Risperidone 4mg tablets

United Kingdom - English - eMC (Electronic Medicines Compendium)

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Active ingredient:
Risperidone
Available from:
Relonchem Ltd
ATC code:
N05AX08
INN (International Name):
Risperidone
Dosage:
4mg
Pharmaceutical form:
Tablet
Administration route:
Oral
Class:
No Controlled Drug Status
Prescription type:
Valid as a prescribable product
Product summary:
BNF: 04020100; GTIN: 05055144200606

Risperidone contains the active substance risperidone.

It belongs to a group of medicines called ‘anti-psychotics’.

Risperidone is used to treat the following:

Schizophrenia, where you may see, hear or feel

things that are not there, believe things that are not

true or feel unusually suspicious, or confused.

Mania, where you may feel very excited, elated,

agitated, enthusiastic or hyperactive Mania

occurs in an illness called “bipolar disorder”.

Short-term treatment (up to 6 weeks) of long-term

aggression in people with Alzheimer’s dementia,

who harm themselves or others. Alternative (non-drug)

treatments should have been used previously.

Short-term treatment (up to 6 weeks) of long-term,

aggression in intellectually disabled children (at least

5 years of age) and adolescents with conduct disorder.

Risperidone can help alleviate the symptoms of your

disease and stop your symptoms from coming back.

Do not take Risperidone:

if you are allergic to risperidone or any of the other

ingredients of this medicine (listed in section 6).

If you are not sure if the above applies to you, talk to

your doctor or pharmacist before using Risperidone.

Warnings and precautions

Talk to your doctor or pharmacist before taking

Risperidone if:

You have a heart problem. Examples include an

irregular heart rhythm or if you are prone to low blood

pressure or if you are using medicines for your blood

pressure. Risperidone may cause low blood pressure.

Your dose may need to be adjusted.

You know of any factors which would favour you having

a stroke, such as high blood pressure, cardiovascular

disorder or blood vessel problems in the brain.

You have ever experienced involuntary movements

of the tongue, mouth and face.

You have ever had a condition whose symptoms

include high temperature, muscle stiffness, sweating

or a lowered level of consciousness (also known as

Neuroleptic Malignant Syndrome).

You have Parkinson’s disease or dementia.

You know that you have had low levels of white blood

cells in the past (which may or may not have been

caused by other medicines).

You are diabetic.

You have epilepsy.

You are a man and you have ever had a prolonged or

painful erection.

You have problems controlling your body temperature

or overheating.

You have kidney problems.

You have liver problems.

You have an abnormally high level of the hormone

prolactin in your blood or if you have a possible

prolactin dependent tumour.

You or someone else in your family has a history of

blood clots, as antipsychotics have been associated

with formation of blood clots.

If you are not sure if any of the above applies to you, talk

to your doctor or pharmacist before using Risperidone.

As dangerously low numbers of a certain type of white

blood cell needed to fight infection in your blood has

been seen very rarely with patients taking Risperidone,

your doctor may check your white blood cell counts.

Risperidone may cause you to gain weight. Significant

weight gain may adversely affect your health. Your doctor

should regularly measure your body weight.

As diabetes mellitus or worsening of pre-existing diabetes

mellitus have been seen with patients taking Risperidone,

your doctor should check for signs of high blood sugar.

In patients with pre-existing diabetes mellitus blood

glucose should be monitored regularly.

Risperidone commonly raises levels of a hormone called

“prolactin”. This may cause side effects such as menstrual

disorders or fertility problems in women, breast swelling

in men (see section 4 “Possible side effects”). If such

side effects occur, evaluation of the prolactin level in the

blood is recommended.

During an operation on the eye for cloudiness of the lens

(cataract), the pupil (the black circle in the middle of your

eye) may not increase in size as needed. Also, the iris

(the coloured part of the eye) may become floppy during

surgery and that may lead to eye damage. If you are

planning to have an operation on your eye, make sure

you tell your eye doctor that you are taking this medicine.

Elderly people with dementia

In elderly patients with dementia, there is an increased

risk of stroke. You should not take risperidone if you have

dementia caused by stroke. During treatment with

risperidone you should frequently see your doctor.

Medical treatment should be sought straight away if you

or your care-giver notices a sudden change in your mental

state or sudden weakness or numbness of your face, arms

or legs, especially on one side, or slurred speech, even for

a short period of time. These may be signs of a stroke.

Children and adolescents

Before treatment is started for conduct disorder, other

causes of aggressive behaviour should have been ruled

out.

If during treatment with risperidone tiredness occurs,

a change in the time of administration might improve

attention difficulties.

Before treatment is started your or your child’s body

weight may be measured and it may be regularly

monitored during treatment.

A small and inconclusive study has reported an increase

in height in children who took risperidone, but whether

this is an effect of the drug or due to some other reason

is not known.

Other medicines and Risperidone

Tell your doctor or pharmacist if you are taking, have

recently taken or might take any other medicines.

It is especially important to talk to your doctor or

pharmacist if you are taking any of the following:

Medicines that work on your brain such as to help you

calm down (benzodiazepines) or some medicines for

pain (opiates), medicines for allergy (some

antihistamines), as risperidone may increase the

sedative effect of all of these.

Medicines that may change the electrical activity of

your heart, such as medicines for malaria, heart rhythm

problems, allergies (antihistamines), some

antidepressants or other medicines for mental problems.

Medicines that cause a slow heartbeat.

Medicines that cause low blood potassium (such as

certain diuretics).

Medicines to treat raised blood pressure.

Risperidone can lower blood pressure.

Medicines for Parkinson’s disease (such as levodopa).

Water tablets (diuretics) used for heart problems or

swelling of parts of your body due to a build up of too

much fluid (such as furosemide or chlorothiazide).

Risperidone taken by itself or with furosemide, may

have an increased risk of stroke or death in elderly

people with dementia.

Medicines that increase the activity of the central

nervous system (psychostimulants, such as

methylphenidate).

The following medicines may reduce the effect of

risperidone

Rifampicin (a medicine for treating some infections)

Carbamazepine, phenytoin (medicines for epilepsy)

Phenobarbital

If you start or stop taking such medicines you may need

a different dose of risperidone.

The following medicines may increase the effect of

risperidone

Quinidine (used for certain types of heart disease)

Antidepressants such as paroxetine, fluoxetine,

tricyclic antidepressants

Medicines known as beta blockers (used to treat high

blood pressure)

Phenothiazines (such as medicines used to treat

psychosis or to calm down)

Cimetidine, ranitidine (blockers of the acidity of stomach)

Itraconazole and ketoconazole (medicines for

treating fungal infections)

Certain medicines used in the treatment of HIV/AIDS,

such as ritonavir

Verapamil, a medicine used to treat high blood

pressure and/or abnormal heart rhythm.

Sertraline and fluvoxamine, medicines used to

treat depression and other psychiatric disorders.

If you start or stop taking such medicines you may need

a different dose of risperidone.

If you are not sure if any of the above applies to you, talk to

your doctor or pharmacist before using Risperidone.

Risperidone with food, drink and alcohol

You can take this medicine with or without food. You

should avoid drinking alcohol when taking Risperidone.

Pregnancy, breast-feeding and fertility

If you are pregnant or breast-feeding, think you may

be pregnant or are planning to have a baby, ask your

doctor or pharmacist for advice before taking this

medicine. Your doctor will decide if you can take it.

The following symptoms may occur in newborn babies,

of mothers who have used Risperidone in the last

trimester (last three months of their pregnancy):

shaking, muscle stiffness and/or weakness, sleepiness,

agitation, breathing problems, and difficulty in feeding.

If your baby develops any of these symptoms you may

need to contact your doctor.

Risperidone can raise your levels of a hormone

called “prolactin” that may impact fertility (see

section 4 “Possible side effects”).

Driving and using machines

Dizziness, tiredness, and vision problems may occur

during treatment with Risperidone. Do not drive or use

any tools or machines without talking to your doctor first.

Risperidone contains lactose

The film-coated tablets contain lactose, a type of sugar.

If you have been told by your doctor that you have an

intolerance to some sugars, contact your doctor before

taking this medicine.

Always take this medicine exactly as your doctor has

told you. Check with your doctor or pharmacist if you

are not sure.

The recommended dose is as follows:

For the treatment of schizophrenia

Adults

The usual starting dose is 2 mg per day, this may

be increased to 4 mg per day on the second day.

Your dose may then be adjusted by your doctor

depending on how you respond to the treatment.

Most people feel better with daily doses of 4 to 6 mg.

This total daily dose can be divided into either one or

two doses a day. Your doctor will tell you which is the

best for you.

Elderly people

Your starting dose will normally be 0.5 mg twice a day.

Your dose may then be gradually increased by

your doctor to 1 mg to 2 mg twice a day.

Your doctor will tell you which is the best for you.

For the treatment of mania

Adults

Your starting dose will usually be 2 mg once a day.

Your dose may then be gradually adjusted by your

doctor depending on how you respond to the

treatment.

Most people feel better with doses of 1 to 6 mg

once a day.

Elderly people

Your starting dose will usually be 0.5 mg twice a day.

Your dose may then be gradually adjusted by your

doctor to 1 mg to 2 mg twice a day depending on how

much you respond to the treatment.

For the treatment of long-standing aggression in

people with Alzheimer’s dementia

Adults (including elderly people)

Your starting dose will normally be 0.25 mg twice a day.

Your dose may then be gradually adjusted by your

doctor depending on how you respond to the treatment.

Most people feel better with 0.5 mg twice a

day. Some patients may need 1 mg twice a day.

Treatment duration in patients with Alzheimer’s

dementia should be not more than 6 weeks.

Use in children and adolescents

Children and adolescents under 18 years old should not

be treated with Risperidone for schizophrenia or

mania.

For the treatment of conduct disorder the dose will

depend on your child’s weight:

For children who weigh less than 50 kg

The starting dose will normally be 0.25 mg once a day.

The dose may be increased every other day in steps

of 0.25 mg per day.

The usual maintenance dose is 0.25 mg to 0.75 mg

once a day.

For children who weigh 50 kg or more

The starting dose will normally be 0.5 mg once a day.

The dose may be increased every other day in steps

of 0.5 mg per day.

The usual maintenance dose is 0.5 mg to 1.5 mg

once a day.

Treatment duration in patients with conduct disorder should

be not more than 6 weeks. Children under 5 years old

should not be treated with Risperidone for conduct

disorder.

People with kidney or liver problems

Regardless of the disease to be treated, all starting doses

and following doses of risperidone should be halved.

Dose increases should be slower in these patients.

Risperidone should be used with caution in this patient

group.

Method of administration

For oral use.

You should swallow your tablet with a drink of water.

If you take more Risperidone than you should

See a doctor right away. Take the medicine pack with

you.

Risperidone 1 mg, 2 mg, 3 mg and 4 mg Tablets

PACKAGE LEAFLET: INFORMATION FOR THE PATIENT

risperidone

Read all of this leaflet carefully before you start taking this medicine because it contains important

information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their

signs of illness are the same as yours.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed

in this leaflet. See section 4.

What is in this leaflet:

What Risperidone is and what it is used for

What you need to know before you take Risperidone

How to take Risperidone

Possible side effects

How to store Risperidone

6.

Contents of the pack and other information

SZ00000LT000

What Risperidone is and what it is

used for

1

What you need to know before you

take Risperidone

2

How to take Risperidone

3

Continued on next page >>

In case of overdose you may feel sleepy or tired, or

have abnormal body movements, problems standing

and walking, feel dizzy due to low blood pressure, or

have abnormal heart beats or fits.

If you forget to take Risperidone

If you forget to take a dose, take it as soon as you

remember it. However, if it is almost time for your next

dose, skip the missed dose and continue as usual.

If you miss two or more doses, contact your doctor.

Do not take a double dose (two doses at the

same time) to make up for a forgotten dose.

If you stop taking Risperidone

You should not stop taking this medicine unless told

to do so by your doctor. Your symptoms may return.

If your doctor decides to stop this medicine, your dose

may be decreased gradually over a few days.

If you have any further questions on the use of this

medicine, ask your doctor or pharmacist.

Like all medicines, this medicine can cause side

effects, although not everybody gets them.

Tell your doctor immediately if you:

Experience blood clots in the veins, especially in the legs

(symptoms include swelling, pain, and redness in the

leg), which may travel through blood vessels to the lungs

causing chest pain and difficulty breathing. If you notice

any of these symptoms seek medical advice

immediately.

Have dementia and experience a sudden change in

your mental state or sudden weakness or numbness

of your face, arms or legs, especially on one side, or

slurred speech, even for a short period of time.

These may be signs of a stroke

Experience fever, muscle stiffness, sweating or a

lowered level of consciousness (a disorder called

“Neuroleptic Malignant Syndrome”). Immediate

medical treatment may be needed.

Are a man and experience prolonged or painful

erection. This is called priapism. Immediate medical

treatment may be needed.

Experience involuntary rhythmic movements of the

tongue, mouth and face. Withdrawal of risperidone

may be needed.

Experience severe allergic reaction characterised

by fever, swollen mouth, face, lip or tongue, shortness

of breath, itching, skin rash or drop in blood pressure.

The following side effects may happen:

Very Common (may affect more than 1 in 10 people):

Difficulty falling or staying asleep

Parkinsonism. This condition may include: slow or

impaired movement, sensation of stiffness or tightness

of the muscles (making your movements jerky), and

sometimes even a sensation of movement “freezing

up” and then restarting. Other signs of parkinsonism

include a slow shuffling walk, a tremor while at rest,

increased saliva and/or drooling, and a loss of

expression on the face.

Feeling sleepy, or less alert

Headache

Common (may affect up to 1 in 10 people):

Pneumonia, Infection of the chest (bronchitis),

Common cold symptoms, Sinus infection, Urinary

tract infection, Ear infection, Feeling like you have the flu

Raised levels of a hormone called “prolactin” found

in a blood test (which may or may not cause symptoms).

Symptoms of high prolactin occur uncommonly and

may include in men breast swelling, difficulty in getting

or maintaining erections, decreased sexual desire or

other sexual dysfunction. In women they may include

breast discomfort, leakage of milk from the breasts,

missed menstrual periods, or other problems with

your cycle or fertility problems.

Weight gain, Increased appetite, Decreased appetite

Sleep disorder, Irritability, Depression, Anxiety,

Restlessness

Dystonia: This is a condition involving slow or sustained

involuntary contraction of muscles. While it can involve

any part of the body (and may result in abnormal

posture), dystonia often involves muscles of the face,

including abnormal movements of the eyes, mouth,

tongue or jaw.

Dizziness

Dyskinesia: This is a condition involving involuntary

muscle movements, and can include repetitive,

spastic or writhing movements, or twitching.

Tremor (shaking)

Blurry vision, Eye infection or “pink eye”

Rapid heart rate, High blood pressure, Shortness

of breath

Sore throat, Cough, Nosebleeds, Stuffy nose

Abdominal pain, Abdominal discomfort, Vomiting,

Nausea, Constipation, Diarrhea, Indigestion, Dry

mouth, Toothache

Rash, Skin redness

Muscle spasms, Bone or muscle ache, Back pain,

Joint pain

Incontinence (lack of control) of urine

Swelling of the body, arms or legs, Fever, Chest

pain, Weakness, Fatigue (tiredness), Pain

Fall.

Uncommon (may affect up to 1 in 100 people):

Infection of the breathing passages, Bladder infection,

Eye infection, Tonsillitis, Fungal infection of the nails,

Infection of the skin, An infection confined to a single

area of skin or part of the body, Viral infection, Skin

inflammation caused by mites

Decrease in the type of white blood cells that help to

protect you against infection, White blood cell count

decreased, Decrease in platelets (blood cells that help

you stop bleeding), Anaemia, Decrease in red blood

cells, Increase in eosinophils (a type of white blood

cell) in your blood

Allergic reaction

Diabetes or worsening of diabetes, High blood sugar,

Excessive drinking of water

Weight loss, Loss of appetite resulting in malnutrition

and low body weight

Increased cholesterol in your blood

Elated mood (mania), Confusion, Decreased sexual

drive, Nervousness, Nightmares

Tardive dyskinesia (twitching or jerking movements that

you cannot control in your face, tongue, or other parts

of your body). Tell your doctor immediately if you

experience involuntary rhythmic movements of the

tongue, mouth and face. Withdrawal of risperidone

may be needed.

Sudden loss of blood supply to brain (stroke or

“mini” stroke)

Unresponsive to stimuli, Loss of consciousness,

Low level of consciousness

Convulsion (fits), Fainting

A restless urge to move parts of your body, Balance

disorder, Abnormal coordination, Dizziness upon

standing, Disturbance in attention, Problems with

speech, Loss or abnormal sense of taste, Reduced

sensation of skin to pain and touch, A sensation of

tingling, pricking, or numbness skin

Oversensitivity of the eyes to light, Dry eye, Increased

tears, Redness of the eyes

Sensation of spinning (vertigo), Ringing in the ears,

Ear pain

Atrial fibrillation (an abnormal heart rhythm), An

interruption in conduction between the upper and lower

parts of the heart, Abnormal electrical conduction of

the heart, Prolongation of the QT interval from your

heart, Slow heart rate, Abnormal electrical tracing of

the heart (electrocardiogram or ECG), A fluttering or

pounding feeling in your chest (palpitations)

Low blood pressure, Low blood pressure upon standing

(consequently, some people taking risperidone may feel

faint, dizzy, or may pass out when they stand up or sit

up suddenly, Flushing

Pneumonia caused by inhaling food, Lung congestion,

Congestion of breathing passages, Crackly lung sounds,

Wheezing, Voice disorder, Breathing passage disorder

Stomach or intestinal infection, Stool incontinence,

Very hard stool, Difficulty swallowing, Excessive

passing of gas or wind

Hives (or “nettle rash”), Itching, Hair loss, Thickening

of skin, Eczema, Dry skin, Skin discoloration, Acne,

Flaky, itchy scalp or skin, Skin disorder, Skin lesion

An increase of CPK (creatine phosphokinase) in

your blood, an enzyme which is sometimes

released with muscle breakdown

Abnormal posture, Joint stiffness, Joint swelling,

Muscle weakness, Neck pain

Frequent passing of urine,Inability to pass urine,

Pain when passing urine

Erectile dysfunction, Ejaculation disorder

Loss of menstrual periods, Missed menstrual

periods or other problems with your cycle (females),

Development of breasts in men, Leakage of milk from

the breasts, Sexual dysfunction, Breast pain, Breast

discomfort, Vaginal discharge

Swelling of the face, mouth, eyes, or lips

Chills, An increase in body temperature

A change in the way you walk

Feeling thirsty, Feeling unwell, Chest discomfort,

Feeling “out of sorts”, Discomfort

Increased liver transaminases in your blood, Increased

GGT (a liver enzyme called gamma-

glutamyltransferase) in your blood, Increased liver

enzymes in your blood

Procedural pain.

Rare (may affect up to 1 in 1,000 people):

Infection

Inappropriate secretion of a hormone that controls

urine volume

Sugar in the urine, Low blood sugar, High blood

triglycerides (a fat)

Lack of emotion, Inability to reach orgasm

Neuroleptic malignant syndrome (confusion, reduced

or loss of consciousness, high fever, and severe

muscle stiffness)

Blood vessel problems in the brain

Coma due to uncontrolled diabetes

Shaking of the head

Glaucoma (increased pressure within the

eyeball), Problems with movement of your eyes,

Eye rolling, Eyelid margin crusting

Eye problems during cataract surgery. During cataract

surgery, a condition called intraoperative floppy iris

syndrome (IFIS) can happen if you take or have taken

Risperidone. If you need to have cataract surgery, be

sure to tell your eye doctor if you take or have taken

this medicine.

Dangerously low numbers of a certain type of white

blood cell needed to fight infection in your blood

Severe allergic reaction characterised by fever, swollen

mouth, face, lip or tongue, shortness of breath, itching,

skin rash and sometimes drop in blood pressure

Dangerously excessive intake of water

Irregular heart beat

Blood clot in the legs, Blood clot in the lungs

Trouble breathing during sleep (sleep apnea),

Fast, shallow breathing

Inflammation of the pancreas, A blockage in the bowels

Swollen tongue, Chapped lips, Rash on skin

related to drug

Dandruff

Breakdown of muscle fibers and pain in muscles

(rhabdomyolysis)

A delay in menstrual periods, Enlargement of

the glands in your breasts, Breast enlargement,

Discharge from the breasts

Increased insulin (a hormone that controls blood

sugar levels) in your blood

Priapism (a prolonged penile erection that may

require surgical treatment)

Hardening of the skin

Decreased body temperature, Coldness in arms and

legs

Symptoms of drug withdrawal

Yellowing of the skin and the eyes (jaundice).

Very rare (may affect up to 1 in 10,000 people):

Life threatening complications of uncontrolled diabetes.

Serious allergic reaction with swelling that may

involve the throat and lead to difficulty breathing

Lack of bowel muscle movement that causes blockage.

The following side effect has been seen with the use of

another medicine called paliperidone that is very similar

to risperidone, so these can also be expected with

risperidone: Rapid heartbeat upon standing.

Additional side effects in children and adolescents

In general, side effects in children are expected to be

similar to those in adults.

The following side effects were reported more often in

children and adolescents (5 to 17 years) than in adults:

feeling sleepy, or less alert, fatigue (tiredness), headache,

increased appetite, vomiting, common cold symptoms,

nasal congestion, abdominal pain, dizziness, cough,

fever, tremor (shaking), diarrhoea, and incontinence

(lack of control) of urine.

Reporting of side effects

If you get any side effects, talk to your doctor or

pharmacist. This includes any possible side effects not

listed in this leaflet. You can also report side effects

directly via the Yellow Card Scheme (www.mhra.gov.uk/

yellowcard) or search for MHRA Yellow Card in Google

play or Apple App store. By reporting side effects you

can help provide more information on the safety of this

medicine.

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is

stated on the carton, the blister and the tablet container

after EXP. The expiry date refers to the last day of that

month.

This medicine does not require any special storage

conditions.

Do not throw away any medicines via wastewater or

household waste. Ask your pharmacist how to throw

away medicines you no longer use. These measures will

help to protect the environment.

What Risperidone Tablets contain

The active substance is: risperidone.

Each film-coated tablet contains 1, 2, 3 or 4 mg

risperidone.

The other ingredients are:

Core of the tablets:

Lactose monohydrate, cellulose microcrystalline (E460),

maize starch, pregelatinised, silica colloidal anhydrous,

Magnesium stearate (E470b).

Coating of the tablets:

1 mg Film-coated Tablets:

Hypromellose (E464), titanium dioxide (E171),

macrogol (4000).

2 mg Film-coated Tablets:

Hypromellose (E464), titanium dioxide (E171), macrogol

(4000), iron oxide (red and yellow) (E172).

3 mg Film-coated Tablets:

Hypromellose (E464), titanium dioxide (E171), macrogol

(4000), quinoline yellow aluminum lake (E104).

4 mg Film-coated Tablets:

hypromellose (E464), titanium dioxide (E171), indigotine

(E132), quinoline yellow (E104), macrogol (4000).

What Risperidone looks like and contents of the pack

Risperidone 1 mg Film-coated Tablets: White, oval

film-coated tablets with breaking notch and embossed with

“1” on one side.Risperidone 2 mg Film-coated Tablets:

Apricot, oval film-coated tablets with breaking notch and

embossed with “2” on one side.

Risperidone 3 mg Film-coated Tablets:

Yellow, oval film-coated tablets with breaking notch and

embossed with “3” on one side.

Risperidone 4 mg Film-coated Tablets:

Green, oval film-coated tablets with breaking notch and

embossed with “4” on one side.

Risperidone are packed in PVC/COC/PVDC/Alu

blisters or PVC/PE/PVDC/Alu blisters or HDPE tablet

containers with PP cap with desiccant.Pack sizes:

Blister: 6, 10, 20, 30, 50, 60, 100, 100x1 and 250

film- coated tablets

Tablet container: 6, 10, 20, 30, 50, 60, 100 and 250

film- coated tablets

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder

Sandoz Ltd

Frimley Business Park, Frimley, Camberley, Surrey,

GU16 7SR, UK.

Manufacturer

Lek Pharmaceuticals d.d. Verovskova 57, 1526 Ljubljana,

Slovenia Or S.C. Sandoz S.R.L , 7A Livezeni Street,

540472 Targu Mures, Romania Or Salutas Pharma GmbH,

Otto-von-Guericke-Allee 1, 39179 Barleben, GERMANY

Or Lek Pharmaceuticals, Lek Pharmaceuticals, Lek

Lendava, Slovenia Or Lek S.A. ul. Domaniewska 50 C,

02-672 Warszawa, Poland

This leaflet was last revised in 08/2019.

Possible side effects

4

How to store Risperidone

5

Contents of the pack and other

information

6

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT

Risperidone 4 mg Orodispersible Tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each orodispersible tablet contains 4 mg of risperidone.

For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM

Orodispersible tablet

Mottled light pink, flat, round tablets, plain on both sides, rough on borders an

face

4

CLINICAL PARTICULARS

4.1

Therapeutic indications

Risperidone is indicated for the treatment of schizophrenia.

Risperidone is indicated for the treatment of moderate to severe manic episodes

associated with bipolar disorders.

Risperidone is indicated for the short-term treatment (up to 6 weeks) of persistent

aggression in patients with moderate to severe Alzheimer’s dementia unresponsive to

non-pharmacological approaches and when there is a risk of harm to self or others.

Risperidone is indicated for the short-term symptomatic treatment (up to 6 weeks) of

persistent aggression in conduct disorder in children from the age of 5 years and

adolescents with subaverage intellectual functioning or mental retardation diagnosed

according to DSM-IV criteria, in whom the severity of aggressive or other disruptive

behaviours require pharmacologic treatment. Pharmacological treatment should be an

integral part of a more comprehensive treatment programme, including psychosocial

and educational intervention. It is recommended that risperidone be prescribed by a

specialist in child neurology and child and adolescent psychiatry or physicians well

familiar with the treatment of conduct disorder of children and adolescents.

4.2

Posology and method of administration

Posology

Schizophrenia

Adults

Risperidone may be given once daily or twice daily.

Patients should start with 2 mg/day risperidone. The dosage may be increased on the

second day to 4 mg.

Subsequently, the dosage can be maintained unchanged, or further individualised, if

needed. Most patients will benefit from daily doses between 4 and 6 mg. In some

patients, a slower titration phase and a lower starting and maintenance dose may be

appropriate.

Doses above 10 mg/day have not demonstrated superior efficacy to lower doses and

may cause increased incidence of extrapyramidal symptoms. Safety of doses above 16

mg/day has not been evaluated, and are therefore not recommended.

Elderly

A starting dose of 0.5 mg twice daily is recommended. This dosage can be

individually adjusted with 0.5 mg twice daily increments to 1 to 2 mg twice daily.

Paediatric population

Risperidone is not recommended for use in children below age 18 with schizophrenia

due to a lack of data on efficacy.

Manic episodes in bipolar disorder

Adults

Risperidone should be administered on a once daily schedule, starting with 2 mg

risperidone. Dosage adjustments, if indicated, should occur at intervals of not less

than 24 hours and in dosage increments of 1 mg per day. Risperidone can be

administered in flexible doses over a range of 1 to 6 mg per day to optimize each

patient’s level of efficacy and tolerability. Daily doses over 6 mg risperidone have not

been investigated in patients with manic episodes.

As with all symptomatic treatments, the continued use of risperidone must be

evaluated and justified on an ongoing basis.

Elderly

A starting dose of 0.5 mg twice daily is recommended. This dosage can be

individually adjusted with 0.5 mg twice daily increments to 1 to 2 mg twice daily.

Since clinical experience in elderly is limited, caution should be exercised.

Paediatric population

Risperidone is not recommended for use in children below age 18 with bipolar mania

due to a lack of data on efficacy.

Persistent aggression in patients with moderate to severe Alzheimer’s dementia

A starting dose of 0.25 mg twice daily is recommended. This dosage can be

individually adjusted by increments of 0.25 mg twice daily, not more frequently than

every other day, if needed. The optimum dose is 0.5 mg twice daily for most patients.

Some patients, however, may benefit from doses up to 1 mg twice daily.

Risperidone should not be used more than 6 weeks in patients with persistent

aggression in Alzheimer’s dementia. During treatment, patients must be evaluated

frequently and regularly, and the need for continuing treatment reassessed.

Conduct disorder

Children and adolescents from 5 to 18 years of age

For 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. For 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.

Risperidone is not recommended in children less than 5 years of age, as there is no

experience in children less than 5 years of age with this disorder.

Renal and hepatic impairment

Patients with renal impairment have less ability to eliminate the active antipsychotic

fraction than in adults with normal renal function. Patients with impaired hepatic

function have increases in plasma concentration of the free fraction of risperidone.

Irrespective of the indication, starting and consecutive dosing should be halved, and

dose titration should be slower for patients with renal or hepatic impairment.

Risperidone should be used with caution in these groups of patients.

Method of administration

Risperidone is for oral use. Food does not affect the absorption of risperidone.

Do not open the blister until ready to administer. Peel open the blister to expose the

tablet. Do not push the tablet through the foil because it may break. Remove the tablet

from the blister with dry hands.

Immediately place the tablet on the tongue. The tablet will begin disintegrating within

seconds. Water may be used if desired.

Upon discontinuation, gradual withdrawal is advised. Acute withdrawal symptoms,

including nausea, vomiting, sweating, and insomnia have very rarely been described

after abrupt cessation of high doses of antipsychotic medicines (see section 4.8).

Recurrence of psychotic symptoms may also occur, and the emergence of involuntary

movement disorders (such as akathisia, dystonia and dyskinesia) has been reported.

Switching from other antipsychotics.

When medically appropriate, gradual discontinuation of the previous treatment while

risperidone therapy is initiated is recommended. Also, if medically appropriate, when

switching patients from depot antipsychotics, initiate risperidone therapy in place of

the next scheduled injection. The need for continuing existing anti-Parkinson

medicines should be re-evaluated periodically.

4.3

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section

6.1.

4.4

Special warnings and precautions for use

Elderly patients with dementia

Increased mortality in elderly people with dementia

In a meta-analysis of 17 controlled trials of atypical antipsychotics, including

risperidone, elderly patients with dementia treated with atypical antipsychotics have

an increased mortality compared to placebo. In placebo-controlled trials with oral

risperidone in this population, the incidence of mortality was 4.0% for risperidone-

treated patients compared to 3.1% for placebo-treated patients. The odds ratio (95%

exact confidence interval) was 1.21 (0.7, 2.1). The mean age (range) of patients who

died was 86 years (range 67-100). Data from two large observational studies showed

that elderly people with dementia who are treated with conventional antipsychotics

are also at a small increased risk of death compared with those who are not treated.

There are insufficient data to give a firm estimate of the precise magnitude of the risk

and the cause of the increased risk is not known. The extent to which the findings of

increased mortality in observational studies may be attributed to the antipsychotic

drug as opposed to some characteristic(s) of the patients is not clear

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%; mean age 89 years, range 75-97) when compared to patients

treated with risperidone alone (3.1%; mean age 84 years, range 70-96) or furosemide

alone (4.1%; mean age 80 years, range 67-90). The increase in mortality in patients

treated with furosemide plus risperidone was observed in two of the four clinical

trials.

Concomitant use of risperidone with other diuretics (mainly thiazide diuretics used in

low dose) was not associated with similar findings.

No pathophysiological mechanism has been identified to explain this finding, and no

consistent pattern for cause of death observed. Nevertheless, caution should be

exercised and the risks and benefits of this combination or co-treatment with other

potent diuretics should be considered prior to the decision to use.

There was no increased incidence of mortality among patients taking other diuretics

as concomitant treatment with risperidone. 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 (CVAE)

An approximately 3-fold increased risk of cerebrovascular adverse events has been

seen in randomised placebo-controlled clinical trials in the dementia population with

some atypical antipsychotics..The pooled data from six placebo-controlled studies

with risperidone in mainly elderly patients (>65 years of age) with dementia showed

that CVAEs (serious and non-serious, combined) occurred in 3.3% (33/1009) of

patients treated with risperidone and 1.2% (8/712) of patients treated with placebo.

The odds ratio (95% exact confidence interval) was 2.96 (1.34, 7.50). The mechanism

for this increased risk is not known. An increased risk cannot be excluded for other

antipsychotics or other patient populations. Risperidone should be used with caution

in patients with risk factors for stroke.

The risk of CVAEs was significantly higher in patients with mixed or vascular type of

dementia when compared to Alzheimer’s dementia. Therefore, patients with other

types of dementias than Alzheimer’s should not be treated with risperidone.

Physicians are advised to assess the risks and benefits of the use of risperidone in

elderly patients with dementia, taking into account risk predictors for stroke in the

individual patient. Patients/caregivers should be cautioned to immediately report signs

and symptoms of potential CVAEs such as sudden weakness or numbness in the face,

arms or legs, and speech or vision problems. All treatment options should be

considered without delay, including discontinuation of risperidone.

Risperidone should only be used short term for persistent aggression in patients with

moderate to severe Alzheimer’s dementia to supplement non-pharmacological

approaches which have had limited or no efficacy and when there is potential risk of

harm to self or others.

Patients should be reassessed regularly, and the need for continuing treatment

reassessed.

Orthostatic hypotension

Due to the alpha-blocking activity of risperidone, (orthostatic) hypotension can occur,

especially during the initial dose-titration period. Clinically significant hypotension

has been observed post-marketing with concomitant use of risperidone and

antihypertensive treatment. Risperidone should be used with caution in patients with

known cardiovascular disease (e.g., heart failure, myocardial infarction, conduction

abnormalities, dehydration, hypovolemia, or cerebrovascular disease), and the dosage

should be gradually titrated as recommended (see section 4.2). A dose reduction

should be considered if hypotension occurs.

Leukopenia, neutropenia, and agranulocytosis

Events of leucopenia, neutropenia and agranulocytosis have been reported with

antipsychotic agents, including risperidone. Agranulocytosis has been reported very

rarely (< 1/10,000 patients) during post-marketing surveillance.

Patients with a history of a clinically significant low white blood cell count (WBC) or

a drug-induced leukopenia/neutropenia should be monitored during the first few

months of therapy and discontinuation of risperidone should be considered at the first

sign of a 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 10

should discontinue risperidone and have their WBC followed until recovery.

Tardive dyskinesia/extrapyramidal symptoms (TD/EPS)

Medicines with dopamine receptor antagonistic properties have been associated with

the induction of tardive dyskinesia characterised by rhythmical involuntary

movements, predominantly of the tongue and/or face.

The onset of extrapyramidal symptoms is a risk factor for tardive dyskinesia. If signs

and symptoms of tardive dyskinesia appear, the discontinuation of all antipsychotics

should be considered.

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 stimulant

treatment is recommended (see section 4.5).

Neuroleptic malignant syndrome (NMS)

Neuroleptic Malignant Syndrome, characterised by hyperthermia, muscle rigidity,

autonomic instability, altered consciousness and elevated serum creatine

phosphokinase levels has been reported to occur with antipsychotics. Additional signs

may include myoglobinuria (rhabdomyolysis) and acute renal failure. In this event, all

antipsychotics, including risperidone, should be discontinued.

Parkinson’s disease and dementia with Lewy bodies

Physicians should weigh the risks versus the benefits when prescribing antipsychotics,

including risperidone, to patients with Parkinson’s Disease or Dementia with Lewy

Bodies (DLB). Parkinson’s Disease may worsen with risperidone. Both groups may

be at increased risk of Neuroleptic Malignant Syndrome as well as having an

increased sensitivity to antipsychotic medicinal products; these patients were excluded

from clinical trials. Manifestation of this increased sensitivity can include confusion,

obtundation, postural instability with frequent falls, in addition to extrapyramidal

symptoms.

Hyperglycemia and diabetes mellitus

Hyperglycemia , diabetes mellitus, and exacerbation of pre-existing diabetes have

been reported during treatment with risperidone. In some cases, a prior increase in

body weight has been reported which may be a predisposing factor. Association with

ketoacidosis has been reported very rarely and rarely with diabetic coma. Appropriate

clinical monitoring is advisable in accordance with utilised antipsychotic guidelines.

Patients treated with any atypical antipsychotic, including risperidone, should be

monitored for symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia

and weakness) and patients with diabetes mellitus should be monitored regularly for

worsening of glucose control

Weight gain

Significant weight gain has been reported with risperidone use. Weight should be

monitored regularly.

Hyperprolactinaemia

Hyperprolactinaemia is a common side-effect of treatment with risperidone.

Evaluation of the prolactin plasma level is recommended in patients with evidence of

possible prolactin-related side-effects (e.g. gynaecomastia, menstrual disorders,

anovulation, fertility disorder, decreased libido, erectile dysfunction, and

galactorrhea).

Tissue culture studies suggest that cell growth in human breast tumours may be

stimulated by prolactin. Although no clear association with the administration of

antipsychotics has so far been demonstrated in clinical and epidemiological studies,

caution is recommended in patients with relevant medical history. Risperidone should

be used with caution in patients with pre-existing hyperprolactinaemia and in patients

with possible prolactin-dependent tumours.

QT prolongation

QT prolongation has very rarely been reported post-marketing. As with other

antipsychotics, caution should be exercised when risperidone is prescribed in patients

with known cardiovascular disease, family history of QT prolongation, bradycardia,

or electrolyte disturbances (hypokalaemia, hypomagnesaemia), as it may increase the

risk of arrhythmogenic effects, and in concomitant use with medicines known to

prolong the QT interval.

Seizures

Risperidone should be used cautiously in patients with a history of seizures or other

conditions that potentially lower the seizure threshold.

Priapism

Priapism may occur with risperidone treatment due to its alpha-adrenergic blocking

effects.

Body temperature regulation

Disruption of the body’s ability to reduce core body temperature has been attributed to

antipsychotic medicines. 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 treatment 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

medicines or of conditions such as intestinal obstruction, Reye’s syndrome, and brain

tumour.

Renal and hepatic impairment

Patients with renal impairment have less ability to eliminate the active antipsychotic

fraction than adults with normal renal function. Patients with impaired hepatic

function have increases in plasma concentration of the free fraction of risperidone (see

section 4.2).

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.

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).

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.

Paediatric population

Before risperidone is prescribed to a child or adolescent with conduct disorder they

should be fully assessed for physical and social causes of the aggressive behaviour

such as pain or inappropriate environmental demands.

The sedative effect of risperidone should be closely monitored in this population

because of possible consequences on learning ability. A change in the time of

administration of risperidone could improve the impact of the sedation on attention

faculties of children and adolescents.

Risperidone was associated with mean increases in body weight and body mass index

(BMI). Baseline weight measurement prior to treatment and regular weight

monitoring are recommended. Changes in height in the long-term open-label

extension studies were within expected age-appropriate norms. The effect of long-

term risperidone treatment on sexual maturation and height has not been adequately

studied.

Because of the potential effects of prolonged hyperprolactinemia on growth and

sexual maturation in children and adolescents, regular clinical evaluation of

endocrinological status should be considered, including measurements of height,

weight, sexual maturation, monitoring of menstrual functioning, and other potential

prolactin-related effects.

During treatment with risperidone regular examination for extrapyramidal symptoms

and other movement disorders should also be conducted.

For specific posology recommendations in children and adolescents see section 4.2.

4.5

Interaction with other medicinal products and other forms of interaction

Pharmacodynamic-related interactions

Drugs known to prolong the QT

interval

As with other antipsychotics, caution is advised when prescribing risperidone with

medicinal products known to prolong the QT interval, such as antiarrhythmics (e.g.,

quinidine, dysopiramide, procainamide, propafenone, amiodarone, sotalol), tricyclic

antidepressants (i.e., amitriptyline), tetracyclic antidepressants (i.e., maprotiline),

some antihistamines, other antipsychotics, some antimalarials (i.e., quinine and

mefloquine), and with medicines causing electrolyte imbalance (hypokalaemia,

hypomagnesiaemia), bradycardia, or those which inhibit the hepatic metabolism of

risperidone. This list is indicative and not exhaustive.

Centrally-acting drugs and

alcohol

Risperidone should be used with caution in combination with other centrally-acting

substances notably including alcohol, opiates, antihistamines and benzodiazepines due

to the increased risk of sedation.

Levodopa and dopamine

agonists

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

this combination is deemed necessary, particularly in end-stage Parkinson’s disease,

the lowest effective dose of each treatment should be prescribed.

Drugs with hypotensive

effect

Clinically significant hypotension has been observed post-marketing with

concomitant use of risperidone and antihypertensive treatment.

Paliperidone

Concomitant use of oral risperidone with paliperidone is not recommended as

paliperidone is the active metabolite of risperidone and the combination of the two

may lead to additive active antipsychotic fraction exposure.

Psychostimulants

The combined use of psychostimulants (e.g. methylphenidate) with risperidone can

lead to extrapyramidal symptoms upon change of either or both treatments (see

section 4.4).

Pharmacokinetic-related

interactions

Food does not affect the absorption of

risperidone.

Risperidone is mainly metabolized through CYP2D6, and to a lesser extent through

CYP3A4. Both risperidone and

active metabolite 9-hydroxyrisperidone are

substrates of P-glycoprotein (P-gp). Substances that modify

CYP2D6

activity, or

substances strongly inhibiting or inducing CYP3A4 and/or P-gp activity, may

influence the pharmacokinetics of the risperidone active antipsychotic

fraction.

Strong CYP2D6

inhibitors

Co-administration of risperidone with a strong CYP2D6 inhibitor may increase the

plasma concentrations

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, see below). It is expected

that

other

CYP2D6 inhibitors, such as quinidine, may affect the plasma

concentrations of risperidone in a similar way.

When

concomitant paroxetine,

quinidine, or another strong CYP2D6 inhibitor, especially at higher doses, is

initiated

discontinued, the physician should re-evaluate the dosing of

risperidone.

CYP3A4 and/or P-gp

inhibitors

Co-administration of risperidone with a strong CYP3A4 and/or P-gp inhibitor may

substantially elevate

plasma

concentrations of the risperidone active antipsychotic

fraction. When concomitant itraconazole or another

strong

CYP3A4 and/or P-gp

inhibitor is initiated or discontinued, the physician should re-evaluate the dosing of

risperidone.

CYP3A4 and/or P-gp

inducers

Co-administration of risperidone with a strong CYP3A4 and/or P-gp inducer may

decrease the

plasma concentrations

of the risperidone active antipsychotic fraction.

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.

CYP3A4 inducers exert their effect in a time-dependent manner, and may take at

least 2 weeks to reach

maximal

effect after introduction. Conversely, on

discontinuation, CYP3A4 induction may take at least 2 weeks to

decline.

Highly protein-bound

drugs

When risperidone is taken together with highly protein-bound drugs, there is no

clinically relevant displacement

either drug from the plasma

proteins.

When using concomitant medication, the corresponding label should be consulted

for information on the route

metabolism and the possible need to adjust

dosage.

Paediatric Population

Interaction studies have only been performed in adults. The relevance of the results

UKPAR Risperidone 0.5mg, 1mg, 2mg, 3mg, 4mg and 6mg Film-Coated Tablets

PL 29412/0002-7

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RISPERIDONE 0.5MG, 1MG, 2MG, 3MG, 4MG AND 6MG

FILM-COATED TABLETS

PL 29412/0002-7

UKPAR

TABLE OF CONTENTS

Lay Summary

Page 2

Scientific discussion

Page 4

Steps taken for assessment

Page 13

Steps taken after authorisation – summary

Page 14

Summary of Product Characteristics

Page 15

Product Information Leaflet

Page 93

Labelling

Page 97

UKPAR Risperidone 0.5mg, 1mg, 2mg, 3mg, 4mg and 6mg Film-Coated Tablets

PL 29412/0002-7

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RISPERIDONE 0.5MG, 1MG, 2MG, 3MG, 4MG AND 6MG

FILM-COATED TABLETS

LAY SUMMARY

On 21

June 2011, the MHRA granted Hikma Limited Marketing Authorisations (licences)

for Risperidone 0.5mg, 1mg, 2mg, 3mg, 4mg and 6mg film-coated tablets.

Risperidone 0.5mg, 1mg, 2mg, 3mg, 4mg and 6mg film-coated tablets contain the active

ingredient, risperidone. Risperidone belongs to a group of medicines called antipsychotics.

Risperidone 0.5mg, 1mg, 2mg, 3mg, 4mg and 6mg film-coated tablets are used to treat the

following:

Schizophrenia, where you may see, hear or feel things that are not there, believe things that

are not true or feel unusually suspicious, or confused

Mania, where you may feel very excited, elated, agitated, enthusiastic or hyperactive Mania

occurs in an illness called “bipolar disorder”

Short-term treatment (up to 6 weeks) of long-term aggression in people with Alzheimer’s

dementia, who harm themselves or others. Alternative (non-drug) treatments should have

been used previously

Short-term treatment (up to 6 weeks) of long-standing, aggression in intellectually disabled

children (at least 5 years of age) and adolescents with conduct disorder.

No new or unexpected safety concerns arose from these applications and it was, therefore,

judged that the benefits of taking Risperidone 0.5mg, 1mg, 2mg, 3mg, 4mg and 6mg

film-coated tablets outweigh the risks; hence Marketing Authorisations have been granted.

UKPAR Risperidone 0.5mg, 1mg, 2mg, 3mg, 4mg and 6mg Film-Coated Tablets

PL 29412/0002-7

3

RISPERIDONE 0.5MG, 1MG, 2MG, 3MG, 4MG AND 6MG

FILM-COATED TABLETS

PL 29412/0002-7

SCIENTIFIC DISCUSSION

TABLE OF CONTENTS

Introduction

Page 4

Pharmaceutical assessment

Page 5

Non-clinical assessment

Page 9

Clinical assessment (including statistical assessment)

Page 10

Overall conclusions and risk benefit assessment

Page 12

UKPAR Risperidone 0.5mg, 1mg, 2mg, 3mg, 4mg and 6mg Film-Coated Tablets

PL 29412/0002-7

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INTRODUCTION

The UK granted Hikma Limited Marketing Authorisations for the medicinal products

Risperidone 0.5mg, 1mg, 2mg, 3mg, 4mg and 6mg film-coated tablets (PL 29412/0002-7) on

June 2011. Risperidone 0.5mg, 1mg, 2mg, 3mg, 4mg and 6mg film-coated tablets are

prescription only medicines (POM) and are indicated for:

the treatment of schizophrenia.

the treatment of moderate to severe manic episodes associated with bipolar disorders.

the short-term treatment (up to 6 weeks) of persistent aggression in patients with

moderate to severe Alzheimer’s dementia unresponsive to non-pharmacological

approaches and when there is a risk of harm to self or others.

the short-term symptomatic treatment (up to 6 weeks) of persistent aggression in

conduct disorder in children from the age of 5 years and adolescents with subaverage

intellectual functioning or mental retardation diagnosed according to DSM-IV criteria,

in whom the severity of aggressive or other disruptive behaviours require

pharmacologic treatment.

These applications for Risperidone 0.5mg, 1mg, 2mg, 3mg, 4mg and 6mg film-coated tablets

are submitted under Article 10.1 of Directive 2001/83/EC, claiming to be generic medicinal

products to Risperdal 0.5mg, 1mg, 2mg, 3mg, 4mg and 6mg film-coated tablets

(PL 00242/0347, 0186-9 and 0317), first authorised in the UK to Janssen-Cilag Limited on

December 1992 (PL 00242/0186-9), 15

July 1997 (PL 00242/0317) and 30

June 2000

(PL 00242/0347).

Risperidone is an antipsychotic agent used to treat schizophrenia. The antipsychotic effect is

thought to be related to its ability to block dopamine (DA) D2 receptors and serotonin

(5-HT2) receptors. Risperidone is also a potent α1-adrenergic and histamine H1 antagonist.

The pharmacodynamic effects of the major metabolite, 9-hydroxyrisperidone, are very

similar to those of risperidone itself.

The pharmacovigilance system as described by the Marketing Authorisation Holder (MAH)

fulfils the requirements and provides adequate evidence that the MAH has the services of a

qualified person responsible for pharmacovigilance and has the necessary means for the

notification of any adverse reaction suspected of occurring.

The MAH did not submit a Risk Management Plan (RMP) and one is not required for this

generic application.

UKPAR Risperidone 0.5mg, 1mg, 2mg, 3mg, 4mg and 6mg Film-Coated Tablets

PL 29412/0002-7

5

PHARMACEUTICAL ASSESSMENT

DRUG SUBSTANCE

INN:

Risperidone

Chemical name:

3-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperidine-1-yl]ethyl]-2-methyl06,7,8,9-tetrahydro-

4H-pyrido [1,2-α] pyrimidin-4-one

Structure:

Physical form:

White to off-white powder

Solubility:

Solubility in water is pH dependant (> 200 mg/ ml at pH 2.1 to 0.29

mg/ml at pH 7.6. The minimum solubility of risperidone at pH 2.1 –

8.0 is 0.08 mg/ml. Freely soluble in methylene chloride and sparingly

soluble in ethanol.

Molecular formula:

Molecular weight:

410.49

Risperidone is the subject of a European Pharmacopoeia monograph.

Synthesis of the drug substance from the designated starting materials has been adequately

described, and appropriate in-process controls and intermediate specifications are applied.

Satisfactory specifications are in place for all starting materials and reagents, and these are

supported by relevant Certificates of Analysis.

Appropriate proof of structure data has been supplied for the drug substance. All potential

known impurities have been identified and characterised.

An appropriate specification is provided for the drug substance, with suitable test methods

and limits. Analytical methods have been appropriately validated and are satisfactory for

ensuring compliance with the relevant specifications. Batch analysis data are provided and

comply with the proposed specification. Satisfactory Certificates of Analysis have been

provided for all reference standards used.

Satisfactory specifications and Certificates of Analysis have been provided for all aspects of

the container-closure system. A declaration has been provided that the primary packaging

complies with current regulations concerning contact with foodstuff.

UKPAR Risperidone 0.5mg, 1mg, 2mg, 3mg, 4mg and 6mg Film-Coated Tablets

PL 29412/0002-7

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Appropriate stability data have been generated showing the drug substance to be a physically

and chemically stable drug, and supporting an appropriate retest period.

DRUG PRODUCT

Other ingredients

Other ingredients are pharmaceutical excipients microcrystalline cellulose, corn starch

826/maize starch, lactose monohydrate fast flow, colloidal silicone dioxide, sodium lauryl

sulphate and magnesium stearate.

Ingredients in the film-coating are:

0.5mg: Opadry II Red (85F25467) containing: hydrolyzed polyvinyl alcohol-part,

macrogol/PEG 3350, titanium dioxide (E171), talc (E553b), iron oxide red (E172) and iron

oxide yellow (E172).

1mg: Opadry II White (85F28751) containing: hydrolyzed polyvinyl alcohol-part,

macrogol/PEG 3000, titanium dioxide (E171) and talc.

2mg: Opadry II Orange (85F23793) containing: hydrolyzed polyvinyl alcohol-part,

macrogol/PEG 3350, titanium dioxide (E171), talc (E553B), FD&C yellow #6\sunset yellow

FCF (E110), aluminum lake and iron oxide yellow (E172).

3mg: Opadry II Yellow (85F32426) containing: hydrolyzed polyvinyl alcohol-part,

macrogol/PEG 3350, titanium dioxide (E171), talc (E553B) and iron oxide yellow (E172).

4mg: Opadry II Green (85F21708) containing hydrolyzed polyvinyl alcohol-part,

macrogol/PEG 3350, titanium dioxide (E171), talc (E553b), iron oxide yellow (E172), FD&C

yellow #5/tartrazine Aluminium Lake (E102), FD&C Blue #1/brilliant blue FCF and

aluminium lake (E133)

6mg: Opadry II Yellow (85F22165) containing hydrolyzed polyvinyl alcohol-part,

macrogol/PEG 3350, titanium dioxide (E171), talc (E553b) and iron oxide yellow (E172).

All the ingredients with the exception of sodium lauryl sulphate, Opadry II Red (85F25467),

Opadry II White (85F28751), Opadry II Orange (85F23793), Opadry II Yellow (85F32426),

Opadry II Green (85F21708) and Opadry II Yellow (85F22165) comply with their relevant

European Pharmacopoeia monographs. Sodium lauryl sulphate complies with the US

National Formulary. The film-coatings comply with in-house specifications.

All of the ingredients in the film coatings with the exception of iron oxide yellow (E172),

iron oxide red (E172), FD&C Blue #1/brilliant blue FCF and aluminium lake (E133), FD&C

yellow #5/tartrazine Aluminium Lake (E102) and FD&C yellow #6\sunset yellow FCF

(E110) comply with their relevant European Pharmacopoeia monographs. Iron oxide yellow

(E172) and iron oxide red (E172) comply with the US National Formulary. FD&C Blue

#1/brilliant blue FCF and aluminium lake (E133), FD&C yellow #5/tartrazine Aluminium

Lake (E102) and FD&C yellow #6\sunset yellow FCF (E110) comply with suitable in-house

specifications.

None of the excipients used contain material of human origin. The supplier has confirmed

that the magnesium stearate contained in this product is sourced from vegetable origin.

UKPAR Risperidone 0.5mg, 1mg, 2mg, 3mg, 4mg and 6mg Film-Coated Tablets

PL 29412/0002-7

7

The applicant has provided a declaration that milk used in the production of lactose

monohydrate is sourced from healthy animals under the same conditions as those intended for

human consumption and it is prepared without the use of any other ruminant materials, with

the exception of calf rennet, the production of which complies with EU legislation.

Product development

The objective of the development programme was to produce risperidone containing products

that could be considered generic medicinal products of Risperdal 0.5mg, 1mg, 2mg, 3mg,

4mg and 6mg film-coated tablets.

The applicant has provided a suitable product development section. Justifications for the use

and amounts of each excipient have been provided and are valid. Comparative

in vitro

impurity and dissolution profiles have been provided for the proposed and reference products.

Manufacture

A description and flow-chart of the manufacturing method has been provided. Satisfactory

batch formulae have been provided for the manufacture of the products.

In-process controls are satisfactory based on batch data and controls on the finished products.

The manufacturing process has been validated and has shown satisfactory results.

Finished product specification

The finished product specifications are satisfactory. Test methods have been described and

have been adequately validated, as appropriate. Batch data have been provided and comply

with the release specifications. Certificates of Analysis for all working standards used have

been provided and are satisfactory.

Container-Closure System

The tablets are packaged in:

Blisters composed of:

254 µ polyvinylchloride (PVC)

51 µ aclar (polychlorotrifluoroethylene (PCTFE) and aluminium foil.

The strips are packed in cardboard cartons.

Pack sizes are:

0.5mg: 20 film-coated tablets

1mg: 20 and 60 film-coated tablets

2mg: 60 film-coated tablets

3mg: 60 film-coated tablets

4mg: 60 film-coated tablets

6mg: 28 film-coated tablets

Specifications and Certificates of Analysis have been provided. All primary product

packaging complies with EU legislation.

Stability

Finished product stability studies have been conducted in accordance with current guidelines.

Based on the results, a shelf life of 2 years has been set, with storage instructions ‘do not

store above 30

C’. This is satisfactory.

ADMINISTRATIVE

Quality Overall Summary

A quality overall summary has been written by a suitably qualified person and is satisfactory.

UKPAR Risperidone 0.5mg, 1mg, 2mg, 3mg, 4mg and 6mg Film-Coated Tablets

PL 29412/0002-7

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Summary of Product Characteristics (SmPCs)

These are pharmaceutically satisfactory.

Labelling

These are pharmaceutically satisfactory.

Patient Information Leaflet (PILs)

This is pharmaceutically satisfactory.

User testing results have been submitted for the PIL for this product. The results indicate that

the PIL is well-structured and organised, easy to understand and written in a comprehensive

manner. The test shows that the patients/users are able to act upon the information that it

contains.

MAA Forms

These are pharmaceutically satisfactory.

Conclusion

It is recommended that Marketing Authorisations are granted for these applications.

UKPAR Risperidone 0.5mg, 1mg, 2mg, 3mg, 4mg and 6mg Film-Coated Tablets

PL 29412/0002-7

9

NON-CLINICAL ASSESSMENT

No new non-clinical data have been supplied with these applications and none are required

for applications of this type.

The non-clinical expert report has been written by an appropriately qualified person and is a

suitable summary of the non-clinical aspects of the dossier.

The Marketing Authorisation Holder has provided adequate justification for the absence of an

Environmental Risk Assessment.

UKPAR Risperidone 0.5mg, 1mg, 2mg, 3mg, 4mg and 6mg Film-Coated Tablets

PL 29412/0002-7

10

CLINICAL ASSESSMENT

CLINICAL PHARMACOLOGY

To support the applications, the Marketing Authorisation Holder has included a single

bioequivalence study:

Pharmacokinetics

A randomised, open-label, two-treatment, two-period, two-sequence, single dose,

crossover bioequivalence study comparing the pharmacokinetics of Risperidone 1mg

film-coated tablets (Test) versus Risperdal

®

(risperidone) 1mg film-coated tablets

(Reference) in healthy volunteers under fasting conditions.

Blood sampling was performed pre-dose and up to 96 hours post dose in each treatment

period. There was a washout period of 14 days. Pharmacokinetic parameters were calculated

and statistically analysed.

Results from this study are presented below as log-transformed values:

Geometric Least Mean Squares and 90% Confidence Interval

Pharmacokinetic parameters of risperidone

Treatment

AUC

0-t

(pg.h/mL)

AUC

0-∞

(pg.h/mL)

C

max

(pg/mL)

Test

3.2696

3.3745

1.6677

Reference

3.2606

3.3358

1.6496

Ratio (90% CI)

100.91

(91.39 – 111.40)

95.11

(83.01 – 108.96)

101.82

(91.54 – 113.25)

The lower dose of 1mg was used in the bioequivalence study rather than the usual higher

dose (6mg) for safety reasons. A single bioequivalence study using the 1mg strength is

satisfactory, as the pharmacokinetics of risperidone are linear over the therapeutic range.

The results for the primary variables indicated that the 90% confidence intervals

test/reference ratio of geometric means for AUC

and C

for risperidone lie within the

normal 80-125% limits. Thus, bioequivalence has been shown between the test and reference

products.

As the 0.5mg, 1mg, 2mg, 3mg, 4mg and 6mg film-coated tablet strengths meet all the criteria

as specified in the Note for Guidance on the Investigation of Bioavailability and

Bioequivalence (CPMP/EWP/QWP/1401/98), the results and conclusions of the

bioequivalence study on the 1mg strength can be extrapolated to 0.5mg, 2mg, 3mg, 4mg and

6mg film-coated tablets.

EFFICACY

These are generic applications based on demonstration of bioequivalence and new data

relating to efficacy are not required as per EU legislation once bioequivalence has been

demonstrated.

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