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.
2 years
Not applicable
3 mg
Core
Polyethylene oxide 200K
Sodium chloride
Povidone (K29-32)
Stearic acid
Butyl hydroxytoluene (E321)
Ferric oxide (yellow) (E172)
Polyethylene oxide 7000K
Ferric oxide (red) (E172)
Hydroxyethyl cellulose
Polyethylene glycol 3350
Cellulose acetate
Overcoat
Hypromellose
Titanium dioxide (E171)
Lactose monohydrate
Triacetin
Carnauba wax
Printing ink
Iron oxide (black) (E172)
Propylene glycol
Hypromellose
6 mg
Core
Polyethylene oxide 200K
Sodium chloride
Povidone (K29-32)
Stearic acid
Butyl hydroxytoluene (E321)
Polyethylene oxide 7000K
Ferric oxide (red) (E172)
Hydroxyethyl cellulose
Polyethylene glycol 3350
Cellulose acetate
Overcoat
Hypromellose
Titanium dioxide (E171)
Polyethylene glycol 400
Ferric oxide (yellow) (E172)
Ferric oxide (red) (E172)
Carnauba wax
Printing ink
Iron oxide (black) (E172)
Propylene glycol
Hypromellose
9 mg
Core
Polyethylene oxide 200K
Sodium chloride
Povidone (K29-32)
Stearic acid
Butyl hydroxytoluene (E321)
Polyethylene oxide 7000K
Ferric oxide (red) (E172)
Iron oxide (black) (E172)
Hydroxyethyl cellulose
Polyethylene glycol 3350
Cellulose acetate
Overcoat
Hypromellose
Titanium dioxide (E171)
Polyethylene glycol 400
Ferric oxide (red) (E172)
Carnauba wax
Printing ink
Iron oxide (black) (E172)
Propylene glycol
Hypromellose
12 mg
Core
Polyethylene oxide 200K
Sodium chloride
Povidone (K29-32)
Stearic acid
Butyl hydroxytoluene (E321)
Polyethylene oxide 7000K
Ferric oxide (red) (E172)
Ferric oxide (yellow) (E172)
Hydroxyethyl cellulose
Polyethylene glycol 3350
Cellulose acetate
Overcoat
Hypromellose
Titanium dioxide (E171)
Polyethylene glycol 400
Ferric oxide (yellow) (E172)
Carnauba wax
Printing ink
Iron oxide (black) (E172)
Propylene glycol
Hypromellose
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 INVEGA dose group who were receiving concomitant therapy with an antidepressant or mood stabiliser experienced adverse events as compared to those subjects treated with INVEGA 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 INVEGA 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 INVEGA clinical studies but observed in post-marketing environment with paliperidone d In placebo-controlled pivotal trials, diabetes mellitus was reported in 0.05% in INVEGA-treated subjects compared to a rate of 0% in placebo group. Overall incidence from all clinical trials was 0.14% in all INVEGA-treated subjects e Insomnia includes: initial insomnia, middle insomnia; Convulsion includes: grand mal convulsion; Oedema includes: generalised oedema, oedema peripheral, pitting oedema. Menstrual disorder includes: menstruation irregular, oligomenorrhoea | |||||
Undesirable effects noted with risperidone formulations
Paliperidone is the active metabolite of risperidone, therefore, the adverse reaction profiles of 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 INVEGA.
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 INVEGA. Dose dependence for EPS was seen with the two higher doses of INVEGA (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 INVEGA 3 mg and 6 mg compared with placebo, and a higher incidence of weight gain for INVEGA 9 mg and 12 mg compared with placebo.
In schizoaffective disorder clinical trials, a higher percentage of INVEGA-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 INVEGA 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. INVEGA 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 INVEGA, 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 INVEGA than adults receiving INVEGA (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 INVEGA with an increased frequency of EPS at higher doses. Across all adolescent studies, EPS was more common in adolescents than in adults for each INVEGA dose.
Weight gain
In the short-term, placebo-controlled, fixed-dose adolescent study, a higher percentage of INVEGA-treated subjects (6-19% depending on dose) had an increase in body weight of >7% compared to placebo-treated subjects (2%). There was no clear dose relationship. In the long-term 2-year study, the subjects who were exposed to INVEGA 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 INVEGA 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.
Pharmacologic group: Psycholeptics, other antipsychotics ATC code: N05AX13
INVEGA 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 INVEGA in the treatment of schizophrenia was established in three multi-centre, placebo-controlled, double-blind, 6-week trials in subjects who met DSM-IV criteria for schizophrenia. INVEGA 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 INVEGA separated from placebo on day 4 (p<0.05). Predefined secondary endpoints included the Personal and Social Performance (PSP) scale and the Clinical Global Impression - Severity (CGI-S) scale. In all three studies, INVEGA was superior to placebo on PSP and CGI-S. Efficacy was 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 |
INVEGA 3 mg |
INVEGA 6 mg |
INVEGA 9 mg |
INVEGA 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 |
INVEGA 3 mg |
INVEGA 6 mg |
INVEGA 9 mg |
INVEGA 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, INVEGA 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 INVEGA (doses ranging from 3 to 15 mg once daily) patients were then randomised in a double-blind manner to either continue on INVEGA 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 INVEGA compared to placebo (p=0.0053).
Schizoaffective disorder
The efficacy of INVEGA 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 INVEGA (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 INVEGA: 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 INVEGA 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 INVEGA 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 INVEGA 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), INVEGA 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 INVEGA higher dose in the second study.
Taking the results of both studies together (pooled study-data), INVEGA 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, INVEGA 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 INVEGA 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 |
INVEGA Lower Dose (3-6 mg) |
INVEGA Higher Dose (9-12 mg) |
INVEGA 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 |
INVEGA Lower Dose (3-6 mg) |
INVEGA Higher Dose (9-12 mg) |
INVEGA 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 INVEGA in all subsets of the paediatric population in the treatment of schizoaffective disorders.
The efficacy of INVEGA in the treatment of schizophrenia in adolescents between 12 and 14 years old has not been established.
The efficacy of INVEGA in adolescent subjects with schizophrenia (INVEGA N = 149, placebo N = 51) was studied in a randomised, double-blind, placebo-controlled, 6-week study using 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 INVEGA 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.
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Adolescent Schizophrenia Study: R076477-PSZ-3001: 6-week, fixed-dose, placebo-controlled Intent-to-Treat Analysis Set. LOCF endpoint change from baseline | ||||
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Placebo
N=51 |
INVEGA Low Dose 1.5 mg N=54 |
INVEGA Medium Dose 3 or 6 mg* N=48 |
INVEGA High Dose 6 or 12 mg** N=47 | |
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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) |
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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 |
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Response defined as decrease from baseline in PANSS Total Score > 20% Note: Negative change in score indicates improvement. LOCF = last observation carried forward. * Medium dose group: 3 mg for subjects < 51 kg, 6 mg for subjects > 51 kg ** High dose group: 6 mg for subjects < 51 kg, 12 mg for subjects > 51 kg | ||||
Efficacy of INVEGA over a flexible dose range of 3 mg/day to 9 mg/day in adolescent subjects (12 years and older) with schizophrenia (INVEGA N = 112, aripiprazole N = 114) was also 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 INVEGA 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.
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Adolescent Schizophrenia Study: R076477-PSZ-3003: 26-week, flexible-dose, active-controlled Intent-to-Treat Analysis Set. LOCF endpoint change from baseline | ||
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INVEGA 3-9 mg N=112 |
Aripiprazole 5-15 mg N=114 | |
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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)
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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) |
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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) |
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Response defined as decrease from baseline in PANSS Total Score > 20% Note: Negative change in score indicates improvement. LOCF = last observation carried forward. | ||
The pharmacokinetics of paliperidone following INVEGA administration are dose proportional within the available dose range.
Absorption
Following a single dose, INVEGA 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 INVEGA, 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 INVEGA 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 INVEGA 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 INVEGA 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 INVEGA 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 INVEGA administration.
Gender
The apparent clearance of paliperidone following INVEGA administration is approximately 19% lower in women than men. This difference is largely explained by differences in lean body mass 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.
24 August 2017
Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium
Bottles: Do not store above 30°C. Keep the bottle tightly closed in order to protect from moisture.
Blisters: Do not store above 30°C. Store in the original package in order to protect from moisture.
Bottles:
White high-density polyethylene (HDPE) bottle with induction sealing and polypropylene child-resistant closure. Each bottle contains two 1 g dessicant silica gel (silicone dioxide) pouches (pouch is food approved polyethylene).
Pack sizes of 30 and 350 prolonged-release tablets.
Blisters:
Polyvinyl chloride (PVC) laminated with polychloro-trifluoroethylene (PCTFE)/aluminium push-through layer.
Pack sizes of 14, 28, 30, 49, 56, and 98 prolonged-release tablets.
Or
White polyvinyl chloride (PVC) laminated with polychloro-trifluoroethylene (PCTFE)/aluminium push-through layer.
Pack sizes of 14, 28, 30, 49, 56, and 98 prolonged-release tablets.
Or
Oriented polyamide (OPA)-aluminium-polyvinyl chloride (PVC)/aluminium push-through layer.
Pack sizes of 14, 28, 49, 56, and 98 prolonged-release tablets.
Not all pack sizes may be marketed.
3 mg
EU/1/07/395/001 - 005
EU/1/07/395/021 - 025
EU/1/07/395/041 - 044
EU/1/07/395/057 - 058
EU/1/07/395/065 - 067
6 mg
EU/1/07/395/006 - 010
EU/1/07/395/026 - 030
EU/1/07/395/045 - 048
EU/1/07/395/059 - 060
EU/1/07/395/068 - 070
9 mg
EU/1/07/395/011 - 015
EU/1/07/395/031 - 035
EU/1/07/395/049 - 052
EU/1/07/395/061 - 062
EU/1/07/395/071 - 073
12 mg
EU/1/07/395/016 - 020
EU/1/07/395/036 - 040
EU/1/07/395/053 - 056
EU/1/07/395/063 - 064
EU/1/07/395/074 - 076
Pregnancy
There are no adequate data from the use of paliperidone during pregnancy.
Paliperidone was not teratogenic in animal studies, but other types of reproductive toxicity were observed. Neonates exposed to antipsychotics (including 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. INVEGA should not be used during pregnancy unless clearly necessary. If discontinuation during pregnancy is necessary, it should not be done abruptly.
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. INVEGA should not be used while breast feeding.
Fertility
There were no relevant effects observed in the non-clinical studies.
Paliperidone can have minor or moderate influence on the ability to drive and use machines due to potential nervous system and visual effects. Therefore, patients should be advised not to drive or operate machines until their individual susceptibility to INVEGA is known.
No special requirements for disposal.
Date of first authorisation: 25 June 2007
Date of latest renewal: 14 May 2012
