Consumer medicine information

OLANZAPINE ODT GENERICHEALTH

Olanzapine

BRAND INFORMATION

Brand name

Olanzapine ODT Generichealth Orally disintegrating tablets

Active ingredient

Olanzapine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using OLANZAPINE ODT GENERICHEALTH.

What is in this leaflet

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

The information in this leaflet was last updated on the date shown on the final page. More recent information about this medicine may be available. Make sure you speak to your pharmacist or doctor to obtain the most up to date information on this medicine. The updated leaflet may contain important information about Olanzapine ODT generichealth and its use that you should be aware of.

All medicines have risks and benefits.

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

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

Keep this leaflet with this medicine.

You may need to read it again.

What Olanzapine ODT generichealth is used for

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

Olanzapine ODT generichealth is used to treat symptoms of schizophrenia and related psychoses. Schizophrenia is a mental illness with disturbances in thinking, feelings and behaviour.

Olanzapine ODT generichealth alone, or in combination with lithium or valproate, is used for the short-term treatment of acute manic episodes associated with Bipolar I Disorder. Olanzapine ODT generichealth is also a mood stabiliser that prevents further occurrences of the disabling high and low (depressed) extremes of mood associated with Bipolar I Disorder.

Bipolar I Disorder is a mental illness with symptoms such as feeling “high”, having excessive amounts of energy, needing much less sleep than usual, talking very quickly with racing ideas and sometimes severe irritability.

Your doctor may have prescribed Olanzapine ODT generichealth for another reason.

Ask your doctor if you have any questions about why Olanzapine ODT generichealth has been prescribed for you.

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

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

Before taking Olanzapine ODT generichealth

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

When you must not take it

Do not take Olanzapine ODT generichealth:

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

If you are not sure whether you should start taking Olanzapine ODT generichealth, talk to your doctor or pharmacist.

Before you start to take it

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

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

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

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

Like most antipsychotic medicines, Olanzapine ODT generichealth is not recommended for use during pregnancy. If there is a need to consider Olanzapine ODT generichealth during your pregnancy, your doctor will discuss with you the benefits and risks of using it.

Tell your doctor if you are breast-feeding or plan to breast-feed.

It is recommended that you do not breast-feed while taking Olanzapine ODT generichealth.

Tell your doctor if you suffer from lactose intolerance (because Olanzapine ODT generichealth tablets contain lactose).

Tell your doctor if you suffer from phenylketonuria (because Olanzapine ODT generichealth wafers contain aspartame).

Tell your doctor if you will be in a hot environment or do a lot of vigorous exercise.

Olanzapine ODT generichealth may make you sweat less, causing your body to overheat.

Tell your doctor if you smoke.

Smoking may affect Olanzapine ODT generichealth or may affect how it works.

Taking other medicines

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

Some medicines may be affected by Olanzapine ODT generichealth or may affect how it works. These include:

  • Medicines used to treat a fast or irregular heart beat (arrhythmia).
  • Medicines taken for anxiety or to help you sleep.
  • Medicines taken for depression.
  • Carbamazepine, a medicine used for mood stabilisation and to treat epilepsy.
  • Other centrally acting medicines (eg. tranquillisers).
  • Ciprofloxacin, a medicine used to treat bacterial infections.
  • Medicines that lower blood pressure.
  • Medicines used for Parkinson’s disease.
  • Medicines that can change the heart’s electrical activity or make it more likely to change.

Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking Olanzapine ODT generichealth.

Tell your doctor about these things before you take Olanzapine ODT generichealth.

How to take Olanzapine ODT generichealth

Follow all directions given to you by your doctor or pharmacist carefully.

These may differ from the information contained in this leaflet.

How much to take

Your doctor will tell you how many Olanzapine ODT generichealth orally disintegrating tablets you should take. The dose your doctor will prescribe for you will usually be in the range 5 mg to 20 mg per day.

Your doctor may increase or decrease your dose in order to find the appropriate dose for your condition.

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

How to take it

Do not handle the tablets with wet hands as the tablet may break up.

Olanzapine ODT generichealth orally disintegrating tablets break easily, so you should handle them carefully.

To take a tablet directly into your mouth:

  1. Hold the blister strip at the edges and separate one blister cell from the rest of the strip by gently tearing along the perforations around it.
  2. Carefully peel off the coloured backing.
  3. Gently push the tablet out.
  4. Put the tablet in your mouth. It will dissolve directly in your mouth, so that it can be easily swallowed.

To take a tablet in a drink:
You can also place the tablet in a full glass or cup of water, orange juice, apple juice, milk or coffee, and stir.

Drink it straight away.

With some drinks, the mixture may change colour and possibly become cloudy.

Do not place the tablet in cola drinks.

When to take it

Olanzapine ODT generichealth should be taken once a day as advised by your doctor.

Take your prescribed dose at the same time each day.

Olanzapine ODT generichealth can be taken with or without food.

How long do I take it

Do not stop taking Olanzapine ODT generichealth just because you feel better. It is important that you do NOT stop taking Olanzapine ODT generichealth unless your doctor tells you.

If you forget to take it

If it is almost time for your next dose skip the dose you missed and take your next dose when you are meant to.

Otherwise, take it as soon as you remember then go back to taking your medicine as you would normally.

Do not take a double dose to make up for the dose that you missed.

If you are not sure what to do, ask your doctor or pharmacist.

If you take too much

Immediately telephone your doctor or the Australian Poisons Information Centre (telephone 13 11 26) or the New Zealand National Poisons Centre (0800 POISON or 0800 764 766), or go to Accident and Emergency at your nearest hospital, if you think that you or anyone else has taken too much Olanzapine ODT generichealth. Do this even if there are no signs of discomfort or poisoning.

If you have taken too much Olanzapine ODT generichealth, the most common signs are fast heart beat, agitation/aggression, difficulty speaking, uncontrollable movements and sedation.

While you are taking Olanzapine ODT generichealth

Things you must do

It is important that you remember to take Olanzapine ODT generichealth daily and at the dose prescribed by your doctor.

Tell all doctors, dentists and pharmacists who are treating you that you are taking Olanzapine ODT generichealth.

While you are taking Olanzapine ODT generichealth, tell your doctor or pharmacist before you start any new medicine.

If you become pregnant while taking Olanzapine ODT generichealth, tell your doctor.

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

  • Your doctor should monitor your weight while you are taking Olanzapine ODT generichealth.
  • Patients with diabetes or who have a higher chance of developing diabetes should have their blood sugar checked often.
  • If you are over 65, your doctor may measure your blood pressure from time to time.

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

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 must not do

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

Do not give Olanzapine ODT generichealth to anyone else, even if their symptoms seem similar or they have the same condition as you.

Your doctor has prescribed Olanzapine ODT generichealth for you and your condition.

Things to be careful of

Be careful driving or operating machinery until you know how Olanzapine ODT generichealth affects you.

Olanzapine ODT generichealth may cause drowsiness in some people.

Be careful when drinking alcohol while taking Olanzapine ODT generichealth.

The effects of alcohol could be made worse while taking Olanzapine ODT generichealth.
Your doctor may suggest you avoid alcohol while you are being treated with Olanzapine ODT generichealth.

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

Getting up slowly may help.

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

Olanzapine ODT generichealth may cause your skin to be much more sensitive to sunlight than it is normally.
Exposure to sunlight may cause a skin rash, itching, redness, or severe sunburn.

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

Make sure you keep cool in hot weather and keep warm in cool weather.

Olanzapine ODT generichealth may affect the way your body reacts to temperature changes

Side Effects

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

Like other medicines, Olanzapine ODT generichealth 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 Olanzapine ODT generichealth. 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 Olanzapine ODT generichealth you are taking.

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

  • Drowsiness.
  • Restlessness or difficulty sitting still.
  • Fevers.
  • Dizziness, confusion, forgetfulness.
  • Increased appetite, weigh gain.
  • Constipation, bloating.
  • Dry mouth.
  • Swelling of your hands, feet and ankles.
  • Aching joints.
  • Nose bleeds.
  • Unusual tiredness or weakness.

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 Olanzapine ODT generichealth for a few days.

Tell your doctor if you notice any of the above side effects and they worry you.

These are the more common side effects of Olanzapine ODT generichealth.

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

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

These side effects are uncommon but may require medical attention.

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

  • Sudden signs of an allergic reaction such as a skin rash, itching, shortness of breath or swelling of the face, lips or tongue.
  • Frequent infections such as fever, severe chills, sore throat or mouth ulcers.
  • Bleeding or bruising more easily than normal.
  • Seizures, fits or convulsions.
  • Yellowing of the skin and/or eyes.
  • Nausea, vomiting, loss of appetite, generally feeling unwell, fever, itching, yellowing of the skin and/or eyes.
  • Severe upper stomach pain often with nausea and vomiting (inflammation of the pancreas).
  • Worm-like movements of the tongue, or other uncontrolled movements of the tongue, mouth, cheeks, or jaw which may progress to the arms and legs.
  • Sudden increase in body temperature, sweating, fast heart beat, muscle stiffness, high blood pressure and convulsions.
  • Sharp chest pain, coughing of blood, or sudden shortness of breath.
  • Pain/tenderness in the calf muscle area.
  • Muscle pain, muscle weakness and brown urine.
  • Heart palpitations and dizziness, which may lead to collapse.

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

All of these side effects are very rare.

The following additional side effects may occur in some groups of people taking Olanzapine ODT generichealth:

Elderly patients with dementia-related psychosis

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

  • Unusual manner of walking.
  • Falls.
  • Pneumonia.
  • Involuntary passing of urine.

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.

Olanzapine ODT generichealth in combination with lithium or valproate

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

  • Tremors.
  • Speech disorder.

Tell your doctor if you notice anything unusual or if you are concerned about any aspect of your health, even if you think the problems are not connected with this medicine and are not referred to in this leaflet.

Also, some side effects, such as changes to liver function, cholesterol or triglycerides can occur. These can only be found when your doctor does tests from time to time to check your progress.

Do not be alarmed by this list of side effects.

You may not experience any of them.

Other side effects not listed above may also occur in some patients.

Tell your doctor if you notice anything else that is making you feel unwell.

After taking Olanzapine ODT generichealth

Storage

Keep the orally disintegrating tablets in the blister pack until it is time to take them.

Keep your tablets in a cool, dry place where the temperature stays below 30°C.

Olanzapine ODT generichealth tablets should be kept out of direct light.

Do not store Olanzapine ODT generichealth or any other medicine in the bathroom or near a sink.

Do not leave your tablets in the car on hot days or on window sills.

Heat and dampness can destroy some medicines.

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

A locked cupboard at least one and a half metres above the ground is a good place to store medicines.

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

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

Disposal

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

Product Description

What it looks like

Olanzapine ODT generichealth 5, 5 mg tablets are yellow coloured, round shaped, flat orally disintegrating tablets.

Olanzapine ODT generichealth 10, 10 mg tablets are yellow coloured, round shaped, flat orally disintegrating tablets.

Ingredients

Active Ingredient:

  • Olanzapine ODT generichealth 5 - 5 mg olanzapine per tablet
  • Olanzapine ODT generichealth 10 - 10 mg olanzapine per tablet.

Inactive ingredients - mannitol, aspartame, crospovidone, cellulose microcrystalline, magnesium stearate.

Supplier

Olanzapine ODT generichealth is distributed in Australia by:
Generic Health Pty Ltd
Level 1, 1102 Toorak Road
Camberwell VIC 3124

Australian Registration Numbers

  • Olanzapine ODT generichealth 5 -
    AUST R 177790
  • Olanzapine ODT generichealth 10 -
    AUST R 177793

This leaflet was prepared in November 2013.

BRAND INFORMATION

Brand name

Olanzapine ODT Generichealth Orally disintegrating tablets

Active ingredient

Olanzapine

Schedule

S4

 

Name of the medicine

Olanzapine.

Excipients.

Mannitol, aspartame, crospovidone, microcrystalline cellulose, magnesium stearate.

Description

Chemical name: 2-methyl-4-(4-methyl- 1-piperazinyl)-10H-thieno (2,3-b)(1,5) benzodiazepine. Molecular formula: C17H20N4S. MW: 312.44. CAS: 132539-06-1. Olanzapine is a yellow crystalline solid that is practically insoluble in water.
Olanzapine ODT Generichealth orally disintegrating tablets are a freeze dried, rapid dispersing preparation to be placed in the mouth or alternatively to be dispersed in water or other suitable beverage (not cola beverages) for administration.

Pharmacology

Pharmacodynamics.

Actions.

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 response in an anxiolytic test.
In a single 10 mg oral dose positron emission tomography (PET) study in healthy volunteers, olanzapine produced higher receptor occupancy at the 5HT2A receptor than at the dopamine D2-receptor. A single photon emission computed tomography (SPECT) imaging study in schizophrenic patients revealed that olanzapine responsive patients had lower striatal D2 occupancy than some other antipsychotic and risperidone responsive patients, while being comparable to clozapine responsive patients.
In two of two placebo and two of three comparator controlled clinical trials with over 2,900 schizophrenic patients, with both positive and negative symptoms, olanzapine was associated with statistically significantly greater improvements in negative as well as positive symptoms of schizophrenia.

Pharmacokinetics.

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 metabolites 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/hour (12 to 47 L/hour for the 5th to 95th percentile). Olanzapine pharmacokinetics varied on the basis of smoking status, gender and age.
In healthy elderly (≥ 65 years) subjects versus nonelderly healthy subjects, the mean elimination half-life of olanzapine was prolonged (51.8 vs. 33.8 hours) and the clearance was reduced (17.5 vs.18.2 L/hour). The pharmacokinetic variability observed in elderly subjects is within the variability seen in nonelderly subjects. In 44 patients with schizophrenia > 65 years of age, dosing from 5 to 20 mg/day was not associated with any distinguishing profile of adverse events.
In female versus male subjects, the mean elimination half-life was somewhat prolonged (36.7 vs. 32.3 hours) and the clearance was reduced (18.9 vs. 27.3 L/hour). However, olanzapine (5-20 mg) demonstrated a comparable safety profile in female (n = 467) as in male patients (n = 869).
Smoking induces the CYP1A2 metabolism of olanzapine. Therefore, in smokers the clearance of olanzapine is higher, on average, than the clearance in nonsmokers.
The plasma clearance of olanzapine is lower in elderly versus nonelderly subjects and in females versus males. The magnitude of the impact of age, gender or smoking on olanzapine clearance and half-life is small in comparison to the overall variability between individuals.
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 patients with renal impaired patients (creatinine clearance < 10 mL/minute) versus healthy subjects, suggesting there was no significant difference in mean elimination half-life (37.7 vs. 32.4 hours) or drug clearance (21.2 vs. 25.0 L/hour). 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, 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.

Clinical Trials

Schizophrenia and related disorders.

The efficacy of olanzapine 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 olanzapine (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 olanzapine 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 olanzapine was statistically significantly superior to placebo and to haloperidol on the Scale for the Assessment of Negative Symptoms (SANS). Efficacy of olanzapine generally increased with dose.
(2) A 6 week, placebo controlled trial (n = 152) compared 2 fixed doses of olanzapine (1 or 10 mg/day (once daily)) and placebo. Olanzapine, 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 olanzapine (5 ± 2.5, 10 ± 2.5 and 15 ± 2.5 mg/day (once daily)), olanzapine (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 olanzapine, which was statistically significantly superior to olanzapine, 1 mg, on the BPRS positive psychosis cluster, PANSS positive subscale and the CGI-S scale.
(4) A 6 week comparator controlled trial (n = 1996, 2:1 randomisation, olanzapine: haloperidol) compared 1 dosage range of olanzapine (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 olanzapine and 11.8 mg/day for haloperidol. Olanzapine was statistically significantly superior to haloperidol on the BPRS total, the BPRS negative psychosis cluster, the PANSS negative subscale and the CGI-S scale. Olanzapine was also statistically significantly superior to haloperidol on the Montgomery-Asberg Depression Rating Scale (MADRS).
(5) The effectiveness of olanzapine 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. Olanzapine was statistically significantly superior to placebo in the one placebo controlled trial and was comparable or statistically significantly superior to haloperidol in 3 of 3 active comparator controlled trials.
The above trials (including open label extension) and an additional trial comprising geriatric patients with primary degenerative dementia of the Alzheimer's type constitute the integrated primary database (n = 2,500 patients treated with olanzapine, corresponding to 1,122.2 patient years; n = 810 patients treated with haloperidol, corresponding to 193.0 patient years; n = 236 patients treated with placebo, corresponding to 27.1 patient years).

Acute mania associated with bipolar disorder.

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

Preventing recurrence in bipolar disorder.

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

Indications

Olanzapine ODT Generichealth is indicated for the following.
Treatment of schizophrenia and related psychoses.
Short-term treatment, alone or in combination with lithium or valproate, of acute manic episodes associated with bipolar I disorder.
Preventing recurrence of manic, mixed or depressive episodes in bipolar I disorder.

Contraindications

Olanzapine ODT Generichealth is contraindicated in those patients with a known hypersensitivity to any ingredient of the product.

Precautions

During antipsychotic treatment, improvement in the patient's clinical condition may take several days to some weeks. Patients should be closely monitored during this period.

Concomitant illness.

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

Hyperglycaemia and diabetes mellitus.

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

Lipid alterations.

Undesirable alterations in lipids have been observed in olanzapine treated patients in placebo controlled trials. Olanzapine treated patients had a greater mean increase in fasting total cholesterol, low density lipoprotein (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 Adverse Effects).

Weight gain.

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

Hepatic.

Transient, asymptomatic elevations of hepatic transaminases, alanine transferase (ALT) and 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 Adverse 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. In the event of elevated ALT and/or AST during treatment, follow-up should be organised and dose reduction should be considered.

Blood.

As with other neuroleptic drugs, caution should be exercised in patients with low leucocyte 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 a history of clozapine related neutropenia or agranulocytosis received olanzapine 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 haematological effects were seen in dogs receiving 5 mg/kg/day. In clinical trials, there were no data to suggest olanzapine adversely affected bone marrow function, even in patients with a history of drug associated neutropenia or leucopenia (see Adverse Effects).

Neuroleptic malignant syndrome (NMS).

Neuroleptic malignant syndrome, a potentially fatal syndrome complex, is associated with antipsychotic drugs, including olanzapine (see Adverse 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 phosphokinase, 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 olanzapine, should be discontinued.

Seizures.

Olanzapine should be used cautiously in patients who have a history of seizures or are subject to factors which may lower the seizure threshold. Seizures have been reported to occur rarely in such patients when treated with olanzapine (see Adverse Effects).

Tardive dyskinesia.

In comparator studies of one year or less in duration, olanzapine 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 olanzapine, a dose reduction or drug discontinuation should be considered. These symptoms can temporally deteriorate or even arise after discontinuation of treatment.

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, olanzapine 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 olanzapine is prescribed with drugs known to increase QTc interval, especially in elderly patients.

Sudden cardiac death.

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

Safety experience in elderly patients with dementia related psychosis.

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

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

Cerebrovascular adverse events (e.g. stroke, transient ischaemic attack), including fatalities, were reported in trials of olanzapine in elderly patients with dementia related psychosis. In placebo controlled studies, there was a higher incidence of CVAE in patients treated with olanzapine compared to patients treated with placebo (1.3 versus 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.

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 olanzapine 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. Olanzapine and other antipsychotic agents should be used cautiously in patients at risk for aspiration pneumonia.

Suicide.

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

Use in the elderly.

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

Carcinogenesis, mutagenesis, impairment of fertility.

Carcinogenicity and mutagenicity.

Carcinogenicity studies in mice and rats showed the development of mammary adenocarcinomas at oral doses greater than 0.5 and 1 mg/kg/day respectively. Olanzapine was not mutagenic or clastogenic in a full range of standard tests, which included bacterial mutation tests and in vitro and in vivo tests, indicating that it is not a genotoxic carcinogen. 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 olanzapine in patients with a familial history or previously detected breast cancer should be avoided. Caution should also be exercised when considering olanzapine treatment in patients with pituitary tumours.

Impairment of fertility.

In male rats dosed orally with olanzapine at 22.5 mg/kg/day, mating performance was impaired as a result of the drug's sedative activity, but fertility was normal 10 days after stopping treatment. In male dogs, hypospermatogenesis was seen at oral doses greater than 5 mg/kg/day. In female rats, oestrous cycles were disrupted at oral doses greater than 0.25 mg/kg/day and fertility was impaired at dose levels greater than 1 mg/kg/day.

Use in pregnancy.

(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 olanzapine.

Nonteratogenic class effect.

Neonates exposed to antipsychotic drugs (including olanzapine) during the third trimester of pregnancy are at risk of experiencing extra pyramidal neurological disturbances and/or withdrawal symptoms following delivery. There have been postmarket reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self limited, in other cases neonates have required additional medical treatment or monitoring.
Olanzapine should only be used during pregnancy only if the anticipated benefit outweighs the risks and administered dose and duration of treatment should be as low and as short as possible.
Olanzapine had no teratogenic effects in rats or rabbits at oral dose levels up to 18 and 30 mg/kg/day respectively. However, resorptions were increased in rats at oral doses greater than 4 mg/kg/day. Foetal weight was decreased in both species at oral doses greater than 1 and 8 mg/kg/day respectively, and foetal development was retarded in rats at doses greater than 4 mg/kg/day. Oral administration of olanzapine to pregnant rats resulted in prolonged gestation and an increased incidence of stillbirths at doses greater than 5 mg/kg/day. Oral administration of olanzapine to rats prior to mating and throughout mating, gestation and lactation was associated with transient decreases in offspring activity levels at doses of 0.25 mg/kg/day or greater.

Labour and delivery.

In rats, oral administration of olanzapine to pregnant rats resulted in prolonged gestation and an increased incidence of stillbirths at doses greater than 5 mg/kg/day.

Use in lactation.

In a study in lactating, healthy women olanzapine was excreted in breast milk. Mean infant exposure (mg/kg) at steady state was estimated to be 1.8% of the maternal olanzapine dose (mg/kg). Patients should be advised not to breastfeed if they are taking olanzapine.

Hyperprolactinaemia.

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

Effect on ability to drive or operate machinery.

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

Interactions

Given the primary central nervous system effects of olanzapine, caution should be used when it is taken 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 olanzapine is used concomitantly with medicines known to cause electrolyte imbalance or to increase QT interval (see Precautions, Cardiac).

Potential for other medicines to affect olanzapine.

Single doses of antacids (containing aluminium and magnesium) or cimetidine do not affect the oral bioavailability of olanzapine.
The concomitant administration of activated charcoal reduces the oral bioavailability of olanzapine by 50 to 60%.
Fluoxetine (60 mg single dose or 60 mg daily for eight 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 nonsmokers compared to smokers) or carbamazepine therapy (clearance is increased 44% and the terminal elimination half-life is reduced by 20% when administered with carbamazepine). Smoking and carbamazepine therapy induce P450-1A2 activity. The pharmacokinetics of theophylline, which is metabolised by P450-1A2, are 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 nonsmokers and 77% in male smokers. The mean increase in olanzapine AUC is 52% and 108%, respectively. Lower doses of olanzapine should be considered in patients receiving concomitant treatment with fluvoxamine or any other P450-1A2 inhibitor, such as ciprofloxacin.

Potential for olanzapine to affect other medicines.

In clinical trials with single doses of olanzapine, 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. Olanzapine showed no interaction when coadministered with lithium or biperiden. The in vitro ability of olanzapine to inhibit metabolism by five principal cytochromes has been examined. These studies found inhibitory constants for 3A4 (491 micromolar), 2C9 (751 micromolar), 1A2 (36 micromolar), 2C19 (920 micromolar) and 2D6 (89 micromolar) that, compared to olanzapine plasma concentrations of approximately 0.2 micromolar, 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 olanzapine 10 mg for two weeks did not affect steady-state plasma concentrations of valproate. Therefore, concomitant olanzapine administration does not require dosage adjustment of valproate.

Effects on laboratory tests.

No information is available on the effect of olanzapine on laboratory tests.
Olanzapine ODT Generichealth orally disintegrating tablets contain aspartame, which is a source of phenylalanine.

Adverse Effects

Adverse events identified from clinical trials of oral 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. Uncommon (≥ 0.1% and < 1%): photosensitivity reaction.

Weight.

In an analysis of 13 placebo controlled olanzapine monotherapy studies, olanzapine 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 significantly weight gain was observed across all baseline body mass index (BMI) categories. Discontinuation due to weight gain occurred in 0.2% of olanzapine 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 olanzapine treated patients who had a clinically significant weight gain were greater than in the short-term studies. Gain of ≥ 25% of baseline body weight was very common with long-term exposure to olanzapine. Discontinuation due to weight gain occurred in 0.4% of olanzapine treated patients following at least 48 weeks of exposure.

Cardiovascular system.

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

Digestive system.

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

Metabolic.

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

Nervous system.

Very common (≥ 10%): somnolence. Common (≥ 1% and < 10%): dizziness; akathisia.
In active controlled studies, olanzapine 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 olanzapine 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.

Glucose.

In adult clinical trials (up to 52 weeks) olanzapine was associated with a greater mean increase in both nonfasting and fasting blood glucose concentrations than placebo. In patients with baseline glucose dysregulation (including those with diabetes mellitus or who met criteria suggestive of hyperglycaemia) the mean increase in the nonfasting blood glucose concentration was significantly greater in those treated with olanzapine compared to placebo. A smaller between treatment difference was also seen in fasting blood glucose concentrations in patients with baseline glucose dysregulation. Olanzapine 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 olanzapine 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, olanzapine 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. For fasting high density lipoprotein (HDL) cholesterol, no statistically significant differences were observed between olanzapine 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 nonfasting total cholesterol did not increase further after approximately 4 to 6 months.

Prolactin.

Plasma prolactin levels were sometimes elevated, but associated clinical manifestations (e.g. gynaecomastia, galactorrhoea and breast enlargement) were rare. In most patients, levels returned to normal ranges without cessation of treatment.

Haematology.

Common (≥ 1% and < 10%): eosinophilia.

Eosinophilia.

Asymptomatic eosinophilia was occasionally seen.

Undesirable effects for special populations.

Undesirable effects associated with the use of olanzapine in clinical trials with elderly patients with dementia related psychosis are as follows.

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 are as follows.

Nervous system.

Very common (≥ 10%): hallucinations and worsening of parkinsonian symtomatology. In these trials, patients were required to be stable on the lowest effective dose of antiparkinsonian medications (dopamine agonist) prior to the beginning of the study and to remain on the same antiparkinsonian 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 judgment.
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) was 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 olanzapine 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 olanzapine 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 body weight. 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 olanzapine treated adolescent patients following at least 24 weeks of exposure.
Increases in fasting glucose were similar in adolescents and adults treated with olanzapine, however the difference between olanzapine 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 olanzapine; however, in short-term studies the differences between olanzapine and placebo were similar between adolescents and adults.
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 bodyweight (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 upper limit of normal (ULN) (all randomised patients with ALT baseline ≤ 3 x ULN) (12.1%), AST increased (27.6%), total bilirubin decreased (22.1%), gamma glutaryl transferase (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%).

Adverse events based on postmarketing spontaneous reports with oral olanzapine.

Body as a whole.

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

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.

Urogenital system.

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

Haematology.

Rare (< 0.1% and ≥ 0.01%): leucopenia, including neutropenia. 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%): alkaline phosphatase increased, total bilirubin increased, creatine phosphokinase increased.

Dosage and Administration

Schizophrenia and related disorders.

The recommended starting dose for olanzapine is 5 to 10 mg/day, administered as a single daily dose without regard to meals. Daily dosage may subsequently be adjusted on the basis of individual clinical status within the range of 5 to 20 mg daily. An increase to a dose greater than the routine therapeutic dose of 10 mg/day is recommended only after appropriate clinical reassessment.

Acute mania associated with bipolar disorder.

The recommended starting dose for olanzapine is 10 or 15 mg administered once a day as monotherapy or 10 mg administered once daily in combination therapy with lithium or valproate. It may be given without regard to meals. Dosage adjustments, if indicated, should generally occur at intervals of not less than 24 hours. When dosage adjustments are necessary, dose increments/ decrements of 5 mg daily are recommended. Antimanic efficacy was demonstrated in a dose range of 5 to 20 mg/day in clinical trials. The safety of doses above 20 mg/day has not been evaluated in clinical trials.

Preventing recurrence in bipolar disorder.

Patients who have been receiving olanzapine for the treatment of acute mania should initially continue therapy for preventing recurrence in bipolar disorder at the same dose. For patients already in remission, the suggested starting dose for olanzapine is 10 mg once a day. Subsequent daily dosage should be adjusted on the basis of clinical status within a range of 5 to 20 mg/day. Olanzapine may be given without regard to meals, as its absorption is not affected by food.
Olanzapine ODT Generichealth orally disintegrating tablet should be placed in the mouth, where the tablet will rapidly disperse in saliva, so it can be easily swallowed. Removal of the intact tablet from the mouth is difficult. Since the tablet is fragile, it should be taken immediately on opening the blister. Alternatively, it may be dispersed in a full glass of water or other suitable beverage (orange juice, apple juice, milk or coffee) immediately before administration. The tablet should not be dispersed in cola beverages.
Olanzapine ODT Generichealth olanzapine orally disintegrating tablets have been demonstrated to be bioequivalent to Zyprexa Zydis wafers with respect to Cmax, AUC0-∞ and AUC0-t under single dose and fasted state conditions.
Olanzapine ODT Generichealth olanzapine orally disintegrating tablets, Zyprexa Zydis wafers and Zyprexa coated tablets have the same dosage and frequency of administration and have a similar rate and extent of absorption. Olanzapine ODT Generichealth olanzapine orally disintegrating tablets, Zyprexa coated tablets and Zyprexa Zydis wafers are all interchangeable.

Children.

The safety and efficacy of olanzapine has not been established in patients under 18 years of age.

Elderly patients.

A low starting dose of 5 mg/day should be considered for those patients 65 years of age and over when clinical factors warrant.

Patients with hepatic and/or renal impairment.

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

Female compared with male patients.

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

Nonsmoking patients compared with smoking patients.

The starting dose and dose range need not be routinely altered for nonsmoking patients relative to smoking patients.

Slower metabolism.

When more than one factor is present which might result in slower metabolism (female gender, geriatric age, nonsmoking status), consideration should be given to decreasing the starting dose. Dose escalation, when indicated, should be conservative in such patients (see Interactions with Other Medicines; Pharmacology).

Overdosage

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

Signs and symptoms.

Very common symptoms (≥ 10% incidence) reported in olanzapine overdose include tachycardia, agitation/ aggressiveness, dysarthria, various extrapyramidal symptoms and reduced level of consciousness ranging from sedation to coma.
Other medically significant sequelae of olanzapine 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 olanzapine. 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 olanzapine. Cardiovascular monitoring should be considered to detect possible arrhythmias.
Close medical supervision and monitoring should continue until the patient recovers.
For information on the management of overdose, contact the Poisons Information Centre on 131 126 (Australia).

Presentation

Orally disintegrating tablets (yellow, round, flat, bevel edged, uncoated, scored, plain on reverse), 5 mg (AUST R 177790), 10 mg (AUST R 177793): 28's (blister pack).

Storage

Store below 30°C. Protect from light and moisture.