Junior Strenght Advil

Ingredient matches for Junior Strenght Advil

Ibuprofen

Ibuprofen is reported as an ingredient of Junior Strenght Advil in the following countries:

• United States

International Drug Name Search

Xyloproct 5% / 0.275% Ointment

Xyloproct 5%/0.275% Ointment

lidocaine, hydrocortisone acetate

Read all of this leaflet carefully before you start using this medicine.

• 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. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.


• If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

In this leaflet:

• 1. What Xyloproct Ointment is and what it is used for


• 2. Before you use Xyloproct Ointment


• 3. How to use Xyloproct Ointment


• 4. Possible side effects


• 5. How to store Xyloproct Ointment


• 6. Further information

What Xyloproct Ointment is and what it is used for

What Xyloproct Ointment is

The name of your medicine is ‘Xyloproct 5%/0.275% Ointment’. It is referred to as ‘Xyloproct Ointment’ in the rest of this leaflet.

Xyloproct Ointment contains two medicines: lidocaine and hydrocortisone.

• Lidocaine (sometimes known as lignocaine) belongs to a group of medicines called local anaesthetics.


• Hydrocortisone belongs to a group of medicines called corticosteroids.

What Xyloproct Ointment is used for

• Xyloproct Ointment can be used to relieve itching around the back passage (anus) or female private parts (genitals).


• It can also be used to relieve the symptoms of piles (haemorrhoids) and other problems that affect the back passage. These symptoms include pain and inflammation.

Before you use Xyloproct Ointment

Do not use Xyloproct Ointment if:

• You are allergic (hypersensitive) to lidocaine or hydrocortisone or any of the other ingredients of Xyloproct Ointment (listed in Section 6: Further information).


• You have ever had an allergic reaction to other local anaesthetics or to other corticosteroid medicines.


• You have an infection where the ointment is going to be put and the infection is not being treated.


• You are not in hospital and you are taking medicines for an uneven heart beat (such as amiodarone or sotalol).

Do not use Xyloproct Ointment if any of the above apply to you. If you are not sure, talk to your doctor or pharmacist before using Xyloproct Ointment.

Take special care with Xyloproct Ointment

Check with your doctor or pharmacist before using Xyloproct Ointment if:

• Your skin is very thin or fragile where the ointment is going to be put.


• You have an infection where the ointment is going to be put. If this applies to you, your doctor may ask you to use another medicine as well as Xyloproct Ointment.


• You have ever been told that you have a rare disease of the blood pigment called ‘porphyria’ or anyone in your family has it.

Taking other medicines

Please tell your doctor or pharmacist if you are taking, or have recently taken, any other medicines. This includes medicines that you buy without a prescription and herbal medicines. This is because Xyloproct Ointment can affect the way some medicines work and some medicines can have an effect on Xyloproct Ointment.

In particular, tell your doctor or pharmacist if you are taking or using any of the following medicines:

• Medicines for an uneven heart beat (such as amiodarone or sotalol).


• Other local anaesthetics.

Pregnancy and breast-feeding

Talk to your doctor before using Xyloproct Ointment if you are pregnant, may become pregnant or are breast-feeding.

Your doctor will decide if you can use Xyloproct Ointment during this time.

How to use Xyloproct Ointment

Always use Xyloproct Ointment exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure. Always wash your hands well before and after using this medicine.

How much Xyloproct Ointment to use

• Your doctor will tell you how much ointment to use and how often to use it.


• Usually the ointment should be put on the affected area several times a day.


• Up to 6 g (grams) of ointment can be used each day. This is about a third of a tube.

How long to use Xyloproct Ointment for

• Xyloproct Ointment should only be used for limited periods of time.


• With longer periods of treatment (up to 3 weeks) your doctor may suggest that you have a break from treatment, especially if you are getting irritation around or inside where the ointment is applied.


• If you get irritation, your doctor may do a patch test to see if it is being caused by Xyloproct Ointment.

Using the applicator

• The ointment comes with an applicator. Your doctor will tell you if you need to use this.


• If your doctor tells you to use the applicator, be careful not to put too much ointment inside the back passage, especially if it is being given to a child.


• Clean the applicator very well after each use.

If you use more Xyloproct Ointment than you should

• If you use too much ointment talk to your doctor as soon as possible.


• It is particularly important to talk to your doctor as soon as possible if a child has been given too much ointment.
  This is because fits have sometimes happened in children who have been given too much.

Possible side effects

Like all medicines, Xyloproct Ointment can cause side effects, although not everybody gets them.

Stop using Xyloproct Ointment and talk to your doctor straight away if you notice any of the following – you may need urgent medical treatment:

• Sudden onset of rash, itching or hives on the skin.


• Swelling of the face, lips, tongue or other parts of the body.


• Shortness of breath, wheezing or trouble breathing.

This may mean that you are having an allergic reaction.

Stop using Xyloproct Ointment and talk to your doctor if you notice any of the following:

• Soreness in your back passage.


• Bleeding from your back passage.

Other possible side effects:

• Redness, swelling and itching where Xyloproct Ointment has been put on your body.

If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

How to store Xyloproct Ointment

• The ointment should be kept in a safe place where children cannot reach and see it.


• Xyloproct Ointment can be stored between 2°C and 8°C (in a refrigerator).


• When you start using the ointment, the tube can be stored at room temperature (up to 25°C) for up to 2 months. Any remaining ointment should then be discarded.


• Do not use Xyloproct Ointment after the expiry date which is stated on the tube.


• Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines that are no longer required. This will help to protect the environment.

Further information

What Xyloproct Ointment contains

The active substances in Xyloproct Ointment are lidocaine and hydrocortisone acetate. Each gram of Xyloproct Ointment contains 50 mg (milligrams) of lidocaine and 2.75 mg of hydrocortisone acetate.

The other ingredients are zinc oxide, aluminium acetate, stearyl alcohol, cetyl alcohol, purified water and macrogol (3350 and 400).

What Xyloproct Ointment looks like and contents of the pack

Xyloproct Ointment is white to slightly yellow in colour. It comes in an aluminium tube that contains 20 g (grams) of the ointment. An applicator is provided.

Marketing Authorisation Holder and Manufacturer

The Marketing Authorisation for Xyloproct Ointment is held by

AstraZeneca UK Limited

600 Capability Green

Luton

LU1 3LU

UK

Xyloproct Ointment is manufactured by

AstraZeneca AB

S-151 85

Södertälje

Sweden

To listen to or request a copy of this leaflet in Braille, large print or audio please call, free of charge:

0800 198 5000 (UK only)

Please be ready to give the following information:

Product name Xyloproct Ointment

Reference number 17901/0179

This is a service provided by the Royal National Institute of Blind People.

Leaflet prepared: October 2009

© AstraZeneca 2009

Xyloproct is a trade mark of the AstraZeneca group of companies.

PAI 09 0049

48 076 00 28

Juvela N

Juvela N may be available in the countries listed below.

Ingredient matches for Juvela N

Tocopherol, α-

Tocopherol, α- nicotinate (a derivative of Tocopherol, α-) is reported as an ingredient of Juvela N in the following countries:

• Japan


• Taiwan

International Drug Name Search

Jurox Domperidone

Jurox Domperidone may be available in the countries listed below.

In some countries, this medicine may only be approved for veterinary use.

Ingredient matches for Jurox Domperidone

Domperidone

Domperidone is reported as an ingredient of Jurox Domperidone in the following countries:

• New Zealand

International Drug Name Search

Junior Parapaed

Junior Parapaed may be available in the countries listed below.

Ingredient matches for Junior Parapaed

Paracetamol

Paracetamol is reported as an ingredient of Junior Parapaed in the following countries:

• Malta


• New Zealand

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Jutalex

Jutalex may be available in the countries listed below.

Ingredient matches for Jutalex

Sotalol

Sotalol hydrochloride (a derivative of Sotalol) is reported as an ingredient of Jutalex in the following countries:

• Germany

International Drug Name Search

Jodbalance

Jodbalance may be available in the countries listed below.

Ingredient matches for Jodbalance

Potassium Iodide

Potassium Iodide is reported as an ingredient of Jodbalance in the following countries:

• Georgia


• Russian Federation

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Jodgamma

Jodgamma may be available in the countries listed below.

Ingredient matches for Jodgamma

Potassium Iodide

Potassium Iodide is reported as an ingredient of Jodgamma in the following countries:

• Germany

International Drug Name Search

Jactuss

Jactuss may be available in the countries listed below.

Ingredient matches for Jactuss

Zipeprol

Zipeprol dihydrochloride (a derivative of Zipeprol) is reported as an ingredient of Jactuss in the following countries:

• Greece

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Xylocaine 1% and 2% with Adrenaline

P023526

Xylocaine 1% and 2% with adrenaline (epinephrine) 1:200,000 Solution for Injection

lidocaine, adrenaline (epinephrine)

Read all of this leaflet carefully before Xylocaine with adrenaline is given to you.

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


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


• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.


• If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or nurse.

In this leaflet:

• 1. What Xylocaine with adrenaline is and what it is used for


• 2. Before Xylocaine with adrenaline is given to you


• 3. How Xylocaine with adrenaline is given to you


• 4. Possible side effects


• 5. How to store Xylocaine with adrenaline


• 6. Further information

What Xylocaine with adrenaline is and what it is used for

The name of your medicine is ‘Xylocaine 1% with adrenaline (epinephrine) 1:200,000’ or ‘Xylocaine 2% with adrenaline (epinephrine) 1:200,000’. It is referred to as ‘Xylocaine with adrenaline’ in the rest of this leaflet.

Xylocaine with adrenaline contains two different medicines: lidocaine and adrenaline (epinephrine). Each of these works in a different way.

• Lidocaine belongs to a group of medicines called local anaesthetics. These medicines numb (anaesthetise) parts of the body.


• Adrenaline (epinephrine) belongs to a group of medicines called vasoconstrictors. These medicines make the blood vessels where the injection is given narrower. This means you will bleed less and the effects of the medicine will last longer.

Xylocaine with adrenaline is used to stop pain happening during medical procedures and surgery (operations).

Before Xylocaine with adrenaline is given to you

You must not be given Xylocaine with adrenaline if:

• You are allergic (hypersensitive) to lidocaine, adrenaline or any of the other ingredients of Xylocaine with adrenaline (see Section 6: Further information).


• You are allergic to any other local anaesthetics.

You must not be given Xylocaine with adrenaline if any of the above apply to you. If you are not sure, talk to your doctor before you are given it.

Take special care with Xylocaine with adrenaline

Check with your doctor before having Xylocaine with adrenaline if:

• You have high blood pressure or heart problems such as a slow heart beat.


• You have been told that you have hypovolaemia (decreased volume of blood).


• You have liver or kidney problems.


• You have difficulty breathing.


• You have epilepsy.


• You have diabetes.


• You have thyroid problems.


• You have ever had a stroke.


• You have an infection or inflammation at the site where the injection is to be given.


• You have ever been told that you have a rare disease of the blood pigment called ‘porphyria’ or anyone in your family has it.

If you are not sure if any of the above apply to you, talk to your doctor before having Xylocaine with adrenaline.

Taking other medicines

Please tell your doctor if you are taking, or have recently taken, any other medicines. This includes medicines that you buy without a prescription and herbal medicines. This is because Xylocaine with adrenaline can affect the way some medicines work and some medicines can have an effect on Xylocaine with adrenaline.

In particular, tell your doctor if you are taking any of the following medicines:

• Other local anaesthetics.


• Other medicines that contain adrenaline.


• Halothane (a general anaesthetic).


• Medicines used to treat an uneven heart beat (arrhythmia) such as amiodarone.


• Beta-blockers medicines such as propranolol.


• Butyrophenone medicines for sickness, such as domperidone.


• Other butyrophenone medicines for mental problems, such as haloperidol.


• Phenothiazine medicines for mental problems, such as chlorpromazine.


• Medicines for depression such as monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants.


• Medicines that induce labour.


• Cimetidine.

Pregnancy and breast-feeding

Before you are given Xylocaine with adrenaline, tell your doctor if you are pregnant, planning to get pregnant, or if you are breast-feeding.

Ask your doctor or pharmacist for advice before taking any medicine if you are pregnant or breast-feeding.

Driving and using machines

Xylocaine with adrenaline may make you feel sleepy and affect the speed of your reactions. After you have been given Xylocaine with adrenaline, you should not drive or use tools or machines until the next day.

Important information about some of the ingredients of Xylocaine with adrenaline

• Xylocaine with adrenaline contains 2.49 mg of sodium per millilitre (ml), equivalent to 49.8 mg per 20 ml. Your doctor will take this into account if you are on a sodium controlled diet.


• Xylocaine with adrenaline contains methyl parahydroxybenzoate (E218). This may cause an allergic reaction such as skin rashes. This may happen a while after you have been given the medicine. Rarely, you may have a reaction immediately with a skin rash and breathlessness.


• Xylocaine with adrenaline contains sodium metabisulphite. This may rarely cause an allergic reaction and breathlessness.

How Xylocaine with adrenaline is given to you

Xylocaine with adrenaline will be given to you by a doctor. It will be given to you as an injection. The dose that your doctor gives you will depend on the type of pain relief that you need. It will also depend on your body size, age, physical condition and the part of your body that the medicine is being injected into. You will be given the smallest dose possible to produce the required effect.

Xylocaine with adrenaline will usually be given near the part of the body to be operated on. It stops the nerves from being able to pass pain messages to the brain. It will stop you feeling pain. It will start to work a few minutes after being injected and will slowly wear off when the medical procedure is over.

If you have been given too much Xylocaine with adrenaline

Serious side effects from getting too much Xylocaine with adrenaline need special treatment and the doctor treating you is trained to deal with these situations. The first signs of being given too much Xylocaine with adrenaline are usually as follows:

• Feeling dizzy or light-headed.


• Numbness of the lips and around the mouth.


• Numbness of the tongue.


• Hearing problems.


• Problems with your sight (vision).

To reduce the risk of serious side effects, your doctor will stop giving you Xylocaine with adrenaline as soon as these signs appear. This means that if any of these happen to you, or you think you have received too much Xylocaine with adrenaline, tell your doctor immediately.

More serious side effects from being given too much Xylocaine with adrenaline include problems with your speech, irrational behaviour, twitching of your muscles, fits (seizures), effects on your heart and blood vessels, loss of consciousness, coma and stopping breathing for a short while (apnoea).

Possible side effects

Like all medicines, Xylocaine with adrenaline may cause side effects although not everybody gets them.

Severe allergic reactions (rare, affect less than 1 in 1,000 people)

If you have a severe allergic reaction, tell your doctor immediately. The signs may include sudden onset of:

• Swelling of your face, lips, tongue or throat. This may make it difficult to swallow.


• Severe or sudden swelling of your hands, feet and ankles.


• Difficulty breathing.


• Severe itching of the skin (with raised lumps).

Other possible side effects:

• Numbness where the injection is given. This will go away slowly.

Common (affects less than 1 in 10 people)

• Low blood pressure. This might make you feel dizzy or light-headed.


• High blood pressure.


• Feeling sick (nausea) or being sick (vomiting).


• Pins and needles.


• Feeling dizzy.


• Slow heart beat.

Uncommon (affects less than 1 in 100 people)

• Ringing in the ears (tinnitus) or being sensitive to sound.


• Difficulty in speaking.


• Numbness of the tongue or around the mouth.


• Fits (seizures).


• Feeling sleepy.


• Shakiness.


• Blurred vision.

Rare (affects less than 1 in 1,000 people)

• Uneven heart beat (arrhythmias).


• Nerve damage that may cause changes in sensation or muscle weakness (neuropathy). This may include peripheral nerve damage.


• A condition called arachnoiditis (inflammation of a membrane that surrounds the spinal cord). The signs include a stinging or burning pain in the lower back or legs and tingling, numbness or weakness in the legs.


• Double vision.


• Slowed or stopped breathing or stopped heart beat.

Possible side effects seen with other local anaesthetics which might also be caused by Xylocaine with adrenaline include:

• Damaged nerves which may cause permanent problems.

Do not be concerned by this list of possible side effects. You may not get any of them. If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or nurse.

How to store Xylocaine with adrenaline

• Keep out of the reach and sight of children.


• Do not use after the expiry date which is stated on the vial and container after EXP. The expiry date refers to the last day of that month.


• Store between 2 and 8°C in a fridge.


• Your doctor or the hospital will normally store Xylocaine with adrenaline and they are responsible for the quality of the product when it has been opened if it is not used immediately. They are also responsible for disposing of any unused Xylocaine with adrenaline correctly.

Further information

What Xylocaine 1% and 2% with adrenaline (epinephrine) 1:200,000 contains

The active ingredients are lidocaine and adrenaline (epinephrine). Each millilitre (ml) of solution contains 10 milligrams or 20 milligrams of lidocaine hydrochloride anhydrous as the monohydrate and 5 micrograms of adrenaline (epinephrine) as the acid tartrate.

The other ingredients are sodium chloride, sodium metabisulphite, methyl parahydroxybenzoate, sodium hydroxide, hydrochloric acid and water for injections.

What Xylocaine 1% and 2% with adrenaline (epinephrine) 1:200,000 looks like and contents of the pack

Xylocaine 1% and 2% with adrenaline (epinephrine) 1:200,000 is a solution for injection. It comes in multi-dose vials of 20 ml or 50 ml. Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

The Marketing Authorisations for Xylocaine 1% and 2% with adrenaline (epinephrine) 1:200,000 are held by

AstraZeneca UK Ltd

600 Capability Green

Luton

LU1 3LU

UK

Xylocaine 1% and 2% with adrenaline (epinephrine) 1:200,000 is manufactured by

AstraZeneca UK Ltd

Silk Road Business Park

Macclesfield

Cheshire

SK10 2NA

UK

To listen to or request a copy of this leaflet in Braille, large print or audio please call, free of charge:

0800 198 5000 (UK only)

Please be ready to give the following information:

Product name : Reference number

Xylocaine 1% with Adrenaline (epinephrine) : 17901/0174

Xylocaine 2% with Adrenaline (epinephrine) : 17901/0175

This is a service provided by the Royal National Institute of Blind People.

Leaflet prepared: June 2009.

© AstraZeneca 2009.

Xylocaine is a trade mark of the AstraZeneca group of companies.

PAI 09 0042

Jectyl

Jectyl may be available in the countries listed below.

In some countries, this medicine may only be approved for veterinary use.

Ingredient matches for Jectyl

Tylosin

Tylosin is reported as an ingredient of Jectyl in the following countries:

• Portugal

International Drug Name Search

Jectofer

Jectofer may be available in the countries listed below.

Ingredient matches for Jectofer

Iron Sorbitex

Iron Sorbitex is reported as an ingredient of Jectofer in the following countries:

• Bahrain


• Cyprus


• Egypt


• Iraq


• Jordan


• Kuwait


• Lebanon


• Libya


• Qatar


• Saudi Arabia


• Syria


• United Arab Emirates


• Yemen

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Jasovit-E

Jasovit-E may be available in the countries listed below.

Ingredient matches for Jasovit-E

Tocopherol, α-

Tocopherol, α- is reported as an ingredient of Jasovit-E in the following countries:

• Bangladesh

International Drug Name Search

Jarvis

Jarvis may be available in the countries listed below.

Ingredient matches for Jarvis

Venlafaxine

Venlafaxine hydrochloride (a derivative of Venlafaxine) is reported as an ingredient of Jarvis in the following countries:

• Hungary

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Jalra

Jalra may be available in the countries listed below.

Ingredient matches for Jalra

Vildagliptin

Vildagliptin is reported as an ingredient of Jalra in the following countries:

• Germany


• Greece


• Slovakia

International Drug Name Search

Josty Antiparasite Classic

Josty Antiparasite Classic may be available in the countries listed below.

In some countries, this medicine may only be approved for veterinary use.

Ingredient matches for Josty Antiparasite Classic

Dimpylate

Dimpylate is reported as an ingredient of Josty Antiparasite Classic in the following countries:

• Switzerland

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Jutaxan

Jutaxan may be available in the countries listed below.

Ingredient matches for Jutaxan

Enalapril

Enalapril maleate (a derivative of Enalapril) is reported as an ingredient of Jutaxan in the following countries:

• Germany

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Xomolix® 2.5mg / ml solution for injection

1. Name Of The Medicinal Product

Xomolix^®

2. Qualitative And Quantitative Composition

Each millilitre of the solution contains 2.5 mg droperidol.

Excipient: sodium < 23 mg per ml.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Solution for injection.

Clear colourless solution, free from visible particles.

The pH of droperidol solution for injection is 3.0 – 3.8 and has an osmolarity of approximately 300 milliosmol /kg water.

4. Clinical Particulars

4.1 Therapeutic Indications

• Prevention and treatment of post-operative nausea and vomiting in adults and, as second line, in children and adolescents.

• Prevention of nausea and vomiting induced by morphine derivates during post-operative patient controlled analgesia (PCA) in adults.

Certain precautions are required when administering droperidol: see sections 4.2, 4.3, and 4.4.

4.2 Posology And Method Of Administration

For intravenous use.

Prevention and treatment of post-operative nausea and vomiting (PONV).

Adults: 0.625 mg to 1.25 mg (0.25 to 0.5 ml).

Elderly: 0.625 mg (0.25 ml)

Renal/hepatic impairment: 0.625 mg (0.25 ml)

Children (over the age of 2 years) and adolescents: 20 to 50 microgram/kg (up to a maximum of 1.25 mg).

Children (below the age of 2 years): not recommended.

Administration of droperidol is recommended 30 minutes before the anticipated end of surgery. Repeat doses may be given every 6 hours as required.

The dosage should be adapted to each individual case. The factors to be considered here include age, body weight, use of other medicinal products, type of anaesthesia and surgical procedure.

Prevention of nausea and vomiting induced by morphine derivatives during post-operative patient controlled analgesia (PCA).

Adults: 15 to 50 micrograms droperidol per mg of morphine, up to a maximum daily dose of 5 mg droperidol.

Elderly, renal and hepatic impairment: no data in PCA available.

Children (over the age of 2 years) and adolescents: not indicated in PCA.

Continuous pulse oximetry should be performed in patients with identified or suspected risk of ventricular arrhythmia and should continue for 30 minutes following single i.v. administration.

For instructions on dilution of the product before administration, see section 6.6.

See also sections 4.3, 4.4 and 5.1.

4.3 Contraindications

Droperidol is contraindicated in patients with:

• Hypersensitivity to droperidol or to any of the excipients;

• Hypersensitivity to butyrophenones;

• Known or suspected prolonged QT interval (QTc of > 450 msec in females and > 440 msec in males). This includes patients with congenitally long QT interval, patients who have a family history of congenital QT prolongation and those treated with medicinal products known to prolong the QT interval (see section 4.5);

• Hypokalaemia or hypomagnesaemia;

• Bradycardia (< 55 heartbeats per minute);

• Known concomitant treatment leading to bradycardia;

• Phaeochromocytoma;

• Comatose states;

• Parkinson's Disease;

• Severe depression.

4.4 Special Warnings And Precautions For Use

Central Nervous System

Droperidol may enhance CNS depression produced by other CNS-depressant drugs. Any patient subjected to anaesthesia and receiving potent CNS depressant medicinal products or showing symptoms of CNS depression should be monitored closely.

Concomitant use of metoclopramide and other neuroleptics may lead to an increase in extrapyramidal symptoms and should be avoided (see section 4.5).

Use with caution in patients with epilepsy (or a history of epilepsy) and conditions predisposing to epilepsy or convulsions.

Cardiovascular

Mild to moderate hypotension and occasionally (reflex) tachycardia have been observed following the administration of droperidol. This reaction usually subsides spontaneously. However, should hypotension persist, the possibility of hypovolaemia should be considered and appropriate fluid replacement administered.

Patients with, or suspected of having, the following risk factors for cardiac arrhythmia should be carefully evaluated prior to administration of droperidol:

- a history of significant cardiac disease including serious ventricular arrhythmia, second or third degree atrio-ventricular block, sinus node dysfunction, congestive heart failure, ischemic heart disease and left ventricular hypertrophy;

- family history of sudden death;

- renal failure (particularly when on chronic dialysis);

- significant chronic obstructive pulmonary disease and respiratory failure;

- risk factors for electrolyte disturbances, as seen in patients taking laxatives, glucocorticoids, potassium-wasting diuretics, in association with the administration of insulin in acute settings, or in patients with prolonged vomiting and/or diarrhoea.

Patients at risk for cardiac arrhythmia should have serum electrolytes and creatinine levels assessed and the presence of QT prolongation excluded prior to administration of droperidol.

Continuous pulse oximetry should be performed in patients with identified or suspected risk of ventricular arrhythmia and should continue for 30 minutes following single i.v. administration.

General

To prevent QT prolongation, caution is necessary when patients are taking medicinal products likely to induce electrolyte imbalance (hypokalaemia and/or hypomagnesaemia) e.g. potassium-wasting diuretics, laxatives and glucocorticoids.

Substances inhibiting the activity of cytochrome P450 iso-enzymes (CYP) CYP1A2, CYP3A4 or both could decrease the rate at which droperidol is metabolised and prolong its pharmacological action. Hence, caution is advised if droperidol is given concomitantly with strong CYP1A2 and CYP3A4 inhibitors (see section 4.5).

Patients who have, or are suspected of having, a history of alcohol abuse or recent high intakes, should be thoroughly assessed before droperidol is administered.

In case of unexplained hyperthermia, it is essential to discontinue treatment, since this sign may be one of the elements of malignant syndrome reported with neuroleptics.

The dose should be reduced in the elderly and those with impaired renal and hepatic function (see section 4.2).

This medicinal product contains less than 1 mmol sodium (23 mg) per 1 ml, i.e. essentially 'sodium-free'.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Contraindicated for concomitant use

Medicinal products known to prolong the QTc interval should not be concomitantly administered with droperidol. Examples include certain antiarrhythmics, such as those of Class IA (e.g. quinidine, disopyramide, procainamide) and Class III (e.g. amiodarone, sotalol); macrolide antibiotics (e.g. azithromycin, erythromycin, clarithromycin), fluoroquinolone antibiotics (e.g. sparfloxacin); certain antihistamines (e.g. astemizole, terfenadine); tricyclic antidepressants (e.g. amitriptyline); certain tetracyclic antidepressants (e.g. maprotiline); certain antipsychotic medications (e.g. amisulpride, chlorpromazine, haloperidol, melperone, phenothiazines, pimozide, sulpiride, sertindole, tiapride); SSRIs (e.g. fluoxetine, sertraline, fluvoxamine); anti-malaria agents (e.g. quinine, chloroquine, halofantrine); cisapride, pentamidine, tacrolimus, tamoxifen, and vincamine.

Concomitant use of medicinal products that induce extrapyramidal symptoms, e.g. metoclopramide and other neuroleptics, may lead to an increased incidence of these symptoms and should therefore be avoided.

Consumption of alcoholic beverages and medicines should be avoided.

Caution is advised for concomitant use

To prevent QT prolongation, caution is necessary when patients are taking medicinal products likely to induce electrolyte imbalance (hypokalaemia and/or hypomagnesaemia) e.g. potassium-wasting diuretics, laxatives and glucocorticoids.

Droperidol may potentiate the action of sedatives (barbiturates, benzodiazepines, morphine derivatives). The same applies to antihypertensive agents, so that orthostatic hypotension may ensue.

Like other sedatives, droperidol may potentiate respiratory depression caused by opioids.

Since droperidol blocks dopamine receptors, it may inhibit the action of dopamine agonists, such as bromocriptine, lisuride, and of L-dopa.

Substances inhibiting the activity of cytochrome P450 iso-enzymes (CYP) CYP1A2, CYP3A4 or both could decrease the rate at which droperidol is metabolised and prolong its pharmacological action. Hence, caution is advised if droperidol is given concomitantly with CYP1A2 (e.g. ciprofloxacin, ticlopidine), CYP3A4 inhibitors (e.g. diltiazem, erythromycin, fluconazole, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, verapamil) or both (e.g. cimetidine, mibefradil).

4.6 Pregnancy And Lactation

Pregnancy

In a prospective study, 80 patients suffering from hyperemesis gravidarum received high doses of droperidol (average 1 mg/h over 50 hours) to control nausea and vomiting. Gestational age at delivery, mean birth weight, incidence of pre-term birth and incidence of 'small for gestational age' were comparable to a historic control group. Another study, in which 28 patients received droperidol 1 mg/hour over 40 hours on average, showed no statistically significant differences between treatment and historic control groups for spontaneous abortions, elective abortions, Apgar scores, gestational age at delivery and birth weight.

Droperidol has not been shown to be teratogenic in rats. Animal studies are insufficient with respect to the effects on pregnancy and embryonal/foetal, parturition and postnatal development.

In newborn babies from mothers under long-term treatment and high doses of neuroleptics, temporary neurological disturbances of extrapyramidal nature have been described.

In practice, as a precautionary measure, it is preferable not to administer droperidol during pregnancy. In late pregnancy, if its administration is necessary, monitoring of the newborn's neurological functions is recommended.

Lactation

Neuroleptics of the butyrophenone type are known to be excreted in breast milk; treatment with droperidol should be limited to a single administration. Repeat administration is not recommended.

4.7 Effects On Ability To Drive And Use Machines

Droperidol has major influence on the ability to drive and use machines.

Patients should not drive or operate a machine for 24 hours after droperidol administration.

4.8 Undesirable Effects

The most frequently reported events during clinical experience are incidents of drowsiness and sedation. In addition, less frequent reports of hypotension, cardiac arrhythmias, neuroleptic malignant syndrome (NMS) and symptoms associated with NMS, plus movement disorders, such as dyskinesias, plus incidents of anxiety or agitation have occurred.

System Organ Class	Common	Uncommon	Rare	Very Rare < 1/10,000	Not known (cannot be estimated from the available data)
Blood and lymphatic systems disorders				Blood dyscrasias
Immune system disorders			Anaphylactic reaction; Angioneurotic oedema; Hypersensitivity
Metabolism and nutrition disorders					Inappropriate anti-diuretic hormone secretion
Psychiatric disorders		Anxiety; Restlessness/Akathisia;	Confusional states; Agitation	Dysphoria	Hallucinations
Nervous system disorders	Drowsiness	Dystonia; Oculogyration		Extrapyramidal disorder; Convulsions; Tremor	Epileptic fits; Parkinson's disease; Psychomotor hyperactivity; Coma
Cardiac disorders		Tachycardia; Dizziness	Cardiac arrhythmias, including ventricular arrhythmias	Cardiac arrest	Torsade de pointes; Electrogram QT prolonged
Vascular disorders	Hypotension				Syncope
Respiratory, thoracic and mediastinal disorders					Bronchospasm; Laryngospasm
Skin and subcutaneous system disorders			Rash
General disorders and administration site conditions			Neuroleptic malignant syndrome (NMS)	Sudden death

Symptoms potentially associated with NMS have occasionally been reported i.e. changes in body temperature, stiffness and fever. An alteration in mental status with confusion or agitation and altered consciousness, have been seen. Autonomic instability may manifest as tachycardia, fluctuating blood pressure, excessive sweating/salivation and tremor. In extreme cases NMS may lead to coma, or renal and/or hepato-biliary problems.

Isolated cases of amenorrhoea, galactorrhoea, gynaecomastia, hyperprolactinaemia, and oligomenorrhoea have been associated with prolonged exposure in psychiatric indications.

4.9 Overdose

Symptoms

The manifestations of droperidol overdose are an extension of its pharmacologic actions.

Symptoms of accidental overdose are psychic indifference with a transition to sleep, sometimes in association with lowered blood pressure.

At higher doses or in sensitive patients, extrapyramidal disorders may occur (salivation, abnormal movements, sometimes muscle rigidity). Convulsions may occur at toxic doses.

Cases of QT-interval prolongation, ventricular arrhythmias and sudden death have been reported rarely.

Treatment

No specific antidote is known. However, when extrapyramidal reactions occur, an anticholinergic should be administered.

Patients with droperidol overdose should be closely monitored for signs of QT interval prolongation.

Factors which predispose to torsades de pointes, e.g. electrolyte disturbances (especially hypokalaemia or hypomagnesaemia) and bradycardia should be taken into consideration.

Pronounced hypotension should be treated by boosting circulation volume and taking other appropriate measures. Clear airways and adequate oxygenation should be maintained; an oropharyngeal airway or endotracheal tube might be indicated.

If required, the patient should be observed carefully for 24 hours or longer; body warmth and adequate fluid intake should be maintained.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Butyrophenone derivatives. ATC code: N05AD08.

Droperidol is a butyrophenone neuroleptic. Its pharmacologic profile is characterised mainly by dopamine-blocking and weak α₁-adrenolytic effects. Droperidol is devoid of anticholinergic and antihistaminic activity.

Droperidol's inhibitory action on dopaminergic receptors in the chemotrigger zone in the area postrema, gives it a potent antiemetic effect, especially useful for the prevention and treatment of postoperative nausea and vomiting and/or induced by opioid analgesics.

At a dose of 0.15 mg/kg, droperidol induces a fall in mean blood pressure (MBP), due to a decrease in cardiac output in a first phase, and then subsequently due to a decrease in pre-load. These changes occur independently of any alteration in myocardial contractility or vascular resistance. Droperidol does not affect myocardial contractility or heart rate, therefore has no negative inotropic effect. Its weak α₁-adrenergic blockade can cause a modest hypotension and decreased peripheral vascular resistance and may decrease pulmonary arterial pressure (particularly if it is abnormally high). It may also reduce the incidence of epinephrine-induced arrhythmia, but it does not prevent other forms of cardiac arrhythmia.

Droperidol has a specific antiarrhythmic effect at a dose of 0.2 mg/kg by an effect on myocardial contractility (prolongation of the refractory period) and a decrease in blood pressure.

Two studies (one placebo-controlled and one comparative active treatment-controlled) performed in the general anaesthesia setting and designed to better identify the QTc changes associated with postoperative nausea and vomiting treatment by small dose of droperidol (0.625 and 1.25 mg intravenous, and 0.75 mg intravenous, respectively) identified a QT interval prolongation at 3-6 min after administration of 0.625 and 1.25 mg droperidol (respectively 15 ± 40 and 22 ± 41 ms), but these changes did not differ significantly from that seen with saline (12 ± 35 ms). There were no statistically significant differences amongst the droperidol and saline groups in the number of patients with greater than 10% prolongation in QTc versus baseline. There was no evidence of droperidol-induced QTc prolongation after surgery.

No ectopic heartbeats were reported from the electrocardiographic records or 12-lead recordings during the perioperative period. The comparative active-treatment study with 0.75 mg intravenous droperidol identified a significant QTc interval prolongation (maximal of 17 ± 9 ms at the second minute after droperidol injection when compared with pre-treatment QTc measurement), with the QTc interval significantly lower after the 90^th minute.

5.2 Pharmacokinetic Properties

The action of a single intravenous dose commences 2-3 minutes following administration. The tranquillising and sedative effects tend to persist for 2 to 4 hours, although alertness may be affected for up to 12 hours.

Distribution

Following intravenous administration, plasma concentrations fall rapidly during the first 15 minutes. Plasma protein binding amounts to 85 – 90 %. The distribution volume is approximately 1.5 l/kg.

Metabolism

Droperidol is extensively metabolised in the liver, and undergoes oxidation, dealkylation, demethylation and hydroxylation by cytochrome P450 isoenzymes 1A2 and 3A4, and to a lesser extent by 2C19. The metabolites are devoid of neuroleptic activity.

Elimination

Elimination occurs mainly through metabolism; 75% are excreted via the kidneys. Only 1% of the active substance is excreted unchanged with urine, and 11% with faeces. Plasma clearance is 0.8 (0.4 - 1.8) l/min. The elimination half-life (t_½ß) is 134 ± 13 min.

5.3 Preclinical Safety Data

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity, genotoxic or carcinogenic potential, and reproductive toxicity.

Electrophysiological in vitro and in vivo studies indicate an overall risk of droperidol to prolong the QT interval in humans.

In humans, the free peak plasma concentration estimated above is approximately 4-fold higher to 25-fold lower than the droperidol concentrations affecting the endpoints examined in the different in vitro and in vivo test systems used to assess the impact of this drug on cardiac repolarisation. Plasma levels fall by about one order of magnitude over the first twenty minutes after administration.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Mannitol

Tartaric acid

Sodium hydroxide (for pH adjustment)

Water for injections

6.2 Incompatibilities

Incompatible with barbiturates. This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf Life

Unopened: 3 years.

After first opening: For immediate use.

Following dilution: Compatibility of droperidol with morphine sulphate in 0.9% sodium chloride (14 days at room temperature) has been demonstrated in plastic syringes. From a microbiological point of view, the diluted product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8 °C, unless dilution has taken place in controlled and validated aseptic conditions.

6.4 Special Precautions For Storage

Store in the original package.

6.5 Nature And Contents Of Container

Type I amber glass ampoules containing 1 ml solution for injection, in packs of 5 and 10 ampoules.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

For single use only. Any unused solution should be discarded.

The solution should be inspected visually prior to use. Only clear and colourless solutions free from visible particles should be used.

For use in PCA: Draw droperidol and morphine into a syringe and make up the volume with 0.9% sodium chloride for injection.

Any unused product or waste material should be disposed of in accordance with local requirements.

7. Marketing Authorisation Holder

ProStrakan Ltd

Galabank Business Park

Galashiels

TD1 1QH

United Kingdom

Tel. +44 (0)1896 664000

8. Marketing Authorisation Number(S)

PL 16508/0036

9. Date Of First Authorisation/Renewal Of The Authorisation

28.01.2008

10. Date Of Revision Of The Text

10/2009

11. LEGAL CLASSIFICATION

POM

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XEPLION 50 mg, 75 mg, 100 mg and 150 mg prolonged release suspension for injection

1. Name Of The Medicinal Product

XEPLION

XEPLION

XEPLION

XEPLION

2. Qualitative And Quantitative Composition

Each pre-filled syringe contains 78 mg paliperidone palmitate equivalent to 50 mg paliperidone.

Each pre-filled syringe contains 117 mg paliperidone palmitate equivalent to 75 mg paliperidone.

Each pre-filled syringe contains 156 mg paliperidone palmitate equivalent to 100 mg paliperidone.

Each pre-filled syringe contains 234 mg paliperidone palmitate equivalent to 150 mg paliperidone.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Prolonged release suspension for injection.

The suspension is white to off-white. The suspension is pH neutral (approximately 7.0).

4. Clinical Particulars

4.1 Therapeutic Indications

XEPLION is indicated for maintenance treatment of schizophrenia in adult patients stabilised with paliperidone or risperidone.

In selected adult patients with schizophrenia and previous responsiveness to oral paliperidone or risperidone, XEPLION may be used without prior stabilisation with oral treatment if psychotic symptoms are mild to moderate and a long-acting injectable treatment is needed.

4.2 Posology And Method Of Administration

Posology

Recommended initiation of XEPLION is with a dose of 150 mg on treatment day 1 and 100 mg one week later (day 8), both administered in the deltoid muscle in order to attain therapeutic concentrations rapidly (see section 5.2). The recommended monthly maintenance dose is 75 mg; some patients may benefit from lower or higher doses within the recommended range of 25 to 150 mg based on individual patient tolerability and/or efficacy. Patients who are overweight or obese may require doses in the upper range (see section 5.2). Following the second dose, monthly maintenance doses can be administered in either the deltoid or gluteal muscle.

Adjustment of the maintenance dose may be made monthly. When making dose adjustments, the prolonged release characteristics of XEPLION should be considered (see section 5.2), as the full effect of maintenance doses may not be evident for several months.

Switching from oral paliperidone or oral risperidone

Previous oral paliperidone or oral risperidone can be discontinued at the time of initiation of treatment with XEPLION. XEPLION should be initiated as described at the beginning of section 4.2 above.

Switching from Risperidone long acting injection.

When switching patients from risperidone long acting injection, initiate XEPLION therapy in place of the next scheduled injection. XEPLION should then be continued at monthly intervals. The one-week initiation dosing regimen including the intramuscular injections (day 1 and 8, respectively) as described in section 4.2 above is not required.

Patients previously stabilised on different doses of risperidone long acting injection can attain similar paliperidone steady-state exposure during maintenance treatment with XEPLION monthly doses according to the following:

Doses of Risperidone long acting injection and XEPLION needed to attain similar paliperidone exposure at steady-state

Previous Risperidone long acting injection dose	XEPLION injection
25 mg every 2 weeks	50 mg monthly
37.5 mg every 2 weeks	75 mg monthly
50 mg every 2 weeks	100 mg monthly

Discontinuation of antipsychotic medicinal products should be made in accordance with appropriate prescribing information. If XEPLION is discontinued, its prolonged release characteristics must be considered. As recommended with other antipsychotic medicinal products, the need for continuing existing extrapyramidal symptoms (EPS) medicine should be re-evaluated periodically.

Missed doses

Avoiding missed doses

It is recommended that the second initiation dose of XEPLION be given one week after the first dose. To avoid a missed dose, patients may be given the second dose 2 days before or after the one-week (day 8) time point. Similarly, the third and subsequent injections after the initiation regimen are recommended to be given monthly. To avoid a missed monthly dose, patients may be given the injection up to 7 days before or after the monthly time point.

If the target date for the second XEPLION injection (day 8 ± 2 days) is missed, the recommended reinitiation depends on the length of time which has elapsed since the patient's first injection.

Missed second initiation dose (< 4 weeks from first injection)

If less than 4 weeks have elapsed since the first injection, then the patient should be administered the second injection of 100 mg in the deltoid muscle as soon as possible. A third XEPLION injection of 75 mg in either the deltoid or gluteal muscles should be administered 5 weeks after the first injection (regardless of the timing of the second injection). The normal monthly cycle of injections in either the deltoid or gluteal muscle of 25 mg to 150 mg based on individual patient tolerability and/or efficacy should be followed thereafter.

Missed second initiation dose (4-7 weeks from first injection)

If 4 to 7 weeks have elapsed since the first injection of XEPLION, resume dosing with two injections of 100 mg in the following manner:

1. a deltoid injection as soon as possible,

2. another deltoid injection one week later,

3. resumption of the normal monthly cycle of injections in either the deltoid or gluteal muscle of 25 mg to 150 mg based on individual patient tolerability and/or efficacy.

Missed second initiation dose (> 7 weeks from first injection)

If more than 7 weeks have elapsed since the first injection of XEPLION, initiate dosing as described for the initial recommended initiation of XEPLION above.

Missed monthly maintenance dose (1 month to 6 weeks)

After initiation, the recommended injection cycle of XEPLION is monthly. If less than 6 weeks have elapsed since the last injection, then the previously stabilised dose should be administered as soon as possible, followed by injections at monthly intervals.

Missed monthly maintenance dose (> 6 weeks to 6 months)

If more than 6 weeks have elapsed since the last injection of XEPLION, the recommendation is as follows:

For patients stabilised with doses of 25 to 100mg:

1. a deltoid injection as soon as possible at the same dose the patient was previously stabilised on

2. another deltoid injection (same dose) one week later (day 8)

3. resumption of the normal monthly cycle of injections in either the deltoid or gluteal muscle of 25 mg to 150 mg based on individual patient tolerability and/or efficacy

For patients stabilised with 150mg:

1. a deltoid injection as soon as possible at the 100 mg dose

2. another deltoid injection one week later (day 8) at the 100 mg dose

3. resumption of the normal monthly cycle of injections in either the deltoid or gluteal muscle of 25 mg to 150 mg based on individual patient tolerability and/or efficacy

Missed monthly maintenance dose (> 6 months). If more than 6 months have elapsed since the last injection of XEPLION, initiate dosing as described for the initial recommended initiation of XEPLION above.

Special populations

Elderly population

Efficacy and safety in elderly > 65 years have not been established.

In general, recommended dosing of XEPLION for elderly patients with normal renal function is the same as for younger adult patients with normal renal function. However, because elderly patients may have diminished renal function, dose adjustment may be necessary (see Renal impairment below for dosing recommendations in patients with renal impairment).

Renal impairment

XEPLION has not been systematically studied in patients with renal impairment (see section 5.2). For patients with mild renal impairment (creatinine clearance

XEPLION is not recommended in patients with moderate or severe renal impairment (creatinine clearance < 50 ml/min) (see section 4.4).

Hepatic impairment

Based on experience with oral paliperidone, no dose adjustment is required in patients with mild or moderate hepatic impairment. As paliperidone has not been studied in patients with severe hepatic impairment, caution is recommended in such patients.

Other special populations

No dose adjustment for XEPLION is recommended based on gender, race, or smoking status.

Paediatric population

The safety and efficacy of XEPLION in children < 18 years of age have not been established. No data are available.

Method of administration

XEPLION is intended for intramuscular use only. It should be injected slowly, deep into the muscle. Each injection should be administered by a health care professional. Administration should be in a single injection. The dose should not be given in divided injections. The dose should not be administered intravascularly or subcutaneously.

The day 1 and day 8 initiation doses must each be administered in the deltoid muscle in order to attain therapeutic concentrations rapidly (see section 5.2). Following the second dose, monthly maintenance doses can be administered in either the deltoid or gluteal muscle. A switch from gluteal to deltoid (and vice versa) should be considered in the event of injection site pain if the injection site discomfort is not well tolerated (see section 4.8). It is also recommended to alternate between left and right sides (see below).

For instructions for use and handling of XEPLION, see package leaflet (information intended for medical or healthcare professionals).

Deltoid muscle administration

The recommended needle size for initial and maintenance administration of XEPLION into the deltoid muscle is determined by the patient's weight. For those

Gluteal muscle administration

The recommended needle size for maintenance administration of XEPLION into the gluteal muscle is the 1½-inch, 22 gauge needle (38.1 mm x 0.72 mm). Administration should be made into the upper-outer quadrant of the gluteal area. Gluteal injections should be alternated between the two gluteal muscles.

4.3 Contraindications

Hypersensitivity to the active substance, to risperidone or to any of the excipients.

4.4 Special Warnings And Precautions For Use

Use in patients who are in an acutely agitated or severely psychotic state

XEPLION should not be used to manage acutely agitated or severely psychotic states when immediate symptom control is warranted.

QT interval

Caution should be exercised when paliperidone is prescribed in patients with known cardiovascular disease or family history of QT prolongation, and in concomitant use with other medicinal products thought to prolong the QT interval.

Neuroleptic malignant syndrome

Neuroleptic Malignant Syndrome (NMS), characterised by hyperthermia, muscle rigidity, autonomic instability, altered consciousness, and elevated serum creatine phosphokinase levels has been reported to occur with paliperidone. Additional clinical signs may include myoglobinuria (rhabdomyolysis) and acute renal failure. If a patient develops signs or symptoms indicative of NMS, all antipsychotics, including paliperidone, should be discontinued.

Tardive dyskinesia

Medicinal products 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. If signs and symptoms of tardive dyskinesia appear, the discontinuation of all antipsychotics, including paliperidone, should be considered.

Hyperglycaemia

Rare cases of glucose related adverse reactions, e.g. increase in blood glucose, have been reported in clinical trials with paliperidone. Appropriate clinical monitoring is advisable in diabetic patients and in patients with risk factors for the development of diabetes mellitus.

Hyperprolactinaemia

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. Paliperidone should be used with caution in patients with possible prolactin-dependent tumours.

Orthostatic hypotension

Paliperidone may induce orthostatic hypotension in some patients based on its alpha-blocking activity.

Based on pooled data from the three placebo-controlled, 6-week, fixed-dose trials with oral paliperidone prolonged release tablets (3, 6, 9, and 12 mg), orthostatic hypotension was reported by 2.5% of subjects treated with oral paliperidone compared with 0.8% of subjects treated with placebo. XEPLION should be used with caution in patients with known cardiovascular disease (e.g., heart failure, myocardial infarction or ischaemia, conduction abnormalities), cerebrovascular disease, or conditions that predispose the patient to hypotension (e.g. dehydration and hypovolemia).

Seizures

XEPLION should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold.

Renal impairment

The plasma concentrations of paliperidone are increased in patients with renal impairment and therefore, dose adjustment is recommended in patients with mild renal impairment. XEPLION is not recommended in patients with moderate or severe renal impairment (creatinine clearance < 50 ml/min) (see sections 4.2 and 5.2).

Hepatic impairment

No data are available in patients with severe hepatic impairment (Child-Pugh class C). Caution is recommended if paliperidone is used in such patients.

Elderly patients with dementia

XEPLION has not been studied in elderly patients with dementia. XEPLION should be used with caution in elderly patients with dementia with risk factors for stroke.

The experience from risperidone cited below is considered valid also for paliperidone.

Overall mortality

In a meta-analysis of 17 controlled clinical trials, elderly patients with dementia treated with other atypical antipsychotics, including risperidone, aripiprazole, olanzapine, and quetiapine had an increased risk of mortality compared to placebo. Among those treated with risperidone, the mortality was 4% compared with 3.1% for placebo.

Cerebrovascular adverse reactions

An approximately 3-fold increased risk of cerebrovascular adverse reactions has been seen in randomised placebo-controlled clinical trials in the dementia population with some atypical antipsychotics, including risperidone, aripiprazole, and olanzapine. The mechanism for this increased risk is not known.

Parkinson's disease and dementia with Lewy bodies

Physicians should weigh the risks versus the benefits when prescribing XEPLION 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 antipsychotics. Manifestation of this increased sensitivity can include confusion, obtundation, postural instability with frequent falls, in addition to extrapyramidal symptoms.

Priapism

Antipsychotic medicinal products (including risperidone) with alpha-adrenergic blocking effects have been reported to induce priapism. During postmarketing surveillance, priapism has also been reported with oral paliperidone, which is the active metabolite of risperidone. Patients should be informed to seek urgent medical care in case that priapism has not been resolved within 3-4 hours.

Body temperature regulation

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic medicinal products. Appropriate care is advised when prescribing XEPLION 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 medicinal products with anticholinergic activity or being subject to dehydration.

Venous thromboembolism

Cases of venous thromboembolism (VTE) have been reported with antipsychotic medicinal products. 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 XEPLION and preventative measures undertaken.

Antiemetic effect

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

Weight gain

Patients should be advised of the potential for weight gain. Weight should be measured regularly.

Administration

Care must be taken to avoid inadvertent injection of XEPLION into a blood vessel.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Caution is advised when prescribing XEPLION with medicinal products known to prolong the QT interval, e.g. class IA antiarrhythmics (e.g., quinidine, disopyramide) and class III antiarrhythmics (e.g. amiodarone, sotalol), some antihistaminics, some other antipsychotics and some antimalarials (e.g. mefloquine). This list is indicative and not exhaustive.

Potential for XEPLION to affect other medicinal products

Paliperidone is not expected to cause clinically important pharmacokinetic interactions with medicinal products that are metabolised by cytochrome P-450 isozymes.

Given the primary central nervous system (CNS) effects of paliperidone (see section 4.8), XEPLION should be used with caution in combination with other centrally acting medicinal products, e.g., anxiolytics, most antipsychotics, hypnotics, opiates, etc. or alcohol.

Paliperidone 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.

Because of its potential for inducing orthostatic hypotension (see section 4.4), an additive effect may be observed when XEPLION is administered with other therapeutic agents that have this potential, e.g., other antipsychotics, tricyclics.

Caution is advised if paliperidone is combined with other medicinal products known to lower the seizure threshold (i.e., phenothiazines or butyrophenones, tricyclics or SSRIs, tramadol, mefloquine, etc.).

Co-administration of oral paliperidone prolonged release tablets at steady-state (12 mg once daily) with divalproex sodium prolonged release tablets (500 mg to 2000 mg once daily) did not affect the steady-state pharmacokinetics of valproate.

No interaction study between XEPLION and lithium has been performed, however, a pharmacokinetic interaction is not likely to occur.

Potential for other medicinal products to affect XEPLION

In vitro studies indicate that CYP2D6 and CYP3A4 may be minimally involved in paliperidone metabolism, but there are no indications in vitro nor in vivo that these isozymes play a significant role in the metabolism of paliperidone. Concomitant administration of oral paliperidone with paroxetine, a potent CYP2D6 inhibitor, showed no clinically significant effect on the pharmacokinetics of paliperidone.

Co-administration of oral paliperidone prolonged release once daily with carbamazepine 200 mg twice daily caused a decrease of approximately 37% in the mean steady-state C_max and AUC of paliperidone. This decrease is caused, to a substantial degree, by a 35% increase in renal clearance of paliperidone likely as a result of induction of renal P-gp by carbamazepine. A minor decrease in the amount of active substance excreted unchanged in the urine suggests that there was little effect on the CYP metabolism or bioavailability of paliperidone during carbamazepine co-administration. Larger decreases in plasma concentrations of paliperidone could occur with higher doses of carbamazepine. On initiation of carbamazepine, the dose of XEPLION should be re-evaluated and increased if necessary. Conversely, on discontinuation of carbamazepine, the dose of XEPLION should be re-evaluated and decreased if necessary.

Co-administration of a single dose of an oral paliperidone prolonged release tablet 12 mg with divalproex sodium prolonged release tablets (two 500 mg tablets once daily) resulted in an increase of approximately 50% in the C_max and AUC of paliperidone, likely as a result of increased oral absorption. Since no effect on the systemic clearance was observed, a clinically significant interaction would not be expected between divalproex sodium prolonged release tablets and XEPLION intramuscular injection. This interaction has not been studied with XEPLION.

Concomitant use of XEPLION with risperidone

Risperidone administered orally or intramuscularly will be metabolised to a variable degree to paliperidone. Consideration should be given if risperidone or oral paliperidone is co-administered with XEPLION.

4.6 Pregnancy And Lactation

Pregnancy

There are no adequate data from the use of paliperidone during pregnancy. Intramuscularly injected paliperidone palmitate and orally administered paliperidone were not teratogenic in animal studies, but other types of reproductive toxicity were seen (see section 5.3). Neonates exposed to antipsychotics (including paliperidone) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully. XEPLION should not be used during pregnancy unless clearly necessary.

Breastfeeding

Paliperidone is excreted in the breast milk to such an extent that effects on the breastfed infant are likely if therapeutic doses are administered to breastfeeding women. XEPLION should not be used while breast feeding.

Fertility

There were no relevant effects observed in the non-clinical studies.

4.7 Effects On Ability To Drive And Use Machines

Paliperidone can have minor or moderate influence on the ability to drive and use machines due to potential nervous system and visual effects, such as sedation, somnolence, syncope, vision blurred (see section 4.8). Therefore, patients should be advised not to drive or operate machines until their individual susceptibility to XEPLION is known.

4.8 Undesirable Effects

The most frequently reported adverse drug reactions (ADRs) in clinical trials were insomnia, headache, weight increased, injection site reactions, agitation, somnolence, akathisia, nausea, constipation, dizziness, tremor, vomiting, upper respiratory tract infection, diarrhoea, and tachycardia. Of these, akathisia appeared to be dose-related.

The following are all ADRs that were reported in XEPLION-treated subjects in clinical trials. The following terms and frequencies are applied: very common (common (uncommon (rare (very rare (< 1/10,000), and not known (cannot be estimated from the available data).

System Organ Class	Adverse Drug Reaction
Frequency
Very common	Common	Uncommon	Rare
Infections and infestations		upper respiratory tract infection
Immune system disorders			hypersensitivity
Endocrine disorders			hyperprolactinaemia
Metabolism and nutrition disorders		weight increased, blood glucose increased, blood triglycerides increased	hyperglycaemia, hyperinsulinaemia, increased appetite, decreased appetite, blood cholesterol increased
Psychiatric disorders	insomnia	agitation	nightmare
Nervous system disorders	headache	dystonia, parkinsonism, akathisia, dyskinesia, extrapyramidal disorder, tremor, dizziness, somnolence	syncope, convulsion, tardive dyskinesia, dysarthria, psychomotor hyperactivity, dizziness postural, lethargy	neuroleptic malignant syndrome, cerebrovascular accident
Eye disorders			vision blurred	eye rolling, eye movement disorder
Ear and labyrinth disorders			vertigo
Cardiac disorders		tachycardia	sinus tachycardia, conduction disorder, atrioventricular block first degree, bradycardia, postural orthostatic tachycardia syndrome, palpitations, electrocardiogram QT prolonged, electrocardiogram abnormal
Vascular disorders		hypertension	orthostatic hypotension
Gastrointestinal disorders		vomiting, abdominal discomfort/abdominal pain upper, diarrhoea, nausea, constipation, toothache	dry mouth
Skin and subcutaneous tissue disorders		rash	urticaria, pruritus generalised, pruritus	drug eruption
Musculoskeletal and connective tissue disorders		back pain, pain in extremity	myalgia, joint stiffness
Reproductive system and breast disorders			gynaecomastia, erectile dysfunction, sexual dysfunction, galactorrhoea, amenorrhoea, menstruation irregular, menstrual disorder, menstruation delayed	breast discharge
General disorders and administration site conditions		asthenia, injection site induration, fatigue, injection site pain	injection site pruritus	administration site pain, administration site reaction, injection site nodule

The following is a list of additional ADRs that have been reported with oral paliperidone:

System Organ Class	Adverse Drug Reaction
Infections and infestations	Common: nasopharyngitis Uncommon: urinary tract infection, rhinitis
Immune system disorders	Rare: anaphylactic reaction
Psychiatric disorders	Uncommon: sleep disorder
Nervous system disorders	Rare: transient ischaemic attack, grand mal convulsion
Cardiac disorders	Uncommon: sinus arrhythmia Rare: bundle branch block left
Vascular disorders	Uncommon: hypotension Rare: ischaemia
Respiratory, thoracic and mediastinal disorders	Common: cough, pharyngolaryngeal pain, nasal congestion Not known: pneumonia aspiration
Gastrointestinal disorders	Common: dyspepsia Uncommon: flatulence Rare: small intestinal obstruction Not known: swollen tongue
Skin and subcutaneous tissue disorders	Rare: angioedema, rash papular
Musculoskeletal and connective tissue disorders	Common: arthralgia Uncommon: musculoskeletal pain
Renal and urinary disorders	Uncommon: urinary retention Rare: urinary incontinence
Pregnancy, puerperium and perinatal conditions	Not known: drug withdrawal syndrome neonatal (see section 4.6)
Reproductive system and breast disorders	Rare: breast engorgement, breast pain, breast tenderness, retrograde ejaculation Not known: priapism
General disorders and administration site conditions	Uncommon: oedema peripheral Rare: oedema

Description of selected adverse reactions

Injection site reactions

The most commonly reported injection site related adverse reaction was pain. The majority of these reactions were reported to be of mild to moderate severity. Subject evaluations of injection site pain based on a visual analogue scale tended to lessen in frequency and intensity over time in all Phase 2 and 3 studies. Injections into the deltoid were perceived as slightly more painful than corresponding gluteal injections. Other injection site reactions were mostly mild in intensity and included induration (common), pruritus (uncommon) and nodules (rare).

Weight gain

In the 13-week study involving the 150 mg initiation dosing, the proportion of subjects with an abnormal weight increase

During the 33-week open-label transition/maintenance period of the long-term recurrence prevention trial, 12% of XEPLION-treated subjects met this criterion (weight gain of

Laboratory tests

Serum prolactin

In clinical trials, median increases in serum prolactin were observed in subjects of both genders who received XEPLION. Adverse reactions that may suggest increase in prolactin levels (e.g. amenorrhoea, galactorrhoea and gynaecomastia) were reported overall in <1% of subjects.

Class effects

QT prolongation, ventricular arrhythmias (ventricular fibrillation, ventricular tachycardia), sudden unexplained death, cardiac arrest, and Torsade de pointes may occur with antipsychotics. Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis, have been reported with antipsychotic medicinal products (frequency unknown).

4.9 Overdose

In general, expected signs and symptoms are those resulting from an exaggeration of paliperidone's known pharmacological effects, i.e., drowsiness and sedation, tachycardia and hypotension, QT prolongation, and extrapyramidal symptoms. Torsade de pointes and ventricular fibrillation have been reported in a patient in the setting of overdose with oral paliperidone. In the case of acute overdose, the possibility of multiple drug involvement should be considered.

Consideration should be given to the prolonged release nature of the medicinal product and the long elimination half-life of paliperidone when assessing treatment needs and recovery. There is no specific antidote to paliperidone. General supportive measures should be employed. Establish and maintain a clear airway and ensure adequate oxygenation and ventilation.

Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring for possible arrhythmias. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluid and/or sympathomimetic agents. In case of severe extrapyramidal symptoms, anticholinergic agents should be administered. Close supervision and monitoring should continue until the patient recovers.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Psycholeptics, other antipsychotics. ATC code: N05AX13

XEPLION contains a racemic mixture of (+)- and (-)-paliperidone.

Mechanism of action

Paliperidone is a selective blocking agent of monoamine effects, whose pharmacological properties are different from that of traditional neuroleptics. Paliperidone binds strongly to serotonergic 5-HT2- and dopaminergic D2-receptors. Paliperidone also blocks alpha 1-adrenergic receptors and slightly less, H1-histaminergic and alpha 2-adrenergic receptors. The pharmacological activity of the (+)- and (-)-paliperidone enantiomers are qualitatively and quantitatively similar.

Paliperidone is not bound to cholinergic receptors. Even though paliperidone is a strong D2-antagonist, which is believed to relieve the positive symptoms of schizophrenia, it causes less catalepsy and decreases motor functions less than traditional neuroleptics. Dominating central serotonin antagonism may reduce the tendency of paliperidone to cause extrapyramidal side effects.

Clinical efficacy

Acute treatment of schizophrenia

The efficacy of XEPLION in the acute treatment of schizophrenia was established in four short-term (one 9-week and three 13-week) double-blind, randomised, placebo-controlled, fixed-dose studies of acutely relapsed adult inpatients who met DSM-IV criteria for schizophrenia. The fixed doses of XEPLION in these studies were given on days 1, 8, and 36 in the 9-week study, and additionally on day 64 of the 13-week studies. No additional oral antipsychotic supplementation was needed during the acute treatment of schizophrenia with XEPLION. The primary efficacy endpoint was defined as a decrease in Positive and Negative Syndrome Scale (PANSS) total scores as shown in the table below. The PANSS is a validated multi-item inventory composed of five factors to evaluate positive symptoms, negative symptoms, disorganised thoughts, uncontrolled hostility/excitement and anxiety/depression. Functioning was evaluated using the Personal and Social Performance (PSP) scale. The PSP is a validated clinician rated scale that measures personal and social functioning in four domains: socially useful activities (work and study), personal and social relationships, self-care and disturbing and aggressive behaviours.

In a 13-week study (n=636) comparing three fixed doses of XEPLION (initial deltoid injection of 150 mg followed by 3 gluteal or deltoid doses of either 25 mg/4 weeks, 100 mg/4 weeks or 150 mg/4 weeks) to placebo, all three doses of XEPLION were superior to placebo in improving the PANSS total score. In this study, both the 100 mg/4 weeks and 150 mg /4 weeks, but not the 25 mg/4 weeks, treatment groups demonstrated statistical superiority to placebo for the PSP score. These results support efficacy across the entire duration of treatment and improvement in PANSS and was observed as early as day 4 with significant separation from placebo in the 25 mg and 150 mg XEPLION groups by day 8.

The results of the other studies yielded statistically significant results in favour of XEPLION, except for the 50 mg dose in one study (see table below).

Positive and Negative Syndrome Scale for Schizophrenia (PANSS) Total Score - Change From Baseline to End Point- LOCF for Studies R092670-SCH-201, R092670-PSY-3003, R092670-PSY-3004 and R092670-PSY-3007: Primary Efficacy Analysis Set
	Placebo	25 mg	50 mg	100 mg	150 mg
R092670-PSY-3007* Mean baseline (SD) Mean change (SD) P-value (vs. Placebo)	n = 160 86.8 (10.31) -2.9 (19.26) --