

 

 

 

 

 

High Uric Acid 10

 

 

 

 

 

 

 

 

 

 

 

Not known

Pregnancy, puerperium and perinatal conditions

 

 

 

 

 

 

 

 

Drug withdrawal

 

 

 

 

 

 

syndrome neonatal

 

 

 

 

 

 

(see section 4.6)

1 Clinically significant weight gain was observed across all baseline Body Mass Index (BMI) categories. Following short term treatment (median duration 47 days), weight gain ≥ 7% of baseline body weight was very common (22.2 %), ≥ 15 % was common (4.2 %) and ≥ 25 % was uncommon (0.8 %). Patients gaining ≥ 7 %, ≥ 15 % and ≥ 25 % of their baseline body weight with long-term exposure (at least 48 weeks) were very common (64.4 %, 31.7 % and 12.3 % respectively).

2 Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were greater in patients without evidence of lipid dysregulation at baseline.

3 Observed for fasting normal levels at baseline (< 5.17 mmol/l) which increased to high

(≥ 6.2 mmol/l). Changes in total fasting cholesterol levels from borderline at baseline (≥ 5.17 - < 6.2 mmol/l) to high (≥ 6.2 mmol/l) were very common.

4 Observed for fasting normal levels at baseline (< 5.56 mmol/l) which increased to high (≥ 7 mmol/l). Changes in fasting glucose from borderline at baseline (≥ 5.56 - < 7 mmol/l) to high (≥ 7 mmol/l) were very common.

5 Observed for fasting normal levels at baseline (< 1.69 mmol/l) which increased to high

(≥ 2.26 mmol/l). Changes in fasting triglycerides from borderline at baseline (≥ 1.69 mmol/l - < 2.26 mmol/l) to high (≥ 2.26 mmol/l) were very common.

6 In clinical trials, the incidence of Parkinsonism and dystonia in olanzapine-treated patients was numerically higher, but not statistically significantly different from placebo. Olanzapine-treated patients had a lower incidence of Parkinsonism, akathisia and dystonia compared with titrated doses of haloperidol. In the absence of detailed information on the pre-existing history of individual acute and tardive extrapyramidal movement disorders, it cannot 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.

authorised

9 Adverse event identified from clinical trials in the Olanzapine Integrated Database.

10 As assessed by measured values from clinical trials in the Olanzapine Integrated Database.

 

 

no

Adverse event identified from spontaneous post-marketinglongerreporting with frequency determined

utilising the Olanzapine Integrated Database.

 

 

product

 

Adverse event identified from spontaneous post-marketing reporting with frequency estimated at

the upper limit of the 95% confidence interval utilising the Olanzapine Integrated Database.

Long-term exposure (at least 48 weeks)

Additional information on special populations

The proportion of patients who had adverse, clinically significant changes in weight gain, glucose, total/LDL/HDLMedicinalcholesterol 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.

In clinical trials 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

Common: Dry mouth
Gastrointestinal disorders

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 orderauthorisedof decreasing seriousness.

The frequency terms listed are defined as follows: Very common (≥ 1/10), common (≥ 1/100 to < 1/10).

Metabolism and nutrition disorders

Very common: Weight gain13, elevated triglyceride levels14, increased appetite. Common: Elevated cholesterol levels15

Nervous system disorders

Very common: Sedation (including: hypersomnia, lethargy,longersomnolence).

Hepato-biliary disorders

Investigationsno

Very common: Elevations of hepatic aminotransferases (ALT/AST; see section 4.4).

Very common: Decreased total bilirubin,productincreased GGT, elevated plasma prolactin levels16.

13 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.

14 ObservedMedicinalfor 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).

15 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.

16 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 450 mg but survival has also been reported following acute overdose of approximately 2 g of oral olanzapine.

Management

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

 

 

authorised

Pharmacotherapeutic group: diazepines, oxazepines and thiazepines., ATC code: N05A H03.

Pharmacodynamic effects

longer

 

 

 

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 rangenoof receptor affinities (Ki < 100 nM) for serotonin 5

HT , 5 HT , 5 HT ; dopamine D , D , D , D , D ; cholinergic muscarinic receptors M -M ;

adrenergic; and histamine H1 receptors. Animal behavioural studies with olanzapine indicated 5HT, dopamine, and cholinergic antagonism, consistent with the receptor-binding profile. Olanzapine

demonstrated a greater in vitro affinity for serotonin 5HT2 than dopamine D2 receptors and greater 5 HT2 than D2 activity in vivo models. Electrophysiological studies demonstrated that olanzapine

2A/2C 3 6product1 2 3 4 51 5 1

effect indicative of motor side-effects. Unlike some other antipsychotic agents, olanzapine increases responding an “anxiolytic” test.

selectively reduced the firing of mesolimbic (A10) dopaminergic neurons, while having little effect on the striatal (A9)Medicinalpathways involved in motor function. Olanzapine reduced a conditioned avoidance response, a test indicative of antipsychotic activity, at doses below those producing catalepsy, an

In a single oral dose (10 mg) Positron Emission Tomography (PET) study in healthy volunteers, olanzapine produced higher 5 HT2A than dopamine D2 receptor occupancy. In addition, a Single Photon Emission Computed Tomography (SPECT) imaging study in schizophrenic patients revealed that olanzapine-responsive patients had lower striatal D2 occupancy than some other antipsychotic- and risperidone-responsive patients, while being comparable to clozapine-responsive patients.

Clinical efficacy

In two of two placebo and two of three comparator controlled trials with over 2,900 schizophrenic patients presenting with both positive and negative symptoms, olanzapine was associated with statistically significantly greater improvements in negative as well as positive symptoms.

In a multinational, double-blind, comparative study of schizophrenia, schizoaffective, and related disorders which included 1,481 patients with varying degrees of associated depressive symptoms (baseline mean of 16.6 on the Montgomery-Asberg Depression Rating Scale), a prospective secondary analysis of baseline to endpoint mood score change demonstrated a statistically significant improvement (p= 0.001) favouring olanzapine (-6.0) versus haloperidol (-3.1).

In patients with a manic or mixed episode of bipolar disorder, olanzapine demonstrated superior efficacy to placebo and valproate semisodium (divalproex) in reduction of manic symptoms over 3 weeks. Olanzapine also demonstrated comparable efficacy results to haloperidol in terms of the proportion of patients in symptomatic remission from mania and depression at 6 and 12 weeks. In a co-therapy study of patients treated with lithium or valproate for a minimum of 2 weeks, the addition of olanzapine 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.

 

authorised

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 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 valproate was

not statistically significantly superior to lithium or valproate alone in delaying bipolar recurrence, defined according to syndromic (diagnostic) criteria. longer

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, adolescentsno gained significantly more weight compared with adults. The magnitude of changes in fasting total cholesterol, LDL cholesterol, triglycerides, and

5.2 Pharmacokinetic properties

prolactin (see sections 4.4 and 4.8)productwere 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).

Absorption

Olanzapine Medicinalis well absorbed after oral administration, reaching peak plasma concentrations within 5 to 8 hours. The absorption is not affected by food. Absolute oral bioavailability relative to intravenous

administration has not been determined

Distribution

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

about 1000 ng/ml. Olanzapine is bound predominantly to albumin and 1-acid-glycoprotein.

Biotransformation

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.

Elimination

After oral administration, the mean terminal elimination half-life of olanzapine in healthy subjects varied on the basis of age and gender.

In healthy elderly (65 and over) versus non-elderly subjects, the mean elimination half-life was prolonged (51.8 versus 33.8 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).

Renal impairment

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.

Smokers

authorised

 

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.

longer

In a study of Caucasians, Japanese, and Chinesenosubjects, there were no differences in the

 

product

pharmacokinetic parameters among the three populations.

Paediatric population

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

higher average exposure observed in adolescents.

adolescents and adults. In clinical studies, the average olanzapine exposure was approximately 27% higher in adolescents.MedicinalDemographic differences between the adolescents and adults include a lower average body weight and fewer adolescents were smokers. Such factors possibly contribute to the

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 anaemia 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 foetal development and transient decreases in offspring activity levels were seen.

Mutagenicity

authorised

 

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 not carcinogenic.

Tablet core

 

 

longer

6.

PHARMACEUTICAL PARTICULARS

 

6.1

List of excipients

 

no

 

Lactose monohydrate,

 

 

 

 

 

Maize starch

product

 

 

Hydroxypropyl cellulose

 

 

 

 

 

Magnesium stearate

 

 

 

Tablet coat

 

 

 

Opadry II White containing:

 

 

 

 

Medicinal

 

 

 

Hypromellose (E464)

 

 

 

Titanium dioxide (E171)

 

 

 

Lactose monohydrate

 

 

 

Polyethylene glycol 3000

 

 

 

Glycerol triacetate

 

 

 

6.2

Incompatibilities

 

 

 

Not applicable.

 

 

 

6.3Shelf life

3 years

6.4Special precautions for storage

Store in the original package.

Store below 30°C.

6.5Nature 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. MARKETING AUTHORISATION HOLDER

Cipla (EU) Limited

 

 

Hillbrow House

 

authorised

Hillbrow Road

 

 

 

Esher

 

 

 

Surrey

 

 

KT10 9NW

 

 

UK

 

 

 

8.

MARKETING AUTHORISATION NUMBER(S)

 

EU/1/07/426/003 – Olanzapine Cipla – 5 mg – coated tablets – 28 tablets per box

 

 

no

 

EU/1/07/426/004 – Olanzapine Cipla – 5 mg – coatedlongertablets – 56 tablets per box

 

product

 

 

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 14 November 2007

Date of latest renewal: 01 October 2012

10.DATEOF THE TEXTOF REVISION

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMA) http://www.ema.europa.eu/.

1. NAME OF THE MEDICINAL PRODUCT
Olanzapine Cipla 7.5 mg coated tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each coated tablet contains 7.5 mg olanzapine.
Excipient with known effect: Each coated tablet contains 242 mg lactose monohydrate For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM

Coated tablet

White, round, biconvex, coated tablets with ‘OLZ 7.5’ debossing on one side and ‘NEO’ on the other.

4.

CLINICAL PARTICULARS

 

 

authorised

4.1

Therapeutic indications

 

 

 

 

 

Adults

 

 

 

 

Olanzapine is indicated for the treatment of schizophrenia.

 

 

 

 

longer

 

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

patients who have shown an initial treatment response.

 

 

 

no

 

 

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

 

product

 

 

 

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 PosologyMedicinaland 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.

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 patients

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).

Patients with 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

authorised

 

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)

 

no

longer

4.3

Contraindications

 

 

 

 

 

 

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Patients with known risk for narrow-angle glaucoma.

 

4.4

Special warnings and precautions for use

 

 

 

product

 

 

During antipsychoticMedicinaltreatment, improvement in the patient's clinical condition may take several days to some weeks. Patients should be closely monitored during this period.

Dementia-related psychosis and/or behavioural disturbances

Olanzapine is not approved for the treatment of dementia-related psychosis and/or behavioural disturbances and is not recommended for use in this particular group of patients because of an increase in mortality and the risk of cerebrovascular accident. In placebo-controlled clinical trials (6- 12 weeks duration) of elderly patients (mean age 78 years) with dementia-related psychosis and/or disturbed behaviours, there was a 2-fold increase in the incidence of death in olanzapine-treated patients compared to patients treated with placebo (3.5% vs. 1.5%, respectively). The higher incidence of death was not associated with olanzapine dose (mean daily dose 4.4 mg) or duration of treatment. Risk factors that may predispose this patient population to increased mortality include age > 65 years, dysphagia, sedation, malnutrition and dehydration, pulmonary conditions (e.g., pneumonia, with or without aspiration), or concomitant use of benzodiazepines. However, the incidence of death was higher in olanzapine-treated than in placebo-treated patients independent of these risk factors.

In the same clinical trials, cerebrovascular adverse events (CVAE e.g., stroke, transient ischemic attack), including fatalities, were reported. There was a 3-fold increase in CVAE in patients treated with olanzapine compared to patients treated with placebo (1.3% vs. 0.4%, respectively). All

olanzapine- and placebo-treated patients who experienced a cerebrovascular event had pre-existing risk factors. Age > 75 years and vascular/mixed type dementia were identified as risk factors for CVAE in association with olanzapine treatment. The efficacy of olanzapine was not established in these trials.

Parkinson's disease

The use of olanzapine in the treatment of dopamine agonist associated psychosis in patients with Parkinson's disease is not recommended. In clinical trials, worsening of Parkinsonian symptomatology and hallucinations were reported very commonly and more frequently than with placebo (see section 4.8), and olanzapine was not more effective than placebo in the treatment of psychotic symptoms. In these trials, patients were initially required to be stable on the lowest effective dose of anti- Parkinsonian medicinal products (dopamine agonist) and to remain on the same anti-Parkinsonian medicinal products and dosages throughout the study. Olanzapine was started at 2.5 mg/day and titrated to a maximum of 15 mg/day based on investigator judgement.

Neuroleptic Malignant Syndrome (NMS)

authorised

 

NMS is a potentially life-threatening condition associated with antipsychotic medicinal products. 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 belongerdiscontinued.

Hyperglycaemia and diabetes

Hyperglycaemia and/or development or exacerbation of diabetes occasionally associated with ketoacidosis or coma has been reported uncommonly,no including some fatal cases (see section 4.8). In some cases, a prior increase in body weight has been reported which may be a predisposing factor. Appropriate clinical monitoring is advisable in accordance with utilised antipsychotic guidelines, e.g. measuring of blood glucose at baseline, 12 weeks after starting olanzapine treatment and annually thereafter. Patients treated with any antipsychotic agents, including Olanzapine Cipla, should be observed for signs and symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia, and weakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus should be

monitored regularly for worsening of glucose control. Weight should be monitored regularly, e.g. at

 

 

product

baseline, 4, 8 and 12 weeks after starting olanzapine treatment and quarterly thereafter.

Lipid alterations

 

 

Undesirable alterations

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

dyslipidemic patients and in patients with risk factors for the development

Medicinal

 

of lipids disorders. Patients treated with any antipsychotic agents, including Olanzapine Cipla, should be monitored regularly for lipids in accordance with utilised antipsychotic guidelines, e.g. at baseline, 12 weeks after starting olanzapine treatment and every 5 years thereafter.

Anticholinergic activity

While olanzapine demonstrated anticholinergic activity in vitro, experience during the clinical trials revealed a low incidence of related events. However, as clinical experience with olanzapine in patients with concomitant illness is limited, caution is advised when prescribing for patients with prostatic hypertrophy, or paralytic ileus and related conditions.

Hepatic function

Transient, asymptomatic elevations of hepatic 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.

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).

QT interval

authorised

Discontinuation of treatment

 

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

rarely (≥0.01% and < 0.1%) when olanzapine is stopped abruptly.

 

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. longer

Thromboembolism

Temporal association of olanzapine treatment and venous thromboembolism has been reported uncommonly (≥ 0.1% and < 1%). A causal relationship between the occurrence of venous thromboembolism and treatment with olanzapine has not been established. However, since patients

General CNS activity

with schizophrenia often present with acquired risk factors for venous thromboembolism all possible

 

 

no

risk factors of VTE e.g. immobilisation of patients, should be identified and preventive measures

undertaken.

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Given the primary CNS effects of olanzapine, caution should be used when it is taken in combination with other centrallyMedicinalacting 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 uncommonly in patients when treated with olanzapine. In most of these cases, a history of seizures or risk factors for seizures were reported.

Tardive Dyskinesia

In comparator studies of one year or less duration, olanzapine was associated with a statistically significant lower incidence of treatment emergent dyskinesia. However the risk of tardive dyskinesia increases with long term exposure, and therefore if signs or symptoms of tardive dyskinesia appear in a patient on olanzapine, a dose reduction or discontinuation should be considered. These symptoms can temporally deteriorate or even arise after discontinuation of treatment.

Postural hypotension

Postural hypotension was infrequently observed in the elderly in olanzapine clinical trials. As with other antipsychotics, it is recommended that blood pressure is measured periodically in patients over 65 years.

Sudden cardiac death

In postmarketing reports with olanzapine, the event of sudden cardiac death has been reported in patients with olanzapine. In a retrospective observational cohort study, the risk of presumed sudden cardiac death in patients treated with olanzapine was approximately twice the risk in patients not using antipsychotics. In the study, the risk of olanzapine was comparable to the risk of atypical antipsychotics included in a pooled analysis.

Paediatric population

Olanzapine is not indicated for use in the treatment of children and adolescents. Studies in patients aged 13-17 years showed various adverse reactions, including weight gain, changes in metabolic parameters and increases in prolactin levels. Long-term outcomes associated with these events have not been studied and remain unknown (see sections 4.8 and 5.1).

Lactose

OLANZAPINE CIPLA tablets contain lactose. Patients with rare hereditary problems of galactose authorised

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

4.5 Interaction with other medicinal products and other forms of interaction

Paediatric population

Interaction studies have only been performed in adults.

Potential interactions affecting olanzapine

Since olanzapine is metabolised by CYP1A2, substances that can specifically induce or inhibit this

isoenzyme may affect the pharmacokinetics of olanzapine.

Induction of CYP1A2

longer

The metabolism of olanzapine may be induced bynosmoking 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).

Fluvoxamine, a specific CYP1A2productinhibitor, has been shown to significantly inhibit the metabolism of olanzapine. The mean increase in olanzapine Cmax following fluvoxamine was 54 % in female non-

Inhibition of CYP1A2

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.

smokers andMedicinal77 % 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

Decreased bioavailability

Activated charcoal reduces the bioavailability of oral olanzapine by 50 to 60% and should be taken at least 2 hours before or after olanzapine.

Fluoxetine (a CYP2D6 inhibitor), single doses of antacid (aluminium, magnesium) or cimetidine have not been found to significantly affect the pharmacokinetics of olanzapine.

Potential for olanzapine to affect other medicinal products

Olanzapine may antagonise the effects of direct and indirect dopamine agonists.

Olanzapine does not inhibit the main CYP450 isoenzymes in vitro (e.g. 1A2, 2D6, 2C9, 2C19, 3A4). Thus no particular interaction is expected as verified through in vivo studies where no inhibition of metabolism of the following active substances was found: tricyclic antidepressant (representing mostly CYP2D6 pathway), warfarin (CYP2C9), theophylline (CYP1A2) or diazepam (CYP3A4 and 2C19).

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

Therapeutic monitoring of valproate plasma levels did not indicate that valproate dosage adjustment is required after the introduction of concomitant olanzapine.

General CNS activity

Caution should be exercised in patients who consume alcohol or receive medicinal products that can cause central nervous system depression.

The concomitant use of olanzapine with anti-Parkinsonian medicinal products in patients with Parkinson's disease and dementia is not recommended (see section 4.4).

QTc interval

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

4.6 Fertility, pregnancy and lactation

Pregnancy

authorised

 

There are no adequate and well-controlled studies in pregnant women. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during treatment with olanzapine. Nevertheless, because human experience is limited, olanzapine should be used in pregnancy only if the potential benefit justifies the potential risk to the foetus.

Neonates exposed to antipsychotics (including olanzapine) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in

 

 

no

severity and duration following delivery. There have beenlongerreports of agitation, hypertonia, hypotonis,

tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be

monitored carefully.

product

 

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 EffectsMedicinalon ability to drive and use machines

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

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, leukopenia, neutropenia (see section 4.4), dyskinesia, orthostatic hypotension, anticholinergic effects, transient asymptomatic elevations of hepatic aminotransferases (see section 4.4), rash, asthenia, fatigue, pyrexia, arthralgia, increased alkaline phosphatase, high gamma glutamyltransferase, high uric acid, high creatine phosphokinase and oedema.

Tabulated list of adverse reactions

The following table lists the adverse reactions and laboratory investigations observed from spontaneous reporting and in clinical trials. Within each frequency grouping, adverse reactions are

presented in order of decreasing seriousness. The frequency terms listed are defined as follows: Very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the data available).

 

 

 

longer

authorised

 

 

no

 

 

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Medicinal

 

 

 

 

 

 

 

Very common

Common

 

 

Uncommon

 

Rare

Blood and the lymphatic system disorders

 

 

 

 

 

 

Eosinophilia

 

 

 

 

Thrombocytopenia11

 

Leukopenia10

 

 

 

 

 

 

Neutropenia10

 

 

 

 

 

Immune system disorders

 

 

 

 

 

 

 

 

 

Hypersensitivity11

 

 

Metabolism and nutrition disorders

 

 

 

 

 

Weight gain1

Elevated cholesterol

 

 

Development or

 

Hypothermia12

 

levels2,3

 

 

exacerbation of

 

 

 

Elevated glucose

 

 

diabetes occasionally

 

 

levels4

 

 

associated with

 

 

 

Elevated triglyceride

 

 

ketoacidosis or coma,

 

 

levels2,5

 

 

including some fatal

 

 

Dyskinesia6

 

 

for seizures wereauthorisedDiscontinuation

 

Glucosuria

 

 

cases (see section 4.4)

 

 

Increased appetite

 

 

 

 

Nervous system disorders

 

 

 

 

 

Somnolence

Dizziness

 

 

Seizures where in most

Neuroleptic malignant

 

Akathisia6

 

 

cases a history of

 

syndrome (see section

 

Parkinsonism6

 

 

seizures or risk factors

4.4)

 

 

 

 

longer

symptoms7, 12

 

 

 

 

reported 11

 

 

 

 

 

Dystonia (including

 

 

 

 

 

oculogyration)11

 

 

 

product

 

 

Tardive dyskinesia

 

 

 

noAmnesia 9

 

 

 

 

 

 

 

 

 

 

Dysarthria

 

 

 

 

 

 

 

Respiratory, thoracic and mediastinal disorders

 

 

 

 

 

 

 

Epistaxis9

 

 

Cardiac disorders

 

 

 

 

 

 

 

 

 

 

Bradycardia

 

Ventricular

 

 

 

 

QTc prolongation (see

tachycardia/fibrillation

 

 

 

 

section 4.4)

 

, sudden death (see

 

 

 

 

 

 

section 4.4)11

Vascular disorders

 

 

 

 

 

 

Medicinal

 

 

 

 

Orthostatic 10

 

 

 

Thromboembolism

 

hypotension

 

 

 

(including pulmonary

 

 

 

 

 

embolism and deep

 

 

 

 

 

vein thrombosis) (see

 

 

 

 

 

section 4.4)

 

 

Gastrointestinal disorders

 

 

 

 

 

 

Mild, transient

 

 

Abdominal distension9

Pancreatitis11

 

anticholinergic effects

 

 

 

 

 

including constipation

 

 

 

 

 

and dry mouth

 

 

 

 

 

Hepato-biliary disorders

 

 

 

 

 

 

Transient,

 

 

 

 

Hepatitis (including

 

asymptomatic

 

 

 

 

hepatocellular,

 

elevations of hepatic

 

 

 

 

cholestatic or mixed

 

aminotransferases

 

 

 

 

liver injury)11

 

 

 

 

 

(ALT, AST), especially in early treatment (see section 4.4)

Skin and subcutaneous tissue disorders

 

Rash

 

Photosensitivity

 

 

 

 

reaction

 

 

 

 

Alopecia

 

Musculoskeletal and connective tissue disorders

 

 

 

Arthralgia9

 

 

Rhabdomyolysis11

Renal and urinary disorders

 

 

 

 

 

Urinary incontinence,

Urinary hesitation

 

 

 

urinary retention

 

 

 

 

Urinary hesitation11

 

 

 

 

 

 

 

 

 

Reproductive system and breast disorders

 

 

 

Erectile dysfunction in

 

Amenorrhea

Priapism12

 

males

 

Breast enlargement

 

 

Decreased libido in

 

Galactorrhea in

 

 

males and females

 

females

 

 

 

 

Gynaecomastia/breast

 

 

 

 

enlargement in malesauthorised

General disorders and administration site conditions

 

 

Asthenia

 

longer

 

 

Fatigue

 

 

 

Oedema

 

 

 

Pyrexia10

 

 

Investigations

 

 

no

Elevated plasma

Increased alkaline

 

 

Increased total

 

prolactin levels8

phosphatase10

 

 

bilirubin

 

 

High creatine

 

 

 

 

 

phosphokinase11

 

 

 

 

 

High Gamma

 

 

 

 

 

 

 

 

 

Glutamyltransferaseproduct

 

 

 

 

High Uric Acid 10

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Not known

Pregnancy, puerperium and perinatal conditions

Medicinal

 

 

 

Drug withdrawal

 

 

 

syndrome neonatal

 

 

 

(see section 4.6)

1 Clinically significant weight gain was observed across all baseline Body Mass Index (BMI) categories. Following short term treatment (median duration 47 days), weight gain ≥ 7% of baseline body weight was very common (22.2 %), ≥ 15 % was common (4.2 %) and ≥ 25 % was uncommon (0.8 %). Patients gaining ≥ 7 %, ≥ 15 % and ≥ 25 % of their baseline body weight with long-term exposure (at least 48 weeks) were very common (64.4 %, 31.7 % and 12.3 % respectively).

2 Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were greater in patients without evidence of lipid dysregulation at baseline.

3 Observed for fasting normal levels at baseline (< 5.17 mmol/l) which increased to high

(≥ 6.2 mmol/l). Changes in total fasting cholesterol levels from borderline at baseline (≥ 5.17 - < 6.2 mmol/l) to high (≥ 6.2 mmol/l) were very common.

4 Observed for fasting normal levels at baseline (< 5.56 mmol/l) which increased to high (≥ 7 mmol/l). Changes in fasting glucose from borderline at baseline (≥ 5.56 - < 7 mmol/l) to high (≥ 7 mmol/l) were very common.

5 Observed for fasting normal levels at baseline (< 1.69 mmol/l) which increased to high

(≥ 2.26 mmol/l). Changes in fasting triglycerides from borderline at baseline (≥ 1.69 mmol/l - < 2.26 mmol/l) to high (≥ 2.26 mmol/l) were very common.

6 In clinical trials, the incidence of Parkinsonism and dystonia in olanzapine-treated patients was numerically higher, but not statistically significantly different from placebo. Olanzapine-treated patients had a lower incidence of Parkinsonism, akathisia and dystonia compared with titrated doses of haloperidol. In the absence of detailed information on the pre-existing history of individual acute and

tardive extrapyramidal movement disorders, it cannot be concluded at present that olanzapine produces

less tardive dyskinesia and/or other tardive extrapyramidal syndromes.

 

authorised

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.

9 Adverse event identified from clinical trials in the Olanzapine Integrated Database.

As assessed by measured values from clinical trials in the Olanzapine Integrated Database.

 

 

 

longer

Adverse event identified from spontaneous post-marketing reporting with frequency determined

 

utilising the Olanzapine Integrated Database.

 

 

 

no

 

Adverse event identified from spontaneous post-marketing reporting with frequency estimated at

 

the upper limit of the 95% confidence interval utilising the Olanzapine Integrated Database.

 

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Long-term exposureMedicinal(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 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 (≥ 1/10), common (≥ 1/100 to

< 1/10).

Metabolism and nutrition disorders

 

 

Very common: Weight gain13, elevated triglyceride levels14, increased appetite.

Common: Elevated cholesterol levels15

longer

authorised

 

 

 

Nervous system disorders

Very common: Sedation (including: hypersomnia, lethargy, somnolence).

Gastrointestinal disorders

Common: Dry mouth

Hepato-biliary disorders

product

 

Very common: Elevations of hepatic aminotransferasesno

(ALT/AST; see section 4.4).

Investigations

 

 

Very common: Decreased total bilirubin, increased GGT, elevated plasma prolactin levels16.

13 Following short term treatment (median duration 22 days), weight gain ≥ 7 % of baseline body

14 Observed for fasting normal levels at baseline (< 1.016 mmol/l) which increased to high

weight (kg) was very common (40.6 %), ≥ 15 % of baseline body weight was common (7.1 %) and ≥ 25 % was commonMedicinal(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.

(≥ 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).

15 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.

16 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 450 mg but survival has also been reported following acute overdose of approximately 2 g of oral olanzapine.

Management

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. Cardiovascularauthorisedmonitoring 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: N05A H03.

Pharmacodynamic effects

no

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

pharmacologic profile across a number of receptor systems.

product

 

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; 1 adrenergic; and histamine H1 receptors. Animal behavioural studies with olanzapine indicated 5HT,

dopamine, and cholinergic antagonism, consistent with the receptor-binding profile. Olanzapine

demonstrated a greater in vitro affinity for serotonin 5HT2 than dopamine D2 receptors and greater 5

Medicinal

HT2 than D2 activity

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 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 Single Photon Emission Computed Tomography (SPECT) imaging study in schizophrenic patients revealed that olanzapine-responsive patients had lower striatal D2 occupancy than some other antipsychotic- and risperidone-responsive patients, while being comparable to clozapine-responsive patients.

Clinical efficacy

In two of two placebo and two of three comparator controlled trials with over 2,900 schizophrenic patients presenting with both positive and negative symptoms, olanzapine was associated with statistically significantly greater improvements in negative as well as positive symptoms.

In a multinational, double-blind, comparative study of schizophrenia, schizoaffective, and related disorders which included 1,481 patients with varying degrees of associated depressive symptoms (baseline mean of 16.6 on the Montgomery-Asberg Depression Rating Scale), a prospective secondary

analysis of baseline to endpoint mood score change demonstrated a statistically significant improvement (p= 0.001) favouring olanzapine (-6.0) versus haloperidol (-3.1).

In patients with a manic or mixed episode of bipolar disorder, olanzapine demonstrated superior efficacy to placebo and valproate semisodium (divalproex) in reduction of manic symptoms over 3 weeks. Olanzapine also demonstrated comparable efficacy results to haloperidol in terms of the proportion of patients in symptomatic remission from mania and depression at 6 and 12 weeks. In a co-therapy study of patients treated with lithium or valproate for a minimum of 2 weeks, the addition of olanzapine 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.

authorised

 

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 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

no

longer

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 wasproductused 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 PharmacokineticMedicinalproperties

Absorption

Olanzapine is well absorbed after oral administration, reaching peak plasma concentrations within 5 to 8 hours. The absorption is not affected by food. Absolute oral bioavailability relative to intravenous administration has not been determined

Distribution

The plasma protein binding of olanzapine was about 93 % over the concentration range of about 7 to about 1000 ng/ml. Olanzapine is bound predominantly to albumin and 1-acid-glycoprotein.

Biotransformation

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.

Elimination

After oral administration, the mean terminal elimination half-life of olanzapine in healthy subjects varied on the basis of age and gender.

In healthy elderly (65 and over) versus non-elderly subjects, the mean elimination half-life was prolonged (51.8 versus 33.8 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).

Renal impairment

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.

authorised

 

Smokers

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

Paediatric population

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 smalllongerin comparison to the overall variability

between individuals.

 

no

 

 

In a study of Caucasians, Japanese, and Chinese subjects, there were no differences in the

pharmacokinetic parameters among the three populations.

 

product

 

average body weight and fewer adolescents were smokers. Such factors possibly contribute to the higher average exposure observed in adolescents.

Adolescents (ages 13 to 17 years): The pharmacokinetics of olanzapine are similar between adolescents Medicinaland adults. In clinical studies, the average olanzapine exposure was approximately 27% higher in adolescents. Demographic differences between the adolescents and adults include a lower

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 anaemia 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 foetal development and transient decreases in offspring activity levels were seen.

Mutagenicity

authorised

 

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 not carcinogenic.

6.

PHARMACEUTICAL PARTICULARS

longer

 

6.1

List of excipients

 

no

 

Tablet core

 

 

 

 

 

 

 

Lactose monohydrate,

product

 

 

Maize starch

 

 

 

 

 

Hydroxypropyl cellulose

 

 

 

Magnesium stearate

 

 

 

Tablet coat

Medicinal

 

 

 

Opadry II White containing:

 

 

 

Hypromellose (E464)

 

 

 

Titanium dioxide (E171)

 

 

 

Lactose monohydrate

 

 

 

Polyethylene glycol 3000

 

 

 

Glycerol triacetate

 

 

 

6.2

Incompatibilities

 

 

 

Not applicable.

 

 

 

6.3Shelf life

3 years

6.4Special precautions for storage

Store in the original package.

Store below 30°C.

6.5Nature 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. MARKETING AUTHORISATION HOLDER

Cipla (EU) Limited

 

 

Hillbrow House

 

authorised

Hillbrow Road

 

 

 

Esher

 

 

 

Surrey

 

 

KT10 9NW

 

 

UK

 

 

 

8.

MARKETING AUTHORISATION NUMBER(S)

 

EU/1/07/426/005 – Olanzapine Cipla – 7.5 mg – coated tablets – 28 tablets per box

 

 

no

 

EU/1/07/426/006 – Olanzapine Cipla – 7.5 mg – coatedlongertablets – 56 tablets per box

 

product

 

 

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 14 November 2007

Date of latest renewal: 01 October 2012

10.DATEOF THE TEXTOF REVISION

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMA) http://www.ema.europa.eu/.

1. NAME OF THE MEDICINAL PRODUCT

Olanzapine Cipla 10 mg coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each coated tablet contains 10 mg olanzapine.

Excipient with known effect: Each coated tablet contains 322.6 mg lactose monohydrate

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

authorised

Coated tablet

 

White, round, biconvex, coated tablets with ‘OLZ 10’ debossing on one side and ‘NEO’ on the other.

4.

CLINICAL PARTICULARS

 

 

4.1

Therapeutic indications

 

longer

Adults

 

 

 

 

 

Olanzapine is indicated for the treatment of schizophrenia.

 

 

no

 

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

patients who have shown an initial treatment response.

 

product

 

 

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 PosologyMedicinaland 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.

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 patients

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).

Patients with 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

authorised

 

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)

 

no

longer

4.3

Contraindications

 

 

 

 

 

 

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Patients with known risk for narrow-angle glaucoma.

 

4.4

Special warnings and precautions for use

 

 

 

product

 

 

During antipsychoticMedicinaltreatment, improvement in the patient's clinical condition may take several days to some weeks. Patients should be closely monitored during this period.

Dementia-related psychosis and/or behavioural disturbances

Olanzapine is not approved for the treatment of dementia-related psychosis and/or behavioural disturbances and is not recommended for use in this particular group of patients because of an increase in mortality and the risk of cerebrovascular accident. In placebo-controlled clinical trials (6- 12 weeks duration) of elderly patients (mean age 78 years) with dementia-related psychosis and/or disturbed behaviours, there was a 2-fold increase in the incidence of death in olanzapine-treated patients compared to patients treated with placebo (3.5% vs. 1.5%, respectively). The higher incidence of death was not associated with olanzapine dose (mean daily dose 4.4 mg) or duration of treatment. Risk factors that may predispose this patient population to increased mortality include age > 65 years, dysphagia, sedation, malnutrition and dehydration, pulmonary conditions (e.g., pneumonia, with or without aspiration), or concomitant use of benzodiazepines. However, the incidence of death was higher in olanzapine-treated than in placebo-treated patients independent of these risk factors.

In the same clinical trials, cerebrovascular adverse events (CVAE e.g., stroke, transient ischemic attack), including fatalities, were reported. There was a 3-fold increase in CVAE in patients treated with olanzapine compared to patients treated with placebo (1.3% vs. 0.4%, respectively). All

olanzapine- and placebo-treated patients who experienced a cerebrovascular event had pre-existing risk factors. Age > 75 years and vascular/mixed type dementia were identified as risk factors for CVAE in association with olanzapine treatment. The efficacy of olanzapine was not established in these trials.

Parkinson's disease

The use of olanzapine in the treatment of dopamine agonist associated psychosis in patients with Parkinson's disease is not recommended. In clinical trials, worsening of Parkinsonian symptomatology and hallucinations were reported very commonly and more frequently than with placebo (see section 4.8), and olanzapine was not more effective than placebo in the treatment of psychotic symptoms. In these trials, patients were initially required to be stable on the lowest effective dose of anti- Parkinsonian medicinal products (dopamine agonist) and to remain on the same anti-Parkinsonian medicinal products and dosages throughout the study. Olanzapine was started at 2.5 mg/day and titrated to a maximum of 15 mg/day based on investigator judgement.

Neuroleptic Malignant Syndrome (NMS)

authorised

 

NMS is a potentially life-threatening condition associated with antipsychotic medicinal products. 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 belongerdiscontinued.

Hyperglycaemia and diabetes

Hyperglycaemia and/or development or exacerbation of diabetes occasionally associated with ketoacidosis or coma has been reported uncommonly,no including some fatal cases (see section 4.8). In some cases, a prior increase in body weight has been reported which may be a predisposing factor. Appropriate clinical monitoring is advisable in accordance with utilised antipsychotic guidelines, e.g. measuring of blood glucose at baseline, 12 weeks after starting olanzapine treatment and annually thereafter. Patients treated with any antipsychotic agents, including Olanzapine Cipla, should be observed for signs and symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia, and weakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus should be

monitored regularly for worsening of glucose control. Weight should be monitored regularly, e.g. at

 

 

product

baseline, 4, 8 and 12 weeks after starting olanzapine treatment and quarterly thereafter.

Lipid alterations

 

 

Undesirable alterations

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

dyslipidemic patients and in patients with risk factors for the development

Medicinal

 

of lipids disorders. Patients treated with any antipsychotic agents, including Olanzapine Cipla, should be monitored regularly for lipids in accordance with utilised antipsychotic guidelines, e.g. at baseline, 12 weeks after starting olanzapine treatment and every 5 years thereafter.

Anticholinergic activity

While olanzapine demonstrated anticholinergic activity in vitro, experience during the clinical trials revealed a low incidence of related events. However, as clinical experience with olanzapine in patients with concomitant illness is limited, caution is advised when prescribing for patients with prostatic hypertrophy, or paralytic ileus and related conditions.

Hepatic function

Transient, asymptomatic elevations of hepatic 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.

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).

QT interval

authorised

Discontinuation of treatment

 

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

rarely (≥ 0.01% and < 0.1%) when olanzapine is stopped abruptly.

 

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. longer

Thromboembolism

Temporal association of olanzapine treatment and venous thromboembolism has been reported uncommonly (≥ 0.1% and < 1%). A causal relationship between the occurrence of venous thromboembolism and treatment with olanzapine has not been established. However, since patients

General CNS activity

with schizophrenia often present with acquired risk factors for venous thromboembolism all possible

 

 

no

risk factors of VTE e.g. immobilisation of patients, should be identified and preventive measures

undertaken.

product

 

 

 

Given the primary CNS effects of olanzapine, caution should be used when it is taken in combination with other centrallyMedicinalacting 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 uncommonly in patients when treated with olanzapine. In most of these cases, a history of seizures or risk factors for seizures were reported.

Tardive Dyskinesia

In comparator studies of one year or less duration, olanzapine was associated with a statistically significant lower incidence of treatment emergent dyskinesia. However the risk of tardive dyskinesia increases with long term exposure, and therefore if signs or symptoms of tardive dyskinesia appear in a patient on olanzapine, a dose reduction or discontinuation should be considered. These symptoms can temporally deteriorate or even arise after discontinuation of treatment.

Postural hypotension

Postural hypotension was infrequently observed in the elderly in olanzapine clinical trials. As with other antipsychotics, it is recommended that blood pressure is measured periodically in patients over 65 years.

Sudden cardiac death

In postmarketing reports with olanzapine, the event of sudden cardiac death has been reported in patients with olanzapine. In a retrospective observational cohort study, the risk of presumed sudden cardiac death in patients treated with olanzapine was approximately twice the risk in patients not using antipsychotics. In the study, the risk of olanzapine was comparable to the risk of atypical antipsychotics included in a pooled analysis.

Paediatric population

Olanzapine is not indicated for use in the treatment of children and adolescents. Studies in patients aged 13-17 years showed various adverse reactions, including weight gain, changes in metabolic parameters and increases in prolactin levels. Long-term outcomes associated with these events have not been studied and remain unknown (see sections 4.8 and 5.1).

Lactose

OLANZAPINE CIPLA tablets contain lactose. Patients with rare hereditary problems of galactose authorised

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

4.5 Interaction with other medicinal products and other forms of interaction

Paediatric population

Interaction studies have only been performed in adults.

Potential interactions affecting olanzapine

Since olanzapine is metabolised by CYP1A2, substances that can specifically induce or inhibit this

isoenzyme may affect the pharmacokinetics of olanzapine.

Induction of CYP1A2

longer

The metabolism of olanzapine may be induced bynosmoking 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).

Fluvoxamine, a specific CYP1A2productinhibitor, has been shown to significantly inhibit the metabolism of olanzapine. The mean increase in olanzapine Cmax following fluvoxamine was 54 % in female non-

Inhibition of CYP1A2

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.

smokers andMedicinal77 % 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

Decreased bioavailability

Activated charcoal reduces the bioavailability of oral olanzapine by 50 to 60% and should be taken at least 2 hours before or after olanzapine.

Fluoxetine (a CYP2D6 inhibitor), single doses of antacid (aluminium, magnesium) or cimetidine have not been found to significantly affect the pharmacokinetics of olanzapine.

Potential for olanzapine to affect other medicinal products

Olanzapine may antagonise the effects of direct and indirect dopamine agonists.

Olanzapine does not inhibit the main CYP450 isoenzymes in vitro (e.g. 1A2, 2D6, 2C9, 2C19, 3A4). Thus no particular interaction is expected as verified through in vivo studies where no inhibition of metabolism of the following active substances was found: tricyclic antidepressant (representing mostly CYP2D6 pathway), warfarin (CYP2C9), theophylline (CYP1A2) or diazepam (CYP3A4 and 2C19).

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

Therapeutic monitoring of valproate plasma levels did not indicate that valproate dosage adjustment is required after the introduction of concomitant olanzapine.

General CNS activity

Caution should be exercised in patients who consume alcohol or receive medicinal products that can cause central nervous system depression.

The concomitant use of olanzapine with anti-Parkinsonian medicinal products in patients with Parkinson's disease and dementia is not recommended (see section 4.4).

QTc interval

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

4.6 Fertility, pregnancy and lactation

Pregnancy

authorised

 

There are no adequate and well-controlled studies in pregnant women. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during treatment with olanzapine. Nevertheless, because human experience is limited, olanzapine should be used in pregnancy only if the potential benefit justifies the potential risk to the foetus.

Neonates exposed to antipsychotics (including olanzapine) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in

 

 

no

severity and duration following delivery. There have beenlongerreports of agitation, hypertonia, hypotonis,

tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be

monitored carefully.

product

 

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 EffectsMedicinalon ability to drive and use machines

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

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, leukopenia, neutropenia (see section 4.4), dyskinesia, orthostatic hypotension, anticholinergic effects, transient asymptomatic elevations of hepatic aminotransferases (see section 4.4), rash, asthenia, fatigue, pyrexia, arthralgia, increased alkaline phosphatase, high gamma glutamyltransferase, high uric acid, high creatine phosphokinase and oedema.

Tabulated list of adverse reactions

The following table lists the adverse reactions and laboratory investigations observed from spontaneous reporting and in clinical trials. Within each frequency grouping, adverse reactions are

presented in order of decreasing seriousness. The frequency terms listed are defined as follows: Very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the data available).

 

 

 

longer

authorised

 

 

no

 

 

product

 

 

Medicinal

 

 

 

 

 

 

 

Very common

Common

 

 

Uncommon

 

Rare

Blood and the lymphatic system disorders

 

 

 

 

 

 

Eosinophilia

 

 

 

 

Thrombocytopenia11

 

Leukopenia10

 

 

 

 

 

 

Neutropenia10

 

 

 

 

 

Immune system disorders

 

 

 

 

 

 

 

 

 

Hypersensitivity11

 

 

Metabolism and nutrition disorders

 

 

 

 

 

Weight gain1

Elevated cholesterol

 

 

Development or

 

Hypothermia12

 

levels2,3

 

 

exacerbation of

 

 

 

Elevated glucose

 

 

diabetes occasionally

 

 

levels4

 

 

associated with

 

 

 

Elevated triglyceride

 

 

ketoacidosis or coma,

 

 

levels2,5

 

 

including some fatal

 

 

Dyskinesia6

 

 

for seizures wereauthorised

 

Glucosuria

 

 

cases (see section 4.4)

 

 

Increased appetite

 

 

 

 

Nervous system disorders

 

 

 

 

 

Somnolence

Dizziness

 

 

Seizures where in most

Neuroleptic malignant

 

Akathisia6

 

 

cases a history of

 

syndrome (see section

 

Parkinsonism6

 

 

seizures or risk factors

4.4)12

 

 

 

 

longer

Discontinuation

 

 

 

 

reported11

 

 

 

 

 

Dystonia (including

symptoms7, 12

 

 

 

 

 

 

 

 

 

oculogyration)11

 

 

 

product

 

 

Tardive dyskinesia

 

 

 

noAmnesia 9

 

 

 

 

 

 

 

 

 

 

Dysarthria

 

 

 

 

 

 

 

Respiratory, thoracic and mediastinal disorders

 

 

 

 

 

 

 

Epistaxis9

 

 

Cardiac disorders

 

 

 

 

 

 

 

 

 

 

Bradycardia

 

Ventricular

 

 

 

 

QTc prolongation (see

tachycardia/fibrillation

 

 

 

 

section 4.4)

 

, sudden death (see

 

 

 

 

 

 

section 4.4)11

Vascular disorders

 

 

 

 

 

 

Medicinal

 

 

 

 

Orthostatic 10

 

 

 

Thromboembolism

 

hypotension

 

 

 

(including pulmonary

 

 

 

 

 

embolism and deep

 

 

 

 

 

vein thrombosis) (see

 

 

 

 

 

section 4.4)

 

 

Gastrointestinal disorders

 

 

 

 

 

 

Mild, transient

 

 

Abdominal distension9

Pancreatitis11

 

anticholinergic effects

 

 

 

 

 

including constipation

 

 

 

 

 

and dry mouth

 

 

 

 

 

Hepato-biliary disorders

 

 

 

 

 

 

Transient,

 

 

 

 

Hepatitis (including

 

asymptomatic

 

 

 

 

hepatocellular,

 

elevations of hepatic

 

 

 

 

cholestatic or mixed

 

aminotransferases

 

 

 

 

liver injury)11

 

 

 

 

 

Very common

Common

 

 

 

Uncommon

Rare

 

(ALT, AST),

 

 

 

 

 

 

 

especially in early

 

 

 

 

 

 

 

treatment (see section

 

 

 

 

 

 

4.4)

 

 

 

 

 

 

Skin and subcutaneous tissue disorders

 

 

 

 

 

 

 

Rash

 

 

 

Photosensitivity

 

 

 

 

 

 

reaction

 

 

 

 

 

 

Alopecia

 

Musculoskeletal and connective tissue disorders

 

 

 

 

Arthralgia9

 

 

 

 

 

Rhabdomyolysis11

Renal and urinary disorders

 

 

 

 

 

 

 

 

 

 

 

Urinary incontinence,

 

 

 

 

 

 

urinary retention

 

 

 

 

 

 

Urinary hesitation11

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Reproductive system and breast disorders

 

 

 

 

 

 

Erectile dysfunction in

 

Amenorrhea

Priapism12

 

males

 

 

 

Breast enlargement

 

 

Decreased libido in

 

 

Galactorrhea in

 

 

males and females

 

 

 

females

 

 

 

 

 

 

Gynaecomastia/breastauthorised

 

 

 

 

 

enlargement in males

 

General disorders and administration site conditions

 

 

Asthenia

 

 

 

 

longer

 

 

Fatigue

 

no

 

 

Oedema

 

 

 

 

 

 

 

Pyrexia10

 

 

 

Investigations

 

 

 

 

 

 

 

Elevated plasma

Increased alkaline

 

 

 

Increased total

 

prolactin levels8

phosphatase10

 

 

 

bilirubin

 

 

High creatine

 

 

 

 

 

 

 

phosphokinase11

 

 

 

 

 

 

 

High Gammaproduct

 

 

 

 

 

 

Glutamyltransferase

 

 

 

 

 

 

High Uric Acid 10

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Not known

Pregnancy, puerperium and perinatal conditions

 

 

Medicinal

 

 

 

 

 

Drug withdrawal

 

 

 

 

 

syndrome neonatal

 

 

 

 

 

 

 

(see section 4.6)

1 Clinically significant weight gain was observed across all baseline Body Mass Index (BMI) categories. Following short term treatment (median duration 47 days), weight gain ≥ 7% of baseline body weight was very common (22.2 %), ≥ 15 % was common (4.2 %) and ≥ 25 % was uncommon (0.8 %). Patients gaining ≥ 7 %, ≥ 15 % and ≥ 25 % of their baseline body weight with long-term exposure (at least 48 weeks) were very common (64.4 %, 31.7 % and 12.3 % respectively).

2 Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were greater in patients without evidence of lipid dysregulation at baseline.

3 Observed for fasting normal levels at baseline (< 5.17 mmol/l) which increased to high

(≥ 6.2 mmol/l). Changes in total fasting cholesterol levels from borderline at baseline (≥ 5.17 - < 6.2 mmol/l) to high (≥ 6.2 mmol/l) were very common.

4 Observed for fasting normal levels at baseline (< 5.56 mmol/l) which increased to high (≥ 7 mmol/l). Changes in fasting glucose from borderline at baseline (≥ 5.56 - < 7 mmol/l) to high (≥ 7 mmol/l) were very common.

5 Observed for fasting normal levels at baseline (< 1.69 mmol/l) which increased to high

(≥ 2.26 mmol/l). Changes in fasting triglycerides from borderline at baseline (≥ 1.69 mmol/l - < 2.26 mmol/l) to high (≥ 2.26 mmol/l) were very common.

6 In clinical trials, the incidence of Parkinsonism and dystonia in olanzapine-treated patients was numerically higher, but not statistically significantly different from placebo. Olanzapine-treated

patients had a lower incidence of Parkinsonism, akathisia and dystonia compared with titrated doses of haloperidol. In the absence of detailed information on the pre-existingauthorisedhistory of individual acute and

tardive extrapyramidal movement disorders, it cannot 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 treatedlongerpatients 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.

 

 

 

no

As assessed by measured values from clinical trials in the Olanzapine Integrated Database.

 

 

product

 

Adverse event identified from spontaneous post-marketing reporting with frequency determined

 

utilising the Olanzapine Integrated Database.

 

Adverse event identified from spontaneous post-marketing reporting with frequency estimated at

 

Medicinal

 

 

 

the upper limit of the 95% confidence interval utilising the Olanzapine Integrated Database.

-12

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 (≥ 1/10), common (≥ 1/100 to

< 1/10).

authorised

 

 

longer

Nervous system disorders

 

 

Very common: Sedation (including: hypersomnia, lethargy, somnolence).

 

no

 

Gastrointestinal disorders

 

 

Common: Dry mouth

 

 

Metabolism and nutrition disorders

Very common: Weight gain13, elevated triglyceride levels14, increased appetite. Common: Elevated cholesterol levels15

Hepato-biliary disorders

Very common: Elevations of hepaticproductaminotransferases (ALT/AST; see section 4.4).

Investigations

Very common: Decreased total bilirubin, increased GGT, elevated plasma prolactin levels16.

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.

13 FollowingMedicinalshort 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 ≥

14 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).

15 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.

16 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 450 mg but survival has also been reported following acute overdose of approximately 2 g of oral olanzapine.

Management

There is no specific antidote for olanzapine. Induction of emesis is not recommended. Standard procedures for management of overdose may be indicated (i.e. gastricauthorisedlavage, 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 longer

necessary to detect possible arrhythmias. Close medical supervision and monitoring should continue until the patient recovers.

5. PHARMACOLOGICAL PROPERTIESnoPharmacodynamic properties5.1

Pharmacotherapeutic group: diazepines,productoxazepines and thiazepines., ATC code: N05A H03.

Pharmacodynamic effects

Olanzapine is an antipsychotic, antimanic and mood stabilising agent that demonstrates a broad pharmacologicMedicinalprofile across 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; 1 adrenergic; and histamine H1 receptors. Animal behavioural studies with olanzapine indicated 5HT,

dopamine, and cholinergic antagonism, consistent with the receptor-binding profile. Olanzapine demonstrated greater 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 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 HT2A than dopamine D2 receptor occupancy. In addition, a Single Photon Emission Computed Tomography (SPECT) imaging study in schizophrenic patients revealed that olanzapine-responsive patients had lower striatal D2 occupancy than some other antipsychotic- and risperidone-responsive patients, while being comparable to clozapine-responsive patients.

Clinical efficacy

In two of two placebo and two of three comparator controlled trials with over 2,900 schizophrenic patients presenting with both positive and negative symptoms, olanzapine was associated with statistically significantly greater improvements in negative as well as positive symptoms.

In a multinational, double-blind, comparative study of schizophrenia, schizoaffective, and related disorders which included 1,481 patients with varying degrees of associated depressive symptoms (baseline mean of 16.6 on the Montgomery-Asberg Depression Rating Scale), a prospective secondary analysis of baseline to endpoint mood score change demonstrated a statistically significant improvement (p= 0.001) favouring olanzapine (-6.0) versus haloperidol (-3.1).

In patients with a manic or mixed episode of bipolar disorder, olanzapine demonstrated superior efficacy to placebo and valproate semisodium (divalproex) in reduction of manic symptoms over 3 weeks. Olanzapine also demonstrated comparable efficacy results to haloperidol in terms of the proportion of patients in symptomatic remission from mania and depression at 6 and 12 weeks. In a

co-therapy study of patients treated with lithium or valproate for a minimum of 2 weeks, the addition of olanzapine 10 mg (co-therapy with lithium or valproate) resulted inauthorisedgreater 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.

alone, olanzapine was statistically non-inferior to lithiumongel therprimary endpoint of bipolar recurrence (olanzapine 30.0%, lithium 38.3%; pno= 0.055).

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

In an 18-month co-therapy study in manic or mixed episode patients stabilised with olanzapine plus a mood stabiliser (lithium or valproate),productlong-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

200 adolescents. Olanzapine was used as a flexible dose starting with 2.5 and ranging up to

The experienceMedicinaladolescents (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

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).

5.2Pharmacokinetic properties

Absorption

Olanzapine is well absorbed after oral administration, reaching peak plasma concentrations within 5 to 8 hours. The absorption is not affected by food. Absolute oral bioavailability relative to intravenous administration has not been determined

Distribution

The plasma protein binding of olanzapine was about 93 % over the concentration range of about 7 to about 1000 ng/ml. Olanzapine is bound predominantly to albumin and 1-acid-glycoprotein.

Biotransformation

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.

Elimination

After oral administration, the mean terminal elimination half-life of olanzapine in healthy subjects varied on the basis of age and gender.

In healthy elderly (65 and over) versus non-elderly subjects, the mean elimination half-life was prolonged (51.8 versus 33.8 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).

Renal impairment

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) 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.

longer

authorised

 

Smokers

 

14.1 l/hr, respectively).

 

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

In non-smoking versus smoking subjects (males noand females) the mean elimination half-life was prolonged (38.6 versus 30.4 hr) productand 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

In a study of Caucasians, Japanese, and Chinese subjects, there were no differences in the pharmacokinetic parameters among the three populations.

smoking on olanzapine clearance and half-life is small in comparison to the overall variability between individuals.Medicinal

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.

5.3Preclinical 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

anaemia 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

authorised

 

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 foetal development and transient decreases in offspring activity levels were seen.

Mutagenicity

Olanzapine was not mutagenic or clastogenic in a full range of standard tests, which included bacterial mutation tests and in vitro and in vivo mammalian tests.

Carcinogenicity

 

no

longer

Based on the results of studies in mice and rats, it was concluded that olanzapine is not carcinogenic.

 

 

 

product

 

 

6.

PHARMACEUTICAL PARTICULARS

 

6.1

List of excipients

 

 

 

Tablet core

Medicinal

 

 

 

 

 

 

 

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

6.2Incompatibilities

Not applicable.

6.3Shelf 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 7, 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.

 

 

authorised

 

 

 

7.

MARKETING AUTHORISATION HOLDER

 

Cipla (EU) Limited

 

 

 

Hillbrow House

 

 

 

Hillbrow Road

 

longer

 

Esher

 

 

 

 

 

 

 

Surrey

 

 

 

KT10 9NW

 

 

 

UK

 

no

 

 

 

 

 

 

EU/1/07/426/008 – OlanzapineproductCipla – 10 mg – coated tablets – 28 tablets per box

8.

MARKETING AUTHORISATION NUMBER(S)

 

EU/1/07/426/007 – Olanzapine Cipla – 10 mg – coated tablets – 7 tablets per box

9.DATEMedicinalOF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of latest renewal: 01 October 2012

10.DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMA) http://www.ema.europa.eu/.

1. NAME OF THE MEDICINAL PRODUCT

Olanzapine Cipla 15 mg coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each coated tablet contains 15 mg olanzapine.

Excipient with known effect: Each coated tablet contains 315 mg lactose monohydrate For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

authorised

 

Coated tablet

 

Blue, elliptical, convex, coated tablets with ‘NEO’ debossed on one side and plain on the other side.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Adultslonger

Olanzapine is indicated for the treatment of schizophrenia.no

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

Olanzapine is effective in maintaining the clinical improvement during continuation therapy in patients who have shown an initialproducttreatment response.

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

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.

(See sections 4.5 and 5.2)

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 patients

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).

Patients with renal and/or hepatic impairment

A lower starting dose (5 mg) should be considered for such patients. In cases of moderate hepatic authorised

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 routinelylongeraltered 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 conservativenoin such patients.

4.3

Contraindications

product

 

 

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Patients with known risk for narrow-angle glaucoma.

 

Medicinal

 

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.

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

manifestations of NMS are hyperpyrexia, muscle rigidity, altered mentalauthorisedstatus, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac

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 products. Rare cases reported as NMS have also been received in association with olanzapine. Clinical

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

 

 

longer

 

 

 

Hyperglycaemia and/or development or exacerbation of diabetes occasionally associated with

 

 

no

 

ketoacidosis or coma has been reported uncommonly, including some fatal cases (see section 4.8). In

 

product

 

 

some cases, a prior increase in body weight has been reported which may be a predisposing factor. Appropriate clinical monitoring is advisable in accordance with utilised antipsychotic guidelines, e.g. measuring of blood glucose at baseline, 12 weeks after starting olanzapine treatment and annually

thereafter. Patients treated with any antipsychotic agents, including Olanzapine Cipla, should be observed forMedicinalsigns and symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia, and weakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus should be

monitored regularly for worsening of glucose control. Weight should be monitored regularly, e.g. at baseline, 4, 8 and 12 weeks after starting olanzapine treatment and quarterly thereafter.

Lipid alterations

Undesirable alterations 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 Cipla, should be monitored regularly for lipids in accordance with utilised antipsychotic guidelines, e.g. at baseline, 12 weeks after starting olanzapine treatment and every 5 years thereafter.

Anticholinergic activity

While olanzapine demonstrated anticholinergic activity in vitro, experience during the clinical trials revealed a low incidence of related events. However, as clinical experience with olanzapine in patients with concomitant illness is limited, caution is advised when prescribing for patients with prostatic hypertrophy, or paralytic ileus and related conditions.

Hepatic function

Transient, asymptomatic elevations of hepatic 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.

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).

authorised

 

Discontinuation of treatment

Acute symptoms such as sweating, insomnia, tremor, anxiety, nausea, vomiting have been reported rarely ( ≥0.01% and < 0.1%) 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,longercongestive heart failure, heart

hypertrophy, hypokalaemia or hypomagnesaemia.

Thromboembolism

no

 

Temporal association of olanzapine treatment and venous thromboembolism has been reported

uncommonly (≥ 0.1% and < 1%). A causal relationship between the occurrence of venous

thromboembolism and treatment with olanzapine has not been established. However, since patients

 

product

with schizophrenia often present with acquired risk factors for venous thromboembolism all possible

Medicinal

 

risk factors of VTE .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 uncommonly in patients when treated with olanzapine. In most of these cases, a history of seizures or risk factors for seizures were reported.

Tardive Dyskinesia

In comparator studies of one year or less duration, olanzapine was associated with a statistically significant lower incidence of treatment emergent dyskinesia. However the risk of tardive dyskinesia increases with long term exposure, and therefore if signs or symptoms of tardive dyskinesia appear in a patient on olanzapine, a dose reduction or discontinuation should be considered. These symptoms can temporally deteriorate or even arise after discontinuation of treatment.

Postural hypotension

Postural hypotension was infrequently observed in the elderly in olanzapine clinical trials. As with other antipsychotics, it is recommended that blood pressure is measured periodically in patients over 65 years.

Sudden cardiac death

In postmarketing reports with olanzapine, the event of sudden cardiac death has been reported in patients with olanzapine. In a retrospective observational cohort study, the risk of presumed sudden cardiac death in patients treated with olanzapine was approximately twice the risk in patients not using antipsychotics. In the study, the risk of olanzapine was comparable to the risk of atypical antipsychotics included in a pooled analysis.

Paediatric population

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

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

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 CIPLA tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

longer

Potential interactions affecting olanzapine

 

Since olanzapine is metabolised by CYP1A2, substancesno

that can specifically induce or inhibit this

isoenzyme may affect the pharmacokinetics of olanzapine.

product

 

Paediatric population

Interaction studies have only been performed in adults.

Induction of CYP1A2

The metabolism of olanzapine may be induced by smoking and carbamazepine, which may lead to

Inhibition of CYP1A2

reduced olanzapine concentrations. Only slight to moderate increase in olanzapine clearance has been observed. TheMedicinalclinical 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).

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

Decreased bioavailability

Activated charcoal reduces the bioavailability of oral olanzapine by 50 to 60% and should be taken at least 2 hours before or after olanzapine.

Fluoxetine (a CYP2D6 inhibitor), single doses of antacid (aluminium, magnesium) or cimetidine have not been found to significantly affect the pharmacokinetics of olanzapine.

Potential for olanzapine to affect other medicinal products

Olanzapine may antagonise the effects of direct and indirect dopamine agonists.

Olanzapine does not inhibit the main CYP450 isoenzymes in vitro (e.g. 1A2, 2D6, 2C9, 2C19, 3A4). Thus no particular interaction is expected as verified through in vivo studies where no inhibition of metabolism of the following active substances was found: tricyclic antidepressant (representing mostly CYP2D6 pathway), warfarin (CYP2C9), theophylline (CYP1A2) or diazepam (CYP3A4 and 2C19).

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

Therapeutic monitoring of valproate plasma levels did not indicate that valproate dosage adjustment is required after the introduction of concomitant olanzapine.

General CNS activity

Caution should be exercised in patients who consume alcohol or receive medicinal products that can cause central nervous system depression.

The concomitant use of olanzapine with anti-Parkinsonian medicinalauthorisedproducts 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

 

no

olanzapine. Nevertheless, because human experience islongerlimited, olanzapine should be used in

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

product

 

Neonates exposed to antipsychotics (including olanzapine) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonis, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be

monitored carefully.

Breast feedingMedicinal

In a study in breast feeding, healthy women, olanzapine was excreted in breast milk. Mean infant exposure (mg/kg) at steady state was estimated to be 1.8% of the maternal olanzapine dose (mg/kg). Patients should be advised not to breast feed an infant if they are taking olanzapine.

4.7 Effects on ability to drive and use machines

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

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, leukopenia, neutropenia (see section 4.4), dyskinesia, orthostatic hypotension, anticholinergic effects, transient asymptomatic elevations of hepatic aminotransferases

(see section 4.4), rash, asthenia, fatigue, pyrexia, arthralgia, increased alkaline phosphatase, high gamma glutamyltransferase, high uric acid, high creatine phosphokinase and oedema.

Tabulated list of adverse reactions

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

 

 

 

longer

authorised

 

 

no

 

 

product

 

 

Medicinal

 

 

 

 

 

 

 

Very common

Common

 

 

Uncommon

 

Rare

Blood and the lymphatic system disorders

 

 

 

 

 

 

Eosinophilia

 

 

 

 

Thrombocytopenia11

 

Leukopenia10

 

 

 

 

 

 

Neutropenia10

 

 

 

 

 

Immune system disorders

 

 

 

 

 

 

 

 

 

Hypersensitivity11

 

Allergic reaction

Metabolism and nutrition disorders

 

 

 

 

 

Weight gain1

Elevated cholesterol

 

 

Development or

 

Hypothermia12

 

levels2,3

 

 

exacerbation of

 

 

 

Elevated glucose

 

 

diabetes occasionally

 

 

levels4

 

 

associated with

 

 

 

Elevated triglyceride

 

 

ketoacidosis or coma,

 

 

levels2,5

 

 

including some fatal

 

 

Dyskinesia6

 

 

for seizures wereauthorised

 

Glucosuria

 

 

cases (see section 4.4)

 

 

Increased appetite

 

 

 

 

Nervous system disorders

 

 

 

 

 

Somnolence

Dizziness

 

 

Seizures where in most

Neuroleptic malignant

 

Akathisia6

 

 

cases a history of

 

syndrome (see section

 

Parkinsonism6

 

 

seizures or risk factors

4.4)12

 

 

 

 

longer

Discontinuation

 

 

 

 

reported11

 

 

 

 

 

Dystonia (including

symptoms7, 12

 

 

 

 

 

 

 

 

 

oculogyration)11

 

 

 

product

 

 

Tardive dyskinesia

 

 

 

noAmnesia9

 

 

 

 

 

 

 

 

 

 

Dysarthria

 

 

 

 

 

 

 

Respiratory, thoracic and mediastinal disorders

 

 

 

 

 

 

 

Epistaxis9

 

 

Cardiac disorders

 

 

 

 

 

 

 

 

 

 

Bradycardia

 

Ventricular

 

 

 

 

QTc prolongation (see

tachycardia/fibrillation

 

 

 

 

section 4.4)

 

, sudden death (see

 

 

 

 

 

 

section 4.4)11

Vascular disorders

 

 

 

 

 

 

Medicinal

 

 

 

 

Orthostatic 10

 

 

 

Thromboembolism

 

hypotension

 

 

 

(including pulmonary

 

 

 

 

 

embolism and deep

 

 

 

 

 

vein thrombosis) (see

 

 

 

 

 

section 4.4)

 

 

Gastrointestinal disorders

 

 

 

 

 

 

Mild, transient

 

 

Abdominal distension9

Pancreatitis11

 

anticholinergic effects

 

 

 

 

 

including constipation

 

 

 

 

 

and dry mouth

 

 

 

 

 

Hepato-biliary disorders

 

 

 

 

 

 

Transient,

 

 

 

 

Hepatitis (including

 

asymptomatic

 

 

 

 

hepatocellular,

 

elevations of hepatic

 

 

 

 

cholestatic or mixed

 

aminotransferases

 

 

 

 

liver injury)11

 

 

 

 

 

(ALT, AST), especially in early treatment (see section 4.4)

Skin and subcutaneous tissue disorders

 

Rash

 

Photosensitivity

 

 

 

 

reaction

 

 

 

 

Alopecia

 

Musculoskeletal and connective tissue disorders

 

 

 

Arthralgia9

 

 

Rhabdomyolysis11

Renal and urinary disorders

 

 

 

 

 

Urinary incontinence,

 

 

 

 

urinary retention

 

 

 

 

Urinary hesitation11

 

 

 

 

 

 

 

 

 

Reproductive system and breast disorders

 

 

 

Erectile dysfunction in

 

Amenorrhea

Priapism12

 

males

 

Breast enlargement

 

 

Decreased libido in

 

Galactorrhea in

 

 

males and females

 

females

 

 

 

 

Gynaecomastia/breast

 

 

 

 

enlargement in malesauthorised

General disorders and administration site conditions

 

 

Asthenia

 

longer

 

 

Fatigue

 

 

 

Oedema

 

 

 

Pyrexia10

 

 

Investigations

 

 

no

Elevated plasma

Increased alkaline

 

 

Increased total

 

prolactin levels8

phosphatase10

 

 

bilirubin

 

 

High creatine

 

 

 

 

 

phosphokinase11

 

 

 

 

 

High Gamma

 

 

 

 

 

 

 

 

 

Glutamyltransferaseproduct

 

 

 

 

High Uric Acid 10

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Not known

Pregnancy, puerperium and perinatal conditions

Medicinal

 

 

 

Drug withdrawal

 

 

 

syndrome neonatal

 

 

 

(see section 4.6)

1 Clinically significant weight gain was observed across all baseline Body Mass Index (BMI) categories. Following short term treatment (median duration 47 days), weight gain ≥ 7% of baseline body weight was very common (22.2 %), ≥ 15 % was common (4.2 %) and ≥ 25 % was uncommon (0.8 %). Patients gaining ≥ 7 %, ≥ 15 % and ≥ 25 % of their baseline body weight with long-term exposure (at least 48 weeks) were very common (64.4 %, 31.7 % and 12.3 % respectively).

2 Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were greater in patients without evidence of lipid dysregulation at baseline.

3 Observed for fasting normal levels at baseline (< 5.17 mmol/l) which increased to high

(≥ 6.2 mmol/l). Changes in total fasting cholesterol levels from borderline at baseline (≥ 5.17 - < 6.2 mmol/l) to high (≥ 6.2 mmol/l) were very common.

4 Observed for fasting normal levels at baseline (< 5.56 mmol/l) which increased to high (≥ 7 mmol/l). Changes in fasting glucose from borderline at baseline (≥ 5.56 - < 7 mmol/l) to high (≥ 7 mmol/l) were very common.

5 Observed for fasting normal levels at baseline (< 1.69 mmol/l) which increased to high

(≥ 2.26 mmol/l). Changes in fasting triglycerides from borderline at baseline (≥ 1.69 mmol/l - < 2.26 mmol/l) to high (≥ 2.26 mmol/l) were very common.

6 In clinical trials, the incidence of Parkinsonism and dystonia in olanzapine-treated patients was numerically higher, but not statistically significantly different from placebo. Olanzapine-treated patients had a lower incidence of Parkinsonism, akathisia and dystonia compared with titrated doses of haloperidol. In the absence of detailed information on the pre-existing history of individual acute and

tardive extrapyramidal movement disorders, it cannot be concluded at present that olanzapine produces

less tardive dyskinesia and/or other tardive extrapyramidal syndromes.

 

authorised

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.

 

9 Adverse event identified from clinical trials in the Olanzapine Integrated Database.

As assessed by measured values from clinical trials in the Olanzapine Integrated Database.

 

 

longer

Adverse event identified from spontaneous post-marketing reporting with frequency determined

 

utilising the Olanzapine Integrated Database.

 

 

no

 

12 Adverse event identified fromproductspontaneous post-marketing reporting with frequency estimated at the upper limit of the 95% confidence interval utilising the Olanzapine Integrated Database.

Long-term exposure (at least 48 weeks)

The proportion of patients who had adverse, clinically significant changes in weight gain, glucose,

total/LDL/HDLMedicinalcholesterol 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 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 orderauthorisedof decreasing seriousness.

The frequency terms listed are defined as follows: Very common (≥ 1/10), common (≥ 1/100 to < 1/10).

Metabolism and nutrition disorders

Very common: Weight gain13, elevated triglyceride levels14, increased appetite. Common: Elevated cholesterol levels15

Nervous system disorders

Very common: Sedation (including: hypersomnia, lethargy, somnolence).

Gastrointestinal disorders

 

longer

Common: Dry mouth

 

Hepato-biliary disorders

 

 

Very common: Elevations of hepatic aminotransferases (ALT/AST; see section 4.4).

 

no

 

Investigations

 

 

Very common: Decreased total bilirubin,productincreased GGT, elevated plasma prolactin levels16.

13 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 ≥

14 Observed for fasting normal levels at baseline (< 1.016 mmol/l) which increased to high

25 % was common (2.5 %). With long-term exposure (at least 24 weeks), 89.4 % gained ≥ 7 %, 55.3 % gained ≥ Medicinal15 % and 29.1 % gained ≥ 25% of their baseline body weight.

(≥ 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).

15 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.

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

4.9Overdose

Signs and symptoms

Very common symptoms in overdose (> 10% incidence) include tachycardia, agitation/aggressiveness, dysarthria, various extrapyramidal symptoms, and reduced level of consciousness ranging from sedation to coma.

Other medically significant sequelae of overdose include delirium, convulsion, coma, possible neuroleptic malignant syndrome, respiratory depression, aspiration, hypertension or hypotension, cardiac arrhythmias (< 2% of overdose cases) and cardiopulmonary arrest. Fatal outcomes have been reported for acute overdoses as low as 450 mg but survival has also been reported following acute overdose of approximately 2 g of oral olanzapine.

Management

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. Cardiovascularauthorisedmonitoring 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: N05A H03.

Pharmacodynamic effects

no

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

pharmacologic profile across a number of receptor systems.

product

 

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; 1 adrenergic; and histamine H1 receptors. Animal behavioural studies with olanzapine indicated 5HT,

dopamine, and cholinergic antagonism, consistent with the receptor-binding profile. Olanzapine

demonstrated a greater in vitro affinity for serotonin 5HT2 than dopamine D2 receptors and greater 5

Medicinal

HT2 than D2 activity

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 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 Single Photon Emission Computed Tomography (SPECT) imaging study in schizophrenic patients revealed that olanzapine-responsive patients had lower striatal D2 occupancy than some other antipsychotic- and risperidone-responsive patients, while being comparable to clozapine-responsive patients.

Clinical efficacy

In two of two placebo and two of three comparator controlled trials with over 2,900 schizophrenic patients presenting with both positive and negative symptoms, olanzapine was associated with statistically significantly greater improvements in negative as well as positive symptoms.

In a multinational, double-blind, comparative study of schizophrenia, schizoaffective, and related disorders which included 1,481 patients with varying degrees of associated depressive symptoms (baseline mean of 16.6 on the Montgomery-Asberg Depression Rating Scale), a prospective secondary

analysis of baseline to endpoint mood score change demonstrated a statistically significant improvement (p= 0.001) favouring olanzapine (-6.0) versus haloperidol (-3.1).

In patients with a manic or mixed episode of bipolar disorder, olanzapine demonstrated superior efficacy to placebo and valproate semisodium (divalproex) in reduction of manic symptoms over 3 weeks. Olanzapine also demonstrated comparable efficacy results to haloperidol in terms of the proportion of patients in symptomatic remission from mania and depression at 6 and 12 weeks. In a co-therapy study of patients treated with lithium or valproate for a minimum of 2 weeks, the addition of olanzapine 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.

authorised

 

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 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

no

longer

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 wasproductused 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 PharmacokineticMedicinalproperties

Absorption

Olanzapine is well absorbed after oral administration, reaching peak plasma concentrations within 5 to 8 hours. The absorption is not affected by food. Absolute oral bioavailability relative to intravenous administration has not been determined

Distribution

The plasma protein binding of olanzapine was about 93 % over the concentration range of about 7 to about 1000 ng/ml. Olanzapine is bound predominantly to albumin and 1-acid-glycoprotein.

Biotransformation

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.

Elimination

After oral administration, the mean terminal elimination half-life of olanzapine in healthy subjects varied on the basis of age and gender.

In healthy elderly (65 and over) versus non-elderly subjects, the mean elimination half-life was prolonged (51.8 versus 33.8 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).

Renal impairment

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.

authorised

 

Smokers

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

Paediatric population

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 smalllongerin comparison to the overall variability

between individuals.

 

no

 

 

In a study of Caucasians, Japanese, and Chinese subjects, there were no differences in the

pharmacokinetic parameters among the three populations.

 

product

 

average body weight and fewer adolescents were smokers. Such factors possibly contribute to the higher average exposure observed in adolescents.

Adolescents (ages 13 to 17 years): The pharmacokinetics of olanzapine are similar between adolescents Medicinaland adults. In clinical studies, the average olanzapine exposure was approximately 27% higher in adolescents. Demographic differences between the adolescents and adults include a lower

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 anaemia 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 foetal development and transient decreases in offspring activity levels were seen.

Mutagenicity

authorised

 

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 not carcinogenic.

6.

PHARMACEUTICAL PARTICULARS

longer

 

6.1

List of excipients

 

no

 

Tablet core

 

 

 

 

 

 

 

Lactose monohydrate,

product

 

 

Maize starch

 

 

 

 

 

Hydroxypropyl cellulose

 

 

 

Magnesium stearate

 

 

 

Tablet coat

Medicinal

 

 

 

Opadry Blue containing:

 

 

 

Hypromellose (E464)

Titanium dioxide (E171)

Polyethylene glycol 6000

Indigo carmine aluminium lake (E132)

Brilliant blue FCF aluminium lake (E133)

Iron oxide black (E172)

6.2Incompatibilities

Not applicable.

6.3 Shelf life

2 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. MARKETING AUTHORISATION HOLDER

Cipla (EU) Limited

 

 

authorised

Hillbrow House

 

 

 

 

 

Hillbrow Road

 

 

 

Esher

 

 

 

 

Surrey

 

 

 

KT10 9NW

 

 

 

UK

 

 

longer

 

 

 

 

 

8.

MARKETING AUTHORISATION NUMBER(S)

 

EU/1/07/426/010 – Olanzapine Cipla – 15 mg – coated tablets – 28 tablets per box

 

 

no

 

 

EU/1/07/426/011 – Olanzapine Cipla – 15 mg – coated tablets – 56 tablets per box

 

product

 

 

 

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 14 November 2007

Date of latest renewal: 01 October 2012

10.DATEOF THE TEXTOF REVISION

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMA) http://www.ema.europa.eu/.

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