Consumer medicine information

Zyprexa IM

Olanzapine

BRAND INFORMATION

Brand name

Zyprexa IM

Active ingredient

Olanzapine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Zyprexa IM.

What is in this leaflet

This leaflet is designed to provide you with answers to some common questions about this medicine. It does not contain all the available information and does not take the place of talking with your doctor.

The information in this leaflet was last updated on the date shown on the final page. More recent information about this medicine may be available. Make sure you speak to your pharmacist or doctor to obtain the most up to date information on this medicine. You can also download the most up to date leaflet from www.lilly.com.au. The updated leaflet may contain important information about ZYPREXA and its use that you should be aware of.

All medicines have risks and benefits. Your doctor has more information about this medicine than is contained in this leaflet. Also, your doctor has had the benefit of taking a full and detailed history from you and is in the best position to make an expert judgement to meet your individual needs.

If you have any concerns about taking this medicine, talk to your doctor or pharmacist.

Keep this leaflet with this medicine. You may need to read it again.

What ZYPREXA is used for

ZYPREXA belongs to a group of medicines called antipsychotics. It helps to correct chemical imbalances in the brain, which may cause mental illness.

ZYPREXA IM injection is used for the rapid control of agitation and disturbed behaviours in patients with schizophrenia and related psychoses and in patients with acute mania associated with Bipolar I Disorder.

Schizophrenia is a mental illness with disturbances in thinking, feelings and behaviour. Bipolar I Disorder is a mental illness with symptoms such as feeling "high", having excessive amounts of energy, needing much less sleep than usual, talking very quickly with racing ideas and sometimes severe irritability.

ZYPREXA IM injection is given when treatment with ZYPREXA tablets is not appropriate. Your doctor will change your treatment to ZYPREXA tablets or ZYPREXA Zydis wafers as soon as practicable.

Your doctor may have prescribed ZYPREXA for another reason.

Ask your doctor if you have any questions about why ZYPREXA has been prescribed for you. This medicine is available only with a doctor's prescription.

ZYPREXA is not recommended for use in children under the age of 18 years as there is not enough information on its effects in this age group.

Before you are given ZYPREXA

Tell your doctor if you have any of the following conditions or if you have ever experienced any of these conditions.

When you must not be given it

Do not have it:

  • if you have had an allergic reaction to any type of ZYPREXA or to any of the ingredients listed at the end of this leaflet (see 'Product Description').
    Signs of an allergic reaction may include a skin rash, itching, shortness of breath or swelling of the face, lips or tongue.
  • if the packaging is torn or shows signs of tampering.
  • if the expiry date on the pack has passed.
    If you take this medicine after the expiry date has passed it may not work as well.

Use of ZYPREXA IM is not recommended simultaneously with:

  • a benzodiazepine medication by injection (to treat a range of conditions such as anxiety, nervousness, panic attacks, seizures, muscle spasm and insomnia).

If you are not sure whether you should have ZYPREXA, talk to your doctor or pharmacist.

Before you have it

Tell your doctor if you have had an allergic reaction to any medicine which you have taken previously to treat your current condition.

Tell your doctor if you have or have had any medical conditions, especially the following:

  • tumour of the pituitary gland (a small gland at the base of the brain)
  • disease of the blood or bone marrow with a reduced number of white or red blood cells
  • disease of the blood vessels of the brain, including stroke
  • prostate problems
  • kidney or liver disease
  • high blood sugar, diabetes or a family history of diabetes
  • breast cancer or a family history of breast cancer
  • paralytic ileus, a condition where the small bowel does not work properly
  • epilepsy, seizures or fits
  • glaucoma, a condition in which there is usually a build up of fluid in the eye
  • heart disease, including irregular heart rhythm
  • neuroleptic malignant syndrome, a reaction to some medicines with a sudden increase in body temperature, extremely high blood pressure and severe convulsions
  • tardive dyskinesia, a reaction to some medicines with uncontrollable twitching or jerking movements of the arms and legs.
  • sleep apnoea, a sleep disorder where a person has pauses in breathing or periods of shallow breathing during sleep.

Tell your doctor if you are pregnant or intend to become pregnant. Like most antipsychotic medicines, ZYPREXA is not recommended for use during pregnancy. Newborn babies of mothers taking antipsychotic drugs (including ZYPREXA) during the last trimester of pregnancy are at risk of experiencing extrapyramidal neurological disturbances and/or withdrawal symptoms following delivery. These may include, but are not limited to agitation, tremor, muscle stiffness or weakness, drowsiness, feeding problems, and breathing difficulty. If there is a need to consider ZYPREXA during your pregnancy, your doctor will discuss with you the benefits and risks of using it.

Tell your doctor if you are breast-feeding or plan to breast-feed. It is recommended that you do not breast-feed while taking ZYPREXA.

Tell your doctor if you will be in a hot environment or do a lot of vigorous exercise. ZYPREXA may make you sweat less, causing your body to overheat.

Tell your doctor if you smoke. Smoking may affect ZYPREXA or may affect how it works.

If you are elderly with dementia-related psychosis, tell your doctor if you have previously had a stroke or transient ischaemic attack (ministroke) or if you have high blood pressure.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may be affected by ZYPREXA or may affect how it works. These include:

  • medicines used to treat a fast or irregular heart beat (arrhythmia)
  • medicines taken for anxiety or to help you sleep
  • medicines taken for depression
  • carbamazepine, a medicine used for mood stabilisation and to treat epilepsy
  • other centrally acting medicines (e.g. tranquillisers or strong painkillers)
  • ciprofloxacin, a medicine used to treat bacterial infections
  • medicines that lower blood pressure
  • medicines used for Parkinson's disease
  • medicines that can change the heart's electrical activity or make it more likely to change.

Your doctor or pharmacist has more information on medicines to be careful with or avoid while having ZYPREXA.

Tell your doctor about these things before you have ZYPREXA.

How you are given ZYPREXA

Follow all directions given to you by your doctor or pharmacist carefully. These may differ from the information contained in this leaflet.

How much is given

Your doctor will decide how much ZYPREXA you need and how long you need it for.

The dosage you receive will usually be 10 mg in one injection. Up to three injections in 24 hours may be given.

A lower starting dose may be prescribed for elderly patients over the age of 65 years.

How it is given

ZYPREXA is injected into your muscle. Your doctor or nurse will inject ZYPREXA for you.

Overdose

AS ZYPREXA IM is given to you under the supervision of your doctor, it is unlikely that you will receive too much. However, if you experience any side effects after being given ZYPREXA IM, tell your doctor immediately or go to Accident and Emergency at your nearest hospital The most common signs of too much ZYPREXA are fast heart beat, agitation/aggression, difficulty speaking, uncontrollable movements and sleepiness (sedation).

While you are having ZYPREXA

Things you must do

Tell all doctors, dentists and pharmacists who are treating you that you are having ZYPREXA.

While you are having ZYPREXA, tell your doctor or pharmacist before you start any new medicine.

If you become pregnant while having ZYPREXA, tell your doctor.

Keep all of your doctor's appointments so that your progress can be checked.

  • Your doctor should monitor your weight if you are having ZYPREXA.
  • Patients with diabetes or who have a higher chance of developing diabetes should have their blood sugar checked often.
  • Your doctor may request you have a blood test from time to time to monitor your cholesterol levels.
  • If you are over 65, your doctor may measure your blood pressure from time to time.

Tell your doctor if you are female and your monthly periods are absent for six months or more.

All thoughts of suicide or violence must be taken seriously. Talk to your doctor or mental health professional if you have thoughts or talk about death or suicide; or thoughts or talk about self-harm or harm to others. These may be signs of changes or worsening in your mental illness.

Things you must not do

Do not stop taking ZYPREXA, or lower the dosage, even if you are feeling better, without checking with your doctor.

Do not give ZYPREXA to anyone else, even if their symptoms seem similar or they have the same condition as you. Your doctor has prescribed ZYPREXA for you and your condition.

Things to be careful of

Be careful driving or operating machinery until you know how ZYPREXA affects you.

ZYPREXA may cause drowsiness in some people.

Be careful when drinking alcohol while taking ZYPREXA. The effects of alcohol could be made worse while taking ZYPREXA.

Your doctor may suggest you avoid alcohol while you are being treated with ZYPREXA.

If ZYPREXA makes you feel light-headed, dizzy or faint, be careful when getting up from a sitting or lying position. Getting up slowly may help.

If outdoors, wear protective clothing and use at least a 30+ sunscreen. ZYPREXA may cause your skin to be much more sensitive to sunlight than it is normally.

Exposure to sunlight may cause a skin rash, itching, redness, or severe sunburn.

If your skin does appear to be burning, tell your doctor.

Make sure you keep cool in hot weather and keep warm in cool weather. ZYPREXA may affect the way your body reacts to temperature changes.

Antipsychotics have the potential to cause cardiac complications and sudden cardiac death.

Side effects

All medicines may have some unwanted side effects. Sometimes they are serious, but most of the time they are not. Your doctor has weighed the risks of using this medicine against the benefits they expect it will have for you.

Like other medicines, ZYPREXA may cause some unwanted side effects. These are likely to vary from patient to patient. Some side effects may be related to the dose of ZYPREXA. Accordingly, it is important that you tell your doctor as soon as possible about any unwanted effects. Your doctor may then decide to adjust the dose of ZYPREXA you are taking.

Tell your doctor if you notice any of the following side effects and they worry you:

  • drowsiness
  • unusual tiredness or weakness
  • fever
  • restlessness or difficulty sitting still
  • increased appetite, weight gain
  • constipation, bloating
  • dry mouth
  • swelling of your hands, feet and ankles
  • aching joints
  • nose bleeds
  • changes to heart rate, such as fast heart beat or slow heart beat
  • low blood pressure
  • dizziness, confusion, forgetfulness.
  • speech disorder
  • sleepwalking
  • sleep eating

Some people may feel dizzy in the early stages of treatment, especially when getting up from a lying or sitting position. This side effect usually passes after taking ZYPREXA for a few days.

Tell your doctor if you notice any of the above side effects and they worry you. These are the more common side effects of ZYPREXA or ZYPREXA IM.

Tell your doctor as soon as possible if you notice any of the following side effects:

  • symptoms of sunburn (such as redness, itching, swelling or blistering of the skin) which occur more quickly than normal
  • rash or allergic reaction
  • slow heart beat
  • changes in sexual functioning or sex drive in men or women
  • prolonged and/or painful erection
  • unusual secretion of breast milk
  • breast enlargement in men or women
  • symptoms of high sugar levels in the blood (including passing large amounts of urine, excessive thirst, having a dry mouth and skin and weakness). These may indicate the onset or worsening of diabetes
  • reaction following abrupt discontinuation (profuse sweating, nausea or vomiting)
  • absence of menstrual periods and changes in the regularity of menstrual periods
  • involuntary passing of urine or difficulty in initiating urination
  • unusual hair loss or thinning.

These side effects are uncommon but may require medical attention.

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital if you notice any of the following:

  • Sudden signs of an allergic reaction such as a skin rash, itching, shortness of breath or swelling of the face, lips or tongue.
  • frequent infections such as fever, severe chills, sore throat or mouth ulcers
  • bleeding or bruising more easily than normal
  • painful swollen leg, chest pain, or shortness of breath as these can be signs of blood clots in the lungs or legs
  • seizures, fits or convulsions
  • yellowing of the skin and/or eyes
  • nausea, vomiting, loss of appetite, generally feeling unwell, fever, itching, yellowing of the skin and/or eyes
  • severe upper stomach pain often with nausea and vomiting (inflammation of the pancreas)
  • worm-like movements of the tongue, or other uncontrolled movements of the tongue, mouth, cheeks, or jaw which may progress to the arms and legs
  • sudden increase in body temperature, sweating, fast heart beat, muscle stiffness, high blood pressure and convulsions
  • sharp chest pain, coughing of blood, or sudden shortness of breath
  • pain/tenderness in the calf muscle area
  • muscle pain, muscle weakness and brown urine
  • heart attack
  • heart palpitations and dizziness, which may lead to collapse.
  • fast breathing, shortness of breath, fever with chills, feeling tired or weak, chest pain while coughing, fast heartbeat. You may have pneumonia.
  • fever or swollen glands, especially if they occur together with or shortly after a skin rash

These are very serious side effects. You may need urgent medical attention or hospitalisation.

Most of these side effects are very rare.

The following additional side effects may occur in some groups of people taking ZYPREXA:

Elderly patients with dementia-related psychosis

Elderly patients with dementia-related psychosis may notice the following side effects:

  • unusual manner of walking
  • falls
  • pneumonia
  • involuntary passing of urine
  • stroke
  • transient ischemic attack – symptoms maybe, but not limited to, paralysis in face, arm or leg

Parkinson's disease psychosis

Some patients with Parkinson's disease may hallucinate (see, feel or hear things that are not there) or develop worsening symptoms of Parkinson's disease.

Zyprexa in combination with lithium or valproate

Patients with bipolar mania taking ZYPREXA in combination with lithium or valproate may notice the following additional side effects:

  • tremors
  • speech disorder.

Tell your doctor if you notice anything unusual or if you are concerned about any aspect of your health, even if you think the problems are not connected with this medicine and are not referred to in this leaflet. Also, some side effects, such as changes to liver function, blood cell counts, cholesterol or triglycerides can occur. These can only be found when your doctor does tests from time to time to check your progress.

Do not be alarmed by this list of side effects. You may not experience any of them.

Other side effects not listed above may also occur in some patients. Tell your doctor if you notice anything else that is making you feel unwell.

After having ZYPREXA

Storage

ZYPREXA IM Injection vials should be stored below 25° C.

The vials are usually stored in the hospital ward or in the pharmacy.

All medicines should be kept where young children cannot reach them.

There will be an expiry date (month, year) on your ZYPREXA container.

The medicine should not be taken after this date because it may have lost some of its strength.

Disposal

If your doctor tells you to stop taking ZYPREXA or you find that the tablets or wafers have passed their expiry date, please return any left over tablets or wafers to your pharmacist.

Product Description

What it looks like

ZYPREXA IM Injection comes as a yellow powder in a clear glass vial. A vial of ZYPREXA IM Injection can provide you with 10 mg of olanzapine.

Ingredients

Active Ingredient - 10 mg olanzapine.

Inactive Ingredients:

  • lactose monohydrate
  • tartaric acid.

Supplier

ZYPREXA is a product of:

Eli Lilly Australia Pty Ltd
Level 9, 60 Margaret Street, Sydney,
NSW 2000
AUSTRALIA

ZYPREXA is distributed in New Zealand by:

Eli Lilly and Company (NZ) Limited.
PO Box 107 197 Newmarket,
Auckland
NEW ZEALAND

®= Registered Trademark

Australian Registration Number

AUST R 76867

This leaflet was revised in
November 2023.

vA13

Published by MIMS January 2024

BRAND INFORMATION

Brand name

Zyprexa IM

Active ingredient

Olanzapine

Schedule

S4

 

1 Name of Medicine

Zyprexa IM (olanzapine).

2 Qualitative and Quantitative Composition

Olanzapine 10 mg.
The active ingredient in Zyprexa IM is olanzapine 10 mg. Zyprexa IM also contains excipients: lactose monohydrate and tartaric acid. Hydrochloride acid and/or sodium hydroxide may have been added during manufacture to adjust pH.

3 Pharmaceutical Form

Zyprexa IM 10 mg is yellow lyophilised powder in a clear glass vial. It is intended for intramuscular use only.

4 Clinical Particulars

4.1 Therapeutic Indications

Zyprexa IM is indicated for the rapid control of agitation and disturbed behaviours in patients with schizophrenia and related psychoses and in patients with acute mania associated with bipolar 1 disorder, when oral therapy is not appropriate.

4.2 Dose and Method of Administration

Zyprexa IM is for intramuscular use. Do not administer intravenously or subcutaneously.
Zyprexa IM is intended for short-term use only.

Agitated patients with schizophrenia or bipolar mania.

The recommended dose for Zyprexa IM is 10 mg, administered as a single intramuscular injection. In clinical trials, Zyprexa IM was effective following a dose of 5 to 10 mg. Therefore, a lower dose may be given on the basis of individual clinical status. A second injection, up to 10 mg, may be administered as early as 2 hours after the first injection on the basis of individual clinical status. A third injection, up to 10 mg, may be administered as early as 4 hours after the second injection. In clinical trials, 30 mg olanzapine was the maximum dose administered intramuscularly in any 24 hour period. There is limited information on the safety and efficacy of higher doses of Zyprexa IM, as less than 10% of agitated clinical trial patients received doses higher than 20 mg in any 24 hour period. Vital signs should be closely monitored in patients who receive the maximum dose of 30 mg within the specified minimum time period of 6 hours in order to detect adverse cardiovascular effects, such as hypotension.
The maximum daily dose of Zyprexa IM is 30 mg, not more than 3 injections in any 24 hour period.
The efficacy and safety of the use of Zyprexa IM for longer than 24 hours has not been systematically studied.
Treatment with Zyprexa IM should be discontinued and the use of oral Zyprexa should be initiated as soon as clinically appropriate.
For further information on continued treatment with oral Zyprexa (5 to 20 mg daily), see the Product Information for Zyprexa tablets and Zyprexa Zydis wafers.

Elderly patients.

A low starting dose of 5 mg per injection should be considered for those patients 65 and over when clinical factors warrant.

Patients with hepatic and/or renal impairment.

Small, single dose clinical pharmacology studies did not reveal any major alterations in olanzapine pharmacokinetics in subjects with renal or hepatic impairment. However, as clinical experience is limited in these patients, a lower starting dose (5 mg/day) should be considered. Further dose adjustments, when indicated, should be conservative in these patients.

Female compared with male patients.

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

Nonsmoking patients compared with smoking patients.

The starting dose and dose range need not be routinely altered for nonsmoking patients relative to smoking patients.
When more than one factor is present which might result in slower metabolism (female gender, geriatric age, nonsmoking status), consideration should be given to decreasing the starting dose. Dose escalation, when indicated, should be conservative in such patients (see Section 4.4 Special Warnings and Precautions for Use; Section 5.1 Pharmacodynamic Properties).

Instructions for use/ handling Zyprexa IM vial.

Zyprexa IM should be reconstituted only with sterile water for injection.
Zyprexa IM should not be combined in a syringe nor should be used simultaneously with parenteral benzodiazepines (see Section 4.4 Special Warnings and Precautions for Use).
Zyprexa IM should not be combined in a syringe with haloperidol injection because the resulting low pH has been shown to degrade olanzapine over time.
Reconstitute using standard aseptic techniques for reconstitution of parenteral products.
Use immediately within 1 hour after reconstitution.
Discard any unused portion.
Following reconstitution, the resulting solution should be clear and yellow in colour.
Parenteral drug products should be inspected visually for particulate matter prior to administration whenever solution and container permit.

Reconstitution of Zyprexa IM with sterile water for injection.

1. Reconstitute using 2.1 mL of sterile water for injection.
2. Rotate the vial until the contents have completely dissolved, giving a yellow coloured solution. Table 1 indicates the volume required to deliver the desired dose of olanzapine.
3. Administer the solution intramuscularly. Do not administer intravenously or subcutaneously.

4.3 Contraindications

Zyprexa IM is contraindicated in those patients with a known hypersensitivity to any ingredient of the product.
Simultaneous administration of Zyprexa IM and parenteral benzodiazepines is not recommended due to the potential for excessive sedation, cardiorespiratory depression and, in very rare cases, death (see Section 4.4 Special Warnings and Precautions for Use).

4.4 Special Warnings and Precautions for Use

Hypotension and/or bradycardia have been observed during intramuscular administration of Zyprexa IM (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients should remain recumbent if drowsy or dizzy after injection, until examination has indicated that they are not experiencing hypotension, postural hypotension, bradycardia and/or hypoventilation.
In view of the possibility of bradycardia and/or hypotension with Zyprexa IM, caution should be considered in patients with serious cardiovascular disease where the occurrence of syncope, or hypotension and/or bradycardia might put the patient at increased medical risk.
Caution is necessary in patients who receive treatment with other drugs having effects that can induce hypotension, bradycardia, respiratory or central nervous system depression. Simultaneous administration of Zyprexa IM and parenteral benzodiazepines is not recommended due to the potential for excessive sedation, cardiorespiratory depression and, in very rare cases, death. In the event of use of a parenteral benzodiazepine with Zyprexa IM, whether intentional or inadvertent, the patient should be closely monitored for excessive sedation and cardiorespiratory depression.

Concomitant illnesses.

While Zyprexa demonstrated anticholinergic activity in vitro, experience during clinical trials revealed a low incidence of related events. As clinical experience with Zyprexa in patients with concomitant illness is limited, caution is advised when prescribing for patients with prostatic hypertrophy, narrow angle glaucoma or paralytic ileus and related conditions.

Hyperglycaemia and diabetes mellitus.

Hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including Zyprexa. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycaemia related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment emergent hyperglycaemia related adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycaemia related adverse events in patients treated with atypical antipsychotics are not available.
Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g. obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycaemia including polydipsia, polyuria, polyphagia and weakness. Patients who develop symptoms of hyperglycaemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycaemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug.

Lipid alterations.

Undesirable alterations in lipids have been observed in Zyprexa treated patients in placebo controlled trials. Zyprexa treated patients had a greater mean increase in fasting total cholesterol, LDL cholesterol, and triglycerides compared to placebo treated patients. Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were greater in patients without evidence of lipid dysregulation at baseline. Appropriate clinical monitoring is recommended (see Section 4.8 Adverse Effects (Undesirable Effects)).

Weight gain.

Potential consequences of weight gain should be considered prior to starting Zyprexa. As with all antipsychotics, patients receiving Zyprexa should receive regular monitoring of weight. In clinical trials significant weight gain was observed across all baseline body mass index (BMI) categories in Zyprexa treated patients (see Section 4.8 Adverse Effects (Undesirable Effects)).

Blood.

As with other neuroleptic drugs, caution should be exercised in patients with low leukocyte and/or neutrophil counts for any reason, 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. Thirty two patients with clozapine related neutropenia or agranulocytosis histories received Zyprexa without decreases in baseline neutrophil counts.
In animal studies, dose related reductions in circulating leucocytes were observed in mice and rats at oral doses greater than 3 to 4 mg/kg/day; 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. In cytopenic dogs, there were no adverse effects on progenitor and proliferating cells in the bone marrow. No haematologic effects were seen in dogs receiving 5 mg/kg/day. In clinical trials, there were no data to suggest Zyprexa adversely affected bone marrow function, even in patients with a history of drug associated neutropenia or leucopenia (see Section 4.8 Adverse Effects (Undesirable Effects)).

Neuroleptic malignant syndrome (NMS).

NMS, a potentially fatal symptom complex, is associated with antipsychotic drugs, including olanzapine (see Section 4.8 Adverse Effects (Undesirable Effects)). 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 kinase, myoglobinuria (rhabdomyolysis) and acute renal failure. In such an event or with unexplained high fever without additional clinical manifestations of NMS, all antipsychotic drugs, including Zyprexa, should be discontinued.

Seizures.

Zyprexa 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 such patients when treated with Zyprexa (see Section 4.8 Adverse Effects (Undesirable Effects)).

Drug reaction with eosinophilia and systemic symptoms (DRESS).

Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported with olanzapine exposure. DRESS consists of a combination of three or more of the following: cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, lymphadenopathy and one or more systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and pericarditis. Discontinue olanzapine if DRESS is suspected.

Tardive dyskinesia.

In comparator studies of one year or less duration, Zyprexa was associated with a statistically significantly 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 Zyprexa, a dose reduction or drug discontinuation should be considered. These symptoms can temporarily deteriorate or even arise after discontinuation of treatment.

Akathisia.

The presentation of akathisia may be variable and comprises subjective complaints of restlessness and an overwhelming urge to move, and either distress or motor phenomena such as pacing, swinging of the legs while seated, rocking from foot to foot, or both. Particular attention should be paid to monitoring for such signs and symptoms as, left untreated, akathisia is associated with poor compliance and an increased risk of relapse.

Cardiac.

Postural hypotension was infrequently observed in elderly subjects in clinical trials. As with other antipsychotics, it is recommended that blood pressure is measured periodically in patients over 65 years.
In clinical trials, Zyprexa was not associated with a persistent increase in absolute QT intervals. Only 8 of 1,685 subjects had an increase in the corrected QT interval (QTc) on multiple occasions. As with other antipsychotics, caution should be exercised when Zyprexa is prescribed with drugs known to increase QTc interval, especially in elderly patients.

Sudden cardiac death.

In a retrospective observational study, patients treated with atypical antipsychotics (including olanzapine) or typical antipsychotics had a similar dose related increase of presumed sudden cardiac death compared to nonusers of antipsychotics, with almost twice the risk than that for nonusers. In postmarketing reports with olanzapine, the event of sudden cardiac death has been reported very rarely.

Safety experience in elderly patients with dementia related psychosis.

In elderly patients with dementia related psychosis, the efficacy of olanzapine has not been established. In placebo controlled clinical trials of elderly patients with dementia related psychosis, the incidence of death in olanzapine treated patients was significantly greater than placebo treated patients (3.5% vs 1.5%, respectively). Risk factors that may predispose this patient population to increased mortality when treated with olanzapine include age > 80 years, sedation, concomitant use of benzodiazepines, or presence of pulmonary conditions (e.g. pneumonia, with or without aspiration).

Cerebrovascular adverse events (CVAE), including stroke, in elderly patients with dementia.

Cerebrovascular adverse events (e.g. stroke, transient ischaemic attack), including fatalities, were reported in trials of olanzapine in elderly patients with dementia related psychosis. In placebo controlled studies, there was a higher incidence of CVAE in patients treated with olanzapine compared to patients treated with placebo (1.3% vs 0.4%, respectively). All patients who experienced a cerebrovascular event had pre-existing risk factors known to be associated with an increased risk for a CVAE (e.g. history of previous CVAE or transient ischaemic attack, hypertension, cigarette smoking) and presented with concurrent medical conditions and/or concomitant medications having a temporal association with CVAE. Olanzapine is not approved for the treatment of patients with dementia related psychosis.
There are insufficient data to determine if any differences exist in the incidence of cerebrovascular accidents and/or mortality between oral olanzapine and olanzapine for injection in elderly patients with dementia. In this patient population, the increased incidence of cerebrovascular accidents and/or mortality compared to placebo, and the risk factors identified for oral olanzapine, cannot be excluded for olanzapine for injection.

Body temperature regulation.

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing Zyprexa for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g. exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.

Dysphagia.

Oesophageal dysmotility and aspiration have been associated with antipsychotic drug use. Zyprexa and other antipsychotic agents should be used cautiously in patients at risk for aspiration pneumonia.

Suicide.

The possibility of a suicide attempt is inherent in schizophrenia and in bipolar disorder and close supervision of high risk patients should accompany therapy. Prescriptions for olanzapine should be written for the smallest quantity possible, consistent with good patient management, in order to reduce the risk of overdose.

Sleep apnoea.

Sleep apnoea and related disorders have been reported in patients treated with olanzapine, with or without prior history of sleep apnoea, and with or without concomitant weight-gain. Olanzapine should be used with caution in patients who have sleep apnoea or risk factors for developing sleep apnoea, and also in patients who are concomitantly using central nervous system depressants.

Use in hepatic impairment.

Transient, asymptomatic elevations of hepatic transaminases, alanine transferase (ALT), aspartate transferase (AST) have been seen occasionally, especially in early treatment. Rare postmarketing reports of hepatitis have been received. Very rare cases of jaundice, cholestatic or mixed liver injury have also been reported in the postmarketing period (see Section 4.8 Adverse Effects (Undesirable Effects)). Caution should be exercised 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 drugs.

Use in the elderly.

Caution should be used when Zyprexa is administered to the elderly, especially if there are other factors that may influence drug metabolism and/or pharmacodynamic parameters.

Paediatric use.

The safety and efficacy of Zyprexa have not been established in patients under 18 years of age.

Effects on laboratory tests.

No information is available on the effect of Zyprexa on laboratory tests.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Administration of intramuscular lorazepam (2 mg) one hour after intramuscular olanzapine (5 mg) did not significantly affect the pharmacokinetics of olanzapine, unconjugated lorazepam or total lorazepam. However, this coadministration of intramuscular lorazepam and intramuscular olanzapine added to the somnolence observed with either drug alone. Simultaneous use of Zyprexa IM and parenteral benzodiazepines is not recommended (see Section 4.4 Special Warnings and Precautions for Use).
Hypotension and/or bradycardia have been observed during intramuscular administration of Zyprexa IM. Olanzapine has alpha-1 adrenergic antagonist activity. Caution should be exercised in patients who receive treatment with medicinal products that can lower blood pressure by mechanisms other than alpha-1 adrenergic antagonism.
Given the primary central nervous system effects of Zyprexa, caution should be used when it is taken in combination with other centrally acting drugs and alcohol. As it exhibits in vitro dopamine antagonism, Zyprexa may antagonise the effects of direct and indirect dopamine agonists.
Caution should be exercised when Zyprexa is used concomitantly with medicines known to cause electrolyte imbalance or to increase QT interval (see Section 4.4 Special Warnings and Precautions for Use, Cardiac).

Potential for other medicines to affect Zyprexa.

Single doses of antacids (containing aluminium and magnesium) or cimetidine do not affect the oral bioavailability of Zyprexa. The concomitant administration of activated charcoal reduces the oral bioavailability of Zyprexa by 50% to 60%.
Fluoxetine (60 mg single dose or 60 mg daily for 8 days) caused a 16% increase in the maximum plasma concentration of olanzapine and a 16% decrease in olanzapine clearance. The magnitude of this is small in comparison to the overall variability between individuals and therefore dose modification is not routinely recommended.
The metabolism of Zyprexa may be induced by concomitant smoking (the clearance of Zyprexa is 33% lower and the terminal elimination half-life is 21% longer in nonsmokers compared to smokers) or carbamazepine therapy (clearance is increased 44% and the terminal elimination half-life is reduced by 20% when administered with carbamazepine). Smoking and carbamazepine therapy induce P450 1A2 activity. The pharmacokinetics of theophylline, which is metabolised by P450 1A2, is not altered by Zyprexa.
Fluvoxamine, a CYP1A2 inhibitor, decreases the clearance of olanzapine. This results in a mean increase in olanzapine Cmax following fluvoxamine of 54% in female nonsmokers and 77% in male smokers. The mean increase in olanzapine AUC is 52% and 108%, respectively. Lower doses of olanzapine should be considered in patients receiving concomitant treatment with fluvoxamine or any other P450 1A2 inhibitor, such as ciprofloxacin.

Potential for Zyprexa to affect other medicines.

In clinical trials with single doses of Zyprexa, no inhibition of the metabolism of imipramine/ desipramine (P450 2D6, P450 3A or P450 1A2), warfarin (P450 2C19), theophylline (P450 1A2) or diazepam (P450 3A4 and P450 2C19) was evident. Zyprexa showed no interaction when coadministered with lithium or biperiden. The in vitro ability of Zyprexa to inhibit metabolism by five principle cytochromes has been examined. These studies found inhibitory constants for 3A4 (491 micromolar), 2C9 (751 micromolar), 1A2 (36 micromolar), 2C19 (920 micromolar) and 2D6 (89 micromolar) that, compared to Zyprexa plasma concentrations of approximately 0.2 micromolar, would mean maximum inhibition of these P450 systems by Zyprexa would be less than 0.7%. The clinical relevance of these findings is unknown.
Steady-state concentrations of olanzapine had no effect on the pharmacokinetics of ethanol (45 mg/70 kg). However, additive pharmacological effects such as increased sedation may occur when ethanol is ingested together with olanzapine.
Studies in vitro using human liver microsomes showed that olanzapine has little potential to inhibit the major metabolic pathway of valproate, which is glucuronidation. Further, valproate was found to have little effect on the oxidative metabolism of olanzapine in vitro. Daily concomitant in vivo administration of 10 mg olanzapine for 2 weeks did not affect steady-state plasma concentrations of valproate. Therefore, concomitant olanzapine administration does not require dosage adjustment of valproate.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

In male rats dosed orally with olanzapine at 22.5 mg/kg/day, mating performance was impaired as a result of the drug's sedative activity, but fertility was normal 10 days after stopping treatment. In male dogs, hypospermatogenesis was seen at oral doses greater than 5 mg/kg/day. In female rats, oestrous cycles were disrupted at oral doses greater than 0.25 mg/kg/day and fertility was impaired at dose levels greater than 1 mg/kg/day.
(Category C)
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 Zyprexa.
Neonates exposed to antipsychotic drugs (including Zyprexa) during the third trimester of pregnancy are at risk of experiencing extrapyramidal neurological disturbances and/or withdrawal symptoms following delivery. There have been postmarket reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self limited, in other cases neonates have required additional medical treatment or monitoring.
Zyprexa should be used during pregnancy only if the anticipated benefit outweighs the risk, and the administered dose and duration of treatment should be as low and as short as possible.
Olanzapine had no teratogenic effects in rats or rabbits at oral dose levels up to 18 and 30 mg/kg/day respectively. However, resorptions were increased in rats at oral doses greater than 4 mg/kg/day. Foetal weight was decreased in both species at oral doses greater than 1 and 8 mg/kg/day, respectively, and foetal development was retarded in rats at doses greater than 4 mg/kg/day. Oral administration of olanzapine to pregnant rats resulted in prolonged gestation and an increased incidence of stillbirths at doses greater than 5 mg/kg/day. Oral administration of olanzapine to rats prior to mating and throughout mating, gestation and lactation was associated with transient decreases in offspring activity levels at doses of 0.25 mg/kg/day or greater.

Labour and delivery.

In rats, oral administration of olanzapine to pregnant rats resulted in prolonged gestation and an increased incidence of stillbirths at doses greater than 5 mg/kg/day.
 In a study in lactating, 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 breastfeed if they are receiving Zyprexa.

Hyperprolactinaemia.

When prescribing Zyprexa, there is the possibility of secondary amenorrhoea and hypoestrogenism arising from treatment (see Section 4.8 Adverse Effects (Undesirable Effects)). Premenopausal women should be questioned regarding menstrual irregularities and those who experience secondary amenorrhoea for longer than six months duration while taking Zyprexa should be appropriately investigated and offered appropriate therapy.

4.7 Effects on Ability to Drive and Use Machines

Patients should be cautioned about operating hazardous machinery, including motor vehicles, because Zyprexa may cause somnolence.

4.8 Adverse Effects (Undesirable Effects)

Additional adverse events identified from clinical trials with Zyprexa IM rather than oral Zyprexa were as follows.

Cardiovascular system.

Common (≥ 1% and < 10%): hypotension; bradycardia with or without hypotension or syncope; tachycardia.
The adverse events listed below have been observed following administration of oral Zyprexa, but may also occur following administration of Zyprexa IM.

Adverse events identified from clinical trials with oral olanzapine.

Body as a whole.

Very common (≥ 10%): weight gain, weight gain ≥ 7% baseline body weight. Common (≥ 1% and < 10%): asthenia, fatigue, weight gain ≥ 15% of baseline body weight, pyrexia. Uncommon (≥ 0.1% and < 1%): photosensitivity reaction.

Weight.

In an analysis of 13 placebo controlled olanzapine monotherapy studies, Zyprexa treated patients gained an average of 2.6 kg compared to an average 0.3 kg weight loss in placebo treated patients with a median exposure of 6 weeks. Clinically significant weight gain was observed across all baseline body mass index (BMI) categories. Discontinuation due to weight gain occurred in 0.2% of Zyprexa treated patients and 0% of placebo treated patients.
In long-term studies (at least 48 weeks) the mean weight gain was 5.6 kg. Both the magnitude of weight gain and the proportion of Zyprexa treated patients who had a clinically significant weight gain were greater than in the short-term studies. Gain of ≥ 25% of baseline body weight was very common with long-term exposure to Zyprexa. Discontinuation due to weight gain occurred in 0.4% of Zyprexa treated patients following at least 48 weeks of exposure.

Cardiovascular system.

Very common (≥ 10%): orthostatic hypotension. Uncommon (≥ 0.1% and < 1%): bradycardia.

Digestive system.

Common (≥ 1% and < 10%): constipation, dry mouth, increased appetite. Uncommon (≥ 0.1% and < 1%): abdominal distension.

Metabolic.

Common (≥ 1% and < 10%): peripheral oedema. Rare (< 0.1% and ≥ 0.01%): elevated creatine kinase levels.

Musculoskeletal system.

Common (≥ 1% and < 10%): arthralgia.

Nervous system.

Very common (≥ 10%): somnolence. Common (≥ 1% and < 10%): dizziness; akathisia. Uncommon (≥ 0.1% and < 1%): amnesia, restless legs syndrome.
In active controlled studies, Zyprexa treated patients had a lower incidence of parkinsonism, akathisia, dyskinesia 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 Zyprexa produces less tardive dyskinesia and/or other tardive extrapyramidal syndromes.

Clinical chemistry.

Very common (≥ 10%): prolactin increased, cholesterol total (fasting borderline to high), triglycerides (fasting borderline to high), glucose (fasting borderline to high). Common (≥ 1% and < 10%): alanine transferase (ALT) increased; aspartate transferase (AST) increased, cholesterol total (fasting normal to high), triglycerides (fasting normal to high), glucose (fasting normal to high), glycosuria, alkaline phosphatase increased, gamma glutamyl transferase (GGT) high, uric acid high.

Glucose.

In adult clinical trials (up to 52 weeks) Zyprexa was associated with a greater mean increase in both nonfasting and fasting blood glucose concentrations than placebo. In patients with baseline glucose dysregulation (including those with diabetes mellitus or who met criteria suggestive of hyperglycaemia) the mean increase in the nonfasting blood glucose concentration was significantly greater in those treated with Zyprexa compared to placebo. A smaller between treatment difference was also seen in fasting blood glucose concentrations in patients with baseline glucose dysregulation. Zyprexa was also associated with a greater increase in HbA1c concentration than placebo in patients with baseline glucose dysregulation.
The proportion of patients who had a change in glucose level from normal or borderline at baseline to high increased over time. In patients who had at least 48 weeks exposure to olanzapine, 12.8% of patients who had normal baseline fasting glucose levels experienced high glucose levels at least once. For patients with borderline baseline fasting glucose levels, 26.0% experienced high glucose levels at least once. In an analysis of patients who completed 9 to 12 months of Zyprexa therapy, the rate of increase in mean blood glucose slowed after approximately 6 months.

Hepatic transaminases.

Transient, asymptomatic elevations of hepatic transaminases, ALT and AST, have been seen occasionally.

Lipids.

In an analysis of five placebo controlled clinical trials of up to 12 weeks in duration, Zyprexa treated adult patients had a greater mean increase in fasting total cholesterol, LDL cholesterol, and triglycerides compared to placebo treated patients. Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were greater in patients without evidence of lipid dysregulation at baseline. For fasting HDL cholesterol, no statistically significant differences were observed between Zyprexa treated patients and placebo treated patients.
The proportion of patients who had changes in total cholesterol, LDL cholesterol or triglycerides from normal or borderline to high, or changes in HDL cholesterol from normal or borderline to low, was greater in long-term studies (at least 48 weeks) than in short-term studies. In long-term studies, the proportion of patients who had normal or borderline baseline levels of fasting triglycerides and experienced high levels was 32.4% and 70.7%, respectively. In long-term studies, the proportion of patients who had normal or borderline baseline levels of fasting total cholesterol and experienced high levels was 14.8% and 55.2%, respectively. In long-term studies, the proportion of patients who had normal or borderline baseline levels of fasting LDL cholesterol and experienced high levels was 7.3% and 31.0%, respectively. In an analysis of patients who completed 12 months of therapy, the mean non-fasting total cholesterol did not increase further after approximately 4 to 6 months.

Prolactin.

In clinical trials of olanzapine in schizophrenia and other psychiatric indications of up to 12 weeks duration, plasma prolactin levels were elevated from normal at baseline to high in approximately 30% of olanzapine treated patients compared with 10.5% of placebo treated patients. In the majority of patients these elevations were mild. Across all indications, potentially associated clinical manifestations included sexual function related events such as erectile dysfunction in males and decreased libido in both genders (commonly observed), menstrual related events such as amenorrhoea (uncommonly observed), and breast related events such as breast enlargement and galactorrhoea in females and gynaecomastia and breast enlargement in males (uncommonly observed).

Haematology.

Common (≥ 1% and < 10%): eosinophilia; leucopenia including neutropenia.

Eosinophilia.

Asymptomatic eosinophilia was occasionally seen.

Respiratory.

Uncommon (≥ 0.1% and < 1%): epistaxis.

Undesirable effects for special populations.

Undesirable effects associated with the use of olanzapine in clinical trials with elderly patients with dementia related psychosis:

Body as a whole.

Very common (≥ 10%): falls.

Nervous system.

Very common (≥ 10%): abnormal gait.

Urogenital system.

Common (≥ 1% and < 10%): urinary incontinence.

Respiratory system.

Common (≥ 1% and < 10%): pneumonia.
Undesirable effects associated with the use of olanzapine in clinical trials in patients with drug induced (dopamine agonist) psychosis associated with Parkinson's disease:

Nervous system.

Very common (≥ 10%): hallucinations and worsening of parkinsonian symptomatology. In these trials, patients were required to be stable on the lowest effective dose of anti-parkinsonian medications (dopamine agonist) prior to the beginning of the study and to remain on the same anti-parkinsonian medications and dosages throughout the study. Olanzapine was started at 2.5 mg/day and titrated up to a maximum of 15 mg/day based on investigator judgement.
In clinical trials in patients with bipolar mania, 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 (1% to 10%).

Adolescents (ages 13 to 17 years).

The types of undesirable effects observed in adolescent patients treated with olanzapine were similar to those seen in adult patients. Although no clinical trials designed to compare adolescents to adults were conducted, the data from the adolescent trials were compared to those of the adult trials.
Mean increases in weight in adolescents (4.6 kg over 3 weeks' median duration of exposure) were greater than in adults (2.6 kg over 7 weeks' median duration of exposure). In four placebo controlled trials, discontinuation due to weight gain occurred in 1% of Zyprexa treated adolescent patients compared to 0% of placebo treated adolescent patients.
In long-term studies (at least 24 weeks), both the magnitude of weight gain and the proportion of adolescent patients treated with Zyprexa who had clinically significant weight gain were greater than in short-term studies, and were greater than in adult patients with comparable exposure. The mean weight gain in adolescent patients in long-term studies was 11.2 kg. With long-term exposure, approximately half of adolescent patients gained ≥ 15% and almost a third gained ≥ 25% of their baseline bodyweight. Among adolescent patients, mean weight gain was greatest in patients who were overweight or obese at baseline. Discontinuation due to weight gain occurred in 2.2% of Zyprexa treated adolescent patients following at least 24 weeks of exposure.
Increases in fasting glucose were similar in adolescents and adults treated with Zyprexa; however, the difference between Zyprexa and placebo groups was greater in adolescents compared to adults.
In long-term studies (at least 24 weeks), changes in fasting glucose from normal at baseline to high in adolescents were uncommon. Changes from borderline at baseline to high were very common.
Increases in fasting total cholesterol, LDL cholesterol and triglycerides were generally greater in adolescents than in adults treated with Zyprexa. However, in short-term studies, the differences between Zyprexa and placebo were similar for adolescents and adults.
Adolescents treated with olanzapine experienced a significantly higher incidence of elevated prolactin levels and significantly higher mean increases in prolactin levels compared with adults. In adolescents elevated plasma prolactin levels were reported in approximately 47% of olanzapine treated patients and 7% of placebo treated patients.
The information below summarises core adverse drug reaction terms and their frequencies identified only during clinical trials in adolescent patients (ages 13 to 17 years). Actual percentages are provided for aggregate data from up to four separate studies of olanzapine in adolescent patients.

Body as a whole.

Very common (≥ 10%): weight gain ≥ 7% of baseline body weight 40.6%. Common (≥ 1% and < 10%): weight gain ≥ 15% of baseline body weight 7.1%.

Digestive system.

Very common (≥ 10%): increased appetite 24.0%. Common (≥ 1% and < 10%): dry mouth 6.1%.

Nervous system.

Very common (≥ 10%): sedation (including hypersomnia, lethargy, sedation, somnolence) 44.1%.

Clinical chemistry.

Very common (≥ 10%): ALT > 3 x ULN (all randomised patients with ALT baseline ≤ 3 x ULN) 12.1%, AST increased 27.6%, total bilirubin decreased 22.1%, GGT increased 10.1%, prolactin increased 47.4%, cholesterol total (fasting borderline to high) 38.9%, triglycerides (fasting normal to high) 26.9%, triglycerides (fasting borderline to high) 59.5%, glucose (fasting borderline to high) 14.3%. Common (≥ 1% and < 10%): cholesterol total (fasting normal to high) 6.9%. Very rare (< 0.01%): glucose (fasting normal to high).

Adverse events based on postmarketing spontaneous reports with oral olanzapine.

Body as a whole.

Very rare (< 0.01%): allergic reaction (e.g. anaphylactoid reaction, angioedema, pruritus or urticaria); discontinuation reaction (acute symptoms such as sweating, insomnia, tremor, anxiety, nausea or vomiting have been reported very rarely when Zyprexa is stopped suddenly).

Digestive system.

Very rare (< 0.01%): pancreatitis.

Hepatobiliary disorders.

Rare (< 0.1% and ≥ 0.01%): hepatitis. Very rare (< 0.01%): jaundice.

Metabolic.

Rare (< 0.1% and ≥ 0.01%): hyperglycaemia. Very rare (< 0.01%): diabetic coma, diabetic ketoacidosis, exacerbation of pre-existing diabetes; hypertriglyceridemia (random triglyceride levels of ≥ 11.29 mmol/L); hypercholesterolaemia (random cholesterol levels of ≥ 6.21 mmol/L).

Nervous system.

Uncommon (< 1% and ≥ 0.1%): stuttering. Rare (< 0.1% and ≥ 0.01%): seizures. Very rare (< 0.01%): neuroleptic malignant syndrome.

Skin and appendages.

Rare (< 0.1% and ≥ 0.01%): rash. Very rare (< 0.01%): alopecia, drug reaction with eosinophilia and systemic symptoms (DRESS).

Urogenital system.

Very rare (< 0.01%): priapism, urinary hesitation, urinary retention, urinary incontinence.

Haematology.

Very rare (< 0.01%): thrombocytopenia.

Cardiovascular.

Very rare (< 0.01%): venous thromboembolism, including pulmonary embolism and deep vein thrombosis.
Cases of QT prolongation, ventricular arrhythmia, sudden unexplained death, cardiac arrest and torsades de pointes have been reported very rarely with the use of neuroleptics and may be considered a class effect.

Musculoskeletal system.

Very rare (< 0.01%): rhabdomyolysis.

Clinical chemistry.

Very rare (< 0.01%): total bilirubin increased, creatine kinase increased.

Adverse events based on post marketing spontaneous reports with olanzapine.

Digestive system.

Uncommon (< 1% and ≥ 0.1%): salivary hypersecretion.

Respiratory.

Sleep apnoea syndrome. A causal association between olanzapine and sleep apnoea syndrome is suspected but has not been definitively established.

Psychiatric disorders.

Somnambulism (sleepwalking) and sleep-related eating disorder have been reported with the use of atypical antipsychotic medicines, including olanzapine.
Frequency: Not known.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

Signs of oral toxicity in rodents were characteristic of potent neuroleptic compounds: hypoactivity, coma, tremors, clonic convulsions and salivation. In dogs, olanzapine caused sedation, ataxia, tremors, tachycardia, laboured respiration, miosis and anorexia. In monkeys, prostration and semiconsciousness were observed.

Signs and symptoms.

Very common symptoms (≥ 10% incidence) reported in Zyprexa overdose include tachycardia, agitation/ aggressiveness, dysarthria, various extrapyramidal symptoms and reduced level of consciousness ranging from sedation to coma.
Other medically significant sequelae of Zyprexa overdose include delirium, convulsion, 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 overdoses as low as 450 mg but survival has also been reported following acute overdose of 2 g.

Management of overdose.

There is no specific antidote to Zyprexa. Induction of emesis is not recommended. Standard procedures for management of overdose may be indicated. The possibility of multiple drug involvement should be considered.
In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation and ventilation. The use of activated charcoal for overdose should be considered because the concomitant administration of activated charcoal was shown to reduce the oral bioavailability of olanzapine by 50% to 60%. In patients who are not fully conscious or who have impaired gag reflex, consideration should be given to administering activated charcoal via a nasogastric tube, once the airway is protected. Olanzapine is not substantially removed by haemodialysis.
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. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids and/or sympathomimetic agents such as noradrenaline. Adrenaline, dopamine or other sympathomimetic agents should not be used since beta stimulation may worsen hypotension in the setting of alpha blockade induced by Zyprexa. Cardiovascular monitoring should be considered to detect possible arrhythmias. Close medical supervision and monitoring should continue until the patient recovers.
Contact the Poisons Information Centre in Australia (telephone 13 11 26) or the National Poisons Centre in New Zealand (telephone 0800 POISON or 0800 764 766) for advice on management of overdose with Zyprexa.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Olanzapine is an atypical antipsychotic, antimanic and mood stabilising agent that demonstrates a broad pharmacological profile across a number of receptor systems.
In preclinical studies, olanzapine exhibited a range of receptor affinities (Ki < 100 nanomol) for serotonin 5HT2A/2C, 5HT3, 5HT6; dopamine D1, D2, D3, D4, D5; cholinergic muscarinic receptors m1-m5; α1-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 5HT2 than dopamine D2-receptors and in in vivo models, greater 5HT2 than D2 activity. 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 increased responding in an anxiolytic test.
In a single 10 mg oral dose positron emission tomography (PET) study in healthy volunteers, olanzapine produced higher receptor occupancy at the 5HT2A receptor than at the dopamine D2-receptor. A single photon emission computed tomography (SPECT) imaging study in schizophrenic patients revealed that olanzapine responsive patients had lower striatal D2 occupancy than some other antipsychotic and risperidone responsive patients, while being comparable to clozapine responsive patients.
In two of two placebo and two of three comparator controlled clinical trials with over 2,900 schizophrenic patients, with both positive and negative symptoms, Zyprexa was associated with statistically significantly greater improvements in negative as well as positive symptoms of schizophrenia.

Clinical trials.

Schizophrenia and related disorders.

The efficacy of Zyprexa in the reduction of and maintenance of the reduction of the manifestations of schizophrenia and related psychotic disorders was established in 3 well controlled clinical trials of psychotic inpatients who, at entry, met the DSM-III-R criteria for schizophrenia (most with a course at entry of chronic with acute exacerbation) and 1 well controlled clinical trial of psychotic inpatients and outpatients who, at entry, met the DSM-III-R criteria for schizophrenia, schizophreniform disorder or schizoaffective disorder. The age range of patients in these pivotal efficacy studies were 18 to 86 years. The results of the trials follow.
1. A 6 week placebo controlled trial (n = 335) compared 3 fixed dosage ranges of Zyprexa [5 ± 2.5, 10 ± 2.5 and 15 ± 2.5 mg/day (once daily)], 1 dosage range of haloperidol (15 ± 5 mg/day BID) and placebo. The 2 higher dosage ranges of Zyprexa were statistically significantly superior to placebo on the brief psychiatric rating scale (BPRS) total, the clinical global impressions - severity of illness (CGI-S) scale, and the BPRS positive psychosis cluster. The highest dosage range of Zyprexa was statistically significantly superior to placebo and to haloperidol on the scale for the assessment of negative symptoms (SANS). Efficacy of Zyprexa generally increased with dose.
2. A 6 week placebo controlled trial (n = 152) compared 2 fixed doses of Zyprexa [1 or 10 mg/day (once daily)] and placebo. Zyprexa 10 mg/day was statistically significantly superior to placebo on the BPRS total, the BPRS positive psychosis cluster, the CGI-S scale, the positive and negative syndrome scale (PANSS) total, the PANSS positive subscale and the PANSS negative subscale.
3. A 6 week dose comparison trial (n = 431) compared 3 fixed dosage ranges of Zyprexa [5 ± 2.5, 10 ± 2.5 and 15 ± 2.5 mg/day (once daily)], Zyprexa [1 mg/day (once daily)] and haloperidol (15 ± 5 mg/day BD). There were no statistically significant differences between groups on efficacy measures except for the highest dosage range of Zyprexa, which was statistically significantly superior to Zyprexa 1 mg on the BPRS positive psychosis cluster, PANSS positive subscale and the CGI-S scale.
4. A 6 week comparator controlled trial (n = 1,996, 2:1 randomisation, Zyprexa: haloperidol) compared 1 dosage range of Zyprexa [5 to 20 mg/day (once daily)] and 1 dosage range of haloperidol [5 to 20 mg/day (once daily)]. The acute mean maintenance modal doses (for those patients with at least 3 weeks of treatment) were 13.2 mg/day for Zyprexa and 11.8 mg/day for haloperidol. Zyprexa was statistically significantly superior to haloperidol on the BPRS total, the BPRS negative psychosis cluster, the PANSS negative subscale and the CGI-S scale. Zyprexa was also statistically significantly superior to haloperidol on the Montgomery-Asberg depression rating scale (MADRS).
5. The effectiveness of Zyprexa in long-term therapy, i.e. > 6 weeks, was evaluated in 3 double blind, controlled extension maintenance trials (of acute trials 1, 3 and 4, above). Patients who showed adequate clinical improvement following double blind acute therapy were allowed to continue on their acute dosage regime in a double blind, long-term extension maintenance phase. Long-term maintenance of response (i.e. continued reduction in signs and symptoms sufficient to not require hospitalisation for psychosis) was compared over time and the percentage of patients completing one year of treatment was compared. Zyprexa was statistically significantly superior to placebo in the one placebo controlled trial and was comparable or statistically significantly superior to haloperidol in 3 active comparator controlled trials.
The above trials (including open label extension) and an additional trial comprising geriatric patients with primary degenerative dementia of the Alzheimer's type constitute the integrated primary database (n = 2,500 patients treated with Zyprexa, corresponding to 1,122.2 patient years; n = 810 patients treated with haloperidol, corresponding to 193.0 patient years; n = 236 patients treated with placebo, corresponding to 27.1 patient years).

Acute mania associated with bipolar disorder.

The efficacy of olanzapine in the treatment of acute manic episodes was established in 2 short-term (one 3 week and one 4 week) placebo controlled trials and one 6 week comparator controlled trial, comparing olanzapine to placebo when each was added to lithium or valproate, in patients who met the DSM-IV criteria for bipolar I disorder with manic or mixed episodes. These trials included patients with or without psychotic features and with or without a rapid cycling course.
Several instruments were used for assessing manic symptoms in these trials. The Young mania rating scale (Y-MRS) is an 11 item clinician rated scale traditionally used to assess the degree of manic symptomatology in a range from 0 (no manic features) to 60 (maximum score). A second assessment, the clinical global impression - bipolar version (CGI-BP), reflects the clinician's impression of the severity of the patient's mania and overall bipolar illness in a range from 1 (normal, not ill) to 7 (very severely ill). Additional secondary assessments in the comparator controlled trial included the positive and negative symptom scale (PANSS) (total, positive and negative) and the Hamilton depression rating scale-21 (HAMD-21). The results of the trials follow.
1. In a 3 week placebo controlled trial (n = 139) which involved a dose range of olanzapine (5-20 mg/day, once daily, starting at 10 mg/day), olanzapine was superior to placebo in the reduction of Y-MRS total score, the PANSS total score, the PANSS positive subscale and the CGI-BP severity of mania score.
2. In a 4 week placebo controlled trial (n = 115) which involved a dose range of olanzapine (5-20 mg/day, once daily, starting at 15 mg/day), olanzapine was superior to placebo in the reduction of Y-MRS total score, the PANSS total score, the PANSS positive subscale, the CGI-BP severity of mania score and the CGI-BP severity of overall bipolar illness score.
3. In a 6 week cotherapy study (n = 344) of patients treated with lithium or valproate for a minimum of 2 weeks, the addition of olanzapine 10 mg (cotherapy with lithium or valproate) resulted in a greater reduction in symptoms of mania (Y-MRS total score) than lithium or valproate monotherapy after 6 weeks.
In patients with a manic or mixed episode of bipolar disorder, olanzapine demonstrated superior efficacy to valproate semisodium (divalproex) in reduction of manic symptoms over 3 weeks.

Preventing recurrence in bipolar disorder.

In a 12 month recurrence prevention study, patients (n = 361) who met DSM-IV criteria for bipolar I disorder and who were in symptomatic remission following a 6 to 12 week period of olanzapine treatment, were randomised to continuation of their current olanzapine doses (ranging from 5 to 20 mg) or placebo for up to 12 months. Olanzapine demonstrated statistically significant superiority over placebo in delaying time to symptomatic bipolar recurrence (174 days until 50% of olanzapine patients experienced recurrence vs 22 days for placebo). Olanzapine also showed a statistically significant advantage over placebo in terms of either recurrence into mania or recurrence into depression, although a greater advantage was seen in preventing recurrence into mania. The criteria for recurrence were hospitalisation for relapse or worsening in total scores of Young mania rating scale (Y-MRS) or Hamilton psychiatric rating scale for depression-21 Items (HAMD-21). In a second 12 month recurrence prevention study in manic episode patients stabilised with a combination of olanzapine and lithium and then randomised to olanzapine or lithium alone, olanzapine was numerically but not statistically superior to lithium in rate of symptomatic bipolar recurrence (30.0% vs 38.8%, respectively; p = 0.055). Olanzapine showed a statistically significant advantage over lithium on recurrence into mania and was not statistically significantly different from lithium on recurrence into depression.
In an 18 month cotherapy recurrence prevention study in manic episode patients stabilised with olanzapine plus mood stabilisers (lithium or valproate), olanzapine cotherapy was numerically but not statistically superior to mood stabiliser alone in delaying time to syndromic bipolar recurrence (119 days until 25% of olanzapine patients experienced recurrence vs 29 days for placebo). The incidence of recurrence of mania was statistically significantly less for olanzapine cotherapy than for patients receiving placebo plus mood stabiliser.

Agitation and disturbed behaviour in schizophrenia and related psychoses, in acute mania associated with bipolar I disorder.

The efficacy of intramuscular olanzapine for injection for the rapid control of agitation was established in 3 short-term (24 hours of IM treatment) placebo controlled trials in agitated inpatients with schizophrenia, schizophreniform disorder, schizoaffective disorder or bipolar I disorder (manic or mixed episodes).
The primary efficacy measure used for assessing agitation signs and symptoms in these trials was the change from baseline in the PANSS excited component (PANSS-EC) at 2 hours postinjection. The PANSS-EC consists of 5 items which rate poor impulse control, tension, hostility, uncooperativeness and excitement. Several additional efficacy measures including the agitation calmness evaluation scale (ACES) and the Corrigan agitated behaviour scale (CABS; used in schizophrenia and bipolar mania studies only) were also utilised. Patients could receive up to three injections during the 24 hour IM treatment periods; however, patients could not receive the second injection until after the initial 2 hour period when the primary efficacy measure was assessed. The results of the trials follow.
1. In a placebo controlled trial in agitated inpatients meeting DSM-IV criteria for schizophrenia, schizophreniform disorder or schizoaffective disorder, 270 patients were randomised to olanzapine IM at doses of 2.5 mg, 5 mg, 7.5 mg, 10 mg or haloperidol 7.5 mg IM or placebo IM.
As defined a priori in the protocol, patients with a reduction of ≥ 40% in the PANSS-EC at 2 hours postfirst IM injection compared to baseline were classified as responders. Numerically, the number and percentage of responders increased with increasing doses of olanzapine, ranging from 50.0% responders in the IM olanzapine 2.5 mg treatment group to 80.4% responders in the IM olanzapine 10 mg treatment group. In the IM haloperidol 7.5 mg and IM placebo treatment groups, 60.0% and 20.0%, respectively, were responders.
From the pairwise comparisons, statistically significantly greater response rates were observed in each IM olanzapine treatment group compared with IM placebo (p = 0.004 for the IM olanzapine 2.5 mg treatment group and p < 0.001 for the 5, 7.5 and 10 mg IM olanzapine treatment groups). The IM olanzapine 7.5 and 10 mg treatment groups also demonstrated significantly greater response rates compared with the IM olanzapine 2.5 mg treatment group (p = 0.021 and p = 0.002, respectively). There were no statistically significant differences between the IM haloperidol 7.5 mg treatment group and any of the IM olanzapine treatment groups, although a trend toward significance was observed in favour of the IM olanzapine 10 mg treatment group (p = 0.056).
2. In a second placebo controlled trial in agitated inpatients meeting DSM-IV criteria for schizophrenia, schizophreniform disorder or schizoaffective disorder, 311 patients were randomised to olanzapine 10 mg IM, haloperidol 7.5 mg IM or placebo IM. The 24 hour IM period was followed by a 4 day treatment period in which patients who had received either olanzapine IM or placebo were treated with oral olanzapine 5-20 mg/day, while patients who had received haloperidol IM were treated with oral haloperidol 5-20 mg/day.
As defined a priori in the protocol, patients with a reduction of ≥ 40% in the PANSS-EC at 2 hours postfirst IM injection compared to baseline were classified as responders. Ninety six (73.3%) IM olanzapine treated patients were responders compared to 87 (69.0%) IM haloperidol treated patients and 18 (33.3%) IM placebo treated patients. Using a Fisher's exact test, both the IM olanzapine and IM haloperidol treatment groups demonstrated significantly greater response rates compared with the IM placebo treatment group (p < 0.001 in both cases), but did not differentiate between themselves (p = 0.492).
3. In a placebo controlled trial in agitated inpatients meeting DSM-IV criteria for bipolar I disorder (and currently displaying an acute manic or mixed episode with or without psychotic features), 201 patients were randomised to olanzapine 10 mg IM, lorazepam 2 mg IM or placebo IM.
As defined a priori in the protocol, patients with a reduction of ≥ 40% in the PANSS-EC at 2 hours postfirst IM injection compared to baseline were classified as responders. There were 79 (80.6%) IM olanzapine treated patients classified as responders compared to 33 (64.7%) IM lorazepam treated patients and 22 (44.0%) IM placebo treated patients. Using a Fisher's exact test, both the IM olanzapine and IM lorazepam treatment groups demonstrated significantly greater response rates compared with the IM placebo treatment group (p < 0.001 and p = 0.046, respectively). The IM olanzapine treatment group also showed a significantly greater response rate compared with the IM lorazepam treatment group (p = 0.045).

5.2 Pharmacokinetic Properties

Zyprexa IM results in rapid absorption with peak plasma concentrations occurring within 15 to 45 minutes. The Cmax occurs earlier after intramuscular use compared to oral use (15 to 45 minutes versus 5 to 8 hours). Based upon a pharmacokinetic study in healthy subjects, a 5 mg intramuscular dose of olanzapine for injection produces, on average, a maximum plasma concentration which is approximately 5 times higher than the maximum plasma concentration produced by a 5 mg oral dose. The area under the olanzapine plasma concentration time curve attained after intramuscular injection is essentially equivalent to the area under the curve achieved when the same amount is administered orally. A crossover study in healthy subjects comparing 5 mg IM and 5 mg oral olanzapine showed that the geometric mean AUC IM/ oral ratio was 1.23 with a 90% confidence interval of 1.15 to 1.31. These results provide an estimate that the AUC for the IM product is on average about 23% larger than the AUC produced by the same amount of olanzapine administered orally, a difference which does not require dose adjustments. As with oral use, Cmax and area under the curve after intramuscular use are directly proportional to the dose administered. For the same dose of olanzapine administered intramuscularly and orally, the half-life, clearance and volume of distribution are very similar. After IM administration, olanzapine exhibits linear pharmacokinetics over the dose range of 0.1 to 12.5 mg. Metabolic profiles after intramuscular administration are quantitatively similar and qualitatively identical to metabolic profiles after oral administration. See Table 2.
Additional pharmacokinetic data following administration of oral olanzapine are described below.

Absorption.

Olanzapine is well absorbed after oral administration, reaching peak plasma concentrations within 5 to 8 hours. Absorption is not affected by food. Plasma concentrations of olanzapine after oral administration were linear and dose proportional in trials studying doses from 1 to 20 mg.

Distribution.

The plasma protein binding of olanzapine is about 93% over the concentration range of about 7 to about 1,000 nanogram/mL. Olanzapine is bound to albumin and α1-acid glycoprotein.

Metabolism.

Olanzapine is metabolised in the liver by conjugative and oxidative pathways. The major circulating metabolite is the 10-N-glucuronide which does not pass the blood brain barrier. Cytochromes P450 CYP1A2 and P450 CYP2D6 contribute to the formation of the N-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.

Excretion.

After oral administration to healthy subjects, the mean terminal elimination half-life was 33 hours (21 to 54 hours for 5th to 95th percentile) and the mean olanzapine plasma clearance was 26 L/hr (12 to 47 L/hr for the 5th to 95th percentile). Olanzapine pharmacokinetics varied on the basis of smoking status, gender and age.
In healthy elderly (≥ 65 years) subjects versus nonelderly healthy subjects, the mean elimination half-life of olanzapine was prolonged (51.8 hr vs 33.8 hr) and the clearance was reduced (17.5 L/hr vs 18.2 L/hr). The pharmacokinetic variability observed in elderly subjects is within the variability seen in nonelderly subjects. 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 female versus male subjects, the mean elimination half-life was somewhat prolonged (36.7 hr vs 32.3 hr) and the clearance was reduced (18.9 L/hr vs 27.3 L/hr). However, Zyprexa (5-20 mg) demonstrated a comparable safety profile in female (n = 467) as in male patients (n = 869).
Smoking induces the CYP1A2 metabolism of olanzapine. Therefore, in smokers the clearance of olanzapine is higher, on average, than the clearance in nonsmokers.
The plasma clearance of olanzapine is lower in elderly versus nonelderly subjects and in females versus males. The magnitude of the impact of age, gender or smoking on olanzapine clearance and half-life is small in comparison to the overall variability between individuals.
Approximately 57% of radiolabelled olanzapine is excreted in urine, principally as metabolites, approximately 7% is excreted unchanged in the urine after a single oral dose and approximately 30% is excreted in the faeces.

Renal impairment.

Only incomplete information is available on excretion in renal impaired patients (creatinine clearance < 10 mL/min) versus healthy subjects, suggesting there was no significant difference in mean elimination half-life (37.7 hr vs 32.4 hr) or drug clearance (21.2 L/hr vs 25.0 L/hr). The available data indicate a trend for decreased clearance and increased half-life with renal impairment. Consequently, caution should be exercised in prescribing olanzapine for patients with renal impairment and particularly in those with severe renal disease, and in the elderly. Olanzapine is not removed by dialysis. The effect of renal impairment on metabolite elimination has not been studied.

Hepatic impairment.

Although the presence of hepatic impairment may be expected to reduce the clearance of olanzapine, a study of the effect of impaired liver function in male subjects (n = 6) with clinically significant (Child-Pugh classification A and B) cirrhosis revealed little effect on the pharmacokinetics of olanzapine in the dose range 2.5 to 7.5 mg daily. Consequently, dosage adjustment may not be necessary if hepatic impairment is the sole consideration.

5.3 Preclinical Safety Data

Genotoxicity.

Olanzapine was not mutagenic or clastogenic in a full range of standard tests, which included bacterial mutation tests and in vitro and in vivo tests, indicating that it is not a genotoxic carcinogen.

Carcinogenicity.

Carcinogenicity studies in mice and rats showed the development of mammary adenocarcinomas at oral doses greater than 0.5 and 0.1 mg/kg/day respectively.
The increased incidence of mammary tumours may be due to an endocrine mechanism, possibly involving elevation of circulating prolactin levels in response to the dopamine D2-receptor antagonistic activity of olanzapine. Mammary tumours are known to occur in rats and mice treated with other drugs that antagonise dopamine D2-receptors. Neither clinical studies nor epidemiological studies conducted to date have shown an association between these drugs and carcinogenesis, but the available evidence is considered too limited to be conclusive at this time. The use of Zyprexa in patients with familial history or previously detected breast cancer should be avoided. Caution should also be exercised when considering Zyprexa treatment in patients with pituitary tumours.

6 Pharmaceutical Particulars

6.1 List of Excipients

For full list of excipients, see Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG).

6.4 Special Precautions for Storage

Solution following reconstitution of the vial can be stored for 1 hour. Protect from light.

6.5 Nature and Contents of Container

Zyprexa IM 10 mg is available in a Type 1 glass flint vial. One carton contains 1 vial or 10 vials.
(Cartons containing 10 vials are not marketed in Australia or New Zealand).

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

Chemically, olanzapine is 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thienol[2,3-b] [1,5]benzodiazepine and its empirical formula is C17H20N4S. Olanzapine is a yellow crystalline solid, practically insoluble in water with a molecular weight of 312.44.
Olanzapine has the following structural formula:

CAS number.

The CAS number for olanzapine is 132539-06-1.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription only Medicine.

Summary Table of Changes