XEPLION 75mg long-release injection suspension medication leaflet

Xeplion 25 mg prolonged release suspension for injection

Xeplion 50 mg prolonged release suspension for injection

Xeplion 75 mg prolonged release suspension for injection

Xeplion 100 mg prolonged release suspension for injection

Xeplion 150 mg prolonged release suspension for injection

25 mg prolonged release suspension for injection

Each pre-filled syringe contains 39 mg paliperidone palmitate in 0.25 mL equivalent to 25 mgpaliperidone.

50 mg prolonged release suspension for injection

Each pre-filled syringe contains 78 mg paliperidone palmitate in 0.5 mL equivalent to 50 mgpaliperidone.

75 mg prolonged release suspension for injection

Each pre-filled syringe contains 117 mg paliperidone palmitate in 0.75 mL equivalent to 75 mgpaliperidone.

100 mg prolonged release suspension for injection

Each pre-filled syringe contains 156 mg paliperidone palmitate in 1 mL equivalent to 100 mgpaliperidone.

150 mg prolonged release suspension for injection

Each pre-filled syringe contains 234 mg paliperidone palmitate in 1.5 mL equivalent to 150 mgpaliperidone.

For the full list of excipients, see section 6.1.

Prolonged release suspension for injection.

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

Xeplion is indicated for maintenance treatment of schizophrenia in adult patients stabilised withpaliperidone or risperidone.

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

Recommended initiation of Xeplion is with a dose of 150 mg on treatment day 1 and 100 mgone week later (day 8), both administered in the deltoid muscle in order to attain therapeuticconcentrations rapidly (see section 5.2). The third dose should be administered one month after thesecond initiation dose. The recommended monthly maintenance dose is 75 mg; some patients maybenefit from lower or higher doses within the recommended range of 25 to 150 mg based onindividual patient tolerability and/or efficacy. Patients who are overweight or obese may require dosesin the upper range (see section 5.2). Following the second initiation dose, monthly maintenance dosescan be administered in either the deltoid or gluteal muscle.

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

Switching from oral prolonged release paliperidone or oral risperidone to Xeplion

Xeplion should be initiated as described at the beginning of section 4.2 above. During monthlymaintenance treatment with Xeplion, patients previously stabilised on different doses of paliperidoneprolonged release tablets can attain similar paliperdone steady-state exposure by injection. The

Xeplion maintenance doses needed to attain similar steady-state exposure are shown as follows:

Doses of paliperidone prolonged release tablets and Xeplion needed to attain similar steady-state paliperidone exposure during maintenance treatment

Previous paliperidone Xeplion injectionprolonged release tablet dose3 mg daily 25-50 mg monthly6 mg daily 75 mg monthly9 mg daily 100 mg monthly12 mg daily 150 mg monthly

Previous oral paliperidone or oral risperidone can be discontinued at the time of initiation of treatmentwith Xeplion. Some patients may benefit from gradual withdrawal. Some patients switching fromhigher paliperidone oral doses (e.g., 9-12 mg daily) to gluteal injections with Xeplion may have lowerplasma exposure during the first 6 months after the switch. Therefore, alternatively, it could beconsidered to give deltoid injections for the first 6 months.

Switching from risperidone long acting injection to Xeplion

When switching patients from risperidone long acting injection, initiate Xeplion therapy in place ofthe next scheduled injection. Xeplion should then be continued at monthly intervals. The one-weekinitiation dosing regimen including the intramuscular injections (day 1 and 8, respectively) asdescribed in section 4.2 above is not required. Patients previously stabilised on different doses ofrisperidone long acting injection can attain similar paliperidone steady-state exposure duringmaintenance treatment with Xeplion monthly doses according to the following:

Doses of risperidone long acting injection and Xeplion needed to attain similar paliperidoneexposure at steady-state

Previous risperidone long acting injection dose Xeplion injection25 mg every 2 weeks 50 mg monthly37.5 mg every 2 weeks 75 mg monthly50 mg every 2 weeks 100 mg monthly

Discontinuation of antipsychotic medicinal products should be made in accordance with appropriateprescribing information. If Xeplion is discontinued, its prolonged release characteristics must beconsidered. The need for continuing existing extrapyramidal symptoms (EPS) medicine should bere-evaluated periodically.

Avoiding missed doses

It is recommended that the second initiation dose of Xeplion be given one week after the first dose. Toavoid a missed dose, patients may be given the second dose 4 days before or after the one-week(day 8) time point. Similarly, the third and subsequent injections after the initiation regimen arerecommended to be given monthly. To avoid a missed monthly dose, patients may be given theinjection up to 7 days before or after the monthly time point.

If the target date for the second Xeplion injection (day 8 ± 4 days) is missed, the recommendedreinitiation depends on the length of time which has elapsed since the patient's first injection.

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

If less than 4 weeks have elapsed since the first injection, then the patient should be administered thesecond injection of 100 mg in the deltoid muscle as soon as possible. A third Xeplion injection of75 mg in either the deltoid or gluteal muscles should be administered 5 weeks after the first injection(regardless of the timing of the second injection). The normal monthly cycle of injections in either thedeltoid or gluteal muscle of 25 mg to 150 mg based on individual patient tolerability and/or efficacyshould be followed thereafter.

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

If 4 to 7 weeks have elapsed since the first injection of Xeplion, resume dosing with two injections of100 mg in the following manner:1. a deltoid injection as soon as possible2. another deltoid injection one week later3. resumption of the normal monthly cycle of injections in either the deltoid or gluteal muscle of25 mg to 150 mg based on individual patient tolerability and/or efficacy.

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

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

Missed monthly maintenance dose (1 month to 6 weeks)

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

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

If more than 6 weeks have elapsed since the last injection of Xeplion, the recommendation is asfollows:

For patients stabilised with doses of 25 to 100 mg1. a deltoid injection as soon as possible at the same dose the patient was previously stabilised on2. another deltoid injection (same dose) one week later (day 8)3. resumption of the normal monthly cycle of injections in either the deltoid or gluteal muscle of25 mg to 150 mg based on individual patient tolerability and/or efficacy.

For patients stabilised with 150 mg1. a deltoid injection as soon as possible at the 100 mg dose2. another deltoid injection one week later (day 8) at the 100 mg dose3. resumption of the normal monthly cycle of injections in either the deltoid or gluteal muscle of25 mg to 150 mg based on individual patient tolerability and/or efficacy.

Missed monthly maintenance dose (> 6 months)

If more than 6 months have elapsed since the last injection of Xeplion, initiate dosing as described forthe initial recommended initiation of Xeplion above.

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

In general, recommended dosing of Xeplion for elderly patients with normal renal function is the sameas for younger adult patients with normal renal function. However, because elderly patients may havediminished renal function, dose adjustment may be necessary (see Renal impairment below for dosingrecommendations in patients with renal impairment).

Xeplion has not been systematically studied in patients with renal impairment (see section 5.2). Forpatients with mild renal impairment (creatinine clearance ≥ 50 to < 80 mL/min), recommendedinitiation of Xeplion is with a dose of 100 mg on treatment day 1 and 75 mg one week later, bothadministered in the deltoid muscle. The recommended monthly maintenance dose is 50 mg with arange of 25 to 100 mg based on patient tolerability and/or efficacy.

Xeplion is not recommended in patients with moderate or severe renal impairment (creatinineclearance < 50 mL/min) (see section 4.4).

Based on experience with oral paliperidone, no dose adjustment is required in patients with mild ormoderate hepatic impairment. As paliperidone has not been studied in patients with severe hepaticimpairment, caution is recommended in such patients (see section 5.2).

The safety and efficacy of Xeplion in children and adolescents < 18 years of age have not beenestablished. No data are available.

Xeplion is intended for intramuscular use only. It must not be administered by any other route. Itshould be injected slowly, deep into the deltoid or gluteal muscle. Each injection should beadministered by a healthcare professional. Administration should be in a single injection. The doseshould not be given in divided injections.

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

For instructions for use and handling of Xeplion, see package leaflet (information intended for medicalor healthcare professionals).

Deltoid muscle administration

The recommended needle size for initial and maintenance administration of Xeplion into the deltoidmuscle is determined by the patient’s weight. For those ≥ 90 kg, the 1½ inch, 22 gauge needle(38.1 mm x 0.72 mm) is recommended. For those < 90 kg, the 1-inch, 23 gauge needle (25.4 mm x0.64 mm) is recommended. Deltoid injections should be alternated between the two deltoid muscles.

Gluteal muscle administration

The recommended needle size for maintenance administration of Xeplion into the gluteal muscle is the1½-inch, 22 gauge needle (38.1 mm x 0.72 mm). Administration should be made into the upper-outerquadrant of the gluteal area. Gluteal injections should be alternated between the two gluteal muscles.

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

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

Xeplion should not be used to manage acutely agitated or severely psychotic states when immediatesymptom control is warranted.

Caution should be exercised when paliperidone is prescribed in patients with known cardiovasculardisease or family history of QT prolongation, and in concomitant use with other medicinal productsthought to prolong 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, paliperidone should bediscontinued.

Medicinal products with dopamine receptor antagonistic properties have been associated with theinduction of tardive dyskinesia characterised by rhythmical, involuntary movements, predominantly ofthe tongue and/or face. If signs and symptoms of tardive dyskinesia appear, the discontinuation of allantipsychotics, including paliperidone, 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 Xeplion.

Agranulocytosis has been reported very rarely (< 1/10,000 patients) during post-marketingsurveillance. Patients with a history of a clinically significant low white blood cell count (WBC) or adrug-induced leucopenia/neutropenia should be monitored during the first few months of therapy anddiscontinuation of Xeplion should be considered at the first sign of a clinically significant decline in

WBC in the absence of other causative factors. Patients with clinically significant neutropenia shouldbe carefully monitored for fever or other symptoms or signs of infection and treated promptly if suchsymptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count < 1 x 109/L)should discontinue Xeplion and have their WBC followed until recovery.

Anaphylactic reactions in patients who have previously tolerated oral risperidone or oral paliperidonehave been rarely reported during post-marketing experience (see sections 4.1 and 4.8).

If hypersensitivity reactions occur, discontinue use of Xeplion; initiate general supportive measures asclinically appropriate and monitor the patient until signs and symptoms resolve (see sections 4.3 and4.8).

Hyperglycaemia, diabetes mellitus, and exacerbation of pre-existing diabetes including diabetic comaand ketoacidosis, have been reported during treatment with paliperidone. Appropriate clinicalmonitoring is advisable in accordance with utilised antipsychotic guidelines. Patients treated with

Xeplion should be monitored for symptoms of hyperglycaemia (such as polydipsia, polyuria,polyphagia and weakness) and patients with diabetes mellitus should be monitored regularly forworsening of glucose control.

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

Use in patients with prolactin-dependent tumours

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 a pre-existing tumour thatmay be prolactin-dependent.

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 oralpaliperidone prolonged release tablets (3, 6, 9, and 12 mg), orthostatic hypotension was reported by2.5% of subjects treated with oral paliperidone compared with 0.8% of subjects treated with placebo.

Xeplion should be used with caution in patients with known cardiovascular disease (e.g., heart failure,myocardial infarction or ischaemia, conduction abnormalities), cerebrovascular disease, or conditionsthat predispose the patient to hypotension (e.g. dehydration and hypovolaemia).

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

The plasma concentrations of paliperidone are increased in patients with renal impairment andtherefore, dose adjustment is recommended in patients with mild renal impairment. Xeplion is notrecommended in patients with moderate or severe renal impairment (creatinine clearance< 50 mL/min) (see sections 4.2 and 5.2).

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

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

The experience from risperidone cited below is considered 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 has 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.

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

Parkinson’s Disease or Dementia with Lewy Bodies (DLB) since both groups may be at increased 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 alpha-adrenergic blocking effects havebeen reported to induce priapism. During post-marketing surveillance, priapism has also been reportedwith oral paliperidone, which is the active metabolite of risperidone. Patients should be informed toseek urgent medical care in case that priapism has not been resolved within 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 Xeplion 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 medicinal products 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 Xeplion and preventativemeasures 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 medicinal products or ofconditions such as intestinal obstruction, Reye’s syndrome and brain tumour.

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

Intraoperative floppy iris syndrome (IFIS) has been observed during cataract surgery in patientstreated with medicinal products with alpha 1a-adrenergic antagonist effect, such as Xeplion (seesection 4.8).

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

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

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

Potential for Xeplion to affect other medicines

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

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

Paliperidone may antagonise the effect of levodopa and other dopamine agonists. If this 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 Xeplion is administered with other therapeutic agents that have this potential, e.g.,other antipsychotics, tricyclics.

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

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

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

Potential for other medicines to affect Xeplion

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 oral paliperidone with paroxetine, apotent CYP2D6 inhibitor, showed no clinically significant effect on the pharmacokinetics ofpaliperidone.

Co-administration of oral paliperidone prolonged release once daily with carbamazepine 200 mg twicedaily caused a decrease of approximately 37% in the mean steady-state Cmax and AUC of paliperidone.

This decrease is caused, to a substantial degree, by a 35% increase in renal clearance of paliperidonelikely as a result of induction of renal P-gp by carbamazepine. A minor decrease in the amount ofactive substance excreted unchanged in the urine suggests that there was little effect on the CYPmetabolism or bioavailability of paliperidone during carbamazepine co-administration. Largerdecreases in plasma concentrations of paliperidone could occur with higher doses of carbamazepine.

On initiation of carbamazepine, the dose of Xeplion should be re-evaluated and increased if necessary.

Conversely, on discontinuation of carbamazepine, the dose of Xeplion should be re-evaluated anddecreased if necessary.

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

Concomitant use of Xeplion with risperidone or with oral paliperidone

Since paliperidone is the major active metabolite of risperidone, caution should be exercised when

Xeplion is co-administered with risperidone or with oral paliperidone for extended periods of time.

Safety data involving concomitant use of Xeplion with other antipsychotics is limited.

Concomitant use of Xeplion with psychostimulants

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).

There are no adequate data from the use of paliperidone during pregnancy. Intramuscularly injectedpaliperidone palmitate and orally administered paliperidone were not teratogenic in animal studies, butother types of reproductive toxicity were seen (see section 5.3). Neonates exposed to paliperidoneduring the third 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. Xeplion should not be used duringpregnancy unless clearly necessary.

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. Xeplion 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, such as sedation, somnolence, syncope, vision blurred (seesection 4.8). Therefore, patients should be advised not to drive or operate machines until theirindividual susceptibility to Xeplion is known.

The adverse reactions most frequently reported in clinical trials were insomnia, headache, anxiety,upper respiratory tract infection, injection site reaction, parkinsonism, weight increased, akathisia,agitation, sedation/somnolence, nausea, constipation, dizziness, musculoskeletal pain, tachycardia,tremor, abdominal pain, vomiting, diarrhoea, fatigue, and dystonia. Of these, akathisia andsedation/somnolence appeared to be dose-related.

The following are all adverse reactions that were reported with paliperidone by frequency categoryestimated from paliperidone palmitate clinical trials. The following 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 not known (cannot be estimated from theavailable data).

System Organ Adverse reactions

Class Frequency

Very Common Uncommon Rare Not knownacommon

Infections and upper respiratory pneumonia, bronchitis, eye infection,infestations tract infection, respiratory tract acarodermatitisurinary tract infection, sinusitis,infection, influenza cystitis, ear infection,tonsillitis,onychomycosis,cellulitis,subcutaneous abscess

Blood and white blood cell count neutropenia, agranulocytosislymphatic system decreased, anaemia thrombocytopenia,disorders eosinophil countincreased

Immune system hypersensitivity anaphylacticdisorders reaction

Endocrine hyperprolactinaemiab inappropriatedisorders antidiuretichormonesecretion, glucoseurine present

Metabolism and hyperglycaemia, diabetes mellitusd, diabetic water intoxicationnutrition weight increased, hyperinsulinaemia, ketoacidosis,disorders weight decreased, increased appetite, hypoglycaemia,decreased appetite anorexia, blood polydipsiatriglycerides increased,blood cholesterolincreased

Psychiatric insomniae agitation, depression, sleep disorder, mania, catatonia, sleep-relateddisorders anxiety libido decreased, confusional state, eating disordernervousness, somnambulism,nightmare blunted affect,anorgasmia

Nervous system parkinsonismc, tardive dyskinesia, neuroleptic diabetic comacdisorders akathisia , syncope, psychomotor malignantsedation/somnolence, hyperactivity, syndrome,dystoniac, dizziness, dizziness postural, cerebraldyskinesiac, tremor, disturbance in ischaemia,headache attention, dysarthria, unresponsive todysgeusia, stimuli, loss ofhypoaesthesia, consciousness,paraesthesia depressed level ofconsciousness,convulsione,balance disorder,coordinationabnormal, headtitubation

Eye disorders vision blurred, glaucoma, eye floppy irisconjunctivitis, dry eye movement syndromedisorder, eye (intraoperative)rolling,photophobia,lacrimationincreased, ocularhyperaemia

Ear and labyrinth vertigo, tinnitus, eardisorders pain

Cardiac disorders tachycardia atrioventricular block, atrial fibrillation,conduction disorder, sinus arrhythmiaelectrocardiogram QTprolonged, posturalorthostatic tachycardiasyndrome,bradycardia,electrocardiogramabnormal, palpitations

Vascular hypertension hypotension, pulmonary ischaemiadisorders orthostatic hypotension embolism, venousthrombosis,flushing

Respiratory, cough, nasal dyspnoea, sleep apnoea hyperventilation,thoracic and congestion pharyngolaryngeal syndrome, pneumoniamediastinal pain, epistaxis pulmonary aspiration,disorders congestion, dysphoniarespiratory tractcongestion, rales,wheezing

Gastrointestinal abdominal pain, abdominal discomfort, pancreatitis, ileusdisorders vomiting, nausea, gastroenteritis, intestinalconstipation, dysphagia, dry mouth, obstruction,diarrhoea, dyspepsia, flatulence swollen tongue,toothache faecalincontinence,faecaloma,cheilitis

Hepatobiliary transaminases gamma- jaundicedisorders increased glutamyltransferaseincreased, hepaticenzyme increased

Skin and urticaria, pruritus, rash, drug eruption, Stevens-Johnsonsubcutaneous alopecia, eczema, dry hyperkeratosis, syndrome/toxictissue disorders skin, erythema, acne seborrhoeic epidermaldermatitis, necrolysis,dandruff angioedema, skindiscolouration

Musculoskeletal musculoskeletal pain, blood creatine rhabdomyolysis, posture abnormaland connective back pain, arthralgia phosphokinase joint swellingtissue disorders increased, musclespasms, joint stiffness,muscular weakness

Renal and urinary incontinence, urinary retentionurinary disorders pollakiuria, dysuria

Pregnancy, drug withdrawalpuerperium and syndromeperinatal neonatal (seeconditions section 4.6)

Reproductive amenorrhoea erectile dysfunction, priapism, breastsystem and breast ejaculation disorder, discomfort, breastdisorders menstrual disordere, engorgement,gynaecomastia, breastgalactorrhoea, sexual enlargement,dysfunction, breast vaginal dischargepain

General disorders pyrexia, asthenia, face oedema, oedemae, hypothermia, body temperatureand fatigue, injection site body temperature chills, thirst, drug decreased,administration reaction increased, gait withdrawal injection sitesite conditions abnormal, chest pain, syndrome, necrosis,chest discomfort, injection site injection sitemalaise, induration abscess, injection ulcersite cellulitis,injection site cyst,injection sitehaematoma

Injury, poisoning falland proceduralcomplicationsa The frequency of adverse reactions is qualified as “not known” because they were not observed in paliperidone palmitateclinical trials. They were either derived from spontaneous post-marketing reports and frequency cannot be determined, or theywere derived from risperidone (any formulation) or oral paliperidone clinical trials data and/or post-marketing reports.

b Refer to ‘Hyperprolactinaemia’ below.c Refer to ‘Extrapyramidal symptoms’ below.d In placebo-controlled trials, diabetes mellitus was reported in 0.32% in Xeplion-treated subjects compared to a rate of 0.39%in placebo group. Overall incidence from all clinical trials was 0.65% in all Xeplion 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 delayed, menstruationirregular, 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.

Rarely, cases of anaphylactic reaction after injection with Xeplion have been reported duringpost-marketing experience in patients who have previously tolerated oral risperidone or oralpaliperidone (see section 4.4).

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

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, glabellar reflex abnormal, and 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 the 13-week study involving the 150 mg initiation dosing, the proportion of subjects with anabnormal weight increase ≥ 7% showed a dose-related trend, with a 5% incidence rate in the placebogroup compared with rates of 6%, 8% and 13% in the Xeplion 25 mg, 100 mg, and 150 mg groups,respectively.

During the 33-week open-label transition/maintenance period of the long-term recurrence preventiontrial, 12% of Xeplion-treated subjects met this criterion (weight gain of ≥ 7% from double-blind phaseto endpoint); the mean (SD) weight change from open-label baseline was + 0.7 (4.79) kg.

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

QT prolongation, ventricular arrhythmias (ventricular fibrillation, ventricular tachycardia), suddenunexplained death, cardiac arrest, and Torsade de pointes may occur with antipsychotics.

Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep veinthrombosis, have been reported with antipsychotic medicinal products (frequency unknown).

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 a patient in the setting of overdose with oral paliperidone. In the case of acute overdose,the possibility of multiple drug involvement should be considered.

Consideration should be given to the prolonged release nature of the medicinal product and the longelimination half-life of paliperidone when assessing treatment needs and recovery. There is no specificantidote to paliperidone. General supportive measures should be employed. Establish and maintain aclear 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. Incase of severe extrapyramidal symptoms, anticholinergic agents should be administered. Closesupervision and monitoring should continue until the patient recovers.

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

Xeplion 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 alpha 1-adrenergic receptors and slightlyless, H1-histaminergic and alpha 2-adrenergic receptors. The pharmacological activity of the (+)- and(-)-paliperidone enantiomers are qualitatively and quantitatively similar.

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

D2-antagonist, which is believed to relieve the positive symptoms of schizophrenia, it causes lesscatalepsy and decreases motor functions less than traditional neuroleptics. Dominating centralserotonin antagonism may reduce the tendency of paliperidone to cause extrapyramidal side effects.

Acute treatment of schizophrenia

The efficacy of Xeplion in the acute treatment of schizophrenia was established in four short-term(one 9-week and three 13-week) double-blind, randomised, placebo-controlled, fixed-dose studies ofacutely relapsed adult inpatients who met DSM-IV criteria for schizophrenia. The fixed doses of

Xeplion in these studies were given on days 1, 8, and 36 in the 9-week study, and additionally onday 64 of the 13-week studies. No additional oral antipsychotic supplementation was needed duringthe acute treatment of schizophrenia with Xeplion. The primary efficacy endpoint was defined as adecrease in Positive and Negative Syndrome Scale (PANSS) total scores as shown in the table below.

The PANSS is a validated multi-item inventory composed of five factors to evaluate positivesymptoms, negative symptoms, disorganised thoughts, uncontrolled hostility/excitement andanxiety/depression. Functioning was evaluated using the Personal and Social Performance (PSP) scale.

The PSP is a validated clinician rated scale that measures personal and social functioning in fourdomains: socially useful activities (work and study), personal and social relationships, self-care anddisturbing and aggressive behaviours.

In a 13-week study (n = 636) comparing three fixed doses of Xeplion (initial deltoid injection of150 mg followed by 3 gluteal or deltoid doses of either 25 mg/4 weeks, 100 mg/4 weeks or150 mg/4 weeks) to placebo, all three doses of Xeplion were superior to placebo in improving the

PANSS total score. In this study, both the 100 mg/4 weeks and 150 mg /4 weeks, but not the25 mg/4 weeks, treatment groups demonstrated statistical superiority to placebo for the PSP score.

These results support efficacy across the entire duration of treatment and improvement in PANSS andwas observed as early as day 4 with significant separation from placebo in the 25 mg and 150 mg

Xeplion groups by day 8.

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

Positive and Negative Syndrome Scale for Schizophrenia (PANSS) Total Score - Change From Baseline to End

Point- LOCF for Studies R092670-SCH-201, R092670-PSY-3003, R092670-PSY-3004 and

R092670-PSY-3007: Primary Efficacy Analysis Set

Placebo 25 mg 50 mg 100 mg 150 mg

R092670-PSY-3007* n = 160 n = 155 n = 161 n = 160

Mean baseline (SD) 86.8 (10.31) 86.9 (11.99) 86.2 (10.77) 88.4 (11.70)

Mean change (SD) -2.9 (19.26) -8.0 (19.90) -- -11.6 (17.63) -13.2 (18.48)

P-value (vs. Placebo) -- 0.034 < 0.001 < 0.001

R092670-PSY-3003 n = 132 n = 93 n = 94 n = 30

Mean baseline (SD) 92.4 (12.55) 89.9 (10.78) 90.1 (11.66) 92.2 (11.72)

Mean change (SD) -4.1 (21.01) -- -7.9 (18.71) -11.0 (19.06) -5.5 (19.78)

P-value (vs. Placebo) -- 0.193 0.019 --

R092670-PSY-3004 n = 125 n = 129 n = 128 n = 131

Mean baseline (SD) 90.7 (12.22) 90.7 (12.25) 91.2 (12.02) 90.8 (11.70)

Mean change (SD) -7.0 (20.07) -13.6 (21.45) -13.2 (20.14) -16.1 (20.36) --

P-value (vs. Placebo) -- 0.015 0.017 < 0.001

R092670-SCH-201 n = 66 n = 63 n = 68

Mean baseline (SD) 87.8 (13.90) 88.0 (12.39) 85.2 (11.09)

Mean change (SD) 6.2 (18.25) -- -5.2 (21.52) -7.8 (19.40) --

P-value (vs. Placebo) -- 0.001 < 0.0001

* For Study R092670-PSY-3007 an initiation dose of 150 mg was given to all subjects in the Xeplion treatment groups onday 1 followed by the assigned dose afterwards.

Note: Negative change in score indicates improvement.

Maintaining symptom control and delaying relapse of schizophrenia

The efficacy of Xeplion in maintaining symptomatic control and delaying relapse of schizophreniawas established in a longer-term double-blind, placebo-controlled, flexible-dose study involving 849non-elderly adult subjects who met DSM-IV criteria for schizophrenia. This study included a 33-weekopen-label acute treatment and stabilisation phase, a randomised, double-blind placebo-controlledphase to observe for relapse, and a 52-week open-label extension period. In this study, doses of

Xeplion included 25, 50, 75, and 100 mg administered monthly; the 75 mg dose was allowed only inthe 52-week open-label extension. Subjects initially received flexible doses (25-100 mg) of Xeplionduring a 9-week transition period, followed by a 24-week maintenance period, where subjects wererequired to have a PANSS score of ≤ 75. Dosing adjustments were only allowed in the first 12 weeksof the maintenance period. A total of 410 stabilised patients were randomised to either Xeplion(median duration 171 days [range 1 day to 407 days]) or to placebo (median duration 105 days [range8 days to 441 days]) until they experienced a relapse of schizophrenia symptoms in the variable lengthdouble-blind phase. The trial was stopped early for efficacy reasons as a significantly longer time torelapse (p < 0.0001, Figure 1) was seen in patients treated with Xeplion compared to placebo (hazardratio = 4.32; 95% CI: 2.4-7.7).

20 Placebo N=156 Log-rank test, P-value<0.0001

XEPLION N=15620 40 60 80 100 120 140 160 180 200 220 240 260 280 300

Days since Randomisation

Figure 1: Kaplan-Meier Plot of Time to Relapse - Interim Analysis (Intent-to-Treat Interim

Analysis Set)

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

Xeplion in all subsets of the paediatric population in schizophrenia. See section 4.2 for information onpaediatric use.

Paliperidone palmitate is the palmitate ester prodrug of paliperidone. Due to its extremely low watersolubility, paliperidone palmitate dissolves slowly after intramuscular injection before beinghydrolysed to paliperidone and absorbed into the systemic circulation. Following a singleintramuscular dose, the plasma concentrations of paliperidone gradually rise to reach maximumplasma concentrations at a median Tmax of 13 days. The release of the active substance starts as earlyas day 1 and lasts for at least 4 months.

Following intramuscular injection of single doses (25-150 mg) in the deltoid muscle, on average, a28% higher Cmax was observed compared with injection in the gluteal muscle. The two initial deltoidintramuscular injections of 150 mg on day 1 and 100 mg on day 8 help attain therapeuticconcentrations rapidly. The release profile and dosing regimen of Xeplion results in sustainedtherapeutic concentrations. The total exposure of paliperidone following Xeplion administration wasdose-proportional over a 25-150 mg dose range, and less than dose-proportional for Cmax for dosesexceeding 50 mg. The mean steady-state peak:trough ratio for a Xeplion dose of 100 mg was 1.8following gluteal administration and 2.2 following deltoid administration. The median apparent

Estimated Percent of Subjects Without Relapsehalf-life of paliperidone following Xeplion administration over the dose range of 25-150 mg rangedfrom 25-49 days.

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

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

The plasma protein binding of racemic paliperidone is 74%.

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 in 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 oral paliperidone between extensivemetabolisers and poor metabolisers of CYP2D6 substrates. In vitro studies in human liver microsomesshowed that paliperidone does not substantially inhibit the metabolism of medicinal productsmetabolised by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6,

CYP2E1, CYP3A4, and CYP3A5.

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.

Long acting paliperidone palmitate injection versus oral prolonged release paliperidone

Xeplion is designed to deliver paliperidone over a monthly period while prolonged release oralpaliperidone is administered on a daily basis. The initiation regimen for Xeplion (150 mg/100 mg inthe deltoid muscle on day 1/day 8) was designed to rapidly attain steady-state paliperidoneconcentrations when initiating therapy without the use of oral supplementation.

In general, overall initiation plasma levels with Xeplion were within the exposure range observed with6-12 mg prolonged release oral paliperidone. The use of the Xeplion initiation regimen allowedpatients to stay in this exposure window of 6-12 mg prolonged release oral paliperidone even ontrough pre-dose days (day 8 and day 36). Because of the difference in median pharmacokineticprofiles between the two medicinal products, caution should be exercised when making a directcomparison of their pharmacokinetic properties.

Paliperidone is not extensively metabolised in the liver. Although Xeplion was not studied on patientswith hepatic impairment, no dose adjustment is required in patients with mild or moderate hepaticimpairment. In a study with oral paliperidone in subjects with moderate hepatic impairment(Child-Pugh class B), the plasma concentrations of free paliperidone were similar to those of healthysubjects. Paliperidone has not been studied in patients with severe hepatic impairment.

The disposition of a single oral dose paliperidone 3 mg prolonged release tablet was studied insubjects with varying degrees of renal function. Elimination of paliperidone decreased with decreasingestimated creatinine clearance. Total clearance of paliperidone was reduced in subjects with impairedrenal function by 32% on average in mild (CrCl = 50 to < 80 mL/min), 64% in moderate (CrCl = 30 to< 50 mL/min), and 71% in severe (CrCl = 10 to < 30 mL/min) renal impairment, corresponding to anaverage increase in exposure (AUCinf) of 1.5, 2.6, and 4.8 fold, respectively, compared to healthysubjects. Based on a limited number of observations with Xeplion in subjects with mild renalimpairment and pharmacokinetic simulations, a reduced dose is recommended (see section 4.2).

Population pharmacokinetics analysis showed no evidence of age related pharmacokineticsdifferences.

Body mass index (BMI)/body weight

Pharmacokinetic studies with paliperidone palmitate have shown somewhat lower (10-20%) plasmaconcentrations of paliperidone in patients who are overweight or obese in comparison with normalweight patients (see section 4.2).

Population pharmacokinetics analysis of data from studies with oral paliperidone revealed no evidenceof race-related differences in the pharmacokinetics of paliperidone following Xeplion administration.

No clinically significant differences were observed 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. Effect ofsmoking on the pharmacokinetics of paliperidone was not studied with Xeplion. A populationpharmacokinetic analysis based on data with oral paliperidone prolonged release tablets showed aslightly lower exposure to paliperidone in smokers compared with non-smokers. The difference isunlikely to be of clinical relevance.

Repeat-dose toxicity studies of intramuscularly injected paliperidone palmitate (the 1-monthformulation) and orally administered paliperidone in rat and dog showed mainly pharmacologicaleffects, such as sedation and prolactin-mediated effects on mammary glands and genitals. In animalstreated with paliperidone palmitate an inflammatory reaction was seen at the intramuscular injectionsite. Occasionally abscess formation occurred.

In rat reproduction studies with oral risperidone, which is extensively converted to paliperidone in ratsand humans, adverse effects were seen on the birth weight and survival of the offspring. Noembryotoxicity or malformations were observed following intramuscular administration ofpaliperidone palmitate to pregnant rats up to the highest dose (160 mg/kg/day) corresponding to4.1 times the exposure level in humans at the maximum recommended dose of 150 mg. Otherdopamine antagonists, when administered to pregnant animals, have caused negative effects onlearning and motor development in the offspring.

Paliperidone palmitate and paliperidone were not genotoxic. In oral carcinogenicity studies ofrisperidone in rats and mice, increases in pituitary gland adenomas (mouse), endocrine pancreasadenomas (rat), and mammary gland adenomas (both species) were seen. The carcinogenic potentialof intramuscularly injected paliperidone palmitate was assessed in rats. There was a statisticallysignificant increase in mammary gland adenocarcinomas in female rats at 10, 30 and 60 mg/kg/month.

Male rats showed a statistically significant increase in mammary gland adenomas and carcinomas at30 and 60 mg/kg/month which is 1.2 and 2.2 times the exposure level at the maximum recommendedhuman 150 mg dose. These tumours can be related to prolonged dopamine D2 antagonism andhyperprolactinaemia. The relevance of these tumour findings in rodents in terms of human risk isunknown.

Polysorbate 20

Polyethylene glycol 4 000

Citric acid monohydrate

Disodium hydrogen phosphate anhydrous

Sodium dihydrogen phosphate monohydrate

Sodium hydroxide (for pH adjustment)

Water for injections

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

2 years

Do not store above 30°C.

25 mg0.25 mL suspension in a pre-filled syringe (cyclic-olefin-copolymer) with a plunger stopper,backstop, and tip cap (bromobutyl rubber) with a 22G 1½-inch safety needle (0.72 mm x 38.1 mm)and a 23G 1-inch safety needle (0.64 mm x 25.4 mm).

50 mg0.5 mL suspension in a pre-filled syringe (cyclic-olefin-copolymer) with a plunger stopper, backstop,and tip cap (bromobutyl rubber) with a 22G 1½-inch safety needle (0.72 mm x 38.1 mm) and a 23G1-inch safety needle (0.64 mm x 25.4 mm).

75 mg0.75 mL suspension in a pre-filled syringe (cyclic-olefin-copolymer) with a plunger stopper, backstop,and tip cap (bromobutyl rubber) with a 22G 1½-inch safety needle (0.72 mm x 38.1 mm) and a 23G1-inch safety needle (0.64 mm x 25.4 mm).

100 mg1 mL suspension in a pre-filled syringe (cyclic-olefin-copolymer) with a plunger stopper, backstop,and tip cap (bromobutyl rubber) with a 22G 1½-inch safety needle (0.72 mm x 38.1 mm) and a 23G1-inch safety needle (0.64 mm x 25.4 mm).

150 mg1.5 mL suspension in a pre-filled syringe (cyclic-olefin-copolymer) with a plunger stopper, backstop,and tip cap (bromobutyl rubber) with a 22G 1½-inch safety needle (0.72 mm x 38.1 mm) and a 23G1-inch safety needle (0.64 mm x 25.4 mm).

Pack contains 1 pre-filled syringe and 2 needles.

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

Janssen-Cilag International NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

EU/1/11/672/001 (25 mg)

EU/1/11/672/002 (50 mg)

EU/1/11/672/003 (75 mg)

EU/1/11/672/004 (100 mg)

EU/1/11/672/005 (150 mg)

Date of first authorisation: 04 March 2011

Date of latest renewal: 16 December 2015

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

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