Active ingredients: Paliperidone
INVEGA 1.5 mg prolonged-release tablets
INVEGA 3 mg prolonged-release tablets
INVEGA 6 mg prolonged-release tablets
INVEGA 9 mg prolonged-release tablets
INVEGA 12 mg prolonged-release tablets
Indications Why is Invega used? What is it for?
INVEGA contains the active substance paliperidone which belongs to the class of antipsychotic drugs.
INVEGA is used to treat schizophrenia in adults and adolescents from 15 years of age.
Schizophrenia is a disorder whose symptoms include: hearing sounds or voices, seeing or sensing things that are not present, having wrong beliefs or being suspicious in an unusual way, having a tendency to be isolated, making incoherent speech and behavioral and emotional flattening. People with this disorder may also feel depressed, anxious, guilty, or tense.
INVEGA is also used to treat schizoaffective disorder in adults.
Schizoaffective disorder is a mental condition in which a person experiences a combination of symptoms of schizophrenia (as indicated above) in addition to symptoms related to mood disorders (excitement, sadness, agitation, distraction, drowsiness, talkativeness, loss of interest in activities sleeping too much or too little, eating too much or too little and recurring suicidal thoughts) INVEGA can help relieve symptoms of the disease and stop them from returning.
Contraindications When Invega should not be used
Do not take INVEGA
- if you are allergic to paliperidone, risperidone or any of the other ingredients of this medicine
Precautions for use What you need to know before taking Invega
- Talk to your doctor, pharmacist or nurse before taking INVEGA. Patients with schizoaffective disorder treated with this medicine should be carefully monitored for a potential switch from manic to depressive symptoms.
- This medicine has not been studied in elderly patients with dementia. However, elderly patients with dementia who are being treated with other similar types of medicines may be at an increased risk of stroke or death (see section, Possible side effects).
- If you have Parkinson's disease or dementia.
- If you have ever been diagnosed with a disease whose symptoms include increased temperature and muscle stiffness (also called Neuroleptic Malignant Syndrome).
- If you have ever had abnormal movements of the tongue or face (Tardive Dyskinesia). You need to know that both of these latter diseases can be caused by this type of drug.
- 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 heart disease or are taking treatment for a heart disease that tends to lower your blood pressure.
- If you suffer from epilepsy.
- If you have problems with swallowing, stomach or intestines which reduce your ability to swallow or pass food through normal bowel movements.
- If you suffer from diseases associated with diarrhea.
- 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 elevated level of the hormone prolactin 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 antipsychotic medications 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 your dosage needs to be adjusted or monitored for a certain period.
Since dangerously low numbers of a certain type of white blood cells needed to fight infections in the blood have been observed very rarely in patients taking INVEGA, your doctor may check the white blood cell count.
INVEGA can cause weight gain.
Significant weight gain can adversely affect health. Your doctor should check your weight regularly. Since diabetes mellitus or worsening of pre-existing diabetes mellitus has been observed in patients taking INVEGA, the doctor should check for elevated blood sugar levels. Blood glucose levels should be monitored regularly in patients with pre-existing diabetes mellitus.
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 flabby 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
INVEGA should not be used in children and adolescents under 15 years old, for the treatment of schizophrenia.
INVEGA should not be used in children and adolescents under the age of 18 for the treatment of schizoaffective disorder.
This is because it is not known whether INVEGA is safe or effective in these age groups.
Interactions Which drugs or foods may change the effect of Invega
Tell your doctor or pharmacist if you are taking or have recently taken any other medicines.
When the medicine is taken with some heart medicines that control the heart rhythm or some other medicines such as antihistamines, antimalarials or other antipsychotics, abnormalities in the electrical function of the heart may occur.
Since this medicine acts mainly on the brain, interference with other drugs (or alcohol) that act on the brain may occur due to the additive effect on brain function. As this medicine may lower blood pressure, be careful when taking this medicine. medicine with other medicines that reduce blood pressure.
This medicine may reduce the effect of medicines used to treat Parkinson's disease and restless legs syndrome (eg levodopa).
The effects of this medicine may be affected if you are taking medicines that affect the speed of bowel movements (eg metoclopramide).
Consider dose reduction for this medicine when this medicine is co-administered with valproate.
The concomitant use of oral risperidone with this medicine is not recommended as the combination of the two medicines could lead to more side effects.
INVEGA with alcohol
Avoid the consumption of alcohol while taking this medicine.
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 take this medicine during pregnancy unless you have 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. your child has any of these symptoms you may need to contact your doctor.
Avoid breastfeeding while taking this medicine.
Driving and using machines
Dizziness and vision problems may occur during treatment with this medicine (see section, Possible side effects). This should be taken into account in cases where complete vigilance is required, eg when driving a car or operating machinery.
INVEGA 3 mg tablets contain lactose
The 3 mg tablets of this medicine contain lactose, a type of sugar. If you have been told by your doctor that you have an "intolerance to some sugars, contact your doctor before taking this medicine.
Dose, Method and Time of Administration How to use Invega: Posology
Take this medicine exactly as your doctor, pharmacist or nurse has told you
Use in adults
The recommended dose for adults is 6 mg once a day to be taken in the morning.The dose can be increased or decreased by your doctor in the range of 3 mg to 12 mg once a day for schizophrenia or from 6 mg to 12 mg once a day for schizoaffective disorder. This depends on how the medicine works. for her.
Use in adolescents
The recommended starting dose for the treatment of schizophrenia in adolescents from 15 years of age is 3 mg once daily taken in the morning.
For adolescents weighing 51 kg or more the dose can be increased within the range of 6 mg to 12 mg once daily.
For adolescents weighing less than 51 kg, the dose can be increased up to 6 mg once daily.
Your doctor will decide the right dose for you. The dose you take depends on how the medicine works for you.
How and when to take INVEGA
This drug should be taken orally, the tablet should be swallowed whole with water or other liquid. It must not be chewed, nor divided, nor crushed.
This medicine should be taken every morning with breakfast or on an empty stomach, but in the same way every day. Do not alternate taking the medicine one day on an empty stomach and the next on a full stomach.
The active ingredient, paliperidone, dissolves once swallowed and the tablet shell is eliminated from the body as waste.
Patients with kidney problems
Based on your kidney function, your doctor may adjust the dose of this medicine.
Senior citizens
Your doctor may reduce the dose of the medicine in case of decreased kidney function
Overdose What to do if you have taken too much Invega
If you take more INVEGA than you should
Contact your doctor immediately. You may experience sleepiness, tiredness, abnormal body movements, problems with standing and walking, dizziness caused by low blood pressure and abnormal heartbeats.
If you forget to take INVEGA
Do not take a double dose to make up for a forgotten dose. If you miss a tablet, take your next dose the next day. If you miss two or more doses, contact your doctor.
If you stop taking INVEGA
Do not stop taking INVEGA as you will lose the effects of the drug. You should not stop taking the medicine unless your doctor asks you to, as your symptoms may return.
If you have any other questions about taking this drug, ask your doctor, pharmacist or nurse.
Side Effects What are the side effects of Invega
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 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 can." be the signs of a stroke.
- have fever, muscle stiffness, sweating or 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 required.
- He 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').
Very common: may affect more than 1 in 10 users
- difficulty falling asleep or staying asleep
- parkinsonism. This condition can include: slow or impaired body movements, a feeling of muscle stiffness or tension (making movements jerky), and sometimes a feeling of movement that freezes and then restarts. Other signs of parkinsonism include, slow shuffling walking, tremor at rest, increased saliva and / or drooling, and a loss of facial expression
- restlessness
- feeling sleepy or less alert
- headache.
Common side effects: may affect up to 1 in 10 users
- chest infection (bronchitis), common cold symptoms, sinusitis, urinary tract infection, feeling like you have the flu
- weight gain, increased appetite, weight loss, decreased appetite
- high mood (mania), irritability, depression, anxiety
- 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
- blurred vision
- an interruption of cardiac conduction between the upper and lower parts of the heart, abnormal electrical conduction of the heart, prolongation of the heart's QT interval, slow heart rate, rapid heart rate
- low blood pressure when standing up (as a result, some patients taking INVEGA may feel faint, dizzy or faint when suddenly standing up or sitting down), high blood pressure
- sore throat, cough, stuffy nose
- abdominal pain or discomfort, vomiting, nausea, constipation, diarrhea, indigestion, dry mouth, toothache
- increase in hepatic transaminases in the blood
- itching, rash
- bone or muscle pain, back pain, joint pain
- loss of menstruation
- fever, weakness, fatigue
Uncommon side effects: may affect up to 1 in 100 users
- pneumonia, respiratory tract infection, bladder infection, ear infection, tonsillitis
- decreased white blood cell count, decreased platelets (blood cells that help stop bleeding), anemia, decreased red blood cells
- INVEGA 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 an erection or other sexual dysfunction, (in women) breast discomfort, loss of milk from the breasts , loss of your period or other problems with your period
- diabetes or worsening of diabetes, high blood sugar, increased abdominal circumference, loss of appetite resulting in malnutrition and low body weight, high levels of triglycerides (a fat)
- sleep disturbances, confusion, decreased sexual urge, inability to reach orgasm, nervousness, nightmares
- tardive dyskinesia (twitching or jerking movements of the face, tongue or other parts of the body that cannot be controlled). Tell your doctor immediately if you experience rhythmic involuntary movements of the tongue, mouth and face. It may be necessary to stop taking INVEGA
- convulsions (seizures), fainting, an urgent need to move a part of the body, dizziness when standing up, disturbance 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
- hypersensitivity of the eyes to light, infection of the eye or "slightly red", dry eye
- sensation of spinning (vertigo), ringing in the ears, pain in the ears
- irregular heartbeat, abnormal electrical tracing of the heart (electrocardiogram or ECG), a feeling of racing or throbbing in the chest (palpitations)
- low blood pressure
- shortness of breath, wheezing, nosebleeds
- swollen tongue, stomach or bowel infection, difficulty swallowing, 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), hair loss, eczema, acne
- an increase in CPK (creatine phosphokinase) in the blood, an enzyme that is sometimes released when there is muscle damage, muscle spasms, joint stiffness, joint swelling, muscle weakness, neck pain
- incontinence (lack of control) of urine, frequent urination, inability to pass urine, pain when urinating
- erectile dysfunction, ejaculation disorders
- loss of menstrual periods or problems with your period (females), loss of milk from the breasts, sexual dysfunction, breast pain, breast discomfort
- swelling of the face, mouth, eyes or lips, swelling of the body, arms or legs
- chills, increased body temperature
- change in the way you walk
- feeling thirsty
- chest pain, chest discomfort, feeling sick
- fall
Rare side effects: may affect up to 1 in 1,000 users
- eye infection, fungal nail infection, skin infection, skin inflammation caused by mites
- dangerously low number of a certain type of white blood cell needed to fight infections
- decrease in a type of white blood cell in the blood which serves to protect the body from infection, increase in eosinophils (a type of white blood cell)
- severe allergic reaction characterized by fever, swelling of the mouth, face, lips or tongue, shortness of breath, itching, rash and sometimes drop in blood pressure, allergic reaction
- sugar in the urine
- inappropriate secretion of the hormone that controls urine volume
- life-threatening complications from uncontrolled diabetes
- dangerously excessive intake of water, decreased blood sugar, drinking too much water, increased blood cholesterol
- lack of emotion
- neuroleptic malignant syndrome (confusion, decreased or loss of consciousness, high fever and severe muscle stiffness)
- loss of consciousness, balance disturbances, abnormal coordination
- problems with blood vessels in the brain, coma caused by uncontrolled diabetes, unresponsiveness to stimuli, head tremor
- glaucoma (increased pressure inside the eyeball), increased tearing, red eyes, eye movement problems, eye rolling towards the back of the head
- atrial fibrillation (an abnormal heart rhythm), fast heart rate when standing up
- 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.
- decrease in the level of 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, respiratory tract congestion, voice problems
- intestinal blockage, fecal incontinence, hard stools, lack of bowel muscle movement causing blockage
- yellowing of the skin and eyes (jaundice)
- inflammation of the pancreas
- severe allergic reaction with swelling which can involve the throat and lead to breathing difficulties
- thickening of the skin, dry skin, redness of the skin, discolouration of the skin, flaky and itchy scalp or skin, dandruff
- breakdown of muscle fibers and muscle pain (rhabdomyolysis), abnormal posture
- priapism (a prolonged erection of the penis which may require surgical treatment)
- breast development in men, enlargement of the mammary glands, discharge from the breasts, vaginal discharge
- a delay in the menstrual cycle, breast enlargement
- very low body temperature, a decrease in body temperature
- drug withdrawal symptoms
Not known: frequency cannot be estimated from the available data
- pulmonary congestion
- increased levels of insulin (a hormone that controls blood sugar levels) in the blood
The following side effects have been seen with the use of another medicine called risperidone which is very similar to paliperidone, so these effects can also be expected with INVEGA: Other types of brain blood vessel problems and pulmonary crepitus sounds. eye problems during cataract surgery. During cataract surgery, a condition called intraoperative floppy iris syndrome (IFIS) can occur if you take or have taken INVEGA. If you are going to have cataract surgery, be sure to tell your doctor if you take or have taken this medicine.
Other side effects in adolescents
The side effects generally experienced by adolescents are similar to those seen in adults, with the exception of the following which were most commonly observed:
- feeling sleepy or less alert
- parkinsonism: this condition can include: slow or impaired movements, a feeling of stiffness or muscle tension (making movements jerky) and sometimes even a feeling of movement that freezes and then restarts. Other signs of parkinsonism include slow shuffling walking, tremor at rest, increased saliva and / or drooling, and a loss of facial expression
- weight gain
- common cold symptoms
- restlessness
- tremor
- stomach ache
- breast milk loss in girls
- breast swelling in males
- acne
- speech problems
- stomach or intestinal infection
- nose bleeds
- ear infection
- high levels of triglycerides (a fat) in the blood
- spinning sensation (vertigo)
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. By reporting 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 blister / bottle and carton after EXP. The expiry date refers to the last day of the month.
Bottles: Do not store above 30 ° C. Keep the bottle tightly closed to protect the medicine from moisture.
Blisters: Do not store above 30 ° C. Store the blister in the original package to protect the medicine from moisture.
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.
What INVEGA contains
The active ingredient is paliperidone
Each INVEGA 1.5 mg prolonged-release tablet contains 1.5 mg of paliperidone.
Each INVEGA 3 mg prolonged-release tablet contains 3 mg of paliperidone.
Each INVEGA 6 mg prolonged-release tablet contains 6 mg of paliperidone.
Each INVEGA 9 mg prolonged-release tablet contains 9 mg of paliperidone.
Each INVEGA 12 mg prolonged-release tablet contains 12 mg of paliperidone.
The other ingredients are:
Core of the coated tablet:
200K polyethylene oxide
Sodium chloride Povidone (K29-32)
Stearic acid
Butylated hydroxytoluene (E321)
Iron oxide (yellow) (E172) (3 and 12 mg tablets only)
Polyethylene oxide 7000K
Iron oxide (red) (E172)
Hydroxyethyl cellulose
Polyethylene glycol 3350
Cellulose acetate
Iron oxide (black) (E172) (1.5 and 9 mg tablets only)
Colored coating:
Hypromellose
Titanium dioxide (E171)
Polyethylene glycol 400 (1.5, 6, 9 and 12 mg tablets only)
Iron oxide (yellow) (E172) (1.5, 6 and 12 mg tablets only)
Iron oxide (red) (E172) (1.5, 6 and 9 mg tablets only)
Lactose monohydrate (3 mg tablets only)
Triacetin (3 mg tablets only)
Carnauba wax
Ink for printing:
Iron oxide (black) (E172)
Hypromellose propylene glycol
Description of what INVEGA looks like and contents of the package
INVEGA prolonged-release tablets are capsule-shaped. The 1.5 mg tablets are brown-orange with the imprint "PAL 1.5", the 3 mg tablets are white with the imprint "PAL 3", the 6 mg tablets are beige with the imprint "PAL 6" , the 9 mg tablets are pink with the imprint "PAL 9" and the 12 mg tablets are dark yellow with the imprint "PAL 12". All tablets are available in the following formats:
- Bottles: The tablets are supplied in white plastic bottles with a child resistant closure.Each bottle contains 30 tablets or 350 tablets. Each bottle contains two silica gel sachets, to absorb moisture and keep the tablets dry.
- Blisters: The tablets are supplied in blisters packed in cartons of 14, 28, 30, 49, 56 and 98 tablets
Not all pack sizes may be marketed.
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.
01.0 NAME OF THE MEDICINAL PRODUCT
INVEGA 3 MG EXTENDED RELEASE TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each prolonged-release tablet contains 3 mg of paliperidone.
Excipient: each tablet contains 13.2 mg of lactose.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Prolonged-release tablets
White three-layer capsule-shaped tablets of 11 mm in length and 5 mm in diameter with the inscription "PAL 3"
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
INVEGA is indicated for the treatment of schizophrenia in adults and adolescents from 15 years of age.
INVEGA is indicated for the treatment of the psychotic or manic symptoms of schizoaffective disorder in adults. The effect on depressive symptoms has not been demonstrated.
04.2 Posology and method of administration
Dosage
Schizophrenia (adults)
The recommended dose of INVEGA for the treatment of schizophrenia in adults is 6 mg as a single daily dose, taken in the morning. No titration of the starting dose is required. Some patients may benefit from higher or lower doses internally. of the recommended range, between 3 mg and 12 mg, always to be taken once daily. Dosage changes, if indicated, should only be made following clinical re-evaluation.
When dosage increases are indicated, it is recommended to proceed in increments of 3 mg per day and should generally take place at intervals greater than 5 days.
Schizoaffective Disorder (adults)
The recommended dose of INVEGA for the treatment of schizoaffective disorder in adults is 6 mg once daily, taken in the morning. No titration of the starting dose is necessary. Some patients may benefit from higher doses within the "Recommended range, from 6 mg to 12 mg, always to be taken once daily. Dose modification, if indicated, should only be made following clinical re-evaluation. When dosage increases are indicated, it is recommended to proceed with increments of 3 mg per day and generally should occur at intervals greater than 4 days. Maintenance of the effect has not been studied.
Switching to other antipsychotic drugs
There are no systematic collections of data relating specifically to the switch of patients from INVEGA to other antipsychotic drugs. Due to the different pharmacodynamic and pharmacokinetic profiles of different antipsychotic drugs, clinical physician supervision is necessary when switching to another antipsychotic is considered clinically appropriate.
Senior citizens
The recommended dose for elderly patients with normal renal function (≥ 80 ml / min) is the same as for adults with normal renal function. However, as renal function may be reduced in the elderly, the dose may need to be adjusted according to the patient's renal function (see below: Patients with renal impairment). INVEGA should be used with caution in elderly patients with dementia in the presence of risk factors for stroke (see section 4.4). The safety and efficacy of INVEGA have not been studied in patients over 65 years of age with schizoaffective disorder.
Patients with hepatic impairment
No dosage adjustment is required in patients with mild or moderate hepatic impairment. As INVEGA has not been studied in patients with severe hepatic impairment, caution is recommended in such patients.
Patients with compromise renal
For patients with mild renal impairment (creatinine clearance ≥ 50 to
For patients with moderate to severe renal impairment (creatinine clearance ≥ 10 to
Pediatric population
Schizophrenia: The recommended starting dose of INVEGA for the treatment of schizophrenia in adolescents from 15 years of age is 3 mg once daily given in the morning.
Weight teenagers
Adolescents weighing ≥ 51 kg: The maximum recommended daily dose of INVEGA is 12 mg.
Dose adjustment, if indicated, should only occur after clinical re-evaluation based on individual patient needs. When dosage increases are indicated, 3 mg / day increments are recommended and should generally occur at intervals of 5 or more days. Not The safety and efficacy of INVEGA in the treatment of schizophrenia in adolescents aged 12-14 years have been established. Currently available data are described in sections 4.8 and 5.1 but no recommendation on a posology can be made. There is no indication for a specific use of INVEGA in children below 12 years of age. Schizoaffective Disorder: The safety and efficacy of INVEGA in the treatment of schizoaffective disorder in patients aged 12-17 years have not been studied or established. There is no indication for a specific use of INVEGA in children below 12 years of age. .
Other special groups
No dose adjustment of INVEGA is recommended based on gender, race or smoking patients.
Method of administration
INVEGA is intended for oral administration. The tablet must be swallowed whole with liquid, it must not be chewed, divided or crushed. The active ingredient is contained in a non-absorbable envelope designed to release it in a controlled manner. The shell and its major insoluble components are eliminated from the body; patients need not worry if they occasionally notice something like a tablet in the stool.
INVEGA should always be administered under the same food conditions (see section 5.2). The patient must be instructed that INVEGA must always be taken in a fasted state or always with breakfast and not to alternate between fasting and a full stomach.
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
Patients with schizoaffective disorder treated with paliperidone should be monitored closely for a potential transition from manic to depressive symptoms.
QT interval
Caution is warranted when administering INVEGA to patients with known cardiovascular disorders or a family history of QT interval prolongation and in case of 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 in association with the use of paliperidone. Additional clinical manifestations may include myoglobinuria. (rhabdomyolysis) and acute renal failure If a patient shows signs or symptoms suggestive of NMS, treatment with any antipsychotic, including INVEGA, should be discontinued.
Tardive dyskinesia
Drugs with antagonist 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. If the signs and symptoms of tardive dyskinesia occur, the opportunity to discontinue should be considered. any antipsychotic, including INVEGA.
Leukopenia, neutropenia and agranulocytosis
Events of leukopenia, neutropenia and agranulocytosis have been reported with the use of antipsychotics, including INVEGA. Agranulocytosis has been reported very rarely (white blood cells (WBC) or drug induced leukopenia / neutropenia should be reported during post-marketing surveillance). monitored during the first months of therapy and discontinuation of INVEGA should be considered at the first sign of clinically significant WBC decrease in the absence of other causative factors. Patients with clinically significant neutropenia should be closely monitored for fever or other symptoms 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 INVEGA, 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 INVEGA. Weight should be evaluated regularly.
Hyperprolactinemia
Cell culture studies suggest that cell growth in human breast cancers 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 can induce orthostatic hypotension in some patients due to its alpha-blocking action.
Based on pooled data from the 3 placebo-controlled, 6-week fixed-dose clinical trials conducted with INVEGA (3, 6, 9 and 12 mg), orthostatic hypotension was reported by 2.5% of patients. INVEGA-treated subjects versus 0.8% of placebo-treated subjects. INVEGA should be administered with caution to patients with known cardiovascular disease (e.g. heart failure, myocardial infarction or myocardial ischaemia, conduction defects), cerebrovascular disease or conditions that predispose the patient to hypotension (such as dehydration and hypovolaemia).
Convulsions
INVEGA should be administered with caution to patients with a history of seizures or other conditions that may lower the seizure threshold.
Potential gastrointestinal obstruction
As INVEGA tablets are non-deformable and do not substantially change shape in the gastrointestinal tract, INVEGA should generally not be given to patients with pre-existing severe gastrointestinal narrowing (pathological or iatrogenic) or to patients with dysphagia or serious difficulty in swallowing tablets. There have been rare reports of obstructive symptoms in patients with known narrowings in association with the ingestion of drugs in non-deformable controlled-release formulations. For the controlled-release form of the pharmaceutical form, INVEGA should only be used by patients who can swallow the drug. whole tablet.
Clinical conditions characterized by a reduction in the gastrointestinal transit time
Conditions that generate a reduction in gastrointestinal transit time, eg. diseases associated with severe chronic diarrhea may cause decreased absorption of paliperidone.
Renal impairment
Paliperidone plasma concentrations are increased in patients with renal impairment and, therefore, dosage adjustment may be necessary in some patients (see sections 4.2 and 5.2). No data are available in patients with creatinine clearance below 10 ml / min. Paliperidone should not be given to such patients.
Hepatic impairment
No data are available in patients with severe hepatic impairment (Child-Pugh Class C). Caution is advised when administering paliperidone to such patients.
Elderly patients with dementia
INVEGA has not been studied in elderly patients with dementia. The experience with risperidone 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 demented patients treated with some atypical antipsychotics, including risperidone, aripiprazole and olanzapine. The mechanism behind the increased risk is unknown. INVEGA should be used with caution in elderly patients with dementia who have risk factors for stroke.
Parkinson's disease and dementia with Lewy bodies
Physicians should weigh the risks and benefits of prescribing INVEGA to patients with Parkinson's disease or dementia with Lewy bodies (DLB), as both patient groups may be at an increased risk of developing Neuroleptic Malignant Syndrome or may exhibit a increased sensitivity to antipsychotics. Manifestations of this increased sensitivity can include confusion, dullness, postural instability with frequent falls, as well as extra-pyramidal symptoms.
Priapism
Antipsychotic drugs (including risperidone) with α-adrenergic blocking effects have been reported to induce priapism. Priapism has also been reported with paliperidone, which is the active metabolite of risperidone, during post-marketing surveillance. Patients should be advised that urgent medical attention should be sought if priapism does not resolve within 3-4 hours.
Body temperature regulation
Impaired the body's ability to lower core body temperature has been attributed to antipsychotic drugs. Caution is advised when prescribing INVEGA to patients who may be exposed to conditions that may contribute to an increase in body temperature, such as eg. strenuous exercise, exposure to extreme heat, concomitant treatment with anticholinergic drugs or in patients prone to dehydration.
Venous thromboembolism
Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Patients treated with antipsychotic drugs often have acquired risk factors for VTE; therefore all possible risk factors for VTE must be identified before and during INVEGA therapy 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 drugs or of conditions such as intestinal obstruction, Reye's syndrome and brain tumor.
Pediatric population
The sedative effect of INVEGA should be closely monitored in this population. A change in the timing of INVEGA may improve / enhance the impact of sedation on the patient.
Due to the potential effects of prolonged hyperprolactinaemia on sexual growth and maturation in adolescents, periodic clinical evaluation of endocrinological status, including measurements of height, weight, sexual maturation, monitoring of menstrual cycle functioning and other potential effects should be considered. prolactin-related.
An examination for extrapyramidal symptoms and other movement disorders should also be conducted regularly during treatment with INVEGA.
For specific dosing recommendations in the pediatric population, see section 4.2.
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 INVEGA (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.
Lactose content (only affects 3 mg tablets)
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this drug.
04.5 Interactions with other medicinal products and other forms of interaction
Caution is advised when prescribing INVEGA in combination with drugs known to prolong the QT interval, such as class IA antiarrhythmics (eg quinidine, disopyramide), and class III antiarrhythmics (eg amiodarone, sotalol), some antihistamines, some antipsychotics and some antimalarials (e.g. mefloquine).
Potential for INVEGA to affect other medicines
Paliperidone is not expected to cause clinically significant pharmacokinetic interactions in association with drugs metabolised by cytochrome P-450 isoenzymes. Education in vitro indicate that paliperidone is not an inducer of CYP1A2 activity.
Given the primary central nervous system effects of paliperidone (see section 4.8), INVEGA should be used with caution in combination with other centrally acting drugs, such as e.g. anxiolytics, most antipsychotics, hypnotics, opiates etc. or with alcohol.
Paliperidone may antagonize the effect of levodopa and other dopamine agonists. If such a combination is deemed necessary, especially in the terminal stages of Parkinson's disease, it is recommended to prescribe the lowest effective dose of each treatment.
Due to its potential to induce orthostatic hypotension (see section 4.4), an additive effect may be observed when INVEGA is administered with other therapeutic agents that possess this potential, e.g. other antipsychotics or tricyclic drugs.
Caution is advised if paliperidone is administered in combination with other drugs thought to lower the seizure threshold (e.g., phenothiazines or butyrophenones, clozapine, tricyclics or SSRIs, tramadol, mefloquine etc.).
No interaction studies have been conducted between INVEGA and lithium, however a pharmacokinetic interaction is unlikely.
Co-administration of INVEGA 12 mg once daily with valproic acid prolonged release tablets + valproate sodium (500 mg to 2000 mg once daily) did not affect the steady-state pharmacokinetics of valproate. Co-administration of INVEGA with valproic acid prolonged-release tablets + sodium valproate increased exposure to paliperidone (see below).
Potential for other medicines to affect INVEGA
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 INVEGA with paroxetine, a potent inhibitor of CYP2D6, did not show clinically significant effects on the pharmacokinetics of paliperidone. Education in vitro showed that paliperidone is a substrate of P-glycoprotein (P-gp).
Co-administration of INVEGA once daily with carbamazepine 200 mg twice daily caused an approximately 37% decrease in mean steady-state Cmax and AUC (steady state) of paliperidone. This decrease is substantially caused by a 35% increase in renal clearance of paliperidone, possibly as a result of carbamazepine's induction of renal P-gp. A minor decrease in the amount of active substance excreted unchanged in the urine suggests 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 INVEGA dose should be be re-evaluated and increased if necessary. Conversely, upon discontinuation of carbamazepine therapy, the INVEGA dose should be re-evaluated and decreased if necessary. It takes 2-3 weeks to achieve full induction and upon discontinuation of inducer treatment the effect gradually diminishes over a similar period of time. Other drugs or preparations based on medicinal plants with inducing action, such as eg. rifampicin and St. John's wort (Hypericum perforatum) could have similar effects on paliperidone.
Drugs that affect gastrointestinal transit time, eg. metoclopramide, could affect the absorption of paliperidone.
Co-administration of a single dose of INVEGA 12 mg with valproic acid + sodium valproate prolonged-release tablets (two 500 mg tablets once daily) resulted in an approximately 50% increase in paliperidone Cmax and AUC. In case of co-administration of INVEGA with valproate, after clinical evaluation, a decrease of the INVEGA dose should be considered.
Concomitant use of INVEGA with risperidone
The concomitant use of INVEGA with oral risperidone is not recommended as paliperidone is the active metabolite of risperidone and the combination of the two could lead to additional exposure to paliperidone.
Pediatric population
Interaction studies have only been performed in adults.
04.6 Pregnancy and lactation
Pregnancy
There are no adequate data on the use of paliperidone during pregnancy. In animal studies, paliperidone was not teratogenic, but other types of reproductive toxicity were 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 which may vary in severity and duration following delivery. There have been reports of restlessness, hypertonia, hypotonia, tremor, somnolence, breathing difficulties, or eating disorders. Consequently, infants need to be monitored closely. INVEGA should not be taken during pregnancy unless absolutely necessary. Should it be necessary to discontinue treatment during pregnancy, discontinuation should not be sudden.
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. INVEGA should not be used during the breastfeeding period.
Fertility
No relevant effects were observed during the 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 (see section 4.8). Therefore, patients should be advised not to drive or operate machinery until the individual sensitivity to INVEGA is known.
04.8 Undesirable effects
Adults
Summary of the safety profile
The most frequently reported adverse drug reactions (ADRs) in clinical trials in adults were: headache, insomnia, sedation / somnolence, parkinsonism, akathisia, tachycardia, tremor, dystonia, upper respiratory tract infection, anxiety, dizziness, increased body weight, nausea, agitation, constipation, vomiting, fatigue, depression, dyspepsia, diarrhea, dry mouth, toothache, musculoskeletal pain, hypertension, asthenia, back pain, prolongation of the EKG QT interval and cough.
ADRs that appeared to be dose related included headache, sedation / somnolence, parkinsonism, akathisia, tachycardia, dystonia, dizziness, tremor, upper respiratory tract infection, dyspepsia, and musculoskeletal pain.
In the schizoaffective disorder studies, a greater proportion of subjects in the total INVEGA group who were receiving concomitant therapy with antidepressants or mood stabilizers reported adverse events compared to subjects treated with INVEGA monotherapy.
Table of adverse reactions
The following ADRs have all been reported during clinical trials and postmarketing with paliperidone by frequency categories estimated from INVEGA clinical trials in adults. 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 data). Within each frequency group, reactions adverse events are presented in descending order of severity.
In adolescents, weight gain should be weighed against that expected with normal growth.
Prolactin
In an open two-year study with INVEGA in adolescents with schizophrenia, the incidence of elevated serum prolactin levels occurred in 48% of females and 60% of males. Adverse reactions that may suggest increased levels of prolactin (eg, amenorrhea, galactorrhea, menstrual disorders, gynecomastia) were found overall in 9.3% of subjects.
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.
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, prolongation of the QT interval and extrapyramidal symptoms. Torsades de pointes and ventricular fibrillation associated with overdose have been reported. In the event of an acute overdose, consideration should be given to the possibility of multiple drugs being involved.
Consider the sustained-release nature of the product when assessing treatment needs and patient recovery. There is no specific antidote to paliperidone, therefore appropriate general supportive measures should be instituted. Establish and maintain a patent airway and ensure adequate oxygenation and ventilation. Cardiovascular monitoring should be initiated immediately and continuous electrocardiographic monitoring should be included for possible arrhythmias. Hypotension and circulatory collapse should be treated with appropriate measures , which fluids ev and / or sympathomimetic agents. Consider performing gastric lavage (after intubation if patient is unconscious) and administering activated charcoal together with a laxative. 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
INVEGA 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 serotonergic 5-HT2 and dopaminergic D2 receptors. Paliperidone also blocks alpha1 adrenergic receptors, and blocks, to a lesser extent, histaminergic H1 and alpha2 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, an antagonism believed to alleviate 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 extra-pyramidal side effects.
Clinical efficacy and safety
Schizophrenia
The efficacy of INVEGA in the treatment of schizophrenia was established in three 6-week, double-blind, placebo-controlled, multicenter clinical trials in subjects meeting DSM-IV criteria for schizophrenia. The doses of INVEGA, in the three studies, they ranged from 3 to 15 mg once daily. The primary efficacy endpoint was defined as a reduction in the total score on the Positive and Negative Syndrome Scale (PANSS), as shown in the following table. The PANSS scale is a validated tool multi-item composed of five dimensions for assessing positive symptoms, negative symptoms, conceptual disorganization, uncontrolled hostility / agitation and anxiety / depression. All INVEGA dosages tested differed from placebo on Day 4 of treatment (pPersonal and Social Performance (PSP) and the Clinical Global Impression - Severity (CGI-S). In all three studies, the efficacy of INVEGA was superior to placebo at PSP and CGI-S. Efficacy was also assessed by calculating response to treatment (defined as a reduction in total PANSS score ≥ 30%) as secondary endpoint.
Studies related to schizophrenia: total score on the scale Positive and Negative Syndrome Scale for Schizophrenia (PANSS) - Change from Baseline to Endpoint - LOCF for Studies R076477-SCH-303, R076477-SCH-304 and R076477-SCH-305: Analysis Intent-to-Treat Studies related to schizophrenia: total score on the scale Positive and Negative Syndrome Scale for Schizophrenia (PANSS) - Change from Baseline to Endpoint - LOCF for Studies R076477- SCH-303, R076477-SCH-304 and R076477-SCH-305: Analysis Intent-to-Treat
Note: Negative change in scores indicates improvement. An active control (olanzapine at a dose of 10 mg) was included in all three studies. LOCF = last observation carried forward (last observation made). Version 1-7 of the PANSS was used. A 15 mg dose was also included in study R076477-SCH-305, but results were not presented as this dose exceeds the maximum recommended daily dose of 12 mg.
In a long-term clinical trial designed to evaluate maintenance of the effect, INVEGA was significantly more effective than placebo in maintaining symptom control and delaying relapse of schizophrenia. After being treated for 6 weeks following a acute episode and stabilized for an additional 8 weeks with INVEGA (at doses ranging from 3 mg to 15 mg once daily), patients were randomized in a double-blind manner to continue treatment with INVEGA or placebo, until they showed a relapse of symptoms of schizophrenia.
The study was terminated prematurely for efficacy reasons, showing a significantly longer time to relapse in patients treated with INVEGA compared to placebo (p = 0.0053).
Schizoaffective Disorder
The efficacy of INVEGA in the acute treatment of psychotic or manic symptoms of schizoaffective disorder was established in two placebo-controlled, 6-week clinical trials in non-elderly adult subjects. Enrolled subjects 1) met DSM-IV criteria for schizoaffective disorder, as confirmed by the "structured clinical interview for DSM-IV (Structured Clinical Interview for DSM-IV Disorders, SCID), 2) had obtained a total score at the Positive and Negative Syndrome Scale (PANSS) of at least 60, and 3) had prominent mood disturbance symptoms as confirmed by a score of at least 16 on the scale Young Mania Rating Scale (YMRS) and / or Hamilton Rating Scale 21 for Depression (HAM-D 21). The population included subjects with bipolar and depressive schizoaffective disorder. In one of these trials, efficacy was evaluated in 211 subjects who were given flexible doses of INVEGA (3-12 mg once daily). In the other trial, efficacy was evaluated in 203 subjects assigned to one of the two dose levels of INVEGA: 6 mg with the option of reducing to 3 mg (n = 105) or 12 mg with the option of reducing to 9 mg (n = 98) once daily. Both studies included subjects who received INVEGA as monotherapy or in combination with mood stabilizers and / or antidepressants. It was taken in the morning regardless of meals. Efficacy was assessed using the PANSS scale.
The INVEGA group in the flexible dose trial (between 3 and 12 mg / day, mean modal dose of 8.6 mg / day) and the INVEGA group with the higher dose in the two dose level trial (12 mg / day with the option to reduce to 9 mg / day) were both superior to placebo in the PANSS score at 6 weeks. In the group with the lowest dose in the trial with two dose levels (6 mg / day with the option to reduce to 3 mg / day), INVEGA was not significantly different from placebo in the PANSS score. Only a few subjects received the 3 mg strength in both studies and the efficacy of this dosage could not be established.
Statistically greater improvements in manic symptoms as measured by the YMRS (secondary efficacy scale) were observed in patients in the flexible-dose study and in the INVEGA group with the highest dose in the second trial. The effect of schizoaffective disorder on depressive symptoms and maintenance of the effect have not been studied.
Considering the overall results of the two trials, (pooled study data), INVEGA improved psychotic and manic symptoms of schizoaffective disorder at the endpoint compared to placebo when given as monotherapy or in combination with mood stabilizers and / or antidepressants. However, on monotherapy the magnitude of effect with regard to PANSS and YMRS was greater than that seen with concomitant use of antidepressants and / or mood stabilizers. Furthermore, in the pooled population, INVEGA was not effective in controlling psychotic symptoms in patients who were receiving simultaneous mood stabilizers and / or antidepressants, but this population was small (30 responders in the paliperidone group and 20 responders in the placebo group).
Furthermore, in the SCA-3001 study in the ITT population the effect on psychotic symptoms as measured by PANSS was clearly less pronounced and did not reach statistical significance for patients who were receiving simultaneously mood stabilizers and antidepressants. An effect of INVEGA on depressive symptoms has not been demonstrated.
An examination of the population subgroups revealed no evidence of a differential response based on gender, age, or geographic area. The data were insufficient to explore differential effects based on race. Efficacy was also assessed by calculating response to treatment as a secondary endpoint (defined as reduction in PANSS total score ≥ 30% and CGI-C score ≤ 2).
Schizoaffective Disorder Studies: Primary Efficacy Parameter, Change in PANSS Total Score from Baseline for Studies R076477-SCA-3001 and R076477-SCA-3002: Analysis Intent-to-Treat
Schizoaffective Disorder Studies: Primary Efficacy Parameter, Change in PANSS Total Score from Baseline for Studies R076477-SCA-3001 and R076477-SCA-3002: Analysis Intent-to-Treat
Note: Negative change in scores indicates improvement. LOCF = last observation carried forward (last observation made).
Studies related to schizoaffective disorder: secondary efficacy parameter, proportion of subjects with responder status at the "End Point LOCF: studies R076477-SCA-3001 and R076477-SCA-3002: Analysis Intent-to-Treat
Response defined as reduction from baseline in PANSS total score ≥ 30% and CGI-C ≤ 2
Pediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with INVEGA in all subsets of the pediatric population for the treatment of schizoaffective disorder. See section 4.2 for information on pediatric use.
The efficacy of INVEGA in the treatment of schizophrenia in adolescents aged 12-14 years has not been established.
The efficacy of INVEGA in adolescent subjects with schizophrenia (INVEGA N = 149, placebo n = 51) was evaluated in a randomized, double-blind, placebo-controlled, 6-week study using a grouped design. Weight-based fixed-dose treatment with a dose range of 1.5 mg / day to 12 mg / day. Subjects were 12-17 years of age and met DSM-IV criteria for schizophrenia. Efficacy is was assessed using the PANSS scale. This study demonstrated the efficacy of INVEGA in the medium dose group of adolescent subjects with schizophrenia. A dose-based secondary analysis demonstrated the efficacy of 3 mg, 6 mg and 12 mg doses administered once daily. .
* Medium dose group: 3 mg per subjects
** High dose group: 6 mg per subjects
The efficacy of INVEGA over a flexible dosing range of 3 mg / day to 9 mg / day in adolescent subjects (12 years and older) with schizophrenia (INVEGA N = 112, aripiprazole N = 114) was also evaluated in one Randomized, double-blind, active-controlled study, which included 8 weeks double-blind acute phase and 18 weeks double-blind maintenance phase. Changes from baseline in PANSS total score at week 8 and week 26 were numerically similar between the INVEGA and aripiprazole treatment groups In addition, the difference in the proportion of patients who demonstrated improvement in PANSS total score ≥ 20% at week 26 between the two treatment groups was numerically similar.
Schizophrenia study in adolescents: R076477-PSZ-3003: 26 weeks, flexible dose, controlled versus active control, analysis Intent-to-Treat. LOCF change from baseline to endpoint
Response defined as reduction from baseline in PANSS total score ≥ 20%
Note: Negative change in scores indicates improvement. LOCF = last observation carried forward (last observation made).
05.2 Pharmacokinetic properties
The pharmacokinetics of paliperidone following INVEGA administration are dose proportional over the available dose range.
Absorption
Following single dose administration, INVEGA exhibits a gradual ascending release rate, allowing paliperidone plasma concentrations to steadily increase and reach maximum plasma concentration (Cmax) approximately 24 hours after administration. With a once-daily dose of INVEGA, steady-state concentrations (steady state) of paliperidone are achieved within 4-5 days of starting treatment in most subjects.
Paliperidone is the active metabolite of risperidone. The release characteristics of INVEGA translate into minimal fluctuations in the peak-trough concentrations of the active substance, when compared to those observed with immediate-release risperidone (fluctuation index of 38% vs 125%).
The absolute oral bioavailability of paliperidone following INVEGA administration is 28% (90% CI 23% -33%).
Administration of paliperidone prolonged release tablets in conjunction with a standard high calorie / high fat meal increases paliperidone Cmax and AUC by up to 50-60% compared to administration in the fasted state.
Distribution
Paliperidone is rapidly distributed. The apparent volume of distribution is 487 L. Plasma protein binding of paliperidone is 74% and mainly affects α1-acid glycoprotein and albumin.
Biotransformation and elimination
After one week following administration of a single 1 mg immediate-release oral 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 dose was excreted unchanged in the urine. The administered radioactivity was recovered in the urine and 11% in the faeces. In vivo 4 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 INVEGA between extensive metabolisers and poor metabolisers of CYP2D6 substrates. Studies in vitro on human liver microsomes, paliperidone has shown that paliperidone does not substantially inhibit the metabolism of drugs metabolised by cytochrome P450 isoenzymes, including CYP1A2, CYP2A6, CYP2C8 / 9/10, CYP2D6, CYP2E1, CYP3A4 and CYP3A5.
The terminal elimination half-life of paliperidone is approximately 23 hours.
Studies in vitro demonstrated that paliperidone is a substrate of P-gp and a weak inhibitor of P-gp at high concentrations. No in vivo data are available and the clinical relevance is unknown.
Hepatic impairment
Paliperidone is not extensively metabolised in the liver. In a study in subjects with moderate hepatic impairment (Child-Pugh class B), plasma concentrations of free paliperidone were similar to those in healthy subjects. No data are available in patients with severe hepatic impairment (Child-Pugh Class C).
Renal impairment
Elimination of paliperidone decreases with decreasing renal function. Total clearance of paliperidone was reduced by 32% in subjects with mildly impaired renal function (Creatinine Clearance [CrCl] = 50 to
Senior citizens
Data collected from a pharmacokinetic study in elderly subjects (≥ 65 years, n = 26) showed that apparent clearance at steady state (steady state) of paliperidone following INVEGA administration was 20% lower than that in adult subjects (18-45 years, n = 28). However, there was no discernible effect of age in the population pharmacokinetic analysis which included subjects with schizophrenia after correcting age-related reductions in CrCL.
Teenagers
Systemic exposure to paliperidone in adolescent subjects (15 years of age and older) was comparable to that in adults.
Race
Population pharmacokinetic analysis showed no signs of race-related differences in the pharmacokinetics of paliperidone following administration of INVEGA.
Sex
The apparent clearance of paliperidone following INVEGA administration is approximately 19% lower in women than in men. The difference can be largely explained by the difference in lean mass and creatinine clearance between the two sexes.
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 showed" slightly lower paliperidone exposure in smokers compared to non-smokers. However, the difference is unlikely to be of clinical relevance.
05.3 Preclinical safety data
Repeated dose toxicity studies of paliperidone in rats and dogs revealed mainly pharmacological effects, such as sedation and prolactin-mediated effects on mammary glands and genitals. Paliperidone was not teratogenic in rats and rabbits. In reproductive studies in rats using risperidone, which is extensively converted to paliperidone in rats and humans, a reduction in the birth weight and survival of the offspring was observed. Other dopamine antagonists, when administered to pregnant animals, caused adverse effects on learning and motor development in the offspring. Paliperidone was not genotoxic in a battery of tests. In oral carcinogenicity studies of risperidone in mice and rats, they were increases in pituitary gland adenomas (in mice), endocrine pancreatic adenomas (in rats) and mammary gland adenomas (in both species) have been detected. These tumors may be linked to prolonged antagonism at the level of dopaminergic D2 receptors and hyperprolactinaemia. The relevance of these findings of tumors in rodents in terms of human risk is unknown.
In a 7-week juvenile toxicity study in rats administered oral doses of paliperidone up to 2.5 mg / kg / day, corresponding to an exposure of approximately the clinical exposure based on AUC, no effects on growth, sexual maturation and reproductive capacity were observed. Paliperidone did not impair neurobehavioral development in males with doses up to 2.5 mg / kg / day. At 2.5 mg / kg / day, an effect on learning and memory was observed in females. This effect was not observed after discontinuation of treatment. In a 40-week juvenile toxicity study in dogs with oral doses of risperidone (which is extensively converted to paliperidone) up to 5 mg / kg / day, effects on sexual maturation, long bone growth and mineral density were observed. femur 3 times the clinical exposure based on AUC.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
For 3 mg tablets:
Nucleus:
200K polyethylene oxide
Sodium chloride
Povidone (K29-32)
Stearic acid
Butylated hydroxytoluene (E321)
Iron oxide (yellow) (E172)
Polyethylene oxide 7000K
Iron oxide (red) (E172)
Hydroxyethyl Cellulose
Polyethylene glycol 3350
Cellulose acetate
Coating:
Hypromellose
Titanium dioxide (E171)
Lactose monohydrate
Triacetin
Carnauba wax
Ink for printing:
Iron oxide (black) (E172)
Propylene glycol
Hypromellose
06.2 Incompatibility
Not applicable
06.3 Period of validity
2 years
06.4 Special precautions for storage
Bottles: Do not store above 30 ° C. Keep the bottle tightly closed to protect the medicine from moisture.
Blisters: Do not store above 30 ° C. Store the blister in the original package to protect the medicine from moisture.
06.5 Nature of the immediate packaging and contents of the package
Bottles:
White high density polyethylene (HDPE) bottles with induction seal and child resistant polypropylene closure. Each bottle contains two 1 g sachets of desiccant silica gel (Silicon dioxide), in polyethylene for food use.
Packs of 30 and 350 prolonged-release tablets.
Blister:
Polyvinyl chloride (PVC) laminated with polychlorotrifluoroethylene (PCTFE) / aluminum layer pushthrough.
Packs of 14, 28, 30, 49, 56 and 98 prolonged-release tablets.
Or
White polyvinyl chloride (PVC) laminated with polychlorotrifluoroethylene (PCTFE) / layer of
aluminum push-through.
Packs of 14, 28, 30, 49, 56 and 98 prolonged-release tablets.
Or
Oriented polyamide (OPA) -Aluminium-Polyvinyl chloride (PVC) / aluminum layer push-through.
Packs of 14, 28, 49, 56 and 98 prolonged-release tablets.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
No special instructions for disposal.
07.0 MARKETING AUTHORIZATION HOLDER
Janssen-Cilag International NV,
Turnhoutseweg 30,
B-2340 Beerse,
Belgium.
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/07/395 / 001-005
038024016
038024028
038024030
038024042
038024055
EU / 1/07/395 / 021-025
038024218
038024220
038024232
038024244
038024257
EU / 1/07/395 / 041-044
038024410
038024422
038024434
038024446
EU / 1/07/395 / 057-058
038024574
038024586
EU / 1/07/395 / 065-067
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 25 June 2007
Date of last renewal: 25 June 2012
10.0 DATE OF REVISION OF THE TEXT
May 2014
