Zypadhera

1.

NAME OF THE MEDICINAL PRODUCT

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

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains olanzapine pamoate monohydrate equivalent to 210 mg olanzapine. After

reconstitution each ml of suspension contains 150 mg olanzapine.

For a 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

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. 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.).

Patients should be treated initially with oral olanzapine before administering ZYPADHERA, to

establish tolerability and response.

For Instructions for Use, see section 6.6.

Do not confuse ZYPADHERA 210 mg powder and solvent for prolonged release suspension for

injection with olanzapine 10 mg powder for solution for injection.

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

considered.

Table 1 Recommended dose scheme between oral olanzapine and ZYPADHERA

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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

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.

Elderly patients

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).

Patients with 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.

Gender

The starting dose and dose range need not be routinely altered for female patients relative to male

patients.

Smokers

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

When more than one factor is present which might result in slower metabolism (female gender,

geriatric age, non-smoking status), consideration should be given to decreasing the dose. When

indicated, dose escalation should be performed with caution in these patients.

Paediatric population

ZYPADHERA is not recommended for use in children and adolescents below 18 years due to a lack

of data on safety and efficacy.

4.3 Contraindications

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Hypersensitivity to the active substance or to any of the excipients.

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.

Prior to giving the injection, the healthcare professional should determine that the patient will not

travel alone to their destination. 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.

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.

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 approved for the treatment of dementia-related psychosis and/or behavioural

disturbances and is not recommended for use in this particular group of patients because of an increase

in mortality and the risk of cerebrovascular accident. In placebo-controlled clinical trials (6-12 weeks

duration) of elderly patients (mean age 78 years) with dementia-related psychosis and/or disturbed

behaviours, there was a 2-fold increase in the incidence of death in oral olanzapine-treated patients

compared to patients treated with placebo (3.5% vs. 1.5%, respectively). The higher incidence of death

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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

(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 rarely, 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.

Patients treated with any antipsychotic agents, 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.

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 antipsychotic agents, including ZYPADHERA, should be

monitored regularly for lipids in accordance with utilised antipsychotic guidelines.

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.

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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

very rarely (<0.01%) 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, as with other antipsychotics, caution

should be exercised when olanzapine is prescribed with medicines known to increase QTc interval,

especially in the elderly, in patients with congenital long QT syndrome, congestive heart failure, heart

hypertrophy, hypokalaemia or hypomagnesaemia.

Thromboembolism

Temporal association of olanzapine treatment and venous thromboembolism has very rarely (< 0.01%)

been reported. 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 rarely 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.

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Postural hypotension

Postural hypotension was infrequently observed in the elderly in olanzapine clinical trials. As with

other antipsychotics, it is recommended that blood pressure is measured periodically in patients over

65 years.

Sudden cardiac death

In postmarketing reports with olanzapine, the event of sudden cardiac death has been reported in

patients with olanzapine. In a retrospective observational cohort study, the risk of presumed sudden

cardiac death in patients treated with olanzapine was approximately twice the risk in patients not using

antipsychotics. In the study, the risk of olanzapine was comparable to the risk of atypical

antipsychotics included in a pooled analysis.

Paediatric population

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

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

parameters and increases in prolactin levels. Long-term outcomes associated with these events have

not been studied and remain unknown (see sections 4.8 and 5.1).

Use in elderly patients (>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

Paediatric population

Interaction studies have only been performed in adults.

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

sedation.

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 C max 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

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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.

Spontaneous reports have been very rarely received on tremor, hypertonia, lethargy and sleepiness, in

infants born to mothers who had used olanzapine during the 3rd trimester.

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.

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

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

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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.

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

but may occur following administration of ZYPADHERA.

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 (see section 4.4), dyskinesia, orthostatic hypotension, anticholinergic effects,

transient asymptomatic elevations of hepatic aminotransferases (see section 4.4), rash, asthenia,

fatigue and oedema.

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 (≥10%), common (≥ 1% and < 10%), uncommon (≥ 0.1% and < 1%), rare (≥ 0.01% and

< 0.1%), very rare (< 0.01%), not known (cannot be estimated from the data available).

Very common

Common

Uncommon

Not known

Blood and the lymphatic system disorders

Eosinophilia

Leukopenia

Neutropenia

Thrombocytopenia

Immune system disorders

Allergic reaction

Metabolism and nutrition disorders

Weight gain 1

Elevated cholesterol

levels 2,3

Elevated glucose

levels 4

Elevated triglyceride

levels 2,5

Glucosuria

Increased appetite

Development or

exacerbation of

diabetes occasionally

associated with

ketoacidosis or coma,

including some fatal

cases (see section 4.4)

Hypothermia

Nervous system disorders

Somnolence

Dizziness

Akathisia 6

Parkinsonism 6

Dyskinesia 6

Seizures where in most

cases a history of

seizures or risk factors

for seizures were

reported

Neuroleptic malignant

syndrome (see section

4.4)

Dystonia (including

oculogyration)

Tardive dyskinesia

Discontinuation

9

symptoms 7

Cardiac disorders

Bradycardia

QT c prolongation (see

section 4.4)

Ventricular

tachycardia/fibrillation,

sudden death (see

section 4.4)

Vascular disorders

Orthostatic

hypotension

Thromboembolism

(including pulmonary

embolism and deep

vein thrombosis)

Gastrointestinal disorders

Mild, transient

anticholinergic effects

including constipation

and dry mouth

Pancreatitis

Hepato-biliary 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)

Skin and subcutaneous tissue disorders

Rash

Photosensitivity

reaction

Alopecia

Musculoskeletal and connective tissue disorders

Rhabdomyolysis

Renal and urinary disorders

Urinary incontinence

Urinary hesitation

Reproductive system and breast disorders

Priapism

General disorders and administration site conditions

Asthenia

Fatigue

Oedema

Investigations

Elevated plasma

prolactin levels 8

High creatine

phosphokinase

Increased total

bilirubin

Increased alkaine

phosphatase

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.

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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 can not 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. Generally in olanzapine-treated patients potentially associated

breast- and menstrual related clinical manifestations (e.g. amenorrhoea, breast enlargement,

galactorrhea in females, and gynaecomastia/breast enlargement in males) were uncommon. Potentially

associated sexual function-related adverse reactions (e.g. erectile dysfunction in males and decreased

libido in both genders) were commonly observed.

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.

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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 (≥ 10%), common (≥ 1% and

< 10%).

Metabolism and nutrition disorders

Very common: Weight gain 9 , elevated triglyceride levels 10 , increased appetite.

Common: Elevated cholesterol levels 11

Nervous system disorders

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

Gastrointestinal disorders

Common: Dry mouth

Hepato-biliary disorders

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

Investigations

Very common: Decreased total bilirubin, increased GGT, elevated plasma prolactin levels 12 .

9 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.

10 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).

11 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.

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

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.

12

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 of overdose

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.

5.

PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: diazepines, oxazepines and thiazepines, ATC code N05AH03.

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 (K i ; < 100 nM) for serotonin

5-HT 2A/2C , 5-HT 3 , 5-HT 6 ; dopamine D 1 , D 2 , D 3 , D 4 , D 5 ; cholinergic muscarinic receptors M 1 -M 5 ; α- 1

adrenergic; and histamine H 1 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-HT 2 than dopamine D 2 receptors and greater 5-

HT 2 than D 2 activity in viv o, 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.

The effectiveness of ZYPADHERA in the treatment and maintenance treatment of schizophrenia is

consistent with the established effectiveness of the oral formulation of olanzapine.

In a Positron Emission Tomography (PET) study in patients treated with ZYPADHERA

(300 mg/4 weeks), mean D 2 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.

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

13

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 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 . The experience in adolescents (ages

13 to 17 years) is limited to short term oral olanzapine efficacy data 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 data on maintenance

of effect and limited data on long term safety (see sections 4.4 and 4.8) .

5.2 Pharmacokinetic properties

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.

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.

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 nonsmokers 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.

After repeated IM injections with 150 to 300 mg ZYPADHERA every two weeks, the 10 th to 90 th

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

14

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.

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 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.

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).

In smoking subjects with mild hepatic dysfunction, mean elimination half-life (39.3 hours) of orally

administered olanzapine was prolonged and clearance (18.0 l/hr) was reduced analogous to non-

smoking healthy subjects (48.8 hours and 14.1 l/hr, respectively). 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.

15

Haematologic toxicity: Effects on haematology parameters were found in each species, including

dose-related reductions in circulating leukocytes in mice and non-specific reductions of circulating

leukocytes in rats; however, no evidence of bone marrow cytotoxicity was found. Reversible

neutropenia, thrombocytopenia, or anaemia developed in a few dogs treated with 8 or 10 mg/kg/day

(total olanzapine exposure [AUC] is 12- to 15-fold greater than that of a man given a 12 mg dose). In

cytopenic dogs, there were no 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

No excipients.

Solvent

Croscarmellose 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.

16

6.4 Special precautions for storage

Do not refrigerate or freeze.

6.5 Nature and contents of container

210 mg powder: Type I glass vial. Bromobutyl stopper with rust 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 Needle-Pro 3ml

syringe with pre-attached 19-gauge, 38 mm safety needle, one 19-gauge, 38 mm Hypodermic Needle-

Pro safety needle and one 19-gauge, 50 mm Hypodermic Needle-Pro safety needle.

6.6 Special precautions for disposal and other handling

FOR DEEP INTRAMUSCULAR GLUTEAL INJECTION ONLY. DO NOT ADMINISTER

INTRAVENOUSLY OR SUBCUTANEOUSLY.

Any unused 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 Needle-Pro syringe and needle with needle protection device.

Peel blister pouch and remove device. Insure needle is firmly seated on the Needle-Pro 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, THE NEEDLE IS FIRMLY ENGAGED INTO THE SHEATH (Figure 1

and 2)

8. Visually confirm that the needle is fully engaged into the needle protection sheath. (Figure 3) Only

remove the Needle-Pro 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

17

thumb and forefinger, keeping the free fingers clear of the end of the device containing the needle

point.

Figure 1

Figure 2

Figure 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

300

2.0

405

2.7

18

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 remaining 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. (Figure 1 and 2)

8. Discard the vials, syringe, needles and any unused solvent in accordance with appropriate clinical

procedures. The vial is for single use only.

7.

MARKETING AUTHORISATION HOLDER

Eli Lilly Nederland BV, Grootslag 1 – 5, NL-3991 RA, Houten, The Netherlands.

8.

MARKETING AUTHORISATION NUMBER(S)

EU/1/08/479/001

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 19/11/2008

10. DATE OF REVISION OF THE TEXT

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

http://www.ema.europa.eu

19

1.

NAME OF THE MEDICINAL PRODUCT

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

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains olanzapine pamoate monohydrate equivalent to 300 mg olanzapine. After

reconstitution each ml of suspension contains 150 mg olanzapine.

For a 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

FOR INTRAMUSCULAR USE ONLY. DO NOT ADMINISTER INTRAVENOUSLY OR

SUBCUTANEOUSLY. (see section 4.4)