ZALASTA 15mg orodispersable tablets medication leaflet

Zalasta 5 mg orodispersible tablets

Zalasta 7.5 mg orodispersible tablets

Zalasta 10 mg orodispersible tablets

Zalasta 15 mg orodispersible tablets

Zalasta 20 mg orodispersible tablets

Zalasta 5 mg orodispersible tablets

Each orodispersible tablet contains 5 mg olanzapine.

Zalasta 7.5 mg orodispersible tablets

Each orodispersible tablet contains 7.5 mg olanzapine.

Zalasta 10 mg orodispersible tablets

Each orodispersible tablet contains 10 mg olanzapine.

Zalasta 15 mg orodispersible tablets

Each orodispersible tablet contains 15 mg olanzapine.

Zalasta 20 mg orodispersible tablets

Each orodispersible tablet contains 20 mg olanzapine.

Zalasta 5 mg orodispersible tablets

Each orodispersible tablet contains 0.50 mg aspartame.

Zalasta 7.5 mg orodispersible tablets

Each orodispersible tablet contains 0.75 mg aspartame.

Zalasta 10 mg orodispersible tablets

Each orodispersible tablet contains 1.00 mg aspartame.

Zalasta 15 mg orodispersible tablets

Each orodispersible tablet contains 1.50 mg aspartame.

Zalasta 20 mg orodispersible tablets

Each orodispersible tablet contains 2.00 mg aspartame.

For the full list of excipients, see section 6.1.

Orodispersible tablet.

Zalasta 5 mg orodispersible tablets

Tablets are round, slightly biconvex, yellow marbled tablets with possible individual spots.

Zalasta 7.5 mg orodispersible tablets

Tablets are round, slightly biconvex, yellow marbled tablets with possible individual spots.

Zalasta 10 mg orodispersible tablets

Tablets are round, slightly biconvex, yellow marbled tablets with possible individual spots.

Zalasta 15 mg orodispersible tablets

Tablets are round, slightly biconvex, yellow marbled tablets with possible individual spots.

Zalasta 20 mg orodispersible tablets

Tablets are round, slightly biconvex, yellow marbled tablets with possible individual spots.

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. Forpatients who have been receiving olanzapine for treatment of manic episode, continue therapy forpreventing 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 supplementarytherapy 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 therange 5-20 mg/day. An increase to a dose greater than the recommended starting dose is advisedonly after appropriate clinical reassessment and should generally occur at intervals of not less than24 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.

Zalasta orodispersible tablet should be placed in the mouth, where it will rapidly disperse in saliva,so it can be easily swallowed. Removal of the intact orodispersible tablet from the mouth isdifficult. Since the orodispersible tablet is fragile, it should be taken immediately on opening theblister. Alternatively, it may be dispersed in a full glass of water immediately beforeadministration.

Olanzapine orodispersible tablet is bioequivalent to olanzapine tablets, with a similar rate andextent of absorption. It has the same dosage and frequency of administration as olanzapine tablets.

Olanzapine orodispersible tablets may be used as an alternative to olanzapine tablets.

A lower starting dose (5 mg/day) is not routinely indicated but should be considered for those 65and over when clinical factors warrant (see also 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 recommendedand an 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.

Dose escalation, 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 prolactinalterations has been reported in short term studies of adolescent patients than in studies of adultpatients (see sections 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 with known risk for narrow-angle glaucoma.

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

Dementia-related psychosis and/or behavioural disturbances

Olanzapine is not recommended for use in patients with dementia-related psychosis and/orbehavioural disturbances because of an increase in mortality and the risk of cerebrovascularaccident. In placebo-controlled clinical trials (6-12 weeks duration) of elderly patients (mean age78 years) with dementia-related psychosis and/or disturbed behaviours, there was a 2-fold increasein 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 olanzapinedose (mean daily dose 4.4 mg) or duration of treatment. Risk factors that may predispose thispatient population to increased mortality include age > 65 years, dysphagia, sedation, malnutritionand dehydration, pulmonary conditions (e.g., pneumonia, with or without aspiration), orconcomitant 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 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% vs. 0.4%, respectively). Allolanzapine- and placebo-treated patients who experienced a cerebrovascular event had pre-existingrisk 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 inthese 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 Parkinsoniansymptomatology and hallucinations were reported very commonly and more frequently than withplacebo (see section 4.8), and olanzapine was not more effective than placebo in the treatment ofpsychotic symptoms. In these trials, patients were initially required to be stable on the lowesteffective dose of anti-Parkinsonian medicinal products (dopamine agonist) and to remain on thesame anti-Parkinsonian medicinal products and dosages throughout the study. Olanzapine wasstarted 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. 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,all antipsychotic 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).

In some cases, a prior increase in body weight has been reported which may be a predisposingfactor. Appropriate clinical monitoring is advisable in accordance with utilised antipsychoticguidelines, e.g. measuring of blood glucose at baseline, 12 weeks after starting olanzapinetreatment and annually thereafter. Patients treated with any antipsychotic medicines, including

Zalasta, 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 fordiabetes mellitus should be monitored regularly for worsening of glucose control. Weight should bemonitored regularly, e.g. at baseline, 4, 8 and 12 weeks after starting olanzapine treatment andquarterly 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 thedevelopment of lipids disorders. Patients treated with any antipsychotic medicines, including

Zalasta, should be monitored regularly for lipids in accordance with utilised antipsychoticguidelines, e.g. at baseline, 12 weeks after starting olanzapine treatment and every 5 yearsthereafter.

While olanzapine demonstrated anticholinergic activity in vitro, experience during the clinicaltrials revealed 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, ALT, AST have been seencommonly, especially in early treatment. Caution should be exercised and follow-up organised inpatients with elevated ALT and/or AST, in patients with signs and symptoms of hepaticimpairment, in patients with pre-existing conditions associated with limited hepatic functionalreserve, and in patients who are being treated with potentially hepatotoxic medicines. In caseswhere hepatitis (including hepatocellular, cholestatic or mixed liver injury) has been diagnosed,olanzapine treatment should be discontinued.

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 byconcomitant illness, radiation therapy or chemotherapy and in patients with hypereosinophilicconditions or with myeloproliferative disease. Neutropenia has been reported commonly whenolanzapine and valproate are used concomitantly (see section 4.8).

Acute symptoms such as sweating, insomnia, tremor, anxiety, nausea, or vomiting have beenreported rarely ≥ 0.01% and < 0.1%) when olanzapine is stopped abruptly.

In clinical trials, clinically meaningful QTc prolongations (Fridericia QT correction [QTcF] ≥ 500milliseconds [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,in patients with congenital long QT syndrome, congestive heart failure, heart hypertrophy,hypokalaemia or hypomagnesaemia.

Thromboembolism

Temporal association of olanzapine treatment and venous thromboembolism has 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 allpossible risk factors of VTE e.g. immobilisation of patients, should be identified and preventivemeasures undertaken.

General CNS activity

Given the primary CNS effects of olanzapine, caution should be used when it is taken incombination with other centrally acting medicines and alcohol. As it exhibits in vitro dopamineantagonism, 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 uncommonlyin patients when treated with olanzapine. In most of these cases, a history of seizures or risk factorsfor seizures was 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 tardivedyskinesia increases with long term exposure, and therefore if signs or symptoms of tardivedyskinesia appear in a patient on olanzapine, a dose reduction or discontinuation should beconsidered.

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. 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 patientsaged 13-17 years showed various adverse reactions, including weight gain, changes in metabolicparameters and increases in prolactin levels (see sections 4.8 and 5.1).

Aspartame

Aspartame is a source of phenylalanine. It may be harmful for patient with phenylketonuria (PKU).

This medicine should be used with caution in patients 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 hasbeen observed. The clinical consequences are likely to be limited, but clinical monitoring isrecommended and an increase of olanzapine dose may be considered if necessary (see section 4.2).

Inhibition of CYP1A2

Fluvoxamine, a specific CYP 1A2 inhibitor, has been shown to significantly inhibit the metabolismof olanzapine. The mean increase in olanzapine Cmax following fluvoxamine was 54% in femalenon-smokers and 77% in male smokers. The mean increase in olanzapine AUC was 52% and 108%respectively. A lower starting dose of olanzapine should be considered in patients who are usingfluvoxamine or any other CYP1A2 inhibitors, such as ciprofloxacin. A decrease in the dose ofolanzapine should be considered if treatment with an inhibitor of CYP 1A2 is initiated.

Decreased bioavailability

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

Fluoxetine (a CYP2D6 inhibitor), single doses of antacid (aluminium, magnesium) or cimetidinehave 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 noinhibition of metabolism of the following active substances was found: tricyclic antidepressant(representing mostly CYP2D6 pathway), warfarin (CYP2C9), theophylline (CYP1A2) ordiazepam (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 dosageadjustment is required after the introduction of concomitant olanzapine.

General CNS activity

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

There are no adequate and well-controlled studies in pregnant women. Patients should be advisedto notify their physician if they become pregnant or intend to become pregnant during treatmentwith olanzapine. 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 symptomsthat 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.

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.

Because olanzapine may cause somnolence and dizziness, patients should be cautioned aboutoperating machinery, 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 hepaticaminotransferases (see section 4.4), rash, asthenia, fatigue, pyrexia, arthralgia, increased alkalinephosphatase, high gamma glutamyltransferase, high uric acid, high creatine phosphokinase andoedema.

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 (≥ 1/10,000to < 1/1,000), very rare (< 1/10,000), 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 gain1 Elevated cholesterol Development or Hypothermia12levels2,3 exacerbation of

Elevated glucose diabetes occasionallylevels4 associated with

Elevated triglyceride ketoacidosis or coma,levels2,5 including some fatal

Glucosuria cases (see section

Increased appetite 4.4)11

Somnolence Dizziness Seizures where in most Neuroleptic

Akathisia6 cases a history of malignant

Parkinsonism6 seizures or risk factors syndrome (see

Dyskinesia6 for seizures were section 4.4)12reported11 Discontinuation

Dystonia (including symptoms7, 12oculogyration)11

Tardive dyskinesia11

Amnesia9

Dysarthria

Stuttering11

Restless legssyndrome11

Bradycardia Ventricular

QTc prolongation (see tachycardia/fibrillatsection 4.4) ion, sudden death(see section 4.4)11

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

Epistaxis9

Mild, transient Abdominal distension9 Pancreatitis11anticholinergic effects Salivaryincluding constipation hypersecretion11and dry mouth

Transient, Hepatitis (includingasymptomatic hepatocellular,elevations of hepatic cholestatic oraminotransferases mixed liver(ALT, AST), injury)11especially in earlytreatment (see section4.4)

Rash Photosensitivity Drug Reactionreaction with Eosinophilia

Alopecia and Systemic

Symptoms(DRESS)

Arthralgia9 Rhabdomyolysis11

Urinary incontinence,urinary retention

Urinary hesitation11

Pregnancy, puerperium and perinatal conditions

Drug withdrawalsyndrome neonatal(see section 4.6)

Erectile dysfunction in Amenorrhea Priapism12males Breast enlargement

Decreased libido in Galactorrhea inmales and females females

Gynaecomastia/breastenlargement in males

Asthenia

Oedema

Pyrexia10

Elevated plasma Increased alkaline Increased totalprolactin levels8 phosphatase10 bilirubin

High creatinephosphokinase11

High Gamma

Glutamyltransferase10

High uric acid10

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% ofbaseline body weight was very common (22.2 %), ≥ 15 % was common (4.2 %) and ≥ 25 % wasuncommon (0.8 %). Patients gaining ≥ 7 %, ≥ 15 % and ≥ 25 % of their baseline body weight withlong-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 titrateddoses of haloperidol. In the absence of detailed information on the pre-existing history ofindividual acute and tardive extrapyramidal movement disorders, it cannot be concluded atpresent that olanzapine produces less tardive dyskinesia and/or other tardive extrapyramidalsyndromes.

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 approximately 6months.

Additional information on special populations

In clinical trials in elderly patients with dementia, olanzapine treatment was associated with ahigher incidence of death and cerebrovascular adverse reactions compared to placebo (see section4.4). Very common adverse reactions associated with the use of olanzapine in this patient groupwere abnormal gait and falls. Pneumonia, increased body temperature, lethargy, erythema, visualhallucinations 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 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 highplasma valproate levels. Olanzapine administered with lithium or valproate resulted in increasedlevels ( 10%) of tremor, dry mouth, increased appetite, and weight gain. Speech disorder was alsoreported 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 acutetreatment (up to 6 weeks). Long-term olanzapine treatment (up to 12 months) for recurrenceprevention in patients with bipolar disorder was associated with an increase of  7% from baselinebody 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 inadolescent patients (aged 13-17 years) than in adult patients or adverse reactions only identifiedduring 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 comparableexposures. The magnitude of weight gain and the proportion of adolescent patients who hadclinically significant weight gain were greater with long-term exposure (at least 24 weeks) thanwith short-term exposure.

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

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

Common: Elevated cholesterol levels15

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

Common: Dry mouth

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

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 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 fromborderline 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.

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 ofconsciousness ranging 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 havebeen reported for acute overdoses as low as 450 mg but survival has also been reported followingacute overdose of approximately 2 g of oral olanzapine.

There is no specific antidote for olanzapine. Induction of emesis is not recommended. Standardprocedures for management of overdose may be indicated (i.e. gastric lavage, administration ofactivated 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 withbetaagonist activity since beta stimulation may worsen hypotension. Cardiovascular monitoring isnecessary to detect possible arrhythmias. Close medical supervision and monitoring shouldcontinue until the patient recovers.

Pharmacotherapeutic group: psycholeptics, diazepines, oxazepines, thiazepines and oxepines, ATCcode: N05AH03.

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) forserotonin 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 behavioural studies with olanzapineindicated 5HT, dopamine, and cholinergic antagonism, consistent with the receptor-binding profile.

Olanzapine demonstrated a greater in vitro affinity for serotonin 5 HT2 than dopamine D2receptors and greater 5 HT2 than D2 activity in vivo, models. Electrophysiological studiesdemonstrated that olanzapine selectively reduced the firing of mesolimbic (A10) dopaminergicneurons, 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, atdoses below those producing catalepsy, an effect indicative of motor side-effects. Unlike someother 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 patientsrevealed that olanzapine-responsive patients had lower striatal D2 occupancy than some otherantipsychotic- and risperidone-responsive patients, while being comparable to clozapine-responsivepatients.

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 prospectivesecondary analysis of baseline to endpoint mood score change demonstrated a statisticallysignificant 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 superiorefficacy to placebo and valproate semisodium (divalproex) in reduction of manic symptoms over 3weeks. 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, theaddition of olanzapine 10 mg (co-therapy with lithium or valproate) resulted in a greater reductionin 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 onolanzapine and were then randomised to olanzapine or placebo, olanzapine demonstratedstatistically significant superiority over placebo on the primary endpoint of bipolar recurrence.

Olanzapine also showed a statistically significant advantage over placebo in terms of preventingeither recurrence into mania or recurrence into depression.

In a second 12-month recurrence prevention study in manic episode patients who achievedremission with a combination of olanzapine and lithium and were then randomised to olanzapine orlithium alone, olanzapine was statistically non-inferior to lithium on the primary endpoint ofbipolar 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 plusa mood stabiliser (lithium or valproate), long-term olanzapine co-therapy with lithium or valproatewas not statistically significantly superior to lithium or valproate alone in delaying bipolarrecurrence, 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 weightcompared 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 controlled data on maintenance of effect or long term safety (see sections 4.4 and 4.8).

Information on long term safety is primarily limited to open-label, uncontrolled data.

Olanzapine orodispersible tablet is bioequivalent to olanzapine tablets, with a similar rate andextent of absorption. Olanzapine orodispersible tablets may be used as an alternative to olanzapinetablets.

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 7to about 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 majorcirculating 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-desmethyland 2-hydroxymethyl metabolites, both exhibited significantly less in vivo pharmacologicalactivity than olanzapine in animal studies. The predominant pharmacologic activity is from theparent 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. In 44patients 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 hr) and the clearance was reduced (18.9 versus 27.3 l/hr). However, olanzapine (5-20 mg)demonstrated a comparable safety profile in female (n=467) as in male patients (n=869).

In renally impaired patients (creatinine clearance < 10 ml/min) versus healthy subjects, there wasno significant difference in mean elimination half-life (37.7 versus 32.4 hr) or clearance (21.2versus 25.0 l/hr). A mass balance study showed that approximately 57% of radiolabelledolanzapine appeared 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 thepharmacokinetics of orally administered olanzapine (2.5 - 7.5 mg single dose): Subjects with mildto moderate hepatic dysfunction had slightly increased systemic clearance and faster eliminationhalf-time compared to subjects with no hepatic dysfunction (n = 3). There were more smokersamong 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,or smoking 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. Themedian lethal doses were approximately 210 mg/kg (mice) and 175 mg/kg (rats). Dogs toleratedsingle 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 oraldoses 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 predominanteffects 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 ovariesand 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 reductionsin 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 (totalolanzapine exposure [AUC] is 12- to 15-fold greater than that of a man given a 12-mg dose). Incytopenic dogs, there were no adverse effects on progenitor and proliferating cells in the bonemarrow.

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 humandose). In the offspring of rats given olanzapine, delays in foetal development and transientdecreases in offspring 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 notcarcinogenic.

Mannitol

Microcrystalline cellulose

Crospovidone

Low-substituted hydroxypropylcellulose

Aspartame

Calcium silicate

Magnesium stearate

Not applicable.

5 years

Store in the original package in order to protect from light and moisture. This medicinal productdoes not require any special temperature storage conditions.

Zalasta orodispersible tablets are available in boxes of 14, 28, 35, 56 or 70 tablets in blisters(Alu/OPA/Alu/PVC).

Any unused product or waste material should be disposed of in accordance with local requirements.

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

Zalasta 5 mg orodispersible tablets

EU/1/07/415/032-036

Zalasta 7.5 mg orodispersible tablets

EU/1/07/415/037-041

Zalasta 10 mg orodispersible tablets

EU/1/07/415/042-046

Zalasta 15 mg orodispersible tablets

EU/1/07/415/047-051

Zalasta 20 mg orodispersible tablets

EU/1/07/415/052-056

Date of first authorisation: 27 September 2007

Date of latest renewal: 26 July 2012

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

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