TREVICTA 263mg long-release injection suspension medication leaflet

TREVICTA 175 mg prolonged release suspension for injection

TREVICTA 263 mg prolonged release suspension for injection

TREVICTA 350 mg prolonged release suspension for injection

TREVICTA 525 mg prolonged release suspension for injection

175 mg prolonged release suspension for injection

Each pre-filled syringe contains 273 mg paliperidone palmitate in 0.88 mL equivalent to 175 mgpaliperidone.

263 mg prolonged release suspension for injection

Each pre-filled syringe contains 410 mg paliperidone palmitate in 1.32 mL equivalent to 263 mgpaliperidone.

350 mg prolonged release suspension for injection

Each pre-filled syringe contains 546 mg paliperidone palmitate in 1.75 mL equivalent to 350 mgpaliperidone.

525 mg prolonged release suspension for injection

Each pre-filled syringe contains 819 mg paliperidone palmitate in 2.63 mL equivalent to 525 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).

TREVICTA, a 3-monthly injection, is indicated for the maintenance treatment of schizophrenia inadult patients who are clinically stable on 1-monthly paliperidone palmitate injectable product (seesection 5.1).

Patients who are adequately treated with 1-monthly paliperidone palmitate injectable (preferably forfour months or more) and do not require dose adjustment may be switched to 3-monthly paliperidonepalmitate injection.

TREVICTA should be initiated in place of the next scheduled dose of 1-monthly paliperidonepalmitate injectable (± 7 days). The TREVICTA dose should be based on the previous 1-monthlypaliperidone palmitate injectable dose using a 3.5-fold higher dose shown in the following table:

TREVICTA doses for patients adequately treated with 1-monthly paliperidone palmitateinjectable

If the last dose of 1-monthly paliperidone Initiate TREVICTA at the following dosepalmitate injectable is50 mg 175 mg75 mg 263 mg100 mg 350 mg150 mg 525 mg

There is no equivalent dose of TREVICTA for the 25 mg dose of 1-monthly paliperidone palmitateinjectable which was not studied.

Following the initial TREVICTA dose, TREVICTA should be administered by intramuscular injectiononce every 3 months (± 2 weeks, see also Missed dose section).

If needed, dose adjustment of TREVICTA can be made every 3 months in increments within the rangeof 175 mg to 525 mg based on individual patient tolerability and/or efficacy. Due to the long-actingnature of TREVICTA, the patient’s response to an adjusted dose may not be apparent for severalmonths (see section 5.2). If the patient remains symptomatic, they should be managed according toclinical practice.

Switching from other antipsychotic medicinal products

Patients should not be switched directly from other antipsychotics as 3-monthly paliperidone palmitateinjectable should only be initiated after the patient is stabilised on the 1-monthly paliperidonepalmitate injectable.

Switching from TREVICTA to other antipsychotic medicinal products

If TREVICTA is discontinued, its prolonged release characteristics must be considered.

Switching from TREVICTA to 1-monthly paliperidone palmitate injectable

For switching from TREVICTA to 1-monthly paliperidone palmitate injectable, 1-monthlypaliperidone palmitate injectable should be administered at the time the next TREVICTA dose was tobe administered using a 3.5-fold lower dose shown in the following table. The initiation dosing asdescribed in the prescribing information for 1-monthly paliperidone palmitate injectable is notrequired. The 1-monthly paliperidone palmitate injectable should then continue to be dosed at monthlyintervals as described within its prescribing information.

Doses of 1-monthly paliperidone palmitate injectable for patients switching from TREVICTA

If the last dose of TREVICTA is Initiate 1-monthly paliperidone palmitateinjectable 3 months later at the following dose175 mg 50 mg263 mg 75 mg350 mg 100 mg525 mg 150 mg

Switching from TREVICTA to oral daily paliperidone prolonged release tablets

For switching from TREVICTA to paliperidone prolonged release tablets, the daily dosing ofpaliperidone prolonged release tablets should be started 3 months after the last TREVICTA dose andtreatment continued with paliperidone prolonged release tablets as described in the table below. Thefollowing table provides recommended dose conversion regimens to allow patients previouslystabilised on different doses of TREVICTA to attain similar paliperidone exposure with paliperidoneprolonged release tablets.

Doses of paliperidone prolonged release tablets for patients switching from TREVICTA*

Week number after last TREVICTA dose

Last TREVICTA dose Week 12 to Week 18, Week 19 to Week 24, From Week 25(Week 0) inclusive inclusive onwards

Daily dose of paliperidone prolonged release tablets175 mg 3 mg 3 mg 3 mg263 mg 3 mg 3 mg 6 mg350 mg 3 mg 6 mg 9 mg525 mg 6 mg 9 mg 12 mg

* All doses of once daily paliperidone prolonged release tablets should be individualised to the specific patient, takinginto consideration variables such as reasons for switching, response to previous paliperidone treatment, severity ofpsychotic symptoms, and/or propensity for side effects.

Dosing window

TREVICTA should be injected once every 3 months. To avoid a missed dose of TREVICTA patientsmay be given the injection up to 2 weeks before or after the 3-month time point.

If scheduled dose is missed and the time since Actionlast injection is> 3½ months up to 4 months The injection should be administered as soon aspossible and then resume the 3-monthlyinjection schedule.

4 months to 9 months Use the recommended re-initiation regimenshown in the table below.

> 9 months Re-initiate treatment with 1-monthlypaliperidone palmitate injectable as described inthe prescribing information for that product.

TREVICTA can then be resumed after thepatient has been adequately treated with1-monthly paliperidone palmitate injectablepreferably for four months or more.

Recommended re-initiation regimen after missing 4 months to 9 months of TREVICTA

Administer 1-monthly paliperidone palmitate Then administerinjectable, two doses one week apart (into TREVICTA (into

If the last dose ofdeltoid muscle) deltoida or gluteal

TREVICTA wasmuscle)

Day 1 Day 8 1 month after day 8175 mg 50 mg 50 mg 175 mg263 mg 75 mg 75 mg 263 mg350 mg 100 mg 100 mg 350 mg525 mg 100 mg 100 mg 525 mga See also Information intended for medical or healthcare professionals for deltoid injection needle selection based onbody weight.

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

In general, recommended dosing of TREVICTA for elderly patients with normal renal function is thesame as for younger adult patients with normal renal function. As elderly patients may have reducedrenal function, see Renal impairment below for dosing recommendations in patients with renalimpairment.

TREVICTA has not been studied in patients with renal impairment (see section 5.2). For patients withmild renal impairment (creatinine clearance ≥ 50 to < 80 mL/min), dose should be adjusted and thepatient stabilised using 1-monthly paliperidone palmitate injectable, and then transitioned to

TREVICTA.

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

TREVICTA has not been studied in patients with hepatic impairment. Based on experience with oralpaliperidone, no dose adjustment is required in patients with mild or moderate hepatic impairment. Aspaliperidone has not been studied in patients with severe hepatic impairment, caution is recommendedin such patients (see section 5.2).

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

TREVICTA is intended for intramuscular use only. It must not be administered by any other route.

Each injection must be administered only by a healthcare professional giving the full dose in a singleinjection. It should be injected slowly, deep into the deltoid or gluteal muscle. A switch from gluteal todeltoid (and vice versa) should be considered for future injection in the event of injection sitediscomfort (see section 4.8).

TREVICTA must be administered using only the thin wall needles that are provided in the

TREVICTA pack. Needles from the 1-monthly paliperidone palmitate injectable pack or othercommercially available needles must not be used when administering TREVICTA (see Informationintended for medical or healthcare professionals).

The contents of the pre-filled syringe should be inspected visually for foreign matter anddiscolouration prior to administration. It is important to shake the syringe vigourously with the tipup and a loose wrist for at least 15 seconds to ensure a homogeneous suspension. TREVICTAshould be administered within 5 minutes after shaking. If more than 5 minutes pass beforeinjection, shake vigourously again for at least 15 seconds to re-suspend the medicinal product. (See

Information intended for medical or healthcare professionals).

Deltoid muscle administration

The specified needle for administration of TREVICTA into the deltoid muscle is determined by thepatient’s weight.

- For those ≥ 90 kg, the thin wall 1½ inch, 22 gauge (0.72 mm x 38.1 mm) needle should be used.

- For those < 90 kg, the thin wall 1 inch, 22 gauge (0.72 mm x 25.4 mm) needle should be used.

It should be administered into the centre of the deltoid muscle. Deltoid injections should be alternatedbetween the two deltoid muscles.

Gluteal muscle administration

The needle to be used for administration of TREVICTA into the gluteal muscle is the thin wall1½ inch, 22 gauge (0.72 mm x 38.1 mm) needle regardless of body weight. It should be administeredinto the upper-outer quadrant of the gluteal muscle. Gluteal injections should be alternated betweenthe two gluteal muscles.

Incomplete administration

To avoid incomplete administration of TREVICTA, the pre-filled syringe must be shaken vigourouslyfor at least 15 seconds within 5 minutes prior to administration to ensure a homogeneous suspension(see Information intended for medical or healthcare professionals).

However, in the event of an incompletely injected dose, the dose remaining in the syringe should notbe re-injected and another dose should not be given since it is difficult to estimate the proportion of thedose actually administered. The patient should be closely monitored and managed as clinicallyappropriate until the next scheduled 3-monthly injection of TREVICTA.

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

TREVICTA should not be used to manage acutely agitated or severely psychotic states whenimmediate symptom 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. Consideration should be given to the long-acting nature of TREVICTA.

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. Consideration should be given to thelong-acting nature of TREVICTA.

Caution is warranted in patients receiving both, psychostimulants (e.g., methylphenidate) andpaliperidone concomitantly, as extrapyramidal symptoms could emerge when adjusting one or bothmedicinal products. 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 paliperidone. Patientswith a history of a clinically significant low white blood cell count (WBC) or a drug-inducedleucopenia/neutropenia should be monitored during the first few months of therapy anddiscontinuation of TREVICTA should be considered at the first sign of a clinically significant declinein WBC in the absence of other causative factors. Patients with clinically significant neutropeniashould be carefully monitored for fever or other symptoms or signs of infection and treated promptly ifsuch symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count< 1 x 109/L) should discontinue TREVICTA and have their WBC followed until recovery.

Consideration should be given to the long-acting nature of TREVICTA.

Hypersensitivity reactions can occur even in patients who have previously tolerated oral risperidone ororal paliperidone (see section 4.8).

Hyperglycaemia, diabetes mellitus, and exacerbation of pre-existing diabetes, including diabetic comaand ketoacidosis, have been reported with paliperidone. Appropriate clinical monitoring is advisable inaccordance with utilised antipsychotic guidelines. Patients treated with TREVICTA should bemonitored for symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia, and weakness)and patients with diabetes mellitus should be monitored regularly for worsening of glucose control.

Significant weight gain has been reported with TREVICTA use. Weight should be monitoredregularly.

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-adrenergicblocking activity. In the clinical trials of TREVICTA, 0.3% of subjects reported orthostatichypotension related adverse reaction. TREVICTA should be used with caution in patients with knowncardiovascular disease (e.g., heart failure, myocardial infarction or ischaemia, conductionabnormalities), cerebrovascular disease, or conditions that predispose the patient to hypotension (e.g.,dehydration and hypovolaemia).

TREVICTA 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. Forpatients with mild renal impairment (creatinine clearance ≥ 50 mL/min to < 80 mL/min), dose shouldbe adjusted and the patient stabilised using 1-monthly paliperidone palmitate injectable, thentransitioned to TREVICTA. TREVICTA is not recommended in patients with moderate or severerenal 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.

TREVICTA has not been studied in elderly patients with dementia. TREVICTA is not recommendedto treat elderly patients with dementia due to increased risk of overall mortality and cerebrovascularadverse reactions.

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 TREVICTA 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 paliperidone) with alpha-adrenergic blocking effectshave been reported to induce priapism. Patients should be informed to seek urgent medical care in casethat 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 TREVICTA 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 TREVICTA andpreventative measures 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 TREVICTA into a blood vessel.

Intraoperative floppy iris syndrome

Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in patientstreated with medicinal products with alpha 1a-adrenergic antagonist effect, such as TREVICTA (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 TREVICTA 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 antibiotics (e.g., fluoroquinolones), some otherantipsychotics and some antimalarials (e.g., mefloquine). This list is indicative and not exhaustive.

Potential for TREVICTA to affect other medicines

Paliperidone is not expected to cause clinically important pharmacokinetic interactions with medicinalproducts that are metabolised by cytochrome P450 isozymes.

Given the primary central nervous system (CNS) effects of paliperidone (see section 4.8), TREVICTAshould 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 TREVICTA is administered with other medicinal products 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 TREVICTA and lithium has been performed, however, apharmacokinetic interaction is not likely to occur.

Potential for other medicines to affect TREVICTA

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 TREVICTA should be re-evaluated and increased ifnecessary. Conversely, on discontinuation of carbamazepine, the dose of TREVICTA should bere-evaluated and decreased if necessary. Consideration should be given to the long-acting nature of

TREVICTA.

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 TREVICTAintramuscular injection. This interaction has not been studied with TREVICTA.

Concomitant use of TREVICTA with risperidone or oral paliperidone

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

TREVICTA is co-administered with risperidone or with oral paliperidone for extended periods oftime. Safety data involving concomitant use of TREVICTA with other antipsychotics is limited.

Concomitant use of TREVICTA 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. TREVICTA should not be usedduring pregnancy unless clearly necessary.

Since paliperidone has been detected in plasma up to 18 months after a single dose of TREVICTA,consideration should be given to the long-acting nature of TREVICTA as maternal exposure to

TREVICTA before and during pregnancy may lead to adverse reactions in the newborn child.

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. Since paliperidone has beendetected in plasma up to 18 months after a single dose administration of TREVICTA, considerationshould be given to the long-acting nature of TREVICTA as breastfed infants may be at risk even from

TREVICTA administration long before breast-feeding. TREVICTA should not be used whilebreast-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 TREVICTA is known.

The most frequently observed adverse reactions reported in ≥ 5% of patients in two double-blindcontrolled clinical trials of TREVICTA were weight increased, upper respiratory tract infection,anxiety, headache, insomnia, and injection site reaction.

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 tract pneumonia, eye infection,infestations infection, urinary tract bronchitis, acarodermatitisinfection, influenza respiratory tractinfection, sinusitis,cystitis, earinfection,tonsillitis,onychomycosis,cellulitis,subcutaneousabscess

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

Immune system hypersensitivity anaphylacticdisorders reaction

Endocrine hyperprolactinaemiab inappropriatedisorders antidiuretichormone secretion,glucose urinepresent

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

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

Nervous system parkinsonismc, tardive dyskinesia, neuroleptic diabetic comadisorders akathisiac, sedation/ syncope, malignantpsychomotor syndrome, cerebralsomnolence, dystoniac, hyperactivity, ischaemia,dizziness, dyskinesiac, dizziness postural, unresponsive totremor, headache disturbance in stimuli, loss ofattention, consciousness,dysarthria, depressed level ofdysgeusia, consciousness,hypoaesthesia, convulsione,paraesthesia balance disorder,coordinationabnormal, headtitubation

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

Ear and labyrinth vertigo, tinnitus,disorders ear pain

Cardiac disorders tachycardia atrioventricular atrial fibrillation,block, conduction sinus arrhythmiadisorder,electrocardiogram

QT prolonged,postural orthostatictachycardiasyndrome,bradycardia,electrocardiogramabnormal,palpitations

Vascular disorders hypertension hypotension, pulmonary ischaemiaorthostatic embolism, venoushypotension thrombosis,flushing

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

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

Hepatobiliary transaminases increased gamma- jaundicedisorders glutamyltransferase increased,hepatic enzymeincreased

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

Musculoskeletal musculoskeletal pain, blood creatine rhabdomyolysis, posture abnormaland connective back pain, arthralgia phosphokinase joint swellingtissue disorders increased, musclespasms, jointstiffness, muscularweakness

Renal and urinary urinary urinary retentiondisorders incontinence,pollakiuria,dysuria

Pregnancy, drug withdrawalpuerperium and syndromeperinatal neonatalconditions (see section 4.6)

Reproductive amenorrhoea erectile priapism, breastsystem and breast dysfunction, discomfort, breastdisorders ejaculation engorgement,disorder, breast enlargement,menstrual vaginal dischargedisordere,gynaecomastia,galactorrhoea,sexualdysfunction, breastpain

General disorders pyrexia, asthenia, face oedema, hypothermia, body temperatureand administration fatigue, injection site oedemae, body chills, thirst, drug decreased,site conditions reaction temperature withdrawal injection siteincreased, gait syndrome, necrosis, injectionabnormal, chest injection site site ulcerpain, chest abscess, injectiondiscomfort, site cellulitis,malaise, induration 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 paliperidonepalmitate clinical trials. They were either derived from spontaneous post-marketing reports and frequency cannot bedetermined, or they were derived from risperidone (any formulation) or oral paliperidone clinical trials data and/orpost-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 subjects treated with 1-monthly paliperidonepalmitate injectable compared to a rate of 0.39% in placebo group. Overall incidence from all clinical trials was 0.65%in all subjects treated 1-monthly paliperidone palmitate injectable.

e Insomnia includes: initial insomnia, middle insomnia; Convulsion includes: grand mal convulsion; Oedemaincludes: generalised oedema, oedema peripheral, pitting oedema; Menstrual disorder includes: menstruationdelayed, 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.

Rarely, cases of anaphylactic reaction after injection with 1-monthly paliperidone palmitate injectablehave been reported during post-marketing experience in patients who have previously tolerated oralrisperidone or oral paliperidone (see section 4.4).

In clinical trials of TREVICTA, 5.3% of subjects reported injection site related adverse reaction. Noneof these events were serious or led to discontinuation. Based on the investigators’ ratings, induration,redness, and swelling were absent or mild in ≥ 95% of the assessments. Subject-rated injection sitepain based on a visual analogue scale was low and decreased in intensity over time.

In the clinical trials of TREVICTA, akathisia, dyskinesia, dystonia, parkinsonism, and tremor werereported in 3.9%, 0.8%, 0.9%, 3.6%, and 1.4% of subjects, respectively.

Extrapyramidal symptoms (EPS) included a pooled analysis of the following terms: parkinsonism(includes extrapyramidal disorder, extrapyramidal symptoms, on and off phenomenon, Parkinson’sdisease, parkinsonian crisis, salivary hypersecretion, musculoskeletal stiffness, parkinsonism,drooling, cogwheel rigidity, bradykinesia, hypokinesia, masked facies, muscle tightness, akinesia,nuchal rigidity, muscle rigidity, parkinsonian gait, glabellar reflex abnormal, and parkinsonian resttremor), akathisia (includes akathisia, restlessness, hyperkinesia, and restless leg syndrome),dyskinesia (dyskinesia, chorea, movement disorder, muscle twitching, choreoathetosis, athetosis, andmyoclonus), dystonia (includes dystonia, cervical spasm, emprosthotonus, oculogyric crisis,oromandibular dystonia, risus sardonicus, tetany, hypertonia, torticollis, muscle contractionsinvoluntary, muscle contracture, blepharospasm, oculogyration, tongue paralysis, facial spasm,laryngospasm, myotonia, opisthotonus, oropharyngeal spasm, pleurothotonus, tongue spasm, andtrismus), and tremor.

In the long-term randomised withdrawal study, abnormal increases of ≥ 7% in body weight fromdouble-blind baseline to double-blind end point were reported for 10% subjects in the TREVICTAgroup and 1% subjects in the placebo group. Conversely, abnormal decreases in body weight (≥ 7%)from double-blind baseline to double-blind end point were reported for 1% subjects in the TREVICTAgroup and 8% subjects in the placebo group. The mean changes in body weight from double-blindbaseline to double-blind end point were +0.94 kg and -1.28 kg for the TREVICTA and placebogroups, respectively

During the double-blind phase of the long-term randomised withdrawal study, elevations of prolactinto above the reference range (> 13.13 ng/mL in males and > 26.72 ng/mL in females) were noted in ahigher percentage of males and females in the TREVICTA group than in the placebo group (9% vs.3% and 5% vs. 1%, respectively). In the TREVICTA group, the mean change from double-blindbaseline to double-blind end point was +2.90 ng/mL for males (vs. -10.26 ng/mL in the placebo group)and +7.48 ng/mL for females (vs. -32.93 ng/mL in the placebo group). One female (2.4%) in the

TREVICTA group experienced an adverse reaction of amenorrhea, while no potentially prolactinrelated adverse reactions were noted among females in the placebo group. There were no potentiallyprolactin related adverse reactions among males in either group.

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 long-acting 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

TREVICTA 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 symptoms of schizophrenia, it causes less catalepsy anddecreases motor functions less than traditional neuroleptics. Dominating central serotonin antagonismmay reduce the tendency of paliperidone to cause extrapyramidal side effects.

The efficacy of TREVICTA in the maintenance treatment of schizophrenia in subjects who have beenadequately treated for at least four months with 1-monthly paliperidone palmitate injectable and thelast two doses of the same dosage strength was evaluated in one long-term randomised withdrawaldouble-blind, placebo-controlled study and one long-term double-blind, active-controlled,non-inferiority study. For both studies, the primary outcome was based on relapse.

In the long-term randomised withdrawal study, 506 adult subjects who met DSM-IV criteria forschizophrenia were enrolled into the open-label transition phase and treated with flexible doses of1-monthly paliperidone palmitate injectable administered into the deltoid or gluteal muscle(50-150 mg) for 17 weeks (dose adjustments occurred at weeks 5 and 9). A total of 379 subjects thenreceived a single dose of TREVICTA in either the deltoid or gluteal muscle in the open-labelstabilisation phase (dose was a 3.5 multiple of the last dose of 1-monthly paliperidone palmitate).

Subjects who were considered clinically stable at the end of the 12-week stabilisation phase were thenrandomised 1:1 to TREVICTA or placebo in a variable duration double-blind phase (the dose of

TREVICTA was the same as the last dose received during the stabilisation phase; this dose remainedfixed throughout the double-blind phase). In this period, 305 symptomatically stable subjects wererandomised to continue treatment with TREVICTA (n = 160) or placebo (n = 145) until relapse, earlywithdrawal, or the end of study. The primary efficacy variable was time to first relapse. The study wasterminated on the basis of a pre-planned interim analysis conducted when 283 subjects had beenrandomised and 42 relapse events had been observed.

Based on the final analysis (N = 305), 42 subjects (29.0%) in the placebo group and 14 subjects(8.8%) in the TREVICTA group had experienced a relapse event during the double blind phase. Thehazard ratio was 3.81 (95% CI: 2.08, 6.99) indicating a 74% decrease in relapse risk with TREVICTAcompared to placebo. A Kaplan Meier plot of time to relapse by treatment group is shown in Figure 1.

There was a significant difference (p < 0.0001) between the two treatment groups in the time torelapse in favour of TREVICTA. The time to relapse of the placebo group (median 395 days) wassignificantly shorter than for the TREVICTA group (the median could not be estimated due to the lowpercentage of subjects with relapse [8.8%]).

TREVICTA (N=160) logrank test, p-value<0.0001

Placebo (N=145)28 56 84 112 140 168 196 224 252 280 308 336 364 392 420 448

Time(days) since Randomization

Figure 1: Kaplan-Meier plot of time to relapse - Final analysis

Estimated Percent of Subjects Without Relapse

In the non-inferiority study, 1,429 acutely ill subjects (baseline mean PANSS total score: 85.7) whomet DSM-IV criteria for schizophrenia were enrolled into the open-label phase and treated with1-monthly paliperidone palmitate injectable for 17 weeks. The dose could be adjusted (i.e., 50 mg,75 mg, 100 mg, or 150 mg) at the week 5 and 9 injections and the injection site could be deltoid orgluteal. For subjects that met randomisation criteria at weeks 14 and 17, 1,016 were randomised in a1:1 ratio to continue on monthly injections of 1-monthly paliperidone palmitate injectable or to switchto TREVICTA with a 3.5 multiple of the week 9 and 13 dose of 1-monthly paliperidone palmitateinjectable for 48 weeks. Subjects received TREVICTA once every 3 months and receivedplacebo-injectable medication for the other months to maintain the blind. The primary efficacyendpoint of the study was the percentage of subjects who had not relapsed at the end of the 48-weekdouble-blind phase based on the Kaplan-Meier 48-week estimate (TREVICTA: 91.2%, 1-monthlypaliperidone palmitate injectable: 90.0%). The median time to relapse in either group could not beestimated due to low percentage of subjects with relapse. The difference (95% CI) between thetreatment groups was 1.2% (-2.7%, 5.1%), meeting non-inferiority criterion based on a margin of

- 10%. Thus, the TREVICTA treatment group was non-inferior to 1-monthly paliperidone palmitateinjectable. Improvements in functioning, as measured by the Personal and Social Performance scale(PSP), which was observed during the open-label stabilisation phase were maintained during thedouble-blind phase for both treatment groups.

Figure 2: Kaplan-Meier plot of time to relapse comparing TREVICTA and 1-monthly paliperidonepalmitate injectable

The efficacy results were consistent across population subgroups (gender, age, and race) in bothstudies.

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

TREVICTA in all subsets of the paediatric population in schizophrenia. (See section 4.2 forinformation on paediatric use).

Due to its extremely low water solubility, the 3-monthly formulation of paliperidone palmitatedissolves slowly after intramuscular injection before being hydrolysed to paliperidone and absorbedinto the systemic circulation. The release of the active substance starts as early as day 1 and lasts for aslong as 18 months.

The data presented in this paragraph are based on a population pharmacokinetic analysis. Following asingle intramuscular dose of TREVICTA, the plasma concentrations of paliperidone gradually rise toreach maximum plasma concentrations at a median Tmax of 30-33 days. Following intramuscularinjection of TREVICTA at doses of 175-525 mg in the deltoid muscle, on average, an 11-12% higher

Cmax was observed compared with injection in the gluteal muscle. The release profile and dosingregimen of TREVICTA results in sustained therapeutic concentrations. The total exposure ofpaliperidone following TREVICTA administration was dose-proportional over a 175-525 mg doserange, and approximately dose-proportional for Cmax. The mean steady-state peak:trough ratio for a

TREVICTA dose was 1.6 following gluteal administration and 1.7 following deltoid administration.

The plasma protein binding of racemic paliperidone is 74%.

Following administration of TREVICTA, the (+) and (-) enantiomers of paliperidone interconvert,reaching an AUC (+) to (-) ratio of approximately 1.7-1.8.

In a study with oral immediate release 14C-paliperidone, one week following administration of a singleoral dose of 1 mg immediate release 14C-paliperidone, 59% of the dose was excreted unchanged intourine, indicating that paliperidone is not extensively metabolised in the liver. Approximately 80% ofthe administered radioactivity was recovered in urine and 11% in the faeces. Four metabolic pathwayshave been identified in vivo, none of which accounted for more than 10% of the dose: dealkylation,hydroxylation, dehydrogenation, and benzisoxazole scission. Although in vitro studies suggested arole for CYP2D6 and CYP3A4 in the metabolism of paliperidone, there is no evidence in vivo thatthese isozymes play a significant role in the metabolism of paliperidone. Population pharmacokineticsanalyses indicated no discernible difference on the apparent clearance of paliperidone afteradministration of oral paliperidone between extensive metabolisers and poor metabolisers of CYP2D6substrates. In vitro studies in human liver microsomes showed that paliperidone does not substantiallyinhibit the metabolism of medicines metabolised 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.

Based on population pharmacokinetic analysis, the median apparent half-life of paliperidone following

TREVICTA administration over the dose range of 175-525 mg ranged from 84-95 days followingdeltoid injections and 118-139 days following gluteal injections.

Long-acting 3-monthly paliperidone palmitate injection versus other paliperidone formulations

TREVICTA is designed to deliver paliperidone over a 3-month period, while 1-monthly paliperidonepalmitate injection is administered on a monthly basis. TREVICTA, when administered at doses thatare 3.5-fold higher than the corresponding dose of 1-monthly paliperidone palmitate injection (seesection 4.2), results in paliperidone exposures similar to those obtained with corresponding monthlydoses of 1-monthly paliperidone palmitate injection and corresponding once daily doses ofpaliperidone prolonged release tablets. The exposure range for TREVICTA is encompassed within theexposure range for the approved dose strengths of paliperidone prolonged release tablets.

Paliperidone is not extensively metabolised in the liver. Although TREVICTA was not studied inpatients with hepatic impairment, no dose adjustment is required in patients with mild or moderatehepatic impairment. 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.

TREVICTA has not been systematically studied in patients with renal impairment. The disposition ofa single oral dose of a paliperidone 3 mg prolonged release tablet was studied in subjects with varyingdegrees of renal function. Elimination of paliperidone decreased with decreasing estimated creatinineclearance. Total clearance of paliperidone was reduced in subjects with impaired renal function by32% 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 an averageincrease in exposure (AUCinf) of 1.5, 2.6, and 4.8-fold, respectively, compared to healthy subjects.

Population pharmacokinetics analysis showed no evidence of age related pharmacokineticsdifferences.

Body mass index (BMI)/body weight

Lower Cmax was observed in overweight and obese subjects. At apparent steady-state with

TREVICTA, the trough concentrations were similar among normal, overweight, and obese subjects.

Population pharmacokinetics analysis showed no evidence of race related pharmacokineticsdifferences.

Population pharmacokinetics analysis showed no evidence of gender related pharmacokineticsdifferences.

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 TREVICTA. 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 is notlikely to be of clinical relevance.

Repeat-dose toxicity studies of intramuscularly injected paliperidone palmitate (the 1-monthlyformulation) 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 to2.2 times the exposure level in humans at the maximum recommended dose of 525 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 0.6 and 1.2 times the exposure level at the maximum recommendedhuman 525 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

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

This medicinal product does not require any special storage conditions.

175 mg0.88 mL suspension in a pre-filled syringe (cyclic-olefin-copolymer) with a plunger stopper, backstop,and tip cap (bromobutyl rubber) with a thin wall 22G 1½ inch (0.72 mm x 38.1 mm) safety needle anda thin wall 22G 1 inch (0.72 mm x 25.4 mm) safety needle.

263 mg1.32 mL suspension in a pre-filled syringe (cyclic-olefin-copolymer) with a plunger stopper, backstop,and tip cap (bromobutyl rubber) with a thin wall 22G 1½ inch (0.72 mm x 38.1 mm) safety needle anda thin wall 22G 1 inch (0.72 mm x 25.4 mm) safety needle.

350 mg1.75 mL suspension in a pre-filled syringe (cyclic-olefin-copolymer) with a plunger stopper, backstop,and tip cap (bromobutyl rubber) with a thin wall 22G 1½ inch (0.72 mm x 38.1 mm) safety needle anda thin wall 22G 1 inch (0.72 mm x 25.4 mm) safety needle.

525 mg2.63 mL suspension in a pre-filled syringe (cyclic-olefin-copolymer) with a plunger stopper, backstop,and tip cap (bromobutyl rubber) with a thin wall 22G 1½ inch (0.72 mm x 38.1 mm) safety needle anda thin wall 22G 1 inch (0.72 mm x 25.4 mm) safety needle.

Pack contains 1 pre-filled syringe and 2 needles

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

Full instructions for use and handling of TREVICTA are provided in the package leaflet (See

Information intended for medical or healthcare professionals).

Janssen-Cilag International NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

EU/1/14/971/007

EU/1/14/971/008

EU/1/14/971/009

EU/1/14/971/010

Date of first authorisation: 05 December 2014

Date of latest renewal:

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

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