Consumer medicine information

Risperdal Consta

Risperidone

BRAND INFORMATION

Brand name

Risperdal Consta

Active ingredient

Risperidone

Schedule

What is in this leaflet

This leaflet contains important information about RISPERDAL CONSTA. It does not contain all of the available information. It does not take the place of talking to your doctor or pharmacist.

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

Keep this leaflet with your RISPERDAL CONSTA. You may need to read it again.

What RISPERDAL CONSTA is used for?

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

RISPERDAL CONSTA is also used to treat bipolar disorder to prevent or delay mood swings which consist of alternating periods of high (manic) or elevated mood with periods of depression. During the manic episodes you may feel very excited, elated, agitated, enthusiastic, or hyperactive, or have poor judgment including disruptive or aggressive behaviours. During the episodes of depression you may experience sadness, low energy, lack of motivation, feelings of guilt and worthlessness, and changes in sleep or appetite.

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

RISPERDAL CONSTA has been approved for the uses mentioned above. However, your doctor may prescribe this medicine for another use.

If you want more information, ask your doctor.

RISPERDAL CONSTA is not addictive.

Before you are given RISPERDAL CONSTA

When you must not be given it

You should not be given RISPERDAL CONSTA:

if you know you are allergic to any of its ingredients (see the last section of this leaflet for a list of ingredients)
Signs of allergy include skin rash, itching, shortness of breath, and/or swollen face
if the packaging is torn or shows signs of having been tampered with.

Before you start to use it

RISPERDAL CONSTA should be used with caution in some patients.

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

irregular heart rhythm, abnormalities in electrical activity of the heart, high or low blood pressure, or you've had a heart attack or stroke in the past or heart failure.
unusual, excessive sweating or diarrhoea, dehydration or problems with your body temperature regulation
kidney or liver problems
you are prone to dizziness when standing up from lying or sitting position
Parkinson's disease (a progressive movement and thinking disorder that tends to affect older people)
dementia or Lewy body dementia
Older people suffering dementia may be at increased risk of stroke or death with RISPERDAL CONSTA.
sugar diabetes
unusual thirst, tiredness, blurred vision, upset stomach or need to urinate - common signs of high blood sugars
epilepsy, seizures or fits
continuous and/or painful erections (called 'priapism')
involuntary movements or unusual restlessness or difficulty sitting still
suicidal thoughts or past suicide attempts
low blood potassium levels (hypokalaemia)
breast cancer
cancer of the pituitary gland
Neuroleptic Malignant Syndrome (a serious reaction to some medicines that causes sudden increase in body temperature, very fast heartbeat, extremely high or low blood pressure and severe muscle stiffness or fits)
Tardive dyskinesia (a reaction to some medicines with uncontrollable twitching or jerking movements of the tongue, face, mouth, jaw, arms and legs)
blood clots
Tell your doctor if you or someone else in your family has a history of blood clots. Blood clots in the lungs and legs can occur with RISPERDAL CONSTA. Blood clots in the lungs can result in death
low white blood cell count
If you have low numbers of some white blood cells, your risk of contracting an infection or developing a fever is increased with RISPERDAL CONSTA).

Tell your doctor if:

you have any eye surgery planned.
Your doctor will need to assess whether you are at risk of a surgical complication (called Intraoperative Floppy Iris Syndrome). You may be recommended to stop your RISPERDAL CONSTA temporarily prior to your eye surgery.
you are pregnant or are planning to become pregnant
Your doctor will advise you whether you should take RISPERDAL CONSTA
Newborn babies of mother taking RISPERDAL CONSTA in their last trimester may be at risk of having difficulty feeding or breathing, shaking, muscle stiffness and/or weakness, sleepiness or agitation.
you are breast feeding
As RISPERDAL CONSTA is excreted in breast milk, it is recommended that you do not breastfeed while using this medicine.
You will be in a hot environment or do a lot of vigorous exercise
RISPERDAL CONSTA may make you sweat less, causing your body to overheat.

If you have not told your doctor or nurse about any of the above, tell them before you are given RISPERDAL CONSTA.

Taking other medicines

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

In particular, tell your doctor if you are taking:

sleeping tablets, tranquillisers, strong painkillers, or some allergy medications called antihistamines and alcohol
medicines that increase the activity of the central nervous system (psychostimulants such as methylphenidate).
medicines used to treat bacterial infections such as rifampicin
medicines used to treat fungal infections such as itraconazole and ketoconazole
medicines to treat HIV/AIDS, such as ritonavir and tipranavir
other medicines to treat mental illness or psychotic conditions
medicines to treat depression, panic disorder, anxiety or obsessive-compulsive disorder, such as fluoxetine, paroxetine, sertraline and fluvoxamine
medicines for your heart or blood pressure
verapamil, a medicine used to treat high blood pressure and/or abnormal heart rhythm
frusemide, a medicine used to treat high blood pressure and fluid build up
There is an increased risk of side effects or death in older people if frusemide is also taken with RISPERDAL CONSTA.
medicines to treat epilepsy
carbamazepine, a drug mainly used for epilepsy or trigeminal neuralgia (severe pain attacks in the face)
medicines to treat Parkinson's disease or tremor.

Using it for the first time

Treatment with RISPERDAL CONSTA will not be started until it is known that you can tolerate RISPERDAL treatment by mouth (tablets or oral solution).

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

Using RISPERDAL CONSTA

RISPERDAL CONSTA cannot be recommended for use in children and adolescents under 18 years at the present time as there is no experience with the product in this group.

How it is given

RISPERDAL CONSTA will be given to you by injection by a healthcare professional. It is a medicine designed to gradually release the active ingredient in your body so that you do not have to take this medicine every day.

The information for your doctor or nurse on the right way to reconstitute (make up) RISPERDAL CONSTA is included in the package.

Your doctor or healthcare provider will give you the injection in the arm or buttock every two weeks. Next time the injection will be given into the other arm or buttock, and so on. Injection is not to be given intravenously.

The usual dose of RISPERDAL CONSTA is 25mg once every two weeks. Your doctor will decide on the dose of RISPERDAL CONSTA that is right for you.

Because risperidone is released gradually into your body, you will need an injection only every two weeks. During the first three weeks of treatment additional risperidone tablets or liquid, which can be taken by mouth, must be used, because the first injection will not start to work straight away. Your doctor will explain this to you.

Later, depending on how well the treatment is working, your doctor may decide to further adjust the dose of RISPERDAL CONSTA or to add oral RISPERDAL (tablets or solution) for a short time.

Do not stop your treatment just because you feel better. If you have to stop RISPERDAL CONSTA on the advice of your doctor, it is best to do it gradually. Stopping treatment suddenly may cause effects such as feeling sick, vomiting, sweating, sleeplessness, muscle stiffness, or jerky movements, or your original medical problem may come back.

Patients with kidney and liver problems.
RISPERDAL CONSTA has not been studied in patients whose kidney or liver is not working properly. Your doctor will decide the dose suitable for you. A starting dose of 0.5mg twice-daily oral risperidone is recommended during the first week. In the second week 1mg twice daily or 2mg once daily can be given. If a daily total oral dose of at least 2mg is well tolerated (i.e. the drug does not upset you), an injection of RISPERDAL CONSTA can be administered every 2 weeks.

What if you missed a dose

It is very important to keep all your appointments and get your medicine on time.

Contact your doctor as soon as you can if you think you are going to miss or have missed your appointment.

Your doctor will decide what you should do next.

Overdose

As RISPERDAL CONSTA is given to you under the supervision of your doctor, it is very unlikely that you will receive too much.

However, if you experience any side effects after being given RISPERDAL CONSTA, tell you doctor immediately or go to Accident and Emergency at your nearest hospital. You may need urgent medical attention.

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

While you are using RISPERDAL CONSTA

Things you must do

Always follow your doctor's instructions carefully. Do not miss an injection or stop the treatment without consulting your doctor first. Your doctor will be happy to discuss any questions you may have with your treatment.

Tell all doctors, dentists and pharmacists who are treating you, that you are using RISPERDAL CONSTA.

If you become pregnant while using RISPERDAL CONSTA, tell your doctor.

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

Tell your doctor immediately if you notice any involuntary movements of the tongue, mouth, cheeks or jaw which may progress to the arms and legs. These may be symptoms of a condition called Tardive Dyskinesia, which can develop in people taking antipsychotic medicines, including RISPERDAL CONSTA. This condition is more likely to occur during longer treatment in older women. In very rare cases, these symptoms may be permanent. However, if detected early, these symptoms are usually reversible.

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

Do not drink alcohol. RISPERDAL CONSTA can increase the effects of alcohol.

Things to be careful of

Ask your doctor before taking any other medicines. RISPERDAL CONSTA can increase the effects of medicines which slow your reactions. Always ask your doctor or pharmacist before taking other medicines, including herbal treatments and medicines that can be bought in a pharmacy or supermarket.

Avoid driving or operating machinery until you are sure RISPERDAL CONSTA does not affect your alertness. RISPERDAL CONSTA may cause dizziness or light-headedness in some people, especially after the first dose. Make sure you know how you react to RISPERDAL CONSTA before you drive a car, operate machinery, or do anything else that could be dangerous if you are dizzy.

If the medicine makes you feel light-headed, dizzy or faint, be careful when getting up from a sitting or lying position. Getting up slowly may help.

Avoid excessive eating. There is a possibility of weight gain when using RISPERDAL CONSTA. Your doctor may monitor your body weight or recommend strategies to assist with weight management.

Side Effects

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

All medicines can have side effects. You may need medical treatment if you get some of the side effects.

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

Tell your doctor as soon as possible if you do not feel well while you are using RISPERDAL CONSTA.

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

difficulty thinking, working or carrying out your usual daily activities because of:
- headache
- trembling, muscle weakness, unsteadiness on your feet, lack of coordination or slow, shuffling walk (symptoms of Parkinsonism)
- drowsiness, sleeplessness or difficulty concentrating
- nightmares
- difficulty speaking
- blurred vision
- fainting
- dizziness
- swelling or pain at injection site
- any problems with confusion or unsteadiness
- pain in parts of your body, e.g. tooth ache, in the back, ear, mouth, throat, hands or feet
muscle, joint, nerve or movement changes such as:
- shaking or trembling
- fatigue or weakness
- restlessness in the legs or difficulty sitting still
- uncontrolled muscle spasms, twitching, jerking or writhing movements
- unusually reduced or slow body movement
- a jerky feeling in your arm or leg that you can sense when rotating your limb or joint
- muscle weakness, pain, spasms, twitching or stiffness
- joint stiffness or pain
- tingling or numbness of the hands or feet
- decreased feeling of sensitivity, especially in your skin
- difficulty in walking
- involuntary changes in posture
behavioural changes such as:
- irritability or agitation
- unusual anxiety or depression
other changes such as:
- cold or "flu-like symptoms, e.g. cough, blocked or runny nose, sneezing, sore throat
- fever, chills, shortness of breath, cough, phlegm and occasionally blood (signs of pneumonia)
- indigestion, stomach discomfort or pain, constipation or diarrhoea
- nausea or vomiting
- dry mouth or excessive thirst
- excessive saliva or drooling
- acne
- dry skin
- swelling of any part of your body, e.g. hands, ankles or feet
- fever
- unexplained weight gain or loss
- signs of high blood sugar such as unusual thirst, tiredness or need to urinate more often than usual
- inability to or feeling burning pain when passing urine
- some loss of bladder control
- breast abnormalities - breast discomfort or swelling or unusual secretion of breast milk
- missed or irregular menstrual periods
- sexual function disturbances - erectile dysfunction, problems with ejaculation, decreased sexual drive
- unexplained decreased or increased appetite
- dizziness on standing up, especially when getting up from a sitting or lying position
- fast heart rate or chest discomfort
- shortness of breath or wheezing
- increased sensitivity to light
- rash or itchy, red skin
- an increase of CPK (creatine phosphokinase) in your blood, an enzyme which is sometimes released with muscle breakdown or changes in liver function results.
These can only be detected by blood tests that your doctor may ask to be done.

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

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

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

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

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

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

After using RISPERDAL CONSTA

Storage

RISPERDAL CONSTA will be stored by your doctor or pharmacist. The injection is kept in a refrigerator at 2°C to 8°C or where refrigeration is not available, in a cool dry place, protected from light, where the temperature stays below 25°C for no longer than 7 days.

Your doctor or pharmacist will not use it beyond the expiry date (month and year) printed on the pack.

Medicines cannot be stored indefinitely, even if stored properly.

Product Description

What it looks like

RISPERDAL CONSTA is available in vials (small bottles) which contain different amounts of risperidone. The package contains everything required to reconstitute and administer the product.

A vial with white powder contains the RISPERDAL CONSTA Prolonged Release Powder.
A syringe with diluent, with which the powder is mixed.
Vial Adapter.
Safety needles.

Ingredients

The active ingredient in RISPERDAL CONSTA is risperidone, which is present in amounts of either 25mg, 37.5mg or 50mg in an injection of RISPERDAL CONSTA.

The powder is made from a 7525 DL JN1 poly-(d/l-lactide-co-glycolide) polymer called polyglactin. A polymer is a small particle made up of many smaller, similar particles bound together. Risperidone is attached to this polymer and then slowly released from it once it has been injected into the body. The diluent contains polysorbate 20, carmellose sodium, dibasic sodium phosphate dihydrate, citric acid, sodium chloride, sodium hydroxide and water for injections.

Sponsor

Janssen-Cilag Pty Ltd
1-5 Khartoum Road Macquarie Park NSW 2113
Telephone: 1800 226 334

NZ Office: Auckland, New Zealand
Telephone: 0800 800 806

Registration Numbers

RISPERDAL CONSTA 25mg -
AUST R 81489

RISPERDAL CONSTA 37.5mg -
AUST R 81490

RISPERDAL CONSTA 50mg -
AUST R 81491

This leaflet was prepared in July 2020.

RISPERDAL CONSTA® is a registered trademark of Janssen-Cilag Pty Ltd.

Published by MIMS September 2020

BRAND INFORMATION

Brand name

Risperdal Consta

Active ingredient

Risperidone

Schedule

1 Name of Medicine

Risperidone.

2 Qualitative and Quantitative Composition

Risperdal Consta is an extended release microspheres formulation of risperidone microencapsulated in polyglactin for intramuscular injection, in strengths of 25 mg, 37.5 mg and 50 mg when suspended in 2 mL diluent.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Risperdal Consta contains either 25 mg, 37.5 mg or 50 mg risperidone and is presented as a white to off-white free-flowing powder in a 5 mL vial and a prefilled syringe containing 2 mL diluent, together with:
One Vial Adapter for reconstitution; and
Two Terumo SurGuard-3 Needles for intramuscular injection (a 21G UTW 1-inch safety needle with needle protection device for deltoid administration and a 20G TW 2-inch safety needle with needle protection device for gluteal administration). ("Rx-only" = device to be sold with prescription medicines only).

4 Clinical Particulars

4.1 Therapeutic Indications

Risperdal Consta is indicated for:
treatment of schizophrenia and related psychoses;
adjunctive maintenance treatment with lithium or sodium valproate in treatment refractory patients with bipolar I disorder who have at least 4 relapses in a 12 month period;
monotherapy for maintenance treatment to prevent the recurrence of manic or mixed episodes of bipolar I disorder in patients with a manic or mixed episode, following stabilisation with oral risperidone.

4.2 Dose and Method of Administration

Treatment initiation.

For risperidone naïve patients, it is recommended to establish tolerability with immediate release oral formulations of risperidone prior to initiating treatment with Risperdal Consta.
Risperdal Consta should be administered every two weeks by deep intramuscular deltoid or gluteal injection using the enclosed appropriate safety needle. For deltoid administration, use the 1 inch needle alternating injections between the two arms. For gluteal administration, use the 2 inch needle alternating injections between the two buttocks. Prior to each administration, the site of injection should be examined for any signs of inflammation. If such signs exist, an alternative site should be chosen for injection. Do not administer intravenously (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)). This product does not contain an antimicrobial agent. It is for single use in one patient only. Any residue is to be discarded.
Adults. The recommended dose is 25 mg intramuscular every two weeks. Some patients may benefit from the higher doses of 37.5 mg or 50 mg. No additional benefit was observed with 75 mg in clinical trials in patients with schizophrenia. Doses above 50 mg were not studied in patients with bipolar disorder. Doses higher than 50 mg every 2 weeks are not recommended.
Sufficient antipsychotic coverage should be ensured during the three week lag period following the first Risperdal Consta injection (see Section 5.2 Pharmacokinetic Properties).
Upward dosage adjustment should not be made more frequently than every 4 weeks. The effect of this dose adjustment should not be anticipated earlier than 3 weeks after the first injection with the higher dose.
Elderly. The recommended dose is 25 mg intramuscularly every two weeks. Sufficient antipsychotic coverage should be ensured during the three week lag period following the first Risperdal Consta injection (see Section 5.2 Pharmacokinetic Properties).
Hepatic and renal impairment. Risperdal Consta has not been studied in hepatically and renally impaired patients.
In case hepatically or renally impaired patients would require treatment with Risperdal Consta, a starting dose of 0.5 mg twice daily oral risperidone is recommended during the first week. The second week 1 mg twice daily or 2 mg once daily can be given. If an oral total daily dose of at least 2 mg is well tolerated, an injection of 25 mg Risperdal Consta can be administered every 2 weeks.
Children. Risperdal Consta has not been studied in adolescents and children younger than 18 years.

Instructions for use and handling.

Important information. Risperdal Consta requires close attention to the step by step instructions for use and handling to help ensure successful administration and help avoid difficulties in the use of the kit.

Wait 30 minutes.

Remove dose pack from the refrigerator and allow to sit at room temperature for at least 30 minutes before reconstituting.
Do not warm any other way.

Use components provided.

The components in this dose pack are specifically designed for use with Risperdal Consta. Risperdal Consta must be reconstituted only in the diluent supplied in the dose pack.
Do not substitute any components of the dose pack.

Do not store suspension after reconstitution.

Administer dose as soon as possible after reconstitution to avoid settling.

Proper dosing.

The entire contents of the vial must be administered to ensure intended dose of Risperdal Consta is delivered.

Single use device; do not reuse.

Medical devices require specific material characteristics to perform as intended. These characteristics have been verified for single use only. Any attempt to reprocess the device for subsequent reuse may adversely affect the integrity of the device or lead to deterioration in performance.
See the manufacturer's full product information for diagrams.
Step 1: assemble components.

Connect vial adapter to vial.

Remove cap from vial.
Flip off coloured cap from vial. Wipe top of the grey stopper with an alcohol swab.
Allow to air dry.
Do not remove grey rubber stopper.

Prepare vial adapter.

Hold sterile blister. Peel back and remove paper backing.
Do not remove vial adapter from blister.
Do not touch spike tip at any time. This will result in contamination.

Connect vial adapter to vial.

Place vial on a hard surface and hold by the base. Center vial adapter over the grey rubber stopper. Push vial adapter straight down onto vial top until it snaps securely into place.
Do not place vial adapter on at an angle or diluent may leak upon transfer to the vial.

Connect prefilled syringe to vial adapter.

Remove sterile blister.
Remove vial adapter from sterile blister only when you are ready to remove the white cap from the prefilled syringe.
Keep vial vertical to prevent leakage. Hold base of vial and pull up on the sterile blister to remove.
Do not shake.
Do not touch exposed luer opening on vial adapter. This will result in contamination.
Use proper grip; hold by white collar at the tip of the syringe.
Do not hold syringe by the glass barrel during assembly.

Remove cap.

Holding the white collar, snap off the white cap.
Do not twist or cut off the white cap.
Do not touch syringe tip. This will result in contamination.
The broken off cap can be discarded.

Connect syringe to vial adapter.

Hold vial adapter by skirt to keep stationary.
Hold syringe by white collar then insert tip into the luer opening of the vial adapter.
Do not hold the glass syringe barrel. This may cause the white collar to loosen or detach.
Attach the syringe to the vial adapter with a firm clockwise twisting motion until it feels snug.
Do not overtighten. Overtightening may cause the syringe tip to break.
Step 2: reconstitute microspheres. Vial contents will now be under pressure.
Keep holding the plunger rod down with thumb.

Inject diluent.

Inject entire amount of diluent from syringe into the vial.

Suspend microspheres in diluent.

Continuing to hold down the plunger rod, shake vigorously for at least 10 seconds.
Check the suspension. When properly mixed, the suspension appears uniform, thick and milky in colour. Microspheres will be visible in the liquid.
Immediately proceed to the next step so suspension does not settle.

Transfer suspension to syringe.

Invert vial completely. Slowly pull plunger rod down to withdraw entire contents from the vial into the syringe.

Remove vial adapter.

Hold white collar on the syringe and unscrew from vial adapter.
Tear section of the vial label at the perforation. Apply detached label to the syringe for identification purposes.
Discard both vial and vial adapter appropriately.
Step 3: attach needle.

Select appropriate needle.

Choose needle based on injection location (gluteal or deltoid).

Attach needle.

Peel blister pouch open part way and use to grasp the base of the needle.
Holding the white collar on the syringe, attach syringe to needle luer connection with a firm clockwise twisting motion until snug.
Do not touch needle luer opening. This will result in contamination.

Resuspend microspheres.

Fully remove the blister pouch.
Just before injection, shake syringe vigorously again, as some settling will have occurred.
Step 4: inject dose.

Remove transparent needle protector.

Move the needle safety device back towards the syringe. Then hold white collar on syringe and carefully pull the transparent needle protector straight off.
Do not twist transparent needle protector, as the luer connection may loosen.

Remove air bubbles.

Hold needle upright and tap gently to make any air bubbles rise to the top. Slowly and carefully press plunger rod upward to remove air.

Inject.

Immediately inject entire contents of syringe intramuscularly (IM) into the gluteal or deltoid muscle of the patient.
Gluteal injection should be made into the upper outer quadrant of the gluteal area.
Do not administer intravenously.

Secure needle in safety device.

Using one hand, place needle safety device at a 45 degree angle on a hard, flat surface. Press down with a firm, quick motion until needle is fully engaged in safety device.
Avoid needle stick injury: do not use two hands; do not intentionally disengage or mishandle the needle safety device; do not attempt to straighten the needle or engage the safety device if the needle is bent or damaged.

Properly dispose of needles.

Check to confirm needle safety device is fully engaged. Discard in an approved sharps container.
Also discard the unused needle provided in the dose pack.

4.3 Contraindications

Risperdal Consta is contraindicated in patients with a known hypersensitivity to the medicine or any of its excipients.

4.4 Special Warnings and Precautions for Use

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. The risk/ benefit of further treatment with Risperdal Consta should be assessed if clinically relevant orthostatic hypotension persists with oral treatment.
Patients with a history of clinically significant cardiac disorders were excluded from clinical trials. Risperidone should be used with caution in patients with known cardiovascular disease (e.g. heart failure, myocardial infarction, conduction abnormalities) and other conditions (such as dehydration, hypovolaemia, hypokalaemia or cerebrovascular disease). In these patients the dosage should be gradually increased.

Leukopenia, neutropenia and agranulocytosis.

Events of leukopenia, neutropenia and agranulocytosis have been reported with antipsychotic agents, including Risperdal Consta. 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 Risperdal Consta 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 10⁹/L) should discontinue Risperdal Consta 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 Risperdal Consta and preventative measures undertaken.

Tardive dyskinesia (TD)/Extrapyramidal symptoms.

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 tardive dyskinesia may be less with risperidone. The risk of developing TD and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic medicines 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 drug treatment itself, however, may suppress the signs and symptoms of TD, thereby masking the underlying process. The effect of symptom suppression upon the long-term course of TD is unknown. In view of these considerations, Risperdal Consta should be prescribed in a manner that is most likely to minimise the risk of TD. As with any antipsychotic drug, Risperdal Consta should be reserved for patients who appear to be obtaining substantial benefit from the drug. In such patients, the smallest dose and the shortest duration of treatment should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of TD appear in a patient on antipsychotics, 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).

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.

Neuroleptic malignant syndrome (NMS).

This is a potentially fatal symptom complex that has been reported in association with antipsychotic medicines, including risperidone.
Clinical manifestations of NMS are hyperthermia, muscle rigidity, altered mental status (including catatonic signs) and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, cardiac arrhythmias and diaphoresis). Additional signs may include elevated creatine phosphokinase (CPK) levels, myoglobinuria (rhabdomyolysis), and acute renal failure.
In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g. pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system pathology.
The management of NMS should include: 1) immediate discontinuation of all antipsychotic medicines and other medicines not essential to concurrent therapy. After the last administration of Risperdal Consta, plasma levels of risperidone are measurable for at least 6 weeks; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.
If a patient requires antipsychotic medicine treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.

Parkinson's disease and 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.

Hypersensitivity reactions.

Although tolerability with oral risperidone should be established prior to initiating treatment with Risperdal Consta, very rare cases of anaphylactic reaction have been reported during postmarketing experience in patients who have previously tolerated oral risperidone (see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects)).
If hypersensitivity reactions occur, discontinue use of Risperdal Consta; initiate general supportive measures as clinically appropriate and monitor the patient until signs and symptoms resolve (see Section 4.3 Contraindications; Section 4.8 Adverse Effects (Undesirable Effects)).

Seizures.

Classical neuroleptics are known to lower the seizure threshold. Risperdal Consta 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, Risperdal Consta should be used cautiously in patients with a history of seizures or other conditions that potentially lower seizure threshold.

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 Risperdal Consta. 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 Risperdal Consta is being used.

QT interval.

As with other antipsychotics, caution should be exercised when Risperdal Consta 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 α-adrenergic blocking effects have been reported to induce priapism. Priapism has been reported with Risperdal 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 Risperdal Consta 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.

Premenopausal women with secondary amenorrhoea.

Premenopausal women who develop secondary amenorrhoea of greater than six months duration should receive appropriate preventive therapy to avoid hypo-oestrogenic bone loss.

Suicide.

The possibility of a suicide attempt is inherent in schizophrenia, and close supervision of high risk patients should accompany therapy.

Intraoperative floppy iris syndrome.

Intraoperative floppy iris syndrome (IFIS) has been observed during cataract surgery in patients treated with medicines with α_1a-adrenergic antagonist effect, including Risperdal Consta (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 α_1a-adrenergic antagonist effect should be made known to the ophthalmic surgeon in advance of surgery. The potential benefit of stopping α₁-blocking therapy prior to cataract surgery has not been established and must be weighed against the risk of stopping the antipsychotic therapy.

Administration.

Care must be taken to avoid inadvertent injection of Risperdal Consta into a blood vessel (see Section 4.8 Adverse Effects (Undesirable Effects)).

Use in the elderly.

The recommended dose is 25 mg intramuscular every two weeks. Sufficient antipsychotic coverage should be ensured during the three week lag period following the first Risperdal Consta injection (see Section 5.2 Pharmacokinetic Properties).
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 medicines, including risperidone. In placebo controlled trials with oral risperidone in this population, the incidence of mortality was 4.0% (40/1009) for risperidone treated patients and 3.1% (22/712) for placebo treated patients. The mean age (range) of patients who died was 86 years (range 67-100).

Concomitant use with frusemide.

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

Cerebrovascular adverse events.

In placebo controlled trials in elderly patients with dementia there was a significantly higher incidence of cerebrovascular adverse events, such as stroke (including fatalities) and transient ischaemic attacks in patients (mean age 85 years, range 73-97) treated with oral 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).

Use in patients with hepatic and renal impairment.

Risperdal Consta has not been studied in hepatically and renally impaired patients.
In case hepatically or renally impaired patients would require treatment with Risperdal Consta, a starting dose of 0.5 mg b.i.d. oral risperidone is recommended during the first week. The second week 1 mg b.i.d. or 2 mg o.d. can be given. If an oral dose of at least 2 mg is well tolerated, an intramuscular injection of 25 mg Risperdal Consta can be administered every 2 weeks.

Paediatric use.

Risperdal Consta has not been studied in adolescents and children younger than 18 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.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

The interactions of Risperdal Consta with coadministration of other drugs have not been systematically evaluated. The drug interaction data provided in this section are based on studies with oral Risperdal.

Pharmacodynamic-related interactions.

Centrally-acting drugs and alcohol. Given the primary CNS effects of risperidone, it should be used with caution in combination with other centrally acting 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.
Drugs known to prolong the QT interval. Caution is advised when prescribing Risperdal Consta with drugs known to prolong the QT interval.

Pharmacokinetic-related interactions.

Risperidone is mainly metabolised through CYP2D6, and to a lesser extent through CYP3A4. Both risperidone and its active metabolite 9-hydroxyrisperidone are substrates of P-glycoprotein (P-gp). Substances that modify CYP2D6 activity, or substances strongly inhibiting or inducing CYP3A4 and/or P-gp activity, may influence the pharmacokinetics of the risperidone active antipsychotic fraction.
Strong CYP2D6 inhibitors. Coadministration of Risperdal Consta with a strong CYP2D6 inhibitor may increase the plasma concentrations of risperidone, but less so of the active antipsychotic fraction. Higher doses of a strong CYP2D6 inhibitor may elevate concentrations of the risperidone active antipsychotic fraction (e.g. paroxetine or fluoxetine). (See also section SSRIs and tricyclic antidepressants.)
CYP3A4 and/or P-gp inhibitors. Coadministration of Risperdal Consta 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 Risperdal Consta.
CYP3A4 and/or P-gp inducers. Coadministration of Risperdal Consta 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 Risperdal Consta.
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.
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 the active antipsychotic fraction.
Rifampicin, a strong CYP3A4 inducer and a P-gp inducer, decreased the risperidone active antipsychotic fraction C_max by 41% and AUC_last by 45%, following a single dose of risperidone 1 mg.

Anticholinesterases.

Donepezil and galantamine, both CYP2D6 and CYP3A4 substrates, do not show a clinically relevant effect on the pharmacokinetics of risperidone and the active antipsychotic fraction.

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 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 or injections 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 C_max and AUC by 1.8-fold, and the active antipsychotic fraction C_max 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.

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

Gastrointestinal drugs.

H₂-receptor antagonists: cimetidine and ranitidine, both weak inhibitors of CYP2D6 and CYP3A4, increased the bioavailability of risperidone, but only marginally that of the active antipsychotic fraction.
In volunteer studies, a single 1 mg risperidone dose was administered with cimetidine 400 mg twice daily or ranitidine 150 mg twice daily. Cimetidine produced a relative increase in AUC_0-Inf of 1.95 ± 0.78, 1.01 ± 0.25 and 1.15 ± 0.28 for risperidone, 9-hydroxyrisperidone and risperidone plus 9-hydroxyrisperidone respectively. Relative C_max 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 the AUC_0-Inf and of C_max 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 C_min, C_max and AUC_0-12hr of risperidone plus 9-hydroxyrisperidone. Administration of paroxetine 20 mg/day for 4 weeks to patients stabilised on 4-8 mg risperidone/day produced a relative increase of 1.51 ± 0.34 in C_min of risperidone plus 9-hydroxyrisperidone.
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 4-6 mg/day in the sertraline study and 3-6 mg/day in the fluvoxamine study.
Tricyclic antidepressants may increase the plasma concentrations of risperidone but not those of 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 0-12 hr AUC of 1.21 ± 0.35, 1.15 ± 0.36 and 1.16 ± 0.34 and C_max of 1.17 ± 0.33, 1.11 ± 0.43 and 1.11 ± 0.38 for risperidone, 9-hydroxyrisperidone and risperidone plus 9-hydroxyrisperidone respectively. These modest increases do not necessitate dose modification.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Risperidone impaired mating, but not fertility, in Wistar rats at doses 0.2 to 5 times the maximum human dose on a mg/m² basis. The effect appeared to be in females since the oestrus cycle in rats was disrupted by risperidone and impaired mating behaviour was not noted when males only were treated. In repeat dose toxicity studies in Beagle dogs, risperidone at doses 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)
Risperidone has only been taken by a limited number of pregnant women or women of childbearing age. No increases in the frequency of malformation or other direct or indirect harmful effects on the human fetus have been observed.
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.
In an embryofetal development study in rats, intramuscular administration of Risperdal Consta delayed ossification in the metatarsals and mandible at risperidone plus 9-hydroxyrisperidone levels less than those achieved at the maximal human dose. This is unlikely to be clinically relevant. There was no effect on the incidence of malformations.

Nonteratogenic class effect.

Neonates exposed to antipsychotic drugs (including Risperdal Consta) 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 feeling 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.
Risperdal Consta should be used during pregnancy only if the anticipated benefit outweighs the risk and the administered dose and duration of treatment should be as low and as short as possible.
It has been demonstrated that risperidone and 9-hydroxyrisperidone are excreted in human breast milk. It is recommended that women receiving risperidone should not breastfeed.
Risperidone and 9-hydroxyrisperidone are excreted in milk in lactating dogs. In rats, 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. It is not known whether these deaths were due to a direct effect on the foetuses or pups or to effects on the dams. In one such study there was an increase in stillborn rat pups at a dose 2.5 times the maximum human dose on a mg/m² basis.

4.7 Effects on Ability to Drive and Use Machines

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

4.8 Adverse Effects (Undesirable Effects)

Clinical trial data.

The safety of Risperdal Consta was evaluated from a clinical trial database consisting of 2392 patients exposed to one or more doses of Risperdal Consta for the treatment of schizophrenia. Of these 2392 patients, 332 were patients who received Risperdal Consta while participating in a 12 week double blind, placebo controlled trial. A total of 202 of the 332 were schizophrenic patients who received 25 mg or 50 mg Risperdal Consta. The conditions and duration of treatment with Risperdal Consta 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 4 years) exposures.
The majority of all adverse reactions were mild to moderate in severity.
Double blind, placebo controlled data: schizophrenia. Adverse drug reactions (ADRs) reported by ≥ 2% of Risperdal Consta treated patients with schizophrenia in one 12 week double blind, placebo controlled trial are shown in Table 1.

Double blind, placebo controlled data: bipolar disorder. Adverse drug reactions (ADRs) reported by ≥ 1% of Risperdal Consta treated patients with bipolar disorder in the 24 month, double blind, placebo controlled period in one monotherapy recurrence prevention trial are shown in Table 2.

Adverse drug reactions (ADRs) reported by ≥ 1% of Risperdal Consta treated patients with bipolar disorder in the 52 week, double blind, placebo controlled period in one adjunctive therapy recurrence prevention trial are shown 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. See Table 4.

ADRs reported with risperidone and/or paliperidone by < 2% of Risperdal Consta-treated subjects with schizophrenia are shown in Table 5.

ADRs reported with risperidone and/or paliperidone in other clinical trials but not reported by Risperdal Consta (25 mg or 50 mg)-treated subjects with schizophrenia are shown in Table 6.

Postmarketing data.

Adverse events first identified as ADRs during postmarketing experience with risperidone and/or risperidone based on spontaneous reporting rates 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; Not known cannot be estimated from the available data.

There have also been reports of benign pituitary adenoma that were temporally related, but not necessarily causally related, to risperidone therapy.
Very rarely, cases of anaphylactic reaction after injection with Risperdal Consta have been reported during postmarketing experience in patients who have previously tolerated oral risperidone.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Symptoms.

In general, reported signs and symptoms have been those resulting from an exaggeration of known pharmacological effects of risperidone. These include drowsiness and sedation, tachycardia and hypotension, and extrapyramidal symptoms.
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. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias.
There is no specific antidote to risperidone. Therefore appropriate supportive measures should be instituted. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids and/or sympathomimetic agents. In case of severe extrapyramidal symptoms, anticholinergic medication should be administered. Close medical supervision and monitoring should continue until the patient recovers. Due to the lag period with absorption of Risperdal Consta, adverse effects may not be seen for 2-6 weeks after the overdose.
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 Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

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-hydroxyrisperidone.
Central dopamine D₂-receptor antagonism is considered to be the mechanism of action by which conventional neuroleptics improve the positive symptoms of schizophrenia, but also induce extrapyramidal symptoms and release of prolactin.
Although risperidone antagonises dopamine D₂-receptors and causes release of prolactin, it is less potent than classical neuroleptics for depression of motor activity and for induction of catalepsy in animals.
Balanced central serotonin and dopamine antagonism may reduce extrapyramidal side effect liability and extend the therapeutic activity to the negative and affective symptoms of schizophrenia.
Due to the α-blocking activity of risperidone, orthostatic hypotension can occur, especially during the initial dose titration period. This α-blocking activity may also induce nasal mucosal swelling, which is probably related to the observed incidence of rhinitis associated with the use of risperidone.
Antagonism of serotoninergic and histaminergic receptors may induce body weight gain.
In controlled clinical trials, risperidone was found to improve positive symptoms (such as hallucinations, delusions, thought disturbances, hostility, suspiciousness), as well as negative symptoms (such as blunted affect, emotional and social withdrawal, poverty of speech). Risperidone may also alleviate affective symptoms (such as depression, guilt feelings, anxiety) associated with schizophrenia.

Clinical trials.

Schizophrenia.

The effectiveness of Risperdal Consta (25 mg and 50 mg) in the management of the manifestations of psychotic disorders (schizophrenia/ schizoaffective) was established in one 12 week, placebo controlled trial in adult psychotic inpatients and outpatients who met the DSM-IV criteria for schizophrenia (RIS-USA-121; see Figure 1).
Further trials included a 12 week noninferiority comparative trial in stable patients with schizophrenia, in which Risperdal Consta was shown to be as effective as the oral tablet formulation (RIS-INT-61). The long-term (50 weeks) safety and efficacy of Risperdal Consta was also evaluated in an open label trial of stable psychotic inpatients and outpatients who met the DSM-IV criteria for schizophrenia or schizoaffective disorder (RIS-INT-57; see Figure 2). Over time efficacy was maintained with Risperdal Consta.
These efficacy trials used the internationally recognised PANSS scale. The total score (30 items) is divided into subscales: 8 items covering positive symptoms (e.g. hallucinations and delusions), 7 covering negative symptoms (e.g. blunted affect), 7 covering disorganised thought, 4 covering uncontrolled hostility/ excitement and 4 covering anxiety/ depression. Each item is scored on a seven point item specific Likert scale ranging from 1 to 7.
The safety information is available in the safety section of this document.

Bipolar I disorder.

In a pivotal 24 month placebo controlled trial (RIS-BIM-3003) male and female patients aged 18 to 65 with bipolar disorder type I who achieved remission on Risperdal Consta during an open label 26 week initial stabilisation phase were randomised to receive either Risperdal Consta as monotherapy or placebo during a 2 year, double blind treatment period. A total of 559 patients were enrolled in the study, of which a total of 303 subjects (54%) were randomly assigned to double blind treatment with Risperdal Consta (n = 154) or placebo (n = 149). Patients receiving Risperdal Consta demonstrated superiority over placebo in preventing recurrence of a mood episode. There was a statistically significant difference (p < 0.001; log rank test) between treatment groups in the time to recurrence during double blind treatment in favour of Risperdal Consta, with 30% of patients experiencing a recurrence in the Risperdal Consta group versus 56% in the placebo group during the 2 year double blind follow-up period. The relative reduction in risk of recurrence, as reflected by the treatment:placebo hazard ratio [95% CI], was 0.40 [0.27, 0.59]. The majority of recurrences were due to manic rather than depressive symptoms. Risperdal Consta was not effective in delaying the time to occurrence of a depressed mood episode. (See Figure 3.)

In a supporting 52 week placebo controlled study (RIS-BIP-302), male and female patients, aged 18 to 70, with primarily bipolar disorder type I (87%, with 13% bipolar disorder type II) who had at least 4 episodes of mood disorder requiring psychiatric/ clinical intervention in the 12 months prior to study entry (at least 2 of which were in the 6 months prior to study entry) were enrolled. Patients entered a 16 week open label stabilisation period prior to randomisation and received Risperdal Consta as adjunctive therapy to their usual treatments for bipolar disorder. The usual treatments for bipolar disorder included one or more of the following: valproic acid derivatives, lithium carbonate, lamotrigine, benzodiazepines, and/or antidepressants (serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, tricyclic antidepressants, mirtazapine, bupropion, trazodone). Patients taking carbamazepine, oxcarbazepine, paroxetine or fluoxetine were excluded from the study. A total of 275 patients were enrolled, of which 139 (51%) patients were randomised to receive either Risperdal Consta plus treatment as usual (n = 72) or placebo plus treatment as usual (n = 67) in the 52 week double blind follow-up period. Treatment as usual was valproate or lithium (or both) for 89% of patients in the Risperdal Consta group and 96% of patients in the placebo group. There was a statistically significant difference (p < 0.004; log rank test) between treatment groups in the time to recurrence during double blind treatment in favour of Risperdal Consta, with 22% of patients in the Risperdal Consta group versus 48% in the placebo group experiencing a recurrence. Risperdal Consta as adjunctive therapy to treatment as usual demonstrated superiority over placebo plus treatment as usual in preventing recurrence of both elevated and depressed mood episodes.

5.2 Pharmacokinetic Properties

Absorption.

The absorption of risperidone from Risperdal Consta is presumably complete following breakdown of the microspheres.

Distribution.

Risperidone is rapidly distributed following oral administration. 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 90% and that of 9-hydroxyrisperidone is 77%.

Metabolism.

In vitro data suggests that drugs that inhibit the metabolism of risperidone to 9-hydroxyrisperidone by inhibition of cytochrome P450 2D6 would increase the plasma concentration of risperidone and lower the plasma concentration of 9-hydroxyrisperidone. Drugs metabolised by other P450 isoenzymes are only weak inhibitors of risperidone metabolism in vitro. Although in vitro studies suggest that risperidone can inhibit cytochrome P4502D6, 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.

Excretion.

Risperidone plus 9-hydroxyrisperidone and risperidone clearances were 5.0 and 13.7 L/hour in extensive metabolisers, respectively, and 3.2 and 3.3 L/hour in poor metabolisers of CYP2D6, respectively.

Disposition of risperidone after administration of Risperdal Consta.

After a single IM injection with Risperdal Consta the release profile consists of a small initial release of drug (< 1% of the dose), followed by a lag time of 3 weeks. Following IM injection, the main release of drug starts from 3 weeks onwards, is maintained from 4 to 6 weeks and subsides by week 7. Oral antipsychotic supplementation should therefore be given during the first 3 weeks of Risperdal Consta treatment.
The combination of the release profile and the dosage regimen (IM injection every two weeks) result in sustained therapeutic plasma concentrations. Therapeutic plasma concentrations remain until 4 to 6 weeks after the last Risperdal Consta injection. The elimination phase is complete approximately 7 to 8 weeks after the last injection.
After repeated IM injections with 25 or 50 mg Risperdal Consta every two weeks, median trough and peak plasma concentrations of risperidone plus 9-hydroxyrisperidone fluctuated between 9.9-19.2 nanogram/mL and 17.9-45.5 nanogram/mL respectively. The pharmacokinetics of risperidone are linear in the dose range of 25-50 mg injected every 2 weeks. No accumulation of risperidone was observed during long-term use (12 months) in patients who were injected with 25-50 mg every two weeks.
The above studies were conducted with gluteal intramuscular injection. Deltoid and gluteal intramuscular injections at the same doses are bioequivalent and, therefore, interchangeable.
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.
One week after administration of oral risperidone, 70% of the dose is excreted in the urine and 14% in faeces. In urine, risperidone and 9-hydroxyrisperidone represent 35-45% of the dose.
An oral, single dose study showed higher active plasma concentrations and a slower elimination of risperidone by 30% in the elderly and 60% in patients with renal insufficiency. Risperidone plasma concentrations were normal in patients with liver insufficiency, but the unbound risperidone was somewhat increased by about 35% due to diminished concentration of both α₁-acid glycoprotein and albumin.

Pharmacokinetic/ pharmacodynamic relationship.

There was no apparent relationship between the plasma concentrations of risperidone plus 9-hydroxyrisperidone and the change in total PANSS (positive and negative syndrome scale) and total ESRS (extrapyramidal symptom rating scale) scores across the assessment visits in any of the phase III trials where efficacy and safety were examined.

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.
In a 2 year IM carcinogenicity study in rats, increased incidences of mammary gland adenocarcinoma, pancreatic islet cell adenoma, adrenal gland phaeochromocytoma, pituitary gland adenoma and renal corticotubular adenoma were observed, with systemic exposure (plasma AUC) to risperidone plus 9-hydroxyrisperidone about twice that anticipated in humans at the maximal recommended clinical dose of Risperdal Consta. Increased incidences of mammary adenocarcinoma were also observed at doses for which the plasma AUC of risperidone plus 9-hydroxyrisperidone was less than anticipated clinical exposure, a no-effect dose for this finding was not determined. Elevated plasma concentrations of prolactin were present after one year of treatment, but the relationship between the renal tubular tumours and prolactin is uncertain. The increase in phaeochromocytomas was associated with hypercalcemia but there was no evidence for a causal relationship. However, phaeochromocytomas associated with hypercalcemia is a common finding in rats and is likely to be of low relevance to humans.
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)).
Local irritation at the injection site was observed in dogs and rats after administration of Risperdal Consta. In a 2 year IM carcinogenicity study in rats, no increased incidence of injection site tumours was seen in either the vehicle or active drug groups.

6 Pharmaceutical Particulars

6.1 List of Excipients

The powder contains risperidone and polyglactin.
The diluent contains carmellose sodium, citric acid, dibasic sodium phosphate dihydrate, polysorbate 20, sodium chloride, sodium hydroxide and water for injections.

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

Before reconstitution, the entire dose pack should be stored in the refrigerator (2-8°C) and protected from light. It should not be exposed to temperatures above 25°C.
If refrigeration is unavailable, Risperdal Consta can be stored at temperatures not exceeding 25°C for no more than 7 days prior to administration. Do not expose unrefrigerated product to temperatures above 25°C.
After reconstitution, the product should be used immediately. The maximum allowable storage time at room temperature is 6 hours. If the product is not used right away it should be shaken vigorously to resuspend. Do not refrigerate or refreeze. Keep out of the reach of children.

6.5 Nature and Contents of Container

Contents of the dose pack:
One vial containing Risperdal Consta extended release microspheres.
One Vial Adapter for reconstitution.
One prefilled syringe containing the diluent for Risperdal Consta.
Two Terumo SurGuard-3 Needles for intramuscular injection (a 21G UTW 1-inch safety needle with needle protection device for deltoid administration and a 20G TW 2-inch safety needle with needle protection device for gluteal administration).

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Risperidone is a white to off white crystalline powder, practically insoluble in water, freely soluble in methylene chloride, sparingly soluble in ethanol (96%) and dissolves in dilute acid solutions.

Chemical structure.

Risperidone is chemically identified as 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. Structural formula:

C₂₃H₂₇FN₄O₂. MW=410.49.

CAS number.

106266-06-2.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

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