ZYPADHERA 405mg powder + solvent for suspension injection with prolonged release medication leaflet

ZYPADHERA 210 mg powder and solvent for prolonged release suspension for injection

ZYPADHERA 300 mg powder and solvent for prolonged release suspension for injection

ZYPADHERA 405 mg powder and solvent for prolonged release suspension for injection

ZYPADHERA 210 mg powder and solvent for prolonged release suspension for injection

Each vial contains olanzapine pamoate monohydrate equivalent to 210 mg olanzapine. Afterreconstitution each ml of suspension contains 150 mg olanzapine.

ZYPADHERA 300 mg powder and solvent for prolonged release suspension for injection

Each vial contains olanzapine pamoate monohydrate equivalent to 300 mg olanzapine. Afterreconstitution each ml of suspension contains 150 mg olanzapine.

ZYPADHERA 405 mg powder and solvent for prolonged release suspension for injection

Each vial contains olanzapine pamoate monohydrate equivalent to 405 mg olanzapine. Afterreconstitution each ml of suspension contains 150 mg olanzapine.

For the full list of excipients see section 6.1.

Powder and solvent for prolonged release suspension for injection

Powder: yellow solid

Solvent: clear, colourless to slightly yellow solution.

Maintenance treatment of adult patients with schizophrenia sufficiently stabilised during acute treatmentwith oral olanzapine.

ZYPADHERA 210 mg, 300 mg or 405 mg powder and solvent for prolonged release suspension forinjection must not be confused with olanzapine 10 mg powder for solution for injection.

Patients should be treated initially with oral olanzapine before administering ZYPADHERA, toestablish tolerability and response.

In order to identify the first ZYPADHERA dose for all patients the scheme in Table 1 should beconsidered.

Table 1 Recommended dose scheme between oral olanzapine and ZYPADHERA

Target oral olanzapine dose Recommended starting dose of Maintenance dose after 2 months of

ZYPADHERA ZYPADHERA treatment10 mg/day 210 mg/2 weeks or 405 mg/4 weeks 150 mg/2 weeks or 300 mg/4 weeks15 mg/day 300 mg/2 weeks 210 mg/2 weeks or 405 mg/4 weeks20 mg/day 300 mg/2 weeks 300 mg/2 weeks

Patients should be monitored carefully for signs of relapse during the first one to two months oftreatment. During antipsychotic treatment, improvement in the patient’s clinical condition may takeseveral days to some weeks. Patients should be closely monitored during this period. During treatmentdose may subsequently be adjusted on the basis of individual clinical status. After clinical reassessmentdose may be adjusted within the range 150 mg to 300 mg every 2 weeks or 300 to 405 mg every 4weeks. (Table 1)

Supplementation

Supplementation with oral olanzapine was not authorised in double-blind clinical studies. If oralolanzapine supplementation is clinically indicated, then the combined total dose of olanzapine from bothformulations should not exceed the corresponding maximum oral olanzapine dose of 20 mg/day.

There are no systematically collected data to specifically address switching patients from

ZYPADHERA to other antipsychotic medicinal products. Due to the slow dissolution of the olanzapinepamoate salt which provides a slow continuous release of olanzapine that is complete approximately sixto eight months after the last injection, supervision by a clinician, especially during the first 2 monthsafter discontinuation of ZYPADHERA, is needed when switching to another antipsychotic product andis considered medically appropriate.

ZYPADHERA has not been systematically studied in elderly patients (> 65 years). ZYPADHERA isnot recommended for treatment in the elderly population unless a well-tolerated and effective doseregimen using oral olanzapine has been established. A lower starting dose (150 mg/4 weeks) is notroutinely indicated, but should be considered for those 65 and over when clinical factors warrant.

ZYPADHERA is not recommended to be started in patients >75 years (see section 4.4).

Unless a well-tolerated and effective dose regimen using oral olanzapine has been established in suchpatients, ZYPADHERA should not be used. A lower starting dose (150 mg every 4 weeks) should beconsidered for such patients. In cases of moderate hepatic insufficiency (cirrhosis, Child-Pugh Class Aor B), the starting dose should be 150 mg every 4 weeks and only increased with caution.

Smokers

The starting dose and dose range need not be routinely altered for non-smokers relative to smokers. Themetabolism of olanzapine may be induced by smoking. Clinical monitoring is recommended and anincrease 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, geriatricage, non-smoking status), consideration should be given to decreasing the dose. When indicated, doseescalation should be performed with caution in these patients.

The safety and efficacy of ZYPADHERA in children and adolescents below 18 years has not beenestablished. Currently available data are described in sections 4.8 and 5.1 but no recommendation on aposology can be made.

FOR INTRAMUSCULAR USE ONLY. DO NOT ADMINISTER INTRAVENOUSLY OR

SUBCUTANEOUSLY (See section 4.4)

ZYPADHERA should only be administered by deep intramuscular gluteal injection by a healthcareprofessional trained in the appropriate injection technique and in locations where post-injectionobservation and access to appropriate medical care in the case of overdose can be assured.

After each injection, patients should be observed in a health care facility by appropriately qualifiedpersonnel for at least 3 hours for signs and symptoms consistent with olanzapine overdose.

Immediately prior to leaving the health care facility, it should be confirmed that the patient is alert,oriented, and absent of any signs and symptoms of overdose. If an overdose is suspected, closemedical supervision and monitoring should continue until examination indicates that signs andsymptoms have resolved (see section 4.4.). The 3-hour observation period should be extended asclinically appropriate for patients who exhibit any signs or symptoms consistent with olanzapineoverdose.

For instructions for use, see section 6.6.

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

Patients with known risk of narrow-angle glaucoma.

Special care must be taken to apply appropriate injection technique to avoid inadvertent intravascular orsubcutaneous injection (see section 6.6).

Use in patients who are in an acutely agitated or severely psychotic state

ZYPADHERA should not be used to treat patients with schizophrenia who are in an acutely agitated orseverely psychotic state such that immediate symptom control is warranted.

Post-injection syndrome

During pre-marketing clinical studies, reactions that presented with signs and symptoms consistentwith olanzapine overdose, were reported in patients following an injection of ZYPADHERA. Thesereactions occurred in <0.1% of injections and approximately 2% of patients. Most of these patientshave developed symptoms of sedation (ranging from mild in severity up to coma) and/or delirium(including confusion, disorientation, agitation, anxiety and other cognitive impairment). Othersymptoms noted include extrapyramidal symptoms, dysarthria, ataxia, aggression, dizziness,weakness, hypertension and convulsion. In most cases, initial signs and symptoms related to thisreaction have appeared within 1 hour following injection, and in all cases full recovery was reported tohave occurred within 24 - 72 hours after injection. Reactions occurred rarely (<1 in 1,000 injections)between 1 and 3 hours, and very rarely (<1 in 10,000 injections) after 3 hours. Patients should beadvised about this potential risk and the need to be observed for 3 hours in a healthcare facility eachtime ZYPADHERA is administered. Post-marketing reports of post-injection syndrome since themarketing authorization of ZYPADHERA are generally consistent with the experience seen in clinicalstudies.

After each injection, patients should be observed in a healthcare facility by appropriately qualifiedpersonnel for at least 3 hours for signs and symptoms consistent with olanzapine overdose.

Immediately prior to leaving the health care facility, it should be confirmed that the patient is alert,oriented, and absent of any signs and symptoms of overdose. If an overdose is suspected, closemedical supervision and monitoring should continue until examination indicates that signs andsymptoms have resolved. The 3-hour observation period should be extended as clinically appropriatefor patients who exhibit any signs or symptoms consistent with olanzapine overdose.

For the remainder of the day after injection, patients should be advised to be vigilant for signs andsymptoms of overdose secondary to post injection adverse reactions, be able to obtain assistance ifneeded and should not drive or operate machinery (see section 4.7).

If parenteral benzodiazepines are essential for management of post injection adverse reactions, carefulevaluation of clinical status for excessive sedation and cardiorespiratory depression is recommended(see section 4.5).

Injection site related adverse events

The most commonly reported injection site related adverse reaction was pain. The majority of thesereactions was reported to be of “mild” to “moderate” severity. In the event of an injection site relatedadverse reaction occuring, appropriate measures to manage these events should be taken (see section4.8).

Dementia-related psychosis and/or behavioural disturbances

Olanzapine is not recommended for use in 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) with dementia-related psychosis and/or disturbed behaviours, there was a 2-fold increase in the incidence of death inoral 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) orduration of treatment. Risk factors that may predispose this patient population to increased mortalityinclude age > 65 years, dysphagia, sedation, malnutrition and dehydration, pulmonary conditions (e.g.,pneumonia, with or without aspiration), or concomitant use of benzodiazepines. However, the incidenceof death was higher in oral olanzapine-treated than in placebo-treated patients independent of these riskfactors.

In the same clinical trials, cerebrovascular adverse reactions (CVAEvents e.g., stroke, transient ischemicattack), including fatalities, were reported. There was a 3-fold increase in CVAE in patients treated withoral olanzapine compared to patients treated with placebo (1.3% vs. 0.4%, respectively). All oralolanzapine- 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 oral 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-Parkinsonianmedicinal products and dosages throughout the study. Oral 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. Rarecases reported as NMS have also been received in association with oral 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 antipsychoticmedicines, including ZYPADHERA, 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-controlledclinical 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 lipidsdisorders. Patients treated with any antipsychoticmedicines, including ZYPADHERA, 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 in patientswith concomitant illness is limited, caution is advised when prescribing for patients with prostatichypertrophy, 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 withelevated ALT and/or AST, in patients with signs and symptoms of hepatic impairment, in patients withpre-existing conditions associated with limited hepatic functional reserve, and in patients who are beingtreated with potentially hepatotoxic medicines. In cases where 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, 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 oral olanzapine is stopped abruptly.

In clinical trials with oral olanzapine, 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 inassociated cardiac events compared to placebo. In clinical trials with olanzapine powder for solution forinjection or ZYPADHERA, olanzapine was not associated with a persistent increase in absolute QT orin QTc intervals. However, caution should be exercised when olanzapine is prescribed with medicinesknown 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 patients withschizophrenia often present with acquired risk factors for venous thromboembolism all possible riskfactors 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 to factorswhich may lower the seizure threshold. Seizures have been reported to occur uncommonly in patientswhen treated with olanzapine. In most of these cases, a history of seizures or risk factors for seizureswere reported.

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 in apatient on olanzapine, a dose reduction or discontinuation should be considered. These symptoms cantemporally 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 not usingantipsychotics. In the study, the risk of olanzapine was comparable to the risk of atypical antipsychoticsincluded in a pooled analysis.

Olanzapine is not indicated for use in the treatment of children and adolescents. Studies in patients aged13-17 years showed various adverse reactions, including weight gain, changes in metabolic parametersand increases in prolactin levels (see sections 4.8 and 5.1).

Use in elderly (>75 years)

No information on the use of ZYPADHERA in patients >75 years is available. Due to biochemical andphysiological modification and reduction of muscular mass, this formulation is not recommended to bestarted in this sub-group of patients.

After reconstitution this medicine contains less than 1 mmol sodium (23 mg) per vial, that is to sayessentially sodium-free.

Interaction studies have only been performed in adults.

Caution should be exercised in patients who receive medicinal products that can induce hypotension orsedation.

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 beenobserved. The clinical consequences are likely to be limited, but clinical monitoring is recommendedand an increase of olanzapine dose may be considered if necessary (see section 4.2).

Inhibition of CYP1A2

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

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 (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 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 in pregnancyonly 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, newbornsshould be monitored carefully.

In a study of oral olanzapine 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.

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. As olanzapinemay cause somnolence and dizziness, patients should be cautioned about operating machinery,including motor vehicles.

Patients should be advised not to drive or operate machinery for the remainder of the day after eachinjection due to the possibility of a post-injection syndrome event leading to symptoms consistent witholanzapine overdose (see section 4.4).

Adverse reactions seen with olanzapine pamoate

Post-injection syndrome reactions have occurred with ZYPADHERA leading to symptoms consistentwith olanzapine overdose (see sections 4.2 and 4.4). Clinical signs and symptoms included symptoms ofsedation (ranging from mild in severity up to coma) and/or delirium (including confusion,disorientation, agitation, anxiety and other cognitive impairment). Other symptoms noted includeextrapyramidal symptoms, dysarthria, ataxia, aggression, dizziness, weakness, hypertension andconvulsion.

Other adverse reactions observed in patients treated with ZYPADHERA were similar to those seen withoral olanzapine. In clinical trials with ZYPADHERA, the only adverse reaction reported at a statisticallysignificantly higher rate in the ZYPADHERA group than in the placebo group was sedation(ZYPADHERA 8.2%, placebo 2.0%). Among all ZYPADHERA treated patients, sedation was reportedby 4.7% of patients.

In clinical trials with ZYPADHERA the incidence of injection site related adverse reactions wasapproximately 8%. The most commonly reported injection site related adverse reaction was pain (5%);some other injection site adverse reactions reported were (in decreasing frequency): nodule typereactions, erythema type reactions, non-specific injection site reactions, irritation, oedema typereactions, bruising, haemorrhage, and anaesthesia. These events occurred in about 0.1 to 1.1% ofpatients.

In a review of safety data from clinical trials and spontaneous postmarketing reports, injection siteabscess was rarely (≥ 1/10,000 to < 1/1,000) reported.

Adverse reactions seen with olanzapine

The undesirable effects listed below have been observed following administration of olanzapine.

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

The following table lists the adverse reactions and laboratory investigations observed from spontaneousreporting and in clinical trials. Within each frequency grouping, adverse reactions are presented in orderof 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), veryrare (< 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 Thrombocytopenia

Leukopenia10 11

Neutropenia10

Hypersensitivity11

Weight gain1 Elevated Development or Hypothermia12cholesterol exacerbation oflevels2,3 diabetes

Elevated glucose occasionallylevels4 associated with

Elevated ketoacidosis ortriglyceride coma, includinglevels2,5 some fatal cases

Glucosuria (see section 4.4)11

Increased appetite

Somnolence Dizziness Seizures where in Neuroleptic

Akathisia6 most cases a malignant

Parkinsonism6 history of seizures syndrome (see

Dyskinesia6 or risk factors for section 4.4)12seizures were Discontinuationreported11 symptoms7, 12

Dystonia(includingoculogyration)11

Tardivedyskinesia11

Amnesia 9

Dysarthria

Stuttering11

Restless Legs

Syndrome 11

Bradycardia Ventricular

QTc prolongation tachycardia/fibrill(see section 4.4) ation, suddendeath (see section4.4) 11

Orthostatic Thromboembolishypotension10 m (includingpulmonaryembolism anddeep veinthrombosis) (seesection 4.4)

Epistaxis9

Mild, transient Abdominal Pancreatitis11anticholinergic distension9effects including Salivaryconstipation and hypersecretion11dry mouth

Transient, Hepatitisasymptomatic (includingelevations of hepatocellular,hepatic cholestatic oraminotransferases mixed liver(ALT, AST), injury)11especially in earlytreatment (seesection 4.4)

Rash Photosensitivity Drug Reactionreaction with Eosinophilia

Alopecia and Systemic

Symptoms(DRESS)

Arthralgia9 Rhabdomyolysis11

Urinaryincontinence

Urinary retention

Urinaryhesitation11

Pregnancy, puerperium and perinatal conditions

Drug withdrawalsyndromeneonatal (seesection 4.6)

Erectile Amenorrhea Priapism12dysfunction in Breastmales enlargement

Decreased libido Galactorrhea inin males and femalesfemales Gynaecomastia/breastenlargement inmales

Asthenia Injection site

Fatigue abscess

Oedema

Pyrexia10

Injection site pain

Elevated plasma Increased alkaline Increased totalprolactin levels8 phosphatase10 bilirubin

High creatinephosphokinase11

High Gamma

Glutamyltransferase 10

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 baseline body weightwas very common (22.2 %), ≥ 15 % was common (4.2 %) and ≥ 25 % was uncommon (0.8 %). Patientsgaining ≥ 7 %, ≥ 15 % and ≥ 25% of their baseline body weight with long-term exposure (at least 48weeks) 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) werevery 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-treated patientshad a lower incidence of Parkinsonism, akathisia and dystonia compared with titrated doses ofhaloperidol. In the absence of detailed information on the pre-existing history of individual acute andtardive extrapyramidal movement disorders, it cannot be concluded at present that olanzapine producesless tardive dyskinesia and/or other tardive extrapyramidal syndromes.

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

8 In clinical trials of up to 12 weeks, plasma prolactin concentrations exceeded the upper limit of normalrange in approximately 30% of olanzapine treated patients with normal baseline prolactin value. In themajority of these patients the elevations were generally mild, and remained below two times the upperlimit 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 at theupper 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 completed 9-12months of therapy, the rate of increase in mean blood glucose slowed after approximately 6 months.

Additional information on special populations

In clinical trials in elderly patients with dementia, olanzapine treatment was associated with a higherincidence 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 wereabnormal 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’sdisease, worsening of Parkinsonian symptomatology and hallucinations were reported very commonlyand 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 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 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, data fromthe 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-termclinical trials in adolescent patients. Clinically significant weight gain (≥ 7%) appears to occur morefrequently in the adolescent population compared to adults with comparable exposures. The magnitudeof weight gain and the proportion of adolescent patients who had clinically significant weight gain weregreater 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. Thefrequency 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 body weight(kg) was very common (40.6 %), ≥ 15% of baseline body weight was common (7.1 %) and ≥ 25 % wascommon (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 borderline atbaseline (≥ 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 system listedin Appendix V.

If signs and symptoms of overdose consistent with post injection syndrome are observed, appropriatesupportive measures should be taken (see section 4.4).

While overdose is less likely with parenteral than oral medicinal products, reference information for oralolanzapine overdose is presented below:

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 sedationto 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 beenreported for acute oral overdoses as low as 450 mg but survival has also been reported following acuteoverdose of approximately 2 g of oral olanzapine.

There is no specific antidote for olanzapine. Symptomatic treatment and monitoring of vital organfunction should be instituted according to clinical presentation, including treatment of hypotension andcirculatory collapse and support of respiratory function. Do not use epinephrine, dopamine, or othersympathomimetic agents with beta-agonist activity since beta 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, ATC code

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; α-1adrenergic; and histamine H1 receptors. Animal behavioural studies with olanzapine indicated 5HT,dopamine, and cholinergic antagonism, consistent with the receptor-binding profile. Olanzapinedemonstrated a greater in vitro affinity for serotonin 5-HT2 than dopamine D2 receptors and greater 5-

HT2 than D2 activity in vivo, models. Electrophysiological studies demonstrated that olanzapineselectively reduced the firing of mesolimbic (A10) dopaminergic neurons, while having little effect onthe striatal (A9) pathways involved in motor function. Olanzapine reduced a conditioned avoidanceresponse, a test indicative of antipsychotic activity, at doses below those producing catalepsy, an effectindicative of motor side-effects. Unlike some other antipsychotic agents, olanzapine increasesresponding in an “anxiolytic” test.

In a Positron Emission Tomography (PET) study in patients treated with ZYPADHERA(300 mg/4 weeks), mean D2 receptor occupancy was 60% or higher at the end of a 6 month period, alevel consistent with that found during treatment with oral olanzapine.

The effectiveness of ZYPADHERA in the treatment and maintenance treatment of schizophrenia isconsistent with the established effectiveness of the oral formulation of olanzapine.

A total of 1469 patients with schizophrenia were included in 2 pivotal trials:

The first, an 8-week, placebo controlled trial conducted in adult patients (n=404) who wereexperiencing acute psychotic symptoms. Patients were randomized to receive injections of

ZYPADHERA 405 mg every 4 weeks, 300 mg every 2 weeks, 210 mg every 2 weeks, or placebo every2 weeks. No oral antipsychotic supplementation was allowed. Total Positive and Negative Symptom

Scores (PANSS) showed significant improvement from baseline (baseline mean Total PANSS Score101) to endpoint (mean changes -22.57, -26.32, -22.49 respectively) with each dose of ZYPADHERA(405 mg every 4 weeks, 300 mg every 2 weeks, and 210 mg every 2 weeks) as compared to placebo(mean change -8.51). Visitwise mean change from baseline to endpoint in PANSS Total score indicatedthat by Day 3, patients in the 300 mg/2 weeks and 405 mg/4 weeks treatment groups had statisticallysignificantly greater reductions in PANSS Total score compared to placebo (-8.6, -8.2, and -5.2,respectively). All 3 ZYPADHERA treatment groups showed statistically significantly greaterimprovement than placebo beginning by end of Week 1. These results support efficacy for

ZYPADHERA over 8 weeks of treatment and a drug effect that was observed as early as 1 week afterstarting treatment with ZYPADHERA.

The second, a long term study in clinically stable patients (n=1065) (baseline mean Total PANSS Score54.33 to 57.75) who were initially treated with oral olanzapine for 4 to 8 weeks and then switched tocontinue on oral olanzapine or to ZYPADHERA for 24 weeks. No oral antipsychotic supplementationwas allowed. ZYPADHERA treatment groups of 150 mg and 300 mg given every 2 weeks (dosespooled for analysis) and 405 mg given every 4 weeks were non inferior to the combined doses of 10, 15and 20 mg of oral olanzapine (doses pooled for analysis) as measured by rates of exacerbation ofsymptoms of schizophrenia (respective exacerbation rates, 10%, 10% 7%). Exacerbation was measuredby worsening of items on the PANSS derived BPRS Positive scale and hospitalization due to worseningof positive psychotic symptoms. The combined 150 mg and 300 mg/2 week treatment group was noninferior to the 405 mg/4 week treatment group (exacerbation rates 10% for each group) at 24 weeksafter randomisation.

ZYPADHERA has not been studied in the paediatric population. Controlled efficacy data inadolescents (ages 13 to 17 years) are limited to short term oral olanzapine studies in schizophrenia (6weeks) and mania associated with bipolar I disorder (3 weeks), involving less than 200 adolescents.

Oral olanzapine was used as a flexible dose starting with 2.5 and ranging up to 20 mg/day. Duringtreatment with oral 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 controlled data onmaintenance of effect or long term safety (see sections 4.4 and 4.8). Information on long term safety isprimarily limited to open-label, uncontrolled data.

Olanzapine is metabolised in the liver by conjugative and oxidative pathways. The major circulatingmetabolite is the 10-N-glucuronide. Cytochromes P450-CYP1A2 and P450-CYP2D6 contribute to theformation of the N-desmethyl and 2-hydroxymethyl metabolites; both exhibited significantly less invivo pharmacological activity than olanzapine in animal studies. The predominant pharmacologicactivity is from the parent, olanzapine.

After a single IM injection with ZYPADHERA the slow dissolution of the olanzapine pamoate salt inmuscle tissue begins immediately and provides a slow continuous release of olanzapine for more thanfour weeks. The release becomes diminishingly smaller within eight to twelve weeks. Antipsychoticsupplementation is not required at the initiation of ZYPADHERA treatment (see section 4.2).

The combination of the release profile and the dosage regimen (IM injection every two or four weeks)result in sustained olanzapine plasma concentrations. Plasma concentrations remain measurable forseveral months after each ZYPADHERA injection. The half-life of olanzapine after ZYPADHERA is30 days compared to 30 hours following oral administration. The absorption and elimination arecomplete approximately six to eight months after the last injection.

Oral olanzapine is rapidly distributed. The plasma protein binding of olanzapine is about 93% over theconcentration range of 7 to about 1000 ng/mL. In plasma, olanzapine is bound to albumin and α1-acidglycoprotein.

After repeated IM injections with 150 to 300 mg ZYPADHERA every two weeks, the 10th to 90thpercentile of steady-state plasma concentrations of olanzapine were between 4.2 and 73.2 ng/ml. Theplasma concentrations of olanzapine observed across the dose range of 150mg every 4 weeks to 300mgevery 2 weeks illustrate increased systemic olanzapine exposure with increased ZYPADHERA doses.

During the initial three months of treatment with ZYPADHERA, accumulation of olanzapine wasobserved but there was no additional accumulation during long-term use (12 months) in patients whowere injected with up to 300 mg every two weeks.

Olanzapine plasma clearance after oral olanzapine is lower in females (18.9 l/hr) versus males(27.3 l/hr), and in non-smokers (18.6 l/hr) versus smokers (27.7 l/hr). Similar pharmacokineticdifferences between males and females and smokers and non-smokers were observed in ZYPADHERAclinical trials. However, the magnitude of the impact of gender, or smoking on olanzapine clearance issmall in comparison to the overall variability between individuals.

No specific investigations have been conducted in the elderly with ZYPADHERA. ZYPADHERA is notrecommended for treatment in the elderly population (65 years and over) unless a well-tolerated andeffective dosage regimen using oral olanzapine has been established. In healthy elderly (65 and over)versus non-elderly subjects, the mean elimination half-life was prolonged (51.8 versus 33.8 hours) andthe clearance was reduced (17.5 versus 18.2 l/hr). The pharmacokinetic variability observed in theelderly 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 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 hours) or clearance (21.2 versus25.0 l/hr). A mass balance study showed that approximately 57% of radiolabelled olanzapine appearedin urine, principally as metabolites. Although patients with renal impairment were not studied with

ZYPADHERA, it is recommended that a well-tolerated and effective dosage regimen using oralolanzapine is established in patients with renal impairment before treatment with ZYPADHERA isinitiated (see section 4.2).

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 %).

Although patients with hepatic impairment were not studied with ZYPADHERA, it is recommendedthat a well-tolerated and effective dosage regimen using oral olanzapine is established in patients withhepatic impairment before treatment with ZYPADHERA is initiated (see section 4.2).

In a study of oral olanzapine given to Caucasians, Japanese, and Chinese subjects, there were nodifferences in the pharmacokinetic parameters among the three populations.

Preclinical safety studies were performed using olanzapine pamoate monohydrate. The main findingsfound in repeat-dose toxicity studies (rat, dog), in a 2-year rat carcinogenicity study, and in toxicity toreproduction studies (rat, rabbit) were limited to injection site reactions for which no NOAEL could bedetermined. No new toxic effect resulting from systemic exposure to olanzapine could be identified.

However, systemic concentrations in these studies were generally less than that seen at effect levels inthe oral studies; thus the information on oral olanzapine is provided below for reference.

Acute (single-dose) toxicity

Signs of oral toxicity in rodents were characteristic of potent antipsychotic compounds: hypoactivity,coma, tremors, clonic convulsions, salivation, and depressed weight gain. The median lethal doses wereapproximately 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,laboured 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. Reversible effectsconsistent 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 in circulating leukocytes in mice and non-specific reductions of circulating leukocytesin 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 olanzapineexposure [AUC] is 12- to 15-fold greater than that of a man given a 12 mg dose). In cytopenic dogs,there were no undesirable effects on progenitor and proliferating cells in the bone marrow.

Olanzapine had no teratogenic effects. Sedation affected mating performance of male rats. Oestrouscycles were affected at doses of 1.1 mg/kg (3 times the maximum human dose) and reproductionparameters were influenced in rats given 3 mg/kg (9 times the maximum human dose). In the offspringof rats given olanzapine, delays in foetal development and transient decreases in offspring activity levelswere seen.

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

Based on the results of oral studies in mice and rats, it was concluded that olanzapine is notcarcinogenic.

None

Carmellose sodium

Mannitol

Polysorbate 80

Water for injections

Hydrochloric acid (for pH adjustment)

Sodium hydroxide (for pH adjustment)

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

2 years

After reconstitution in the vial: 24 hours. If the product is not used right away, it should be shakenvigorously to re-suspend. Once withdrawn from vial into syringe, the suspension should be usedimmediately.

Chemical and physical stability of the suspension in the vials has been demonstrated for 24 hours at 20-25 °C. From a microbiological point of view, the product should be used immediately. If not usedimmediately, in-use storage times and conditions prior to use are the responsibility of the user andwould normally not be longer than 24 hours at 20-25°C.

Do not refrigerate or freeze.

ZYPADHERA 210 mg powder: Type I glass vial. Bromobutyl stopper with rust colour seal.

ZYPADHERA 300 mg powder: Type I glass vial. Bromobutyl stopper with olive colour seal.

ZYPADHERA 405 mg powder: Type I glass vial. Bromobutyl stopper with steel blue colour seal.

3 ml solvent: Type I glass vial. Butyl stopper with purple seal.

One carton contains one vial of powder and one vial of solvent, one Hypodermic 3ml syringe with pre-attached 19-gauge, 38 mm safety needle, one 19-gauge, 38 mm Hypodermic safety needle and two 19-gauge, 50 mm Hypodermic safety needles.

FOR DEEP INTRAMUSCULAR GLUTEAL INJECTION ONLY. DO NOT ADMINISTER

INTRAVENOUSLY OR SUBCUTANEOUSLY.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

STEP 1: Preparing materials

It is recommended that gloves are used as ZYPADHERA may irritate the skin.

Reconstitute ZYPADHERA powder for prolonged release suspension for injection only with the solventprovided in the pack using standard aseptic techniques for reconstitution of parenteral products.

STEP 2: Determining solvent volume for reconstitution

This table provides the amount of solvent required to reconstitute ZYPADHERA powder for prolongedrelease suspension for injection.

ZYPADHERA Volume of solvent to addvial strength (mg) (ml)210 1.3300 1.8405 2.3

It is important to note that there is more solvent in the vial than is needed to reconstitute.

STEP 3: Reconstituting ZYPADHERA1. Loosen the powder by lightly tapping the vial.2. Open the pre-packaged Hypodermic syringe and needle with needle protection device. Peel blisterpouch and remove device. Attach a syringe (if not already attached) to the Luer connection of thedevice with an easy twisting motion. Seat the needle firmly on the device with a push and aclockwise twist, then pull the needle cap straight away from the needle. Failure to follow theseinstructions may result in a needlestick injury.

3. Withdraw the pre-determined solvent volume (Step 2) into the syringe.4. Inject the solvent volume into the powder vial.5. Withdraw air to equalize the pressure in the vial.6. Remove the needle, holding the vial upright to prevent any loss of solvent.7. Engage the needle safety device. Press the needle into the sheath using a one-handed technique.

Perform a one-handed technique by GENTLY pressing the sheath against a flat surface. AS THE

SHEATH IS PRESSED (Fig. 1), THE NEEDLE IS FIRMLY ENGAGED INTO THE SHEATH(Fig. 2)8. Visually confirm that the needle is fully engaged into the needle protection sheath. Only remove thedevice with the engaged needle from the syringe when required by a specific medical procedure.

Remove by grasping the Luer hub of the needle protection device with thumb and forefinger,keeping the free fingers clear of the end of the device containing the needle point (Fig. 3).

9. Tap the vial firmly and repeatedly on a hard surface until no powder is visible. Protect the surfaceto cushion impact. (See Figure A)

Figure A: Tap firmly to mix10. Visually check the vial for clumps. Unsuspended powder appears as yellow, dry clumps clingingto the vial. Additional tapping may be required if clumps remain. (See Figure B)

Unsuspended: visible clumps Suspended: no clumps

Figure B: Check for unsuspended powder and repeat tapping if needed.

11. Shake the vial vigorously until the suspension appears smooth and is consistent in color and texture.

The suspended product will be yellow and opaque. (See Figure C)

Figure C: Vigorously shake vial

If foam forms, let vial stand to allow foam to dissipate. If the product is not used immediately, itshould be shaken vigorously to re-suspend. Reconstituted ZYPADHERA remains stable for up to24 hours in the vial.

STEP 1: Injecting ZYPADHERA

This table confirms the final ZYPADHERA suspension volume to inject. Suspension concentration is150 mg/ml olanzapine.

Dose Final volume to inject(mg) (ml)150 1.0210 1.4300 2.0405 2.71. Determine which needle will be used to administer the injection to the patient. For obese patients,the 50 mm needle is recommended for injection: If the 50 mm needle is to be used for injection, attach the 38 mm safety needle to the syringe towithdraw the required suspension volume. If the 38 mm needle is to be used for the injection, attach the 50 mm safety needle to withdrawthe required suspension volume.2. Slowly withdraw the desired amount. Some excess product will remain in the vial.3. Engage the needle safety device and remove needle from syringe.4. Attach the selected 50 mm or 38 mm safety needle to the syringe prior to injection. Once thesuspension has been removed from the vial, it should be injected immediately.5. Select and prepare a site for injection in the gluteal area. DO NOT INJECT INTRAVENOUSLY

OR SUBCUTANEOUSLY.6. After insertion of the needle, aspirate for several seconds to ensure no blood appears. If any blood isdrawn into the syringe, discard the syringe and the dose and begin reconstitution and administrationprocedure again. The injection should be performed with steady, continuous pressure.

DO NOT MASSAGE THE INJECTION SITE.

7. Engage the needle safety device. (Fig. 1 and 2)8. Discard the vials, syringe, used needles, extra needle and any unused solvent in accordance withappropriate clinical procedures. The vial is for single use only.

CHEPLAPHARM Registration GmbH, Weiler Straße 5e, 79540 Lörrach, Germany.

EU/1/08/479/001

EU/1/08/479/002

EU/1/08/479/003

Date of first authorisation: 19/11/2008

Date of latest renewal: 26/08/2013

{MM/YYYY}

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

Agency https://www.ema.europa.eu