Adverse reactions : תופעות לוואי

4.8   Undesirable effects

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 Invega SPC 9-24
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                                                Adverse Drug Reaction Class                                                            Frequency Very             Common                 Uncommon                           Rare               Not known common
Infections and                     bronchitis, upper       pneumonia, respiratory       eye infection, infestations                       respiratory tract       tract infection, cystitis,   onychomycosis, infection, sinusitis,   ear infection, tonsillitis   cellulitis,
urinary tract                                        acarodermatitis infection, influenza
Blood and                                                  white blood cell count       agranulocytosisc, lymphatic                                                  decreased,                   neutropenia, system                                                     thrombocytopenia,            eosinophil count disorders                                                  anaemia, haematocrit         increased decreased
Immune system                                                                           anaphylactic reaction, disorders                                                                               hypersensitivity Endocrine                                                  hyperprolactinaemiaa         inappropriate disorders                                                                               antidiuretic hormone secretionc, glucose urine present
Metabolism and                     weight increased,       diabetes mellitusd,          water intoxication,       hyperinsulinaemia nutrition                          increased appetite,     hyperglycaemia, waist        diabetic ketoacidosisc, disorders                          weight decreased,       circumference                hypoglycaemia, decreased appetite      increased, anorexia,         polydipsia, blood blood triglycerides          cholesterol increased increased
Psychiatric       insomniae        mania, agitation,       sleep disorder,              catatonia, disorders                          depression, anxiety     confusional state,           somnambulism, libido decreased,            blunted affectc anorgasmia,
nervousness,
nightmare
Nervous system    parkinsonismb,   dystoniab,              tardive dyskinesia,          neuroleptic malignant disorders         akathisiab,      dizziness,              convulsione, syncope,        syndrome, cerebral sedation/        dyskinesiab,            psychomotor                  ischaemia, somnolence,      tremorb                 hyperactivity,               unresponsive to headache                                 dizziness postural,          stimulic, loss of disturbance in               consciousness,
attention, dysarthria,       depressed level of dysgeusia,                   consciousnessc,
hypoaesthesia,               diabetic comac balance paresthaesia                 disorder, coordination abnormal, head titubationc
Eye disorders                      vision blurred          photophobia,                 glaucoma, eye conjunctivitis, dry eye      movement disorderc,
eye rollingc,
lacrimation increased,
ocular hyperaemia
Ear and                                                    vertigo, tinnitus, ear labyrinth                                                  pain disorders

Invega SPC 9-24
Cardiac            atrioventricular      sinus arrhythmia,          atrial fibrillation, disorders          block, conduction     electrocardiogram          postural orthostatic disorder,             abnormal, palpitations     tachycardia syndromec electrocardiogram
QT prolonged,
bradycardia,
tachycardia
Vascular           orthostatic           hypotension                pulmonary embolism, disorders          hypotension,                                     venous thrombosis, hypertension                                     ischaemia, flushing
Respiratory,       pharyngolaryngeal     dyspnoea, wheezing,        sleep apnoea                pulmonary thoracic and       pain, cough, nasal    epistaxis                  syndrome,                   congestion mediastinal        congestion                                       hyperventilation, disorders                                                           pneumonia aspiration, respiratory tract congestion, dysphonia
Gastrointestinal   abdominal pain,       swollen tongue,            pancreatitisc, intestinal disorders          abdominal             gastroenteritis,           obstruction, ileus, discomfort,           dysphagia, flatulence      faecal incontinence, vomiting, nausea,                                faecalomac, cheilitis constipation,
diarrhoea,
dyspepsia, dry mouth, toothache
Hepatobiliary      transaminases         gamma-glutamyltransf       jaundice disorders          increased             erase increased,
hepatic enzyme increased
Skin and           pruritus, rash        urticaria, alopecia,       angioedema, drug subcutaneous                             eczema, acne               eruptionc, tissue disorders                                                    hyperkeratosis, dry skin, erythema, skin discolouration,
seborrhoeic dermatitis,
dandruff
Musculoskeletal    musculoskeletal       blood creatine             rhabdomyolysisc, and connective     pain, back pain,      phosphokinase              posture abnormalc tissue disorders   arthralgia            increased, muscle spasms, joint stiffness,
joint swelling,
muscular weakness,
neck pain
Renal and                                urinary incontinence,
urinary                                  pollakiuria, urinary disorders                                retention, dysuria
Pregnancy,                                                          drug withdrawal puerperium and                                                      syndrome neonatal perinatal                                                           (see section 4.6)c conditions
Reproductive       amenorrhoea           erectile dysfunction,      priapismc, system and                               ejaculation disorder,      menstruation delayedc, breast disorders                         menstrual disordere,       gynaecomastia, breast galactorrhoea, sexual      engorgement, breast dysfunction, breast        enlargementc, breast pain, breast discomfort    discharge, vaginal discharge

Invega SPC 9-24
General                                  pyrexia, asthenia,    face oedema, oedemae,     hypothermiac, body disorders                                fatigue               chills, body              temperature temperature increased,    decreasedc, drug gait abnormal, thirst,    withdrawal syndromec,
chest pain, chest         indurationc discomfort, malaise
Injury,                                                        fall poisoning and procedural complications 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.
Psychiatric disorders: sleep-related eatingdisorder
Nervous system disorders: cerebrovascular disorder
Eye disorders: floppy iris syndrome (intraoperative)
Respiratory, thoracic and mediastinal disorders: rales
Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome/toxic epidermal necrolysis 
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 
Invega SPC 9-24
increase in body weight of ≥ 7% compared with placebo-treated subjects (1%). In the study that examined two dose groups (see section 5.1), 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 (see section 4.4).

Paediatric population
Summary of the safety profile
In one short-term and two longer-term studies with paliperidone extended-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.

Invega SPC 9-24
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 suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: https://sideeffects.health.gov.il