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 association with overdose. In the case of acute overdosage, the possibility of multiple medicinal product involvement should be considered.
Consideration should be given to the prolonged-release nature of the product 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. Administration of activated charcoal together with a laxative should be considered. In case of severe extrapyramidal symptoms, anticholinergic agents should be administered. Close supervision and monitoring should continue until the patient recovers.
Not applicable
Adults
Summary of the safety profile
The adverse drug reactions (ADRs) most frequently reported in clinical trials with adults were headache, insomnia, sedation/somnolence, parkinsonism, akathisia, tachycardia, tremor, dystonia, upper respiratory tract infection, anxiety, dizziness, weight increased, nausea, agitation, constipation, vomiting, fatigue, depression, dyspepsia, diarrhoea, dry mouth, toothache, musculoskeletal pain, hypertension, asthenia, back pain, electrocardiogram QT prolonged, and cough.
The ADRs that appeared to be dose-related included headache, sedation/somnolence, parkinsonism, akathisia, tachycardia, dystonia, dizziness, tremor, upper respiratory tract infection, dyspepsia, and musculoskeletal pain.
In the schizoaffective disorder studies, a greater proportion of subjects in the total Инвега dose group who were receiving concomitant therapy with an antidepressant or mood stabiliser experienced adverse events as compared to those subjects treated with Инвега monotherapy.
Tabulated list of adverse reactions
The following are all the ADRs that were reported in clinical trials and postmarketing experience with paliperidone by frequency category estimated from Инвега clinical trials in adults. The following terms and frequencies are applied: very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1000 to < 1/100), rare (> 1/10,000 to < 1/1000), very rare (< 1/10,000), and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
| System Organ Class | Adverse Drug Reaction | ||||
| Frequency | |||||
| Very common | Common | Uncommon | Rare | Not known | |
| Infections and infestations | bronchitis, upper respiratory tract infection, sinusitis, urinary tract infection, influenza | pneumonia, respiratory tract infection, cystitis, ear infection, tonsillitis | eye infection, onychomycosis, cellulitis, acarodermatitis | ||
| Blood and lymphatic system disorders | white blood cell count decreased, thrombocytopenia, anaemia, haematocrit decreased | agranulocytosisc, neutropenia, eosinophil count increased | |||
| Immune system disorders | anaphylactic reaction, hypersensitivity | ||||
| Endocrine disorders | hyperprolactinaemiaa | inappropriate antidiuretic hormone secretionc, glucose urine present | |||
| Metabolism and nutrition disorders | weight increased, increased appetite, weight decreased, decreased appetite | diabetes mellitusd, hyperglycaemia, waist circumference increased, anorexia, blood triglycerides increased | water intoxication, diabetic ketoacidosisc, hypoglycaemia, polydipsia, blood cholesterol increased | hyperinsulinaemia | |
| Psychiatric disorders | insomniae | mania, agitation, depression, anxiety | sleep disorder, confusional state, libido decreased, anorgasmia, nervousness, nightmare | blunted affectc | |
| Nervous system disorders | parkinsonismb, akathisiab, sedation/ somnolence, headache | dystoniab, dizziness, dyskinesiab, tremorb | tardive dyskinesia, convulsione, syncope, psychomotor hyperactivity, dizziness postural, disturbance in attention, dysarthria, dysgeusia, hypoaesthesia, paresthaesia | neuroleptic malignant syndrome, cerebral ischaemia, unresponsive to stimulic, loss of consciousness, depressed level of consciousnessc, diabetic comac balance disorder, coordination abnormal, head titubationc | |
| Eye disorders | vision blurred | photophobia, conjunctivitis, dry eye | glaucoma, eye movement disorderc, eye rollingc, lacrimation increased, ocular hyperaemia | ||
| Ear and labyrinth disorders | vertigo, tinnitus, ear pain | ||||
| Cardiac disorders | atrioventricular block, conduction disorder, electrocardiogram QT prolonged, bradycardia, tachycardia | sinus arrhythmia, electrocardiogram abnormal, palpitations | atrial fibrillation, postural orthostatic tachycardia syndromec | ||
| Vascular disorders | orthostatic hypotension, hypertension | hypotension | pulmonary embolism, venous thrombosis, ischaemia, flushing | ||
| Respiratory, thoracic and mediastinal disorders | pharyngolaryngeal pain, cough, nasal congestion | dyspnoea, wheezing, epistaxis | sleep apnoea syndrome, hyperventilation, pneumonia aspiration, respiratory tract congestion, dysphonia | pulmonary congestion | |
| Gastrointestinal disorders | abdominal pain, abdominal discomfort, vomiting, nausea, constipation, diarrhoea, dyspepsia, dry mouth, toothache | swollen tongue, gastroenteritis, dysphagia, flatulence | pancreatitisc, intestinal obstruction, ileus, faecal incontinence, faecalomac, cheilitis | ||
| Hepatobiliary disorders | transaminases increased | gamma-glutamyltransferase increased, hepatic enzyme increased | jaundice | ||
| Skin and subcutaneous tissue disorders | pruritus, rash | urticaria, alopecia, eczema, acne | angioedema, drug eruptionc, hyperkeratosis, dry skin, erythema, skin discolouration, seborrhoeic dermatitis, dandruff | ||
| Musculoskeletal and connective tissue disorders | musculoskeletal pain, back pain, arthralgia | blood creatine phosphokinase increased, muscle spasms, joint stiffness, joint swelling, muscular weakness, neck pain | rhabdomyolysisc, posture abnormalc | ||
| Renal and urinary disorders | urinary incontinence, pollakiuria, urinary retention, dysuria | ||||
| Pregnancy, puerperium and perinatal conditions | drug withdrawal syndrome neonatal c | ||||
| Reproductive system and breast disorders | amenorrhoea | erectile dysfunction, ejaculation disorder, menstrual disordere, galactorrhoea, sexual dysfunction, breast pain, breast discomfort | priapismc, menstruation delayedc, gynaecomastia, breast engorgement, breast enlargementc, breast discharge, vaginal discharge | ||
| General disorders | pyrexia, asthenia, fatigue | face oedema, oedemae, chills, body temperature increased, gait abnormal, thirst, chest pain, chest discomfort, malaise | hypothermiac, body temperature decreasedc, drug withdrawal syndromec, indurationc | ||
| Injury, poisoning and procedural complications | fall | ||||
| a Refer to 'Hyperprolactinaemia' below. b Refer to 'Extrapyramidal symptoms' below. c Not observed in Инвега clinical studies but observed in post-marketing environment with paliperidone d In placebo-controlled pivotal trials, diabetes mellitus was reported in 0.05% in Инвега-treated subjects compared to a rate of 0% in placebo group. Overall incidence from all clinical trials was 0.14% in all Инвега-treated subjects e Insomnia includes: initial insomnia, middle insomnia; Convulsion includes: grand mal convulsion; Oedema includes: generalised oedema, oedema peripheral, pitting oedema. Menstrual disorder includes: menstruation irregular, oligomenorrhoea | |||||
Undesirable effects noted with risperidone formulations
Paliperidone is the active metabolite of risperidone, therefore, the adverse reaction profiles of these compounds (including both the oral and injectable formulations) are relevant to one another. In addition to the above adverse reactions, the following adverse reactions have been noted with the use of risperdone products and can be expected to occur with Инвега.
Nervous system disorders: cerebrovascular disorder
Eye disorders: floppy iris syndrome (intraoperative)
Respiratory, thoracic and mediastinal disorders: rales
Description of selected adverse reactions
Extrapyramidal symptoms (EPS)
In schizophrenia clinical trials, there was no difference observed between placebo and the 3 and 6 mg doses of Инвега. Dose dependence for EPS was seen with the two higher doses of Инвега (9 and 12 mg). In the schizoaffective disorder studies, the incidence of EPS was observed at a higher rate than placebo in all dose groups without a clear relationship to dose.
EPS included a pooled analysis of the following terms: Parkinsonism (includes salivary hypersecretion, musculoskeletal stiffness, parkinsonism, drooling, cogwheel rigidity, bradykinesia, hypokinesia, masked facies, muscle tightness, akinesia, nuchal rigidity, muscle rigidity, parkinsonian gait, and glabellar reflex abnormal, parkinsonian rest tremor), akathisia (includes akathisia, restlessness, hyperkinesia, and restless leg syndrome), dyskinesia (dyskinesia, muscle twitching, choreoathetosis, athetosis, and myoclonus), dystonia (includes dystonia, hypertonia, torticollis, muscle contractions involuntary, muscle contracture, blepharospasm, oculogyration, tongue paralysis, facial spasm, laryngospasm, myotonia, opisthotonus, oropharyngeal spasm, pleurothotonus, tongue spasm, and trismus), and tremor. It should be noted that a broader spectrum of symptoms are included that do not necessarily have an extrapyramidal origin.
Weight gain
In schizophrenia clinical trials, the proportions of subjects meeting a weight gain criterion of > 7% of body weight were compared, revealing a similar incidence of weight gain for Инвега 3 mg and 6 mg compared with placebo, and a higher incidence of weight gain for Инвега 9 mg and 12 mg compared with placebo.
In schizoaffective disorder clinical trials, a higher percentage of Инвега-treated subjects (5%) had an increase in body weight of > 7% compared with placebo-treated subjects (1%). In the study that examined two dose groups , the increase in body weight of > 7% was 3% in the lower-dose (3-6 mg) group, 7% in the higher-dose (9-12 mg) group, and 1% in the placebo group.
Hyperprolactinaemia
In schizophrenia clinical trials, increases in serum prolactin were observed with Инвега in 67% of subjects. Adverse reactions that may suggest increase in prolactin levels (e.g., amenorrhoea, galactorrhoea, menstrual disturbances, gynaecomastia) were reported overall in 2% of subjects. Maximum mean increases of serum prolactin concentrations were generally observed on Day 15 of treatment, but remained above baseline levels at study endpoint.
Class effects
QT prolongation, ventricular arrythmias (ventricular fibrillation, ventricular tachycardia), sudden unexplained death, cardiac arrest and Torsade de pointes may occur with antipsychotics. Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis have been reported with antipsychotic drugs - Frequency unknown.
Paliperidone is the active metabolite of risperidone. The safety profile of risperidone may be pertinent.
Elderly
In a study conducted in elderly subjects with schizophrenia, the safety profile was similar to that seen in non-elderly subjects. Инвега has not been studied in elderly patients with dementia. In clinical trials with some other atypical antipsychotics, increased risks of death and cerebrovascular accidents have been reported.
Paediatric population
Summary of the safety profile
In one short-term and two longer-term studies with paliperidone prolonged-release tablets conducted in adolescents 12 years and older with schizophrenia, the overall safety profile was similar to that seen in adults. In the pooled adolescent schizophrenia population (12 years and older, N = 545) exposed to Инвега, the frequency and type of undesirable effects were similar to those in adults except for the following ADRs that were reported more frequently in adolescents receiving Инвега than adults receiving Инвега (and more frequently than placebo): sedation/somnolence, parkinsonism, weight increase, upper respiratory tract infection, akathisia, and tremor were reported very commonly (> 1/10) in adolescents; abdominal pain, galactorrhoea, gynaecomastia, acne, dysarthria, gastroenteritis, epistaxis, ear infection, blood triglyceride increased, and vertigo were reported commonly (> 1/100, < 1/10) in adolescents.
Extrapyramidal Symptoms (EPS)
In the short-term, placebo-controlled, fixed-dose adolescent study, the incidence of EPS was higher than placebo for all doses of Инвега with an increased frequency of EPS at higher doses. Across all adolescent studies, EPS was more common in adolescents than in adults for each Инвега dose.
Weight gain
In the short-term, placebo-controlled, fixed-dose adolescent study, a higher percentage of Инвега-treated subjects (6-19% depending on dose) had an increase in body weight of >7% compared to placebo-treated subjects (2%). There was no clear dose relationship. In the long-term 2-year study, the subjects who were exposed to Инвега during both the double-blind and open-label studies reported a modest weight gain (4.9 kg).
In adolescents, weight gain should be assessed against that expected with normal growth.
Prolactin
In the up to 2-year, open-label treatment study of Инвега in adolescents with schizophrenia, incidence of elevated serum prolactin levels occurred in 48% of females and 60% of males. Adverse reactions that may suggest increase in prolactin levels (e.g., amenorrhoea, galactorrhoea, menstrual disturbances, gynaecomastia) were reported overall in 9.3% of subjects.
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
Repeat-dose toxicity studies of paliperidone in rat and dog showed mainly pharmacological effects, such as sedation and prolactin-mediated effects on mammary glands and genitals. Paliperidone was not teratogenic in rat and rabbit. In rat reproduction studies using risperidone, which is extensively converted to paliperidone in rats and humans, a reduction was observed in the birth weight and survival of the offspring. Other dopamine antagonists, when administered to pregnant animals, have caused negative effects on learning and motor development in the offspring. Paliperidone was not genotoxic in a battery of tests. In oral carcinogenicity studies of risperidone in rats and mice, increases in pituitary gland adenomas (mouse), endocrine pancreas adenomas (rat), and mammary gland adenomas (both species) were seen. 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.
In a 7-week juvenile toxicity study in rats administered oral doses of paliperidone up to 2.5 mg/kg/day, corresponding to an exposure approximately equal to the clinical exposure based on AUC, no effects on growth, sexual maturation and reproductive performance were observed. Paliperidone did not impair the neurobehavioural development in males at doses up to 2.5 mg/kg/day. At 2.5 mg/kg/day in females, an effect on learning and memory was observed. This effect was not observed after discontinuation of treatment. In a 40-week juvenile toxicity study in dogs with oral doses of risperidone (which is extensively converted to paliperidone) up to 5 mg/kg/day, effects on sexual maturation, long bone growth and femur mineral density were observed from 3 times the clinical exposure based on AUC.
Инвега is indicated for the treatment of schizophrenia in adults and in adolescents 15 years and older.
Инвега is indicated for the treatment of schizoaffective disorder in adults.
Pharmacologic group: Psycholeptics, other antipsychotics ATC code: N05AX13
Инвега 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 alfa1-adrenergic receptors and blocks, to a lesser extent, H1-histaminergic and alfa2-adrenergic receptors. The pharmacological activity of the (+)- and (-)-paliperidone enantiomers are qualitatively and quantitatively similar.
Paliperidone is not bound to cholinergic receptors. Even though paliperidone is a strong D2-antagonist, which is believed to relieve the positive symptoms of schizophrenia, it causes less catalepsy and decreases motor functions to a lesser extent than traditional neuroleptics. Dominating central serotonin antagonism may reduce the tendency of paliperidone to cause extrapyramidal side effects.
Clinical efficacy
Schizophrenia
The efficacy of Инвега in the treatment of schizophrenia was established in three multi-centre, placebo-controlled, double-blind, 6-week trials in subjects who met DSM-IV criteria for schizophrenia. Инвега doses, which varied across the three studies, ranged from 3 to 15 mg once daily. The primary efficacy endpoint was defined as a decrease in total Positive and Negative Syndrome Scale (PANSS) scores as shown in the following table. The PANSS is a validated multi-item inventory composed of five factors to evaluate positive symptoms, negative symptoms, disorganised thoughts, uncontrolled hostility/excitement, and anxiety/depression. All tested doses of Инвега separated from placebo on day 4 (p<0.05). Predefined secondary endpoints included the Personal and Social Performance (PSP) scale and the Clinical Global Impression - Severity (CGI-S) scale. In all three studies, Инвега was superior to placebo on PSP and CGI-S. Efficacy was also evaluated by calculation of treatment response (defined as decrease in PANSS Total Score > 30%) as a secondary endpoint.
| Schizophrenia Studies: Positive and Negative Syndrome Scale for Schizophrenia (PANSS) Total Score - Change From Baseline to End Point - LOCF for Studies R076477-SCH-303, R076477-SCH-304, and R076477-SCH-305: Intent-to-Treat Analysis Set | |||||
| Placebo | Инвега 3 mg | Инвега 6 mg | Инвега 9 mg | Инвега 12 mg | |
| R076477-SCH-303 Mean baseline (SD) Mean change (SD) P-value (vs, Placebo) Diff. of LS Means (SE) | (N=126) 94.1 (10.74) -4.1 (23.16) |
| (N=123) 94.3 (10.48) -17.9 (22.23) <0.001 -13.7 (2.63) | (N=122) 93.2 (11.90) -17.2 (20.23) <0.001 -13.5 (2.63) | (N=129) 94.6 (10.98) -23.3 (20.12) <0.001 -18.9 (2.60) |
| R076477-SCH-304 Mean baseline (SD) Mean change (SD) P-value (vs, Placebo) Diff. of LS Means (SE) | (N=105) 93.6 (11.71) -8.0 (21.48) |
| (N=111) 92.3 (11.96) -15.7 (18.89) 0.006 -7.0 (2.36) |
| (N=111) 94.1 (11.42) -17.5 (19.83) <0.001 -8.5 (2.35) |
| R076477-SCH-305 Mean baseline (SD) Mean change (SD) P-value (vs, Placebo) Diff. of LS Means (SE) | (N=120) 93.9 (12.66) -2.8 (20.89) | (N=123) 91.6 (12.19) -15.0 (19.61) <0.001 -11.6 (2.35) |
| (N=123) 93.9 (13.20) -16.3 (21.81) <0.001 -12.9 (2.34) |
|
| Note: Negative change in score indicates improvement. For all 3 studies, an active control (olanzapine at a dose of 10 mg) was included. LOCF = last observation carried forward. The 1-7 version of the PANSS was used. A 15 mg dose was also included in Study R076477-SCH-305, but results are not presented since this is above the maximum recommended daily dose of 12 mg. | |||||
| Schizophrenia Studies: Proportion of Subjects with Responder Status at LOCF End Point Studies R076477-SCH-303, R076477-SCH-304, and R076477-SCH-305: Intent-to-Treat Analysis Set | |||||
| Placebo | Инвега 3 mg | Инвега 6 mg | Инвега 9 mg | Инвега 12 mg | |
| R076477-SCH-303 N Responder, n (%) Non-responder, n (%) P value (vs Placebo) |
126 38 (30.2) 88 (69.8) -- |
|
123 69 (56.1) 54 (43.9) <0.001 |
122 62 (50.8) 60 (49.2) 0.001 |
129 79 (61.2) 50 (38.8) <0.001 |
| R076477-SCH-304 N Responder, n (%) Non-responder, n (%) P value (vs Placebo) |
105 36 (34.3) 69 (65.7) -- |
|
110 55 (50.0) 55 (50.0) 0.025 |
|
111 57 (51.4) 54 (48.6) 0.012 |
| R076477-SCH-305 N Responder, n (%) Non-responder, n (%) P value (vs Placebo) |
120 22 (18.3) 98 (81.7) -- |
123 49 (39.8) 74 (60.2) 0.001 |
|
123 56 (45.5) 67 (54.5) <0.001 |
|
In a long-term trial designed to assess the maintenance of effect, Инвега was significantly more effective than placebo in maintaining symptom control and delaying relapse of schizophrenia. After having been treated for an acute episode for 6 weeks and stabilised for an additional 8 weeks with Инвега (doses ranging from 3 to 15 mg once daily) patients were then randomised in a double-blind manner to either continue on Инвега or on placebo until they experienced a relapse in schizophrenia symptoms. The trial was stopped early for efficacy reasons by showing a significantly longer time to relapse in patients treated with Инвега compared to placebo (p=0.0053).
Schizoaffective disorder
The efficacy of Инвега in the acute treatment of psychotic or manic symptoms of schizoaffective disorder was established in two placebo-controlled, 6-week trials in non-elderly adult subjects. Enrolled subjects 1) met DSM-IV criteria for schizoaffective disorder, as confirmed by the Structured Clinical Interview for DSM-IV Disorders, 2) had a Positive and Negative Syndrome Scale (PANSS) total score of at least 60, and 3) had prominent mood symptoms as confirmed by a score of at least 16 on the Young Mania Rating Scale (YMRS) and/or Hamilton Rating Scale 21 for Depression (HAM-D 21). The population included subjects with schizoaffective bipolar and depressive types. In one of these trials, efficacy was assessed in 211 subjects who received flexible doses of Инвега (3-12 mg once daily). In the other study, efficacy was assessed in 203 subjects who were assigned to one of two dose levels of Инвега: 6 mg with the option to reduce to 3 mg (n = 105) or 12 mg with the option to reduce to 9 mg (n = 98) once daily. Both studies included subjects who received Инвега either as monotherapy or in combination with mood stabilisers and/or antidepressants. Dosing was in the morning without regard to meals. Efficacy was evaluated using the PANSS.
The Инвега group in the flexible-dose study (dosed between 3 and 12 mg/day, mean modal dose of 8.6 mg/day) and the higher dose group of Инвега in the 2 dose-level study (12 mg/day with option to reduce to 9 mg/day) were each superior to placebo in the PANSS at 6 weeks. In the lower dose group of the 2 dose-level study (6 mg/day with option to reduce to 3 mg/day), Инвега was not significantly different from placebo as measured by the PANSS. Only few subjects received the 3 mg dose in both studies and efficacy of this dose could not be established. Statistically superior improvements in manic symptoms as measured by YMRS (secondary efficacy scale) were observed in patients from the flexible-dose study and the Инвега higher dose in the second study.
Taking the results of both studies together (pooled study-data), Инвега improved the psychotic and manic symptoms of schizoaffective disorder at endpoint relative to placebo when administered either as monotherapy or in combination with mood stabilisers and/or antidepressants. However, overall the magnitude of effect in regard to PANSS and YMRS observed on monotherapy was larger than that observed with concomitant antidepressants and/or mood stabilisers. Moreover, in the pooled population, Инвега was not efficacious in patients concomitantly receiving mood stabiliser and antidepressants in regard to the psychotic symptoms, but this population was small (30 responders in the paliperidone group and 20 responders in the placebo group). Additionally, in study SCA-3001 in the ITT population the effect on psychotic symptoms measured by PANSS was clearly less pronounced and not reaching statistical significance for patients receiving concomitantly mood stabilisers and/or antidepressants. An effect of Инвега on depressive symptoms was not demonstrated in these studies, but has been demonstrated in a long-term study with the long-acting injectable formulation of paliperidone (described further down in this section).
An examination of population subgroups did not reveal any evidence of differential responsiveness on the basis of gender, age, or geographic region. There were insufficient data to explore differential effects based on race. Efficacy was also evaluated by calculation of treatment response (defined as decrease in PANSS Total Score > 30% and CGI-C Score ≤ 2) as a secondary endpoint.
| Schizoaffective Disorder Studies: Primary Efficacy Parameter, PANSS Total Score Change from Baseline from Studies R076477-SCA-3001 and R076477-SCA-3002: Intent-to-Treat Analysis Set | ||||
| Placebo | Инвега Lower Dose (3-6 mg) | Инвега Higher Dose (9-12 mg) | Инвега Flexible Dose (3-12 mg) | |
| R076477-SCA-3001 Mean baseline (SD) Mean change (SD) P-value (vs. Placebo) Diff. of LS Means (SE) | (N=107) 91.6 (12.5) -21.7 (21.4) | (N=105) 95.9 (13.0) -27.4 (22.1) 0.187 -3.6 (2.7) | (N=98) 92.7 (12.6) -30.6 (19.1) 0.003 -8.3 (2.8) |
|
| R076477-SCA-3002 Mean baseline (SD) Mean change (SD) P-value (vs. Placebo) Diff. of LS Means (SE) | (N=93) 91.7 (12.1) -10.8 (18.7) |
|
| (N=211) 92.3 (13.5) -20.0 (20.23) <0.001 -13.5 (2.63) |
| Note: Negative change in score indicates improvement. LOCF = last observation carried forward. | ||||
| Schizoaffective Disorder Studies: Secondary Efficacy Parameter, Proportion of Subjects with Responder Status at LOCF End Point: Studies R076477-SCA-3001 and R076477-SCA-3002: Intent-to-Treat Analysis Set | ||||
| Placebo | Инвега Lower Dose (3-6 mg) | Инвега Higher Dose (9-12 mg) | Инвега Flexible Dose (3-12 mg) | |
| R076477-SCA-3001 N Responder, n (%) Non-responder, n (%) P value (vs Placebo) |
107 43 (40.2) 64 (59.8) -- |
104 59 (56.7) 45 (43.3) 0.008 |
98 61 (62.2) 37 (37.8) 0.001 |
|
| R076477-SCA-3002 N Responder, n (%) Non-responder, n (%) P value (vs Placebo) |
93 26 (28.0) 67 (72.0) -- |
|
|
210 85 (40.5) 125 (59.5) 0.046 |
| Response defined as decrease from baseline in PANSS Total Score > 30% and CGI-C Score ≤ 2 | ||||
In a long-term trial designed to assess the maintenance of effect, the long-acting injectable formulation of paliperidone was significantly more effective than placebo in maintaining symptom control and delaying relapse of psychotic, manic, and depressive symptoms of schizoaffective disorder. After having been successfully treated for an acute psychotic or mood episode for 13 weeks and stabilised for an additional 12 weeks with the long-acting injectable formulation of paliperidone (doses ranging from 50 to 150 mg) patients were then randomised to a 15-month double-blind relapse prevention period of the study to either continue on the long-acting injectable formulation of paliperidone or on placebo until they experienced a relapse of schizoaffective symptoms. The study showed a significantly longer time to relapse in patients treated with the long-acting injectable formulation of paliperidone compared to placebo (p<0.001).
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with Инвега in all subsets of the paediatric population in the treatment of schizoaffective disorders.
The efficacy of Инвега in the treatment of schizophrenia in adolescents between 12 and 14 years old has not been established.
The efficacy of Инвега in adolescent subjects with schizophrenia (Инвега N = 149, placebo N = 51) was studied in a randomised, double-blind, placebo-controlled, 6-week study using a fixed-dose weight-based treatment group design over the dose range of 1.5 mg/day to 12 mg/day. Subjects were 12-17 years of age and met DSM-IV criteria for schizophrenia. Efficacy was evaluated using PANSS. This study demonstrated the efficacy of Инвега of the medium dose group in adolescent subjects with schizophrenia. Secondary by dose analysis demonstrated the efficacy of 3 mg, 6 mg, and 12 mg dose given once daily.
| Adolescent Schizophrenia Study: R076477-PSZ-3001: 6-week, fixed-dose, placebo-controlled Intent-to-Treat Analysis Set. LOCF endpoint change from baseline | ||||
| Placebo
N=51 | Инвега Low Dose 1.5 mg N=54 | Инвега Medium Dose 3 or 6 mg* N=48 | Инвега High Dose 6 or 12 mg** N=47 | |
| Change in PANSS Score Mean baseline (SD) Mean change (SD) P-value (vs Placebo) Diff. of LS Means (SE) |
90.6 (12.13) -7.9 (20.15) |
91.6 (12.54) -9.8 (16.31) 0.508 -2.1 (3.17) |
90.6 (14.01) -17.3 (14.33) 0.006 -10.1 (3.27) |
91.5 (13.86) -13.8 (15.74) 0.086 -6.6 (3.29) |
| Responder Analysis Responder, n (%) Non-responder, n (%) P value (vs Placebo) |
17 (33.3) 34 (66.7) |
21 (38.9) 33 (61.1) 0.479 |
31 (64.6) 17 (35.4) 0.001 |
24 (51.1) 23 (48.9) 0.043 |
| Response defined as decrease from baseline in PANSS Total Score > 20% Note: Negative change in score indicates improvement. LOCF = last observation carried forward. * Medium dose group: 3 mg for subjects < 51 kg, 6 mg for subjects > 51 kg ** High dose group: 6 mg for subjects < 51 kg, 12 mg for subjects > 51 kg | ||||
Efficacy of Инвега over a flexible dose range of 3 mg/day to 9 mg/day in adolescent subjects (12 years and older) with schizophrenia (Инвега N = 112, aripiprazole N = 114) was also evaluated in a randomised, double-blind, active-controlled study that included an 8-week, double-blind acute phase and an 18-week, double-blind maintenance phase. The changes in PANSS total scores from baseline to Week 8 and Week 26 were numerically similar between the Инвега and aripiprazole treatment groups. In addition, the difference in the percentage of patients demonstrating > 20% improvement in PANSS total score at Week 26 between the two treatment groups was numerically similar.
| Adolescent Schizophrenia Study: R076477-PSZ-3003: 26-week, flexible-dose, active-controlled Intent-to-Treat Analysis Set. LOCF endpoint change from baseline | ||
| Инвега 3-9 mg N=112 | Aripiprazole 5-15 mg N=114 | |
| Change in PANSS Score 8 week, acute endpoint Mean baseline (SD) Mean change (SD) P-value (vs aripiprazole) Diff. of LS Means (SE) |
89.6 (12.22) -19.3 (13.80) 0.935 0.1 (1.83) |
92.0 (12.09) -19.8 (14.56)
|
| Change in PANSS Score 26 week endpoint Mean baseline (SD) Mean change (SD) P-value (vs aripiprazole) Diff. of LS Means (SE) |
89.6 (12.22) -25.6 (16.88) 0.877 -0.3 (2.20) |
92.0 (12.09) -26.8 (18.82) |
| Responder Analysis 26 week endpoint Responder, n (%) Non-responder, n (%) P value (vs aripiprazole) |
86 (76.8) 26 (23.2) 0.444 |
93 (81.6) 21 (18.4) |
| Response defined as decrease from baseline in PANSS Total Score > 20% Note: Negative change in score indicates improvement. LOCF = last observation carried forward. | ||
The pharmacokinetics of paliperidone following Инвега administration are dose proportional within the available dose range.
Absorption
Following a single dose, Инвега exhibits a gradual ascending release rate, allowing the plasma concentrations of paliperidone to steadily rise to reach peak plasma concentration (Cmax) approximately 24 hours after dosing. With once-daily dosing of Инвега, steady-state concentrations of paliperidone are attained within 4-5 days of dosing in most subjects.
Paliperidone is the active metabolite of risperidone. The release characteristics of Инвега result in minimal peak-trough fluctuations as compared to those observed with immediate-release risperidone (fluctuation index 38% versus 125%).
The absolute oral bioavailability of paliperidone following Инвега administration is 28% (90% CI of 23%-33%).
Administration of paliperidone prolonged-release tablets with a standard high-fat/high-caloric meal increases Cmax and AUC of paliperidone by up to 50-60% compared with administration in the fasting state.
Distribution
Paliperidone is rapidly distributed. The apparent volume of distribution is 487 l. The plasma protein binding of paliperidone is 74%. It binds primarily to α1-acid glycoprotein and albumin.
Biotransformation and elimination
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 by 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 6.5% 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 Инвега 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. The terminal elimination half-life of paliperidone is about 23 hours.
In vitro studies have shown that paliperidone is a P-gp substrate and a weak inhibitor of P-gp at high concentrations. No in vivo data are available and the clinical relevance is unknown.
Hepatic impairment
Paliperidone is not extensively metabolised in the liver. In a study in subjects with moderate hepatic impairment (Child-Pugh class B), the plasma concentrations of free paliperidone were similar to those of healthy subjects. No data are available in patients with severe hepatic impairment (Child-Pugh class C).
Renal impairment
Elimination of paliperidone decreased with decreasing renal function. Total clearance of paliperidone was reduced in subjects with impaired renal function by 32% in mild (Creatinine Clearance [Cr Cl] = 50 to < 80 ml/min), 64% in moderate (CrCl = 30 to < 50 ml/min), and 71% in severe (CrCl = < 30 ml/min) renal impairment. The mean terminal elimination half-life of paliperidone was 24, 40, and 51 hours in subjects with mild, moderate, and severe renal impairment, respectively, compared with 23 hours in subjects with normal renal function (CrCl > 80 ml/min).
Elderly
Data from a pharmacokinetic study in elderly subjects (> 65 years of age, n = 26) indicated that the apparent steady-state clearance of paliperidone following Инвега administration was 20% lower compared to that of adult subjects (18-45 years of age, n = 28). However, there was no discernable effect of age in the population pharmacokinetic analysis involving schizophrenia subjects after correction of age-related decreases in CrCl.
Adolescents
Paliperidone systemic exposure in adolescent subjects (15 years and older) was comparable to that in adults. In adolescents weighing < 51 kg, a 23% higher exposure was observed than in adolescents weighing > 51 kg. Age alone did not influence the paliperidone exposure.
Race
Population pharmacokinetics analysis revealed no evidence of race-related differences in the pharmacokinetics of paliperidone following Инвега administration.
Gender
The apparent clearance of paliperidone following Инвега administration is approximately 19% lower in women than men. This difference is largely explained by differences in lean body mass and creatinine clearance between men and women.
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. A population pharmacokinetic analysis showed a slightly lower exposure to paliperidone in smokers compared with non-smokers. The difference is unlikely to be of clinical relevance, though.
Patients with schizoaffective disorder treated with paliperidone should be carefully monitored for a potential switch from manic to depressive symptoms.
QT interval
Caution should be exercised when Инвега is prescribed in patients with known cardiovascular disease or family history of QT prolongation, and in concomitant use with other medicines 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, all antipsychotics, including Инвега, should be discontinued.
Tardive dyskinesia
Medicines 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 Инвега, should be considered.
Leukopenia, neutropenia, and agranulocytosis
Events of leucopenia, neutropenia, and agranulocytosis have been reported with antipsychotic agents, including Инвега. Agranulocytosis has been reported very rarely (< 1/10,000 patients) during post-marketing surveillance. Patients with a history of a clinically significant low white blood cell count (WBC) or a drug-induced leukopenia/neutropenia should be monitored during the first few months of therapy and discontinuation of Инвега 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 Инвега and have their WBC followed until recovery.
Hyperglycemia and diabetes mellitus
Hyperglycaemia, diabetes mellitus, and exacerbation of pre-existing diabetes have been reported during treatment with paliperidone. In some cases, a prior increase in body weight has been reported which may be a predisposing factor. Association with ketoacidosis has been reported very rarely and rarely with diabetic coma. Appropriate clinical monitoring is advisable in accordance with utilised antipsychotic guidelines. Patients treated with any atypical antipsychotic, including Инвега, 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 Инвега use. Weight should be monitored regularly.
Hyperprolactinaemia
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 possible prolactin-dependent tumours.
Orthostatic hypotension
Paliperidone may induce orthostatic hypotension in some patients based on its alpha-blocking activity.
Based on pooled data from the three, placebo-controlled, 6-week, fixed-dose trials with Инвега (3, 6, 9, and 12 mg), orthostatic hypotension was reported by 2.5% of subjects treated with Инвега compared with 0.8% of subjects treated with placebo. Инвега 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
Инвега should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold.
Potential for gastrointestinal obstruction
Because the Инвега tablet is non-deformable and does not appreciably change shape in the gastrointestinal tract, Инвега should not ordinarily be administered to patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic) or in patients with dysphagia or significant difficulty in swallowing tablets. There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of medicines in non-deformable controlled-release formulations. Due to the controlled-release design of the dosage form, Инвега should only be used in patients who are able to swallow the tablet whole.
Conditions with decreased gastro-intestinal transit time
Conditions leading to shorter gastrointestinal transit time, e.g., diseases associated with chronic severe diarrhoea, may result in a reduced absorption of paliperidone.
Renal impairment
The plasma concentrations of paliperidone are increased in patients with renal impairment and, therefore, dosage adjustment may be required in some patients. No data are available in patients with a creatinine clearance below 10 ml/min. Paliperidone should not be used in patients with creatinine clearance below 10 ml/min.
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
Инвега has not been studied in elderly patients with dementia. The experience from risperidone 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 have 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. Инвега should be used with caution in elderly patients with dementia who have risk factors for stroke.
Parkinson's disease and dementia with Lewy bodies
Physicians should weigh the risks versus the benefits when prescribing Инвега 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 risperidone) with α-adrenergic blocking effects have been reported to induce priapism. During postmarketing surveillance priapism has also been reported with paliperidone, which is the active metabolite of risperidone. Patients should be informed to seek urgent medical care in case that priapism has not been resolved within 3-4 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 Инвега 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 medication 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 Инвега and preventive 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 medicines or of conditions such as intestinal obstruction, Reye's syndrome, and brain tumour.
Paediatric population
The sedative effect of Инвега should be closely monitored in this population. A change in the time of administration of Инвега may improve the impact of sedation on the patient.
Because of the potential effects of prolonged hyperprolactinemia on growth and sexual maturation in adolescents, regular clinical evaluation of endocrinological status should be considered, including measurements of height, weight, sexual maturation, monitoring of menstrual functioning, and other potential prolactin-related effects.
During treatment with Инвега regular examination for extrapyramidal symptoms and other movement disorders should also be conducted.
Intraoperative Floppy Iris Syndrome
Intraoperative floppy iris syndrome (IFIS) has been observed during cataract surgery in patients treated with medicines with alpha1a-adrenergic antagonist effect, such as Инвега.
IFIS may increase the risk of eye complications during and after the operation. Current or past use of medicines with alpha1a-adrenergic antagonist effect should be made known to the ophthalmic surgeon in advance of surgery. The potential benefit of stopping alpha1 blocking therapy prior to cataract surgery has not been established and must be weighed against the risk of stopping the antipsychotic therapy.
Lactose content (pertains only to the 3 mg tablets)
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Paliperidone can have minor or moderate influence on the ability to drive and use machines due to potential nervous system and visual effects. Therefore, patients should be advised not to drive or operate machines until their individual susceptibility to Инвега is known.
Posology
Schizophrenia (adults)
The recommended dose of Инвега for the treatment of schizophrenia in adults is 6 mg once daily, administered in the morning. Initial dose titration is not required. Some patients may benefit from lower or higher doses within the recommended range of 3 mg to 12 mg once daily. Dosage adjustment, if indicated, should occur only after clinical reassessment. When dose increases are indicated, increments of 3 mg/day are recommended and generally should occur at intervals of more than 5 days.
Schizoaffective disorder (adults)
The recommended dose of Инвега for the treatment of schizoaffective disorder in adults is 6 mg once daily, administered in the morning. Initial dose titration is not required. Some patients may benefit from higher doses within the recommended range of 6 mg to 12 mg once daily. Dosage adjustment, if indicated, should occur only after clinical reassessment. When dose increases are indicated, increments of 3 mg/day are recommended and generally should occur at intervals of more than 4 days.
Switching to other antipsychotic medicinal products
There are no systematically collected data to specifically address switching patients from Инвега to other antipsychotic medicinal products. Due to different pharmacodynamic and pharmacokinetic profiles among antipsychotic medicinal products, supervision by a clinician is needed when switching to another antipsychotic product is considered medically appropriate.
Elderly
Dosing recommendations for elderly patients with normal renal function (> 80 ml/min) are the same as for adults with normal renal function. However, because elderly patients may have diminished renal function, dose adjustments may be required according to their renal function status (see Renal impairment below). Инвега should be used with caution in elderly patients with dementia with risk factors for stroke. Safety and efficacy of Инвега in patients > 65 years of age with schizoaffective disorder have not been studied.
Hepatic impairment
No dose adjustment is required in patients with mild or moderate hepatic impairment. As Инвега has not been studied in patients with severe hepatic impairment, caution is recommended in such patients.
Renal impairment
For patients with mild renal impairment (creatinine clearance > 50 to < 80 ml/min), the recommended initial dose is 3 mg once daily. The dose may be increased to 6 mg once daily based on clinical response and tolerability.
For patients with moderate to severe renal impairment (creatinine clearance > 10 to < 50 ml/min), the recommended initial dose of Инвега is 3 mg every other day, which may be increased to 3 mg once daily after clinical reassessment. As Инвега has not been studied in patients with creatinine clearance below 10 ml/min, use is not recommended in such patients.
Paediatric population
Schizophrenia: The recommended starting dose of Инвега for the treatment of schizophrenia in adolescents 15 years and older is 3 mg once daily, administered in the morning.
Adolescents weighing < 51 kg: the maximum recommended daily dose of Инвега is 6 mg.
Adolescents weighing > 51 kg: the maximum recommended daily dose of Инвега is 12 mg.
Dosage adjustment, if indicated, should occur only after clinical reassessment based on the individual need of the patient.1 but no recommendation on a posology can be made. There is no relevant use of Инвега in children aged less than 12 years.
Schizoaffective disorder: The safety and efficacy of Инвега in the treatment of schizoaffective disorder in patients aged 12 to 17 years has not been studied or established. There is no relevant use of Инвега in children aged less than 12 years.
Other special populations
No dose adjustment for Инвега is recommended based on gender, race, or smoking status.
Method of administration
Инвега is for oral administration. It must be swallowed whole with liquid, and must not be chewed, divided, or crushed. The active substance is contained within a non-absorbable shell designed to release the active substance at a controlled rate. The tablet shell, along with insoluble core components, is eliminated from the body; patients should not be concerned if they occasionally notice in their stool something that looks like a tablet.
The administration of Инвега should be standardised in relation to food intake. The patient should be instructed to always take Инвега in the fasting state or always take it together with breakfast and not to alternate between administration in the fasting state or in the fed state.
No special requirements for disposal.
