INVEGA 9mg prolonged tablets medication leaflet

INVEGA 3 mg prolonged-release tablets

INVEGA 6 mg prolonged-release tablets

INVEGA 9 mg prolonged-release tablets

INVEGA 12 mg prolonged-release tablets

Each prolonged-release tablet contains 3 mg of paliperidone.

Each prolonged-release tablet contains 6 mg of paliperidone.

Each prolonged-release tablet contains 9 mg of paliperidone.

Each prolonged-release tablet contains 12 mg of paliperidone.

Each 3 mg tablet contains 13.2 mg lactose.

For the full list of excipients, see section 6.1.

Prolonged-release tablet

Trilayer capsule-shaped white tablets of 11 mm in length and 5 mm in diameter printed with “PAL 3”

Trilayer capsule-shaped beige tablets of 11 mm in length and 5 mm in diameter printed with “PAL 6”

Trilayer capsule-shaped pink tablets of 11 mm in length and 5 mm in diameter printed with “PAL 9”

Trilayer capsule-shaped yellow tablets of 11 mm in length and 5 mm in diameter printed with“PAL 12”

INVEGA is indicated for the treatment of schizophrenia in adults and in adolescents 15 years andolder.

INVEGA is indicated for the treatment of schizoaffective disorder in adults.

Schizophrenia (adults)

The recommended dose of INVEGA for the treatment of schizophrenia in adults is 6 mg once daily,administered in the morning. Initial dose titration is not required. Some patients may benefit fromlower or higher doses within the recommended range of 3 mg to 12 mg once daily. Dosageadjustment, if indicated, should occur only after clinical reassessment. When dose increases areindicated, increments of 3 mg/day are recommended and generally should occur at intervals of morethan 5 days.

The recommended dose of INVEGA for the treatment of schizoaffective disorder in adults is 6 mgonce daily, administered in the morning. Initial dose titration is not required. Some patients maybenefit from higher doses within the recommended range of 6 mg to 12 mg once daily. Dosageadjustment, if indicated, should occur only after clinical reassessment. When dose increases areindicated, increments of 3 mg/day are recommended and generally should occur at intervals of morethan 4 days.

There are no systematically collected data to specifically address switching patients from INVEGA toother antipsychotic medicinal products. Due to different pharmacodynamic and pharmacokineticprofiles among antipsychotic medicinal products, supervision by a clinician is needed when switchingto another antipsychotic product is considered medically appropriate.

Dosing recommendations for elderly patients with normal renal function (≥ 80 mL/min) are the sameas for adults with normal renal function. However, because elderly patients may have diminished renalfunction, dose adjustments may be required according to their renal function status (see Renalimpairment below). INVEGA should be used with caution in elderly patients with dementia with riskfactors for stroke (see section 4.4). Safety and efficacy of INVEGA in patients > 65 years of age withschizoaffective disorder have not been studied.

No dose adjustment is required in patients with mild or moderate hepatic impairment. As INVEGAhas not been studied in patients with severe hepatic impairment, caution is recommended in suchpatients.

For patients with mild renal impairment (creatinine clearance ≥ 50 to < 80 mL/min), the recommendedinitial dose is 3 mg once daily. The dose may be increased to 6 mg once daily based on clinicalresponse and tolerability.

For patients with moderate to severe renal impairment (creatinine clearance  10 to < 50 mL/min), therecommended initial dose of INVEGA is 3 mg every other day, which may be increased to 3 mg oncedaily after clinical reassessment. As INVEGA has not been studied in patients with creatinineclearance below 10 mL/min, use is not recommended in such patients.

Schizophrenia: The recommended starting dose of INVEGA for the treatment of schizophrenia inadolescents 15 years and older is 3 mg once daily, administered in the morning.

Adolescents weighing < 51 kg: the maximum recommended daily dose of INVEGA is 6 mg.

Adolescents weighing ≥ 51 kg: the maximum recommended daily dose of INVEGA is 12 mg.

Dosage adjustment, if indicated, should occur only after clinical reassessment based on the individualneed of the patient. When dose increases are indicated, increments of 3 mg/day are recommended andgenerally should occur at intervals of 5 days or more. The safety and efficacy of INVEGA in thetreatment of schizophrenia in adolescents between 12 and 14 years old has not been established.

Currently available data are described in sections 4.8 and 5.1 but no recommendation on a posologycan be made. There is no relevant use of INVEGA in children aged less than 12 years.

Schizoaffective disorder: The safety and efficacy of INVEGA in the treatment of schizoaffectivedisorder in patients aged 12 to 17 years has not been studied or established. There is no relevant use of

INVEGA in children aged less than 12 years.

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

INVEGA is for oral administration. It must be swallowed whole with liquid, and must not be chewed,divided, or crushed. The active substance is contained within a non-absorbable shell designed torelease the active substance at a controlled rate. The tablet shell, along with insoluble corecomponents, is eliminated from the body; patients should not be concerned if they occasionally noticein their stool something that looks like a tablet.

The administration of INVEGA should be standardised in relation to food intake (see section 5.2). Thepatient should be instructed to always take INVEGA in the fasting state or always take it together withbreakfast and not to alternate between administration in the fasting state or in the fed state.

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

Patients with schizoaffective disorder treated with paliperidone should be carefully monitored for apotential switch from manic to depressive symptoms.

Caution should be exercised when INVEGA is prescribed in patients with known cardiovasculardisease or family history of QT prolongation, and in concomitant use with other medicines thought toprolong the QT interval.

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

Medicines with dopamine receptor antagonistic properties have been associated with the induction oftardive dyskinesia characterised by rhythmical, involuntary movements, predominantly of the tongueand/or face. If signs and symptoms of tardive dyskinesia appear, the discontinuation of allantipsychotics, including INVEGA, should be considered.

Caution is warranted in patients receiving both, psychostimulants (e.g., methylphenidate) andpaliperidone concomitantly, as extrapyramidal symptoms could emerge when adjusting one or bothmedications. Gradual withdrawal of stimulant treatment is recommended (see section 4.5).

Leucopenia, neutropenia, and agranulocytosis

Events of leucopenia, neutropenia, and agranulocytosis have been reported with antipsychotic agents,including INVEGA. Agranulocytosis has been reported very rarely (< 1/10 000 patients) duringpost-marketing surveillance. Patients with a history of a clinically significant low white blood cellcount (WBC) or a drug-induced leucopenia/neutropenia should be monitored during the first fewmonths of therapy and discontinuation of INVEGA should be considered at the first sign of a clinicallysignificant decline in WBC in the absence of other causative factors. Patients with clinicallysignificant neutropenia should be carefully monitored for fever or other symptoms or signs of infectionand treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absoluteneutrophil count < 1 x 109/L) should discontinue INVEGA and have their WBC followed untilrecovery.

Hyperglycaemia, diabetes mellitus, and exacerbation of pre-existing diabetes have been reportedduring treatment with paliperidone. In some cases, a prior increase in body weight has been reportedwhich may be a predisposing factor. Association with ketoacidosis has been reported very rarely andrarely with diabetic coma. Appropriate clinical monitoring is advisable in accordance with utilisedantipsychotic guidelines. Patients treated with any atypical antipsychotic, including INVEGA, shouldbe monitored for symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia, andweakness) and patients with diabetes mellitus should be monitored regularly for worsening of glucosecontrol.

Significant weight gain has been reported with INVEGA use. Weight should be monitored regularly.

Tissue culture studies suggest that cell growth in human breast tumours may be stimulated byprolactin. Although no clear association with the administration of antipsychotics has so far beendemonstrated in clinical and epidemiological studies, caution is recommended in patients with relevantmedical history. Paliperidone should be used with caution in patients with possibleprolactin-dependent tumours.

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

Based on pooled data from the three, placebo-controlled, 6-week, fixed-dose trials with INVEGA (3,6, 9, and 12 mg), orthostatic hypotension was reported by 2.5% of subjects treated with INVEGAcompared with 0.8% of subjects treated with placebo. INVEGA should be used with caution inpatients with known cardiovascular disease (e.g., heart failure, myocardial infarction or ischaemia,conduction abnormalities), cerebrovascular disease, or conditions that predispose the patient tohypotension (e.g., dehydration and hypovolaemia).

INVEGA should be used cautiously in patients with a history of seizures or other conditions thatpotentially lower the seizure threshold.

Because the INVEGA tablet is non-deformable and does not appreciably change shape in thegastrointestinal tract, INVEGA should not ordinarily be administered to patients with preexistingsevere gastrointestinal narrowing (pathologic or iatrogenic) or in patients with dysphagia or significantdifficulty in swallowing tablets. There have been rare reports of obstructive symptoms in patients withknown strictures in association with the ingestion of medicines in non-deformable controlled-releaseformulations. Due to the controlled-release design of the dosage form, INVEGA should only be usedin patients who are able to swallow the tablet whole.

Conditions leading to shorter gastrointestinal transit time, e.g., diseases associated with chronic severediarrhoea, may result in a reduced absorption of paliperidone.

The plasma concentrations of paliperidone are increased in patients with renal impairment and,therefore, dosage adjustment may be required in some patients (see sections 4.2 and 5.2). No data areavailable in patients with a creatinine clearance below 10 mL/min. Paliperidone should not be used inpatients with creatinine clearance below 10 mL/min.

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

INVEGA has not been studied in elderly patients with dementia. The experience from risperidone isconsidered valid also for paliperidone.

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

An approximately 3-fold increased risk of cerebrovascular adverse reactions have been seen inrandomised placebo-controlled clinical trials in the dementia population with some atypicalantipsychotics, including risperidone, aripiprazole, and olanzapine. The mechanism for this increasedrisk is not known. INVEGA should be used with caution in elderly patients with dementia who haverisk factors for stroke.

Physicians should weigh the risks versus the benefits when prescribing INVEGA to patients with

Parkinson’s Disease or Dementia with Lewy Bodies (DLB) since both groups may be at increased riskof Neuroleptic Malignant Syndrome as well as having an increased sensitivity to antipsychotics.

Manifestation of this increased sensitivity can include confusion, obtundation, postural instability withfrequent falls, in addition to extrapyramidal symptoms.

Antipsychotic medicinal products (including risperidone) with α-adrenergic blocking effects havebeen reported to induce priapism. During post-marketing surveillance priapism has also been reportedwith paliperidone, which is the active metabolite of risperidone. Patients should be informed to seekurgent medical care in case that priapism has not been resolved within 3-4 hours.

Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychoticmedicinal products. Appropriate care is advised when prescribing INVEGA to patients who will beexperiencing conditions which may contribute to an elevation in core body temperature, e.g.,exercising strenuously, exposure to extreme heat, receiving concomitant medication withanticholinergic activity, or being subject to dehydration.

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

Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possiblerisk factors for VTE should be identified before and during treatment with INVEGA and preventivemeasures undertaken.

An antiemetic effect was observed in preclinical studies with paliperidone. This effect, if it occurs inhumans, may mask the signs and symptoms of overdosage with certain medicines or of conditionssuch as intestinal obstruction, Reye’s syndrome, and brain tumour.

The sedative effect of INVEGA should be closely monitored in this population. A change in the timeof administration of INVEGA may improve the impact of sedation on the patient.

Because of the potential effects of prolonged hyperprolactinaemia on growth and sexual maturation inadolescents, regular clinical evaluation of endocrinological status should be considered, includingmeasurements of height, weight, sexual maturation, monitoring of menstrual functioning, and otherpotential prolactin-related effects.

During treatment with INVEGA regular examination for extrapyramidal symptoms and othermovement disorders should also be conducted.

For specific posology recommendations in the paediatric population see section 4.2.

Intraoperative floppy iris syndrome (IFIS) has been observed during cataract surgery in patientstreated with medicines with alpha 1a-adrenergic antagonist effect, such as INVEGA (see section 4.8).

IFIS may increase the risk of eye complications during and after the operation. Current or past use ofmedicines with alpha 1a-adrenergic antagonist effect should be made known to the ophthalmicsurgeon in advance of surgery. The potential benefit of stopping alpha 1 blocking therapy prior tocataract surgery has not been established and must be weighed against the risk of stopping theantipsychotic therapy.

Lactose content (pertains only to the 3 mg tablets)

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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

Caution is advised when prescribing INVEGA with medicines known to prolong the QT interval, e.g.,class IA antiarrhythmics (e.g., quinidine, disopyramide) and class III antiarrhythmics (e.g.,amiodarone, sotalol), some antihistaminics, some other antipsychotics and some antimalarials (e.g.,mefloquine).

Paliperidone is not expected to cause clinically important pharmacokinetic interactions with medicinesthat are metabolised by cytochrome P-450 isozymes. In vitro studies indicate that paliperidone is notan inducer of CYP1A2 activity.

Given the primary CNS effects of paliperidone (see section 4.8), INVEGA should be used withcaution in combination with other centrally acting medicines, e.g., anxiolytics, most antipsychotics,hypnotics, opiates, etc. or alcohol.

Paliperidone may antagonise the effect of levodopa and other dopamine agonists. If this combinationis deemed necessary, particularly in end-stage Parkinson’s disease, the lowest effective dose of eachtreatment should be prescribed.

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

Caution is advised if paliperidone is combined with other medicines known to lower the seizurethreshold (i.e., phenothiazines or butyrophenones, clozapine, tricyclics or SSRIs, tramadol,mefloquine, etc.).

No interaction study between INVEGA and lithium has been performed, however, a pharmacokineticinteraction is unlikely to occur.

Co-administration of INVEGA 12 mg once daily with divalproex sodium prolonged-release tablets(500 mg to 2,000 mg once daily) did not affect the steady-state pharmacokinetics of valproate.

Co-administration of INVEGA with divalproex sodium prolonged-release tablets increased theexposure to paliperidone (see below).

In vitro studies indicate that CYP2D6 and CYP3A4 may be minimally involved in paliperidonemetabolism, but there are no indications in vitro nor in vivo that these isozymes play a significant rolein the metabolism of paliperidone. Concomitant administration of INVEGA with paroxetine, a potent

CYP2D6 inhibitor, showed no clinically significant effect on the pharmacokinetics of paliperidone.

In vitro studies have shown that paliperidone is a P-glycoprotein (P-gp) substrate.

Co-administration of INVEGA once daily with carbamazepine 200 mg twice daily caused a decreaseof approximately 37% in the mean steady-state Cmax and AUC of paliperidone. This decrease iscaused, to a substantial degree, by a 35% increase in renal clearance of paliperidone likely as a resultof induction of renal P-gp by carbamazepine. A minor decrease in the amount of active substanceexcreted unchanged in the urine suggests that there was little effect on the CYP metabolism orbioavailability of paliperidone during carbamazepine co-administration. Larger decreases in plasmaconcentrations of paliperidone could occur with higher doses of carbamazepine. On initiation ofcarbamazepine, the dose of INVEGA should be re-evaluated and increased if necessary. Conversely,on discontinuation of carbamazepine, the dose of INVEGA should be re-evaluated and decreased ifnecessary. It takes 2-3 weeks for full induction to be achieved and upon discontinuation of the inducerthe effect wears off over a similar time period. Other medicinal products or herbals which areinducers, e.g., rifampicin and St. John´s wort (Hypericum perforatum) may have similar effects onpaliperidone.

Medicinal products affecting gastrointestinal transit time may affect the absorption of paliperidone,e.g., metoclopramide.

Co-administration of a single dose of INVEGA 12 mg with divalproex sodium prolonged-releasetablets (two 500 mg tablets once daily) resulted in an increase of approximately 50% in the Cmax and

AUC of paliperidone. Dosage reduction for INVEGA should be considered when INVEGA isco-administered with valproate after clinical assessment.

Concomitant use of INVEGA with oral risperidone is not recommended as paliperidone is the activemetabolite of risperidone and the combination of the two may lead to additive paliperidone exposure.

The combined use of psychostimulants (e.g., methylphenidate) with paliperidone can lead toextrapyramidal symptoms upon change of either or both treatments (see section 4.4).

Interaction studies have only been performed in adults.

There are no adequate data from the use of paliperidone during pregnancy.

Paliperidone was not teratogenic in animal studies, but other types of reproductive toxicity wereobserved (see section 5.3). Neonates exposed to antipsychotics (including paliperidone) during thethird trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/orwithdrawal symptoms that may vary in severity and duration following delivery. There have beenreports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feedingdisorder. Consequently, newborns should be monitored carefully. INVEGA should not be used duringpregnancy unless clearly necessary. If discontinuation during pregnancy is necessary, it should not bedone abruptly.

Paliperidone is excreted in the breast milk to such an extent that effects on the breast-fed infant arelikely if therapeutic doses are administered to breast-feeding women. INVEGA should not be usedwhile breast feeding.

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

Paliperidone can have minor or moderate influence on the ability to drive and use machines due topotential nervous system and visual effects (see section 4.8). Therefore, patients should be advised notto drive or operate machines until their individual susceptibility to INVEGA is known.

The adverse drug reactions (ADRs) most frequently reported in clinical trials with adults wereheadache, insomnia, sedation/somnolence, parkinsonism, akathisia, tachycardia, tremor, dystonia,upper respiratory tract infection, anxiety, dizziness, weight increased, nausea, agitation, constipation,vomiting, fatigue, depression, dyspepsia, diarrhoea, dry mouth, toothache, musculoskeletal pain,hypertension, asthenia, back pain, electrocardiogram QT prolonged, and cough.

The ADRs that appeared to be dose-related included headache, sedation/somnolence, parkinsonism,akathisia, tachycardia, dystonia, dizziness, tremor, upper respiratory tract infection, dyspepsia, andmusculoskeletal pain.

In the schizoaffective disorder studies, a greater proportion of subjects in the total INVEGA dosegroup who were receiving concomitant therapy with an antidepressant or mood stabiliser experiencedadverse events as compared to those subjects treated with INVEGA monotherapy.

The following are all the ADRs that were reported in clinical trials and post-marketing experiencewith paliperidone by frequency category estimated from INVEGA clinical trials in adults. Thefollowing terms and frequencies are applied: very common (≥ 1/10), common (≥ 1/100 to < 1/10),uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000), very rare (< 1/10 000), and notknown (cannot be estimated from the available data). Within each frequency grouping, adversereactions are presented in order of decreasing seriousness.

System Organ Adverse Drug Reaction

Class Frequency

Very Common Uncommon Rare Not knowncommon

Infections and bronchitis, upper pneumonia, eye infection,infestations respiratory tract respiratory tract onychomycosis,infection, infection, cystitis, cellulitis,sinusitis, urinary ear infection, acarodermatitistract infection, tonsillitisinfluenza

Blood and white blood cell agranulocytosisc,lymphatic count decreased, neutropenia,system thrombocytopenia, eosinophil countdisorders anaemia, increasedhaematocritdecreased

Immune anaphylacticsystem reaction,disorders hypersensitivity

Endocrine hyperprolactinaemia inappropriatedisorders a antidiuretic hormonesecretionc, glucoseurine present

Metabolism weight increased, diabetes mellitusd, water intoxication, hyperinsulinaemiand nutrition increased hyperglycaemia, diabetic adisorders appetite, weight waist circumference ketoacidosisc,decreased, increased, anorexia, hypoglycaemia,decreased blood triglycerides polydipsia, bloodappetite increased cholesterol increased

Psychiatric insomniae mania, agitation, sleep disorder, catatonia,disorders depression, confusional state, somnambulism,anxiety libido decreased, blunted affectcanorgasmia,nervousness,nightmare

Nervous parkinsonismb dystoniab, tardive dyskinesia, neurolepticb esystem , akathisia , dizziness, convulsion , malignant syndrome,disorders sedation/ dyskinesiab, syncope, cerebral ischaemia,somnolence, tremorb psychomotor unresponsive toheadache hyperactivity, stimulic, loss ofdizziness postural, consciousness,disturbance in depressed level ofattention, dysarthria, consciousnessc,dysgeusia, diabetic comachypoaesthesia, balance disorder,paresthaesia coordinationabnormal, headtitubationc

Eye disorders vision blurred photophobia, glaucoma, eyeconjunctivitis, dry movement disorderc,eye eye rollingc,lacrimationincreased, ocularhyperaemia

Ear and vertigo, tinnitus, earlabyrinth paindisorders

Cardiac atrioventricular sinus arrhythmia, atrial fibrillation,disorders block, electrocardiogram postural orthostaticconduction abnormal, tachycardiadisorder, palpitations syndromecelectrocardiogram QT prolonged,bradycardia,tachycardia

Vascular orthostatic hypotension pulmonarydisorders hypotension, embolism, venoushypertension thrombosis,ischaemia, flushing

Respiratory, pharyngolarynge dyspnoea, wheezing, sleep apnoea pulmonarythoracic and al pain, cough, epistaxis syndrome, congestionmediastinal nasal congestion hyperventilation,disorders pneumoniaaspiration,respiratory tractcongestion,dysphonia

Gastrointestin abdominal pain, swollen tongue, pancreatitisc,al disorders abdominal gastroenteritis, intestinaldiscomfort, dysphagia, obstruction, ileus,vomiting, flatulence faecal incontinence,nausea, faecalomac, cheilitisconstipation,diarrhoea,dyspepsia, drymouth, toothache

Hepatobiliary transaminases gamma-glutamyltran jaundicedisorders increased sferase increased,hepatic enzymeincreased

Skin and pruritus, rash urticaria, alopecia, angioedema, drugcsubcutaneous eczema, acne eruption ,tissue hyperkeratosis, drydisorders skin, erythema, skindiscolouration,seborrhoeicdermatitis, dandruff

Musculoskelet musculoskeletal blood creatine rhabdomyolysisc,cal and pain, back pain, phosphokinase posture abnormalconnective arthralgia increased, muscletissue spasms, jointstiffness, jointdisordersswelling, muscularweakness, neck pain

Renal and urinary incontinence,urinary pollakiuria, urinarydisorders retention, dysuria

Pregnancy, drug withdrawalpuerperium syndrome neonatalcand perinatal (see section 4.6)conditions

Reproductive amenorrhoea erectile dysfunction, priapismc,system and ejaculation disorder, menstruationbreast menstrual disordere, delayedc,disorders galactorrhoea, sexual gynaecomastia,dysfunction, breast breast engorgement,pain, breast breast enlargementc,discomfort breast discharge,vaginal discharge

General pyrexia, asthenia, face oedema, hypothermiac, bodydisorders fatigue oedemae, chills, temperaturebody temperature decreasedc, drugincreased, gait withdrawalabnormal, thirst, syndromec,chest pain, chest indurationcdiscomfort, malaise

Injury, fallpoisoning andproceduralcomplicationsa Refer to ‘Hyperprolactinaemia’ below.b Refer to ‘Extrapyramidal symptoms’ below.c Not observed in INVEGA clinical studies but observed in post-marketing environment with paliperidone.d In placebo-controlled pivotal trials, diabetes mellitus was reported in 0.05% in INVEGA-treated subjects compared to arate of 0% in placebo group. Overall incidence from all clinical trials was 0.14% in all INVEGA-treated subjects.e Insomnia includes: initial insomnia, middle insomnia; Convulsion includes: grand mal convulsion; Oedema includes:

generalised oedema, oedema peripheral, pitting oedema; Menstrual disorder includes: menstruation irregular,oligomenorrhoea.

Undesirable effects noted with risperidone formulations

Paliperidone is the active metabolite of risperidone, therefore, the adverse reaction profiles of thesecompounds (including both the oral and injectable formulations) are relevant to one another. Inaddition to the above adverse reactions, the following adverse reactions have been noted with the useof risperidone products and can be expected to occur with INVEGA.

Psychiatric disorders: sleep-related eating disorder

Nervous system disorders: cerebrovascular disorder

Eye disorders: floppy iris syndrome (intraoperative)

Respiratory, thoracic and mediastinal disorders: rales

Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome/toxic epidermal necrolysis

In schizophrenia clinical trials, there was no difference observed between placebo and the 3 and 6 mgdoses of INVEGA. Dose dependence for EPS was seen with the two higher doses of INVEGA (9 and12 mg). In the schizoaffective disorder studies, the incidence of EPS was observed at a higher ratethan placebo in all dose groups without a clear relationship to dose.

EPS included a pooled analysis of the following terms: Parkinsonism (includes salivaryhypersecretion, musculoskeletal stiffness, parkinsonism, drooling, cogwheel rigidity, bradykinesia,hypokinesia, masked facies, muscle tightness, akinesia, nuchal rigidity, muscle rigidity, parkinsoniangait, and glabellar reflex abnormal, parkinsonian rest tremor), akathisia (includes akathisia,restlessness, hyperkinesia, and restless leg syndrome), dyskinesia (dyskinesia, muscle twitching,choreoathetosis, athetosis, and myoclonus), dystonia (includes dystonia, hypertonia, torticollis, musclecontractions involuntary, muscle contracture, blepharospasm, oculogyration, tongue paralysis, facialspasm, laryngospasm, myotonia, opisthotonus, oropharyngeal spasm, pleurothotonus, tongue spasm,and trismus), and tremor. It should be noted that a broader spectrum of symptoms are included that donot necessarily have an extrapyramidal origin.

In schizophrenia clinical trials, the proportions of subjects meeting a weight gain criterion of ≥ 7% ofbody weight were compared, revealing a similar incidence of weight gain for INVEGA 3 mg and 6 mgcompared with placebo, and a higher incidence of weight gain for INVEGA 9 mg and 12 mgcompared with placebo.

In schizoaffective disorder clinical trials, a higher percentage of INVEGA-treated subjects (5%) hadan increase in body weight of ≥ 7% compared with placebo-treated subjects (1%). In the study thatexamined two dose groups (see section 5.1), the increase in body weight of ≥ 7% was 3% in thelower-dose (3-6 mg) group, 7% in the higher-dose (9-12 mg) group, and 1% in the placebo group.

In schizophrenia clinical trials, increases in serum prolactin were observed with INVEGA in 67% ofsubjects. Adverse reactions that may suggest increase in prolactin levels (e.g., amenorrhoea,galactorrhoea, menstrual disturbances, gynaecomastia) were reported overall in 2% of subjects.

Maximum mean increases of serum prolactin concentrations were generally observed on day 15 oftreatment, but remained above baseline levels at study endpoint.

QT prolongation, ventricular arrythmias (ventricular fibrillation, ventricular tachycardia), suddenunexplained death, cardiac arrest and Torsade de pointes may occur with antipsychotics. Cases ofvenous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosishave been reported with antipsychotic drugs - Frequency unknown.

Paliperidone is the active metabolite of risperidone. The safety profile of risperidone may be pertinent.

In a study conducted in elderly subjects with schizophrenia, the safety profile was similar to that seenin non-elderly subjects. INVEGA has not been studied in elderly patients with dementia. In clinicaltrials with some other atypical antipsychotics, increased risks of death and cerebrovascular accidentshave been reported (see section 4.4).

In one short-term and two longer-term studies with paliperidone prolonged-release tablets conductedin adolescents 12 years and older with schizophrenia, the overall safety profile was similar to that seenin adults. In the pooled adolescent schizophrenia population (12 years and older, N = 545) exposed to

INVEGA, the frequency and type of undesirable effects were similar to those in adults except for thefollowing ADRs that were reported more frequently in adolescents receiving INVEGA than adultsreceiving INVEGA (and more frequently than placebo): sedation/somnolence, parkinsonism, weightincrease, upper respiratory tract infection, akathisia, and tremor were reported very commonly (≥ 1/10)in adolescents; abdominal pain, galactorrhoea, gynaecomastia, acne, dysarthria, gastroenteritis,epistaxis, ear infection, blood triglyceride increased, and vertigo were reported commonly (≥ 1/100,< 1/10) in adolescents.

Extrapyramidal Symptoms (EPS)

In the short-term, placebo-controlled, fixed-dose adolescent study, the incidence of EPS was higherthan placebo for all doses of INVEGA with an increased frequency of EPS at higher doses. Across alladolescent studies, EPS was more common in adolescents than in adults for each INVEGA dose.

In the short-term, placebo-controlled, fixed-dose adolescent study, a higher percentage of

INVEGA-treated subjects (6-19% depending on dose) had an increase in body weight of ≥ 7%compared to placebo-treated subjects (2%). There was no clear dose relationship. In the long-term2-year study, the subjects who were exposed to INVEGA during both the double-blind and open-labelstudies reported a modest weight gain (4.9 kg).

In adolescents, weight gain should be assessed against that expected with normal growth.

Prolactin

In the up to 2-year, open-label treatment study of INVEGA in adolescents with schizophrenia,incidence of elevated serum prolactin levels occurred in 48% of females and 60% of males. Adversereactions that may suggest increase in prolactin levels (e.g., amenorrhoea, galactorrhoea, menstrualdisturbances, gynaecomastia) were reported overall in 9.3% of subjects.

Reporting suspected adverse reactions after authorisation of the medical product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals areasked to report any suspected adverse reactions via the national reporting system listed in

Appendix V.

In general, expected signs and symptoms are those resulting from an exaggeration of paliperidone’sknown pharmacological effects, i.e., drowsiness and sedation, tachycardia and hypotension, QTprolongation, and extrapyramidal symptoms. Torsade de pointes and ventricular fibrillation have beenreported in association with overdose. In the case of acute overdosage, the possibility of multiplemedicinal product involvement should be considered.

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

Cardiovascular monitoring should commence immediately and should include continuouselectrocardiographic monitoring for possible arrhythmias. Hypotension and circulatory collapse shouldbe treated with appropriate measures such as intravenous fluid and/or sympathomimetic agents.

Administration of activated charcoal together with a laxative should be considered. In case of severeextrapyramidal symptoms, anticholinergic agents should be administered. Close supervision andmonitoring should continue until the patient recovers.

Pharmacologic group: Psycholeptics, other antipsychotics, ATC code: N05AX13

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

Paliperidone is a selective blocking agent of monoamine effects, whose pharmacological propertiesare different from that of traditional neuroleptics. Paliperidone binds strongly to serotonergic 5-HT2-and dopaminergic D2-receptors. Paliperidone also blocks alfa1-adrenergic receptors and blocks, to alesser extent, H1-histaminergic and alfa2-adrenergic receptors. The pharmacological activity of the(+)- and (-)-paliperidone enantiomers are qualitatively and quantitatively similar.

Paliperidone is not bound to cholinergic receptors. Even though paliperidone is a strong

D2-antagonist, which is believed to relieve the positive symptoms of schizophrenia, it causes lesscatalepsy and decreases motor functions to a lesser extent than traditional neuroleptics. Dominatingcentral serotonin antagonism may reduce the tendency of paliperidone to cause extrapyramidal sideeffects.

Schizophrenia

The efficacy of INVEGA in the treatment of schizophrenia was established in three multi-centre,placebo-controlled, double-blind, 6-week trials in subjects who met DSM-IV criteria forschizophrenia. INVEGA doses, which varied across the three studies, ranged from 3 to 15 mg oncedaily. The primary efficacy endpoint was defined as a decrease in total Positive and Negative

Syndrome Scale (PANSS) scores as shown in the following table. The PANSS is a validatedmulti-item inventory composed of five factors to evaluate positive symptoms, negative symptoms,disorganised thoughts, uncontrolled hostility/excitement, and anxiety/depression. All tested doses of

INVEGA separated from placebo on day 4 (p < 0.05). Predefined secondary endpoints included the

Personal and Social Performance (PSP) scale and the Clinical Global Impression - Severity (CGI-S)scale. In all three studies, INVEGA was superior to placebo on PSP and CGI-S. Efficacy was alsoevaluated by calculation of treatment response (defined as decrease in PANSS Total Score ≥ 30%) as asecondary endpoint.

Schizophrenia Studies: Positive and Negative Syndrome Scale for Schizophrenia (PANSS) Total Score - Change

From Baseline to End Point - LOCF for Studies R076477-SCH-303, R076477-SCH-304, and

R076477-SCH-305: Intent-to-Treat Analysis Set

Placebo INVEGA INVEGA INVEGA INVEGA3 mg 6 mg 9 mg 12 mg

R076477-SCH-303 (N = 126) (N = 123) (N = 122) (N = 129)

Mean baseline (SD) 94.1 (10.74) 94.3 (10.48) 93.2 (11.90) 94.6 (10.98)

Mean change (SD) -4.1 (23.16) -17.9 (22.23) -17.2 (20.23) -23.3 (20.12)

P-value (vs, Placebo) <0.001 <0.001 <0.001

Diff. of LS Means (SE) -13.7 (2.63) -13.5 (2.63) -18.9 (2.60)

R076477-SCH-304 (N = 105) (N = 111) (N = 111)

Mean baseline (SD) 93.6 (11.71) 92.3 (11.96) 94.1 (11.42)

Mean change (SD) -8.0 (21.48) -15.7 (18.89) -17.5 (19.83)

P-value (vs, Placebo) 0.006 <0.001

Diff. of LS Means (SE) -7.0 (2.36) -8.5 (2.35)

R076477-SCH-305 (N = 120) (N = 123) (N = 123)

Mean baseline (SD) 93.9 (12.66) 91.6 (12.19) 93.9 (13.20)

Mean change (SD) -2.8 (20.89) -15.0 (19.61) -16.3 (21.81)

P-value (vs, Placebo) <0.001 <0.001

Diff. of LS Means (SE) -11.6 (2.35) -12.9 (2.34)

Note: Negative change in score indicates improvement. For all 3 studies, an active control (olanzapine at a dose of 10 mg)was included. LOCF = last observation carried forward. The 1-7 version of the PANSS was used. A 15 mg dose was alsoincluded in Study R076477-SCH-305, but results are not presented since this is above the maximum recommended daily doseof 12 mg.

Schizophrenia Studies: Proportion of Subjects with Responder Status at LOCF End Point

Studies R076477-SCH-303, R076477-SCH-304, and R076477-SCH-305: Intent-to-Treat Analysis Set

Placebo INVEGA INVEGA INVEGA INVEGA3 mg 6 mg 9 mg 12 mg

R076477-SCH-303

N 126 123 122 129

Responder, n (%) 38 (30.2) 69 (56.1) 62 (50.8) 79 (61.2)

Non-responder, n (%) 88 (69.8) 54 (43.9) 60 (49.2) 50 (38.8)

P value (vs Placebo) -- < 0.001 0.001 < 0.001

R076477-SCH-304

N 105 110 111

Responder, n (%) 36 (34.3) 55 (50.0) 57 (51.4)

Non-responder, n (%) 69 (65.7) 55 (50.0) 54 (48.6)

P value (vs Placebo) -- 0.025 0.012

R076477-SCH-305

N 120 123 123

Responder, n (%) 22 (18.3) 49 (39.8) 56 (45.5)

Non-responder, n (%) 98 (81.7) 74 (60.2) 67 (54.5)

P value (vs Placebo) -- 0.001 < 0.001

In a long-term trial designed to assess the maintenance of effect, INVEGA was significantly moreeffective than placebo in maintaining symptom control and delaying relapse of schizophrenia. Afterhaving been treated for an acute episode for 6 weeks and stabilised for an additional 8 weeks with

INVEGA (doses ranging from 3 to 15 mg once daily) patients were then randomised in a double-blindmanner to either continue on INVEGA or on placebo until they experienced a relapse in schizophreniasymptoms. The trial was stopped early for efficacy reasons by showing a significantly longer time torelapse in patients treated with INVEGA compared to placebo (p=0.0053).

The efficacy of INVEGA in the acute treatment of psychotic or manic symptoms of schizoaffectivedisorder was established in two placebo-controlled, 6-week 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 Disorders, 2) had a Positive and Negative Syndrome Scale (PANSS)total score of at least 60, and 3) had prominent mood symptoms as confirmed by a score of at least 16on the Young Mania Rating Scale (YMRS) and/or Hamilton Rating Scale 21 for Depression (HAM-D21). The population included subjects with schizoaffective bipolar and depressive types. In one ofthese trials, efficacy was assessed in 211 subjects who received flexible doses of INVEGA (3-12 mgonce daily). In the other study, efficacy was assessed in 203 subjects who were assigned to one of twodose levels of INVEGA: 6 mg with the option to reduce to 3 mg (n = 105) or 12 mg with the option toreduce to 9 mg (n = 98) once daily. Both studies included subjects who received INVEGA either asmonotherapy or in combination with mood stabilisers and/or antidepressants. Dosing was in themorning without regard to meals. Efficacy was evaluated using the PANSS.

The INVEGA group in the flexible-dose study (dosed between 3 and 12 mg/day, mean modal dose of8.6 mg/day) and the higher dose group of INVEGA in the 2 dose-level study (12 mg/day with optionto reduce to 9 mg/day) were each superior to placebo in the PANSS at 6 weeks. In the lower dosegroup of the 2 dose-level study (6 mg/day with option to reduce to 3 mg/day), INVEGA was notsignificantly different from placebo as measured by the PANSS. Only few subjects received the 3 mgdose in both studies and efficacy of this dose could not be established. Statistically superiorimprovements in manic symptoms as measured by YMRS (secondary efficacy scale) were observed inpatients from the flexible-dose study and the INVEGA higher dose in the second study.

Taking the results of both studies together (pooled study-data), INVEGA improved the psychotic andmanic symptoms of schizoaffective disorder at endpoint relative to placebo when administered eitheras monotherapy or in combination with mood stabilisers and/or antidepressants. However, overall themagnitude of effect in regard to PANSS and YMRS observed on monotherapy was larger than thatobserved with concomitant antidepressants and/or mood stabilisers. Moreover, in the pooledpopulation, INVEGA was not efficacious in patients concomitantly receiving mood stabiliser andantidepressants in regard to the psychotic symptoms, but this population was small (30 responders inthe paliperidone group and 20 responders in the placebo group). Additionally, in study SCA-3001 inthe ITT population the effect on psychotic symptoms measured by PANSS was clearly lesspronounced and not reaching statistical significance for patients receiving concomitantly moodstabilisers and/or antidepressants. An effect of INVEGA on depressive symptoms was notdemonstrated in these studies, but has been demonstrated in a long-term study with the long-actinginjectable formulation of paliperidone (described further down in this section).

An examination of population subgroups did not reveal any evidence of differential responsiveness onthe basis of gender, age, or geographic region. There were insufficient data to explore differentialeffects based on race. Efficacy was also evaluated by calculation of treatment response (defined asdecrease in PANSS Total Score ≥ 30% and CGI-C Score ≤ 2) as a secondary endpoint.

Schizoaffective Disorder Studies: Primary Efficacy Parameter, PANSS Total Score Change from Baseline from

Studies R076477-SCA-3001 and R076477-SCA-3002: Intent-to-Treat Analysis Set

Placebo INVEGA INVEGA Higher INVEGA Flexible

Lower Dose Dose Dose (3-12 mg)(3-6 mg) (9-12 mg)

R076477-SCA-3001 (N=107) (N=105) (N=98)

Mean baseline (SD) 91.6 (12.5) 95.9 (13.0) 92.7 (12.6)

Mean change (SD) -21.7 (21.4) -27.4 (22.1) -30.6 (19.1)

P-value (vs. Placebo) 0.187 0.003

Diff. of LS Means (SE) -3.6 (2.7) -8.3 (2.8)

R076477-SCA-3002 (N=93) (N=211)

Mean baseline (SD) 91.7 (12.1) 92.3 (13.5)

Mean change (SD) -10.8 (18.7) -20.0 (20.23)

P-value (vs. Placebo) < 0.001

Diff. of LS Means (SE) -13.5 (2.63)

Note: Negative change in score indicates improvement. LOCF = last observation carried forward.

Schizoaffective Disorder Studies: Secondary Efficacy Parameter, Proportion of Subjects with Responder Statusat LOCF End Point: Studies R076477-SCA-3001 and R076477-SCA-3002: Intent-to-Treat Analysis Set

Placebo INVEGA INVEGA Higher INVEGA Flexible

Lower Dose Dose Dose (3-12 mg)(3-6 mg) (9-12 mg)

R076477-SCA-3001

N 107 104 98

Responder, n (%) 43 (40.2) 59 (56.7) 61 (62.2)

Non-responder, n (%) 64 (59.8) 45 (43.3) 37 (37.8)

P value (vs Placebo) -- 0.008 0.001

R076477-SCA-3002

N 93 210

Responder, n (%) 26 (28.0) 85 (40.5)

Non-responder, n (%) 67 (72.0) 125 (59.5)

P value (vs Placebo) -- 0.046

Response defined as decrease from baseline in PANSS Total Score ≥ 30% and CGI-C Score ≤ 2

In a long-term trial designed to assess the maintenance of effect, the long-acting injectable formulationof paliperidone was significantly more effective than placebo in maintaining symptom control anddelaying relapse of psychotic, manic, and depressive symptoms of schizoaffective disorder. Afterhaving been successfully treated for an acute psychotic or mood episode for 13 weeks and stabilisedfor an additional 12 weeks with the long-acting injectable formulation of paliperidone (doses rangingfrom 50 to 150 mg) patients were then randomised to a 15-month double-blind relapse preventionperiod of the study to either continue on the long-acting injectable formulation of paliperidone or onplacebo until they experienced a relapse of schizoaffective symptoms. The study showed asignificantly longer time to relapse in patients treated with the long-acting injectable formulation ofpaliperidone compared to placebo (p < 0.001).

The European Medicines Agency has waived the obligation to submit the results of studies with

INVEGA in all subsets of the paediatric population in the treatment of schizoaffective disorders. (Seesection 4.2 for information on paediatric use).

The efficacy of INVEGA in the treatment of schizophrenia in adolescents between 12 and14 years old has not been established.

The efficacy of INVEGA in adolescent subjects with schizophrenia (INVEGA N = 149, placebo

N = 51) was studied in a randomised, double-blind, placebo-controlled, 6-week study using afixed-dose weight-based treatment group design over the 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 was evaluatedusing PANSS. This study demonstrated the efficacy of INVEGA of the medium dose group inadolescent subjects with schizophrenia. Secondary by dose analysis demonstrated the efficacy of3 mg, 6 mg, and 12 mg dose given once daily.

Adolescent Schizophrenia Study: R076477-PSZ-3001: 6-week, fixed-dose, placebo-controlled Intent-to-Treat

Analysis Set. LOCF endpoint change from baseline

Placebo INVEGA INVEGA INVEGA

Low Dose Medium Dose High Dose1.5 mg 3 or 6 mg* 6 or 12 mg**

N=51 N=54 N=48 N=47

Change in PANSS Score

Mean baseline (SD) 90.6 (12.13) 91.6 (12.54) 90.6 (14.01) 91.5 (13.86)

Mean change (SD) -7.9 (20.15) -9.8 (16.31) -17.3 (14.33) -13.8 (15.74)

P-value (vs Placebo) 0.508 0.006 0.086

Diff. of LS Means (SE) -2.1 (3.17) -10.1 (3.27) -6.6 (3.29)

Responder Analysis

Responder, n (%) 17 (33.3) 21 (38.9) 31 (64.6) 24 (51.1)

Non-responder, n (%) 34 (66.7) 33 (61.1) 17 (35.4) 23 (48.9)

P value (vs Placebo) 0.479 0.001 0.043

Response defined as decrease from baseline in PANSS Total Score ≥ 20%

Note: Negative change in score indicates improvement. LOCF = last observation carried forward.

* Medium dose group: 3 mg for subjects < 51 kg, 6 mg for subjects ≥ 51 kg

** High dose group: 6 mg for subjects < 51 kg, 12 mg for subjects ≥ 51 kg

Efficacy of INVEGA over a flexible dose 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 evaluatedin a randomised, double-blind, active-controlled study that included an 8-week, double-blind acutephase and an 18-week, double-blind maintenance phase. The changes in PANSS total scores frombaseline to week 8 and week 26 were numerically similar between the INVEGA and aripiprazoletreatment groups. In addition, the difference in the percentage of patients demonstrating ≥ 20%improvement in PANSS total score at week 26 between the two treatment groups was numericallysimilar.

Adolescent Schizophrenia Study: R076477-PSZ-3003: 26-week, flexible-dose, active-controlled Intent-to-Treat

Analysis Set. LOCF endpoint change from baseline

INVEGA Aripiprazole3-9 mg 5-15 mg

N=112 N=114

Change in PANSS Score8 week, acute endpoint

Mean baseline (SD) 89.6 (12.22) 92.0 (12.09)

Mean change (SD) -19.3 (13.80) -19.8 (14.56)

P-value (vs aripiprazole) 0.935

Diff. of LS Means (SE) 0.1 (1.83)

Change in PANSS Score26 week endpoint

Mean baseline (SD) 89.6 (12.22) 92.0 (12.09)

Mean change (SD) -25.6 (16.88) -26.8 (18.82)

P-value (vs aripiprazole) 0.877

Diff. of LS Means (SE) -0.3 (2.20)

Responder Analysis26 week endpoint

Responder, n (%) 86 (76.8) 93 (81.6)

Non-responder, n (%) 26 (23.2) 21 (18.4)

P value (vs aripiprazole) 0.444

Response defined as decrease from baseline in PANSS Total Score ≥ 20%

Note: Negative change in score indicates improvement. LOCF = last observation carried forward.

The pharmacokinetics of paliperidone following INVEGA administration are dose proportional withinthe available dose range.

Following a single dose, INVEGA exhibits a gradual ascending release rate, allowing the plasmaconcentrations of paliperidone to steadily rise to reach peak plasma concentration (Cmax)approximately 24 hours after dosing. With once-daily dosing of INVEGA, steady-state concentrationsof paliperidone are attained within 4-5 days of dosing in most subjects.

Paliperidone is the active metabolite of risperidone. The release characteristics of INVEGA result inminimal peak-trough fluctuations as compared to those observed with immediate-release risperidone(fluctuation index 38% versus 125%).

The absolute oral bioavailability of paliperidone following INVEGA administration is 28% (90% CIof 23%-33%).

Administration of paliperidone prolonged-release tablets with a standard high-fat/high-caloric mealincreases Cmax and AUC of paliperidone by up to 50-60% compared with administration in the fastingstate.

Paliperidone is rapidly distributed. The apparent volume of distribution is 487 L. The plasma proteinbinding of paliperidone is 74%. It binds primarily to α1-acid glycoprotein and albumin.

One week following administration of a single oral dose of 1 mg immediate-release 14C-paliperidone,59% of the dose was excreted unchanged into urine, indicating that paliperidone is not extensivelymetabolised by the liver. Approximately 80% of the administered radioactivity was recovered in urineand 11% in the faeces. Four metabolic pathways have been identified in vivo, none of which accountedfor more than 6.5% of the dose: dealkylation, hydroxylation, dehydrogenation, and benzisoxazolescission. Although in vitro studies suggested a role for CYP2D6 and CYP3A4 in the metabolism ofpaliperidone, there is no evidence in vivo that these isozymes play a significant role in the metabolismof paliperidone. Population pharmacokinetics analyses indicated no discernible difference on theapparent clearance of paliperidone after administration of INVEGA between extensive metabolisersand poor metabolisers of CYP2D6 substrates. In vitro studies in human liver microsomes showed thatpaliperidone does not substantially inhibit the metabolism of medicines metabolised by cytochrome

P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and

CYP3A5. The terminal elimination half-life of paliperidone is about 23 hours.

In vitro studies have shown that paliperidone is a P-gp substrate and a weak inhibitor of P-gp at highconcentrations. No in vivo data are available and the clinical relevance is unknown.

Paliperidone is not extensively metabolised in the liver. In a study in subjects with moderate hepaticimpairment (Child-Pugh class B), the plasma concentrations of free paliperidone were similar to thoseof healthy subjects. No data are available in patients with severe hepatic impairment (Child-Pughclass C).

Elimination of paliperidone decreased with decreasing renal function. Total clearance of paliperidonewas reduced in subjects with impaired renal function by 32% in mild (Creatinine Clearance[CrCl] = 50 to < 80 mL/min), 64% in moderate (CrCl = 30 to < 50 mL/min), and 71% in severe(CrCl = < 30 mL/min) renal impairment. The mean terminal elimination half-life of paliperidone was24, 40, and 51 hours in subjects with mild, moderate, and severe renal impairment, respectively,compared with 23 hours in subjects with normal renal function (CrCl ≥ 80 mL/min).

Data from a pharmacokinetic study in elderly subjects (≥ 65 years of age, n = 26) indicated that theapparent steady-state clearance of paliperidone following INVEGA administration was 20% lowercompared to that of adult subjects (18-45 years of age, n = 28). However, there was no discernableeffect of age in the population pharmacokinetic analysis involving schizophrenia subjects aftercorrection of age-related decreases in CrCl.

Paliperidone systemic exposure in adolescent subjects (15 years and older) was comparable to that inadults. In adolescents weighing < 51 kg, a 23% higher exposure was observed than in adolescentsweighing ≥ 51 kg. Age alone did not influence the paliperidone exposure.

Population pharmacokinetics analysis revealed no evidence of race-related differences in thepharmacokinetics of paliperidone following INVEGA administration.

The apparent clearance of paliperidone following INVEGA administration is approximately 19%lower in women than men. This difference is largely explained by differences in lean body mass andcreatinine clearance between men and women.

Based on in vitro studies utilising human liver enzymes, paliperidone is not a substrate for CYP1A2;smoking should, therefore, not have an effect on the pharmacokinetics of paliperidone. A populationpharmacokinetic analysis showed a slightly lower exposure to paliperidone in smokers compared withnon-smokers. The difference is unlikely to be of clinical relevance, though.

Repeat-dose toxicity studies of paliperidone in rat and dog showed mainly pharmacological effects,such as sedation and prolactin-mediated effects on mammary glands and genitals. Paliperidone wasnot teratogenic in rat and rabbit. In rat reproduction studies using risperidone, which is extensivelyconverted to paliperidone in rats and humans, a reduction was observed in the birth weight andsurvival of the offspring. Other dopamine antagonists, when administered to pregnant animals, havecaused negative effects on learning and motor development in the offspring. Paliperidone was notgenotoxic in a battery of tests. In oral carcinogenicity studies of risperidone in rats and mice, increasesin pituitary gland adenomas (mouse), endocrine pancreas adenomas (rat), and mammary glandadenomas (both species) were seen. These tumours can be related to prolonged dopamine D2antagonism and hyperprolactinaemia. The relevance of these tumour findings in rodents in terms ofhuman 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 approximately equal to the clinical exposure based on AUC, no effectson growth, sexual maturation and reproductive performance were observed. Paliperidone did notimpair the neurobehavioural development in males at doses up to 2.5 mg/kg/day. At 2.5 mg/kg/day infemales, an effect on learning and memory was observed. This effect was not observed afterdiscontinuation of treatment. In a 40-week juvenile toxicity study in dogs with oral doses ofrisperidone (which is extensively converted to paliperidone) up to 5 mg/kg/day, effects on sexualmaturation, long bone growth and femur mineral density were observed from 3 times the clinicalexposure based on AUC.

3 mg

Core

Polyethylene oxide 200K

Sodium chloride

Povidone (K29-32)

Stearic acid

Butyl hydroxytoluene (E321)

Ferric oxide (yellow) (E172)

Polyethylene oxide 7000K

Ferric oxide (red) (E172)

Hydroxyethyl cellulose

Polyethylene glycol 3350

Cellulose acetate

Hypromellose

Titanium dioxide (E171)

Lactose monohydrate

Triacetin

Carnauba wax

Iron oxide (black) (E172)

Hypromellose6 mg

Core

Polyethylene oxide 200K

Sodium chloride

Povidone (K29-32)

Stearic acid

Butyl hydroxytoluene (E321)

Polyethylene oxide 7000K

Ferric oxide (red) (E172)

Hydroxyethyl cellulose

Polyethylene glycol 3350

Cellulose acetate

Hypromellose

Titanium dioxide (E171)

Polyethylene glycol 400

Ferric oxide (yellow) (E172)

Ferric oxide (red) (E172)

Carnauba wax

Iron oxide (black) (E172)

Hypromellose9 mg

Core

Polyethylene oxide 200K

Sodium chloride

Povidone (K29-32)

Stearic acid

Butyl hydroxytoluene (E321)

Polyethylene oxide 7000K

Ferric oxide (red) (E172)

Iron oxide (black) (E172)

Hydroxyethyl cellulose

Polyethylene glycol 3350

Cellulose acetate

Hypromellose

Titanium dioxide (E171)

Polyethylene glycol 400

Ferric oxide (red) (E172)

Carnauba wax

Iron oxide (black) (E172)

Hypromellose12 mg

Core

Polyethylene oxide 200K

Sodium chloride

Povidone (K29-32)

Stearic acid

Butyl hydroxytoluene (E321)

Polyethylene oxide 7000K

Ferric oxide (red) (E172)

Ferric oxide (yellow) (E172)

Hydroxyethyl cellulose

Polyethylene glycol 3350

Cellulose acetate

Hypromellose

Titanium dioxide (E171)

Polyethylene glycol 400

Ferric oxide (yellow) (E172)

Carnauba wax

Iron oxide (black) (E172)

Hypromellose

Not applicable.

2 years

Bottles: Do not store above 30°C. Keep the bottle tightly closed in order to protect from moisture.

Blisters: Do not store above 30°C. Store in the original package in order to protect from moisture.

White high-density polyethylene (HDPE) bottle with induction sealing and polypropylenechild-resistant closure. Each bottle contains two 1 g dessicant silica gel (silicone dioxide) pouches(pouch is food approved polyethylene).

Pack sizes of 30 and 350 prolonged-release tablets.

Oriented polyamide (OPA)-aluminium-polyvinyl chloride (PVC)/aluminium push-throughchild-resistant blister.

Pack sizes of 14, 28, 49, 56, and 98 prolonged-release tablets.

Not all pack sizes may be marketed.

No special requirements for disposal.

Janssen-Cilag International NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

3 mg

EU/1/07/395/041 - 044

EU/1/07/395/057 - 058

EU/1/07/395/0676 mg

EU/1/07/395/045 - 048

EU/1/07/395/059 - 060

EU/1/07/395/0709 mg

EU/1/07/395/049 - 052

EU/1/07/395/061 - 062

EU/1/07/395/07312 mg

EU/1/07/395/053 - 056

EU/1/07/395/063 - 064

EU/1/07/395/076

Date of first authorisation: 25 June 2007

Date of latest renewal: 14 May 2012

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu