Zypadhera

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
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 
 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
ZYPADHERA 210 mg powder and solvent for prolonged release suspension for injection 
Each vial contains olanzapine pamoate monohydrate equivalent to 210 mg olanzapine. After 
reconstitution 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. After 
reconstitution 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. After 
reconstitution each ml of suspension contains 150 mg olanzapine. 
 
For the full list of excipients see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Powder and solvent for prolonged release suspension for injection 
 
Powder: yellow solid  
Solvent: clear, colourless to slightly yellow solution. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Maintenance treatment of adult patients with schizophrenia sufficiently stabilised during acute treatment 
with oral olanzapine. 
 
4.2 Posology and method of administration 
 
ZYPADHERA 210 mg, 300 mg or  405 mg  powder and solvent for prolonged release suspension for 
injection must not be confused with olanzapine 10 mg powder for solution for injection. 
 
Posology 
 
Patients should be treated initially with oral olanzapine before administering ZYPADHERA, to 
establish tolerability and response. 
 
In order to identify the first ZYPADHERA dose for all patients the scheme in Table 1 should be 
considered.  



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Table 1 Recommended dose scheme between oral olanzapine and ZYPADHERA 

 
Target oral olanzapine dose Recommended starting dose of 

ZYPADHERA 
Maintenance dose after 2 months of 
ZYPADHERA treatment 

10 mg/day 210 mg/2 weeks or 405 mg/4 weeks 150 mg/2 weeks or 300 mg/4 weeks 
15 mg/day 300 mg/2 weeks 210 mg/2 weeks or 405 mg/4 weeks 
20 mg/day 300 mg/2 weeks 300 mg/2 weeks 
 
Dose adjustment 
Patients should be monitored carefully for signs of relapse during the first one to two months of 
treatment. During antipsychotic treatment, improvement in the patient’s clinical condition may take 
several days to some weeks. Patients should be closely monitored during this period. During treatment 
dose may subsequently be adjusted on the basis of individual clinical status. After clinical reassessment 
dose may be adjusted within the range 150 mg to 300 mg every 2 weeks or 300 to 405 mg every 4 
weeks.  (Table 1) 
 
Supplementation 
Supplementation with oral olanzapine was not authorised in double-blind clinical studies.  If oral 
olanzapine supplementation is clinically indicated, then the combined total dose of olanzapine from both 
formulations should not exceed the corresponding maximum oral olanzapine dose of 20 mg/day. 

 
Switching to other antipsychotic medicinal products 
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 olanzapine 
pamoate salt which provides a slow continuous release of olanzapine that is complete approximately six 
to eight months after the last injection, supervision by a clinician, especially during the first 2 months 
after discontinuation of ZYPADHERA, is needed when switching to another antipsychotic product and 
is considered medically appropriate. 
 
Special populations 
 
Elderly 
ZYPADHERA has not been systematically studied in elderly patients (> 65 years). ZYPADHERA is 
not recommended for treatment in the elderly population unless a well-tolerated and effective dose 
regimen using oral olanzapine has been established. A lower starting dose (150 mg/4 weeks) is not 
routinely 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). 
 
Renal and/or hepatic impairment  
Unless a well-tolerated and effective dose regimen using oral olanzapine has been established in such 
patients, ZYPADHERA should not be used. A lower starting dose (150 mg every 4 weeks) should be 
considered for such patients. In cases of moderate hepatic insufficiency (cirrhosis, Child-Pugh Class A 
or 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. The 
metabolism of olanzapine may be induced by smoking. Clinical monitoring is recommended and 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 dose. When indicated, dose 
escalation should be performed with caution in these patients. 
 



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Paediatric population 
The safety and efficacy of ZYPADHERA in children and adolescents below 18 years has not been 
established. Currently available data are described in sections 4.8 and 5.1 but no recommendation on a 
posology can be made. 
 
Method of administration 
 
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 healthcare 
professional trained in the appropriate injection technique and in locations where post-injection 
observation 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 qualified 
personnel 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, close 
medical supervision and monitoring should continue until examination indicates that signs and 
symptoms have resolved (see section 4.4.). The 3-hour observation period should be extended as 
clinically appropriate for patients who exhibit any signs or symptoms consistent with olanzapine 
overdose. 
 
For instructions for use, see section 6.6. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.   
Patients with known risk of narrow-angle glaucoma. 
 
4.4 Special warnings and precautions for use 
 
Special care must be taken to apply appropriate injection technique to avoid inadvertent intravascular or 
subcutaneous 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 or 
severely psychotic state such that immediate symptom control is warranted.  
 
Post-injection syndrome 
During pre-marketing clinical studies, reactions that presented with signs and symptoms consistent 
with olanzapine overdose, were reported in patients following an injection of ZYPADHERA.  These 
reactions occurred in <0.1% of injections and approximately 2% of patients. Most of these patients 
have developed symptoms of sedation (ranging from mild in severity up to coma) and/or delirium 
(including confusion, disorientation, agitation, anxiety and other cognitive impairment). Other 
symptoms noted include extrapyramidal symptoms, dysarthria, ataxia, aggression, dizziness, 
weakness, hypertension and convulsion. In most cases, initial signs and symptoms related to this 
reaction have appeared within 1 hour following injection, and in all cases full recovery was reported to 
have 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 be 
advised about this potential risk and the need to be observed for 3 hours in a healthcare facility each 
time ZYPADHERA is administered. Post-marketing reports of post-injection syndrome since the 
marketing authorization of ZYPADHERA are generally consistent with the experience seen in clinical 
studies. 
 
After each injection, patients should be observed in a healthcare facility by appropriately qualified 
personnel for at least 3 hours for signs and symptoms consistent with olanzapine overdose.  



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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, close 
medical supervision and monitoring should continue until examination indicates that signs and 
symptoms have resolved. The 3-hour observation period should be extended as clinically appropriate 
for 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 and 
symptoms of overdose secondary to post injection adverse reactions, be able to obtain assistance if 
needed and should not drive or operate machinery (see section 4.7). 
 
If parenteral benzodiazepines are essential for management of post injection adverse reactions, careful 
evaluation 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 these 
reactions was reported to be of “mild” to “moderate” severity.  In the event of an injection site related 
adverse reaction occuring, appropriate measures to manage these events should be taken (see section 
4.8). 
 
Dementia-related psychosis and/or behavioural disturbances 
Olanzapine is not recommended for use in patients with dementia-related psychosis and/or behavioural 
disturbances because of an increase in mortality and the risk of cerebrovascular accident. In placebo-
controlled clinical trials (6-12 weeks duration) of elderly patients (mean age 78 years) with dementia-
related psychosis and/or disturbed behaviours, there was a 2-fold increase in the incidence of death in 
oral olanzapine-treated patients compared to patients treated with placebo (3.5% vs. 1.5%, respectively). 
The higher incidence of death was not associated with olanzapine dose (mean daily dose 4.4 mg) or 
duration of treatment. Risk factors that may predispose this patient population to increased mortality 
include age > 65 years, dysphagia, sedation, malnutrition and dehydration, pulmonary conditions (e.g., 
pneumonia, with or without aspiration), or concomitant use of benzodiazepines. However, the incidence 
of death was higher in oral olanzapine-treated than in placebo-treated patients independent of these risk 
factors. 
 
In the same clinical trials, cerebrovascular adverse reactions (CVAEvents e.g., stroke, transient ischemic 
attack), including fatalities, were reported. There was a 3-fold increase in CVAE in patients treated with 
oral olanzapine compared to patients treated with placebo (1.3% vs. 0.4%, respectively). All oral 
olanzapine- and placebo-treated patients who experienced a cerebrovascular event had pre-existing risk 
factors. Age > 75 years and vascular/mixed type dementia were identified as risk factors for CVAE in 
association with olanzapine treatment. The efficacy of olanzapine was not established in these trials. 
 
Parkinson's disease 
The use of olanzapine in the treatment of dopamine agonist associated psychosis in patients with 
Parkinson's disease is not recommended. In clinical trials, worsening of Parkinsonian symptomatology 
and hallucinations were reported very commonly and more frequently than with placebo (see section 
4.8), and 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-Parkinsonian 
medicinal products and dosages throughout the study. Oral olanzapine was started at 2.5 mg/day and 
titrated to a maximum of 15 mg/day based on investigator judgement. 
 
Neuroleptic Malignant Syndrome (NMS)  
NMS is a potentially life-threatening condition associated with antipsychotic medicinal products. Rare 
cases reported as NMS have also been received in association with oral olanzapine. Clinical 
manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of 
autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac 
dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria 



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(rhabdomyolysis), and acute renal failure. If a patient develops signs and symptoms indicative of NMS, 
or presents with unexplained high fever without additional clinical manifestations of NMS, all 
antipsychotic medicines, including olanzapine must be discontinued. 
 
Hyperglycaemia and diabetes 
Hyperglycaemia and/or development or exacerbation of diabetes occasionally associated with 
ketoacidosis 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 predisposing factor. 
Appropriate clinical monitoring is advisable in accordance with utilised antipsychotic guidelines, e.g. 
measuring of blood glucose at baseline, 12 weeks after starting olanzapine treatment and annually 
thereafter.  Patients treated with any antipsychoticmedicines, including ZYPADHERA, should be 
observed for signs and symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia, and 
weakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus should be 
monitored regularly for worsening of glucose control. Weight should be monitored regularly, e.g. at 
baseline, 4, 8 and 12 weeks after starting olanzapine treatment and quarterly thereafter. 
 
Lipid alterations 
Undesirable alterations in lipids have been observed in olanzapine-treated patients in placebo-controlled 
clinical trials (see section 4.8). Lipid alterations should be managed as clinically appropriate, 
particularly in dyslipidemic patients and in patients with risk factors for the development of lipids 
disorders. Patients treated with any antipsychoticmedicines, including ZYPADHERA, should be 
monitored regularly for lipids in accordance with utilised antipsychotic guidelines, e.g. at baseline, 12 
weeks after starting olanzapine treatment and every 5 years thereafter. 
 
Anticholinergic activity  
While olanzapine demonstrated anticholinergic activity in vitro, experience during the clinical trials 
revealed a low incidence of related events. However, as clinical experience with olanzapine in patients 
with concomitant illness is limited, caution is advised when prescribing for patients with prostatic 
hypertrophy, or paralytic ileus and related conditions. 
 
Hepatic function 
Transient, asymptomatic elevations of hepatic aminotransferases, ALT, AST have been seen commonly, 
especially in early treatment. Caution should be exercised and follow-up organised in patients with 
elevated ALT and/or AST, in patients with signs and symptoms of hepatic impairment, in patients with 
pre-existing conditions associated with limited hepatic functional reserve, and in patients who are being 
treated with potentially hepatotoxic medicines. In cases where hepatitis (including hepatocellular, 
cholestatic or mixed liver injury) has been diagnosed, olanzapine treatment should be discontinued. 
 
Neutropenia 
Caution should be exercised in patients with low leukocyte and/or neutrophil counts for any reason, in 
patients receiving medicines known to cause neutropenia, in patients with a history of drug-induced 
bone marrow depression/toxicity, in patients with bone marrow depression caused by concomitant 
illness, radiation therapy or chemotherapy and in patients with hypereosinophilic conditions or with 
myeloproliferative disease. Neutropenia has been reported commonly when olanzapine and valproate 
are used concomitantly (see section 4.8).  
 
Discontinuation of treatment 
Acute symptoms such as sweating, insomnia, tremor, anxiety, nausea, or vomiting have been reported 
rarely (≥0.01% and <0.1%) when oral olanzapine is stopped abruptly.  
 
QT interval 
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 in 
associated cardiac events compared to placebo. In clinical trials with olanzapine powder for solution for 
injection or ZYPADHERA, olanzapine was not associated with a persistent increase in absolute QT or 
in QTc intervals. However, caution should be exercised when olanzapine is prescribed with medicines 



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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 reported 
uncommonly (≥ 0.1% and < 1%). A causal relationship between the occurrence of venous 
thromboembolism and treatment with olanzapine has not been established. However, since patients with 
schizophrenia often present with acquired risk factors for venous thromboembolism all possible risk 
factors of VTE e.g. immobilisation of patients, should be identified and preventive measures 
undertaken. 
 
General CNS activity 
Given the primary CNS effects of olanzapine, caution should be used when it is taken in combination 
with other centrally acting medicines and alcohol. As it exhibits in vitro dopamine antagonism, 
olanzapine may antagonize the effects of direct and indirect dopamine agonists. 
 
Seizures 
Olanzapine should be used cautiously in patients who have a history of seizures or are subject to factors 
which may lower the seizure threshold. Seizures have been reported to occur uncommonly in patients 
when treated with olanzapine. In most of these cases, a history of seizures or risk factors for seizures 
were reported. 
 
Tardive dyskinesia 
In comparator studies of one year or less duration, olanzapine was associated with a statistically 
significant lower incidence of treatment emergent dyskinesia. However the risk of tardive dyskinesia 
increases with long term exposure, and therefore if signs or symptoms of tardive dyskinesia appear in a 
patient on olanzapine, a dose reduction or discontinuation should be considered. These symptoms can 
temporally deteriorate or even arise after discontinuation of treatment.  
 
Postural hypotension 
Postural hypotension was infrequently observed in the elderly in olanzapine clinical trials. It is 
recommended that blood pressure is measured periodically in patients over 65 years. 
 
Sudden cardiac death  
In postmarketing reports with olanzapine, the event of sudden cardiac death has been reported in 
patients with olanzapine. In a retrospective observational cohort study, the risk of presumed sudden 
cardiac death in patients treated with olanzapine was approximately twice the risk in patients not using 
antipsychotics. In the study, the risk of olanzapine was comparable to the risk of atypical antipsychotics 
included in a pooled analysis. 
 
Paediatric population 
Olanzapine is not indicated for use in the treatment of children and adolescents. Studies in patients aged 
13-17 years showed various adverse reactions, including weight gain, changes in metabolic parameters 
and increases in prolactin levels (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 and 
physiological modification and reduction of muscular mass, this formulation is not recommended to be 
started in this sub-group of patients. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Interaction studies have only been performed in adults. 
 
Caution should be exercised in patients who receive medicinal products that can induce hypotension or 
sedation.  
 



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Potential interactions affecting olanzapine 
Since olanzapine is metabolised by CYP1A2, substances that can specifically induce or inhibit this 
isoenzyme may affect the pharmacokinetics of olanzapine.  
 
Induction of CYP1A2 
The metabolism of olanzapine may be induced by smoking and carbamazepine, which may lead to 
reduced olanzapine concentrations. Only slight to moderate increase in olanzapine clearance has been 
observed. The clinical consequences are likely to be limited, but clinical monitoring is recommended 
and an increase of olanzapine dose may be considered if necessary (see section 4.2). 
 
Inhibition of CYP1A2 
Fluvoxamine, a specific CYP1A2 inhibitor, has been shown to significantly inhibit the metabolism of 
olanzapine. The mean increase in olanzapine 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 using 
fluvoxamine or any other CYP1A2 inhibitors, such as ciprofloxacin. A decrease in the dose of 
olanzapine should be considered if treatment with an inhibitor of CYP1A2 is initiated. 
 
Fluoxetine (a CYP2D6 inhibitor), single doses of antacid (aluminium, magnesium) or cimetidine have 
not been found to significantly affect the pharmacokinetics of olanzapine. 
 
Potential for olanzapine to affect other medicinal products 
Olanzapine may antagonise the effects of direct and indirect dopamine agonists. 
 
Olanzapine does not inhibit the main CYP450 isoenzymes in vitro (e.g. 1A2, 2D6, 2C9, 2C19, 3A4). 
Thus no particular interaction is expected as verified through in vivo studies where no inhibition of 
metabolism of the following active substances was found: tricyclic antidepressant (representing mostly 
CYP2D6 pathway), warfarin (CYP2C9), theophylline (CYP1A2) or diazepam (CYP3A4 and 2C19).  
 
Olanzapine showed no interaction when co-administered with lithium or biperiden. 
 
Therapeutic monitoring of valproate plasma levels did not indicate that valproate dosage adjustment is 
required after the introduction of concomitant olanzapine. 
 
General CNS activity 
Caution should be exercised in patients who consume alcohol or receive medicinal products that can 
cause central nervous system depression. 
 
The concomitant use of olanzapine with anti-Parkinsonian medicinal products in patients with 
Parkinson's disease and dementia is not recommended (see section 4.4).  
 
QTc interval 
Caution should be used if olanzapine is being administered concomitantly with medicinal products 
known to increase QTc interval (see section 4.4). 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
There are no adequate and well-controlled studies in pregnant women. Patients should be advised to 
notify their physician if they become pregnant or intend to become pregnant during treatment with 
olanzapine. Nevertheless, because human experience is limited, olanzapine should be used in pregnancy 
only if the potential benefit justifies the potential risk to the foetus. 
 
New-born infants exposed to antipsychotics (including olanzapine) during the third trimester of 
pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that 
may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, 



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hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns 
should be monitored carefully. 
 
Breast-feeding 
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. 
 
Fertility 
Effects on fertility are unknown (see section 5.3 for preclinical information) 
 
4.7 Effects on ability to drive and use machines 
 
No studies on the effects on the ability to drive and use machines have been performed. As olanzapine 
may 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 each 
injection due to the possibility of a post-injection syndrome event leading to symptoms consistent with 
olanzapine overdose (see section 4.4). 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
Adverse reactions seen with olanzapine pamoate 
Post-injection syndrome reactions have occurred with ZYPADHERA leading to symptoms consistent 
with olanzapine overdose (see sections 4.2 and 4.4). Clinical signs and symptoms included symptoms of 
sedation (ranging from mild in severity up to coma) and/or delirium (including confusion, 
disorientation, agitation, anxiety and other cognitive impairment). Other symptoms noted include 
extrapyramidal symptoms, dysarthria, ataxia, aggression, dizziness, weakness, hypertension and 
convulsion. 
 
Other adverse reactions observed in patients treated with ZYPADHERA were similar to those seen with 
oral olanzapine. In clinical trials with ZYPADHERA, the only adverse reaction reported at a statistically 
significantly 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 reported 
by 4.7% of patients. 
 
In clinical trials with ZYPADHERA the incidence of injection site related adverse reactions was 
approximately 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 type 
reactions, erythema type reactions, non-specific injection site reactions, irritation, oedema type 
reactions, bruising, haemorrhage, and anaesthesia. These events occurred in about 0.1 to 1.1% of 
patients.   
 
In a review of safety data from clinical trials and spontaneous postmarketing reports, injection site 
abscess 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.  
 
Adults 
The most frequently (seen in ≥ 1% of patients ) reported adverse reactions associated with the use of 
olanzapine in clinical trials were somnolence, weight gain, eosinophilia, elevated prolactin, cholesterol, 
glucose and triglyceride levels (see section 4.4), glucosuria, increased appetite, dizziness, akathisia, 
parkinsonism, leukopenia, neutropenia (see section 4.4), dyskinesia, orthostatic hypotension, 



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anticholinergic effects, transient asymptomatic elevations of hepatic aminotransferases (see section 4.4), 
rash, asthenia, fatigue, pyrexia, arthralgia, increased alkaline phosphatase, high gamma 
glutamyltransferase, high uric acid, high creatine phosphokinase and oedema. 
 
Tabulated list of adverse reactions 
The following table lists the adverse reactions  and laboratory investigations observed from spontaneous 
reporting and in clinical trials. Within each frequency grouping, adverse reactions are presented in order 
of decreasing seriousness. The frequency terms listed are defined as follows: Very common (≥ 1/10), 
common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very 
rare (< 1/10,000), not known (cannot be estimated from the data available). 
 
Very common Common Uncommon  Rare Not known 
Blood and the lymphatic system disorders 
 Eosinophilia 

Leukopenia10 
Neutropenia10 

 Thrombocytopenia
11 

 

Immune system disorders 
  Hypersensitivity11   
Metabolism and nutrition disorders 
Weight gain1 Elevated 

cholesterol 
levels2,3 
Elevated glucose 
levels4 
Elevated 
triglyceride 
levels2,5 
Glucosuria  
Increased appetite 

Development or 
exacerbation of 
diabetes 
occasionally 
associated with 
ketoacidosis or 
coma, including 
some fatal cases 
(see section 4.4)11 

Hypothermia12  

Nervous system disorders 
Somnolence Dizziness 

Akathisia6 
Parkinsonism6 
Dyskinesia6 

Seizures where in 
most cases a 
history of seizures 
or risk factors for 
seizures were 
reported11 
Dystonia 
(including 
oculogyration)11 
Tardive 
dyskinesia11 
Amnesia 9 
Dysarthria 
Stuttering11 
Restless Legs 
Syndrome 11 

Neuroleptic 
malignant 
syndrome (see 
section 4.4)12 
Discontinuation 
symptoms7, 12 

 

 Cardiac disorders 
  Bradycardia 

QTc prolongation 
(see section 4.4) 

Ventricular 
tachycardia/fibrill
ation, sudden 
death (see section 
4.4) 11 

 



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Vascular disorders  
Orthostatic 
hypotension10 

 Thromboembolis
m (including 
pulmonary 
embolism and 
deep vein 
thrombosis) (see 
section 4.4) 

  

Respiratory, thoracic and mediastinal disorders  
  Epistaxis9   
Gastrointestinal disorders 
 Mild, transient 

anticholinergic 
effects including 
constipation and 
dry mouth 

Abdominal 
distension9  
Salivary 
hypersecretion11 

Pancreatitis11  

Hepatobiliary disorders 
 Transient, 

asymptomatic 
elevations of 
hepatic 
aminotransferases 
(ALT, AST), 
especially in early 
treatment (see 
section 4.4) 

 Hepatitis 
(including 
hepatocellular, 
cholestatic or 
mixed liver 
injury)11 

 

Skin and subcutaneous tissue disorders 
 Rash Photosensitivity 

reaction 
Alopecia 

 Drug Reaction 
with Eosinophilia 
and Systemic 
Symptoms 
(DRESS) 

Musculoskeletal and connective tissue disorders 
 Arthralgia9  Rhabdomyolysis11  
Renal and urinary disorders 
  Urinary 

incontinence 
Urinary retention 
Urinary 
hesitation11 

  

Pregnancy, puerperium and perinatal conditions 
    Drug withdrawal 

syndrome 
neonatal (see 
section 4.6) 

Reproductive system and breast disorders 
 Erectile 

dysfunction in 
males 
Decreased libido 
in males and 
females 

Amenorrhea 
Breast 
enlargement 
Galactorrhea in 
females 
Gynaecomastia/ 
breast 
enlargement in 
males 

Priapism12  



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General disorders and administration site conditions 
 Asthenia 

Fatigue 
Oedema 
Pyrexia10 
Injection site pain 

 Injection site 
abscess 

 

Investigations 
Elevated plasma 
prolactin levels8 

Increased alkaline 
phosphatase10 
High creatine 
phosphokinase11 
High Gamma 
Glutamyltransfera
se 10 
High uric acid 10 

Increased total 
bilirubin 

  

 
1 Clinically significant weight gain was observed across all baseline Body Mass Index (BMI) categories. 
Following short term treatment (median duration 47 days), weight gain ≥ 7% of baseline body weight  
was very common (22.2 %), ≥ 15 % was common (4.2 %) and ≥ 25 % was uncommon (0.8 %). Patients 
gaining ≥ 7 %, ≥ 15 % and ≥ 25% of their baseline body weight with long-term exposure (at least 48 
weeks) were very common (64.4 %, 31.7 % and 12.3 % respectively). 
 
2 Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were 
greater in patients without evidence of lipid dysregulation at baseline. 
 
3 Observed for fasting normal levels at baseline (< 5.17 mmol/l) which increased to high (≥ 6.2 mmol/l). 
Changes in total fasting cholesterol levels from borderline at baseline (≥ 5.17 - < 6.2 mmol/l) to high 
(≥ 6.2 mmol/l) were very common. 
 
4 Observed for fasting normal levels at baseline (< 5.56 mmol/l) which increased to high (≥ 7 mmol/l). 
Changes in fasting glucose from borderline at baseline (≥ 5.56 - < 7 mmol/l) to high (≥ 7 mmol/l) were 
very common.  
 
5 Observed for fasting normal levels at baseline (< 1.69 mmol/l) which increased to high 
(≥ 2.26 mmol/l). Changes in fasting triglycerides from borderline at baseline (≥ 1.69 mmol/l - 
< 2.26 mmol/l) to high (≥ 2.26 mmol/l) were very common. 
 
6 In clinical trials, the incidence of Parkinsonism and dystonia in olanzapine-treated patients was 
numerically higher, but not statistically significantly different from placebo. Olanzapine-treated patients 
had a lower incidence of Parkinsonism, akathisia and dystonia compared with titrated doses of 
haloperidol. In the absence of detailed information on the pre-existing history of individual acute and 
tardive extrapyramidal movement disorders, it cannot be concluded at present that olanzapine produces 
less tardive dyskinesia and/or other tardive extrapyramidal syndromes. 
 
7 Acute symptoms such as sweating, insomnia, tremor, anxiety, nausea and vomiting have been reported 
when olanzapine is stopped abruptly. 
 
8 In clinical trials of up to 12 weeks, plasma prolactin concentrations exceeded the upper limit of normal 
range in approximately 30% of olanzapine treated patients with normal baseline prolactin value. In the 
majority of these patients the elevations were generally mild, and remained below two times the upper 
limit of normal range.   
 
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. 
 



13 

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

 
Long-term exposure (at least 48 weeks) 
The proportion of patients who had adverse, clinically significant changes in weight gain, glucose, 
total/LDL/HDL cholesterol or triglycerides increased over time. In adult patients who completed 9-12 
months of therapy, the rate of increase in mean blood glucose slowed after approximately 6 months. 
 
Additional information on special populations 
In clinical trials in elderly patients with dementia, olanzapine treatment was associated with a higher 
incidence of death and cerebrovascular adverse reactions compared to placebo (see also section 4.4). 
Very common adverse reactions associated with the use of olanzapine in this patient group were 
abnormal gait and falls. Pneumonia, increased body temperature, lethargy, erythema, visual 
hallucinations and urinary incontinence were observed commonly.  
 
In clinical trials in patients with drug-induced (dopamine agonist) psychosis associated with Parkinson’s 
disease, worsening of Parkinsonian symptomatology and hallucinations were reported very commonly 
and more frequently than with placebo. 
 
In one clinical trial in patients with bipolar mania, valproate combination therapy with olanzapine 
resulted in an incidence of neutropenia of 4.1%; a potential contributing factor could be high plasma 
valproate levels. Olanzapine administered with lithium or valproate resulted in increased levels (≥10%) 
of tremor, dry mouth, increased appetite, and weight gain. Speech disorder was also reported 
commonly. During treatment with olanzapine in combination with lithium or divalproex, an increase of 
≥ 7% from baseline body weight occurred in 17.4% of patients during acute treatment (up to 6 weeks). 
Long-term olanzapine treatment (up to 12 months) for recurrence prevention in patients with bipolar 
disorder was associated with an increase of ≥7% from baseline body weight in 39.9% of patients. 
 
Paediatric population 
Olanzapine is not indicated for the treatment of children and adolescent patients below 18 years. 
Although no clinical studies designed to compare adolescents to adults have been conducted, data from 
the adolescent trials were compared to those of the adult trials.  
 
The following table summarises the adverse reactions reported with a greater frequency in adolescent 
patients (aged 13-17 years) than in adult patients or adverse reactions only identified during short-term 
clinical trials in adolescent patients. Clinically significant weight gain (≥ 7%) appears to occur more 
frequently in the adolescent population compared to adults with comparable exposures. The magnitude 
of weight gain and the proportion of adolescent patients who had clinically significant weight gain were 
greater with long-term exposure (at least 24 weeks) than with short-term exposure.  
 
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. The 
frequency terms listed are defined as follows: Very common (≥ 1/10), common (≥ 1/100 to < 1/10). 
 
Metabolism and nutrition disorders 
Very common: Weight gain13, elevated triglyceride levels14, increased appetite. 
Common: Elevated cholesterol levels15 
Nervous system disorders 
Very common: Sedation (including: hypersomnia, lethargy, somnolence). 
Gastrointestinal disorders 
Common: Dry mouth 
Hepatobiliary disorders 
Very common: Elevations of hepatic aminotransferases (ALT/AST; see section 4.4). 



14 

Investigations  
Very common: Decreased total bilirubin, increased GGT, elevated plasma prolactin levels16. 
 
13 Following short term treatment (median duration 22 days), weight gain ≥ 7% of baseline body weight 
(kg) was very common (40.6 %), ≥ 15% of baseline body weight was common (7.1 %) and ≥ 25 % was 
common (2.5 %). With long-term exposure (at least 24 weeks), 89.4 % gained ≥ 7 %, 55.3 % gained ≥ 
15 % and 29.1 % gained ≥ 25% of their baseline body weight.  
 
14  Observed for fasting normal levels at baseline (< 1.016 mmol/l) which increased to high 
(≥ 1.467 mmol/l) and changes in fasting triglycerides from borderline at baseline (≥ 1.016 mmol/l - 
< 1.467 mmol/l) to high (≥ 1.467 mmol/l). 
 
15 Changes in total fasting cholesterol levels from normal at baseline (< 4.39 mmol/l) to high 
(≥ 5.17 mmol/l) were observed commonly. Changes in total fasting cholesterol levels from borderline at 
baseline (≥ 4.39 - < 5.17 mmol/l) to high (≥ 5.17 mmol/l) were very common. 
 
16 Elevated plasma prolactin levels were reported in 47.4% of adolescent patients. 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system listed 
in Appendix V. 
 
4.9 Overdose 
 
If signs and symptoms of overdose consistent with post injection syndrome are observed, appropriate 
supportive measures should be taken (see section 4.4). 
  
While overdose is less likely with parenteral than oral medicinal products, reference information for oral 
olanzapine 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 sedation 
to coma. 
 
Other medically significant sequelae of overdose include delirium, convulsion, coma, possible 
neuroleptic malignant syndrome, respiratory depression, aspiration, hypertension or hypotension, 
cardiac arrhythmias (< 2% of overdose cases) and cardiopulmonary arrest. Fatal outcomes have been 
reported for acute oral overdoses as low as 450 mg but survival has also been reported following acute 
overdose of approximately 2 g of oral olanzapine. 
 
Management  
There is no specific antidote for olanzapine. Symptomatic treatment and monitoring of vital organ 
function should be instituted according to clinical presentation, including treatment of hypotension and 
circulatory collapse and support of respiratory function. Do not use epinephrine, dopamine, or other 
sympathomimetic agents with beta-agonist activity since beta stimulation may worsen hypotension. 
Cardiovascular monitoring is necessary to detect possible arrhythmias. Close medical supervision and 
monitoring should continue until the patient recovers. 
 
 



15 

5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: psycholeptics, diazepines, oxazepines, thiazepines and oxepines, ATC code 
N05A H03. 
 
Pharmacodynamic effects  
Olanzapine is an antipsychotic, antimanic and mood stabilising agent that demonstrates a broad 
pharmacologic profile across a number of receptor systems. 
 
In preclinical studies, olanzapine exhibited a range of receptor affinities (Ki; < 100 nM) for serotonin 5-
HT2A/2C, 5-HT3, 5-HT6; dopamine D1, D2, D3, D4, D5; cholinergic muscarinic receptors M1-M5; α-1 
adrenergic; and histamine H1 receptors. Animal behavioural studies with olanzapine indicated 5HT, 
dopamine, and cholinergic antagonism, consistent with the receptor-binding profile. Olanzapine 
demonstrated a greater in vitro affinity for serotonin 5-HT2 than dopamine D2 receptors and greater 5-
HT2 than D2 activity in vivo, models. Electrophysiological studies demonstrated that olanzapine 
selectively reduced the firing of mesolimbic (A10) dopaminergic neurons, while having little effect on 
the striatal (A9) pathways involved in motor function. Olanzapine reduced a conditioned avoidance 
response, a test indicative of antipsychotic activity, at doses below those producing catalepsy, an effect 
indicative of motor side-effects. Unlike some other antipsychotic agents, olanzapine increases 
responding in an “anxiolytic” test. 
 
In a 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, a 
level consistent with that found during treatment with oral olanzapine. 
 
Clinical efficacy 
The effectiveness of ZYPADHERA in the treatment and maintenance treatment of schizophrenia is 
consistent 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 were 
experiencing 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 every 
2 weeks. No oral antipsychotic supplementation was allowed. Total Positive and Negative Symptom 
Scores (PANSS) showed significant improvement from baseline (baseline mean Total PANSS Score 
101) 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  indicated 
that by Day 3, patients in the 300 mg/2 weeks and 405 mg/4 weeks treatment groups had statistically 
significantly 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 greater 
improvement 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 after 
starting treatment with ZYPADHERA. 
 
The second, a long term study in clinically stable patients (n=1065) (baseline mean Total PANSS Score 
54.33 to 57.75) who were initially treated with oral olanzapine for 4 to 8 weeks and then switched to 
continue on oral olanzapine or to ZYPADHERA for 24 weeks. No oral antipsychotic supplementation 
was allowed. ZYPADHERA treatment groups of 150 mg and 300 mg given every 2 weeks (doses 
pooled for analysis) and 405 mg given every 4 weeks were non inferior to the combined doses of 10, 15 
and 20 mg of oral olanzapine (doses pooled for analysis)  as measured by rates of exacerbation of 
symptoms of schizophrenia (respective exacerbation rates, 10%, 10% 7%). Exacerbation was measured 
by worsening of items on the PANSS derived BPRS Positive scale and hospitalization due to worsening 
of positive psychotic symptoms. The combined 150 mg and 300 mg/2 week treatment group was non 



16 

inferior to the 405 mg/4 week treatment group (exacerbation rates 10% for each group) at 24 weeks 
after randomisation.  
 
Paediatric population 
ZYPADHERA has not been studied in the paediatric population. Controlled efficacy data in 
adolescents (ages 13 to 17 years) are limited to short term oral olanzapine studies in schizophrenia (6 
weeks) 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. During 
treatment 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 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. 
 
5.2 Pharmacokinetic properties 
 
Absorption 
Olanzapine is metabolised in the liver by conjugative and oxidative pathways. The major circulating 
metabolite is the 10-N-glucuronide. Cytochromes P450-CYP1A2 and P450-CYP2D6 contribute to the 
formation of the N-desmethyl and 2-hydroxymethyl metabolites; both exhibited significantly less in 
vivo pharmacological activity than olanzapine in animal studies. The predominant pharmacologic 
activity is from the parent, olanzapine. 
 
After a single IM injection with ZYPADHERA the slow dissolution of the olanzapine pamoate salt in 
muscle tissue begins immediately and provides a slow continuous release of olanzapine for more than 
four weeks. The release becomes diminishingly smaller within eight to twelve weeks. Antipsychotic 
supplementation 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 for 
several months after each ZYPADHERA injection. The half-life of olanzapine after ZYPADHERA is 
30 days compared to 30 hours following oral administration. The absorption and elimination are 
complete approximately six to eight months after the last injection. 
 
Distribution 
Oral olanzapine is rapidly distributed. The plasma protein binding of olanzapine is about 93% over the 
concentration range of 7 to about 1000 ng/mL. In plasma, olanzapine is bound to albumin and α1-acid 
glycoprotein. 
 
After repeated IM injections with 150 to 300 mg ZYPADHERA every two weeks, the 10th to 90th 
percentile of steady-state plasma concentrations of olanzapine were between 4.2 and 73.2 ng/ml. The 
plasma concentrations of olanzapine observed across the dose range of 150mg every 4 weeks to 300mg 
every 2 weeks illustrate increased systemic olanzapine exposure with increased ZYPADHERA doses. 
During the initial three months of treatment with ZYPADHERA, accumulation of olanzapine was 
observed but there was no additional accumulation during long-term use (12 months) in patients who 
were injected with up to 300 mg every two weeks. 
 
Elimination 
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 pharmacokinetic 
differences between males and females and smokers and non-smokers were observed in ZYPADHERA 
clinical trials. However, the magnitude of the impact of gender, or smoking on olanzapine clearance is 
small in comparison to the overall variability between individuals. 
 
Elderly 
No specific investigations have been conducted in the elderly with ZYPADHERA. ZYPADHERA is not 
recommended for treatment in the elderly population (65 years and over) unless a well-tolerated and 



17 

effective 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) and 
the clearance was reduced (17.5 versus 18.2 l/hr). The pharmacokinetic variability observed in the 
elderly is within the range for the non-elderly. In 44 patients with schizophrenia >65 years of age, 
dosing from 5 to 20 mg/day was not associated with any distinguishing profile of adverse events. 
 
Renal impairment 
In renally impaired patients (creatinine clearance < 10 ml/min) versus healthy subjects, there was no 
significant difference in mean elimination half-life (37.7 versus 32.4 hours) or clearance (21.2 versus 
25.0 l/hr). A mass balance study showed that approximately 57% of radiolabelled olanzapine appeared 
in urine, principally as metabolites. Although patients with renal impairment were not studied with 
ZYPADHERA, it is recommended that a well-tolerated and effective dosage regimen using oral 
olanzapine is established in patients with renal impairment before treatment with ZYPADHERA is 
initiated (see section 4.2).  
 
Hepatic impairment 
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 of 
orally administered olanzapine (2.5 – 7.5 mg single dose): Subjects with mild to moderate hepatic 
dysfunction had slightly increased systemic clearance and faster elimination half-time compared to 
subjects 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 recommended 
that a well-tolerated and effective dosage regimen using oral olanzapine is established in patients with 
hepatic 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 no 
differences in the pharmacokinetic parameters among the three populations. 
 
5.3 Preclinical safety data 
 
Preclinical safety studies were performed using olanzapine pamoate monohydrate. The main findings 
found in repeat-dose toxicity studies (rat, dog), in a 2-year rat carcinogenicity study, and in toxicity to 
reproduction studies (rat, rabbit) were limited to injection site reactions for which no NOAEL could be 
determined. 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 in 
the 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 were 
approximately 210 mg/kg (mice) and 175 mg/kg (rats). Dogs tolerated single oral doses up to 
100 mg/kg without mortality. Clinical signs included sedation, ataxia, tremors, increased heart rate, 
laboured respiration, miosis, and anorexia. In monkeys, single oral doses up to 100 mg/kg resulted in 
prostration and, at higher doses, semi-consciousness. 
 
Repeated-dose toxicity 
In studies up to 3 months duration in mice and up to 1 year in rats and dogs, the predominant effects 
were CNS depression, anticholinergic effects, and peripheral haematological disorders. Tolerance 
developed to the CNS depression. Growth parameters were decreased at high doses. Reversible effects 
consistent with elevated prolactin in rats included decreased weights of ovaries and uterus and 
morphologic changes in vaginal epithelium and in mammary gland. 
 
Haematologic toxicity: Effects on haematology parameters were found in each species, including dose-
related reductions in circulating leukocytes in mice and non-specific reductions of circulating leukocytes 
in rats; however, no evidence of bone marrow cytotoxicity was found. Reversible neutropenia, 



18 

thrombocytopenia, or anaemia developed in a few dogs treated with 8 or 10 mg/kg/day (total olanzapine 
exposure [AUC] is 12- to 15-fold greater than that of a man given a 12 mg dose). In cytopenic dogs, 
there were no undesirable effects on progenitor and proliferating cells in the bone marrow. 
 
Reproductive toxicity 
Olanzapine had no teratogenic effects. Sedation affected mating performance of male rats. Oestrous 
cycles were affected at doses of 1.1 mg/kg (3 times the maximum human dose) and reproduction 
parameters were influenced in rats given 3 mg/kg (9 times the maximum human dose). In the offspring 
of rats given olanzapine, delays in foetal development and transient decreases in offspring activity levels 
were seen. 
 
Mutagenicity 
Olanzapine was not mutagenic or clastogenic in a full range of standard tests, which included bacterial 
mutation tests and in vitro and oral in vivo mammalian tests. 
 
Carcinogenicity 
Based on the results of oral studies in mice and rats, it was concluded that olanzapine is not 
carcinogenic. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients  
 
Powder 
None 
 
Solvent 
Carmellose sodium 
Mannitol 
Polysorbate 80 
Water for injections 
Hydrochloric acid (for pH adjustment) 
Sodium hydroxide (for pH adjustment) 
 
6.2 Incompatibilities 
 
This medicinal product must not be mixed with other medicinal products except those mentioned in 
section 6.6. 
 
6.3 Shelf life 
 
2 years 
 
After reconstitution in the vial: 24 hours. If the product is not used right away, it should be shaken 
vigorously to re-suspend. Once withdrawn from vial into syringe, the suspension should be used 
immediately. 
 
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 used 
immediately, in-use storage times and conditions prior to use are the responsibility of the user and 
would normally not be longer than 24 hours at 20-25°C.   
 
6.4 Special precautions for storage 
 
Do not refrigerate or freeze. 
 



19 

6.5 Nature and contents of container 
 
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. 
 
6.6 Special precautions for disposal and other handling 
 
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 local 
requirements. 

Reconstitution  
 
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 solvent 
provided 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 prolonged 
release suspension for injection. 
 

ZYPADHERA  
vial strength (mg) 

Volume of solvent to add 
(ml) 

210 1.3 
300 1.8 
405 2.3 

 
It is important to note that there is more solvent in the vial than is needed to reconstitute. 
 
STEP 3: Reconstituting ZYPADHERA 
1. Loosen the powder by lightly tapping the vial.  
2. Open the pre-packaged Hypodermic syringe and needle with needle protection device. Peel blister 

pouch and remove device. Attach a syringe (if not already attached) to the Luer connection of the 
device with an easy twisting motion. Seat the needle firmly on the device with a push and a 
clockwise twist, then pull the needle cap straight away from the needle. Failure to follow these 
instructions 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 the 
device with the engaged needle from the syringe when required by a specific medical procedure. 



20 

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 surface 

to cushion impact. (See Figure A) 

 
Figure A: Tap firmly to mix 

 
10. Visually check the vial for clumps. Unsuspended powder appears as yellow, dry clumps clinging 

to 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, it 
should be shaken vigorously to re-suspend. Reconstituted ZYPADHERA remains stable for up to 
24 hours in the vial. 

 
Administration 
 
STEP 1: Injecting ZYPADHERA 
This table confirms the final ZYPADHERA suspension volume to inject.  Suspension concentration is 
150 mg/ml olanzapine. 

Dose 
(mg) 

Final volume to inject  
(ml) 

150 1.0 
210 1.4 



21 

300 2.0 
405 2.7 

 
1. 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 to 

withdraw the required suspension volume.  
 If the 38 mm needle is to be used for the injection, attach the 50 mm safety needle to withdraw 

the 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 the 

suspension 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 is 

drawn into the syringe, discard the syringe and the dose and begin reconstitution and administration 
procedure 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 with 

appropriate clinical procedures. The vial is for single use only. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Eli Lilly Nederland B.V., Papendorpseweg 83, 3528 BJ Utrecht, The Netherlands. 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/08/479/001  
EU/1/08/479/002 
EU/1/08/479/003 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 19/11/2008 
Date of latest renewal: 26/08/2013 
 
 
10. DATE OF REVISION OF THE TEXT 
 
{MM/YYYY} 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu 
 
 



22 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT  



23 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer responsible for batch release 
 
Lilly S.A., Avda. de la Industria 30, 28108 Alcobendas, Madrid, Spain. 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION  
 
• Periodic safety update reports (PSURs)  

 
The requirements for submission of (PSURs) for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 

 
 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 
• Risk management plan (RMP) 
 
The marketing authorization holder (MAH) shall perform the required pharmacovigilance activities and 
interventions detailed in the agreed RMP presented in Module 1.8.2. of the Marketing Authorisation and 
any agreed subsequent updates of the RMP.  
 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency.  
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a signficant change to the benefit/risk profile or as the result   
   of an important (pharmacovigilance or risk minimisation) milestone being reached. 

 
•   Additional risk minimisation measures 
 
An education program to the health care professionals (HCP) (doctors-nurses-pharmacist) shall address, 
 
1)   Description of post injection syndrome  
– Education about the 2 intramuscular formulations of olanzapine, including packaging differences 
– Description of reconstitution and proper administration technique 
– Recommendation for a 3-hour on-site observation period post injection 
– Recommendation that, immediately prior to a patient leaving the health care facility, it should be 

confirmed that the patient is alert, oriented, and absent of any signs or symptoms of overdose 
– Recommendation that the 3-hour observation period should be extended as clinically appropriate 

for patients who exhibit any signs or symptoms consistent with olanzapine overdose 
– Recommendation for informing patients that for the remainder of the day of the injection, they 

should not drive or operate machinery, should be vigilant for signs and symptoms of a post injection 
syndrome event, and should be able to obtain assistance if needed 

– Description of the most common symptoms reported with olanzapine overdose that represent the 
clinical manifestation in post injection syndrome events 

– Recommendation for appropriate monitoring until the event resolves if an event should occur 
 



24 

2)   Recommendations for monitoring of patients for glucose, lipids, and weight 
− Promote awareness of appropriate metabolic monitoring by distributing utilized published 

antipsychotic guidelines 
 
A patient card shall be distributed to all patients, including: 
 
– Description of post injection syndrome  
– Recommendation for a 3-hour on-site observation period post injection 
– Recommendation for informing patients that for the remainder of the day of the injection, they 

should not drive or operate machinery, should be vigilant for signs and symptoms of a post injection 
syndrome event, and should be able to obtain assistance if needed 

– Description of the most common symptoms reported with olanzapine overdose that represent the 
clinical manifestation in post injection syndrome events 

– Recommendation for appropriate monitoring until the event resolves if an event should occur 
 
 
 
 
 
 
 
 
 
 
 
 



25 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



26 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



27 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
Outer Carton ZYPADHERA 210 mg powder and solvent for prolonged release suspension for 
injection 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ZYPADHERA 210 mg powder and solvent for prolonged release suspension for injection 
Olanzapine 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Olanzapine pamoate monohydrate equivalent to 210 mg olanzapine. After reconstitution: 150 mg/ml 
olanzapine. 
 
 
3. LIST OF EXCIPIENTS 
 
The solvent excipients are carmellose sodium, mannitol, polysorbate 80, water for injections, 
hydrochloric acid, sodium hydroxide. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
One vial of powder for prolonged release suspension for injection.  
 
One vial of 3 ml solvent. 
One Hypodermic syringe and safety needle.   
Three Hypodermic safety needles. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Intramuscular use.  
Do not administer intravenously or subcutaneously.  
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP {MM/YYYY} 
Vial of suspension after reconstitution: 24 hours.  
Once withdrawn from vial into syringe, suspension should be used immediately. 



28 

 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not refrigerate or freeze. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Eli Lilly Nederland B.V., Papendorpseweg 83, 3528 BJ Utrecht, The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER (S) 
 
EU/1/08/479/001 
 
 
13. BATCH NUMBER 
 
Lot  
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to restricted medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 



29 

 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
Vial Label ZYPADHERA 210 mg powder for prolonged release suspension for injection  
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
ZYPADHERA 210 mg powder for prolonged release injection 
olanzapine 
IM 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot  
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
210 mg  
 
 
6. OTHER 
 



30 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
Outer Carton ZYPADHERA 300 mg powder and solvent for prolonged release suspension for 
injection 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ZYPADHERA 300 mg powder and solvent for prolonged release suspension for injection 
Olanzapine 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Olanzapine pamoate monohydrate equivalent to 300 mg olanzapine. After reconstitution: 150 mg/ml 
olanzapine. 
 
 
3. LIST OF EXCIPIENTS 
 
The solvent excipients are carmellose sodium, mannitol, polysorbate 80, water for injections, 
hydrochloric acid, sodium hydroxide. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
One vial of powder for prolonged release suspension for injection.  
One vial of 3 ml solvent. 
One Hypodermic syringe and safety needle. 
Three Hypodermic safety needles. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Intramuscular use.  
Do not administer intravenously or subcutaneously.  
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP {MM/YYYY} 
Vial of suspension after reconstitution: 24 hours.  
Once withdrawn from vial into syringe, suspension should be used immediately. 
 
 



31 

9. SPECIAL STORAGE CONDITIONS 
 
Do not refrigerate or freeze. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Eli Lilly Nederland B.V., Papendorpseweg 83, 3528 BJ Utrecht, The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER (S) 
 
EU/1/08/479/002 
 
 
13. BATCH NUMBER 
 
Lot  
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to restricted medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 Justification for not including Braille accepted 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 



32 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
Vial Label ZYPADHERA 300 mg powder for prolonged release suspension for injection  
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
ZYPADHERA 300 mg powder for prolonged release injection 
olanzapine 
IM 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot  
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
300 mg  
 
 
6. OTHER 
 
 



33 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
Outer Carton ZYPADHERA 405 mg powder and solvent for prolonged release suspension for 
injection 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ZYPADHERA 405 mg powder and solvent for prolonged release suspension for injection 
Olanzapine 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Olanzapine pamoate monohydrate equivalent to 405 mg olanzapine. After reconstitution: 150 mg/ml 
olanzapine. 
 
 
3. LIST OF EXCIPIENTS 
 
The solvent excipients are carmellose sodium, mannitol, polysorbate 80, water for injections, 
hydrochloric acid, sodium hydroxide. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
One vial of powder for prolonged release suspension for injection. 
One vial of 3 ml solvent. 
One Hypodermic syringe and safety needle. 
Three Hypodermic safety needles. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Intramuscular use. 
Do not administer intravenously or subcutaneously.  
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
8. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP {MM/YYYY} 
Vial of suspension after reconstitution: 24 hours. 
Once withdrawn from vial into syringe, suspension should be used immediately. 
 
 



34 

9. SPECIAL STORAGE CONDITIONS 
 
Do not refrigerate or freeze. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Eli Lilly Nederland B.V., Papendorpseweg 83, 3528 BJ Utrecht, The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER (S) 
 
EU/1/08/479/003 
 
 
13. BATCH NUMBER 
 
Lot  
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to restricted medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 Justification for not including Braille accepted 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
 



35 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
Vial Label ZYPADHER 405 mg powder for prolonged release suspension for injection  
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
ZYPADHERA 405 mg powder for prolonged release injection  
olanzapine 
IM  
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot  
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
405 mg  
 
 
6. OTHER 
 



36 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
Vial Label  
Solvent for ZYPADHERA   
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Solvent for ZYPADHERA  
IM 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
3 ml 
 
6. OTHER 
 
 
 



37 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



38 

Package leaflet: Information for the user 
 

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 

 
Olanzapine 

 
 
Read all of this leaflet carefully before you start using this medicine because it contains important 
information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or nurse. 
- If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not 

listed in this leaflet. See section 4. 
 
What is in this leaflet: 
 
1. What ZYPADHERA is and what it is used for 
2. What you need to know before you are given ZYPADHERA 
3. How ZYPADHERA is given 
4. Possible side effects 
5. How to store ZYPADHERA 
6. Contents of the pack and other information 
 
 
1. What ZYPADHERA is and what it is used for 
 
ZYPADHERA contains the active substance olanzapine. ZYPADHERA belongs to a group of 
medicines called antipsychotics and is used to treat schizophrenia - a disease with symptoms such as 
hearing, seeing or sensing things which are not there, mistaken beliefs, unusual suspiciousness, and 
becoming withdrawn. People with this disease may also feel depressed, anxious or tense. 
 
ZYPADHERA is intended for adult patients who are sufficiently stabilised during treatment with oral 
olanzapine. 
 
2. What you need to know before you are given ZYPADHERA 
 
You should not be given ZYPADHERA if you have: 
•  an allergy (hypersensitivity) to olanzapine or any of the other ingredients of this medicine (listed in 

section 6). An allergic reaction may be recognised as a rash, itching, a swollen face, swollen lips or 
shortness of breath. If this has happened to you, tell your nurse or doctor. 

• been previously diagnosed with eye problems such as certain kinds of glaucoma (increased pressure 
in the eye). 

 
Warnings and precautions 
Talk to your doctor or nurse before you are given ZYPADHERA 
 
• An uncommon but serious reaction might occur after you receive each injection. ZYPADHERA 

can sometimes enter the bloodstream too quickly. If this happens, you may have the symptoms 
listed below after your injection. In some cases, these symptoms can lead to unconsciousness.  
 

• excessive sleepiness • dizziness 

• confusion • disorientation 

• irritability • anxiety 



39 

• aggression • increase in blood pressure 

• difficulty talking • weakness 

• difficulty walking • muscle stiffness or shaking 

• convulsions  

These symptoms typically resolve within 24 to 72 hours after your injection. After each injection 
you will be observed in your healthcare facility for at least 3 hours for the symptoms listed above.  

Although unlikely, you may get the symptoms more than 3 hours after the injection.  If this 
happens, contact your doctor or nurse immediately. Because of this risk, do not drive or operate 
machinery for the remainder of the day after each injection. 

• Tell the doctor or nurse if you feel dizzy or faint after the injection. You will probably need to lie 
down until you feel better. The doctor or nurse may also want to measure your blood pressure and 
pulse. 

• The use of ZYPADHERA in elderly patients with dementia (confusion and memory loss) is not 
recommended as it may have serious side effects. 

• Very rarely, medicines of this type may cause unusual movements mainly of the face or tongue or a 
combination of fever, faster breathing, sweating, muscle stiffness and drowsiness or sleepiness.  If 
this happens after you have been given ZYPADHERA, tell your doctor or nurse immediately.  

• Weight gain has been seen in patients taking ZYPADHERA. You and your doctor should check 
your weight regularly. Consider referral to a dietician or help with a diet plan if necessary. 

• High blood sugar and high levels of fat (triglycerides and cholesterol) have been seen in patients 
taking ZYPADHERA. Your doctor should do blood tests to check blood sugar and certain fat levels 
before you start taking ZYPADHERA and regularly during treatment. Tell the doctor if you or 
someone else in your family has a history of blood clots, as medicines like these have been 
associated with formation of blood clots. 

 
Tell your doctor as soon as possible if any of the following applies to you: 

• Stroke or “mini” stroke (temporary symptoms of stroke) 
• Parkinson’s disease 
• Prostate problems 
• A blocked intestine (Paralytic ileus) 
• Liver or kidney disease 
• Blood disorders  
• A recent heart attack, heart disease, sick sinus syndrome, (abnormal heart rhythms), 

unstable angina or low blood pressure 
• Diabetes  
• Seizures 
• If you know that you may have salt depletion as a result of prolonged severe diarrhoea 

and vomiting (being sick) or usage of diuretics (water tablets) 
 
As a routine precaution, if you are over 65 years your doctor may monitor your blood pressure. 
 
ZYPADHERA is not recommended to be started if you are over 75 years. 
 
Children and adolescents 
ZYPADHERA is not for patients who are under 18 years. 
 
Other medicines and ZYPADHERA 
Tell your doctor if you are taking, have recently taken or might take any other medicines.  
 



40 

In particular, tell your doctor if you are taking: 
• medicines for Parkinson’s disease. 
• carbamazepine (an anti-epileptic and mood stabiliser), fluvoxamine (an antidepressant) or 

ciprofloxacin (an antibiotic) - it may be necessary to change your ZYPADHERA dose. 
 

If you are already taking antidepressants, medicines for anxiety or to help you sleep (tranquillisers), you 
may feel drowsy if ZYPADHERA is given. 

 
ZYPADHERA with alcohol 
Do not drink any alcohol if you have been given ZYPADHERA as together with alcohol it may make 
you feel drowsy. 
 
Pregnancy and breast-feeding 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor for advice before being given this injection.   
You should not be given this injection if you are breast-feeding as small amounts of olanzapine can pass 
into breast milk. 
 
The following symptoms may occur in newborn babies, of mothers that have used ZYPAHDERA in the 
last trimester (last three months of their pregnancy): shaking, muscle stiffness and/or weakness, 
sleepiness, agitation, breathing problems, and difficulty in feeding. If your baby develops any of these 
symptoms you may need to contact your doctor. 
 
Driving and using machines 
Do not drive or operate machinery for the remainder of the day after each injection.  
 
 
3. How ZYPADHERA is given 
 
Your doctor will decide how much ZYPADHERA you need and how often you need to be given an 
injection. ZYPADHERA is given in doses of 150 mg to 300 mg every 2 weeks or 300 mg to 405 mg 
every 4 weeks. 
 
ZYPADHERA comes as a powder which your doctor or nurse will make into a suspension that will then 
be injected into the muscle in your buttock. 

 
If you are given more ZYPADHERA than needed 
This medicine will be given to you under medical supervision, it is therefore unlikely that you will be 
given too much.  
 
Patients who have been given too much olanzapine have also experienced the following symptoms:  
• rapid beating of the heart, agitation/aggressiveness, problems with speech, unusual movements 

(especially of the face or tongue) and reduced level of consciousness.  
Other symptoms may include:  
• acute confusion, seizures (epilepsy), coma, a combination of fever, faster breathing, sweating, 

muscle stiffness, and drowsiness or sleepiness; slower breathing, aspiration, high or low blood 
pressure, abnormal rhythms of the heart.  

 
Contact your doctor or hospital straight away if you experience any of the above symptoms. 
 
If you miss an injection of ZYPADHERA  
Do not stop your treatment just because you feel better. It is important that you carry on receiving 
ZYPADHERA for as long as your doctor has told you to.  
 



41 

If you miss an injection, you should contact your doctor to arrange your next injection as soon as you 
can. 
 
If you have any further questions on the use of this medicine, ask your doctor or nurse. 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 

 
Tell your doctor immediately if you have:  

• excessive sleepiness, dizziness, confusion, disorientation, difficulty talking, difficulty walking, 
muscle stiffness or shaking, weakness, irritability, aggression, anxiety, increase in blood pressure, 
or convulsions and can lead to unconsciousness. These signs and symptoms can sometimes occur 
as a result of ZYPADHERA entering the bloodstream too quickly (a common side effect that may 
affect up to1 in10 people); 

• unusual movement (a common side effect that may affect up to 1 in 10 people) mainly of the 
face or tongue; 

• blood clots in the veins (an uncommon side effect that may affect up to 1in 100 people) especially 
in the legs (symptoms include swelling, pain, and redness in the leg), which may travel through 
blood vessels to the lungs causing chest pain and difficulty in breathing. If you notice any of these 
symptoms seek medical advice immediately; 

• a combination of fever, faster breathing, sweating, muscle stiffness and drowsiness or sleepiness 
(the frequency of this side effect cannot be estimated from the available data). 

 
Other common side effects (may affect up to 1 in 10 people) with ZYPADHERA include sleepiness and 
injection site pain. 
 
Rare side effects (may affect up to 1 in 1000 people) with ZYPADHERA include injection site 
infection.  
 
The side effects listed below have been observed when oral olanzapine has been given but may occur 
following administration of ZYPADHERA. 
 
Other very common side effects (may affect more than 1 in 10 people) include weight gain; and 
increases in levels of prolactin in the blood. In the early stages of treatment, some people may feel 
dizzy or faint (with a slow heart rate), especially when getting up from a lying or sitting position. This 
will usually pass on its own but if it does not, tell your doctor. 

Other common side effects (may affect up to 1 in 10 people) include changes in the levels of some 
blood cells, circulating fats and in early treatment, temporary increases in liver enzymes; increases in 
the level of sugars in the blood and urine; increases in levels of uric acid and creatine phosphokinase in 
the blood; feeling more hungry; dizziness; restlessness; tremor; unusual movements (dyskinesias); 
constipation; dry mouth; rash; loss of strength; extreme tiredness; water retention leading to swelling of 
the hands, ankles or feet; fever; joint pain; and sexual dysfunctions such as decreased libido in males 
and females or erectile dysfunction in males. 
 
Other uncommon side effects (may affect up to 1 in 100 people) include hypersensitivity (e.g. swelling 
in the mouth and throat, itching; rash); diabetes or the worsening of diabetes, occasionally associated 
with ketoacidosis (ketones in the blood and urine) or coma; seizures, usually associated with a history of 
seizures (epilepsy); muscle stiffness or spasms (including eye movements); restless legs syndrome; 
problems with speech; stuttering; slow heart rate; sensitivity to sunlight; bleeding from the nose: 
abdominal distension; drooling; memory loss or forgetfulness; urinary incontinence; lack of ability to 
urinate; hair loss; absence or decrease in menstrual periods; and changes in breasts in males and females 
such as an abnormal production of breast milk or abnormal growth. 
 
Rare side effects (may affect up to 1 in 1000 people) include lowering of normal body temperature; 
abnormal rhythms of the heart; sudden unexplained death; inflammation of the pancreas causing severe 



42 

stomach pain, fever and sickness; liver disease appearing as yellowing of the skin and white parts of the 
eyes; muscle disease presenting as unexplained aches and pains; and prolonged and/or painful erection. 
 
Very rare side effects include serious allergic reactions such as Drug Reaction with Eosinophilia and 
Systemic Symptoms (DRESS).  DRESS appears initially as flu-like symptoms with a rash on the face 
and then with an extended rash, high temperature, enlarged lymph nodes, increased levels of liver 
enzymes seen on blood tests and an increase in a type of white blood cells (eosinophilia). 
 
While taking olanzapine, elderly patients with dementia may suffer from stroke, pneumonia, urinary 
incontinence, falls, extreme tiredness, visual hallucinations, a rise in body temperature, redness of the 
skin and have trouble walking. Some fatal cases have been reported in this particular group of patients. 
 
In patients with Parkinson's disease oral olanzapine may worsen the symptoms. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not 
listed in this leaflet. You can also report side effects directly via the national reporting system listed in 
Appendix V. By reporting side effects you can help provide more information on the safety of this 
medicine. 
 
 
5. How to store ZYPADHERA 
 
Keep this medicine out of the sight and reach of children. 
 
The injection must not be given after the expiry date which is stated on the carton. 
 
Do not refrigerate or freeze. 
 
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 used 
immediately, in-use storage times and conditions prior to use are the responsibility of the user and 
would normally not be longer than 24 hours at 20-25°C. Do not use this product if you notice 
discolouration or other visible signs of deterioration. 
 
If the medicine is not used right away, it should be shaken vigorously to re-suspend. Once withdrawn 
from vial into the syringe, the suspension should be used immediately. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help to protect the environment. 
 
6. Contents of the pack and other information 
 
What ZYPADHERA contains 
The active substance is olanzapine.  
ZYPADHERA 210 mg: Each vial contains olanzapine pamoate monohydrate equivalent to 210 mg 
olanzapine.   
ZYPADHERA 300 mg: Each vial contains olanzapine pamoate monohydrate equivalent to 300 mg  
olanzapine.  
ZYPADHERA 405 mg: Each vial contains olanzapine pamoate monohydrate equivalent to 405 mg 
olanzapine.  
After reconstitution: 1ml suspension contains 150 mg/ml olanzapine. 
 
The solvent ingredients are carmellose sodium, mannitol, polysorbate 80, water for injections, 
hydrochloric acid and sodium hydroxide. 
 



43 

What ZYPADHERA looks like and contents of the pack 
ZYPADHERA powder for prolonged release suspension for injection comes as a yellow powder in a 
clear glass vial. Your doctor or nurse will make it into a suspension that will be given as an injection 
using the vial of solvent for ZYPADHERA that comes as a clear, colourless to slightly yellow solution 
in a clear glass vial.  
 
ZYPADHERA is a powder and solvent for prolonged release suspension for injection. One carton 
contains one vial of powder for prolonged release suspension for injection, one vial of 3 ml solvent, one 
syringe with safety needle, 19 gauge, 38mm, attached and three separate safety needles; one 19 gauge, 
38mm needle and two 19 gauge 50mm needles. 
  
 
Marketing Authorisation Holder  
Eli Lilly Nederland B.V., Papendorpseweg 83, 3528 BJ Utrecht, The Netherlands. 
 
Manufacturer  
 
Lilly S.A., Avda. de la Industria 30, 28108 Alcobendas, Madrid, Spain. 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Eli Lilly Benelux S.A./N.V. 
Tél/Tel: + 32 (0) 2 548 84 84 

Lietuva 
Eli Lilly Lietuva 
Tel: + 370 (5) 2649600 

България 
ТП "Ели Лили Недерланд" Б.В. - България 
Тел: + 359 2 491 41 40 

Luxembourg/Luxemburg 
Eli Lilly Benelux S.A./N.V. 
Tél/Tel: + 32 (0) 2 548 84 84  

Česká republika 
Eli Lilly ČR, s.r.o. 
Tel: + 420 234 664 111 

Magyarország 
Lilly Hungária Kft. 
Tel: + 36 1 328 5100 

Danmark 
Eli Lilly Danmark A/S 
Tlf: + 45 45 26 60 00 

Malta 
Charles de Giorgio Ltd. 
Tel: + 356 25600 500 

Deutschland 
Lilly Deutschland GmbH 
Tel: + 49 (0) 6172 273 2222 

Nederland 
Eli Lilly Nederland B.V. 
Tel: + 31(0) 30 6025800 

Eesti 
Eli Lilly Nederland B.V. 
Tel: + 372 6817 280 

Norge 
Eli Lilly Norge A.S 
Tlf: + 47 22 88 18 00 

Ελλάδa 
ΦΑΡΜΑΣΕΡΒ-ΛΙΛΛΥ Α.Ε.Β.Ε. 
Τηλ: + 30 210 629 4600 

Österreich 
Eli Lilly Ges. m.b.H.  
Tel: + 43 (0) 1 711 780 

España 
Lilly S.A. 
Tel: + 34 91 663 50 00 

Polska 
Eli Lilly Polska Sp. z o.o. 
Tel: + 48 22 440 33 00 

France 
Lilly France SAS 
Tél: + 33 (0) 1 55 49 34 34 

Portugal 
Lilly Portugal Produtos Farmacêuticos, Lda 
Tel: + 351 21 412 66 00 

Hrvatska 
Eli Lilly Hrvatska d.o.o. 
Tel: +385 1 2350 999 

România 
Eli Lilly România S.R.L. 
Tel: + 40 21 4023000 

Ireland 
Eli Lilly and Company (Ireland) Limited 
Tel: + 353 (0) 1 661 4377 

Slovenija 
Eli Lilly farmacevtska družba, d.o.o. 
Tel: + 386 (0) 1 580 00 10 

Ísland 
Icepharma hf. 

Slovenská republika 
Eli Lilly Slovakia s.r.o. 



44 

Sími: + 354 540 8000 Tel: + 421 220 663 111 
Italia 
Eli Lilly Italia S.p.A. 
Tel: + 39 055 42571 

Suomi/Finland 
Oy Eli Lilly Finland Ab 
Puh/Tel: + 358 (0) 9 8545 250 

Κύπρος 
Phadisco Ltd  
Τηλ: + 357 22 715000 

Sverige 
Eli Lilly Sweden AB 
Tel: + 46 (0) 8 7378800 

Latvija 
Eli Lilly (Suisse) S.A Pārstāvniecība Latvijā  
Tel: + 371 67364000 

United Kingdom 
Eli Lilly and Company Limited 
Tel: +44 (0) 1256 315000 

  
  

 
This leaflet was last revised in {mmm YYYY} 
 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu 



45 

 
INSTRUCTIONS FOR HEALTH CARE PROFESSIONALS 
 

RECONSTITUTION AND ADMINISTRATION INSTRUCTIONS 
 
ZYPADHERA olanzapine powder and solvent for prolonged release suspension for injection 
 
FOR DEEP INTRAMUSCULAR GLUTEAL INJECTION ONLY. 
DO NOT ADMINISTER INTRAVENOUSLY OR SUBCUTANEOUSLY 

Reconstitution 
STEP 1: Preparing materials 
Pack includes: 
 
• Vial of ZYPADHERA powder for prolonged release suspension for injection 
• Vial of solvent for ZYPADHERA 
• One Hypodermic syringe and safety needle  (Hypodermic Device) 
• One 19-gauge, 38 mm Hypodermic safety needle 
• Two 19-gauge, 50 mm Hypodermic safety needles 
• Patient Information Leaflet  
• Reconstitution and Administration card (this leaflet) 
• Hypodermic Device Safety Information and Instructions for Use leaflet 
 

 
 

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 solvent 
provided 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 prolonged 
release suspension for injection. 
 
 

ZYPADHERA  
vial strength (mg) 

Volume of solvent to add (ml) 

210 1.3 
300 1.8 
405 2.3 

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



46 

 
STEP 3: Reconstituting ZYPADHERA 
1. Loosen the powder by lightly tapping the vial. 
2. Open the pre-packaged Hypodermic syringe and needle with needle protection device. Peel blister 

pouch and remove device. Attach a syringe (if not already attached) to the Luer connection of the 
device with an easy twisting motion. Seat the needle firmly on the device with a push and a 
clockwise twist, then pull the needle cap straight away from the needle. Failure to follow these 
instructions may result in a needle stick 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 the 
device 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 surface to 

cushion impact. (See Figure A) 

 
Figure A: Tap firmly to mix 

 
10. Visually check the vial for clumps. Unsuspended powder appears as yellow, dry clumps clinging to 

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) 



47 

 
Figure C: Vigorously shake vial 

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

 
Administration 
STEP 1: Injecting ZYPADHERA 
This table confirms the final ZYPADHERA suspension volume to inject.  Suspension concentration is 
150 mg/ml olanzapine. 

Dose 
(mg) 

Final volume to inject  
(ml) 

150 1.0 
210 1.4 
300 2.0 
405 2.7 

 
1. 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 to 

withdraw the required suspension volume. 
 If the 38 mm needle is to be used for the injection, attach the 50 mm safety needle to withdraw 

the 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 the 

suspension 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 is 

drawn into the syringe, discard the syringe and the dose and begin reconstitution and administration 
procedure 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 with 

appropriate clinical procedures. The vial is for single use only. 
 



48 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 

Annex IV 

Scientific conclusions and grounds for the variation to the terms of the marketing 
authorisation(s) 

 
 
 
 
 

 



49 

Scientific conclusions 

Taking into account the PRAC Assessment Report on the PSUR(s) for olanzapine, the scientific 
conclusions of CHMP are as follows:  

Following the review of case reports in the UK Sentinel database, the EudraVigilance database, and 
the literature, a signal for salivary hypersecretion with olanzapine was identified on 14 February 
2019 by the Medicines and Healthcare products Regulatory Agency (MHRA) and validated by the 
PRAC. 

Based on signal analysis presented by the MAH including mechanistic plausibility, number of 
dechallenge/rechallenge cases and strong temporal relationship, the PRAC agrees that salivary 
hypersecretion may be associated with olanzapine and the adverse reaction salivary hypersecretion 
should be added to the product information. 

The CHMP agrees with the scientific conclusions made by the PRAC. 

 

Grounds for the variation to the terms of the marketing authorisation(s) 

On the basis of the scientific conclusions for olanzapine the CHMP is of the opinion that the 
benefit-risk balance of the medicinal product(s) containing olanzapine is unchanged subject to the 
proposed changes to the product information 

The CHMP recommends that the terms of the marketing authorisation(s) should be varied. 

 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION 
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET
	Scientific conclusions and grounds for the variation to the terms of the marketing authorisation(s)