Xeplion - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf life and Storage Composition and pharmaceutical form

Active ingredients: Paliperidone

XEPLION 25 mg prolonged-release suspension for injection
XEPLION 50 mg prolonged-release suspension for injection
XEPLION 75 mg prolonged-release suspension for injection
XEPLION 100 mg prolonged-release suspension for injection
XEPLION 150 mg prolonged-release suspension for injection

Indications Why is Xeplion used? What is it for?

Xeplion contains the active substance paliperidone, which belongs to the class of antipsychotic medicines and is used as a maintenance treatment for the symptoms of schizophrenia in adult patients stabilized on paliperidone or risperidone.

If you have been shown to respond to paliperidone or risperidone in the past and have mild to moderate symptoms, your doctor may start treatment with Xeplion without prior stabilization with paliperidone or risperidone.

Schizophrenia is a disease characterized by "positive" and "negative" symptoms. Positive means an excess of symptoms that are not normally present. For example, a person with schizophrenia may hear voices or see things that don't actually exist (called hallucinations), believe things that aren't true (called delusions), or be unusually suspicious of others. Negative symptoms mean a lack of behaviors or feelings that are normally present. For example, a person with schizophrenia may have a tendency to be isolated and may not react emotionally or may have difficulty speaking clearly and logically. People with this disorder may also feel depressed, anxious, guilty, or tense.

Xeplion can help relieve the symptoms of your disease and prevent them from coming back.

Contraindications When Xeplion should not be used

Do not use Xeplion

  • if you are allergic to paliperidone or any of the other ingredients of this medicine (listed in section 6).
  • if you are allergic to another antipsychotic medicine, including risperidone.

Precautions for use What you need to know before taking Xeplion

Talk to your doctor, pharmacist or nurse before using Xeplion. This medicine has not been studied in elderly patients with dementia. However, elderly patients with dementia treated with other medicines of a similar type may have an increased risk of stroke or death (see section 4, possible side effects).

All medicines have side effects, and some of the side effects of this medicine can worsen the symptoms of other medical conditions. For this reason, it is important that you discuss with your doctor any of the following conditions, which may potentially get worse during treatment with this medicine.

  • If you have Parkinson's disease.
  • If you have ever been diagnosed with a disease whose symptoms include high temperature and muscle stiffness (also known as Neuroleptic Malignant Syndrome).
  • If you have ever had abnormal movements of the tongue or face (Tardive Dyskinesia).
  • If you know that you have had low levels of white blood cells in the past (which may or may not have been caused by other medicines).
  • If you are diabetic or predisposed to diabetes.
  • If you have been diagnosed with breast cancer or a tumor of the pituitary gland in the brain.
  • If you have heart disease or are taking treatment for a heart disease that tends to lower your blood pressure.
  • If you have low blood pressure when you stand up or suddenly switch from lying to sitting.
  • If you suffer from epilepsy.
  • If you have kidney problems.
  • If you have liver problems.
  • If you have a prolonged and / or painful erection.
  • If you have difficulty controlling core body temperature or excessive heat conditions.
  • If you have an abnormally high level of prolactin hormone in your blood or if you have a possible prolactin-dependent tumor.
  • If you or someone else in your family have a history of blood clots (thrombi), as antipsychotics have been associated with the formation of blood clots.

If you have any of these conditions, talk to your doctor so that he can assess whether you need to adjust your dose or follow it closely for a while.

Since dangerously low numbers of a certain type of white blood cells needed to stop infections in the blood have been observed very rarely in patients taking this medicine, your doctor may check your white blood cell count.

Although you have previously tolerated oral paliperidone or oral risperidone, allergic reactions rarely occur after receiving Xeplion injections. See your doctor immediately if you get a rash, swelling of the throat, itching or breathing problems as these may be signs of a severe allergic reaction.

This medicine can cause weight gain. Significant weight gain can adversely affect health. Your doctor must weigh you regularly.

Since diabetes mellitus or worsening of pre-existing diabetes mellitus has been observed in patients taking this medicine, your doctor should check for high blood sugar levels. In patients with pre-existing diabetes mellitus the blood glucose level should be monitored regularly.

Since this medicine may reduce the urge to vomit, there is a possibility that it may mask the body's normal response to the ingestion of toxic substances or other medical conditions.

During an "eye operation" due to clouding of the lens (cataract), the pupil (the black circle in the center of your eye) may not increase in size as needed. Also, the iris (the colored part of the eye) can become flaccid during surgery, which can cause damage to the eye. If you are planning to have eye surgery, be sure to tell your ophthalmologist that you are taking this medicine.

Children and adolescents

This medicine should not be used in children and adolescents under 18 years of age.

Interactions Which drugs or foods may change the effect of Xeplion

Tell your doctor if you are taking, have recently taken or might take any other medicines.

Taking this medicine with carbamazepine (antiepileptic and mood stabilizer) may make it necessary to adjust the dose of this medicine.

Since this medicine acts mainly on the brain, interference with other medicines (or alcohol) that act on the brain, such as other psychiatric drugs, opiates, antihistamines and drugs for sleep disorders, may cause an exaggeration of side effects such as sleepiness or other effects. on the brain.

As this medicine can lower blood pressure, be careful when this medicine is used with other medicines that lower blood pressure.

This medicine may reduce the effect of medicines used to treat Parkinson's disease and restless legs syndrome (eg, levodopa).

This medicine can cause an "electrocardiogram (ECG) abnormality", which is characterized by a longer period for the progression of an electrical impulse through a certain part of the heart (known as "prolongation of the" QT interval "). Other medicines that have this effects include some medicines used to treat heart rhythm or to treat infections and other antipsychotics It is important that you tell your doctor about any medicines you are taking to treat these conditions.

If you are predisposed to developing seizures, this medicine may increase your chance of having them. Other medicines that have this effect include some medicines used to treat depression or infections and other antipsychotics. It is important that you tell your doctor about any medicines you are taking to treat these conditions.

Warnings It is important to know that:

Pregnancy and breastfeeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. You should not use this medicine during pregnancy unless you have already discussed this with your doctor. The following symptoms may occur in newborn babies, of mothers who have used paliperidone in the last trimester (last three months of their pregnancy): shaking, muscle stiffness and / or weakness, sleepiness, agitation, breathing problems, and difficulty in feeding. If your child has any of these symptoms, you may need to contact your doctor.

This medicine can pass from mother to baby through breast milk and can harm the baby. Therefore, do not breastfeed if you use this medicine.

Driving and using machines

Dizziness, extreme tiredness and vision problems may occur during treatment with this medicine (see section 4). This should be taken into account in cases where full vigilance is required, eg when driving a car or operating machinery.

Important information about some of the ingredients of Xeplion

The normal dosage range for this medicinal product contains less than 1 mmol (23 mg) sodium per dose; in practice it is essentially "sodium free".

Dose, Method and Time of Administration How to use Xeplion: Posology

This medicine is given by your doctor or another healthcare professional in a doctor's office or clinic. Your doctor will decide when you should return to the doctor's office or clinic for the injection. It is important not to skip your scheduled dose. If you think you will not be able to attend your doctor's appointment, please contact him immediately to arrange a new one. appointment as soon as possible. You will be given a first injection (150 mg) and a second injection (100 mg) of this medicine in the upper arm approximately one week apart. Next, you will receive an injection (which can range from 25 mg to 150 mg ) or in the upper arm or buttock once a month.

If your doctor switches you from extended-release risperidone to this medicine, you will receive your first injection of this medicine (which can range from 25 mg to 150 mg) either in the upper arm or buttock on the date already scheduled for your next injection. Next, you will receive an injection (which can range from 25mg to 150mg) either into the upper arm or buttock once a month.

Depending on your symptoms, your doctor may increase or decrease the amount of medicine you receive at the time of your scheduled monthly injection by one dose level.

Patients with kidney problems

Your doctor may adjust the dose of the medicine based on your kidney function. If you have mild kidney problems your doctor may prescribe a lower dose. If you have moderate to severe kidney problems this medicine should not be used.

Senior citizens

Your doctor may reduce your dose of this medicine if your kidney function is reduced.

Overdose What to do if you have taken too much Xeplion

If you take more Xeplion than you should

This medicine will be given to you under medical supervision; it is therefore unlikely that you will be given too much.

Patients who have received an overdose of paliperidone may experience the following symptoms: drowsiness or sedation, rapid heartbeat, low blood pressure, abnormal electrocardiogram (tracing of the electrical activity of the heart), or slow or abnormal movements of the face , body, arms or legs.

If you stop using Xeplion

If you stop getting your injections, you will lose the effects of the medicine. You should not stop using this medicine unless your doctor tells you to, as your symptoms may return.

If you have any further questions about taking this medicine, ask your doctor or pharmacist

Side Effects What are the side effects of Xeplion

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Tell your doctor immediately if:

  • You think you have blood clots in your veins, particularly in the legs (symptoms include swelling, pain and redness in the legs), which can travel along the blood vessels to the lungs, causing chest pain and difficulty in breathing. If you notice any of these symptoms, consult your doctor immediately.
  • You have dementia and notice a sudden change in your mental state or a "sudden weakness or numbness of the face, arms or legs, especially on one side, or if your language is incomprehensible, even if for a short time. They may." be the signs of a stroke.
  • You have fever, muscle stiffness, sweating or a reduced level of consciousness (a disorder called "Neuroleptic Malignant Syndrome"). Immediate medical treatment may be needed.
  • He is male and has a prolonged or painful erection. This condition is called priapism. Immediate medical treatment may be needed.
  • It has involuntary rhythmic movements of the tongue, mouth and face. It may be necessary to discontinue paliperidone.
  • You have a severe allergic reaction characterized by fever, swelling of the mouth, face, lips or tongue, shortness of breath, itching, skin rash and sometimes a drop in blood pressure (corresponding to an anaphylactic reaction "). tolerated oral risperidone or oral paliperidone, allergic reactions rarely occur after receiving injections of Xeplion.

The following side effects may occur:

Very common: may affect more than 1 in 10 people

  • difficulty falling asleep or staying asleep
  • headache

Common: may affect up to 1 in 10 people

  • common cold symptoms, urinary tract infection, feeling like you have the flu
  • Xeplion may increase the levels of a hormone called 'prolactin' found in a blood test (which may or may not cause symptoms). When symptoms of a high prolactin level occur, these may include (in men) breast swelling, difficulty in getting or maintaining erections or other sexual dysfunction; (in women) breast discomfort, loss of milk from the breasts, menstrual cycle or other problems with your period
  • high blood sugar, weight gain, weight loss, increase in triglycerides (a fat) in the blood
  • agitation, depression, anxiety
  • parkinsonism: This condition can include slow or abnormal movements, a feeling of muscle stiffness or tension (making movements jerky), and sometimes even a sensation of movement that freezes and then restarts. Other signs of Parkinsonism include slow shuffling walking, a tremor at rest, increased saliva and / or drooling, and a loss of facial expression.
  • restlessness, feeling sleepy or loss of alertness
  • dystonia: This is a condition that involves slow or prolonged involuntary muscle contraction. While it can involve any part of the body (resulting in abnormal posture), dystonia often involves the muscles of the face, including abnormal movements of the eyes, mouth, tongue, or jaw
  • dizziness
  • dyskinesia: This is a condition that involves involuntary muscle movements and can include repetitive, spastic or twisted movements, or twitching.
  • tremor
  • low heart rate, rapid heart rate
  • high blood pressure
  • cough, stuffy nose
  • abdominal pain, vomiting, nausea, constipation, diarrhea, indigestion, toothache
  • increase in hepatic transaminases in the blood
  • rash
  • pain in the bones or muscles, back pain
  • fever, weakness, fatigue (tiredness)
  • a reaction at the injection site, including itching, pain or swelling

Uncommon: may affect up to 1 in 100 people

  • pneumonia, chest infection (bronchitis), respiratory tract infection, sinusitis, bladder infection, ear infection, eye infection, tonsillitis, skin infection, skin inflammation caused by mites, abscess under the skin
  • decrease in white blood cell count, anemia, decrease in red blood cells, increase in blood eosinophils (a type of white blood cell)
  • allergic reaction
  • diabetes or worsening of diabetes, increase in blood insulin (a hormone that controls blood sugar levels)
  • increased appetite, loss of appetite resulting in malnutrition and low body weight
  • increased blood cholesterol
  • sleep disturbances, elevated mood (mania), confusion, decreased sexual urge, nervousness, nightmares
  • tardive dyskinesia (twitching or jerking movements that you cannot control in the face, tongue or other parts of the body). Contact your doctor immediately if you experience involuntary rhythmic movements of the tongue, mouth and face. It may be necessary to stop this medicine
  • seizures (fits), fainting, an urgent need to move a part of the body, dizziness when standing up, disturbances in attention, speech problems, loss or abnormal sense of taste, decreased sensitivity of the skin to pain and to the touch, a tingling, prickling or numb feeling of the skin
  • blurred vision, infection of the 'eye or' slightly red ', dry eye
  • spinning sensation (vertigo), ringing in the ears, ear pain
  • atrial fibrillation (an abnormal heart rhythm), an interruption in conduction between the upper and lower parts of the heart, abnormal electrical conduction of the heart, prolongation of the heart's QT interval, rapid heartbeat when standing up, abnormal electrical tracing of the heart (electrocardiogram or ECG), a feeling of racing or throbbing in the chest (palpitations)
  • low blood pressure, decrease in blood pressure when standing up (as a result, some people taking this medicine may feel faint, dizzy or faint when suddenly standing up or sitting down)
  • shortness of breath, pulmonary congestion, wheezing, sore throat, nosebleed
  • abdominal discomfort, stomach or intestinal infection, dry mouth, excessive passing of gas or air
  • increase in GGT in the blood (a liver enzyme called gamma-glutamyltransferase), increase in liver enzymes in the blood
  • rash (or hives), itching, hair loss, eczema, dry skin, red skin, acne
  • muscle spasms, joint stiffness, neck pain, joint pain
  • incontinence (lack of control) of urine, frequent urination, pain when urinating
  • erectile dysfunction, ejaculation disturbances, loss of menstruation, delayed menstruation, absence of menstruation or other problems with menstruation (females), development of breasts in men, loss of breast milk, sexual dysfunction, vaginal discharge.
  • swelling of the face, mouth, eyes or lips, swelling of the body, arms or legs
  • a change in the way you walk
  • chest pain, chest discomfort, feeling sick
  • hardening of the skin
  • fall

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

  • fungal nail infection
  • dangerously low number of a certain type of white blood cell needed to fight infections
  • decrease in a certain type of white blood cell which serves to protect the body from infection, decrease in platelets (blood cells that help stop bleeding)
  • severe allergic reaction characterized by fever, swelling of the mouth, face, lips or tongue, shortness of breath, itching, rash and sometimes a drop in blood pressure,
  • inappropriate secretion of a hormone that controls urine volume
  • dangerously excessive water intake, life-threatening complications from uncontrolled diabetes
  • low blood sugar, excessive water intake
  • lack of emotion
  • inability to reach orgasm
  • neuroleptic malignant syndrome (confusion, decreased or loss of consciousness, high fever and severe muscle stiffness), sudden loss of blood supply to the brain (stroke or "mini" stroke), lack of response to stimuli, loss of consciousness, low blood of consciousness, disturbances of balance
  • vascular problems in the brain, coma caused by uncontrolled diabetes, abnormal coordination, tremor in the head
  • glaucoma (increased pressure inside the eyeball), problems with eye movement, eye rolling towards the back of the head, eye hypersensitivity to light, increased tears, red eyes
  • irregular heartbeat of the heart
  • blood clots in the veins, particularly in the legs (symptoms include swelling, pain and redness in the legs), which can travel along blood vessels to the lungs, causing chest pain and difficulty in breathing. If you notice any of these symptoms, consult your doctor immediately.
  • decreased oxygen in parts of the body (because blood flow decreases), flushing
  • breathing problems during sleep (sleep apnea), fast and shallow breathing, pneumonia caused by inhalation of food, airway congestion, voice disturbance.
  • inflammation of the pancreas, blockage of the bowel, swollen tongue, fecal incontinence, very hard stools, difficulty in swallowing, chapped lips, lack of bowel muscle movement causing blockage
  • yellowing of the skin and eyes (jaundice)
  • severe allergic reaction with swelling which may affect the throat causing difficulty in breathing,
  • drug-related rash, skin discoloration, skin thickening, peeling and itchy scalp or skin, dandruff
  • breakdown of muscle fibers and muscle pain (rhabdomyolysis), abnormal posture
  • an increase in CPK (creatine phosphokinase) in the blood, an enzyme that is sometimes released when there is muscle damage, joint swelling, muscle weakness
  • inability to urinate
  • priapism (a prolonged erection of the penis which may require surgical treatment)
  • breast pain, breast discomfort, breast enlargement, breast enlargement, breast fluid leaking from the breasts
  • very low body temperature, decrease in body temperature, chills, an increase in body temperature, feeling thirsty, drug withdrawal symptoms
  • accumulation of pus caused by an injection site infection, deep skin infection, a cyst at the injection site, bruising at the injection site

Not known: frequency cannot be estimated from the available data

  • sugar in the urine The following side effects have been seen with the use of another medicine called risperidone which is very similar to paliperidone, so these effects may also be expected with this medicine: other types of brain blood vessel problems, lung crepitus sounds , death of skin cells at the injection site and ulcer at the injection site. Eye problems may also occur during cataract surgery. During cataract surgery, a condition called intraoperative floppy iris syndrome (IFIS) can occur if you take or have taken Xeplion. If you are going to have cataract surgery, be sure to tell your doctor if you take or have taken this medicine.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. side effects you can help provide more information on the safety of this medicine

Expiry and Retention

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

Do not use this medicine after the expiry date which is stated on the carton. The expiry date refers to the last day of the month.

Do not store above 30 ° C.

Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

Composition and pharmaceutical form

What Xeplion contains

The active ingredient is paliperidone.

Each pre-filled syringe of Xeplion 25 mg contains 39 mg of paliperidone palmitate.

Each pre-filled syringe of Xeplion 50 mg contains 78 mg of paliperidone palmitate.

Each pre-filled syringe of Xeplion 75 mg contains 117 mg of paliperidone palmitate.

Each Xeplion 100 mg pre-filled syringe contains 156 mg of paliperidone palmitate.

Each Xeplion 150 mg pre-filled syringe contains 234 mg of paliperidone palmitate.

The other ingredients are: Polysorbate 20 Polyethylene glycol 4000 Citric acid monohydrate Di-sodium hydrogen phosphate anhydrous Sodium dihydrogen phosphate monohydrate Sodium hydroxide (for pH adjustment) Water for injections

What Xeplion looks like and contents of the pack

Xeplion is a white to off-white prolonged-release suspension for injection in a pre-filled syringe.

Each pack contains 1 pre-filled syringe and 2 needles.

Treatment initiation pack: Each pack contains 1 pack of Xeplion 150 mg and 1 pack of Xeplion 100 mg.

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

More information about Xeplion can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction 04.6 Pregnancy and lactation 04.7 Effects on ability to drive and use machines 04.8 Undesirable effects 04.9 Overdose 05.0 PHARMACOLOGICAL PROPERTIES 05.1 Pharmacodynamic properties 05.2 Pharmacokinetic properties 05.3 Preclinical safety data 06.0 PHARMACEUTICAL PARTICULARS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER 08.0 MARKETING AUTHORIZATION NUMBER 09 .0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIO DRUGS, COMPLETE DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS AND QUALITY CONTROLS

01.0 NAME OF THE MEDICINAL PRODUCT

XEPLION 100 MG PROLONGED RELEASE INJECTABLE SUSPENSION

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

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

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Prolonged-release suspension for injection.

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

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

XEPLION is indicated for the maintenance therapy of schizophrenia in adult patients stabilized on paliperidone or risperidone.

In selected adult patients with schizophrenia and who have previously responded to oral paliperidone or risperidone, XEPLION can be used without prior oral stabilization if psychotic symptoms are mild to moderate and long-acting injectable treatment is required.


04.2 Posology and method of administration

Dosage

It is recommended to start XEPLION with a dose of 150 mg on day 1 of treatment and a dose of 100 mg one week later (day 8), in both cases administered into the deltoid muscle in order to rapidly achieve therapeutic concentrations (see section 5.2 ). The third dose should be administered one month after the second dose. The recommended monthly maintenance dose is 75 mg; some patients may benefit from lower or higher doses within the recommended range of 25-150 mg based on subjective tolerability and / or efficacy. Overweight or obese patients may require doses close to the upper range (see section 5.2). After the second dose, monthly maintenance doses can be administered in both the deltoid muscle and the buttock.

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

Switching from oral paliperidone or oral risperidone

In the initial phase of treatment with XEPLION, previous oral paliperidone or oral risperidone may be withdrawn. XEPLION must be started as previously described at the beginning of section 4.2.

Switching from injectable risperidone to prolonged release

When patients switch from injectable risperidone to prolonged release, initiate therapy with XEPLION in place of the next scheduled injection. XEPLION must then be continued at monthly intervals. The initial week 1 dosing schedule, which includes intramuscular injections (on day 1 and day 8, respectively) as described in section 4.2 is not required.

Patients previously stabilized on different doses of prolonged-release injectable risperidone may achieve similar steady-state paliperidone exposure during maintenance treatment with monthly doses of XEPLION according to the following schedule:

Doses of prolonged-release injectable risperidone and XEPLION required to achieve similar steady-state paliperidone exposure

Previous dose of extended-release injectable risperidone Injection of XEPLION 25 mg every 2 weeks 50 mg per month 37.5 mg every 2 weeks 75 mg per month 50 mg every 2 weeks 100 mg per month

Discontinuation of antipsychotic medication should be done in accordance with appropriate prescribing information. If XEPLION is discontinued, its prolonged release characteristics should be considered. As also recommended for other antipsychotic medications, the need to continue any existing antipsychotic medications extrapyramidal symptoms (EPS, ExtraPyramidal Symptoms) should be re-evaluated periodically.

Missed dose

How to avoid missing a dose

It is recommended that the second dose of the initial phase of XEPLION therapy be administered one week after the first dose. To avoid missing a dose, the second dose can be given to patients 4 days before or 4 days after the one week deadline (day 8). Similarly, after the initial phase, it is recommended to give the third injection and subsequent injections once a month. To avoid missing a monthly dose, patients can be injected up to 7 days before or 7 days after the monthly deadline.

If the scheduled date for the second injection of XEPLION (day 8 ± 4 days) has passed, the recommended way to resume therapy depends on the time that has elapsed since the first injection to the patient.

Missed second dose of the initial phase (

If it has been less than 4 weeks since the first injection, then the patient should be given the second injection of 100 mg into the deltoid muscle as soon as possible. A third 75 mg injection of XEPLION into the deltoid or gluteal muscle should be given 5 weeks after the first injection (regardless of when the second injection was given). The normal monthly course of injections into the deltoid or gluteus muscle of 25-150 mg, based on the patient's individual tolerability and / or efficacy, should be followed thereafter.

Missed second dose of the initial phase (4-7 weeks after the first injection)

If 4 to 7 weeks have passed since the first injection of XEPLION, restore the dosage with two injections of 100 mg as follows:

1. an injection into the deltoid as soon as possible

2. another injection into the deltoid one week later

3. resuming the normal monthly cycle of injections into the deltoid or gluteus muscle of 25-150 mg, based on the patient's individual tolerability and / or efficacy.

Missed second dose of initial phase (> 7 weeks after first injection)

If it has been more than 7 weeks since the first injection of XEPLION, start administration as described in the recommendations for the initial phase of XEPLION indicated above.

Missed monthly maintenance dose (1 month to 6 weeks)

After the initial phase, the recommended course of injections of XEPLION is monthly. If it has been less than 6 weeks since the last injection, then the previously set dose should be given as soon as possible, followed by injections at monthly intervals.

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

If it has been more than 6 weeks since the last injection of XEPLION, the recommendations are as follows:

For patients stabilized with doses of 25 to 100 mg:

1. a deltoid injection as soon as possible at the same dose with which the patient was previously stabilized

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

3. resumption of the normal monthly cycle of injections into the deltoid or gluteus muscle of 25-150 mg, based on the patient's individual tolerability and / or efficacy.

For patients stabilized with 150 mg:

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

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

3. resumption of the normal monthly cycle of injections into the deltoid or gluteus muscle of 25-150 mg, based on the patient's individual tolerability and / or efficacy.

Missed monthly maintenance dose (> 6 months). If it has been more than 6 months since the last injection of XEPLION, start the dosing as described in the recommendations for the initial phase of XEPLION indicated above.

Special populations

Elderly population

The efficacy and safety in subjects> 65 years of age have not been established.

In general, the recommended posology of XEPLION for elderly patients with normal renal function is the same as for younger adult patients with normal renal function. However, as older patients may have impaired renal function, a dose adjustment may be required (see section Kidney failure below for dosage recommendations in patients with renal insufficiency).

Kidney failure

XEPLION has not been systematically studied in patients with renal insufficiency (see section 5.2). For patients with mild renal impairment (creatinine clearance ≥ 50 to

XEPLION is not recommended in patients with moderate or severe renal impairment (creatinine clearance

Hepatic insufficiency

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

Other particular populations

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

Pediatric population

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

Method of administration

XEPLION is for intramuscular use only. It must be injected slowly and deeply into the muscle. Each injection must be given by a healthcare professional. Administration should take place in a single injection. The dose should not be given as separate injections. The dose should not be administered intravenously or subcutaneously.

The doses on days 1 and 8 of the initial phase should both be administered into the deltoid muscle in order to rapidly achieve therapeutic concentrations (see section 5.2). After the second dose, monthly maintenance doses can be administered into the deltoid muscle or gluteus maximus. Switching from buttock to deltoid (and vice versa) should be considered for injection site pain if such discomfort is not well tolerated (see section 4.8). Alternating between left and right side is also recommended (see below).

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

Administration into the deltoid muscle

The recommended needle size for initial and maintenance administration of XEPLION into the deltoid muscle is determined by the patient's weight. For a weight ≥ 90 kg, a 1½-inch, 22 G (38.1 mm x 0. 72 mm) For a weight of the deltoid muscles.

Administration into the gluteal muscle

The recommended needle size for maintenance administration of XEPLION into the gluteal muscle is 1½ inch, 22 G (38.1 mm x 0.72 mm). Administration should be performed in the outer upper quadrant of the gluteal area. Injections into the buttock must be alternated between the two gluteal muscles.


04.3 Contraindications

Hypersensitivity to the active substance, to risperidone or to any of the excipients listed in section 6.1.


04.4 Special warnings and appropriate precautions for use

Use in patients in acute agitation or in a severe psychotic state

XEPLION should not be used to manage acute agitation or severe psychotic states when immediate symptom control is required.

QT interval

Caution should be exercised when prescribing paliperidone in patients with known cardiovascular disorders or with a family history of QT prolongation and when concomitant use of other drugs believed to prolong the QT interval.

Neuroleptic malignant syndrome

Neuroleptic Malignant Syndrome (NMS), characterized by hyperthermia, muscle rigidity, autonomic nervous system instability, changes in consciousness, and elevated serum creatine phosphokinase, has been reported with paliperidone Additional clinical manifestations may include myoglobinuria (rhabdomyolysis) and acute renal failure . If a patient exhibits signs or symptoms suggestive of NMS, treatment with any antipsychotic, including paliperidone, should be discontinued.

Tardive dyskinesia

Drugs with antagonistic action on dopaminergic receptors have been associated with the induction of tardive dyskinesia characterized by rhythmic and involuntary movements, especially of the tongue and / or face. discontinue any antipsychotics, including paliperidone.

Leukopenia, neutropenia and agranulocytosis

Events of leukopenia, neutropenia and agranulocytosis have been reported with the use of antipsychotics, including XEPLION. Agranulocytosis has been reported very rarely (white blood cells (WBC) or drug-induced leukopenia / neutropenia should be monitored during post-marketing surveillance). during the first months of therapy and discontinuation of XEPLION should be considered at the first sign of clinically significant decrease in WBC in the absence of other causative factors. Patients with clinically significant neutropenia should be closely 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

Hyperglycemia and diabetes mellitus

Hyperglycaemia, diabetes mellitus and exacerbation of pre-existing diabetes have been reported during treatment with paliperidone. In some cases, previous weight gain has been reported which could be a predisposing factor. The association with ketoacidosis has been reported very rarely and rarely with diabetic coma. Appropriate clinical monitoring is advised in accordance with the guidelines used for antipsychotics. Patients treated with any atypical antipsychotic, including XEPLION, should be monitored for symptoms of hyperglycaemia. (such as polydipsia, polyuria, polyphagia and weakness) and patients with diabetes mellitus should be monitored regularly for worsening glycemic control.

Weight gain

Significant weight gain has been reported during use of XEPLION. Weight should be evaluated regularly.

Hyperprolactinemia

Cell culture studies suggest that cell growth in human breast tumors can 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 tumors.

Orthostatic hypotension

Paliperidone may induce orthostatic hypotension in some patients due to its alpha-blocking action.

Based on pooled data from three placebo-controlled, 6-week, fixed-dose trials with oral prolonged-release paliperidone tablets (3, 6, 9, and 12 mg), orthostatic hypotension was reported by 2.5% of subjects treated with oral paliperidone versus 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 defects), cerebrovascular disease , or conditions that predispose the patient to hypotension (such as dehydration and hypovolaemia).

Convulsions

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

Kidney failure

Paliperidone plasma concentrations are increased in patients with renal insufficiency and, therefore, dose adjustment is recommended in patients with mild renal insufficiency. XEPLION is not recommended in patients with moderate or severe renal impairment (creatinine clearance

Hepatic insufficiency

There are no data available in patients with severe hepatic impairment (Child-Pugh Class C). Caution is advised when using paliperidone in such patients.

Elderly patients with dementia

No studies have been conducted with XEPLION in elderly patients with dementia. XEPLION should be used with caution in elderly patients with dementia with stroke risk factors. The experience with risperidone mentioned below is also considered valid for paliperidone.

Global mortality

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

Cerebrovascular adverse reactions

An approximately three-fold increased risk of cerebrovascular adverse reactions was observed in randomized placebo-controlled clinical trials in dementia patients treated with some atypical antipsychotics, including risperidone, aripiprazole and olanzapine. The mechanism behind the increased risk is unknown.

Parkinson's disease and dementia with Lewy bodies

Physicians should weigh the risks and benefits of prescribing XEPLION to patients with Parkinson's disease or dementia with Lewy bodies (DLB) as both patient groups may be at a greater risk of developing Neuroleptic Malignant Syndrome, as well as showing increased sensitivity to antipsychotics. Manifestations of this increased sensitivity may include confusion, dullness, postural instability with frequent falls, as well as extrapyramidal symptoms.

Priapism

Antipsychotic medicinal products (including risperidone) with alpha-adrenergic blocking effects have been reported to induce priapism. During post-marketing surveillance, priapism has also been reported with oral paliperidone, which is the active metabolite of risperidone. Patients should be advised that if priapism does not resolve within 3-4 hours, they should seek urgent medical assistance.

Body temperature regulation

Impaired the body's ability to lower core body temperature has been attributed to antipsychotic drugs. Particular care is advised when prescribing XEPLION to patients who may be exposed to conditions that may contribute to an increase in core body temperature, such as strenuous exercise, exposure to extreme heat, concomitant treatment of anticholinergic drugs, or be prone to dehydration.

Venous thromboembolism

Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs.

Patients treated with antipsychotics often have acquired risk factors for VTE, therefore all possible risk factors for VTE must be identified before and during treatment with XEPLION and preventive measures undertaken.

Antiemetic effect

An antiemetic effect was observed in preclinical studies with paliperidone. This effect, if it occurs in humans, could mask the signs and symptoms of overdose of certain medicines or of conditions such as intestinal obstruction, Reye's syndrome and brain tumor.

Administration

Care should be taken to avoid inadvertently injecting XEPLION into a blood vessel.

Intraoperative Floppy Iris Syndrome

Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in patients treated with medicinal products with alpha1a-adrenergic antagonist effect, such as XEPLION (see section 4.8).

IFIS may increase the risk of ocular complications during and after the operation. Current or past use of medicinal products with alpha1a-adrenergic antagonist effect should be made known to the ophthalmic surgeon prior to surgery. The potential benefit of discontinuing alpha1 blocker therapy prior to cataract surgery has not been established and must be weighed against the risk of discontinuing antipsychotic therapy.


04.5 Interactions with other medicinal products and other forms of interaction

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

Potential for XEPLION to affect other medicines

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

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 with alcohol.

Paliperidone may antagonize the effect of levodopa and other dopamine agonists. If this combination is deemed necessary, especially in the terminal phase of Parkinson's disease, the lowest effective dose of each treatment should be prescribed.

Due to its potential to induce 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 or tricyclics.

Caution is advised if paliperidone is administered in combination with other medicinal products thought to lower the seizure threshold (e.g., phenothiazines or butyrophenones, tricyclics or SSRIs, tramadol, mefloquine, etc.).

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

No interaction studies have been conducted between XEPLION and lithium, however a pharmacokinetic interaction is unlikely.

Potential for other medicines to affect XEPLION

Education in vitro indicate that CYP2D6 and CYP3A4 may be minimally involved in the metabolism of paliperidone, however there are no indications or in vitro neither in vivo that these isoenzymes play a significant role in the metabolism of paliperidone. Co-administration of oral paliperidone with paroxetine, a potent inhibitor of CYP2D6, did not show clinically significant effects on paliperidone pharmacokinetics.

Co-administration of once daily oral prolonged-release paliperidone with carbamazepine 200 mg twice daily caused an approximately 37% decrease in mean Cmax and AUC at steady state of paliperidone. This decrease is substantially caused by a 35% increase in renal clearance of paliperidone probably as a result of carbamazepine induction of renal P-gp. A minor decrease in the amount of the active substance excreted unchanged in the urine suggests a minimal effect on CYP metabolism or the bioavailability of paliperidone during co-administration with carbamazepine. With higher doses of carbamazepine, greater decreases in plasma concentrations of paliperidone may occur. Upon initiation of carbamazepine treatment, the dose of XEPLION should be re-evaluated and increased if necessary. Conversely, in the event of discontinuation of carbamazepine therapy, the dose of XEPLION should be re-evaluated and decreased if necessary.

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

Concomitant use of XEPLION with risperidone

Risperidone administered orally or intramuscularly will be metabolised to paliperidone to varying degrees. Use caution if oral risperidone or paliperidone is co-administered with XEPLION.


04.6 Pregnancy and breastfeeding

Pregnancy

There are no adequate data on the use of paliperidone during pregnancy. Paliperidone palmitate injected intramuscularly and paliperidone administered orally have not been shown to be teratogenic in animal studies, but other types of reproductive toxicity have been observed (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. restlessness, hypertonia, hypotonia, tremor, drowsiness, difficulty breathing, or eating disorders. Consequently, infants need to be monitored closely. XEPLION should not be taken during pregnancy unless absolutely necessary.

Feeding time

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

Fertility

No relevant effects were observed in non-clinical studies.


04.7 Effects on ability to drive and use machines

Paliperidone may slightly or moderately impair the ability to drive or use machines due to potential nervous system and visual effects such as sedation, somnolence, syncope and blurred vision (see section 4.8). Therefore, patients should be advised not to drive or operate machinery until individual sensitivity to XEPLION is known.


04.8 Undesirable effects

Summary of the safety profile

The most frequently reported adverse drug reactions (ADRs) in clinical trials were insomnia, headache, anxiety, upper respiratory tract infection, injection site reaction, parkinsonism, weight gain, akathisia, agitation, sedation / somnolence. , nausea, constipation, dizziness, musculoskeletal pain, tachycardia, tremor, abdominal pain, vomiting, diarrhea, fatigue and dystonia. Of these, akathisia and sedation / somnolence appear to be dose related.

Table of adverse reactions

The following ADRs were all reported with paliperidone by frequency category estimated from clinical trials of XEPLION. The following terms and frequencies apply: very common (≥ 1/10), common (≥ 1/100 to uncommon (≥ 1/1000 to rare (≥ 1 / 10,000 to very rare (not known (cannot be estimated from the available clinical trial data)).

Organic system classification Adverse drug reactions Frequency Very common common Uncommon Rare Not known Infections and infestations upper respiratory tract infection, urinary tract infection, flu pneumonia, bronchitis, respiratory tract infection, sinusitis, cystitis, ear infection, eye infection, tonsillitis, cellulitis, mite dermatitis, subcutaneous abscess onychomycosis Disorders of the blood and lymphatic system decreased white blood cell count, anemia, decreased hematocrit, increased eosinophil count agranulocytosis, neutropenia, thrombocytopenia Disorders of the immune system hypersensitivity anaphylactic reaction Endocrine pathologies hyperprolactinemia a inappropriate secretion of antidiuretic hormone presence of glucose in the urine Metabolism and nutrition disorders hyperglycaemia, weight gain, weight decrease, blood triglyceride level increase diabetes mellitus, hyperinsulinemia, increased appetite, anorexia, decreased appetite, increased blood cholesterol level water intoxication, diabetic keto acidosis, hypoglycemia, polydipsia Psychiatric disorders insomnia agitation, depression, anxiety sleep disturbances, mania, confusion, decreased libido, nervousness, nightmares affective flattening, anorgasmia Nervous system disorders headache parkinsonismb, akathisiab, sedation / somnolence, dystoniab, dizziness, dyskinesia, tremor tardive dyskinesia, convulsionid, syncope, psychomotor hyperactivity, postural dizziness, attention disturbance, dysarthria, dysgeusia, hypoesthesia, paraesthesia neuroleptic malignant syndrome, cerebral ischaemia, unresponsive to stimuli, loss of consciousness, decreased level of consciousness, diabetic coma, balance disturbances, abnormal coordination, staggering, and Eye disorders blurred vision, conjunctivitis, dry eye glaucomae, ocular motility disorders, oculogyration, photophobia, lacrimation increased, ocular hyperaemia Ear and labyrinth disorders vertigo, tinnitus, ear pain Cardiac pathologies bradycardia, tachycardia atrial fibrillation, atrioventricular block, prolongation of the QT interval of the electrocardiography, postural orthostatic tachycardia syndrome, abnormalities in the electro-cardiogram, palpitations sinus arrhythmia Vascular pathologies hypertension hypotension, orthostatic hypotension pulmonary embolism, venous thrombosis, ischemiae, flushing Respiratory, chest and mediastinal disorders cough, nasal congestion dyspnoea, pulmonary congestion, wheezing, pharyngolaryngeal pain, epistaxis sleep apnea syndrome, hyperventilation, aspiration pneumonia, respiratory tract congestion, dysphonia Gastrointestinal disorders abdominal pain, vomiting, nausea, constipation, diarrhea, dyspepsia, toothache abdominal discomfort, gastroenteritis, dry mouth, flautulence pancreatitis, intestinal obstruction, ileus, swollen tongue, fecal incontinence, fecaloma, dysphagia, cheilitis Hepatobiliary disorders increased transaminases increased gamma-glutamyltransferase, increased liver enzymes jaundice Skin and subcutaneous tissue disorders rash hives, itching, alopecia, eczema, dry skin, erythema, acne angioedemae, drug rupture, hyperkeratosis, skin discolouration, seborrheic dermatitis, dandruff Musculoskeletal and connective tissue disorders musculoskeletal pain, back pain, muscle spasms, joint stiffness, neck pain, arthralgia rhabdomyolysis, blood creatine phosphokinase increased, posture abnormal, joint swelling, muscle weakness Renal and urinary disorders urinary incontinence, pollakiuria, dysuria urinary retention Pregnancy, puerperium and perinatal conditions neonatal withdrawal syndrome (see section 4.6) e Diseases of the reproductive system and breast erectile dysfunction, ejaculation disorder, amenorrhea, delayed menstruation, menstrual disorder, gynaecomastia, galactorrhea, sexual dysfunction, vaginal discharge priapism, breast pain, breast discomfort, breast engorgement, breast enlargement, breast discharge General disorders and administration site conditions pyrexia, asthenia, fatigue, injection site reaction face edema, edemad, abnormal gait, chest pain, chest discomfort, malaise, induration hypothermia, decreased body temperature, chills, increased body temperature, thirst, drug withdrawal syndrome, injection site abscess, injection site cellulitis, injection site cyst, injection site hematoma Injury, poisoning and procedural complications fall

a Refer to "hyperprolactinaemia" below.

b Refer to "extrapyramidal symptoms" below.

c In placebo-controlled clinical trials, diabetes mellitus was reported in 0.32% of patients treated with XEPLION compared to 0.39% in the placebo group. The overall incidence of all clinical studies was 0.47% in all patients treated with XEPLION.

d Insomnia includes: initial insomnia, central insomnia; seizures includes: grand mal seizures; edema includes: generalized edema, peripheral edema, plastic edema; menstrual disorder includes: irregular menstruation, oligomenorrhea

e Not observed in clinical trials of XEPLION but observed in post-marketing experience with paliperidone.

Undesirable effects reported with risperidone formulations

Paliperidone is the active metabolite of risperidone, therefore, the adverse reaction profiles of these compounds (including both oral and injectable formulations) are relevant to each other. In addition to the adverse reactions mentioned above, the following adverse reactions have been reported with the use of risperidone products and can be expected with XEPLION.

Nervous system disorders: cerebrovascular disorders

Eye disorders: sflag iris syndrome (intraoperative)

Respiratory, thoracic and mediastinal disorders: rales

General disorders and administration site conditions (observed with the injectable formulation of risperidone): injection site necrosis, injection site ulcer.

Description of selected adverse reactions

Anaphylactic reaction

Cases of anaphylactic reaction after injection with XEPLION have been reported rarely in post-marketing experience in patients who have previously tolerated oral risperidone or oral paliperidone.

Injection site reactions

The most commonly reported injection site adverse reaction was pain. The majority of these reported reactions were mild to moderate in severity. Subjects' ratings of injection site pain based on a visual analogue scale tended to lessen over time in frequency and intensity in all Phase 2 and Phase 3 studies. Deltoid injections were perceived as mildly painful. greater than the corresponding injections in the buttock. Other injection site reactions were mostly mild in intensity and included induration (common), pruritus (uncommon) and nodules (rare).

Extrapyramidal symptoms (EPS)

EPS included a pooled analysis of the following terms: parkinsonism (includes salivary hypersecretion, musculoskeletal stiffness, parkinsonism, saliva loss, cogwheel stiffness, bradykinesia, hypokinesia, mask facies, muscle tension, akinesia, nuchal stiffness, muscle stiffness, Parkinsonian gait and abnormal glabellar reflex, Parkinsonian tremor at rest), akathisia (includes akathisia, restlessness, hyperkinesia, restless legs syndrome), dyskinesia (includes dyskinesia, muscle twitching, choreoathetosis, athetosis and myoclonia), dystonia (includes dystonia, hypertonia , torticollis, involuntary muscle contractions, muscle contracture, blepharospasm, oculogyration, lingual paralysis, facial spasm, laryngospasm, myotonia, opisthotonus, oropharyngeal spasm, pleurototonus, lingual spasm and trismus) and tremor. It should be noted that a broader spectrum of symptoms is included that do not necessarily have extra-pyramidal origin

Weight gain

In the 13-week study involving initial administration of 150 mg, the proportion of subjects with abnormal weight gain ≥ 7% showed a dose-related trend, with an incidence rate of 5% in the placebo group compared to the percentages of 6%, 8% and 13% in the XEPLION 25 mg, 100 mg and 150 mg groups respectively.

During the 33-week open-label transition / maintenance period of the long-term relapse prevention trial, 12% of subjects treated with XEPLION experienced this effect (≥ 7% weight gain from double-blind phase to endpoint) ; mean (SD) weight change from baseline in the open-label phase was + 0.7 kg.

Hyperprolactinemia

In clinical trials, median increases in serum prolactin were observed in both sexes receiving XEPLION. Adverse reactions that could suggest an increase in prolactin levels (e.g., amenorrhea, galactorrhea, menstrual disturbances, gynaecomastia) have been reported overall in

Category effects

QT interval prolongation, ventricular arrhythmias (ventricular fibrillation, ventricular tachycardia), sudden unexplained death, cardiac arrest and torsades de pointes may occur with the administration of antipsychotics. Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis (frequency not known).

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. in "Annex V.


04.9 Overdose

In general, the expected signs and symptoms are those due to an enhancement of the known pharmacological effects of paliperidone, eg somnolence and sedation, tachycardia and hypotension, QT prolongation and extrapyramidal symptoms. Torsade de pointes and ventricular fibrillation have been reported in a patient in an overdose condition with oral paliperidone. In the event of an acute overdose, consideration should be given to the possibility of multiple drugs being involved.

The prolonged release nature of the drug and the long elimination half-life of paliperidone should be considered when assessing treatment needs and recovery. There is no specific antidote to paliperidone. Appropriate general supportive measures should be instituted. Establish and maintain a clear airway and ensure adequate oxygenation and ventilation.

Cardiovascular monitoring should be initiated immediately and should include continuous electrocardiographic monitoring for possible arrhythmias. 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 agents should be given. Continue close monitoring and medical supervision until the patient is recovered.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 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 those of traditional neuroleptics. Paliperidone strongly binds to the serotonergic and dopaminergic D2 5-HT2 receptors. Paliperidone also blocks alpha 1-adrenergic receptors and, to a lesser extent, H1-histaminergic and alpha 2-adrenergic receptors. The pharmacological activity of the (+) and (-) enantiomers of paliperidone is qualitatively and quantitatively similar.

Paliperidone does not bind to cholinergic receptors. Although paliperidone is a strong D2 antagonist, which is believed to relieve the positive symptoms of schizophrenia, it causes less catalepsy and decreases motor capacity to a lesser extent than traditional neuroleptics. Central dominant 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, randomized, placebo-controlled, fixed-dose studies in hospitalized acute exacerbated adult patients who met DSM-IV criteria for schizophrenia. Fixed doses of XEPLION in these studies were administered on days 1, 8, and 36 in the 9-week study and also on day 64 in the 13-week studies. No further supplementation was required. of oral antipsychotics during acute treatment of schizophrenia with XEPLION. The primary efficacy endpoint was defined as a reduction in the Positive And Negative Syndrome Scale (PANSS) total scores as shown in the table below. The PANSS scale is one multi-item validated tool consisting of five dimensions to assess positive symptoms, negative symptoms, conceptual disorganization, hostility / agitation n on controlled and anxiety / depression. Functioning was assessed using the Personal and Social Performance (PSP) scale. PSP is a clinically validated 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 behaviors.

In a 13-week study (n = 636) comparing three fixed doses of XEPLION (initial deltoid injection of 150 mg followed by 3 buttock or deltoid doses of 25 mg / 4 weeks, 100 mg / 4 weeks or 150 mg / 4 weeks) with 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 treatment groups, but not the 25 mg / 4 weeks, demonstrated statistical superiority over placebo for the PSP score. These results support full-duration efficacy and improvement on PANSS and were seen early on day 4 with significant separation from placebo in the XEPLION 25 mg and 150 mg groups from day 8.

The results of the other studies provided statistically significant results in favor of XEPLION, with the exception of the 50 mg dose in a single study (see table below).

Positive and Negative Syndrome Scale (PANSS) total score for schizophrenia - Change from baseline to endpoint - 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 * n = 160 n = 155 - - n = 161 n = 160 Baseline Mean (SD) 86,8 86,9 86,2 88,4 Mean change (SD) -2,9 -8,0 -11,6 -13,2 P-value (vs. Placebo) - - 0,034 R092670-PSY-3003 n = 132 - - n = 93 n = 94 n = 30 Baseline Mean (SD) 92,4 89,9 90,1 92,2 Mean change (SD) -4,1 -7,9 -11,0 -5,5 P-value (vs. Placebo) - - 0,193 0,019 - - R092670-PSY-3004 n = 125 n = 129 n = 128 n = 131 - - Baseline Mean (SD) 90,7 90,7 91,2 90,8 Mean change (SD) -7,0 -13,6 -13,2 -16,1 P-value (vs. Placebo) - - 0,015 0,017 R092670-SCH-201 n = 66 - - n = 63 n = 68 - - Baseline Mean (SD) 87,8 88,0 85,2 Mean change (SD) 6,2 -5,2 -7,8 P-value (vs. Placebo) - - 0,001

* For study R092670-PSY-3007, an initiation dose of 150 mg was administered on day 1 to all subjects in the XEPLION treatment groups followed by the assigned dose thereafter.

Note: Negative change in scores indicates improvement.

Maintenance of symptom control and delay in relapse of schizophrenia

The efficacy of XEPLION in maintaining symptom control and delaying relapse of schizophrenia was established in a longer-term, double-blind, placebo-controlled, flexible-dose study involving 849 non-elderly adult subjects who met the DSM-IV criteria for schizophrenia. This study included an open-label acute treatment and stabilization phase of 33 weeks, a placebo-controlled double-blind randomization phase to observe possible relapse, and an open-label extension period of 52 weeks. . In this study, the doses of XEPLION included 25, 50, 75 and 100 mg administered monthly; the 75 mg dose was only allowed in the 52-week open label extension period. Subjects initially received flexible doses (25-100 mg) of XEPLION during a 9-week transition period, followed by a 24-week maintenance period, where subjects were required to have a PANSS score ≤ 75. Dose adjustments were only allowed in the first 12 weeks of the maintenance period. A total of 410 stabilized patients were randomized to XEPLION (median duration 171 days [range 1 day to 407 days]) or to placebo (median duration 105 days [range 8 days to 441 days]) until they relapsed. symptoms of schizophrenia in the double-blind phase of variable duration. The trial was stopped early for efficacy reasons as a significantly longer time to relapse was observed (p

Pediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with XEPLION in all subsets of the pediatric population in schizophrenia. See section 4.2 for information on pediatric use.


05.2 "Pharmacokinetic properties

Absorption and distribution

Paliperidone palmitate is the palmitate ester prodrug of paliperidone. Due to its extremely low water solubility, paliperidone palmitate dissolves slowly after intramuscular injection before being hydrolyzed to paliperidone and absorbed into the systemic circulation. Following a single intramuscular dose, paliperidone plasma concentrations gradually rise to reach peak plasma concentrations at a median T of 13 days. The release of the active substance begins as early as day 1 and persists for at least 4 months.

Following intramuscular injection of single doses (25-150 mg) into the deltoid muscle, on average, a 28% higher Cmax was observed compared to injection into the buttock.The two initial intramuscular deltoid injections of 150 mg on day 1 and 100 mg on day 8 help achieve therapeutic concentrations rapidly. The release profile and dosage regimen of XEPLION lead to sustained therapeutic concentrations. The total exposure of paliperidone following administration of XEPLION was dose proportional over a dose range of 25-150 mg, and less than dose proportional for C for doses exceeding 50 mg. The peak: trough ratio Mean steady-state for a XEPLION dose of 100 mg was 1.8 following administration in the buttock and 2.2 following administration in the deltoid. The apparent median half-life of paliperidone following administration of XEPLION in the " 25-150 mg dose range ranged from 25 to 49 days.

The absolute bioavailability of paliperidone palmitate following administration of XEPLION is 100%.

Following administration of paliperidone palmitate, the (+) and (-) enantiomers of paliperidone interconvert, reaching an AUC (+) / (-) ratio of approximately 1.6-1.8.

The plasma protein binding of racemic paliperidone is 74%.

Biotransformation and elimination

After one week following administration of a single oral 1 mg immediate-release dose of 14C-paliperidone, 59% of the dose was excreted unchanged in the urine, demonstrating that paliperidone is not extensively metabolised by the liver. Approximately 80% of the administered radioactivity was recovered in the urine and 11% in the faeces. In vivo Four metabolic pathways were identified, none of which accounted for more than 6.5% of the dose: dealkylation, hydroxylation, dehydrogenation, and benzisoxazole cleavage. Although the studies in vitro have suggested a role for CYP2D6 and CYP3A4 in the metabolism of paliperidone, there is no evidence in vivo that these isoenzymes play a significant role in the metabolism of paliperidone. Population pharmacokinetic analyzes indicate that there is no discernible difference in the apparent clearance of paliperidone following administration of oral paliperidone between extensive metabolisers and poor metabolisers of CYP2D6 substrates. Studies in vitro on human liver microsomes demonstrated that paliperidone does not substantially inhibit the metabolism of medicinal products metabolised by cytochrome P450 isoenzymes, including CYP1A2, CYP2A6, CYP2C8 / 9/10, CYP2D6, CYP2E1, CYP3A4 and CYP3A5.

Studies in vitro demonstrated that paliperidone is a P-gp substrate and a weak inhibitor of P-gp at high concentrations. No data are available in vivo and the clinical relevance is unknown.

Prolonged-release paliperidone palmitate injection versus oral-release paliperidone prolonged

XEPLION was developed to release paliperidone over a period of one month while oral extended-release paliperidone is administered on a daily basis. The initial phase regimen for XEPLION (150 mg / 100 mg in the deltoid muscle on day 1 / day 8) was developed to rapidly achieve paliperidone concentrations at the steady state at the beginning of therapy without the use of any oral supplementation.

In general, the overall plasma levels of the initial phase with XEPLION were within the exposure range observed with 6-12 mg prolonged-release oral paliperidone. Use of the XEPLION initial phase regimen allowed patients to remain within this 6-12 mg oral prolonged-release paliperidone exposure window even in the low concentration days prior to dosing (Day 8 and Day 36). Due to the difference in median pharmacokinetic profiles between the two drugs, due care should be taken when making a direct comparison of their pharmacokinetic properties.

Hepatic insufficiency

Paliperidone is not extensively metabolised in the liver. Although XEPLION has not been studied in patients with hepatic impairment, no dose adjustment is required in patients with mild to moderate hepatic impairment. In a study with oral paliperidone in subjects with moderate hepatic impairment (Child-Plugh class B), plasma concentrations of free paliperidone were similar to those in healthy subjects. No studies have been conducted with paliperidone in patients with severe hepatic impairment.

Kidney failure

The disposition of a single oral dose of paliperidone 3 mg prolonged-release tablets has been studied in subjects with varying degrees of renal function. The elimination of paliperidone decreased as the estimated creatinine clearance decreased. The total clearance of paliperidone was reduced by an average of 32% in subjects with mildly impaired renal function (CrCl = 50 to

Senior citizens

No dose adjustment is recommended based on age alone. However, dose adjustment may be required due to age-related reductions in creatinine clearance (see Renal impairment above and section 4.2).

Weight

Pharmacokinetic studies with paliperidone palmitate have shown sometimes lower (10-20%) plasma concentrations of paliperidone in overweight or obese patients than in normal weight patients (see section 4.2).

Race

Population pharmacokinetic analyzes of data from studies with oral paliperidone revealed no race-related differences in the pharmacokinetics of paliperidone following administration of XEPLION.

Sex

No clinically significant differences were observed between male and female patients.

Smoke

Based on studies in vitro conducted using human liver enzymes, paliperidone is not a substrate for CYP1A2; smoking, therefore, is not expected to have any effect on paliperidone pharmacokinetics. A population pharmacokinetic analysis of data with paliperidone prolonged-release tablets showed slightly lower paliperidone exposure in smokers than in non-smokers. However, the difference is unlikely to be clinically relevant. Smoking has not been evaluated for XEPLION.


05.3 Preclinical safety data

Repeat dose toxicity studies of intramuscularly injected paliperidone palmitate and orally administered paliperidone in rats and dogs have shown mainly pharmacological effects, such as sedation and prolactin-mediated effects on mammary and genital glands. An inflammatory reaction at the intramuscular injection site was noted in animals treated with paliperidone palmitate. Occasionally an abscess has formed.

In rat reproduction studies with oral risperidone, which is extensively converted to paliperidone in rats and humans, adverse effects on birth weight and offspring survival were noted. No embryotoxicity or malformations were observed following intramuscular administration of paliperidone palmitate to pregnant rats up to the highest dose (160 mg / kg / day) corresponding to 4.1 times the human exposure level at the maximum recommended dose of 150 mg. Other dopamine antagonists, when administered to pregnant animals, caused adverse effects on learning and motor development in the offspring.

Paliperidone palmitate and paliperidone were not genotoxic. In oral carcinogenicity studies of risperidone in rats and mice, increases in pituitary gland adenomas (in mice), endocrine pancreatic adenomas (in rats) and mammary gland adenomas (in both species) were found. The carcinogenic potential of intramuscularly injected paliperidone palmitate was evaluated in rats. There was a statistically significant increase in mammary gland adenocarcinomas in female rats at 10, 30 and 60 mg / kg / month. A statistically significant increase in mammary gland adenomas and carcinomas has been demonstrated in males at 30 and 60 mg / kg / month representing 1.2 and 2.2 times the exposure level at the maximum recommended human dose of 150 mg. These tumors may be related to prolonged dopamine D2 receptor antagonism and hyperprolactinaemia. The relevance of these tumor findings in rodents in terms of human risk is unknown.

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

Polysorbate 20

Polyethylene glycol 4000

Citric acid monohydrate

Anhydrous di-sodium hydrogen phosphate

Sodium dihydrogen phosphate monohydrate

Sodium hydroxide (for pH adjustment)

Water for injections


06.2 Incompatibility

This medicinal product must not be mixed with other medicinal products.


06.3 Period of validity

2 years.


06.4 Special precautions for storage

Store at a temperature not exceeding 30 ° C.


06.5 Nature of the immediate packaging and contents of the package

Pre-filled syringe (copolymer with cyclic olefin) with plunger stop, syringe handle wings and locking cap (bromobutyl rubber) with a safety needle 22G, 1 ½ inch (0.72mm x 38.1mm) and a safety needle 23G, 1 inch (0.64mm x 25.4mm).

Packaging:

The pack contains 1 pre-filled syringe and 2 needles


06.6 Instructions for use and handling

Unused medicine and wastes derived from this medicine must be disposed of in accordance with local regulations

07.0 MARKETING AUTHORIZATION HOLDER

Janssen-Cilag International NV, Turnhoutseweg 30,

B-2340 Beerse, Belgium.

08.0 MARKETING AUTHORIZATION NUMBER

EU / 1/11/672/004

041004045

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION

04 March 2011

10.0 DATE OF REVISION OF THE TEXT

D.CCE March 2015

11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY

12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL

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