Consumer medicine information

Pryzex and Pryzex ODT tablets

Olanzapine

BRAND INFORMATION

Brand name

Pryzex

Active ingredient

Olanzapine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Pryzex and Pryzex ODT tablets.

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 to your doctor.

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 your medicine. You may need to read it again.

What PRYZEX is used for

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

PRYZEX is used to treat symptoms of schizophrenia and related psychoses.

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

PRYZEX alone, or in combination with lithium or valproate, is used for the short-term treatment of acute manic episodes associated with Bipolar I Disorder.

PRYZEX 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 PRYZEX for another reason.

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

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

PRYZEX 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 PRYZEX

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 PRYZEX:

  • if you have had an allergic reaction to Olanzapine 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 PRYZEX, talk to your doctor or pharmacist

Before you start to take it

You must tell your doctor:

  • if you have had an allergic reaction to any medicine which you have taken previously to treat your current condition
  • 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 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.
  • If you are pregnant or intend to become pregnant
    Like most antipsychotic medicines, PRYZEX is not recommended for use during pregnancy. If there is a need to consider PRYZEX during your pregnancy, your doctor will discuss with you the benefits and risks of using it.
  • If you are pregnant or plan to breast feed
    It is recommended that you do not breast feed while taking PRYZEX.
  • If you suffer from lactose intolerance (because PRYZEX tablets contain lactose).

PRYZEX is not recommended for use in children.

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

Tell your doctor if you smoke. Smoking may affect PRYZEX 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 a pharmacy, supermarket or health food shop.

Some medicines may be affected by PRYZEX 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 tranquilisers)
  • 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 carefully with or avoid while taking PRYZEX.

Tell your doctor about these things before you take PRYZEX.

How to take PRYZEX

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

PRYZEX film coated or orally dispersible tablets:
Your doctor will tell you how many PRYZEX 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

PRYZEX:
These film coated tablets should be swallowed whole with a glass of water.

PRYZEX ODT:
These orally disintegrating tablets will dissolve in your mouth, therefore do not require water.

You can also place these tablets in a full glass 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.

The orally disintegrating tablets should not be placed in cola drinks.

When to take it

PRYZEX film coated or orally disintegrating tablets should be taken once a day as advised by your doctor. Take your prescribed dose at the same time each day.

PRYZEX tablets can be taken with or without food.

How long to take it

Do not stop taking PRYZEX just because you feel better. It is important that you do NOT stop taking PRYZEX 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 (overdose)

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

If you have taken too much PRYZEX, the most common signs are fast heartbeat, agitation/aggression, difficulty speaking, uncontrollable movements and sedation.

While you are taking PRYZEX

Things you must do

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

Tell all doctors, dentists and pharmacists who are treating you that you are taking PRYZEX.

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

If you become pregnant while taking PRYZEX, 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 PRYZEX.

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 PRYZEX, or lower the dosage, even if you are feeling better, without checking with your doctor.

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

Things to be careful of

PRYZEX may cause drowsiness in some people. Be careful driving or operating machinery until you know how PRYZEX affects you.

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

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

If PRYZEX makes you feel lightheaded, dizzy or faint, be careful 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. PRYZEX 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. PRYZEX may affect the way your body reacts to temperature changes.

Side Effects

Tell your doctor or pharmacist as soon as possible if you experience any undesirable effect or feel unwell while you are taking PRYZEX.

Like other medicines, PRYZEX 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 PRYZEX. 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 PRYZEX you are taking.

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

  • drowsiness
  • unusual tiredness or weakness
  • fever
  • restlessness or difficulty sitting still
  • increased appetite, weight gain
  • constipation, bloating
  • dry mouth
  • swelling of your hands, feet and ankles
  • aching joints
  • nose bleeds
  • dizziness, confusion, forgetfulness.

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 PRYZEX 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 PRYZEX.

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

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

  • symptoms of sunburn (such as redness, itching, swelling or istering 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 and 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 the 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 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 palpitations and dizziness, which may lead to collapse.

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation.

All of these side effects are very rare.

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.

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

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

  • unusual manner of walking
  • falls
  • pneumonia
  • involuntary passing of urine

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.

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

  • tremors
  • speech disorder

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 that is making you feel unwell.

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.

After taking PRYZEX

Storage

Keep your 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.

All medicines should be kept where young children cannot reach them. A locked cupboard one and a half metres above the ground is a good place to store medicines.

Do not take PRYZEX after the expiry date on the pack has passed.

Disposal

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

Product description

PRYZEX
PRYZEX film coated tablets are presented in PA/Al/PVC/Al blister packs.

2.5 mg (AUST R 178975): white, round, biconvex film coated tablets

5 mg (AUST R 178991): white, round, biconvex film coated tablets

7.5mg (AUST R 178987): white, round, biconvex film coated tablets

10mg (AUST R 178996): white, round, biconvex film coated tablets

15mg* (AUST R 178979): light blue, oblong, biconvex film coated tablets tablets

20mg* (AUST R 178995): pink, oblong, biconvex film coated tablets

PRYZEX ODT
PRYZEX Orally Disintegrating Tablets are presented in PA/Al/PVC/Al blister packs.

5 mg (AUST R 179079): yellow, round, biconvex orally disintegrating tablets

10 mg (AUST R 179076): yellow, round, flat orally disintegrating tablets

15 mg (AUST R 179082): yellow, round, biconvex orally disintegrating tablets

20 mg (AUST R 179071): yellow, round, flat orally disintegrating tablets

* Presentations currently not available

Ingredients

Active Ingredient:

PRYZEX and PRYZEX ODT tablets contain the active ingredient, Olanzapine:

  • 2.5mg – 2.5mg Olanzapine per tablet
  • 5mg – 5mg Olanzapine per tablet
  • 7.5mg – 7.5mg Olanzapine per tablet
  • 10mg – 10mg Olanzapine per tablet
  • 15mg – 15mg Olanzapine per tablet
  • 20mg – 20mg Olanzapine per tablet

Inactive Ingredients

PRYZEX film coated tablets:

  • Lactose monohydrate
  • Microcrystalline cellulose
  • Crospovidone
  • Hyprolose
  • Purified talc
  • Magnesium stearate
  • Opadry AMB complete film coating system OY-B-28920
  • Opadry AMB aqueous moisture barrier coating system 80W26503 Grey (15 mg only)
  • Opadry AMB aqueous moisture barrier coating system 80W24003 Pink (20 mg only)

PRYZEX ODT

  • Lactose monohydrate
  • Crospovidone
  • Hyprolose
  • Colloidal anhydrous silica
  • Purified talc
  • Magnesium stearate
  • Mint flavouring E_0613218

Name and Address of the Sponsor

Arrow Pharma Pty Ltd
15-17 Chapel Street
Cremorne VIC 3121

Date of Preparation

January 2020

Published by MIMS March 2020

BRAND INFORMATION

Brand name

Pryzex

Active ingredient

Olanzapine

Schedule

S4

 

1 Name of Medicine

Olanzapine.

2 Qualitative and Quantitative Composition

Pryzex film-coated tablets contain olanzapine 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg and 20 mg.
Pryzex ODT orally disintegrating tablets contain olanzapine 5 mg, 10 mg, 15 mg and 20 mg.

Physical and chemical characteristics.

Olanzapine is a yellow crystalline solid, practically insoluble in water.

Excipients.

Pryzex and Pryzex ODT tablets contain lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Pryzex 2.5 mg: White, round, biconvex film coated tablets.
Pryzex 5 mg: White, round, biconvex film coated tablets.
Pryzex 7.5 mg: White, round, biconvex film coated tablets.
Pryzex 10 mg: White, round, biconvex film coated tablets.
Pryzex 15 mg: Light blue, oblong, biconvex film coated tablets.
Pryzex 20 mg: Pink, oblong, biconvex film coated tablets.
Pryzex ODT 5 mg: Yellow, round, biconvex orally disintegrating tablets.
Pryzex ODT 10 mg: Yellow, round, flat orally disintegrating tablets.
Pryzex ODT 15 mg: Yellow, round, biconvex orally disintegrating tablets.
Pryzex ODT 20 mg: Yellow, round, flat orally disintegrating tablets.

4 Clinical Particulars

4.1 Therapeutic Indications

For the treatment of schizophrenia and related psychoses.
For the short term treatment of acute manic episodes associated with Bipolar I Disorder, when used alone or in combination with lithium or valproate.
For preventing recurrence of manic, mixed or depressive episodes in Bipolar I Disorder.

4.2 Dose and Method of Administration

Schizophrenia and related disorders.

The recommended starting dose for olanzapine is 5-10 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 5-20 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 mg 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 mg to 20 mg per day. Olanzapine may be given without regard to meals, as its absorption is not affected by food.
Olanzapine orally disintegrating tablets should be placed in the mouth, where the tablet will rapidly disperse in saliva, so it can be easily swallowed. Removal of the tablet from the mouth is difficult. 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 orally disintegrating tablets are bioequivalent to olanzapine film coated tablets, with a similar rate and extent of absorption. Olanzapine orally disintegrating tablets have the same dosage and frequency of administration as olanzapine film coated tablets. Olanzapine orally disintegrating tablets may be used as an alternative to olanzapine film coated tablets.

Children.

The safety and efficacy of olanzapine have 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 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.

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 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 5.2 Pharmacokinetic Properties).

4.3 Contraindications

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

4.4 Special Warnings and Precautions for Use

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 illnesses.

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 anti-diabetic 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, 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 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 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 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 3-4 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 olanzapine 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 creatinine 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 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 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, 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.

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, 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 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 ischemic 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 ischemic 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.

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. In the event of elevated ALT and/or AST during treatment, follow-up should be organised and dose reduction should be considered.

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.

Paediatric use.

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

Effects on laboratory tests.

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

4.5 Interactions with Other Medicines and Other Forms of 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 Section 4.4 Special Warnings and Precautions for Use, 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 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 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 principle cytochromes has been examined. These studies found inhibitory constants for 3A4 (491 mcM), 2C9 (751 mcM), 1A2 (36 mcM), 2C19 (920 mcM), 2D6 (89 mcM) that compared to olanzapine plasma concentrations of approximately 0.2 mcM, 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.

In male rats dosed orally with olanzapine at 22.5 mg/kg/day, mating performance was impaired as a result of the drug's sedative activity, but fertility was normal 10 days after stopping treatment. In male dogs, hypospermatogenesis was seen at oral doses greater than 5 mg/kg/day. In female rats, oestrous cycles were disrupted at oral doses greater than 0.25 mg/kg/day and fertility was impaired at dose levels greater than 1 mg/kg/day.
(Category C)
There are no adequate and well-controlled studies in pregnant women. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during treatment with olanzapine.
Neonates exposed to antipsychotic drugs (including olanzapine) 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.
Olanzapine should be used during pregnancy only if the anticipated benefit outweighs the risk and the administered dose and duration of treatment should be as low and as short as possible.
Olanzapine had no teratogenic effects in rats or rabbits at oral dose levels up to 18 and 30 mg/kg/day respectively. However, resorptions were increased in rats at oral doses greater than 4 mg/kg/day. Foetal weight was decreased in both species at oral doses greater than 1 and 8 mg/kg/day respectively, and foetal development was retarded in rats at doses greater than 4 mg/kg/day. Oral administration of olanzapine to pregnant rats resulted in prolonged gestation and an increased incidence of stillbirths at doses greater than 5 mg/kg/day. Oral administration of olanzapine to rats prior to mating and throughout mating, gestation and lactation was associated with transient decreases in offspring activity levels at doses of 0.25 mg/kg/day or greater.

Labour and delivery.

In rats, oral administration of olanzapine to pregnant rats resulted in prolonged gestation and an increased incidence of stillbirths at doses greater than 5 mg/kg/day.
In a study in lactating, healthy women olanzapine was excreted in breast milk. Mean infant exposure (mg/kg) at steady state was estimated to be 1.8% of the maternal olanzapine dose (mg/kg). Patients should be advised not to breast feed if they are taking olanzapine.

Hyperprolactinaemia.

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

4.7 Effects on Ability to Drive and Use Machines

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

4.8 Adverse Effects (Undesirable Effects)

Adverse events identified from clinical trials of olanzapine.

Body as a whole.

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

Weight.

In an analysis of 13 placebo-controlled olanzapine monotherapy studies, 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 significant 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.

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 creatinine 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, 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, alkaline phosphatase increased, gamma glutamyl transferase (GGT) high, uric acid high.

Glucose.

In adult clinical trials (up to 52 weeks) olanzapine 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 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 9-12 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 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 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 non-fasting total cholesterol did not increase further after approximately 4-6 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 symtomatology. 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 13-17 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 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 for adolescents and adults.
Adolescents treated with olanzapine experienced a significantly higher incidence of elevated prolactin levels and significantly higher mean increases in prolactin levels compared with adults. In adolescents elevated plasma prolactin levels were reported in approximately 47% of olanzapine treated patients and 7% of placebo treated patients.
The information below summarises core adverse drug reaction terms and their frequencies identified only during clinical trials in adolescent patients (ages 13 to 17 years). Actual percentages are provided for aggregate data from up to four separate studies of olanzapine in adolescent patients.

Body as a whole.

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

Digestive system.

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

Nervous system.

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

Clinical chemistry.

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

Adverse events based on 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 olanzapine is stopped suddenly).

Digestive system.

Uncommon (< 1% and ≥ 0.1%): salivary hypersecretion. Very rare (< 0.01%): pancreatitis.

Hepatobiliary disorders.

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

Metabolic.

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

Nervous system.

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

Skin and appendages.

Rare (< 0.1 and ≥ 0.01%): rash. Very rare (< 0.01%): alopecia, Drug Reaction with Eosinophilia and Systemic Symptom (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.

Respiratory.

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

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 www.tga.gov.au/reporting-problems.

4.9 Overdose

Signs of oral toxicity in rodents were characteristic of potent neuroleptic compounds: hypoactivity, coma, tremors, clonic convulsions and salivation. In dogs, olanzapine caused sedation, ataxia, tremors, tachycardia, laboured respiration, miosis and anorexia. In monkeys, prostration and semi-consciousness 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 Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Olanzapine is an atypical antipsychotic, antimanic and mood stabilising agent that demonstrates a broad pharmacological profile across a number of receptor systems.
In preclinical studies, olanzapine exhibited a range of receptor affinities (Ki; < 100 nanomol) for serotonin 5HT2A/2C, 5HT3, 5HT6; dopamine D1, D2, D3, D4, D5; cholinergic muscarinic receptors m1-m5; α1 adrenergic; and histamine H1 receptors. Animal behavioural studies with olanzapine indicated 5HT, dopamine and cholinergic antagonism, consistent with the receptor binding profile. Olanzapine demonstrated a greater in-vitro affinity for serotonin 5HT2 than dopamine D2 receptors and in in-vivo models, greater 5HT2 than D2 activity. Electrophysiological studies demonstrated that olanzapine selectively reduced the firing of mesolimbic (A10) dopaminergic neurons, while having little effect on the striatal (A9) pathways involved in motor function. Olanzapine reduced a conditioned avoidance response, a test indicative of antipsychotic activity, at doses below those producing catalepsy, an effect indicative of motor side-effects. Unlike some other antipsychotic agents, olanzapine increased responding in an 'anxiolytic' test.
In a single 10 mg oral dose Positron Emission Tomography (PET) study in healthy volunteers, olanzapine produced higher receptor occupancy at the 5HT2A receptor than at the dopamine D2 receptor. A Single Photon Emission Computed Tomography (SPECT) imaging study in schizophrenic patients revealed that olanzapine-responsive patients had lower striatal D2 occupancy than some other antipsychotic- and risperidone-responsive patients, while being comparable to clozapine-responsive patients.
In two of two placebo and two of three comparator controlled clinical trials with over 2,900 schizophrenic patients, with both positive and negative symptoms, olanzapine was associated with statistically significantly greater improvements in negative as well as positive symptoms of schizophrenia.

Clinical trials.

Schizophrenia and related disorders.

The efficacy of 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 co-therapy study (n=344) of patients treated with lithium or valproate for a minimum of 2 weeks, the addition of olanzapine 10 mg (co-therapy 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 co-therapy recurrence prevention study in manic episode patients stabilised with olanzapine plus mood stabilisers (lithium or valproate), olanzapine co-therapy 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 co-therapy than for patients receiving placebo plus mood stabiliser.

5.2 Pharmacokinetic Properties

Absorption.

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

Distribution.

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

Metabolism.

Olanzapine is metabolised in the liver by conjugative and oxidative pathways. The major circulating metabolite is the 10-N-glucuronide which does not pass the blood brain barrier. Cytochromes P450-CYP1A2 and P450-CYP2D6 contribute to the formation of the N-desmethyl and 2-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.

Excretion.

After oral administration to healthy subjects, the mean terminal elimination half-life was 33 hours (21 to 54 hours for 5th to 95th percentile) and the mean olanzapine plasma clearance was 26 L/hr (12 to 47 L/hr for the 5th to 95th percentile). Olanzapine pharmacokinetics varied on the basis of smoking status, gender and age.
In healthy elderly (≥ 65 years) subjects versus 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, 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 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.
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 2.5-7.5 mg daily. Consequently, dosage adjustment may not be necessary if hepatic impairment is the sole consideration.
Olanzapine orally disintegrating tablets are bioequivalent to Olanzapine film coated tablets, with a similar rate and extent of absorption. Olanzapine orally disintegrating tablets may be used as an alternative to olanzapine film coated tablets. See Table 1.

5.3 Preclinical Safety Data

Genotoxicity.

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

Carcinogenicity.

Carcinogenicity studies in mice and rats showed the development of mammary adenocarcinomas at oral doses greater than 0.5 and 1 mg/kg/day respectively.
The increased incidence of mammary tumours may be due to an endocrine mechanism, possibly involving elevation of circulating prolactin levels in response to the dopamine D2 receptor antagonistic activity of olanzapine. Mammary tumours are known to occur in rats and mice treated with other drugs that antagonise dopamine D2 receptors. Neither clinical studies nor epidemiological studies, conducted to date, have shown an association between these drugs and carcinogenesis, but the available evidence is considered too limited to be conclusive at this time. The use of olanzapine in patients with familial history or previously detected breast cancer should be avoided. Caution should also be exercised when considering olanzapine treatment in patients with pituitary tumours.

6 Pharmaceutical Particulars

6.1 List of Excipients

Pryzex film coated tablets contain lactose monohydrate, hyprolose, crospovidone, microcrystalline cellulose, magnesium stearate and purified talc.
The film coatings used are as follows:
Opadry AMB complete film coating system OY-B-28920 White (Arping 4271) consisting of; part hydrolysed polyvinyl alcohol, titanium dioxide, purified talc, lecithin (soya), xanthan gum - all strengths.
Opadry AMB aqueous moisture barrier coating system 80W26503 Grey (Arping 107459) consisting of; part hydrolysed polyvinyl alcohol, titanium dioxide, purified talc, lecithin (soya), Indigo carmine aluminium lake, iron oxide yellow, xanthan gum, iron oxide black - 15 mg only.
Opadry AMB aqueous moisture barrier coating system 80W24003 Pink (Arping 107460) consisting of; part hydrolysed polyvinyl alcohol, titanium dioxide, purified talc, lecithin (soya), iron oxide red, xanthan gum, iron oxide yellow, iron oxide black - 20 mg only.
Pryzex ODT orally disintegrating tablets contain lactose monohydrate, hyprolose, crospovidone, microcrystalline cellulose, magnesium stearate, purified talc and colloidal anhydrous silica.
Pryzex ODT also contains a proprietary mint flavour (Mint Flavouring E-0613218) consisting of; acacia, cineole, maltodextrin, mint oil, mint oil dementholised, peppermint oil, menthone, isomenthone, menthyl acetate and menthol.

6.2 Incompatibilities

No data available.

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). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

Pryzex 2.5, 5, 7.5, 10, 15 and 20 mg film coated tablets are presented in blister pack (PA-Aluminium/PVC-Aluminium) of 28 tablets.
Pryzex ODT 5, 10, 15 and 20 mg orally disintegrating tablets are presented in blister pack (PA-Aluminium/PVC-Aluminium) of 28 tablets.
Not all presentation are marketed.

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.


CAS number.

132539-06-1.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes