Consumer medicine information

Ozidal

Risperidone

BRAND INFORMATION

Brand name

Ozidal

Active ingredient

Risperidone

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Ozidal.

What is in this leaflet

This leaflet answers some of the common questions about Ozidal (risperidone) tablets.

It does not contain all of the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking this medicine against the benefits it is expected to have for you.

If you have any concerns about using Ozidal, ask your doctor or pharmacist. Your doctor and pharmacist have more information.

Keep this leaflet with your Ozidal tablets. You may need to read it again.

What Ozidal is used for

Ozidal is used to treat symptoms of schizophrenia and other types of related psychoses. These are disorders related to thought, feeling and/or action.

Ozidal may be taken for both sudden (acute) and long-lasting (chronic) schizophrenia.

Ozidal is also used for the short-term treatment of acute mania associated with bipolar 1 disorder. This condition is characterised by symptoms such as elevated, expansive or irritable mood, inflated self esteem, decreased need for sleep, pressured speech, racing thoughts, distractibility or poor judgement including disruptive or aggressive behaviours.

Ozidal is also used to treat behavioural problems in patients with a decline in mental abilitiy (dementia) caused by Alzheimer's disease. These problems include: aggression through words or action, morbid suspiciousness, agitation or wandering.

Ozidal can be used to treat conduct and other disruptive behaviours such as aggression, impulsiveness and self-injury in children (over 5 years old), adolescents and adults who are intellectually disabled.

Ozidal can also be used to treat behavioural symptoms of autism in children and adolescents.

Ozidal helps to correct a chemical imbalance in the brain associated with these conditions.

Ozidal has been approved for the uses mentioned above. However, your doctor may prescribe this medicine for another use. If you want more information, ask your doctor.

Ozidal is not addictive.

Before you take Ozidal

When you must not use it

Do not use Ozidal:

  • If you know you are allergic to any of its ingredients (signs of allergy include skin rash, itching, shortness of breath, and/or swollen face - see the last section of this leaflet for a list of ingredients).
  • If you are intolerant to lactose. This medicine contains small quantities of the inactive ingredient lactose. In case your doctor has told you that you have intolerance to some sugars, you must not take these tablets and should talk to your doctor. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption (which might cause pain in the abdomen, cramps, diarrhoea and gas after taking food) should not take these tablets.
  • If the packaging is torn or shows signs of being tampered with.
  • If the tablets do not look right.
  • To treat any other complaints unless your doctor says it is safe to do so.
  • After the expiry date printed on the pack. If you take it after the expiry date has passed, it may not work as well or may cause harm.

Before you start to use it

  1. Tell your doctor if:
  • you have allergies to
    - any other medicines
    - any other substance such as foods, preservatives or dyes
  • you have any eye surgery planned
    Your doctor will need to assess whether you are at risk of a surgical complication (called 'Intraoperative Floppy Iris Syndrome). You may be recommended to stop your Ozidal temporarily prior to your eye surgery.
  • Tell your doctor if you are pregnant or planning to become pregnant.
    Your doctor will advise you whether or not you should take Ozidal. Agitation, muscle stiffness, unusual muscle slackness, shaking, drowsiness, breathing disorder and difficulty in feeding may occur in newborns, if a mother used risperidone in the last trimester of her pregnancy.
  • Tell your doctor if you are breast-feeding or planning to breastfeed.
    Ozidal is excreted in breast milk. It is recommended that you do not breast-feed while taking Ozidal.
  • you will be in a hot environment or do a lot of vigorous exercise.
    Ozidal may make you sweat less, causing your body to overheat.
  1. Tell your doctor if you have or have ever had any medical conditions, especially the following:
  • Heart or blood vessel diseases, including low blood pressure.
    Low blood pressure can result from using risperidone together with medicines to treat high blood pressure. So, if you need to use both risperidone and medications to reduce blood pressure, consult your doctor
    Risperidone should be used with caution, and only after consultation with your doctor, if you have heart problems, particularly irregular heart rhythm, abnormalities in electrical activity of the heart, or if using medications that can change the heart’s electrical activity.
  • unusual excessive sweating or diarrhea, dehydration or problems with your body temperature regulation
  • kidney or liver problems
  • you are prone to dizziness when standing up from lying or sitting position
  • Parkinson's disease (a progressive movement and thinking disorder that tends to affect older people)
  • dementia or Lewy body dementia. Older people suffering from dementia may be at increased risk of stroke or death with Ozidal
  • epilepsy, seizures or fits
  • continuous and/or painful erections (called 'priapism')
  • low potassium levels (hypokalaemia)
  • breast cancer
  • cancer of the pituitary gland
  • sugar diabetes
  • unusual thirst, tiredness, blurred vision, upset stomach or need to urinate - common signs of high blood sugars
  • disease of the blood vessels of the brain including stroke
  • tardive dyskinesia (a reaction to some medicines with uncontrollable twitching or jerking movements of the tongue, face, mouth, jaws, arms and legs)
  • Neuroleptic Malignant Syndrome (a serious reaction to some medicines with a sudden increase in body temperature, very fast heartbeat, extremely high or low blood pressure and severe convulsions)
  • blood clots
    Tell your doctor if you or someone else in your family has a history of blood clots. Blood clots in the lungs and legs can occur with Ozidal. Blood clots in the lungs can result in death.
  • Involuntary movements or unusual restlessness or difficulty sitting still (akathisia)
  • suicidal thoughts or past suicide attempts
  • low white blood cell count
  • If you have low numbers of some white blood cells, your risk of contracting an infection or developing a fever is increased with Ozidal.

If you have not told your doctor about any of the above, tell him / her before you start taking Ozidal.

Avoid alcoholic beverages until you have discussed their use with your doctor. Ozidal can increase the effect of alcohol. You should not drink alcohol while taking Ozidal.

Taking other medicines

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

Some medicines may affect the way other medicines work.

In particular tell your doctor if you are taking:

  • sleeping tablets, tranquillisers, pain-killers, certain allergy medicines called antihistamines, certain antidepressants
  • medicines that increase the activity of the central nervous system (psychostimulants such as methylphenidate)
  • medicines used to treat bacterial infections such as rifampicin
  • medicines to treat fungal infections such as itraconazole and ketoconazole
  • medicines to treat HIV/AIDS, such as ritonavir and tipranavir
  • carbamazepine, a drug mainly used for epilepsy or trigeminal neuralgia (severe pain attacks in the face), as it may decrease the level of risperidone in your blood
  • medicines to treat Parkinson's disease or tremor
  • medicines to treat epilepsy
  • medicines to treat depression, panic disorder, anxiety or obsessive-compulsive disorder. For example fluoxetine and paroxetine may increase the level of risperidone in your blood. So tell your doctor if you start and/or stop taking fluoxetine or paroxetine.
  • diuretics
  • medicines for your heart or blood pressure
  • verapamil, a medicine used to treat high blood pressure and/or abnormal heart rhythm
  • frusemide, a medicine used to treat high blood pressure and fluid build-up.
    There is an increased risk of side effects or death in older people if frusemide is also taken with Ozidal.
  • other medicines to treat mental illness or psychotic conditions

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

Elderly People

Elderly people should take less Ozidal than is prescribed for other adults (see “How to take it”).

Using Ozidal

Taking it for the first time

At the start of treatment you may have a fall in blood pressure making you feel dizzy on standing up, or your heart may beat faster. These should go away after a few days. Tell your doctor if they continue or worry you.

How much to take

Take only when prescribed by your doctor.

Ozidal may be taken as a single dose, once a day or it may be taken in divided doses twice a day (in the morning and in the evening).

It is very important that you take the correct amount of Ozidal, but this will vary from person to person. Your doctor will adjust the number and strength of the tablets until the desired effect is obtained.

Follow your doctor's instructions carefully and do not change or stop the required dosage without consulting your doctor first.

For Schizophrenia and Related Psychoses

The usual starting dose of Ozidal is 1 mg twice a day. This will be gradually increased by your doctor to suit your needs.

From then on, the dose can be taken once a day or twice a day according to your doctor's instructions. For long-term treatment, 4 to 6 milligrams per day is usually sufficient but your doctor will determine the dose most suitable for you.

Important note: never take more tablets than your doctor tells you to take.

The effects of high doses are not yet known. Please double check with your doctor if your doctor prescribes more than 5 milligrams twice a day.

Ozidal cannot be recommended for use in children with schizophrenia under 15 years at the present time as there is little experience with the product in this group.

For Elderly Patients with Schizophrenia or Related Psychoses

For older patients a starting dose of 0.5 mg (half a 1 mg tablet) twice a day (in the morning and in the evening) is usual. The dose may be increased by 0.5 mg twice daily to 1 to 2 mg twice a day (in the morning and in the evening).

Patients with impaired kidney and liver function

If you have kidney or liver disease a starting dose of 0.5 mg (half a 1 mg tablet) twice a day (in the morning and in the evening) is usual. The dose may be increased by 0.5 mg twice daily to 1 to 2 mg twice a day (in the morning and in the evening).

For acute mania

The recommended starting dose is 2 mg once a day. This dose can be adjusted by dose increases of 1mg when needed every 24 hours. Most people feel better with doses between 2 mg and 6 mg a day. Your doctor may decide you should take another drug called a mood stabiliser as well as Ozidal.

For Behavioural Problems in People with Dementia

The usual starting dose is 0.25 mg twice daily. This may be gradually increased by your doctor to suit your needs.

From then on the dose can be taken once a day or twice a day according to your doctor’s instructions. For long-term treatment, 1 mg daily is the usual dose but your doctor will determine the most suitable dose for you.

For Disruptive Behaviour Disorders in Adults and Children

For people who weigh 50 kg or more, the usual starting dose is 0.5 mg (half a 1 mg tablet) once a day. The dose may be increased by 0.5 mg once every two days, to the usual dose of 0.5 to 1.5 mg once a day.

For people who weigh less than 50 kg, the usual starting dose is 0.25 mg once a day. The dose may be increased by 0.25 mg once every two days, to the usual dose of 0.25 to 0.75 mg once a day.

Your doctor will advise you on how much Ozidal you need.

Ozidal cannot be recommended for use in children with disruptive behaviour disorders under 5 years at the present time as there is little experience with the product in this group.

For Behavioural Disorders Associated with Autism in Children and Adolescents

For people weighing 20 kg or less the usual starting dose is 0.25 mg. On day 4 this dose can be increased to 0.5 mg.

For people weighing more than 20 kg the usual starting dose is 0.5 mg. On day 4 this dose can be increased to 1 mg.

Response should be assessed at day 14; only in patients not achieving sufficient clinical response should additional dose increases be considered. Your doctor will advise you on how much Ozidal you need. When trialled, the maximum dose of risperidone in patients with autism did not exceed 1.5 mg/day in patients less than 20 kg, 2.5 mg in patients weighing 20kg or more, or 3.5mg in patients weighing more than 45 kg.

Follow all directions given to you by your doctor carefully.

They may differ from the information contained in this leaflet.

If you do not understand the instructions on the box, ask your doctor or pharmacist for help.

When and how to take it

Ozidal tablets should be swallowed with water or other liquid.

You may take Ozidal either with or between meals.

How long to take it

Continue taking your medicine for as long as your doctor tells you.

Do not let yourself run out of medicine over the weekend or on holidays.

If you forget to take it

If you forget to take Ozidal, take the missed dose as soon as you remember instead of your next dose. Then go back to taking it as you would normally.

Do not take a double dose to make up for the one you missed. If you forget to take Ozidal for 5 days or more, tell your doctor before starting your medicine again.

If you have problems remembering when to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

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

You may need urgent medical attention. Please keep these phone numbers handy.

Signs of overdose may include drowsiness, sleepiness, excessive trembling, excessive muscle stiffness, increased heart rate, very low blood pressure causing fainting or unconsciousness.

While you are using Ozidal

Things you must do

Always follow your doctor's instructions carefully, and seek your doctor's advice before changing or stopping treatment. Your doctor will be happy to discuss any questions you may have with your treatment.

Contact your doctor if you notice any involuntary movements of the tongue, mouth, cheeks or jaws, which may progress to arms and legs.

These may be symptoms of a condition called Tardive Dyskinesia, which can develop in people taking antipsychotic medicines, including Ozidal. This condition is more likely to occur during longer term treatment and in older women. In very rare cases, these symptoms may be permanent. However, if detected early, these symptoms are usually reversible.

Be careful during strenuous exercise or exposure to extreme heat. Try to drink plenty of water.

Visit your doctor regularly for check ups.

If you suffer from sugar diabetes your doctor may monitor your blood sugar levels regularly to check for worsening of glucose control.

Pre-menopausal women should tell their doctor if they do not have a period for more than six months while taking Ozidal, even if you are not pregnant.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

Try to eat a moderate diet. Ozidal can cause weight gain.

Things you must not do

  • Do not take Ozidal to treat any other complaints unless your doctor tells you to.
  • Do not give your medicine to anyone else, even if they have the same condition as you.
  • Do not stop taking your medicine or lower the dosage without checking with your doctor.
  • Do not drink alcohol. Ozidal can increase the effects of alcohol.

Things to be careful of

  • Ask your doctor before taking any other medicines. Ozidal can increase the effects of medicines which slow your reactions. Always ask your doctor or pharmacist before taking other medicines. These include herbal treatments and those bought in a pharmacy or supermarket.
  • Avoid driving or operating machinery until you know how Ozidal affects you. Ozidal may cause dizziness or light-headedness in some people, especially after the first dose. Make sure you know how you react to Ozidal before you drive a car, operate machinery, or do anything else that could be dangerous if you are dizzy.
  • Avoid excessive eating, as there is a possibility of weight gain when taking Ozidal.
  • If the medicine makes you feel light-headed, dizzy or faint, be careful when getting up from a sitting or lying position.
  • Getting up slowly may help.
  • There is a possibility of weight gain when taking Ozidal. Your doctor may monitor your body weight or recommend strategies to assist with weight management.

Side Effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Ozidal.

Ozidal helps most people but it may have some unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, but most of the time they are not. Risperidone is generally well-tolerated and side effects are often hard to distinguish from the disease symptoms. You may need medical treatment if you get some of the side effects.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking RISPERDAL

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

  • difficulty thinking, working or carrying out your usual daily activities because of:
    - headache
    - trembling, muscle weakness, unsteadiness on your feet, lack of coordination or slow, shuffling walk (symptoms of Parkinsonism).
    - lack of energy, drowsiness or excessive sleeping during the day, sleeplessness or difficulty in concentrating
    - difficulty speaking
    - blurred vision
    - fainting
    - dizziness
    - any problems with confusion or unsteadiness
    - pains in parts of your body, e.g. in the neck, back, ear, hands or feet
    - failing
  • muscle, joint, nerve or movement changes such as:
    - shaking or trembling
    - fatigue or weakness
    - muscle stiffness
    - restlessness in the legs or difficulty sitting still
    - uncontrolled muscle spasms, twitching, jerky or writhing movements
    - muscle aches or pain
    - joint swelling or pain
    - walking abnormally or with difficulty
    - abnormal posture, such as rigid body movements and persistent abnormal positions of the body
  • behavioural changes such as:
    - irritability or agitation
    - unusual anxiety or nervousness
  • other changes such as:
    - cold or "flu-like" symptoms e.g. cough, blocked or runny nose, sneezing, sore throat
    - feeling of tension or fullness in the nose, cheeks and behind your eyes, sometimes with a throbbing ache, fever, stuffy nose and loss of the sense of smell (signs of sinusitis)
    - tiredness, headaches, being short of breath when exercising, dizziness and
    - looking pale (signs of decreased red blood cells)
    - fever, chills, shortness of breath, cough, phlegm and occasionally blood (signs of pneumonia)
    - nosebleeds
    - discharge with itching of the eyes and crusty eyelids
    - unexplained weight gain
    - unexplained increase or decrease in appetite
    - indigestion, stomach discomfort or pain, diarrhoea or constipation
    - nausea or vomiting
    - dry mouth or excessive thirst
    - drooling
    - difficulty swallowing
    - acne
    - dry skin
    - rash, red skin or itchy skin
    - thickening of the skin resulting in warts, corns, calluses
    - skin infection
    - swelling of any part of your body, e.g. hands, ankles or feet
    - inability to or feeling burning pain when passing urine
    - some loss of bladder control
    - bedwetting
    - frequent daytime urination in children
    - sexual function disturbances - problems with ejaculation
    - breast abnormalities - breast discomfort or swelling or unusual secretion of breast milk
    - missed or irregular menstrual periods
    - dizziness on standing up, especially when getting up from a sitting or lying down position
    - shortness of breath
    - chest pain or discomfort
    - an increase of CPK (creatine phosphokinase) in your blood, an enzyme which is sometimes released with muscle breakdown.

These can only be detected by blood tests that your doctor may ask to be done.

These are mild side effects of Ozidal 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:

  • Signs of heart or blood pressure problems including:
    - fainting, blurry vision, light-headedness or dizziness particularly on standing that persists despite sitting or lying down again
    - very fast heart rate, slowed heart rate, heart rhythm irregularities
  • Signs of lung problems including:
    - sudden shortness of breath, trouble breathing, wheezing or gasping when you breathe, light-headedness or dizziness
  • signs of high blood sugar or diabetes such as:
    - unusual thirst, tiredness, upset stomach or need to urinate more often than usual
  • body temperature changes such as:
    - fever
    - unexplained high body temperature, excessive sweating or rapid breathing
    - severe muscle stiffness or fits
  • involuntary movements of the tongue, face, mouth, jaw, arms, legs or trunk
  • rash, itching or hives on the skin; shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body.
    If you have them, you may have had a serious allergic reaction to OzidaL.
  • sudden weakness or numbness of the face, arms, or legs, especially on one side, or instances of slurred speech (these are called ministrokes)

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

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

Do not hesitate to report any other side effects to your doctor or pharmacist.

Do not be alarmed by this list of possible side effects.

You may not experience any of them.

After using it

Storage

Keep Ozidal tablets in a dry place where the temperature stays below 25°C.

Do not store it or any medicines in the bathroom or near a sink. Heat and dampness can destroy some medicines.

Keep your tablets in the pack until it is time to take them. If you take your tablets out of the pack they will not keep as well.

Keep it where young children cannot reach it. A locked cupboard at least one-and-a-half meters above the ground is a good place to store medicines.

Do not use Ozidal tablets beyond the date (month and year) printed on the pack after the letters EXP, even if it has been stored properly. Medicines cannot be stored indefinitely.

Do not use Ozidal if the appearance of the tablets has changed.

Disposal

Once you have finished using Ozidal, ask your pharmacist what to do with any unused medicine.

Product Description

What it looks like

Ozidal 0.5 mg tablets are brown-coloured, film-coated, oval-shaped tablets with a scoreline on both sides and ‘RSN’ and ‘0.5’ debossed on either side of the scoreline on one side, available in packs of 60 tablets.

Ozidal 1 mg tablets are white, film-coated, capsule-shaped tablets with a scoreline on both sides and ‘RSN’ and ‘1’ debossed on either side of the scoreline on one side, available in packs of 60 tablets.

Ozidal 2 mg tablets are peach-coloured, film-coated, capsule-shaped tablets with a scoreline on both sides and ‘RSN’ and ‘2’ debossed on either side of the scoreline on one side, available in pack of 60 tablets.

Ozidal 3 mg tablets are yellow-coloured, film-coated, capsule-shaped tablets with a scoreline on both sides and ‘RSN’ and ‘3’ debossed on either side of the scroreline on one side, available in pack of 60 tablets.

Ozidal 4 mg tablets are green-coloured, film-coated, capsule-shaped tablets with a scoreline on both sides and ‘RSN’ and ‘4’ debossed on either side of the scoreline on one side, available in pack of 60 tablets.

Ingredients

Active ingredient

Ozidal 0.5 mg tablets - 0.5 mg of risperidone

Ozidal 1 mg tablets - 1 mg of risperidone

Ozidal 2 mg tablets - 2 mg of risperidone

Ozidal 3 mg tablets - 3 mg of risperidone

Ozidal 4 mg tablets - 4 mg of risperidone

Inactive ingredients

Lactose monohydrate, pregelatinised starch, microcrystalline cellulose, sodium lauryl sulphate, colloidal anhydrous silica and magnesium stearate. In addition the 0.5 mg tablet contains Opadry II 31G 56729 brown, 1 mg tablet contains Opadry 20H 58983 white, the 2 mg tablet contains Opadry II 31G 53291 orange; the 3 mg tablet contains Opadry II 31G 52408 yellow and the 4 mg tablet contains Opadry II 31G 51195 green.

Australian Registration Numbers

Ozidal 0.5 mg tablets - AUST R 148964

Ozidal 1 mg tablets - AUST R 148967

Ozidal 2 mg tablets - AUST R 148968

Ozidal 3 mg tablets - AUST R 148969

Ozidal 4 mg tablets - AUST R 148970

Sponsor

Sun Pharma ANZ Pty Ltd.
Macquarie Park, NSW 2113
Australia
[email protected]
Tel: 1800 726 229

This leaflet was prepared in October 2019

Published by MIMS August 2020

BRAND INFORMATION

Brand name

Ozidal

Active ingredient

Risperidone

Schedule

S4

 

1 Name of Medicine

Risperidone.

2 Qualitative and Quantitative Composition

Each tablet of Ozidal contains 0.5 mg, 1 mg, 2 mg, 3 mg or 4 mg of risperidone.

Excipient with known effect.

Lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Ozidal 0.5 mg tablets - Available as brown-coloured, film-coated, oval-shaped tablets with a scoreline on both sides and ‘RSN’ and ‘0.5’ debossed on either side of the scoreline on one side.
Ozidal 1 mg tablets - Available as white, film-coated, capsule-shaped tablets with a scoreline on both sides and ‘RSN’ and ‘1’ debossed on either side of the scoreline on one side.
Ozidal 2 mg tablets - Available as peach-coloured, film-coated, capsules-shaped tablets with a scoreline on both sides and ‘RSN’ and ‘2’ debossed on either side of the scoreline on one side.
Ozidal 3 mg tablets - Available as yellow-coloured, film-coated, capsule-shaped tablets with a scoreline on both sides and ‘RSN’ and ‘3’ debossed on either side of the scoreline on one side.
Ozidal 4 mg tablets - Available as green-coloured, film-coated, capsule-shaped tablets with a scoreline on both sides and ‘RSN’ and ‘4’ debossed on either side of the scoreline on one side.

4 Clinical Particulars

4.1 Therapeutic Indications

Ozidal is indicated for the treatment of schizophrenia and related psychoses.
Ozidal is indicated for the short-term treatment of acute mania associated with bipolar 1 disorder.
Ozidal is also indicated for the treatment (up to 12 weeks) of psychotic symptoms, or persistent agitations or aggression unresponsive to non-pharmacological approaches, in patients with moderate to severe dementia of the Alzheimer type.
Ozidal is indicated in the treatment of conduct and other disruptive behaviour disorders in children (over 5 years), adolescents and adults with sub-average intellectual functioning or mental retardation in whom destructive behaviours (e.g. aggression, impulsivity and self-injurious behaviours) are prominent (see Section 5.1 Pharmacodynamic Properties, Clinical trials for maintenance data).
Ozidal is indicated for the treatment of behavioural disorders associated with autism in children and adolescents (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

4.2 Dose and Method of Administration

Dosing instructions for patients.

The absorption of risperidone is not affected by food and thus Ozidal can be given with or without food.

Schizophrenia.

Studies on the efficacy and safety of risperidone have been performed predominantly in patients with schizophrenia. The pivotal studies lasted up to 8 weeks, but more than 600 patients have been treated for at least 12 months.

Switching from other antipsychotics.

When medically appropriate, gradual discontinuation of the previous treatment is recommended while risperidone therapy is initiated.
Alterations in requirements of anti-Parkinson therapy may be required in patients switching to risperidone. These requirements should be evaluated periodically.

Adults.

Ozidal may be given once or twice daily.
Patients, whether acute or chronic, may start with 1 mg risperidone b.i.d. The dosage may be increased on the second day to 2 mg b.i.d. From then on the dosage can be maintained unchanged, or further individualised, if needed. In some patients a slower titration phase and lower starting and maintenance dose may be appropriate. Patients should be titrated gradually in view of the risk of first dose orthostatic hypotension.
In stable patients, Ozidal may be given once daily or twice daily, with a recommended daily dose between 4 and 6 mg. However, some patients may benefit from higher doses.
Doses above 5 mg b.i.d. have not been shown to be superior in efficacy to lower doses and may cause extrapyramidal symptoms.
A benzodiazepine may be added to Ozidal when additional sedation is required.

Elderly.

A starting dose of 0.5 mg b.i.d. is recommended in view of the increased risk of first dose orthostatic hypotension. This dosage can be individually adjusted with 0.5 mg b.i.d. increments to 1 - 2 mg b.i.d.

Renal and hepatic impairment.

A starting dose of 0.5 mg b.i.d. is recommended. This dosage can be individually adjusted with 0.5 mg b.i.d. increments to 1 to 2 mg b.i.d.
Ozidal should be used with caution in this group of patients until further experience is gained.

Children.

Experience is lacking in children with schizophrenia aged less than 15 years.

Bipolar mania.

Ozidal should be administered on a once daily basis, starting with 2 mg. Dosage adjustments, if indicated, should occur at intervals of not less than 24 hours and in dosage increment of 1 mg per day. A dosing range of between 2 - 6 mg per day is recommended.

Behavioural disturbances in dementia.

A starting dose of 0.25 mg b.i.d. is recommended. This dosage can be individually adjusted by increments of 0.25 mg b.i.d., not more frequently than every other day, if needed. The optimum dose is 0.5 mg b.i.d. for most patients. Some patients, however, may benefit from doses up to 1 mg b.i.d.
Once patients have reached their target dose, a once daily dosing regimen can be considered.
As with all symptomatic treatments, the continued use of Ozidal must be evaluated and justified on an on-going basis.
There is no data to support treatment beyond 12 weeks in patients with moderate to severe dementia of the Alzheimer type with agitation, aggression or psychotic symptoms.

Conduct and other disruptive behaviour disorders.

Subjects ≥ 50 kg.

A starting dose of 0.5 mg once daily is recommended. This dosage can be individually adjusted by increments of 0.5 mg once daily not more frequently than every other day, if needed. The optimum dose is 1 mg once daily for most patients. Some patients, however, may benefit from 0.5 mg once daily while others may require 1.5 mg once daily.

Subjects < 50 kg.

A starting dose of 0.25 mg once daily is recommended. This dosage can be individually adjusted by increments of 0.25 mg once daily not more frequently than every other day, if needed. The optimum dose is 0.5 mg once daily for most patients. Some patients however may benefit from 0.25 mg once daily while others may require 0.75 mg once daily.
As with all symptomatic treatments, the continued use of risperidone must be evaluated and justified on an on-going basis.
Experience is lacking in children aged less than 5 years.

Behavioural disorders associated with autism.

Ozidal can be administered once or twice daily.
Ozidal should be administered based on body weight. Dosing should begin at 0.25 mg or 0.5 mg/day based upon weight (see Tables 1-2 for relative weight categories). On day 4 of treatment the dose may be increased up to 0.5 or 1.0 mg/day. This dose should be maintained and response assessed at approximately day 14. Only in patients not achieving sufficient clinical response should additional dose increases be considered. Dose increases may proceed at ≥ 2 week intervals in increments of 0.25 mg for patients < 20 kg or 0.5 mg for patients ≥ 20 kg. In clinical studies the maximum dose studied did not exceed a total daily dose of 1.5 mg in patients < 20 kg, 2.5 mg in patients ≥ 20 kg or 3.5 mg in patients > 45 kg.
Doses by total mg/day and by mg/kg/day for starting doses and incremental increases are shown in Table 1.
For prescribers preferring to dose on a mg/kg/day basis the following guidance is provided in Table 2.
Patients experiencing somnolence may benefit from a switch in dosing from once daily to either once daily at bedtime or twice daily.
Once sufficient response has been achieved and maintained, consideration may be given to gradually lowering the dose to achieve the optimum balance of efficacy and safety. There is insufficient evidence from controlled trials to indicate how long the patient with Autistic Disorder should be treated with risperidone.

4.3 Contraindications

Ozidal is contraindicated in patients with a known hypersensitivity to the drug or any of its excipients.

4.4 Special Warnings and Precautions for Use

Elderly patients with dementia.

Overall mortality.

Elderly patients with dementia treated with atypical antipsychotic drugs have an increased mortality compared to placebo in a meta-analysis of 17 controlled trials of atypical antipsychotic drugs, including risperidone. In placebo-controlled trials with risperidone in this population, the incidence of mortality was 4.0% (40/1009) for risperidone treated patients and 3.1% (22/712) for placebo-treated patients. The mean age (range) of patients who died was 86 years (range 67-100).

Concomitant use with frusemide.

In the risperidone placebo-controlled trials in elderly patients with dementia, a higher incidence of mortality was observed in patients treated with frusemide plus risperidone (7.3% [15/206]; mean age 89 years, range 75-97) compared to treatment with risperidone alone (3.1% [25/803]; mean age 84 years, range 70-96) or frusemide alone (4.1% [5/121]; mean age 80 years, range 67-90). The Odds Ratio (95% exact confidence interval) was 1.82 (0.65, 5.14). The increase in mortality was observed in two of the four clinical trials.
No pathophysiological mechanism has been clearly identified to explain this finding and no consistent pattern for cause of death was observed. Nevertheless, caution should be exercised and the risks and benefits of this combination should be considered prior to the decision to treat. Irrespective of treatment, dehydration was an overall risk factor for mortality and should therefore be carefully avoided in elderly patients with dementia.

Cerebrovascular adverse events.

In placebo-controlled trials in elderly patients with dementia there was a significantly higher incidence of cerebrovascular adverse events, such as stroke (including fatalities) and transient ischaemic attacks in patients (mean age 85 years, range 73-97) treated with risperidone compared to patients treated with placebo.
The pooled data from six placebo-controlled trials in mainly elderly patients (> 65 years of age) with dementia showed that cerebrovascular adverse events (serious and non-serious combined) occurred in 3.3% (33/989) of patients treated with risperidone and 1.2% (8/693) of patients treated with placebo. The Odds Ratio (95% exact confidence interval) was 2.96 (1.33, 7.45).

Orthostatic hypotension.

Due to the α-blocking activity of risperidone, orthostatic hypotension can occur, especially during the initial dose-titration period. Clinically significant hypotension has been observed post-marketing with concomitant use of risperidone and antihypertensive treatment. Risperidone should be used with caution in patients with known cardiovascular disease (e.g. heart failure, myocardial infarction, conduction abnormalities, dehydration, hypovolaemia, or cerebrovascular disease), and the dosage should be gradually titrated as recommended (see Section 4.2 Dose and Method of Administration). A dose reduction should be considered if hypotension occurs. Special care should be taken in patients taking medications to lower blood pressure.

Leukopenia, neutropenia and agranulocytosis.

Events of leukopenia, neutropenia and agranulocytosis have been reported with antipsychotic agents, including risperidone. Agranulocytosis has been reported very rarely (< 1/10,000 patients) during post-marketing surveillance.
Patients with a history of a clinically significant low white blood cell count (WBC) or a drug-induced leukopenia/neutropenia should be monitored during the first few months of therapy and discontinuation of risperidone should be considered at the first sign of clinically significant decline in WBC in the absence of other causative factors.
Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count < 1 X 109/L) should discontinue risperidone and have their WBC followed until recovery.

Venous thromboembolism.

Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with risperidone and preventative measures undertaken.

Use in patients with concomitant illness.

Patients with a history of clinically significant cardiac disorders were excluded from clinical trials. As clinical experience is limited, risperidone should be used with caution in patients with known cardiovascular disease (e.g. heart failure, myocardial infarction, conduction abnormalities) and other conditions (such as dehydration, hypokalaemia and hypovolaemia).

Tardive dyskinesia/ extrapyramidal symptoms.

Tardive dyskinesia (TD), a syndrome consisting of potentially irreversible, involuntary dyskinetic movements may develop in patients treated with conventional neuroleptics. Although this syndrome of TD appears to be most prevalent in the elderly, especially elderly females, it is impossible to predict at the onset of treatment which patients are likely to develop TD.
It has been suggested that the occurrence of Parkinsonian side effects is a predictor for the development of TD. In clinical studies, the observed incidence of drug-induced Parkinsonism was lower with risperidone than with haloperidol. In the optimal clinical dose-range, the difference between risperidone and haloperidol was significant. Therefore the risk of developing tardive dyskinesia may be less with risperidone. The risk of developing TD and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although less commonly, after relatively brief periods of treatment at low doses. There is no known treatment for an established case of TD. The syndrome may remit partially or completely if antipsychotic drug treatment is withdrawn.
Antipsychotic drug treatment itself, however, may suppress the signs and symptoms of TD, thereby masking the underlying process. The effect of symptom suppression upon the long-term course of TD is unknown. In view of these considerations, risperidone should be prescribed in a manner that is most likely to minimise the risk of TD. As with any antipsychotic drug, risperidone should be reserved for patients who appear to be obtaining substantial benefit from the drug. In such patients, the smallest dose and the shortest duration of treatment should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of TD appear in a patient on antipsychotics, drug discontinuation should be considered. However, some patients may require treatment despite the presence of this syndrome.

Extrapyramidal symptoms and psychostimulants.

Caution is warranted in patients receiving both psychostimulants (e.g. methylphenidate) and risperidone concomitantly, as extrapyramidal symptoms could emerge when adjusting one or both medications. Gradual withdrawal of one or both treatments should be considered (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Neuroleptic malignant syndrome.

Neuroleptic malignant syndrome (NMS) is a potentially fatal symptom complex that has been reported in association with antipsychotic drugs, including risperidone.
Clinical manifestations of NMS are hyperthermia, muscle rigidity, altered mental status (including catatonic signs) and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, cardiac arrhythmias and diaphoresis). Additional signs may include elevated creatine phosphokinase (CPK) levels, myoglobinuria (rhabdomyolysis), and acute renal failure.
In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g. pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.
The management of NMS should include: 1) immediate discontinuation of all antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.

Seizures.

Classical neuroleptics are known to lower the seizure threshold. Risperidone has not been studied in patients who also have epilepsy. In clinical trials, seizures have occurred in a few risperidone-treated patients. Therefore, caution is recommended when treating patients having a history of seizures or other predisposing factors.

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 legs while seated, rocking from foot to foot, or both. Particular attention should be paid to the monitoring of such symptoms and signs as, left untreated; akathisia is associated with poor compliance and an increased risk of relapse.

Parkinson's disease/dementia with Lewy bodies.

Physicians should weigh the risks versus benefits when prescribing antipsychotics, including risperidone, to patients with Parkinson's Disease or Dementia with Lewy Bodies (DLB) since both groups may be at increased risk of neuroleptic malignant syndrome as well as having an increased sensitivity to antipsychotic medications. Manifestation of this increased sensitivity can include confusion, obtundation, postural instability with frequent falls, in addition to extrapyramidal symptoms.

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 risperidone. 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 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.

Weight gain.

Significant weight gain has been reported. Monitoring weight gain is advisable when risperidone is being used.

QT interval.

As with other antipsychotics, caution should be exercised when risperidone is prescribed in patients with a history of cardiac arrhythmias, in patients with congenital long QT syndrome, and in concomitant use with drugs known to prolong the QT interval.

Priapism.

Drugs with alpha-adrenergic blocking effects have been reported to induce priapism. Priapism has been reported with risperidone during post-marketing surveillance.

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 risperidone to 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.

Antiemetic effect.

An antiemetic effect was observed in preclinical studies with risperidone. This effect, if it occurs in humans, may mask the signs and symptoms of overdosage with certain drugs or of conditions such as intestinal obstruction, Reye's syndrome and brain tumour.

Suicide.

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

Intraoperative floppy iris syndrome.

Intraoperative floppy iris syndrome (IFIS) has been observed during cataract surgery in patients treated with medicines with alpha1a-adrenergic antagonist effect, including risperidone [see Section 4.8 Adverse Effects (Undesirable Effects)].
IFIS may increase the risk of eye complications during and after the operation. Current or past use of medicines with alpha1a-adrenergic antagonist effect should be made known to the ophthalmic surgeon in advance of surgery. The potential benefit of stopping alpha1 blocking therapy prior to cataract surgery has not been established and must be weighed against the risk of stopping the antipsychotic therapy.

Other precautions.

Premenopausal women who develop secondary amenorrhoea of greater than six months' duration should receive appropriate preventive therapy to avoid hypo-oestrogenic bone loss.
Patients may be advised to refrain from excessive eating in view of the possibility of weight gain.
For the conduct disorder indication, effects on sexual maturation and gonadal function in children and adolescents have not been evaluated beyond 12 months in relation to long-term treatment.
Safety data beyond 12 months is lacking in relation to the effect of long-term treatment for the conduct disorder indication.
Risperidone contains small quantities of an inactive ingredient lactose. In case the patient has intolerance to some sugars, patient must not take these tablets and should talk to the doctor.

Use in hepatic impairment.

Since clinical experience is lacking in this patient population, risperidone should be used with caution until further experience is gained. For hepatically impaired schizophrenic patients, it is recommended to halve both the starting dose and the subsequent dose increments in patients with hepatic insufficiency. In patients with known liver disease, it is advised to monitor the liver function.

Use in renal impairment.

Since clinical experience is lacking in this patient population, risperidone should be used with caution until further experience is gained. For renally impaired schizophrenic patients, it is recommended to halve both the starting dose and the subsequent dose increments in patients with renal insufficiency.

Use in the elderly.

For elderly schizophrenic patients, it is recommended to halve both the starting dose and the subsequent dose increments in geriatric patients.

Paediatric use.

Experience is lacking in children with schizophrenia aged less than 15 years. There is also insufficient preclinical data to adequately define the safety of risperidone in young children. For information on the use of risperidone in children 5 years and older in the treatment of conduct disorder, see Section 5.1 Pharmacodynamic Properties, Clinical trials.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

The risks of using risperidone in combination with other drugs have not been systematically evaluated.

Pharmacodynamic-related interactions.

Centrally-acting drugs and alcohol.

Given the primary CNS effects of risperidone, it should be used with caution in combination with other centrally acting drugs or alcohol.

Levodopa and dopamine agonists.

Risperidone may antagonise the effect of levodopa and other dopamine agonists.

Psychostimulants.

The combined use of psychostimulants (e.g. methylphenidate) with risperidone can lead to the emergence of extrapyramidal symptoms upon change of either or both treatments (see Section 4.4 Special Warnings and Precautions for Use).

Drugs with hypotensive effects.

Clinically significant hypotension has been observed post-marketing with concomitant use of risperidone and antihypertensive treatment.

Drugs known to prolong the QT interval.

Caution is advised when prescribing risperidone with drugs known to prolong the QT interval.

Pharmacokinetic-related interactions.

Risperidone is mainly metabolised through CYP2D6, and to a lesser extent through CYP3A4. Both risperidone and its active metabolite 9-hydroxyrisperidone are substrates of P-glycoprotein (P-gp). Substances that modify CYP2D6 activity, or substances strongly inhibiting or inducing CYP3A4 and/or P-gp activity, may influence the pharmacokinetics of the risperidone active antipsychotic fraction.
Strong CYP2D6 inhibitors. Co-administration of risperidone with a strong CYP2D6 inhibitor may increase the plasma concentrations of risperidone, but less so of the active antipsychotic fraction. Higher doses of a strong CYP2D6 inhibitor may elevate concentrations of the risperidone active antipsychotic fraction (e.g. paroxetine or fluoxetine). See also section SSRIs and tricyclic antidepressants.
CYP3A4 and/or P-gp inhibitors. Coadministration of risperidone with a strong CYP3A4 and/or P-gp inhibitor may substantially elevate plasma concentrations of the risperidone active antipsychotic fraction. When concomitant itraconazole or another strong CYP3A4 and/or P-gp inhibitor is initiated or discontinued, the physician should re-evaluate the dosing of risperidone.
CYP3A4 and/or P-gp Inducers. Co-administration of risperidone with a strong CYP3A4 and/or P-gp inducer may decrease the plasma concentrations of the risperidone active antipsychotic fraction. Similar effects may be observed with other CYP 3A4 hepatic enzyme inducers. On initiation or discontinuation of carbamazepine or other CYP 3A4 hepatic enzyme inducers, the dosage of risperidone should be reevaluated, and, if necessary, reduced.
When concomitant carbamazepine or another strong CYP3A4 and/or P-gp inducer is initiated or discontinued, the physician should re-evaluate the dosing of risperidone.
A formal drug-drug interaction study to investigate the effect of risperidone on carbamazepine was not performed; however the effect of carbamazepine as adjunctive treatment to risperidone was investigated in a pharmacokinetic study. In this study, patients were stabilised on a risperidone dose of 3 mg twice daily, and carbamazepine was administered from 3 weeks (Days 22 to 42) at a dose that was adjusted for the therapeutic concentration (5 to 12 micrograms/mL, average dose 573 ± 168 mg/day). Carbamazepine serum concentrations were determined at the beginning and at the end of the period of co-administration of the 2 compounds. The results showed that co-administration of risperidone with carbamazepine did not affect the serum concentrations of carbamazepine during the observation period of 3 weeks. The values were all within the therapeutic range of 5 to 12 micrograms/mL. Carbamazepine has been shown to decrease the plasma levels of risperidone plus 9-hydroxy risperidone.
Highly protein-bound drugs. In vitro studies, in which risperidone was given in the presence of various, highly protein-bound agents, indicated that clinically relevant changes in protein binding would not occur either for risperidone or for any of the drugs tested.
When using concomitant medication, the corresponding label should be consulted for information on the route of metabolism and the possible need to adjust dosages.
Examples. Examples of drugs that may potentially interact or that were shown not to interact with risperidone are listed below.

Antibacterials.

Erythromycin, a CYP3A4 inhibitor, does not change the pharmacokinetics of risperidone and risperidone plus 9-hydroxy risperidone.
Rifampicin, a strong CYP3A4 inducer and a P-gp inducer, decreased the risperidone active antipsychotic fraction Cmax by 41% and AUClast by 45%, following a single dose of risperidone 1 mg.

Anticholinesterases.

The cholinesterase inhibitors galantamine and donepezil, both CYP2D6 and CYP3A4 substrates, do not show a clinically relevant effect on the pharmacokinetics of risperidone and risperidone plus 9-hydroxy risperidone.

Antiepileptics.

Carbamazepine, a strong CYP3A4 inducer and a P-gp inducer, has been shown to decrease the plasma levels of the active antipsychotic fraction of risperidone.
Topiramate modestly reduces the bioavailability of risperidone, but not that of risperidone plus 9-hydroxy risperidone.
Risperidone does not show a clinically relevant effect on the pharmacokinetics of lithium, valproate or digoxin.

Antifungals.

Itraconazole, a strong CYP3A4 inhibitor and a P-gp inhibitor, at a dosage of 200 mg/day increased the plasma concentrations of the active antipsychotic fraction by about 70%, at risperidone doses of 2 to 8 mg/day.
Ketoconazole, a strong CYP3A4 inhibitor and a P-gp inhibitor, at a dosage of 200 mg/day increased the risperidone AUC by 67%, and decreased the 9-hydroxyrisperidone AUC by 49%, following a single dose of risperidone 2 mg. However, maximal CYP3A4 inhibition may not have been achieved in this study.

Antipsychotics.

Phenothiazines may increase the plasma concentrations of risperidone but not those of risperidone plus 9-hydroxyrisperidone (see Section 5.2 Pharmacokinetic Properties).

Antivirals.

Protease inhibitors: no formal study data are available; protease inhibitors are moderate to strong CYP3A4 inhibitors; ritonavir is also a weak CYP2D6 inhibitor and tipranavir is also a strong CYP2D6 inhibitor. Protease inhibitors therefore may raise concentrations of the risperidone active antipsychotic fraction.

Beta-blockers.

Some beta-blockers may increase the plasma concentrations of risperidone but not those of the active antipsychotic fraction.

Calcium channel blockers.

Verapamil, a moderate inhibitor of CYP3A4 and an inhibitor of P-gp, at a dose of 240 mg/day, increased the risperidone Cmax and AUC by 1.8-fold, and the active antipsychotic fraction Cmax by 1.3-fold and AUC by 1.4-fold, following a single dose of risperidone 1 mg.

Diuretics.

Frusemide: see Section 4.4 Special Warnings and Precautions for Use regarding increased mortality in elderly patients with dementia concomitantly receiving frusemide.

Gastrointestinal drugs.

H2-receptor antagonists: cimetidine and ranitidine, both weak inhibitors of CYP2D6 and CYP3A4, increased the bioavailability of risperidone, but only marginally that of the active antipsychotic fraction.
In volunteer studies, a single 1 mg risperidone dose was administered with cimetidine 400 mg twice daily or ranitidine 150 mg twice daily. Cimetidine produced a relative increase in AUC0-∞ of 1.95 ± 0.78, 1.01 ± 0.25 and 1.15 ± 0.28 for risperidone, 9-hydroxy-risperidone and risperidone plus 9-hydroxyl risperidone, respectively. Relative Cmax increases were 1.90 ± 0.95, 0.95 ± 0.21 and 1.24 ± 0.27. Co-administration of ranitidine produced a relative increase of 1.35 ± 0.32, 1.23 ± 0.44 and 1.25 ± 0.39 in AUC0-∞ and of Cmax of 1.45 ± 0.61, 1.28 ± 0.37 and 1.36 ± 0.35. Dose modification is not considered to be necessary.

Sodium channel blockers.

Quinidine may increase the plasma concentrations of risperidone but not those of the active antipsychotic fraction.

SSRIs and tricyclic antidepressants.

Fluoxetine, a strong CYP2D6 inhibitor, increases the plasma concentration of risperidone, but less so of the active antipsychotic fraction. Co-administration of fluoxetine produced relative increases of 1.63 ± 0.43, 1.54 ± 0.54 and 1.40 ± 0.24 in Cmin, Cmax and AUC0-12 hr of risperidone plus 9-hydroxy risperidone. Administration of paroxetine 20mg/day for 4 weeks to patients stabilised on 4-8 mg risperidone/day produced a relative increase of 1.51 ± 0.34 in Cmin of risperidone plus 9-hydroxy risperidone.
Paroxetine is a strong CYP2D6 inhibitor. At paroxetine doses of 10 mg/day the plasma concentration of risperidone increased by 4-fold, without a significant increase in the active antipsychotic fraction (1.3-fold). Dosages of paroxetine of 20 mg/day resulted in a 7-fold increase in the concentration of risperidone, and a non-significant increase in the active antipsychotic fraction (1.6-fold). Paroxetine 40 mg/day resulted in a significant increase in the concentrations of both risperidone (10-fold) and the active antipsychotic fraction (1.8- fold).
Doses of risperidone of 4 mg/day were used in this study.
When concomitant fluoxetine or paroxetine is initiated or discontinued, the physician should reevaluate the dose of risperidone.
Sertraline, a weak inhibitor of CYP2D6, and fluvoxamine, a weak inhibitor of CYP3A4, at dosages up to 100 mg/day are not associated with clinically significant changes in concentrations of the risperidone active antipsychotic fraction. However, the concentrations of the active antipsychotic fraction increased by 42% in 2 patients treated with sertraline 150 mg/day, and by 26% in 5 patients treated with fluvoxamine 200 mg/day. Doses of risperidone used were 46 mg/day in the sertraline study and 3-6 mg/day in the fluvoxamine study.
Tricyclic antidepressants may increase the plasma concentrations of risperidone but not those of risperidone plus 9-hydroxyrisperidone.
Tricyclic antidepressants may potentiate the postural hypotensive effect of risperidone.
In patients with schizophrenia receiving risperidone 3 mg twice daily for 28 days, the addition of amitryptiline initially at 50 mg twice daily, increasing to 100 mg twice daily for the last 6 days of the study produced relative increases in the AUC0-12 hr of 1.21 ± 0.35, 1.15 ± 0.36 and 1.16 ± 0.34 and Cmax of 1.17 ± 0.33, 1.11 ± 0.43 and 1.11 ± 0.38 for risperidone, 9-hydroxy-risperidone risperidone plus 9-hydroxy risperidone, respectively. These modest increases do not necessitate dose modification.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Risperidone impaired mating, but not fertility, in Wistar rats at doses 0.2 to 5 times the maximum human dose on a mg/m2 basis. The effect appeared to be in females since impaired mating behaviour was not noted when males only were treated. In repeat-dose toxicity studies in Beagle dogs, risperidone at dose of 1 to 17 times the maximum human dose on a mg/m2 basis was associated with adverse effects on the male reproductive system (inhibited ejaculation, incomplete spermatogenesis, reduced sperm motility and concentration, reduced gonadal and prostatic weight, prostatic immaturity, decreased serum testosterone). Serum testosterone and sperm parameters partially recovered but remained decreased after treatment was discontinued. No-effect doses were not determined in either rat or dog.
(Category C)
The safety of risperidone during human pregnancy has not been established. Reversible extrapyramidal symptoms in the neonate were observed following post-marketing use of risperidone during the last trimester of pregnancy. Although in experimental animals, risperidone did not show direct reproductive toxicity, some indirect, prolactin and CNS-mediated effects were observed. No teratogenic effect was noted in rats and rabbits following oral administration of risperidone during the period of organogenesis at doses up to 9 times the human dose on a mg/m2 basis.

Non-teratogenic class effect.

Neonates exposed to antipsychotic drugs (including risperidone) 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.
Risperidone 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.
Australian categorisation definition of Category C: Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human foetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details.
Risperidone and 9-hydroxyrisperidone are excreted in human breast milk. Women receiving risperidone should not breast-feed.
In rats oral administration of risperidone during late gestation and lactation was associated with an increase in pup deaths during the first 4 days of lactation at doses 0.2 to 5 times the maximum human dose on a mg/m2 basis (a no-effect dose was not determined) and with reduced pup weight gain at doses 5 fold or greater than the maximum recommended human dose on a mg/m2 basis. It is not known whether these effects resulted from a direct effect on the foetuses and pups and/or to an effect on the dams. There were also increases in stillborn rat pups at an oral dose 2.5 - 5 times the maximum human dose on a mg/m2 basis.

4.7 Effects on Ability to Drive and Use Machines

Risperidone may interfere with activities requiring mental alertness. Patients should be advised not to drive or operate machinery until their individual susceptibility is known.

4.8 Adverse Effects (Undesirable Effects)

Clinical trial data.

The safety of risperidone was evaluated from a clinical trial database consisting of 9712 patients exposed to one or more doses of risperidone for the treatment of various psychiatric disorders in adults, elderly patients with dementia, and paediatrics. Of these 9712 patients, 2626 were patients who received risperidone while participating in double-blind, placebo-controlled trials. The conditions and duration of treatment with risperidone varied greatly and included (in overlapping categories) double-blind, fixed- and flexible-dose, placebo- or active-controlled studies and open-label phases of studies, inpatients and outpatients, and short-term (up to 12 weeks) and longer-term (up to 3 years) exposures.
The majority of all adverse reactions were mild to moderate in severity.

Double-blind, placebo-controlled - adult patients.

Adverse drug reactions (ADRs) reported by ≥ 1% of risperidone-treated adult patients in nine 3- to 8-week double-blind, placebo-controlled trials are shown in Table 3.

Double-blind, placebo-controlled data - elderly patients with dementia.

Adverse drug reactions (ADRs) reported by ≥ 1% of risperidone-treated elderly patients with dementia in six 4- to 12-week double-blind, placebo-controlled trials are shown in Table 4. Table 4 includes only those ADRs that are either not listed in Table 3 or those ADRs that occurred at ≥ 2 times the frequency of the ADRs listed in Table 3.

Double-blind, placebo-controlled data - paediatric patients.

Adverse drug reactions (ADRs) reported by ≥ 1% of risperidone-treated paediatric patients in eight 3- to 8-week double-blind, placebo-controlled trials are shown in Table 5. Table 5 includes only those ADRs that are either not listed in Table 3 or those ADRs that occurred at ≥ 2 times the frequency of the ADRs listed in Table 3.

Other clinical trial data.

Paliperidone is the active metabolite of risperidone, therefore the adverse reaction profiles of these compounds (including both the oral and injectable formulations) are relevant to one another. This subsection includes additional ADRs reported with risperidone and/or paliperidone in clinical trials.
ADRs reported with risperidone and/or paliperidone by ≥ 1% of risperidone-treated subjects in a pooled dataset of 23 double-blind, placebo-controlled pivotal studies (9 in adults, 6 in elderly patients with dementia, and 8 in paediatric patients) are shown in Table 6.
Adverse drug reactions (ADRs) reported with risperidone and/or paliperidone by < 1 % of risperidone treated subjects in a pooled dataset of 23 double-blind, placebo-controlled pivotal studies (9 in adult, 8 in paediatric patients, 6 in elderly patients with dementia) are shown in Table 7.
ADRs reported with risperidone and/or paliperidone in other clinical trials but not reported by risperidone-treated subjects in a pooled dataset of 23 double-blind, placebo-controlled pivotal studies are shown in Table 8.

Post-marketing data.

Adverse events first identified as ADRs during post-marketing experience with risperidone and/ or paliperidone are included in Table 8. The frequencies are provided according to the following convention: very common ≥ 1/10; common ≥ 1/100 to < 1/10; uncommon ≥ 1/1,000 to < 1/100; rare ≥ 1/10,000 to < 1/1,000; very rare < 1/10,000, including isolated reports; not known: cannot be estimated from the available data.
In Table 9, ADRs are presented by frequency category based on spontaneous reporting rate.

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

For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

Symptoms.

In general, reported signs and symptoms have been those resulting from an exaggeration of the drug's known pharmacological effects. These include drowsiness and sedation, tachycardia and hypotension, and extrapyramidal symptoms.
In overdose, QT prolongation and convulsions have been reported. Torsade de pointes has been reported in association with combined overdose of oral risperidone and paroxetine.
In case of acute overdosage, the possibility of multiple drug involvement should be considered.

Treatment.

Establish and maintain a clear airway, and ensure adequate oxygenation and ventilation. Administration of activated charcoal together with a laxative should be considered. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias.
There is no specific antidote to risperidone. Therefore appropriate supportive measures should be instituted. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids and/or sympathomimetic agents. In case of severe extrapyramidal symptoms, anticholinergic medication should be administered. Close medical supervision and monitoring should continue until the patient recovers.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Risperidone, a novel antipsychotic belonging to a new class of antipsychotic agents, the benzisoxazole-derivatives. It is a selective monoaminergic antagonist with a high affinity for serotoninergic 5-HT2 and dopaminergic D2 receptors. Risperidone binds also to α1-adrenergic receptors, and with lower affinity, to H1-histaminergic and α2-adrenergic receptors. Risperidone has no affinity for cholinergic receptors.
The antipsychotic activity of risperidone is considered to be attributable to both risperidone and its active metabolite 9-hydroxy risperidone.
Central dopamine D2 receptor antagonism is considered to be the mechanism of action by which conventional neuroleptics improve the positive symptoms of schizophrenia, but also induce extrapyramidal symptoms and release of prolactin.
Although risperidone antagonises dopamine D2 receptors and causes release of prolactin, it is less potent than classical neuroleptics for depression of motor activity and for induction of catalepsy in animals.
Balanced central serotonin and dopamine antagonism may reduce extrapyramidal side effect liability and extend the therapeutic activity to the negative and affective symptoms of schizophrenia.
Due to the α-blocking activity of risperidone, orthostatic hypotension can occur, especially during the initial dose-titration period. This α-blocking activity may also induce nasal mucosal swelling, which is probably related to the observed incidence of rhinitis associated with the use of risperidone.
Antagonism of serotoninergic and histaminergic receptors may induce body weight gain.
In controlled clinical trials, risperidone was found to improve positive symptoms (such as hallucinations, delusions, thought disturbances, hostility, suspiciousness), as well as negative symptoms (such as blunted affect, emotional and social withdrawal, poverty of speech). Risperidone may also alleviate affective symptoms (such as depression, guilt feelings, anxiety) associated with schizophrenia.

Clinical trials.

Schizophrenia. Clinical trials have shown that risperidone is indicated for the treatment of schizophrenia including first episode psychoses, acute schizophrenic exacerbations and chronic schizophrenia. Risperidone is also indicated as long-term therapy for the prevention of relapse (acute exacerbations) in chronic schizophrenic patients.

First episode psychosis.

In a 6-week double-blind, parallel-group, active-controlled study in first admission, newly diagnosed schizophrenic patients (N=183, risperidone=99, haloperidol=84) risperidone (1-8 mg twice daily, mean daily dose 6.1 mg) was as effective as haloperidol (1-8 mg twice daily, mean daily dose 5.6 mg) in controlling psychotic symptoms. The average patient age was 26 years (range 15-50) and 31% of the patients were women. There were statistically significant (p < 0.001) reductions in total PANSS, positive, negative and general psychological symptom scores and in derived BRPS scores in both groups.

Acute exacerbations of chronic schizophrenia.

Two new studies were conducted to establish the efficacy of risperidone in the treatment of acute exacerbations of schizophrenia. A third study investigated the efficacy of risperidone in the treatment of resistant schizophrenics.
The first was a double-blind, parallel-group, active-controlled study of 6 weeks duration in 98 patients (risperidone=48, zuclopenthixol=50), 48% of who were male. The dosage was risperidone 2 mg bid and zuclopenthixol 10 mg bid increasing by one tablet a day until adequate control was achieved. The mean daily dose at end point for risperidone was 8 mg and for zuclopenthixol 38 mg. The median age was in the mid 30's (range 18-65). The overall severity of symptoms during the study was lower for risperidone (p=0.06) and the clinical response (58% vs. 42%; p=0.11) was higher for risperidone.
Two dosages of risperidone 4 mg bid and 8 mg od, were studied in the treatment of acute exacerbations of schizophrenia in chronic or subchronic schizophrenics. The study was a double-blind parallel-group study of 6 weeks duration with a patient population of 211 patients (67% males) aged 18-64 (median 34) years. Efficacy was comparable for the two groups although the trough plasma drug concentrations were lower and concentrations in the first 8 hours post dose were higher (statistically not significant) for the 8 mg od dosage. According to basic pharmacokinetic principles, these findings are expected because a once daily dosage regimen will result in higher peaks and lower troughs than after the same daily dose given over two intakes.
The efficacy and tolerability of risperidone (1-6 mg twice daily) compared to clozapine (50-300 mg twice daily) in treatment resistant schizophrenic patients was studied in an 8-week multicentre, double-blind, parallel-group study in 86 patients (risperidone=43, clozapine=43). In both groups of patients, there was a significant reduction in total PANSS scores in the positive, negative and psychopathology subscales and in the PANSS-derived BPRS scores. The percentage of patients showing a clinical response at endpoint on the PANSS and BPRS (at least 20% reduction in base score) was comparable (68%) for both treatment groups.

Long-term therapy for the prevention of relapse (acute exacerbations) in chronic schizophrenic patients.

The long-term efficacy and tolerability of risperidone was established at the time of marketing in open long-term studies involving 402 patients of whom 282 had been treated with risperidone for 6 months, 221 for 12 months and 30 patients for between 12 and 40 months. Additional long-term data are available from an actively controlled study and a study compared to the patient's usual neuroleptic treatment. The total number of patients treated with risperidone in these two studies was 285, while 306 patients were treated with haloperidol or other neuroleptics. In another three long-term open studies, 758 patients were treated with risperidone.
In a multicentre, double-blind, randomised, parallel-group trial of 1-year duration risperidone (91 patients, 63% male) was compared to haloperidol (99 patients, 59% male) to evaluate the incidence of relapse in chronic schizophrenic patients. The mean daily dose at endpoint was 9 mg risperidone and 8.9 mg haloperidol. The incidence of relapse was 14% for risperidone and 16% for haloperidol and the time to withdrawal from the study because of an adverse event and/or psychotic relapse was longer for risperidone (day 99) compared to day 42 under haloperidol (p=0.023). At endpoint response on the total PANSS score defined as a 50% score reduction versus baseline was observed in 43% of patients receiving risperidone compared to 30% of patients receiving haloperidol (p=0.035). The total BPRS score at endpoint, defined as at least a 50% reduction in baseline score value, was 47% of patients receiving risperidone compared with 34% patients receiving haloperidol (p=0.043). The instrumental role functioning on the Quality of Life Scale scored significantly better under risperidone (p=0.037). The Clinical Global Impression scores showed no significant difference between the two treatment groups. The results of the trial show that risperidone is as efficacious and safe as haloperidol.
Mania in bipolar disorder.

Monotherapy.

The efficacy of risperidone in the treatment of acute mania was established in three double-blind placebo-controlled studies of 3-week duration in patients who met the DSM-IV criteria for bipolar 1 disorder. These studies included patients with or without psychotic features.
The primary efficacy variable in all studies was the Young Mania Rating Scale (YMRS), an 11-item clinician rated scale traditionally used to assess the degree of manic symptomatology (irritability, disruptive/aggressive behaviour, sleep, elevated mood, speech, increased activity, sexual interest, language/thought disorder, thought content, appearance and insight). Secondary efficacy measures included the Clinical Global Impression Scale of Severity and the Global Assessment Scale. In order to capture treatment effects on depressive symptomatology the Montgomery Asberg Depression Scale or the Hamiliton Rating Scale for Depression was used. Psychosis and general psychopathology were measured using the PANSS or BPRS.
All studies used a flexible once daily dose of risperidone in the range of 1-6 mg/day.
In studies 1 and 2 (n=246 and n=286) risperidone was superior to placebo in the reduction of YMRS total score regardless of baseline disease severity and the presence or absence of psychosis at baseline. Significant treatment differences were evident at week 1 and increased during the 3-week treatment period. Risperidone also showed significant differences in secondary efficacy measures.
Study 3 (n=438) also included an active comparator arm using haloperidol. Risperidone was superior to placebo and similar to haloperidol in its effects on both primary and secondary efficacy measures. The maintenance phase of this study involved a 9-week double blind treatment of risperidone or haloperidol or a 9-week open-label treatment on risperidone. Efficacy was maintained throughout the treatment period, although change from baseline in the MADRS was not as clearly maintained.
In open-label extension studies, change from baseline in total YMRS showed continued improvement.

Adjunctive therapy.

The efficacy of risperidone in the treatment of acute mania in combination with mood stabilisers was demonstrated in two 3-week double-blind studies in patients who met the DSM-IV criteria for bipolar 1 disorder.
One study (n=148) was in patients on lithium or valproate therapy with inadequately controlled symptoms randomised to receive risperidone, haloperidol or placebo in combination with their original therapy. Risperidone combined with lithium or valproate was superior to lithium or valproate alone in the reduction of YMRS total score.
The second study (n=142) was in patients on lithium, valproate or carbamazepine therapy with inadequately controlled symptoms randomised to receive risperidone or placebo in combination with their original therapy. A failure to demonstrate a significant advantage appeared to be due to carbamazepine induction of the metabolism of risperidone reducing the active antipsychotic fraction plasma concentration. When the carbamazepine group was excluded in post hoc analysis, risperidone combined with lithium or valproate was superior to lithium or valproate alone in the reduction of YMRS total score.
Behavioural distrubances in dementia. The efficacy of risperidone in the treatment of behavioural disturbances, such as aggressiveness (verbal outburst, physical violence), activity disturbances (agitation, wandering) and psychotic symptoms (paranoid and delusional ideation, hallucinations), in patients with dementia was demonstrated in two double-blind, placebo-controlled clinical studies. One study was a randomised, parallel-group, multicentre design involving 617 patients that examined the efficacy of three doses of risperidone (0.5, 1 or 2 mg/day) over a 12-week period. The other involved 344 patients assigned to either placebo, risperidone or haloperidol for a 12-week period. The two studies were pooled and the results from this analysis are presented in Table 10. The primary outcome parameter was the percentage of responders, defined as a reduction at endpoint of at least 30% on the Behave-AD total score. Several important aspects of efficacy were assessed by the secondary endpoints that examined the effect on individual disturbances (e.g. aggressiveness). Aggressive symptoms were the major problem at entry in the two trials.
The rate of discontinuation from the pooled studies was similar for patients receiving placebo (30.2%), risperidone (33.5%) and haloperidol (29.6%). In the combined analysis, risperidone, at a daily dose above 0.75 mg, effectively reduces the severity (measured by means of Behave-AD) and frequency (measured by CMAI) of aggressiveness symptoms in this patient population. Reductions in Behave-AD aggressiveness scores and on each of the aggressive clusters of the CMAI were significantly greater with risperidone (doses above 0.75 mg/day) than placebo at endpoint in both studies and in the combined analysis. Reductions in CMAI total aggressive scores declined throughout the studies in the risperidone patients but changed minimally after Week 2 in patients receiving haloperidol or placebo.
Conduct disorder.

Children and adolescents.

Two double-blind placebo-controlled randomised parallel-group studies of 6 weeks duration were conducted in children and adolescents 5 to 12 years with borderline intellectual functioning or mild to moderate mental retardation. The studies, of identical design, involved a combined population of 120 patients receiving placebo and 105 patients receiving risperidone at 0.02-0.06 mg/kg/day. Twenty six per cent of the patients receiving risperidone had conduct disorder with attention deficit hyperactivity disorder (ADHD), 39% had oppositional defiant disorder with ADHD and 6% had disruptive behavioural disorder with ADHD. A decrease in the primary efficacy parameter of the Conduct Problem Subscale of the Nisonger Child Behaviour Rating Form (N-CBRF) of -6.5 ± 1.02 was observed in placebo-treated patients compared to -15.6 ± 1.04 for risperidone. The improvement for risperidone compared to placebo was statistically significant (p < 0.001). A statistically significant difference between risperidone and placebo was apparent at Week 1 and continued throughout treatment. A sub-analysis of patients with ADHD indicated risperidone was effective for the primary and secondary efficacy parameters whether psychostimulants were or were not being taken.
A 6-month, double-blind, placebo-controlled, relapse-prevention study in children and adolescents with disruptive behaviour disorders who responded to 12 weeks of treatment with risperidone (6 weeks of open-label treatment followed by 6 weeks of single-blind treatment) was performed. The subjects enrolled had either average IQ, borderline intellectual functioning, or mild mental retardation/learning disorder; subjects with moderate or severe mental retardation/learning disorder were excluded. The study consisted of 3 phases: a 6-week, open-label acute treatment phase with risperidone (phase 1); a 6-week single-blind continuation phase with risperidone (phase 2); and a 6-month, double-blind, withdrawal phase during which subjects were randomly assigned to treatment with placebo or continued risperidone (phase 3). The total study duration was 36 weeks. This relapse-prevention study used a flexible dose range of risperidone based on body weight categories, with 0.25 to 0.75 mg/day administered to subjects < 50 kg and 0.5 to 1.5 mg/day given to subjects ≥ 50 kg. A total of 306 children and adolescents aged 5 to 17 years with disruptive behaviour disorders and an IQ of at least 55 (63% had normal intellectual functioning) were maintained on risperidone therapy or switched to placebo. The primary efficacy parameter was the time from initiation of double-blind treatment to discontinuation resulting from relapse, based on predefined criteria. Results of the study demonstrated that children and adolescents with disruptive behaviour disorders who continued treatment with risperidone experienced relapse significantly later than subjects who were switched to placebo (p < 0.001). The time to when 25% of subjects relapsed was 91 days in the risperidone group compared with 32 days in the placebo group. Safety results of this study demonstrated that the overall adverse event rate was similar to that seen in the acute disruptive behaviour disorders trials and consistent with the adverse event profile seen in adults with psychotic disorders.

Adults.

A double-blind placebo-controlled, randomised parallel-group study was conducted in adults with borderline intellectual function or mild to moderate mental retardation and conduct or other disruptive behaviour disorders. Thirty nine patients received 1.0-4.0 mg/day of risperidone (modal dose 1.64 mg/day) and 38 patients received placebo for 4 weeks. The change in the Aberrant Behaviour Checklist (ABC) score from baseline to endpoint, the primary efficacy parameter, was -27.3 in the risperidone group compared to -14.9 in the placebo group (p < 0.05). Significantly greater reduction in the ABC total score was noted at week 2 in patients receiving risperidone and was maintained throughout the double-blind period.

Long-term studies.

Three open-label long-term studies, two in children and adolescents and one in adults, were conducted. One study in children and adolescents (N=107) of 48 weeks duration was an extension of a primary clinical study. A statistically significant improvement from the double-blind (p < 0.001) and open-label (p < 0.01) baselines was observed. In the other long-term study in children (N=319) of 52 weeks duration the mean change in N-CBRF from baseline to endpoint was highly statistically significant. (p < 0.001). The mean modal dose for the long-term studies in children was 1.67 ± 0.039 mg/day (range 0.2 to 4.0). The one-year long-term study in adults (N=58) was a continuation of the 6-week double-blind study. The mean ABC score at open-label baseline was 31.2. At endpoint the mean decrease from OL baseline was 9.0 (p=0.012). The overall mean modal dose in adults during long-term treatment was 1.81 ± 0.125 mg.day (range 1 to 4 mg.day). The safety profile of risperidone in children, adolescents and adults with conduct disorder and other disruptive disorders is comparable to that seen in other populations (e.g. schizophrenia).
The growth observed in children and adolescents after one year of treatment with risperidone was 6.9 cm. On the basis of growth curves in children of the same age, growth is as expected.
Autism. The efficacy of risperidone in the treatment of behavioural disorders associated with autism was established in two 8-week, double-blind, parallel-group, placebo-controlled trials in patients who met the DSM IV criteria for autism disorder.
Efficacy was evaluated using two primary assessment scales: the Aberrant Behaviour Checklist (ABC) and the Clinical Global Impression-Change (CGI-C) scale. The ABC scale, which was completed by the parent or caregiver, is a validated instrument composed of five subscales to assess irritability, lethargy/social withdrawal, stereotypic behaviour, hyperactivity/noncompliance and inappropriate speech. The CGI-C scale, which was completed by a clinician, reflects the impression of a skilled observer, fully familiar with the symptoms of autism, about the overall clinical disposition of the patient.
In Study 1 (N=101) patients aged 5-17 years received twice daily doses of placebo or risperidone 0.5-3.5 mg/day on a weight-adjusted basis. Risperidone titrated to clinical response (mean modal dose of 1.9 mg/day, equivalent to 0.06 mg/kg/day) significantly improved scores on the ABC Irritability subscale and on the CGI-C scale compared to placebo. Risperidone was also superior to placebo in improving scores on the ABC subscales of lethargy/social withdrawal, stereotypic behaviour, hyperactivity/noncompliance and inappropriate speech. (See Table 11.)
Following completion of Study 1, 63 patients entered an open-label extension for up to 4 additional months. Thirty nine patients who were clinically stable and who showed a positive response to risperidone after 6 months were then randomised to receive risperidone or placebo during an 8-week, double blind withdrawal period. The relapse rate was 11/16 and 2/16 in placebo and risperidone treated patients respectively (Odds Ratio 15.4, 95% confidence limits 2.50, 95.05).
In Study 2 (N=55) patients aged 5-12 years received once or twice daily doses of placebo or risperidone 0.02-0.06 mg/kg/day. Risperidone titrated to clinical response (mean modal dose of 1.4 mg/day equivalent to 0.04 mg/kg/day) significantly improved scores on the ABC Irritability subscale compared to placebo. Risperidone was also superior to placebo in improving scores on the CGI-C scale and on the ABC subscales of lethargy/ social withdrawal and hyperactivity/noncompliance. (See Table 12.)
As few autistic children with an IQ > 84 are seen, there is limited clinical experience with risperidone in such children. Experience in autistic adolescents is also limited.

5.2 Pharmacokinetic Properties

Absorption.

Risperidone is well absorbed after oral administration, reaching peak plasma concentrations within 1 to 2 hours. The absorption is not affected by food and thus risperidone can be given with or without meals.

Distribution.

Steady state of risperidone is reached within 1 day in most patients. Steady state of 9-hydroxyrisperidone is reached within 4-5 days of dosing. Risperidone plasma concentrations are dose proportional within the therapeutic dose-range. Risperidone is rapidly distributed. The volume of distribution is 1-2 L/kg. In plasma, risperidone is bound to albumin and α 1-acid glycoprotein. The plasma protein binding of risperidone is 88% and that of 9-hydroxyrisperidone is 77%. The binding of either product was not affected by the presence of the other.

Metabolism.

Risperidone is partly metabolised by CYP 2D6 to 9-hydroxy-risperidone which has two enantiomers with a similar pharmacological activity as risperidone. Another metabolic pathway is oxidative N-dealkylation. 7-hydroxyrisperidone and the metabolite formed by N-dealkylation do not contribute to the activity of risperidone.
In vitro data suggest that drugs that inhibit the metabolism of risperidone to 9-hydroxyrisperidone by inhibition of CYP 2D6 would increase the plasma concentration of risperidone and lower the plasma concentration of 9-hydroxyrisperidone (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Drugs metabolised by other P450 isoenzymes (1A1, 1A2, 2C9, MP, 3A4) are only weak inhibitors of risperidone metabolism in vitro. Although in vitro studies suggest that risperidone can inhibit CYP 2D6, substantial inhibition of the clearance of drugs metabolised by this enzymatic pathway would not be expected at therapeutic risperidone plasma concentrations. However, clinical data to confirm this expectation are not available.
Risperidone and 9-hydroxyrisperidone form the pharmacologically active fraction that is similar in extensive and poor metabolisers. Clinical studies do not suggest that poor and extensive metabolisers have different rates of adverse effects. No comparison of effectiveness in the two groups has been made.

Excretion.

Risperidone has an elimination half-life of about 3 hours in extensive metabolisers and 17 hours in poor metabolisers. The elimination half-life of 9-hydroxyrisperidone and the active fraction is 24 hours. One week after administration, 70% of the dose is excreted in the urine and 14% in the faeces. In urine, risperidone plus 9-hydroxyrisperidone represents 35-45% of the dose.
A single-dose study showed higher active plasma concentrations and a slower elimination of risperidone by 30% in the elderly and 60% in patients with renal insufficiency. Risperidone plasma concentrations were normal in patients with liver insufficiency, but the unbound fraction of risperidone was somewhat increased by about 35% due to diminished concentration of both alpha1-acid glycoprotein and albumin.
The pharmacokinetics of risperidone, 9-hydroxy-risperidone and the active antipsychotic fraction in children is similar to that in adults.

5.3 Preclinical Safety Data

Genotoxicity.

No evidence of genotoxicity was observed in assays for DNA damage, gene mutations or chromosomal damage.

Carcinogenicity.

Risperidone was administered in the diet to Swiss albino mice for 18 months and to Wistar rats for 25 months at doses equivalent to 0.3, 1.3 and 5 times the maximum human dose of 10 mg/day (mice) or 0.6, 2.5 and 10 times the maximum human dose (rats) on a mg/m2 basis. There were statistically significant increases in pituitary gland adenomas in female mice and endocrine pancreas adenomas in male rats at the two highest dose levels, and in mammary gland adenocarcinomas at all dose levels in female mice and female rats and at the highest dose in male rats.
Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum prolactin levels were not measured during the risperidone carcinogenicity studies; however, measurements during subchronic toxicity studies showed that risperidone elevated serum prolactin levels 5- to 6-fold in mice and rats at the same doses used in the carcinogenicity studies. An increase in mammary, pituitary and endocrine pancreas neoplasms has been found in rodents after chronic administration of other dopamine receptor antagonists and is considered to be prolactin mediated.
The relevance for human risk of the findings of prolactin-mediated endocrine tumours in rodents is unknown. In controlled clinical trials, risperidone elevated serum prolactin levels more than haloperidol, although to date neither clinical studies nor epidemiological studies have shown an association between chronic administration of these drugs and mammary tumorigenesis. However, since tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, risperidone should be used cautiously in patients with previously detected breast cancer or in patients with pituitary tumours. Possible manifestations associated with elevated prolactin levels are amenorrhoea, galactorrhoea and menorrhagia (see Section 4.8 Adverse Effects (Undesirable Effects)).

6 Pharmaceutical Particulars

6.1 List of Excipients

Lactose monohydrate, pregelatinised starch, microcrystalline cellulose, sodium lauryl sulphate, colloidal anhydrous silica and magnesium stearate. In addition the 0.5 mg tablet contains Opadry II 31G56729, brown (PI 12611), 1 mg tablet contains Opadry 20H58983 white (PI 11547), the 2 mg tablet contains Opadry II 31 G53291 orange (PI 12676); the 3 mg tablet contains Opadry II 31G52408 yellow (PI 12675) and the 4 mg tablet contains Opadry II 31G51195 green (PI 12677).

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 25°C. Protect from light.

6.5 Nature and Contents of Container

The tablets are packed in blister pack containing 10, 20 and 60 tablets for 0.5 mg, 6 and 60 tablets for 1 mg, 60 tablets for 2 mg, 3 mg and 4 mg.

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.

106266-06-2.
Molecular formula: C23H27FN4O2.
Chemical name: 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl] ethyl]-6,7,8,9-tetrahydro-2methyl-4H-pyrido[1,2-a]pyrimidin-4-one.
Molecular weight: 410.49.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes