Consumer medicine information

Zyprexa Relprevv

Olanzapine pamoate monohydrate

BRAND INFORMATION

Brand name

Zyprexa Relprevv

Active ingredient

Olanzapine pamoate monohydrate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

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

SUMMARY CMI

ZYPREXA RELPREVV®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I being given ZYPREXA RELPREVV?

ZYPREXA RELPREVV contains the active ingredient olanzapine (as pamoate monohydrate). It is used to help correct chemical imbalances in the brain, which may cause mental illness.

For more information, see Section 1. Why am I being given ZYPREXA RELPREVV? in the full CMI.

2. What should I know before being given ZYPREXA RELPREVV?

Do not use if you have ever had an allergic reaction to olanzapine or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before being given ZYPREXA RELPREVV? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with ZYPREXA RELPREVV and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How am I being given ZYPREXA RELPREVV?

ZYPREXA RELPREVV is given as an injection into a large muscle in the buttocks where it is slowly released over 2 to 4 weeks. This injection should only be given by a doctor or nurse.

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

More instructions can be found in Section 4. How am I being given ZYPREXA RELPREVV? in the full CMI.

5. What should I know while having ZYPREXA RELPREVV?

Things you should do
  • Remind any doctor, nurse or pharmacist you visit that you are using ZYPREXA RELPREVV
  • Tell your doctor if you become pregnant while taking ZYPREXA RELPREVV
  • Keep all your doctor's appointments so that your progress can be checked
Things you should not do
  • Do not stop taking your medicine, or change the dosage, without first checking with your doctor.
Driving or using machines
  • Do NOT drive or operate heavy machinery for the remainder of the day after your injection.
  • ZYPREXA RELPREVV may cause drowsiness in some people. If this happens, do not drive or operate any tools or machines
Drinking alcohol
  • Be careful when drinking alcohol while using ZYPREXA RELPREVV. The effects of alcohol could be made worse while taking ZYPREXA RELPREVV
Looking after your medicine
  • ZYPREXA RELPREVV vials should be stored below 30°C
  • The vials will be stored by your doctor or pharmacist
  • Keep this medicine where children cannot reach it

For more information, see Section 5. What should I know while having ZYPREXA RELPREVV? in the full CMI.

6. Are there any side effects?

Like other medicines, ZYPREXA RELPREVV may cause some unwanted side effects. These are likely to vary from patient to patient, although not everybody gets them. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need urgent medical attention.

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.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

ZYPREXA RELPREVV®

Active ingredient(s): Olanzapine (as pamoate monohydrate).

Consumer Medicine Information (CMI)

This leaflet provides important information about using ZYPREXA RELPREVV. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using ZYPREXA RELPREVV.

Where to find information in this leaflet:

1. Why am being given ZYPREXA RELPREVV?
2. What should I know before being given ZYPREXA RELPREVV?
3. What if I am taking other medicines?
4. How am I being given ZYPREXA RELPREVV?
5. What should I know while having ZYPREXA RELPREVV?
6. Are there any side effects?
7. Product details

1. Why am being given ZYPREXA RELPREVV?

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

ZYPREXA RELPREVV Is used to treat symptoms of schizophrenia.

Schizophrenia is a mental illness with disturbances in thinking, feelings and behavior.

ZYPREXA RELPREVV is given as an injection into a large muscle in the buttocks where it is slowly released over 2 to 4 weeks. This injection should only be given by a doctor or nurse.

Your doctor may have prescribed ZYPREXA RELPREVV for another reason.

Ask your doctor if you have any questions about why ZYPREXA RELPREVV has been prescribed for you.

This medicine is available only with a doctor's prescription.

ZYPREXA RELPREVV 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.

2. What should I know before given ZYPREXA RELPREVV?

Warnings

Do not use ZYPREXA RELPREVV if:

  • you have an allergic reaction ZYPREXA, ZYPREXA RELPREVV or to any of the ingredients listed at the end of this leaflet.
    Signs of an allergic reaction may include a skin rash, itching, shortness of breath or swelling of the face, lips or tongue.
  • the packaging is torn or shows signs of tampering, or the injection vials do not look quite right.
  • the expiry date on the pack has passed. If you have this medicine after the expiry date has passed it may not work as well.

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

Check with your doctor if you:

  • have had an allergic reaction to any medicine which you have taken previously to treat your current condition.
  • have any other medical conditions, especially the following:
    - tumor 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 buildup 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 apnea, a sleep disorder where a person has pauses in breathing or periods of shallow breathing during sleep.

Tell your doctor if

  • you will be in a hot environment or do a lot of vigorous exercise. ZYPREXA RELPREVV may make you sweat less, causing your body to overheat.
  • you smoke. Smoking may affect ZYPREXA RELPREVV or may affect how it works.
  • you are elderly with dementia-related psychosis
  • you have previously had a stroke or transient ischaemic attack (mini-stroke) or if you have high blood pressure.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Tell your doctor if you are pregnant or intend to become pregnant.

Like most antipsychotic medicines, ZYPREXA RELPREVV is not recommended for use during pregnancy.

Newborn babies of mothers taking antipsychotic drugs (including ZYPREXA RELPREVV) 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 RELPREVV during your pregnancy, your doctor will discuss with you the benefits and risks of using it.

Tell your doctor if you are breastfeeding or intend to breastfeed.

It is recommended that you do not breast-feed while taking ZYPREXA RELPREVV.

3. What if I am taking other medicines?

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

Some medicines may interfere with ZYPREXA RELPREVV and affect how it works. These include:

  • medicines used to treat a fast or irregular heartbeat (arrhythmia).
  • medicines taken for anxiety or to help you sleep.
  • medicines taken for depression
  • carbamazepine, a medicine used for mood stabilization and to treat epilepsy
  • other centrally acting medicines (eg. Tranquilizers 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, pharmacist or nurse has more information on medicines to be careful with or avoid while taking ZYPREXA RELPREVV.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect ZYPREXA RELPREVV.

4. How am I given ZYPREXA RELPREVV?

How often it is given

Your doctor or nurse will decide what dose you will receive and how often you will need to be given an injection.

It is recommended that ZYPREXA RELPREVV is given every 2 to 4 weeks, depending on how your body responds to the medicine.

ZYPREXA RELPREVV helps control your condition but will not cure it. Therefore, you need regular injections. Do not miss any injections, even if you feel better.

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

How it is given

ZYPREXA RELPREVV comes as a powder. Your doctor or nurse will make it up into a liquid suspension. The information your doctor or nurse needs to prepare the ZYPREXA RELPREVV suspension is included in the package.

After it has been made up, ZYPREXA RELPREVV is given as a deep injection into a large muscle in your buttock. ZYPREXA RELPREVV should never be injected directly into the blood (intravenously or under the skin (subcutaneously).

Do not massage or rub the area where the injection was given.

What happens after an injection

An uncommon but serious reaction might occur after you receive an injection of ZYPREXA RELPREVV.

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

  • excessive sleepiness
  • confusion
  • irritability
  • dizziness, disorientation
  • anxiety
  • aggression
  • difficulty talking or walking
  • weakness
  • muscle stiffness or shaking
  • increases in blood pressure
  • convulsions

The symptoms typically resolve within 24 to 72 hours after your injection. Because of this risk, do not drive or operate machinery for the remainder of the day after each injection.

If these symptoms are going to occur, they will usually first appear within 2 hours after your injection. After each injection you will be observed in your healthcare facility for at least 2 hours for the symptoms listed above. If you have any of the symptoms listed above your doctor or nurse may need to observe you for longer than 2 hours. Your doctor or nurse will check you to confirm that you do not have any of these symptoms before you leave the healthcare facility.

Contact your doctor or nurse immediately if you get these symptoms more than 2 hours after your injection.

You will be given details of how to contact your doctor or nurse if you have any of these symptoms, as you will need their assistance until they have resolved.

If you are given too much ZYPREXA RELPREVV

As ZYPREXA RELPREVV is given under medical supervision, it is very unlikely that you will receive too much. However, if you experience any side effects after being given ZYPREXA RELPREVV, tell your doctor immediately or go to Accident and Emergency at your nearest hospital.

The most common signs of too much ZYPREXA RELPREVV are fast heartbeat, agitation/aggression, difficulty speaking, uncontrollable movements and sleepiness (sedation).

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while having ZYPREXA RELPREVV?

Things you should do

It is important that you remember to attend appointments to receive your ZYPREXA RELPREVV injections.

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

If you are about to start on any new medicine, remind your doctor, nurse or pharmacist that you are having ZYPREXA RELPREVV.

Tell your doctor if you become pregnant while having ZYPREXA RELPREVV.

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

  • Your doctor should monitor your weight while you are taking ZYPREXA RELPREVV.
  • 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 or nurse 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 doing harm to others.

These may be signs of changes or worsening in your mental illness.

Things you should not do

Do not stop taking ZYPREXA RELPREVV even if you are feeling better, without checking with your doctor.

It is important that you carry on receiving ZYPREXA RELPREVV for as long as your doctor has told you to.

Things you should be careful of

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

Getting up slowly may help.

Do NOT drive or operate heavy machinery for the remainder of the day after your injection.

ZYPREXA RELPREVV may cause drowsiness in some people. If this happens, do not drive or operate any tools or machines. Tell your doctor or nurse.

If outdoors, wear protective clothing and use at least a 30+ sunscreen.

ZYPREXA RELPREVV 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 or nurse.

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.

Driving or using machines

Do NOT drive or operate heavy machinery for the remainder of the day after your injection.

ZYPREXA RELPREVV may cause drowsiness in some people. If this happens, do not drive or operate any tools or machines. Tell your doctor or nurse.

Drinking alcohol

Be careful when drinking alcohol while using ZYPREXA RELPREVV.

The effects of alcohol could be made worse while taking ZYPREXA RELPREVV.

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

Looking after your medicine

ZYPREXA RELPREVV will be stored by your doctor or pharmacist. The injection is kept in a cool dry place, protected from light, where the temperature stays below 30°C.

Keep it where young children cannot reach it.

There will be an expiry date (month, year) on your ZYPREXA RELPREVV package and on each glass vial.

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

Getting rid of any unwanted medicine

ZYPREXA RELPREVV is normally administered by your doctor or nurse.

If however you have some ZYPREXA RELPREVV injection that has passed its expiry date, please return any leftover portion to your pharmacist.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Like other medicines, ZYPREXA RELPREVV 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 RELPREVV. 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 RELPREVV you are taking.

A serious side effect can occur if ZYPREXA RELPREVV enters the blood stream too quickly. There is more information about this in the section named "What happens after an injection".

A common side effect seen with ZYPREXA RELPREVV was sleepiness/drowsiness.

A rare side effect seen with ZYPREXA RELPREVV is an abscess (infection) at the place the injection was given.

The information below concerns side effects seen with other forms of ZYPREXA. They may also occur in people who use ZYPREXA RELPREVV.

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.

Less serious side effects

Less serious side effectsWhat to do
  • drowsiness
  • unusual tiredness or weakness
  • fever
  • restlessness or difficulty sitting still
  • increased appetite, weight gain
  • dizziness, confusion, forgetfulness
  • constipation, bloating
  • dry mouth
  • swelling of your hands, feet and ankles
  • aching joints
  • nose bleeds
  • low blood pressure
  • slow heartbeat
  • fast heartbeat
  • speech disorder
  • sleepwalking
  • sleep eating
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • symptoms of sunburn (such as redness, itching, swelling or blistering of the skin) which occur more quickly than normal
  • rash or allergic reaction
  • slow heartbeat
  • 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
  • excessive saliva in the mouth
Tell your doctor as soon as possible if you notice any of these serious side effects.
You may need medical attention.

Very serious side effects

Very serious side effectsWhat to do
  • Sudden signs of an allergic reaction such as a skin rash, itching, shortness of breath or swelling of the face, lips or tongue.
  • Drowsiness, confusion or excessive sleepiness
  • 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
  • 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 heartbeat, 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
Call your doctor straight away or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects. You may need urgent medical attention or hospitalization.

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

Elderly patients with dementia-related psychosis

  • 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.

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.

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. Most of these side effects are very rare. You may not experience any of them. Your doctor has weighed the risks of using this medicine against the benefits they expect it will have for you.

Tell your doctor or nurse if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side affects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What ZYPREXA RELPREVV contains

Active ingredient
(main ingredient)		210 mg, 300 mg or 405 mg olanzapine (as pamoate monohydrate).
Other ingredients
(diluent inactive ingredients)		carmellose sodium, mannitol, polysorbate 80 and water for injections.
Potential allergensNone

ZYPREXA RELPREVV comes as a yellow powder in a clear glass vial. A vial of diluent is provided to prepare the injection, which will be olanzapine 150mg/mL. A syringe with attached safety needle and three additional safety needles to prepare the injection are supplied in the kit containing ZYPREXA RELPREVV.

ZYPREXA RELPREVV 210 mg - AUST R 143658

ZYPREXA RELPREVV 300 mg - AUST R 143657

ZYPREXA RELPREVV 405 mg - AUST R 143636

Who distributes ZYPREXA RELPREVV

Pharmaco (Australia) Ltd
Level 9, Tower A Zenith Towers
821 Pacific Highway
Chatswood, NSW 2067
Australia

Under license of CHEPLAPHARM Schweiz GmbH, Switzerland

This leaflet was prepared in January 2025.

Published by MIMS March 2025

BRAND INFORMATION

Brand name

Zyprexa Relprevv

Active ingredient

Olanzapine pamoate monohydrate

Schedule

S4

 

1 Name of Medicine

Zyprexa Relprevv (olanzapine pamoate monohydrate - alternatively named olanzapine embonate monohydrate).

2 Qualitative and Quantitative Composition

Olanzapine pamoate monohydrate, equivalent to olanzapine 210 mg.
Olanzapine pamoate monohydrate, equivalent to olanzapine 300 mg.
Olanzapine pamoate monohydrate, equivalent to olanzapine 405 mg.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Zyprexa Relprevv 210 mg, 300 mg and 405 mg is available in a Type I cerium oxide vial. One carton provides a kit containing 1 vial of olanzapine pamoate monohydrate, one vial of sterile diluent, one 3 mL syringe with pre-attached 19-gauge 38 mm Hypodermic Needle-Pro safety needle, one 19-gauge 38 mm Hypodermic Needle-Pro safety needle and two 19-gauge 50 mm Hypodermic Needle-Pro safety needles.

4 Clinical Particulars

4.1 Therapeutic Indications

Zyprexa Relprevv is a long-acting injectable formulation of olanzapine indicated for maintenance treatment of schizophrenia in adult patients sufficiently stabilised during acute treatment with oral olanzapine.
The effectiveness of Zyprexa Relprevv is consistent with the established effectiveness of orally administered olanzapine for acute or maintenance treatment of schizophrenia.

4.2 Dose and Method of Administration

Do not confuse Zyprexa Relprevv 210 mg, 300 mg or 405 mg powder and sterile diluent for injection with any other forms of olanzapine, including Zyprexa IM 10 mg powder for solution for injection.
Zyprexa Relprevv is for deep intramuscular gluteal use. Do not administer intravascularly or subcutaneously. (See Section 4.4 Special Warnings and Precautions for Use, Post-injection syndrome.)
Zyprexa Relprevv is for single use in one patient only. Discard any residue.

Schizophrenia.

The efficacy of Zyprexa Relprevv has been demonstrated within the range 150 to 300 mg administered every 2 weeks and with 405 mg administered every four weeks.

Olanzapine-naïve patients.

For olanzapine-naïve patients it is recommended to establish tolerability with immediate release oral olanzapine tablets or wafers prior to starting treatment with Zyprexa Relprevv.

Previously stabilised with olanzapine.

Based on the recommended dose range of 10 to 20 mg/day of oral olanzapine, Table 1 outlines the dose recommendations considering oral olanzapine and olanzapine pamoate.
Supplementation with oral olanzapine is not required at the start of treatment with Zyprexa Relprevv. Supplementation using doses of up to 20 mg per day oral olanzapine was allowed in an open label Zyprexa Relprevv clinical trial but has not been systematically studied in clinical trials (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
Zyprexa Relprevv doses greater than 405 mg every 4 weeks or 300 mg every 2 weeks have not been studied in clinical trials.
Zyprexa Relprevv has not been systematically studied in elderly patients (65 years and over), hepatically or renally impaired patients. Unless a well-tolerated and effective dosage regimen using oral olanzapine has been established in such patients, Zyprexa Relprevv should not be used.

Elderly patients.

A low starting dose of 150 mg of Zyprexa Relprevv every 4 weeks 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 of Zyprexa Relprevv (150 mg every 4 weeks) 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.

Non-smoking patients compared with smoking patients.

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

Instructions for use/handling - Zyprexa Relprevv.

Zyprexa Relprevv must be suspended only with the diluent provided with the product in order to ensure adequate suspension and injectability. Use standard aseptic techniques for the reconstitution of parenteral products. It is recommended that gloves are worn when reconstituting Zyprexa Relprevv, as olanzapine pamoate may be irritating to the skin. Flush with water if contact is made with the skin.
Each Zyprexa Relprevv pack is provided with a card that fully describes the reconstitution and administration instructions. Please refer to the card for instructions on how to reconstitute and administer this product.

4.3 Contraindications

Zyprexa Relprevv is contraindicated in those patients with a known hypersensitivity to any ingredient of the product.

4.4 Special Warnings and Precautions for Use

Post-injection syndrome.

Zyprexa Relprevv is for deep intramuscular gluteal use. Do not administer intravascularly or subcutaneously.
During premarketing clinical studies of Zyprexa Relprevv involving 59,482 injections given to 2054 patients events that presented with signs and symptoms consistent with olanzapine overdose occurred in approximately 0.07% of injections and in 1.85% of patients. Most of these patients have developed symptoms of sedation (ranging from mild in severity up to coma) and/or delirium (including confusion, agitation, anxiety and other cognitive impairment). Other symptoms noted include extrapyramidal symptoms, dysarthria, ataxia, aggression, dizziness, weakness, hypertension or possible convulsions (see Section 4.9 Overdose). In most cases, initial signs and symptoms related to this event have appeared within one hour following injection, and in all cases full recovery was reported to have occurred within 24 to 72 hours after injection.
Based on data from clinical trials of Zyprexa Relprevv, the potential for onset of an event is greatest within the first hour as shown in Table 2.
Healthcare providers are advised to discuss this potential risk with patients each time they prescribe and administer Zyprexa Relprevv.
Zyprexa Relprevv should be administered by appropriately qualified health professionals in a healthcare facility with access to emergency services for management of olanzapine overdose. After each injection, patients should be observed by appropriately trained personnel for at least 2 hours and actively monitored for alertness every 30 minutes. Immediately prior to leaving the facility, it should be confirmed that the patient is alert, oriented, and absent of any signs and symptoms of overdose. The two hour observation period should be extended as clinically appropriate for patients who exhibit any potential signs or symptoms of a post-injection syndrome event.
For the remainder of the day after injection, patients should be advised to be vigilant for symptoms of post-injection adverse reactions, should be able to obtain medical assistance if needed, and should not drive or operate heavy machinery.
If an overdose is suspected at any time, close medical supervision and monitoring should be instituted until examination indicates that signs and symptoms have resolved.
If parenteral benzodiazepines are required for management of post-injection adverse reactions, careful evaluation of clinical status for excessive sedation and cardiorespiratory depression is recommended.

Concomitant illnesses.

While olanzapine 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.
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.

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 anti-diabetic 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 Relprevv. As with all antipsychotics, patients receiving Zyprexa Relprevv 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 Relprevv should be discontinued.

Seizures.

Zyprexa Relprevv 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 Relprevv, 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 Relprevv 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 non-users of antipsychotics, with almost twice the risk than that for non-users. In post-marketing 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 Relprevv 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 Relprevv 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 close supervision of high-risk patients should accompany therapy.

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 Relprevv is administered to the elderly, especially if there are other factors that may influence drug metabolism and/or pharmacodynamic parameters.

Paediatric use.

Zyprexa Relprevv has not been studied in patients under 18 years of age. 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 Relprevv on laboratory tests.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No specific interaction studies with Zyprexa Relprevv have been conducted. The following information refers to data obtained with other formulations of olanzapine.
Administration of intramuscular lorazepam (2 mg) one hour after intramuscular olanzapine (5 mg Zyprexa IM) 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.
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. Caution is necessary in patients who receive treatment with other drugs having effects that can induce hypotension, bradycardia, respiratory or central nervous system depression.
Given the primary central nervous system effects of olanzapine, caution should be used when Zyprexa Relprevv is used in combination with other centrally acting drugs and alcohol. As it exhibits in vitro dopamine antagonism, olanzapine may antagonise the effects of direct and indirect dopamine agonists.
Caution should be exercised when Zyprexa Relprevv 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.

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 olanzapine may be induced by concomitant smoking (the clearance of olanzapine is 33% lower and the terminal elimination half-life is 21% longer in non-smokers 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 olanzapine.
Fluvoxamine, a CYP1A2 inhibitor, decreases the clearance of olanzapine. This results in a mean increase in olanzapine Cmax following fluvoxamine of 54% in female non-smokers 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 olanzapine to inhibit metabolism by five principle cytochromes has been examined. These studies found inhibitory constants for 3A4 (491 microM), 2C9 (751 microM), 1A2 (36 microM), 2C19 (920 microM), 2D6 (89 microM) that compared to olanzapine plasma concentrations of approximately 0.2 microM, would mean maximum inhibition of these P450 systems by olanzapine 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.

Fertility studies with Zyprexa Relprevv were not conducted. In male rats dosed orally with olanzapine at 22.5 mg/kg/day (11 times the maximum recommended oral clinical dose, based on mg/m2), 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 of 10 mg/kg/day (7 times greater than the AUC-based maximum clinical exposure for an oral dose). In female rats, oestrous cycles were disrupted at oral doses of 1 mg/kg/day or greater (but not 0.25 mg/kg/day) and fertility was impaired at 3 (but not 1) mg/kg/day. The oral dose in rats equivalent to the maximum clinical dose on a mg/m2 basis is 2.2 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 Relprevv.
Neonates exposed to antipsychotic drugs (including Zyprexa Relprevv) during the third trimester of pregnancy are at risk of experiencing extrapyramidal neurological disturbances and/or withdrawal symptoms following delivery. There have been post-market 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 Relprevv 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.
In rats or rabbits, there was no evidence of teratogenicity following oral administration of olanzapine during the period of organogenesis at respective doses up to 18 and 30 mg/kg/day (9- and 30-fold the maximum clinical oral dose, based on mg/m2), or following an intramuscular injection of 75 mg/kg olanzapine pamoate monohydrate to rats at the beginning of organogenesis (similar to clinical exposure, based on plasma AUC). In rats, resorptions were increased and foetal development was retarded at an oral olanzapine dose of 18 (but not 4) mg/kg/day. Foetal weight was decreased in both species at oral doses of 4 (but not 1) and 30 (but not 8) mg/kg/day. Oral administration of olanzapine to pregnant rats resulted in prolonged gestation and an increased incidence of stillbirths at a dose of 10 (but not 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 pregnant rats, prolonged gestation was found following oral administration of olanzapine at 10 mg/kg/day (5-fold the maximum clinical dose on a mg/m2 basis) but not at 5 mg/kg/day, and following intramuscular administration of Zyprexa Relprevv at 75 mg/kg (exposure similar to clinical exposure, based on plasma AUC).
 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 breast feed if they are receiving Zyprexa Relprevv.

Hyperprolactinaemia.

When prescribing Zyprexa Relprevv, 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 Relprevv, should be appropriately investigated and offered appropriate therapy.

4.7 Effects on Ability to Drive and Use Machines

Patients receiving an injection of Zyprexa Relprevv should be advised not to drive or operate heavy machinery for the remainder of the day after each injection (see Section 4.4 Special Warnings and Precautions for Use, Post-injection syndrome).

4.8 Adverse Effects (Undesirable Effects)

Potential inadvertent intravascular injection events have occurred with Zyprexa Relprevv leading to symptoms consistent with olanzapine overdose (see Section 4.4 Special Warnings and Precautions for Use, Post-injection syndrome). Clinical signs and symptoms of sedation (ranging from mild in severity up to coma) and/or delirium (including confusion, agitation, anxiety and other cognitive impairment). Other symptoms noted include extrapyramidal symptoms, dysarthria, ataxia, aggression, dizziness, weakness, hypertension or possible convulsions.
Other adverse effects observed in patients treated with Zyprexa Relprevv were similar to those seen with oral olanzapine. In clinical trials with Zyprexa Relprevv, the only adverse event reported at a statistically significantly higher rate in the Zyprexa Relprevv group than in the placebo group was sedation (Zyprexa Relprevv 8.2%, placebo 2.0%). Among all Zyprexa Relprevv treated patients, sedation was reported by 4.7% of patients.
In a 24 week fixed dose study of Zyprexa Relprevv in patients with schizophrenia comparing 150 mg/2 weeks, 405 mg/4 weeks and 300 mg/2 weeks increases in fasting triglycerides from normal at baseline to high at any time were statistically different between different dose groups.
Injection site abscess has been observed as a rare adverse event following use of Zyprexa Relprevv.
The adverse events listed below have been observed following administration of oral Zyprexa, but may also occur following administration of Zyprexa Relprevv.

Adverse events identified from clinical trials with olanzapine.

Body as a whole.

Very common (≥ 10%): weight gain, weight gain ≥ 7% baseline bodyweight. Common (≥ 1% and < 10%): asthenia, fatigue, weight gain ≥ 15% of baseline bodyweight, 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 bodyweight 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 non-fasting 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 non-fasting 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 bodyweight (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) (0.0%).
Additional adverse events identified from clinical trials with Zyprexa IM were as follows:

Cardiovascular system.

Common (≥ 1% and < 10%): hypotension; bradycardia with or without hypotension or syncope; tachycardia.

Adverse events based on post marketing 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; hypertriglyceridaemia (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 casual 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

If signs and symptoms of overdose consistent with inadvertent intravascular administration are observed appropriate supportive measures should be instituted (see Section 4.4 Special Warnings and Precautions for Use, Post-injection syndrome). Although overdose is less likely with this parenteral preparation that is administered by a healthcare professional, reference information for oral olanzapine overdose is presented below.
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 semi-consciousness 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 or Zyprexa Relprevv.

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 a PET study in patients treated with Zyprexa Relprevv (300 mg/4 weeks), mean D2-receptor occupancy was 60% or higher at the end of a 6 month period, a level consistent with that found during treatment with oral olanzapine.
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.

Zyprexa Relprevv in schizophrenia.

The effectiveness of Zyprexa Relprevv in the treatment and maintenance of schizophrenia is consistent with the established effectiveness of the oral formulation of olanzapine.
A total of 1469 patients with schizophrenia were included in two pivotal trials with Zyprexa Relprevv.
The first was an 8-week, placebo-controlled trial conducted in adult patients (n=404) who were experiencing acute psychotic symptoms. Patients were randomised to receive injections of Zyprexa Relprevv 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 -22.6, -26.3, -22.5, respectively) with each dose of Zyprexa Relprevv (405 mg every 4 weeks, 300 mg every 2 weeks and 210 mg every 2 weeks) compared to placebo (mean change -8.5). 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 three Zyprexa Relprevv treatment groups showed statistically significantly greater improvement than placebo beginning by end of Week 1. These results support efficacy for Zyprexa Relprevv over 8 weeks of treatment and a drug effect that was observed as early as one week after starting treatment with Zyprexa Relprevv, without the use of oral antipsychotic supplementation.
The second study was a long term study in clinically stable patients (n=1065, baseline mean Total PANSS score 54.3 to 57.8) who were initially treated with oral olanzapine for 4 to 8 weeks and then switched to continue on oral olanzapine or to Zyprexa Relprevv for 24 weeks. No oral antipsychotic supplementation was allowed. Zyprexa Relprevv treatment groups of 150 mg and 300 mg given every two 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 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 hospitalisation 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. A secondary analysis of this study showed that Total PANSS scores for Zyprexa Relprevv 150 mg/2 weeks, 300 mg/2 weeks and 405 mg/4 weeks remained stable for the duration of the 24 week study (Baseline mean Total PANSS Scores 55.9 with mean changes at the end of 24 weeks of +2.7, -2.2, -0.1 respectively) compared to the low dose of Zyprexa Relprevv 45 mg/4 weeks (Baseline mean Total PANSS Score of 58 with mean changes at the end of 24 weeks of +7.3). In addition, post-hoc analyses demonstrated that the 405 mg/4 weeks treatment group was non inferior to the combined oral olanzapine treatment group. Zyprexa Relprevv doses of 300 mg/2 weeks, 405 mg/4 weeks and 150 mg/2 weeks were superior to Zyprexa Relprevv 45 mg/4 weeks as measured by time to exacerbation (p-Values < 0.01, < 0.01 and 0.06, respectively).
Patients who had enrolled in short term studies of Zyprexa Relprevv were eligible to enrol in a long term open label extension study examining the long term safety and efficacy of Zyprexa Relprevv 45 to 405 mg administered on a flexible 2-, 3- or 4-week interval. This six year, open label, uncontrolled study enrolled 931 patients with a mean PANSS score at baseline of 54.54, indicating mild symptoms. 370 patients (39.7%) continued treatment until the end of the study. There was no significant change from baseline in mean PANSS score for continuing patients, indicating that for those who continued treatment Zyprexa Relprevv was effective in long term maintenance of the treatment effect. Pharmacokinetic analyses revealed no indication of long term systemic accumulation of olanzapine.
The open label long term study permitted supplementation of Zyprexa Relprevv with up to 20 mg/day oral olanzapine when clinically necessary. In this study 31.6% of patients received supplemental oral olanzapine at some time during the study, but the mean modal dose was 0.66 mg/day in those who received supplementation, indicating that most patients who did supplement did not do so every day. Data from the primary efficacy studies indicate that additional use of oral antipsychotic medication to gain efficacy at the start of therapy with Zyprexa Relprevv is not necessary.

Oral olanzapine in 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 18-86 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=2500 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).

5.2 Pharmacokinetic Properties

Olanzapine release from the Zyprexa Relprevv suspension is slow and the resulting prolonged administration sustains the systemic olanzapine plasma concentrations throughout the period of time between injections. Typical systemic concentrations reach a peak level within the first week after injection and are at the lowest trough level immediately prior to the next injection. Throughout an entire injection interval of 2 to 4 weeks, reasonably consistent olanzapine plasma concentrations are sustained. The olanzapine concentration fluctuation between the peak and the trough is comparable to the peak and trough fluctuations associated with once daily oral dosing.
Plasma concentrations remain measurable for several months after the last Zyprexa Relprevv injection. The half-life of olanzapine after Zyprexa Relprevv is 30 days, compared to 30 hours following oral administration. The elimination phase is complete approximately six to eight months after the last injection.

Dose proportionality and oral dose correspondence.

Zyprexa Relprevv provides a dose of 150, 210, 300 or 405 mg olanzapine. Injection of a larger dose produces dose-proportional increases in the systemic exposure. Dose proportional exposure for Zyprexa Relprevv aligns with the corresponding exposure for an oral dose of olanzapine. A dose of 300 mg olanzapine pamoate depot injected every two weeks delivers approximately 20 mg olanzapine per day and a dose of 150 mg olanzapine injected every two weeks delivers approximately 10 mg per day. These doses of Zyprexa Relprevv have been shown to sustain steady state olanzapine concentrations over long periods of treatment that correspond to those maintained by an oral dose of 10 or 20 mg olanzapine administered once daily.

Pharmacokinetic impact of switching to Zyprexa Relprevv from oral olanzapine.

The switch from oral olanzapine to Zyprexa Relprevv changes the pharmacokinetics from elimination-rate controlled to absorption-rate controlled. The switch to Zyprexa Relprevv may require treatment for a period of approximately 3 months to re-establish steady state conditions. Initial treatment with Zyprexa Relprevv is recommended at a dose that is based on the mg/day oral dose (see Section 4.2 Dose and Method of Administration). Plasma concentrations of olanzapine during the first injection interval may be lower than those maintained by a corresponding oral dose. Even though the concentrations are lower, the olanzapine concentrations remained within a therapeutically effective range and supplementation with orally administered olanzapine was generally not necessary in clinical trials.
Additional pharmacokinetic data following administration of oral olanzapine are described below.
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.
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-hydroxy-methyl metabolites, both exhibited significantly less in vivo pharmacological activity than olanzapine in animal studies. The predominant pharmacologic activity is from the parent olanzapine.
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 non-elderly 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 non-elderly 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 non-smokers.
The plasma clearance of olanzapine is lower in elderly versus non-elderly 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.
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.
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 genotoxic in a full range of standard tests, which included bacterial mutation tests and in vitro and in vivo tests. Pamoic acid was positive in an in vitro chromosome aberration assay but negative in a range of other in vitro and in vivo tests, with the weight of evidence indicating that it does not represent a genotoxic liability at the proposed clinical dose.

Carcinogenicity.

Carcinogenicity studies with olanzapine showed the development of mammary adenocarcinomas at oral doses of 2 mg/kg/day or greater in mice and 2.5 mg/kg/day or greater in rats (similar to or less than the maximum recommended clinical oral dose, based on mg/m2. The respective no-effect doses were 0.5 and 1 mg/kg/day (less than the maximum recommended clinical oral dose). Monthly intramuscular administration of olanzapine pamoate monohydrate to rats at doses up to 20 mg/kg (males) or 50 mg/kg (females) for 2 years was not associated with tumour formation, although rat exposures (plasma AUC) to pamoic acid and olanzapine were similar to and less than the respective exposures to pamoic acid and olanzapine at the maximum recommended clinical dose of Zyprexa Relprevv.
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 Relprevv in patients with familial history or previously detected breast cancer should be avoided. Caution should also be exercised when considering Zyprexa Relprevv treatment in patients with pituitary tumours.

6 Pharmaceutical Particulars

6.1 List of Excipients

Carmellose sodium; mannitol; polysorbate 80; water for injections; hydrochloric acid and/or sodium hydroxide may have been added during manufacture to adjust pH.

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

After reconstitution, chemical and physical in-use stability has been demonstrated for 24 hours at 25°C. However, the product should be used as soon after reconstitution as possible. If necessary, the reconstituted product should be stored for not more than 6 hours at room temperature.

6.5 Nature and Contents of Container

Zyprexa Relprevv is supplied in a kit containing two vials, one containing powder and one containing a sterile diluent, one syringe with fixed needle and three needles. Zyprexa Relprevv is a yellow powder for suspension in a clear glass vial. The active ingredient in Zyprexa Relprevv is olanzapine pamoate monohydrate. The powder is suspended using the supplied sterile diluent. The sterile diluent is a clear, colourless to slightly yellow viscous liquid in a clear glass vial. When the product is reconstituted as instructed the resulting suspension contains 150 mg/mL olanzapine. The reconstituted suspension is intended for deep intramuscular gluteal use only. The sterile diluent for Zyprexa Relprevv also contains excipients: carmellose sodium, mannitol, polysorbate 80 and water for injections.

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 pamoate monohydrate is 10H-thieno[2,3-b][1,5]benzodiazepine, 2-methyl-4-(4-methyl-1-piperazinyl)- 4,4'-methylenebis [3-hydroxy-2-naphthalene-carboxylate] (1:1) monohydrate. The formula is C17H22N4SC23H14O6H2O. Olanzapine pamoate monohydrate is a yellow solid that is practically insoluble in water with a molecular weight of 718.8.
Olanzapine pamoate monohydrate has the following structural formula:

CAS number.

The CAS number for olanzapine pamoate monohydrate is 221373-18-8.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription only Medicine.

Summary Table of Changes