OLAZAX DISPERZI 5mg orodispersable tablets medication leaflet

Olazax Disperzi 5 mg orodispersible tablets

Each orodispersible tablet contains 5 mg olanzapine.

Excipient with known effect: Each orodispersible tablet contains 0.23 mg aspartame

For the full list of excipients see section 6.1

Orodispersible tablet

Yellow coloured circular flat bevelled edge orodispersible tablets with ‘B’ debossed on one side.

Olanzapine is indicated for the treatment of schizophrenia.

Olanzapine is effective in maintaining the clinical improvement during continuation therapy inpatients who have shown an initial treatment response.

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

In patients whose manic episode has responded to olanzapine treatment, olanzapine is indicated forthe prevention of recurrence in patients with bipolar disorder (see section 5.1).

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 incombination 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 fortreatment of manic episode, continue therapy for preventing recurrence at the same dose. If a newmanic, mixed, or depressive episode occurs, olanzapine treatment should be continued (with doseoptimisation 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 range5-20 mg/day. An increase to a dose greater than the recommended starting dose is advised only afterappropriate 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. Gradualtapering of the dose should be considered when discontinuing olanzapine.

Olazax Disperzi orodispersible tablets should be placed in the mouth, where it will rapidly disperse insaliva, so it can be easily swallowed. Alternatively, it may be dispersed in a full glass of water orother suitable beverage (orange juice, apple juice, milk or coffee) immediately before theadministration.

Elderly A lower starting dose (5 mg/day) is not routinely indicated but should be considered for those65 and over when clinical factors warrant (see section 4.4).

A lower starting dose (5 mg) should be considered for such patients. In cases of moderate hepaticinsufficiency (cirrhosis, Child-Pugh Class A or B), the starting dose should be 5 mg and onlyincreased with caution.

Smokers

The starting dose and dose range need not be routinely altered for non-smokers relative to smokers.

The metabolism of olanzapine may be induced by smoking. Clinical monitoring is recommended andan increase of olanzapine dose may be considered if necessary (see section 4.5).

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. Doseescalation, when indicated, should be conservative in such patients.

(See sections 4.5 and 5.2.)

Olanzapine is not recommended for use in children and adolescents below 18 years of age due to alack of data on safety and efficacy. A greater magnitude of weight gain, lipid and prolactin alterationshas been reported in short term studies of adolescent patients than in studies of adult patients (seesections 4.4, pct. 4.8, 5.1 and 5.2).

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

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

Dementia-related psychosis and/or behavioural disturbances

Olanzapine is not recommended for use patients with dementia-related psychosis and/or behaviouraldisturbances 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) withdementia-related psychosis and/or disturbed behaviours, there was a 2-fold increase in the incidenceof death in olanzapine-treated patients compared to patients treated with placebo (3.5 % verses 1.5 %,respectively). The higher incidence of death was not associated with olanzapine dose (mean dailydose 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 orwithout aspiration), or concomitant use of benzodiazepines. However, the incidence of death washigher 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 ischemicattack), including fatalities, were reported. There was a 3-fold increase in CVAE in patients treatedwith olanzapine compared to patients treated with placebo (1.3 % verses 0.4 %, respectively). Allolanzapine and placebo-treated patients who experienced a cerebrovascular event had pre-existing riskfactors. Age > 75 years and vascular/mixed type dementia were identified as risk factors for CVAE inassociation with olanzapine treatment. The efficacy of olanzapine was not established in these trials.

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 symptomatologyand hallucinations were reported very commonly and more frequently than with placebo (see section4.8), and olanzapine was not more effective than placebo in the treatment of psychotic symptoms. Inthese 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-Parkinsonianmedicinal products and dosages throughout the study. Olanzapine was started at 2.5 mg/day andtitrated 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. Clinicalmanifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence ofautonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiacdysrhythmia). 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, allantipsychotic medicines, including olanzapine must be discontinued.

Hyperglycaemia and/or development or exacerbation of diabetes occasionally associated withketoacidosis or coma has been reported uncommonly, including some fatal cases (see section 4.8). Insome 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 annuallythereafter. Patients treated with any antipsychotic medicines, including olanzapine, should beobserved for signs and symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia, andweakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus should bemonitored regularly for worsening of glucose control. Weight should be monitored regularly e.g. atbaseline, 4, 8 and 12 weeks after starting olanzapine treatment and quarterly thereafter.

Lipid alterations

Undesirable alterations in lipids have been observed in olanzapine-treated patients in placebo-controlled clinical trials (see section 4.8). Lipid alterations should be managed as clinicallyappropriate, particularly in dyslipidemic patients and in patients with risk factors for the developmentof lipids disorders. Patients treated with any antipsychotic medicines, including olanzapine, should bemonitored regularly for lipids in accordance with utilised antipsychotic guidelines e.g. at baseline, 12weeks after starting olanzapine treatment and every 5 years thereafter.

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

Hepatic function

Transient, asymptomatic elevations of hepatic aminotransferases , alanine transferase (ALT),aspartatetransferase (AST) have been seen commonly, especially in early treatment. Caution shouldbe exercised and follow-up organised in patients with elevated ALT and/or AST, in patients withsigns and symptoms of hepatic impairment, in patients with pre-existing conditions associated withlimited hepatic functional reserve, and in patients who are being treated with potentially hepatotoxicmedicines. In cases where hepatitis (including hepatocellular, cholestatic or mixed liver injury) hasbeen diagnosed, olanzapine treatment should be discontinued.

Caution should be exercised in patients with low leukocyte and/or neutrophil counts for any reason, inpatients receiving medicines known to cause neutropenia, in patients with a history of drug-inducedbone marrow depression/toxicity, in patients with bone marrow depression caused by concomitantillness, radiation therapy or chemotherapy and in patients with hypereosinophilic conditions or withmyeloproliferative disease. Neutropenia has been reported commonly when olanzapine and valproateare used concomitantly (see section 4.8).

Acute symptoms such as sweating, insomnia, tremor, anxiety, nausea, or vomiting have been reportedrarely (≥ 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) wereuncommon (0.1 % to 1 %) in patients treated with olanzapine, with no significant differences inassociated cardiac events compared to placebo. However, caution should be exercised whenolanzapine is prescribed with medicines known to increase QTc interval, especially in the elderly, inpatients with congenital long QT syndrome, congestive heart failure, heart hypertrophy, hypokalaemiaor hypomagnesaemia.

Thromboembolism

Temporal association of olanzapine treatment and venous thromboembolism has been reporteduncommonly (≥ 0.1% and < 1%).. A causal relationship between the occurrence of venousthromboembolism and treatment with olanzapine has not been established. However, since patientswith schizophrenia often present with acquired risk factors for venous thromboembolism all possiblerisk factors of VTE e.g. immobilisation of patients, should be identified and preventive measuresundertaken.

General CNS activity

Given the primary CNS effects of olanzapine, caution should be used when it is taken in combinationwith other centrally acting medicines and alcohol. As it exhibits in vitro dopamine antagonism,olanzapine may antagonize the effects of direct and indirect dopamine agonists.

Olanzapine should be used cautiously in patients who have a history of seizures or are subject tofactors which may lower the seizure threshold. Seizures have been reported to occur uncommonly inpatients when treated with olanzapine. In most of these cases, a history of seizures or risk factors forseizures were reported.

Tardive Dyskinesia

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

Postural hypotension

Postural hypotension was infrequently observed in the elderly in olanzapine clinical trials. It isrecommended 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 inpatients with olanzapine. In a retrospective observational cohort study, the risk of presumed suddencardiac death in patients treated with olanzapine was approximately twice the risk in patients notusing antipsychotics. In the study, the risk of olanzapine was comparable to the risk of atypicalantipsychotics included in a pooled analysis.

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, changesin metabolic parameters and increases in prolactin levels. Long-term outcomes associated with theseevents have not been studied and remain unknown (see sections 4.8 and 5.1).

Phenylalanine

Olazax Disperzi orodispersible tablet contains aspartame, which is a source of phenylalanine. May beharmful for people with phenylketonuria.

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 thisisoenzyme may affect the pharmacokinetics of olanzapine.

Induction of CYP1A2

The metabolism of olanzapine may be induced by smoking and carbamazepine, which may lead toreduced 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 anincrease of olanzapine dose may be considered if necessary (see section 4.2).

Inhibition of CYP1A2

Fluvoxamine, a specific CYP1A2 inhibitor, has been shown to significantly inhibit the metabolism ofolanzapine.

The mean increase in olanzapine Cmax following fluvoxamine was 54 % in female nonsmokers and77 % male smokers.

The mean increase in olanzapine AUC was 52 % and 108 % respectively. A lower starting dose ofolanzapine should be considered in patients who are using fluvoxamine or any other CYP1A2inhibitors, such as ciprofloxacin.

A decrease in the dose of olanzapine should be considered if treatment with an inhibitor of CYP1A2is initiated.

Decreased bioavailability

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

Fluoxetine (a CYP2D6 inhibitor), single doses of antacid (aluminium, magnesium) or cimetidine havenot 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 ofmetabolism of the following active substances was found: tricyclic antidepressant (representingmostly CYP2D6 pathway), warfarin (CYP2C9), theophylline (CYP1A2) or diazepam (CYP3A4 and2C19).

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

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

General CNS activity

Caution should be exercised in patients who consume alcohol or receive medicinal products that cancause 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 productsknown to increase QTc interval (see section 4.4).

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

New born infants exposed to antipsychotics (including olanzapine) during the third trimester ofpregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms thatmay vary in severity and duration following delivery. There have been reports of agitation,hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently,newborns should be monitored carefully.

In a study in breast-feeding, healthy women, olanzapine was excreted in breast milk. Mean infantexposure (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.

Effects on fertility are unknown (see section 5.3 for preclinical information).

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

The most frequently (seen in ≥ 1 % of patients) reported adverse reactions associated with the use ofolanzapine 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, orthostatichypotension, anticholinergic effects, transient asymptomatic elevations of hepatic aminotransferases(see section 4.4), rash, asthenia, fatigue, pyrexia, arthralgia, increased alkaline phosphatase, highgamma glutamyltransferase, high uric acid, high creatine phosphokinase and oedema.

The following table lists the adverse reactions and laboratory investigations observed fromspontaneous reporting and in clinical trials. Within each frequency grouping, adverse reactions arepresented in order of decreasing seriousness. The frequency terms listed are defined as follows: Verycommon (≥ 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 (< 10,000), not known (cannot be estimated from the data available).

Very common Common Uncommon Rare Not known

Blood and the lymphatic system disorders

Eosinophilia Thrombocytopenia1

Leukopenia10 1

Neutropenia10

Hypersensitivity11

Weight gain 1 Elevated Development orcholesterol levels exacerbation of Hypothermia122,3 diabetes occasionally

Elevated glucose associated withlevels 4 ketoacidosis or coma,

Elevated including some fataltriglyceride levels cases (see section 4.4)2,5 11

Glucosuria

Increased appetite

Somnolence Dizziness Seizures where in Neurolepticmost cases a history of malignant

Akathisia 6 seizures or risk factors syndrome (seefor seizures were section 4.4)12

Parkinsonism 6 reported 11

Dystonia (including Discontinuation

Dyskinesia 6 oculogyration) 11 Symptoms 7,12

Tardive dyskinesia11

Amnesia 9

Dysarthria

Stuttering11

Restless legssyndrome11

Bradycardia Ventricular

QTc prolongation (see tachycardia/fibrillatsection 4.4) ionsudden death (seesection 4.4)11

Orthostatic Thromboembolismhypotension10 (including pulmonaryembolism and deepvein thrombosis) (seesection 4.4)

Epistaxis9

Mild, transient Abdominal Pancreatitis11anticholinergic distension9effects including Salivaryconstipation and hypersecretion11dry mouth

Transient, Hepatitis (includingasymptomatic hepatocellular,elevations of cholestatic orhepatic mixedaminotransferases liver injury)11(ALT, AST),especially inearly treatment (seesection 4.4)

Rash Photosensitivity Drugreaction Reactionwith

Alopecia Eosinophiliaand Systemic

Symptoms(DRESS)

Arthralgia9 Rhabdomyolysis11

Urinary incontinence

Urinary retention

Urinary hesitation11

Pregnancy, puerperium and perinatal conditions

Drugwithdrawalsyndromeneonatal (seesection 4.6)

Erectile Amenorrhea Priapism12dysfunction in Breast enlargementmales Galactorrhea in

Decreased libido in femalesmales and females Gynaecomastia/breastenlargement in males

General disordersandadministrationsite conditions

Asthenia

Oedema

Pyrexia10

Elevated plasma Increased alkaline Increased totalprolactin levels 8 phosphatase10 bilirubin

High creatinephosphokinase11

High Gamma

Glutamyltransferase10

High uric acid 101 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 baselinebody 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) weregreater 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 wasnumerically higher, but not statistically significantly different from placebo. Olanzapine-treatedpatients had a lower incidence of Parkinsonism, akathisia and dystonia compared with titrated dosesof haloperidol. In the absence of detailed information on the pre-existing history of individual acuteand tardive extrapyramidal movement disorders, it can not be concluded at present that olanzapineproduces less tardive dyskinesia and/or other tardive extrapyramidal syndromes.

7 Acute symptoms such as sweating, insomnia, tremor, anxiety, nausea and vomiting have beenreported when olanzapine is stopped abruptly.

8 In clinical trials of up to 12 weeks, plasma prolactin concentrations exceeded the upper limit ofnormal range in approximately 30% of olanzapine treated patients with normal baseline prolactinvalue. In the majority of these patients the elevations were generally mild, and remained below twotimes the upper limit of normal range.

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.

11 Adverse event identified from spontaneous post-marketing reporting with frequency determinedutilising the Olanzapine Integrated Database.

12 Adverse event identified from spontaneous post-marketing reporting with frequency estimated atthe 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/HDL cholesterol or triglycerides increased over time. In adult patients who completed9-12 months of therapy, the rate of increase in mean blood glucose slowed after approximately6 months.

Additional information on special populations

In clinical trials in elderly patients with dementia, olanzapine treatment was associated with a higherincidence of death and cerebrovascular adverse reactions compared to placebo (see section 4.4). Verycommon adverse reactions associated with the use of olanzapine in this patient group were abnormalgait and falls. Pneumonia, increased body temperature, lethargy, erythema, visual hallucinations andurinary 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 reportedvery commonly and more frequently than with placebo.

In one clinical trial in patients with bipolar mania, valproate combination therapy with olanzapineresulted in an incidence of neutropenia of 4.1 %; a potential contributing factor could be high plasmavalproate 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 reportedcommonly. During treatment with olanzapine in combination with lithium or divalproex, an increaseof ≥ 7 % from baseline body weight occurred in 17.4 % of patients during acute treatment (up to6 weeks).

Long-term olanzapine treatment (up to 12 months) for recurrence prevention in patients with bipolardisorder was associated with an increase of ≥ 7 % from baseline body weight in 39.9 % of patients.

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, datafrom the adolescent trials were compared to those of the adult trials.

The following table summarises the adverse reactions reported with a greater frequency in adolescentpatients (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 adolescentpopulation compared to adults with comparable exposures. The magnitude of weight gain and theproportion 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).

Very common: Weight gain13, elevated triglyceride levels 14, increased appetite.

Common: Elevated cholesterol levels 15

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

Common: Dry mouth

Hepato-biliary disorders

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

Very common: Decreased total bilirubin, increased GGT, elevated plasma prolactin levels 1613 Following short term treatment (median duration 22 days), weight gain ≥ 7 % of baseline bodyweight (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 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 borderlineat 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.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Signs and symptoms

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

Other medically significant sequelae of overdose include delirium, convulsion, coma, possibleneuroleptic 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 beenreported following acute overdose of approximately 2 g of oral olanzapine.

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, administrationof activated charcoal). The concomitant administration of activated charcoal was shown to reduce theoral bioavailability of olanzapine by 50 to 60 %.

Symptomatic treatment and monitoring of vital organ function should be instituted according toclinical presentation, including treatment of hypotension and circulatory collapse and support ofrespiratory function.

Do not use epinephrine, dopamine, or other sympathomimetic agents with betaagonist activity sincebeta stimulation may worsen hypotension.

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

Pharmacotherapeutic group: psycholeptics, diazepines, oxazepines, thiazepines and oxepines, ATCcode N05A H03.

Olanzapine is an antipsychotic, antimanic and mood stabilising agent that demonstrates a broadpharmacologic profile across a number of receptor systems.

In preclinical studies, olanzapine exhibited a range of receptor affinities (Ki < 100 nM) for serotonin 5

HT2A/2C, 5 HT3, 5 HT6; dopamine D1, D2, D3, D4, D5; cholinergic muscarinic receptors M1-M5; α1 adrenergic; and histamine H1 receptors.

Animal behavioral studies with olanzapine indicated 5HT, dopamine, and cholinergic antagonism,consistent with the receptor-binding profile. Olanzapine demonstrated a greater in vitro affinity forserotonin 5HT2 than dopamine D2 receptors and greater 5 HT2 than D2 activity in vivo, models.

Electrophysiological studies demonstrated that olanzapine selectively reduced the firing ofmesolimbic (A10) dopaminergic neurons, while having little effect on the striatal (A9) pathwaysinvolved in motor function. Olanzapine reduced a conditioned avoidance response, a test indicative ofantipsychotic 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 5HT2A than dopamine D2 receptor occupancy. In addition, a Single

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

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

In a multinational, double-blind, comparative study of schizophrenia, schizoaffective, and relateddisorders 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 secondaryanalysis of baseline to endpoint mood score change demonstrated a statistically significantimprovement (p= 0.001) favouring olanzapine (- 6.0) versus haloperidol (- 3.1).

In patients with a manic or mixed episode of bipolar disorder, olanzapine demonstrated superiorefficacy to placebo and valproate semisodium (divalproex) in reduction of manic symptoms over3 weeks. Olanzapine also demonstrated comparable efficacy results to haloperidol in terms of theproportion of patients in symptomatic remission from mania and depression at 6 and 12 weeks. In aco-therapy study of patients treated with lithium or valproate for a minimum of 2 weeks, the additionof olanzapine 10 mg (co-therapy with lithium or valproate) resulted in a greater reduction insymptoms of mania than lithium or valproate monotherapy after 6 weeks.

In a 12-month recurrence prevention study in manic episode patients who achieved remission onolanzapine and were then randomised to olanzapine or placebo, olanzapine demonstrated statisticallysignificant superiority over placebo on the primary endpoint of bipolar recurrence. Olanzapine alsoshowed a statistically significant advantage over placebo in terms of preventing either recurrence intomania or recurrence into depression.

In a second 12-month recurrence prevention study in manic episode patients who achieved remissionwith a combination of olanzapine and lithium and were then randomised to olanzapine or lithiumalone, olanzapine was statistically non-inferior to lithium on the primary endpoint of bipolarrecurrence (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 amood stabiliser (lithium or valproate), long-term olanzapine co-therapy with lithium or valproate wasnot statistically significantly superior to lithium or valproate alone in delaying bipolar recurrence,defined according to syndromic (diagnostic) criteria.

Controlled efficacy data in adolescents (ages 13 to 17 years)are limited to short term studies inschizophrenia (6 weeks) and mania associated with bipolar I disorder (3 weeks), involving less than200 adolescents. Olanzapine was used as a flexible dose starting with 2.5 and ranging up to20 mg/day. During treatment with olanzapine, adolescents gained significantly more weight comparedwith adults. The magnitude of changes in fasting total cholesterol, LDL cholesterol, triglycerides, andprolactin (see sections 4.4 and 4.8) were greater in adolescents than in adults. There are no controlleddata on maintenance of effect or long term safety (see sections 4.4 and 4.8). Information on long termsafety is primarily limited to open-label, uncontrolled data.

Olanzapine is well absorbed after oral administration, reaching peak plasma concentrations within5 to 8 hours. The absorption is not affected by food. Absolute oral bioavailability relative tointravenous administration has not been determined.

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

Olanzapine is metabolized in the liver by conjugative and oxidative pathways. The major circulatingmetabolite 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 and2-hydroxymethyl metabolites, both exhibited significantly less in vivo pharmacological activity thanolanzapine in animal studies. The predominant pharmacologic activity is from the parent olanzapine.

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

In healthy elderly (65 and over) versus non-elderly subjects, the mean elimination half-life wasprolonged (51.8 versus 33.8 hr) and the clearance was reduced (17.5 versus 18.2 l/hr). Thepharmacokinetic variability observed in the elderly is within the range for the non-elderly. In44 patients with schizophrenia > 65 years of age, dosing from 5 to 20 mg/day was not associated withany distinguishing profile of adverse events.

In female versus male subjects the mean elimination half life was somewhat prolonged (36.7 versus32.3 hrs) and the clearance was reduced (18.9 versus 27.3 l/hr). However, olanzapine (5-20 mg)demonstrated a comparable safety profile in female (n = 467) as in male patients (n = 869).

In renally impaired patients (creatinine clearance < 10 ml/min) versus healthy subjects, there was nosignificant difference in mean elimination half-life (37.7 versus 32.4 hr) or clearance (21.2 versus25.0 l/hr). A mass balance study showed that approximately 57 % of radiolabelled olanzapineappeared in urine, principally as metabolites.

A small study of the effect of impaired liver function in 6 subjects with clinically significant (Childs

Pugh Classification A (n = 5) and B (n = 1)) cirrhosis revealed little effect on the pharmacokinetics oforally administered olanzapine (2.5 - 7.5 mg single dose): Subjects with mild to moderate hepaticdysfunction had slightly increased systemic clearance and faster elimination half-time compared tosubjects with no hepatic dysfunction (n = 3). There were more smokers among subjects with cirrhosis(4/6; 67 %) than among subjects with no hepatic dysfunction (0/3; 0 %).

Smoking

In non-smoking versus smoking subjects (males and females) the mean elimination half-life wasprolonged (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 versusmales, and in non-smokers versus smokers. However, the magnitude of the impact of age, gender, orsmoking on olanzapine clearance and half-life is small in comparison to the overall variabilitybetween individuals.

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

Adolescents (ages 13 to 17 years): The pharmacokinetics of olanzapine are similar betweenadolescents and adults. In clinical studies, the average olanzapine exposure was approximately 27 %higher in adolescents. Demographic differences between the adolescents and adults include a loweraverage body weight and fewer adolescents were smokers. Such factors possibly contribute to thehigher average exposure observed in adolescents.

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 doseswere approximately 210 mg/kg (mice) and 175 mg/kg (rats). Dogs tolerated single oral doses up to100 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 inprostration 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 effectswere CNS depression, anticholinergic effects, and peripheral haematological disorders. Tolerancedeveloped to the CNS depression. Growth parameters were decreased at high doses. Reversibleeffects consistent with elevated prolactin in rats included decreased weights of ovaries and uterus andmorphologic changes in vaginal epithelium and in mammary gland.

Haematologic toxicity

Effects on haematology parameters were found in each species, including dose-related reductions incirculating leukocytes in mice and non-specific reductions of circulating leukocytes in rats; however,no evidence of bone marrow cytotoxicity was found. Reversible neutropenia, thrombocytopenia, oranaemia developed in a few dogs treated with 8 or 10 mg/kg/day (total olanzapine exposure [AUC] is12- to 15-fold greater than that of a man given a 12-mg dose). In cytopenic dogs, there were noadverse effects on progenitor and proliferating cells in the bone marrow.

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) andreproduction 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 inoffspring activity levels were seen.

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

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

Mannitol (E 421)

Microcrystalline cellulose

Aspartame (E 951)

Crospovidone

Magnesium stearate

Not applicable.

30 months

Store below 30 °C.

Aluminium/aluminium blisters in cartons of 28, 56 tablets per carton.

Not all pack sizes may be marketed

No special requirements

Glenmark Pharmaceuticals s.r.o.

Hvězdova 1716/2b, 140 78 Praha 4

Czech Republic

EU/1/09/592/001

EU/1/09/592/006

Date of first authorisation: 10.12.2009

Date of renewal of authorisation: 06.08.2014

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

Agency (EMA) http://www.ema.europa.eu