Consumer medicine information

APO-Risperidone Tablets

Risperidone

BRAND INFORMATION

Brand name

APO-Risperidone

Active ingredient

Risperidone

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APO-Risperidone Tablets.

What is in this leaflet

This leaflet answers some common questions about risperidone. It does not contain all 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 using this medicine against the benefits they expect it will have for you.

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

Keep this leaflet with the medicine.

You may want to read it again.

What this medicine is used for

The name of your medicine is APO-Risperidone. It contains the active ingredient risperidone.

Risperidone belongs to a group of medicines called antipsychotic agents, which improve the symptoms of certain types of mental illness.

Risperidone is used for:

  • symptoms of schizophrenia and other types of related psychoses in adults and adolescents over 15 years of age. These are conditions related to thoughts, feelings and/ or actions
  • short term treatment of acute mania associated with Bipolar 1 Disorder – symptoms of this condition may include elevated, expansive or irritable mood, inflated self-esteem, decreased need for sleep, pressured speech, racing thoughts, distractibility or poor judgment including disruptive or aggressive behaviours
  • short term treatment of behavioural problems in patients with a decline in mental ability (dementia) – these problems include aggression through words or actions, morbid suspiciousness, agitation or wandering
  • conduct and other disruptive disorders such as aggression, impulsiveness and self-injury in adults, adolescents and children aged over 5 years old who are intellectually disabled
  • certain behaviours seen in children and adolescents with autism

How it works

Risperidone helps to correct a chemical imbalance in the brain associated with the above conditions.

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

Your doctor may have prescribed this medicine for another reason.

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

There is no evidence this medicine is addictive.

Before you take this medicine

When you must not use it

Do not use this medicine if you have an allergy to:

  • risperidone
  • any of the ingredients listed at the end of this leaflet

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue, throat or other parts of the body
  • rash, itching or hives on the skin

Do not take this medicine if you are pregnant.

Do not take risperidone whilst pregnant until you and your doctor have discussed the risks and benefits involved.

Newborn babies of mother taking risperidone in their last trimester may be at risk of having difficulty feeding or breathing, shaking, muscle stiffness and/or weakness, sleepiness or agitation.

Do not breastfeed if you are taking this medicine.

Risperidone passes into breast milk and there is a possibility that your baby may be affected.

Do not use this medicine after the expiry date printed on the pack or the packaging is torn or shows signs of tampering.

If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

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

  • heart or blood vessel problems, including problems with blood pressure control or heart rhythm
  • disease of the blood vessels of the brain including stroke
  • unusual excessive sweating or diarrhoea, dehydration or problems with your body temperature regulation
  • prone to dizziness when standing up from a lying or sitting position
  • kidney or liver problems
  • Parkinson's disease
  • dementia or Lewy Body dementia
  • epilepsy or seizures
  • restlessness or difficulty sitting still
  • continuous and/or painful erections (called 'priapism')
  • intraoperative iris syndrome (a complication that may occur during cataract extraction)
  • suicidal thoughts
  • low volume of blood in your body (hypovolaemia) - seen by cold hands and feet, light headedness, infrequent urination, increased heart rate, and weakness
  • breast cancer
  • disease of the pituitary gland
  • diabetes, high or low blood sugar (you may need to monitor your blood glucose levels closely)
  • tardive dyskinesia (a reaction to some medicines with uncontrollable twitching or jerking movements of the tongue, face, mouth, jaw, arms and legs)
  • neuroleptic malignant syndrome (a serious reaction to some medicines with a sudden increase in body temperature, extremely high blood pressure and severe convulsions)
  • blood clots
  • low white blood cell count
  • low blood potassium levels (hypokalaemia)

Tell your doctor if you are pregnant or plan to become pregnant or are breastfeeding.

Do not take risperidone until you and your doctor have discussed the risks and benefits involved.

Tell your doctor if you are planning to have surgery (especially of the eye), dental treatment or an anaesthetic.

If you are having eye surgery, your doctor will need to assess whether you are at risk of a surgical complication (called 'Intraoperative Floppy Iris Syndrome).

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

Risperidone may make you sweat less, causing your body to overheat.

If you have not told your doctor about any of the above, tell them before you take this medicine.

Taking other medicines

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

Some medicines may interact with risperidone. These include:

  • sleeping tablets, tranquillisers, pain-killers or antihistamines which may make you drowsy
  • medicines to treat Parkinson's disease or a tremor
  • medicines that increase the activity of the central nervous system (e.g. psychostimulants such as methylphenidate)
  • medicines to treat epilepsy such as carbamazepine (also used to treat trigeminal neuralgia)
  • medicines to treat depression, panic disorder, anxiety, obsessive-compulsive disorder or premenstrual dysphoric disorder, such as tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) e.g. fluoxetine and paroxetine
  • other medicines to treat mental illness or psychotic conditions
  • diuretics, used to treat high blood pressure or swelling caused by the build-up of too much fluid e.g. frusemide – this combination may increase the risk of side effects or death in elderly people
  • rifampicin, an antibiotic
  • medicines used to treat heart problems or blood pressure
  • medicines to relieve severe nausea and vomiting
  • protease inhibitors, used to treat HIV infection (e.g. tipranavir, ritonavir)
  • cimetidine and ranitidine, used for treating stomach ulcers or excess acid
  • medicines which have an effect on the heart called QT prolongation
  • medicines which affect the liver so that more of an enzyme called CYP3A4 is produced
  • itraconazole and ketoconazole, medicines used to treat fungal infections.

These medicines may be affected by risperidone or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

Other medicines not listed above may also interact with risperidone.

How to take this medicine

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

They may differ to the information contained in this leaflet.

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

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.

Standing up slowly, especially when you get up from bed or chairs, will help your body get used to the change in position and blood pressure.

These symptoms should go away after a few days. Tell your doctor if they continue or worry you.

How much to take

Your doctor or pharmacist will tell you how much of this medicine you should take. This will depend on your condition and whether you are taking any other medicines.

Risperidone 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 risperidone, 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.

For schizophrenia and related psychoses in adults, adolescents and children aged over 15 years old:

The usual starting dose is one 1 mg tablet taken 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 mg 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 mg twice a day.

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

For schizophrenia and related psychoses in elderly patients:

The usual starting dose is one 0.5 mg tablet taken twice a day.

The dose may be increased by 0.5 mg twice daily to 1 to 2 mg twice a day.

Patients who have impaired kidney or liver function:

The usual starting dose is one 0.5 mg tablet taken twice a day. The dose may be increased by 0.5 mg twice daily to 1 to 2 mg twice a day.

For acute mania in patients with Bipolar 1 Disorder:

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

For behavioural problems in people with dementia:

The usual starting dose is 0.25 mg (half a 0.5 mg tablet) taken 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 dose most suitable for you.

For conduct and other disruptive disorders in adults, adolescents and children aged over 5 years old who are intellectually disabled:

For people who weigh 50 kg or more, the usual starting dose is one 0.5 mg tablet taken 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 (half a 0.5 mg tablet) taken 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 risperidone you need.

Risperidone cannot be recommended for use in children under 5 years or age with disruptive behaviour disorders as there is little experience with the product in this group.

For behavioural disorders associated with autism in children and adolescents:

For people weighing less than 20 kg the usual starting dose is 0.25 mg (half a 0.5 mg tablet) daily. On Day 4, this dose can be increased to 0.5 mg.

For people weighing 20 kg or more the usual starting dose is 0.5 mg (0.5 mg tablet or half a 1 mg tablet) daily. On Day 4, this dose can be increased to 1 mg.

After 14 days, the doctor should check that the tablets are working. The doctor will say whether a higher dose is needed if the tablets do not seem to be have the desired effect. Your doctor will advise you on how much risperidone you need.

In clinical trials, people with autism weighing less than 20 kg did not need more than 1.5 mg/day. People weighing over 20 kg did not need more than 2.5 mg of risperidone a day, and people weighing over 45 kg did not need more than 3.5 mg a day.

If you feel sleepy, then the doctor may split up your daily dose so that you take half of it in the morning and half in the evening.

How to take it

Swallow the tablets whole with a full glass of water.

When to take it

Take your medicine at about the same time each day.

Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

It does not matter if you take this medicine before or after food.

How long to take it

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

This medicine helps to control your condition but does not cure it. It is important to keep taking your medicine even if you feel well.

If you forget to take it

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

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

Do not take a double dose to make up for missed doses.

This may increase the chance of you experiencing side effects.

If you forget to take risperidone for 5 days or more, tell your doctor before starting your medicine again.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints to help you remember.

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 your nearest hospital, if you think that you or anyone else may have taken too much of this medicine. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

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

While you are taking this medicine

Things you must do

If you are about to be started on any new medicine, tell your doctor or pharmacist that you are taking risperidone.

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

If you become pregnant or start breastfeeding while you are taking risperidone, tell your doctor immediately.

If you are going to have surgery, tell the surgeon or anaesthetist that you are using this medicine.

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

Your doctor may occasionally do tests to make sure risperidone is working and to prevent side effects.

If a child is taking risperidone, tell the doctor if they do not seem to be developing normally.

Tell your doctor immediately if you notice any unusual movements of the tongue, or other uncontrolled movements of the tongue, mouth, cheeks or jaw which may progress to the arms and legs.

These are symptoms of a condition called tardive dyskinesia, which may develop in people taking antipsychotic medicines, including risperidone. This condition is more likely to occur during long term treatment with risperidone, especially in elderly women. In very rare cases, this may be permanent. However, if detected early, these symptoms are usually reversible.

Pre-menopausal women should tell their doctor if they do not have a period for more than six months while taking risperidone.

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

Things you must not do

Do not take your medicine to treat any other complaints unless your doctor tells you to.

Do not give this medicine to anyone else, even if they have the same condition as you.

Do not stop taking your medicine, or change the dosage, without first checking with your doctor. Do not use more than the recommended dose.

Do not drink alcohol whilst you are taking this medicine.

Risperidone can increase the effects of alcohol.

Things to be careful of

Be careful when driving or operating machinery until you know how this medicine affects you.

Risperidone may cause dizziness, drowsiness or light-headedness in some people, especially after the first dose. Make sure you know how you react to risperidone before you drive a car, operate machinery, or do anything else that could be dangerous if you feel drowsy or dizzy.

Avoid excessive eating and try to eat a moderate diet.

Risperidone can cause weight gain.

Side effects

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

Your doctor will decide whether any change in your treatment is needed.

This medicine helps most people, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not.

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

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

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

  • problems sleeping, listlessness, excessive sleepiness
  • headache
  • trembling, agitation, anxiety
  • muscle or joint pain, swelling, stiffness or weakness
  • dry mouth; dry, swollen or cracked lips
  • increased or decreased appetite, weight gain
  • excessive saliva or drooling
  • nausea, vomiting
  • indigestion, abdominal pain, diarrhoea, constipation
  • restlessness, swinging, or rocking of legs/feet
  • hair loss, dandruff, rash or other skin disorders; nail infection
  • blocked nose, sinusitis, nose bleeds
  • missed, irregular or heavy periods
  • unusual secretion of breast milk
  • breast swelling (men or women)
  • sexual function disturbances
  • fall in blood pressure, particularly on standing - this may appear as light-headedness or dizziness that passes after a few seconds or after sitting down again

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

  • drowsiness, tiredness, listlessness, difficulty in concentrating, excessive sleepiness, slow reactions
  • difficulty speaking
  • dizziness
  • confusion, nervousness
  • breathing problems, cough
  • flushing
  • ear pain or ringing in the ears (tinnitus)
  • fever or infection of the chest, throat, ears, sinuses, tonsils or urinary tract
  • an increased tendency to get infections or sore throats
  • problems swallowing
  • some loss of bladder or bowel control
  • high blood sugar, symptoms of which may include the need to urinate more often or feeling thirsty all the time
  • increased blood cholesterol
  • uncontrollable movements of the tongue, face, mouth and jaws, arms legs or trunk.
  • swelling of the ankles, feet or legs due to fluid build up
  • uncoordinated movements, feeling unbalanced (vertigo)
  • yellow skin or eyes, dark coloured urine (signs of liver problems)
  • eye problems (dryness, swelling, itching, infection, problems seeing, blurred vision)

The above list includes serious side effects. You may need medical attention.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, or other parts of the body; rash, itching or hives on the skin (signs of an allergic reaction)
  • significant changes in body temperature (e.g. very high temperature or chills)
  • high fever, stiff muscles, fast breathing, abnormal sweating or decreased mental alertness (signs of neuroleptic malignant syndrome)
  • fast or slow or irregular or thumping heart beat
  • chest pain
  • loss of consciousness or fainting
  • sudden weakness or numbness of the face, arms or legs, especially on one side, or slurred speech (symptoms of stroke or mini-stroke)
  • in men, a prolonged and painful erection (known as priapism)

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

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

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

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

Storage and disposal

Storage

Keep your tablets in the pack until it is time to take them.

If you take the tablets out of the pack, they may not keep well.

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

Do not store your medicine, or any other medicine, in the bathroom or near a sink. Do not leave it on a window sill or in the car.

Heat and dampness can destroy some medicines.

Keep this medicine where children cannot reach it.

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

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

APO-Risperidone 0.5 mg tablets:

Brick red coloured, round, biconvex, film coated tablets plain on both sides

Blister pack of 20 or 60 tablets. AUST R 304250.

APO-Risperidone 1 mg tablets:

White to off white capsule shaped, biconvex, film coated tablets plain on both sides.

Blister pack of 60 tablets. AUST R 304251.

APO-Risperidone 2 mg tablets:

Light orange coloured, capsule shaped, biconvex, film coated tablets plain on both sides.

Blister pack of 60 tablets. AUST R 304252.

APO-Risperidone 3 mg tablets:

Light yellow coloured, oval shaped, biconvex, film coated tablets with break line on one side and plain on other side.

Blister pack of 60 tablets. AUST R 304253.

APO-Risperidone 4 mg tablets:

Green coloured, capsule shaped, biconvex, film coated tablets plain on both sides.

Blister pack of 60 tablets. AUST R 304254.

*Not all strengths, pack types and/or pack sizes may be available.

Ingredients

Each tablet contains 0.5 mg, 1 mg, 2 mg, 3 mg or 4 mg of risperidone as the active ingredient.

It also contains the following inactive ingredients:

  • lactose monohydrate
  • maize starch
  • microcrystalline cellulose
  • hypromellose
  • magnesium stearate
  • colloidal anhydrous silica
  • sodium lauryl sulfate
  • purified talc
  • propylene glycol
  • titanium dioxide (0.5 mg, 2 mg, 3 mg and 4 mg tablets)
  • iron oxide red (0.5 mg tablets)
  • sunset yellow FCF aluminium lake (2 mg tablets)
  • quinoline yellow aluminium lake (3 mg and 4 mg tablets)
  • indigo carmine aluminium lake (4 mg tablets)

This medicine is gluten-free, contains sugars as lactose, tartrazine-free and free of other azo dyes.

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113

Apotex Pty Ltd is the licensee of the registered trademarks APO and APOTEX from the registered proprietor, Apotex Inc.

This leaflet was prepared in August 2019.

Published by MIMS October 2019

BRAND INFORMATION

Brand name

APO-Risperidone

Active ingredient

Risperidone

Schedule

S4

 

1 Name of Medicine

Risperidone.

6.7 Physicochemical Properties

Chemical name: 3-[2-[4-(6-fluoro-1,2- benzisoxazol-3-yl)-1-piperidinyl]ethyl]- 6,7,8,9-tetrahydro-2-methyl- 4H-pyrido[1,2-a]pyrimidin-4-one.
Molecular Formula: C23H27FN4O2.
Molecular Weight: 410.5.

Chemical structure.


CAS number.

106266-06-2.

2 Qualitative and Quantitative Composition

Each tablet contains 0.5 mg, 1 mg, 2 mg, 3 mg or 4 mg of risperidone as the active ingredient.

Excipient with known effect.

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

3 Pharmaceutical Form

0.5 mg tablets.

Brick red coloured, round, biconvex, film-coated tablets plain on both sides. As the 0.5 mg risperidone tablets do not have a break line, alternative risperidone products should be used if a 0.25 mg dose is required. The 0.5 mg tablets must not be broken in half to give a 0.25 mg dose.

1 mg tablets.

White to off white, capsule shaped, biconvex film-coated tablets, plain on both sides.

2 mg tablets.

Light orange coloured, capsule shaped, biconvex film-coated tablets plain on both sides.

3 mg tablets.

Light yellow coloured, oval shaped, biconvex film-coated tablets with a break line on one side and plain on other side.

4 mg tablets.

Green coloured, capsule shaped, biconvex film-coated tablet plain on both sides.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Risperidone is a novel antipsychotic belonging to a new class of antipsychotic agents, the benzisoxazole derivatives.

Mechanism of action.

Risperidone is a selective monoaminergic antagonist with a high affinity for serotoninergic 5HT2-receptors 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 bodyweight 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, actively 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 to 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 BPRS 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, actively 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 postdose 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, randomized, 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 risperidone 9 mg risperidone and haloperidol 8.9 mg. 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% of 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 Hamilton 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 risperidone plus 9-hydroxy-risperidone 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 disturbances 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 randomized, 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 the following table. 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. (See Table 8.)
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 the Behave-AD) and frequency (measured by the 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. 26% 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 subanalysis 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 bodyweight 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. 39 patients received risperidone 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 1-4 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 to 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 9).
Following completion of study 1, 63 patients entered an open label extension for up to 4 additional months. 39 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 10).
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

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.
Risperidone is partly metabolised by CYP2D6 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-hydroxy-risperidone by inhibition of CYP2D6 would increase the plasma concentration of risperidone and lower the plasma concentration of 9-hydroxy-risperidone (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 CYP2D6, 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-hydroxy-risperidone form the pharmacologically active risperidone plus 9-hydroxy-risperidone that is similar in extensive and poor metabolisers. Risperidone has an elimination half-life of about 3 hours in extensive metabolisers and 17 hours in 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. The elimination half-life of 9-hydroxy-risperidone and risperidone plus 9-hydroxy-risperidone is 24 hours.
Steady state of risperidone is reached within 1 day in most patients. Steady state of 9-hydroxy-risperidone 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 α1-acid glycoprotein. The plasma protein binding of risperidone is 88% and that of 9-hydroxy-risperidone is 77%. The binding of either product was not affected by the presence of the other.
One week after administration, 70% of the dose is excreted in the urine and 14% in the faeces. In urine, risperidone plus 9-hydroxy-risperidone represents 35 to 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 hepatic insufficiency, but the unbound risperidone was somewhat increased by about 35% due to diminished concentration of both α1-acid glycoprotein and albumin.
The pharmacokinetics of risperidone, 9-hydroxy-risperidone and risperidone plus 9-hydroxy-risperidone 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 medicines 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 medicines 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)).

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of schizophrenia and related psychoses.
Short-term treatment of acute mania associated with bipolar 1 disorder.
Treatment (up to 12 weeks) of psychotic symptoms, or persistent agitation or aggression unresponsive to nonpharmacological approaches in patients with moderate to severe dementia of the Alzheimer type. (see Section 4.2 Dose and Method of Administration, Behavioural disturbances in dementia.)
Treatment of conduct and other disruptive behaviour disorders in children (over 5 years), adolescents and adults with subaverage 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).
Treatment of behavioural disorders associated with autism in children and adolescents (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

4.3 Contraindications

Known hypersensitivity to the medicine 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 medicines 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% (40/1,009) 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 to 100).

Concomitant use with furosemide.

In the risperidone placebo controlled trials in elderly patients with dementia, a higher incidence of mortality was observed in patients treated with furosemide 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 furosemide 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 nonserious 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 postmarketing 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, hypovolemia, 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.

Akathisia.

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

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 postmarketing 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 and 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 rhythmical movements, including those of the tongue and/or face 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 TD 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 medicine treatment is withdrawn.
Antipsychotic medicine 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 medicine, risperidone should be reserved for patients who appear to be obtaining substantial benefit from the medicine. 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, medicine 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.
The 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: the immediate discontinuation of all antipsychotic medicines and other medicines not essential to current therapy; intensive symptomatic treatment and medical monitoring; and 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 medicine treatment after recovery from NMS, the potential reintroduction of this 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. As with other antipsychotic drugs, risperidone should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold.

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 antidiabetic treatment despite discontinuation of the suspect medicine.

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 postmarketing 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.

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 hepatic disease, it is advised to monitor the hepatic 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 are also insufficient nonclinical data to adequately define the safety of risperidone in young children. A 39 day oral toxicity study with juvenile rats noted increased pup mortality, a delay in physical development and, in a small proportion of animals, impairment of auditory startle, at exposures (plasma AUC) less than that at the maximum recommended oral paediatric dose (6 mg/day). The clinical relevance of these findings for children of 5 years and above is uncertain, given the relative immaturity of the rat pups upon commencement of treatment. A 40 week oral toxicity study with juvenile dogs noted delayed sexual maturation, probably secondary to hormonal changes. Long bone growth was slightly reduced at exposures (plasma AUC) of 3-fold and greater those at the maximum dose in children and adolescents (6 mg/day); exposure at the no-effect dose was similar to human exposure.
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

Pharmacodynamic related interactions.

Centrally acting drugs and alcohol.

Given the primary central nervous system effects of risperidone, it should be used with caution in combination with other centrally acting medicines 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 postmarketing with concomitant use of risperidone and antihypertensive treatment.
Tricyclic antidepressants may potentiate the postural hypotensive effect of risperidone.

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-hydroxy-risperidone 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.

Coadministration 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 Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Examples, 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.

Coadministration of risperidone with a strong CYP3A4 and/or P-gp inducer may decrease the plasma concentrations of the risperidone active antipsychotic fraction. 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 microgram/mL, average dose 573 ± 168 mg/day).
Carbamazepine serum concentrations were determined at the beginning and at the end of the period of coadministration of the 2 compounds. The results showed that coadministration 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 microgram/mL.
Carbamazepine has been shown to decrease the plasma levels of the active antipsychotic fraction.

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 medicines 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.

Paediatric population.

Interaction studies have only been performed in adults. The relevance of the results from these studies in paediatric patients is unknown.

Examples.

Examples of drugs that may potentially interact or that were shown not to interact with risperidone are listed below.

Antibacterials.

Erythromycin, a moderate CYP3A4 inhibitor, does not change the pharmacokinetics of risperidone and risperidone and the active antipsychotic fraction.
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 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 reduced the bioavailability of risperidone, but not that of risperidone the active antipsychotic fraction. Therefore, this interaction is unlikely to be of clinical significance.
Risperidone does not show a clinically relevant effect on the pharmacokinetics of valproate.

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 the active antipsychotic fraction.

Aripiprazole, a CYP2D6 and CYP3A4 substrate.

Risperidone tablets did not affect the pharmacokinetics of the sum of aripiprazole and its active metabolite, dehydroaripiprazole.

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.

Digitalis glycosides.

Risperidone does not show a clinically relevant effect on the pharmacokinetics of digoxin.

Diuretics.

Furosemide.

See Section 4.4 Special Warnings and Precautions for Use, Use in the elderly regarding increased mortality in elderly patients with dementia concomitantly receiving furosemide.

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-inf of 1.95 ± 0.78, 1.01 ± 0.25 and 1.15 ± 0.28 for risperidone, 9-hydroxy-risperidone and risperidone plus 9-hydroxy-risperidone, respectively. Relative Cmax increases were 1.90 ± 0.95, 0.95 ± 0.21 and 1.24 ± 0.27. Coadministration of ranitidine produced a relative increase of 1.35 ± 0.32, 1.23 ± 0.44 and 1.25 ± 0.39 in AUC0-inf 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.

Lithium.

Risperidone does not show a clinically relevant effect on the pharmacokinetics of lithium.

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. Coadministration of fluoxetine produced relative increases of 1.63 ± 0.43, 1.54 ± 0.54 and 1.40 ± 0.24 in Cmin, Cmax and AUC0 to 12 hr of risperidone plus 9-hydroxy-risperidone. Administration of paroxetine 20 mg/day for 4 weeks to patients stabilised on risperidone 4 to 8 mg/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 nonsignificant 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 re-evaluate 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 4 to 6 mg/day in the sertraline study and 3 to 6 mg/day in the fluvoxamine study.
Tricyclic antidepressants may increase the plasma concentrations of risperidone but not those of the active antipsychotic fraction.
Amitriptyline does not affect the pharmacokinetics of risperidone or the active antipsychotic fraction.
In patients with schizophrenia receiving risperidone 3 mg twice daily for 28 days, the addition of amitriptyline 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 and risperidone plus 9-hydroxy-risperidone, respectively. These modest increases do not necessitate dose modification.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available on human 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.
A retrospective observational cohort study based on a US claims database compared the risk of congenital malformations for live births among women with and without antipsychotic use during the first trimester of pregnancy. The risk of congenital malformations with risperidone, after adjusting for confounder variables available in the database, was elevated compared to no antipsychotic exposure (relative risk=1.26, 95% CI: 1.02-1.56). No biological mechanism has been identified to explain these findings and teratogenic effects have not been observed in non-clinical studies.
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.

Nonteratogenic class effect.

Neonates exposed to antipsychotics 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 postmarket reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self limited, in other cases neonates have required additional medical treatment or monitoring.
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 short as possible.
Risperidone and 9-hydroxy-risperidone are excreted in human breast milk. Women receiving risperidone should not breastfeed.
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 to 5 times the maximum human dose on a mg/m2 basis.

4.8 Adverse Effects (Undesirable Effects)

Clinical trial data.

The safety of risperidone was evaluated from a clinical trial database consisting of 9803 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 9803 patients, 2687 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 data, 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 6A.
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 6B.
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 6C.

Postmarketing data.

Adverse events first identified as ADRs during postmarketing experience with risperidone and/or paliperidone are included in Table 7. 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.
In Table 7, ADRs are presented by frequency category based on spontaneous reporting rate.
There have also been reports of benign pituitary adenoma that were temporally related, but not necessarily causally related, to risperidone therapy.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems and contact Apotex Medical Information enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.2 Dose and Method of Administration

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. In the case of depot injections, it is recommended that risperidone not be administered until the next scheduled injection.
Alterations in requirements of anti-Parkinson therapy may be required in patients switching to risperidone. These requirements should be evaluated periodically.

Adults.

Risperidone may be given once or twice daily.
Patients, whether acute or chronic, may start with risperidone 1 mg twice a day. The dosage may be increased on the second day to 2 mg twice a day. 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, risperidone 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 twice a day have not been shown to be superior in efficacy to lower doses and may cause extrapyramidal symptoms.
A benzodiazepine may be added to risperidone when additional sedation is required.

Elderly.

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

Renal or hepatic impairment.

A starting dose of 0.5 mg twice a day is recommended. This dosage can be individually adjusted with 0.5 mg twice a day increments to 1 to 2 mg twice a day.
Risperidone 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.

Risperidone 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 increments of 1 mg/day. A dosing range of between 2-6 mg/day is recommended.

Behavioural disturbances in dementia.

A starting dose of 0.25 mg twice a day 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 twice a day for most patients. Some patients, however, may benefit from doses up to 1 mg twice a day.
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.
Once patients have reached their target dose, a once daily dosing regimen can be considered.
As with all symptomatic treatments, the continued use of risperidone must be evaluated and justified on an ongoing basis.

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 ongoing basis.
Experience is lacking in children aged less than 5 years.

Behavioural disorders associated with autism.

Risperidone can be administered once or twice daily.
Risperidone should be administered based on bodyweight. Dosing should begin at 0.25 mg or 0.5 mg/day based upon weight (see Table 7 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. In a clinical study, doses of 0.175 mg/day in children ≥ 45 kg and 0.125 mg/day in children 20 kg to < 45 kg were not effective.
Doses by total mg/day and by mg/kg/day for starting doses and incremental increases are shown in Tables 1 and 2.
For prescribers preferring to dose on a mg/kg/day basis the following guidance is provided.
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.

4.7 Effects on Ability to Drive and Use Machines

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

4.9 Overdose

Symptoms.

In general, reported signs and symptoms have been those resulting from an exaggeration of the medicine's known pharmacological effects. These include drowsiness and sedation, tachycardia and hypotension, and extrapyramidal symptoms.
In overdose, QT prolongation and convulsions have been reported. Torsades 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. Gastric lavage (after intubation, if the patient is unconscious) and 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 the case of severe extrapyramidal symptoms, anticholinergic medication should be administered. Close medical supervision and monitoring should continue until the patient recovers.
As strategies for the management of overdose are continually evolving, it is advisable to contact the Poisons Information Centre to determine the latest recommendations for the management of an overdose.
For information on the management of overdose, contact the Poisons Information Centre on 131 126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Lactose monohydrate, maize starch, microcrystalline cellulose, hypromellose, magnesium stearate, colloidal anhydrous silica, sodium lauryl sulfate, purified talc, propylene glycol, iron oxide red [0.5 mg tablet], sunset yellow FCF aluminium lake [2 mg tablet], indigo carmine aluminium lake [4 mg tablet], quinoline yellow aluminium lake [3 mg tablet and 4 mg tablet], titanium dioxide [0.5 mg tablet, 2 mg tablet, 3 mg tablet and 4 mg tablet].

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

Blister packs: Store below 25°C.

6.5 Nature and Contents of Container

0.5 mg tablets.

Blister Packs (PVC /PVDC /Aluminium foil) of 20 or 60 tablets (AUST R 304250).

1 mg tablets.

Blister Pack (PVC /PVDC /Aluminium foil) of 60 tablets (AUST R 304251).

2 mg tablets.

Blister Pack (PVC /PVDC /Aluminium foil) of 60 tablets (AUST R 304252).

3 mg tablets.

Blister Pack (PVC /PVDC /Aluminium foil) of 60 tablets (AUST R 304253).

4 mg tablets.

Blister Pack (PVC /PVDC /Aluminium foil) of 60 tablets (AUST R 304254).
Not all strengths and/or pack sizes may be available.

6.6 Special Precautions for Disposal

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

Summary Table of Changes