Trevicta(paliperidone palmitate)注射用缓释混悬液为每三月注射一次用于治疗精神分裂症 欧盟委员会批准杨森旗下 Trevicta（棕榈酸帕利哌酮一种3个月注射一次的注射剂）用于精神分裂症成年患者的维持治疗。Trevicta 在欧盟将使一款抗精神病药物可以提供最长的给药间隔，与目前可供使用的该抗精神病药物的制剂相比，这将允许患者以更少的给药频次使其血液中保持最佳水平的治疗药物。 棕榈酸帕利哌酮的新制剂可以改善患者、照看人及医疗保健专业人员的结局。Trevicta在临床上旨在对Xeplion稳定的成年患者中用于精神分裂症维持治疗，Xeplion是一种1个月用药一次的棕榈酸帕利哌酮产品，其于2011年在欧盟获批用于精神分裂症维持治疗。 Trevicta(paliperidone palmitate a 3-monthly injection) TREVICTA 175mg, 263mg, 350mg, 525mg prolonged release suspension for injection 1. Name of the medicinal product 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 2. Qualitative and quantitative composition 175 mg prolonged release suspension for injection Each pre-filled syringe contains 273 mg paliperidone palmitate equivalent to 175 mg paliperidone. 263 mg prolonged release suspension for injection Each pre-filled syringe contains 410 mg paliperidone palmitate equivalent to 263 mg paliperidone. 350 mg prolonged release suspension for injection Each pre-filled syringe contains 546 mg paliperidone palmitate equivalent to 350 mg paliperidone. 525 mg prolonged release suspension for injection Each pre-filled syringe contains 819 mg paliperidone palmitate equivalent to 525 mg paliperidone. For the full list of excipients, see section 6.1. 3. Pharmaceutical form Prolonged release suspension for injection. The suspension is white to off-white. The suspension is pH neutral (approximately 7.0). 4. Clinical particulars 4.1 Therapeutic indications TREVICTA, a 3-monthly injection, is indicated for the maintenance treatment of schizophrenia in adult patients who are clinically stable on 1-monthly paliperidone palmitate injectable product (see section 5.1). 4.2 Posology and method of administration Posology Patients who are adequately treated with 1-monthly paliperidone palmitate injectable (preferably for four months or more) and do not require dose adjustment may be switched to TREVICTA. TREVICTA should be initiated in place of the next scheduled dose of 1-monthly paliperidone palmitate injectable (± 7 days). The TREVICTA dose should be based on the previous 1-monthly paliperidone palmitate injectable dose using a 3.5-fold higher dose shown in the following table: There is no equivalent dose of TREVICTA for the 25 mg dose of 1-monthly paliperidone palmitate injectable which was not studied. Following the initial TREVICTA dose, TREVICTA should be administered by intramuscular injection once 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 range of 175 mg to 525 mg based on individual patient tolerability and/or efficacy. Due to the long-acting nature of TREVICTA, the patient's response to an adjusted dose may not be apparent for several months (see section 5.2). If the patient remains symptomatic, they should be managed according to clinical practice. Switching from other antipsychotic medicinal products TREVICTA is to be used only after the patient has been adequately treated with 1-monthly paliperidone palmitate injectable preferably for four months or more. 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-monthly paliperidone palmitate injectable should be administered at the time the next TREVICTA dose was to be administered using a 3.5-fold lower dose shown in the following table. The initiation dosing as described in the prescribing information for 1-monthly paliperidone palmitate injectable is not required. The 1-monthly paliperidone palmitate injectable should then continue to be dosed at monthly intervals as described within its prescribing information. Doses of 1-monthly paliperidone palmitate injectable for patients switching from TREVICTA Switching from TREVICTA to oral daily paliperidone prolonged release tablets For switching from TREVICTA to paliperidone prolonged release tablets, the daily dosing of paliperidone prolonged release tablets should be started 3 months after the last TREVICTA dose and treatment continued with paliperidone prolonged release tablets as described in the table below. The following table provides recommended dose conversion regimens to allow patients previously stabilised on different doses of TREVICTA to attain similar paliperidone exposure with paliperidone prolonged release tablets. * All doses of once daily paliperidone prolonged release tablets should be individualised to the specific patient, taking into consideration variables such as reasons for switching, response to previous paliperidone treatment, severity of psychotic symptoms, and/or propensity for side effects. Missed dose Dosing window TREVICTA should be injected once every 3 months. To avoid a missed dose of TREVICTA patients may be given the injection up to 2 weeks before or after the 3-month time point. Recommended re-initiation regimen after missing 4 months to 9 months of TREVICTA a See also Information intended for medical or healthcare professionals for deltoid injection needle selection based on body weight. Special populations Elderly 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 the same as for younger adult patients with normal renal function. As elderly patients may have reduced renal function, see Renal impairment below for dosing recommendations in patients with renal impairment. Renal impairment TREVICTA has not been systematically studied in patients with renal impairment (see section 5.2). For patients with mild renal impairment (creatinine clearance ≥ 50 to < 80 ml/min), dose should be adjusted and the patient stabilised using 1-monthly paliperidone palmitate injectable, and then transitioned to TREVICTA. TREVICTA is not recommended in patients with moderate or severe renal impairment (creatinine clearance < 50 ml/min). Hepatic impairment TREVICTA has not been studied in patients with hepatic impairment. Based on experience with oral paliperidone, no dose adjustment is required in patients with mild or moderate hepatic impairment. As paliperidone has not been studied in patients with severe hepatic impairment, caution is recommended in such patients. (See section 5.2). Paediatric population The safety and efficacy of TREVICTA in children and adolescents < 18 years of age have not been established. No data are available. Method of administration TREVICTA is intended for intramuscular use only. It must not be administered by any other route. Each injection must be administered only by a health care professional giving the full dose in a single injection. It should be injected slowly, deep into the deltoid or gluteal muscle. A switch from gluteal to deltoid (and vice versa) should be considered for future injection in the event of injection site discomfort (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 other commercially available needles must not be used when administering TREVICTA (see Information intended for medical or health care professionals). The contents of the pre-filled syringe should be inspected visually for foreign matter and discolouration prior to administration. It is important to shake the syringe vigorously with the tip up and a loose wrist for at least 15 seconds to ensure a homogeneous suspension. TREVICTA should be administered within 5 minutes after shaking. If more than 5 minutes pass before injection, shake vigorously again for at least 15 seconds to re-suspend the medicinal product. (See Information intended for medical or health care professionals). Deltoid muscle administration The specified needle for administration of TREVICTA into the deltoid muscle is determined by the patient'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 alternated between the two deltoid muscles. Gluteal muscle administration The needle to be used for administration of TREVICTA into the gluteal muscle is the thin wall 1½ inch, 22 gauge (0.72 mm x 38.1 mm) needle regardless of body weight. It should be administered into the upper-outer quadrant of the gluteal muscle. Gluteal injections should be alternated between the two gluteal muscles. Incomplete administration To avoid incomplete administration of TREVICTA, the pre-filled syringe must be shaken vigorously for at least 15 seconds within 5 minutes prior to administration to ensure a homogeneous suspension (see Information intended for medical or health care professionals). However, in the event of an incompletely injected dose, the dose remaining in the syringe should not be re-injected and another dose should not be given since it is difficult to estimate the proportion of the dose actually administered. The patient should be closely monitored and managed as clinically appropriate until the next scheduled 3-monthly injection of TREVICTA. 4.3 Contraindications Hypersensitivity to the active substance, to risperidone or to any of the excipients listed in section 6.1. 4.4 Special warnings and precautions for use 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 when immediate symptom control is warranted. QT interval Caution should be exercised when paliperidone is prescribed in patients with known cardiovascular disease or family history of QT prolongation, and in concomitant use with other medicinal products thought to prolong the QT interval. Neuroleptic malignant syndrome Neuroleptic Malignant Syndrome (NMS), characterised by hyperthermia, muscle rigidity, autonomic instability, altered consciousness, and elevated serum creatine phosphokinase levels has been reported to occur with paliperidone. Additional clinical signs may include myoglobinuria (rhabdomyolysis) and acute renal failure. If a patient develops signs or symptoms indicative of NMS, paliperidone should be discontinued. Consideration should be given to the long-acting nature of TREVICTA. Tardive dyskinesia Medicinal products with dopamine receptor antagonistic properties have been associated with the induction of tardive dyskinesia characterised by rhythmical, involuntary movements, predominantly of the tongue and/or face. If signs and symptoms of tardive dyskinesia appear, the discontinuation of all antipsychotics, including paliperidone, should be considered. Consideration should be given to the long-acting nature of TREVICTA. Leucopenia, neutropenia, and agranulocytosis Events of leucopenia, neutropenia, and agranulocytosis have been reported with paliperidone. Patients with a history of a clinically significant low white blood cell count (WBC) or a drug-induced leucopenia/neutropenia should be monitored during the first few months of therapy and discontinuation of TREVICTA 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 should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count < 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 Hypersensitivity reactions can occur even in patients who have previously tolerated oral risperidone or oral paliperidone (see section 4.8). Hyperglycaemia and diabetes mellitus Hyperglycaemia, diabetes mellitus, and exacerbation of pre-existing diabetes, including diabetic coma and ketoacidosis, have been reported with paliperidone. Appropriate clinical monitoring is advisable in accordance with utilised antipsychotic guidelines. Patients treated with TREVICTA should be monitored for symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia, and weakness) and patients with diabetes mellitus should be monitored regularly for worsening of glucose control. Weight gain Significant weight gain has been reported with TREVICTA 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 by prolactin. Although no clear association with the administration of antipsychotics has so far been demonstrated in clinical and epidemiological studies, caution is recommended in patients with relevant medical history. Paliperidone should be used with caution in patients with a pre-existing tumour that may be prolactin-dependent. Orthostatic hypotension Paliperidone may induce orthostatic hypotension in some patients based on its alpha-adrenergic blocking activity. In the clinical trials of TREVICTA, 0.3% of subjects reported orthostatic hypotension related adverse reaction. TREVICTA should be used with caution in patients with known cardiovascular disease (e.g., heart failure, myocardial infarction or ischaemia, conduction abnormalities), cerebrovascular disease, or conditions that predispose the patient to hypotension (e.g., dehydration and hypovolemia). Seizures TREVICTA should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold. Renal impairment The plasma concentrations of paliperidone are increased in patients with renal impairment. For patients with mild renal impairment (creatinine clearance ≥ 50 ml/min to < 80 ml/min), dose should be adjusted and the patient stabilised using 1-monthly paliperidone palmitate injectable, then transitioned to TREVICTA. TREVICTA is not recommended in patients with moderate or severe renal impairment (creatinine clearance < 50 ml/min). (See sections 4.2 and 5.2). Hepatic impairment No data are available in patients with severe hepatic impairment (Child-Pugh class C). Caution is recommended if paliperidone is used in such patients. Elderly patients with dementia TREVICTA has not been studied in elderly patients with dementia. TREVICTA is not recommended to treat elderly patients with dementia due to increased risk of overall mortality and cerebrovascular adverse reactions. The experience from risperidone cited below is considered valid also for paliperidone. Overall mortality In a meta-analysis of 17 controlled clinical trials, elderly patients with dementia treated with other atypical antipsychotics, including risperidone, aripiprazole, olanzapine, and quetiapine had an increased risk of mortality compared to placebo. Among those treated with risperidone, the mortality was 4% compared with 3.1% for placebo. Cerebrovascular adverse reactions An approximately 3-fold increased risk of cerebrovascular adverse reactions has been seen in randomised placebo-controlled clinical trials in the dementia population with some atypical antipsychotics, including risperidone, aripiprazole, and olanzapine. The mechanism for this increased risk is not known. Parkinson's disease and dementia with Lewy bodies 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 risk of Neuroleptic Malignant Syndrome as well as having an increased sensitivity to antipsychotics. Manifestation of this increased sensitivity can include confusion, obtundation, postural instability with frequent falls, in addition to extrapyramidal symptoms. Priapism Antipsychotic medicinal products (including paliperidone) with alpha-adrenergic blocking effects have been reported to induce priapism. Patients should be informed to seek urgent medical care in case that priapism has not been resolved within 4 hours. Body temperature regulation Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic medicinal products. Appropriate care is advised when prescribing TREVICTA to patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medicinal products with anticholinergic activity or being subject to dehydration. Venous thromboembolism 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 possible risk factors for VTE should be identified before and during treatment with TREVICTA and preventative measures undertaken. Antiemetic effect An antiemetic effect was observed in preclinical studies with paliperidone. This effect, if it occurs in humans, may mask the signs and symptoms of overdosage with certain medicinal products or of conditions such as intestinal obstruction, Reye's syndrome and brain tumour. Administration 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 patients treated with medicinal products with alpha 1a-adrenergic antagonist effect, such as TREVICTA (see section 4.8). IFIS may increase the risk of eye complications during and after the operation. Current or past use of medicinal products with alpha 1a-adrenergic antagonist effect should be made known to the ophthalmic surgeon in advance of surgery. The potential benefit of stopping alpha 1 blocking therapy prior to cataract surgery has not been established and must be weighed against the risk of stopping the antipsychotic therapy. 4.5 Interaction with other medicinal products and other forms of interaction Caution is advised when prescribing TREVICTA with medicinal products known to prolong the QT interval, e.g., class IA antiarrhythmics (e.g., quinidine, disopyramide) and class III antiarrhythmics (e.g., amiodarone, sotalol), some antihistaminics, some antibiotics (e.g., fluoroquinolones), some other antipsychotics 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 medicinal products that are metabolised by cytochrome P450 isozymes. Given the primary central nervous system (CNS) effects of paliperidone (see section 4.8), TREVICTA should 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 combination is deemed necessary, particularly in end-stage Parkinson's disease, the lowest effective dose of each treatment should be prescribed. Because of its potential for inducing orthostatic hypotension (see section 4.4), an additive effect may be observed when TREVICTA 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 the seizure 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 the steady-state pharmacokinetics of valproate. No interaction study between TREVICTA and lithium has been performed, however, a pharmacokinetic 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 paliperidone metabolism, but there are no indications in vitro nor in vivo that these isozymes play a significant role in the metabolism of paliperidone. Concomitant administration of oral paliperidone with paroxetine, a potent CYP2D6 inhibitor, showed no clinically significant effect on the pharmacokinetics of paliperidone. Co-administration of oral paliperidone prolonged release once daily with carbamazepine 200 mg twice daily 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 paliperidone likely as a result of induction of renal P-gp by carbamazepine. A minor decrease in the amount of active substance excreted unchanged in the urine suggests that there was little effect on the CYP metabolism or bioavailability of paliperidone during carbamazepine co-administration. Larger decreases 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 if necessary. Conversely, on discontinuation of carbamazepine, the dose of TREVICTA should be re-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 with divalproex sodium prolonged release tablets (two 500 mg tablets once daily) resulted in an increase of approximately 50% in the Cmax and AUC of paliperidone, likely as a result of increased oral absorption. Since no effect on the systemic clearance was observed, a clinically significant interaction would not be expected between divalproex sodium prolonged release tablets and TREVICTA intramuscular 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 of time. Safety data involving concomitant use of TREVICTA with other antipsychotics is limited. 4.6 Fertility, pregnancy and lactation Pregnancy There are no adequate data from the use of paliperidone during pregnancy. Intramuscularly injected paliperidone palmitate and orally administered paliperidone were not teratogenic in animal studies, but other types of reproductive toxicity were seen (see section 5.3). Neonates exposed to paliperidone during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully. 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. Breast-feeding Paliperidone is excreted in the breast milk to such an extent that effects on the breast-fed infant are likely if therapeutic doses are administered to breast-feeding women. Since paliperidone has been detected in plasma up to 18 months after a single dose administration of TREVICTA, consideration should 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 while breast-feeding. Fertility There were no relevant effects observed in the non-clinical studies. 4.7 Effects on ability to drive and use machines Paliperidone can have minor or moderate influence on the ability to drive and use machines due to potential nervous system and visual effects, such as sedation, somnolence, syncope, vision blurred (see section 4.8). Therefore, patients should be advised not to drive or operate machines until their individual susceptibility to TREVICTA is known. 4.8 Undesirable effects Summary of the safety profile The most frequently observed adverse drug reactions reported in ≥ 5% of patients in two double-blind controlled clinical trials of TREVICTA were weight increased, upper respiratory tract infection, anxiety, headache, insomnia, and injection site reaction. Tabulated list of adverse reactions The following are all ADRs that were reported with paliperidone by frequency category estimated from TREVICTA and 1-monthly paliperidone palmitate injectable 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 the available data). a The frequency of adverse reactions reported during post-marketing use cannot be determined as they are derived from spontaneous reports. Consequently, the frequency of these adverse events is qualified as 'not known'. b Refer to 'Hyperprolactinaemia' below. c Refer to 'Extrapyramidal symptoms' below. d Insomnia includes: initial insomnia, middle insomnia; Convulsion includes: convulsion, grand mal convulsion; Menstrual disorder includes: menstrual disorder, menstruation delayed, menstruation irregular, oligomenorrhoea; Oedema includes: generalised oedema, oedema, oedema peripheral, pitting oedema. Undesirable effects noted with risperidone formulations Paliperidone is the active metabolite of risperidone, therefore, the adverse reaction profiles of these compounds (including both the oral and injectable formulations) are relevant to one another. Description of selected adverse reactions Anaphylactic reaction Rarely, cases of anaphylactic reaction after injection with 1-monthly paliperidone palmitate injectable have been reported during post-marketing experience in patients who have previously tolerated oral risperidone or oral paliperidone (see section 4.4). Injection site reactions In clinical trials of TREVICTA, 5.3% of subjects reported injection site related adverse reaction. None of 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 site pain based on a visual analogue scale was low and decreased in intensity over time. Extrapyramidal symptoms (EPS) In the clinical trials of TREVICTA, akathisia, dyskinesia, dystonia, parkinsonism, and tremor were reported 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's disease, 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 rest tremor), akathisia (includes akathisia, restlessness, hyperkinesia, and restless leg syndrome), dyskinesia (dyskinesia, chorea, movement disorder, muscle twitching, choreoathetosis, athetosis, and myoclonus), dystonia (includes dystonia, cervical spasm, emprosthotonus, oculogyric crisis, oromandibular dystonia, risus sardonicus, tetany, hypertonia, torticollis, muscle contractions involuntary, muscle contracture, blepharospasm, oculogyration, tongue paralysis, facial spasm, laryngospasm, myotonia, opisthotonus, oropharyngeal spasm, pleurothotonus, tongue spasm, and trismus), and tremor. Weight gain In the long-term randomised withdrawal study, abnormal increases of ≥ 7% in body weight from double-blind baseline to double-blind end point were reported for 10% subjects in the TREVICTA group 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 TREVICTA group and 8% subjects in the placebo group. The mean changes in body weight from double-blind baseline to double-blind end point were +0.94 kg and -1.28 kg for the TREVICTA and placebo groups, respectively. Hyperprolactinaemia During the double-blind phase of the long-term randomised withdrawal study, elevations of prolactin to above the reference range (> 13.13 ng/ml in males and > 26.72 ng/ml in females) were noted in a higher 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-blind baseline 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 prolactin related adverse reactions were noted among females in the placebo group. There were no potentially prolactin related adverse reactions among males in either group. Class effects QT prolongation, ventricular arrhythmias (ventricular fibrillation, ventricular tachycardia), sudden unexplained death, cardiac arrest, and Torsade de pointes may occur with antipsychotics. Cases of VTE, including cases of pulmonary embolism and cases of deep vein thrombosis, have been reported with antipsychotic medicinal products. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medical product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via: United Kingdom Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard. Ireland HPRA Pharmacovigilance Earlsfort Terrace IRL - Dublin 2 Tel: +353 1 6764971 Fax: +353 1 6762517 Website: www.hpra.ie E-mail: medsafety@hpra.ie 4.9 Overdose Symptoms In general, expected signs and symptoms are those resulting from an exaggeration of paliperidone's known pharmacological effects, i.e., drowsiness and sedation, tachycardia and hypotension, QT prolongation, and extrapyramidal symptoms. Torsade de pointes and ventricular fibrillation have been reported 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. Management Consideration should be given to the long-acting nature of the medicinal product and the long elimination half-life of paliperidone when assessing treatment needs and recovery. There is no specific antidote to paliperidone. General supportive measures should be employed. Establish and maintain a clear airway and ensure adequate oxygenation and ventilation. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring for possible arrhythmias. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluid and/or sympathomimetic agents. In case of severe extrapyramidal symptoms, anticholinergic agents should be administered. Close supervision and monitoring should continue until the patient recovers. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Psycholeptics, other antipsychotics. ATC code: N05AX13 TREVICTA contains a racemic mixture of (+)- and (-)-paliperidone. Mechanism of action Paliperidone is a selective blocking agent of monoamine effects, whose pharmacological properties are different from that of traditional neuroleptics. Paliperidone binds strongly to serotonergic 5-HT2- and dopaminergic D2-receptors. Paliperidone also blocks alpha 1-adrenergic receptors and slightly less, 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 and decreases motor functions less than traditional neuroleptics. Dominating central serotonin antagonism may reduce the tendency of paliperidone to cause extrapyramidal side effects. Clinical efficacy The efficacy of TREVICTA in the maintenance treatment of schizophrenia in subjects who have been adequately treated for at least four months with 1-monthly paliperidone palmitate injectable and the last two doses of the same dosage strength was evaluated in one long-term randomised withdrawal double-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 for schizophrenia were enrolled into the open-label transition phase and treated with flexible doses of the 1-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 then received a single dose of TREVICTA in either the deltoid or gluteal muscle in the open-label stabilisation 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 then randomised 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 remained fixed throughout the double-blind phase). In this period, 305 symptomatically stable subjects were randomised to continue treatment with TREVICTA (n = 160) or placebo (n = 145) until relapse, early withdrawal, or the end of study. The primary efficacy variable was time to first relapse. A pre-planned interim analysis conducted when 283 subjects had been randomised and 42 relapse events had been observed, showed a statistically significantly longer time to relapse (p < 0.001) in subjects treated with TREVICTA compared to placebo. Twenty-three percent (23%) of subjects in the placebo group and 7.4% of subjects in the TREVICTA group experienced a relapse event. The study was terminated on the basis of these efficacy results. The hazard ratio was 3.45 (95% CI: 1.73, 6.88) indicating a 71% decrease in relapse risk with TREVICTA compared to placebo. A Kaplan-Meier plot of time to relapse by treatment group is shown in Figure 1. Also depicted is the time to relapse of the placebo group (median 274 days), which was significantly shorter than for the TREVICTA group (the median could not be estimated due to the low percentage of subjects with relapse [7.4%]). Figure 1: Kaplan-Meier plot of time to relapse – Interim analysis In the non-inferiority study, 1,429 acutely ill subjects (baseline mean PANSS total score: 85.7) who met DSM-IV criteria for schizophrenia were enrolled into the open-label phase and treated with 1-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 or gluteal. For subjects that met randomisation criteria at weeks 14 and 17, 1,016 were randomised in a 1:1 ratio to continue on monthly injections of 1-monthly paliperidone palmitate injectable or to switch to TREVICTA with a 3.5 multiple of the week 9 and 13 dose of 1-monthly paliperidone palmitate injectable for 48 weeks. Subjects received TREVICTA once every 3 months and received placebo-injectable medication for the other months to maintain the blind. The primary efficacy endpoint of the study was the percentage of subjects who had not relapsed at the end of the 48-week double-blind phase based on the Kaplan-Meier 48-week estimate (TREVICTA: 91.2%, 1-monthly paliperidone palmitate injectable: 90.0%). The median time to relapse in either group could not be estimated due to low percentage of subjects with relapse. The difference (95% CI) between the treatment 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 palmitate injectable. 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 the double-blind phase for both treatment groups. Figure 2: Kaplan-Meier plot of time to relapse comparing TREVICTA and 1-monthly paliperidone palmitate injectable The efficacy results were consistent across population subgroups (gender, age, and race) in both studies. Paediatric population 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 for information on paediatric use. 5.2 Pharmacokinetic properties Absorption and distribution Due to its extremely low water solubility, the 3-monthly formulation of paliperidone palmitate dissolves slowly after intramuscular injection before being hydrolysed to paliperidone and absorbed into the systemic circulation. The release of the active substance starts as early as day 1 and lasts for as long as 18 months. The data presented in this paragraph are based on a population pharmacokinetic analysis. Following a single intramuscular dose of TREVICTA, the plasma concentrations of paliperidone gradually rise to reach maximum plasma concentrations at a median Tmax of 30-33 days. Following intramuscular injection 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 dosing regimen of TREVICTA results in sustained therapeutic concentrations. The total exposure of paliperidone following TREVICTA administration was dose-proportional over a 175-525 mg dose range, 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. Biotransformation and elimination In a study with oral immediate release 14C-paliperidone, 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 extensively metabolised in the liver. Approximately 80% of the administered radioactivity was recovered in urine and 11% in the faeces. Four metabolic pathways have 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 a role for CYP2D6 and CYP3A4 in the metabolism of paliperidone, there is no evidence in vivo that these isozymes play a significant role in the metabolism of paliperidone. Population pharmacokinetics analyses indicated no discernible difference on the apparent clearance of paliperidone after administration of oral paliperidone between extensive metabolisers and poor metabolisers of CYP2D6 substrates. In vitro studies in human liver microsomes showed that paliperidone does not substantially inhibit 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 high concentrations. 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 following deltoid 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 paliperidone palmitate injection is administered on a monthly basis. TREVICTA, when administered at doses that are 3.5-fold higher than the corresponding dose of 1-monthly paliperidone palmitate injection (see section 4.2), results in paliperidone exposures similar to those obtained with corresponding monthly doses of 1-monthly paliperidone palmitate injection and corresponding once daily doses of paliperidone prolonged release tablets. The exposure range for TREVICTA is encompassed within the exposure range for the approved dose strengths of paliperidone prolonged release tablets. Hepatic impairment Paliperidone is not extensively metabolised in the liver. Although TREVICTA was not studied in patients with hepatic impairment, no dose adjustment is required in patients with mild or moderate hepatic 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 healthy subjects. Paliperidone has not been studied in patients with severe hepatic impairment. Renal impairment TREVICTA has not been systematically studied in patients with renal impairment. The disposition of a single oral dose of a paliperidone 3 mg prolonged release tablet was studied in subjects with varying degrees of renal function. Elimination of paliperidone decreased with decreasing estimated creatinine clearance. Total clearance of paliperidone was reduced in subjects with impaired renal 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 an average increase in exposure (AUCinf) of 1.5, 2.6, and 4.8-fold, respectively, compared to healthy subjects. Elderly Population pharmacokinetics analysis showed no evidence of age related pharmacokinetics differences. 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. Race Population pharmacokinetics analysis showed no evidence of race related pharmacokinetics differences. Gender Population pharmacokinetics analysis showed no evidence of gender related pharmacokinetics differences. Smoking status 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 of smoking on the pharmacokinetics of paliperidone was not studied with TREVICTA. A population pharmacokinetic analysis based on data with oral paliperidone prolonged release tablets showed a slightly lower exposure to paliperidone in smokers compared with non-smokers. The difference is not likely to be of clinical relevance. 5.3 Preclinical safety data Repeat-dose toxicity studies of intramuscularly injected paliperidone palmitate (the 1-monthly formulation) and orally administered paliperidone in rat and dog showed mainly pharmacological effects, such as sedation and prolactin-mediated effects on mammary glands and genitals. In animals treated with paliperidone palmitate an inflammatory reaction was seen at the intramuscular injection site. Occasionally abscess formation occurred. In rat reproduction studies with oral risperidone, which is extensively converted to paliperidone in rats and humans, adverse effects were seen on the birth weight and survival of the offspring. No embryotoxicity or malformations were observed following intramuscular administration of paliperidone palmitate to pregnant rats up to the highest dose (160 mg/kg/day) corresponding to 2.2 times the exposure level in humans at the maximum recommended dose of 525 mg. Other dopamine antagonists, when administered to pregnant animals, have caused negative effects on learning and motor development in the offspring. Paliperidone palmitate and paliperidone were not genotoxic. In oral carcinogenicity studies of risperidone in rats and mice, increases in pituitary gland adenomas (mouse), endocrine pancreas adenomas (rat), and mammary gland adenomas (both species) were seen. The carcinogenic potential of intramuscularly injected paliperidone palmitate was assessed in rats. There was a statistically significant 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 at 30 and 60 mg/kg/month which is 0.6 and 1.2 times the exposure level at the maximum recommended human 525 mg dose. These tumours can be related to prolonged dopamine D2-antagonism and hyperprolactinemia. The relevance of these tumour findings in rodents in terms of human risk is unknown. 6. Pharmaceutical particulars 6.1 List of excipients Polysorbate 20 Polyethylene glycol 4000 Citric acid monohydrate Sodium dihydrogen phosphate monohydrate Sodium hydroxide (for pH adjustment) Water for injections 6.2 Incompatibilities This medicinal product must not be mixed with other medicinal products. 6.3 Shelf life 2 years 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container 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 and a thin wall 22G 1 inch (0.72 mm x 25.4 mm) safety needle. Pack sizes: Pack contains 1 pre-filled syringe and 2 needles 6.6 Special precautions for disposal and other handling 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 health care professionals). 7. Marketing authorisation holder Janssen-Cilag International NV Turnhoutseweg 30 B-2340 Beerse Belgium 8. Marketing authorisation number(s) EU/1/14/971/007 EU/1/14/971/008 EU/1/14/971/009 EU/1/14/971/010 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 05 December 2014 10. Date of revision of the text 26 May 2016 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. http://www.medicines.org.uk/emc/medicine/32050