Adverse reactions : תופעות לוואי

4.8    Undesirable effects

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

Tabulated list of adverse reactions

The following are all adverse reactions that were reported with paliperidone by frequency category estimated from paliperidone palmitate clinical trials. The following terms and frequencies are applied: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); and not known (cannot be estimated from the available data).

System Organ Cass                                             Adverse reaction Frequency
Very           Common                  Uncommon                    Rare             Not knowna common
Infections and                  upper respiratory tract pneumonia,                  eye infection, infestations                    infection, urinary tract bronchitis,                acarodermatitis, infection, influenza     respiratory tract infection, sinusitis,
cystitis, ear infection,
tonsillitis,
onychomycosis,
cellulitis,
subcutaneous abscess
Blood and                                                white blood cell           neutropenia,         agranulocytosis lymphatic system                                         count decreased,           thrombocytopenia, disorders                                                anaemia                    eosinophil count increased
Immune system                                            hypersensitivity                                anaphylactic disorders                                                                                                reaction Endocrine                       hyperprolactinaemiab                                inappropriate disorders                                                                           antidiuretic hormone secretion,
glucose urine present

Metabolism and                   hyperglycaemia,         diabetes mellitusd,      diabetic               water intoxication nutrition disorders              weight increased,       hyperinsulinaemia,       ketoacidosis, weight decreased,       increased appetite,      hypoglycaemia,
decreased appetite      anorexia, blood          polydipsia triglycerides increased, blood cholesterol increased
Psychiatric           insomniae agitation, depression,   sleep disorder,          catatonia,             sleep-related disorders                       anxiety                  mania, libido            confusional state,     eating disorder decreased,               somnambulism,
nervousness,             blunted affect,
nightmare                anorgasmia



Nervous system                   parkinsonismc,          tardive dyskinesia,      neuroleptic            diabetic coma disorders                        akathisiac, sedation/   syncope,                 malignant psychomotor              syndrome, cerebral somnolence,
hyperactivity,           ischaemia,
dystoniac, dizziness,   dizziness postural,      unresponsive to dyskinesiac, tremor,    disturbance in           stimuli, loss of headache                attention, dysarthria,   consciousness,
dysgeusia,               depressed level of hypoaesthesia,           consciousness,
paraesthesia             convulsione,
balance disorder,
coordination abnormal, head titubation
Eye disorders                                            vision blurred,          glaucoma, eye          floppy iris conjunctivitis, dry      movement               syndrome eye                      disorder, eye          (intraoperative) rolling,
photophobia,
lacrimation increased, ocular hyperaemia
Ear and labyrinth                                        vertigo, tinnitus, ear disorders                                                pain
Cardiac disorders                tachycardia             atrioventricular         atrial fibrillation, block, conduction        sinus arrhythmia disorder,
electrocardiogram
QT prolonged,
postural orthostatic tachycardia syndrome,
bradycardia,
electrocardiogram abnormal,
palpitations
Vascular disorders               hypertension            hypotension,             pulmonary              ischaemia orthostatic              embolism, venous hypotension              thrombosis,
flushing
Respiratory,                     cough, nasal            dyspnoea,                sleep apnoea           hyperventilation, thoracic and                     congestion              pharyngolaryngeal        syndrome,              pneumonia mediastinal                                              pain, epistaxis          pulmonary              aspiration, disorders                                                                         congestion,            dysphonia respiratory tract congestion rales,
wheezing



Gastrointestinal                      abdominal pain,           abdominal             pancreatitis,        ileus disorders                             vomiting, nausea,         discomfort,           intestinal constipation,             gastroenteritis,      obstruction,
diarrhoea, dyspepsia,     dysphagia, dry        swollen tongue,
toothache                 mouth, flatulence     faecal incontinence,
faecaloma, cheilitis
Hepatobiliary                         transaminases             gamma-glutamyltran                         jaundice disorders                             increased                 sferase increased, hepatic enzyme increased
Skin and                                                        urticaria, pruritus,  drug eruption,       Stevens-Johnson subcutaneous                                                    rash alopecia,        hyperkeratosis, ,    syndrome/toxic tissue disorders                                                eczema, dry skin,     seborrhoeic          epidermal erythema, acne        dermatitis,          necrolysis,
dandruff             angioedema, skin discolouration
Musculoskeletal                       musculoskeletal pain,     blood creatine        rhabdomyolysis,      posture abnormal and connective                        back pain, arthralgia     phosphokinase         joint swelling tissue disorders                                                increased, muscle spasms, joint stiffness, muscular weakness
Renal and urinary                                               urinary incontinence, urinary retention disorders                                                       pollakiuria, dysuria Pregnancy,                                                                                                 drug withdrawal puerperium and                                                                                             syndrome perinatal                                                                                                  neonatal conditions                                                                                                 (see section 4.6) Reproductive                          amenorrhoea,              erectile dysfunction,   priapism , breast system and breast                                               ejaculation disorder,   discomfort, breast disorders                                                       menstrual disordere,    engorgement, gynaecomastia,          breast enlargement,
galactorrhoea,          vaginal discharge sexual dysfunction,
breast pain
General disorders                     pyrexia, asthenia,        face oedema,            hypothermia,           body temperature and administration                    fatigue, injection site   oedemae, body           chills, thirst, drug   decreased, site conditions                       reaction                  temperature             withdrawal             injection site increased, gait         syndrome,              necrosis, injection abnormal, chest pain,   injection site         site ulcer chest discomfort,       abscess, injection malaise, induration     site cellulitis,
injection site cyst,
injection site haematoma
Injury, poisoning                                               fall and procedural complications a
The frequency of adverse reactions is qualified as “not known” because they were not observed in paliperidone palmitate clinical trials. They were either derived from spontaneous post marketing reports and frequency cannot be determined, or they were derived from risperidone (any formulation) or oral paliperidone clinical trials data and/or post marketing reports.
b
Refer to ‘Hyperprolactinaemia’ below.
c
Refer to ‘Extrapyramidal symptoms’ below.
d
In placebo-controlled trials, diabetes mellitus was reported in 0.32% in subjects treated with 1 monthly paliperidone palmitate injectable compared to a rate of 0.39% in placebo group. Overall incidence from all clinical trials was 0.65% in all subjects treated 1 monthly paliperidone palmitate injectable.
e
Insomnia includes: initial insomnia, middle insomnia; Convulsion includes: grand mal convulsion; Oedema includes: generalised oedema, oedema peripheral, pitting oedema Menstrual disorder includes menstruation delayed, 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.
Description of selected adverse reactions

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

Injection site reactions
In clinical trials of TREVICTA, 5.3% of subjects reported injection site related adverse reaction. None of these events were serious or led to discontinuation. Based on the investigators’ ratings, induration, redness, and swelling were absent or mild in ≥ 95% of the assessments. Subject-rated injection site pain based on a visual analogue scale was low and decreased in intensity over time.

Extrapyramidal symptoms (EPS)
In the clinical trials of TREVICTA, akathisia, dyskinesia, dystonia, parkinsonism, and tremor were reported in 3.9%, 0.8%, 0.9%, 3.6%, and 1.4% of subjects, respectively.

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

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

Hyperprolactinaemia
During the double-blind phase of the long-term randomised withdrawal study, elevations of prolactin to above the reference range (> 13.13 ng/mL in males and > 26.72 ng/mL in females) were noted in a higher percentage of males and females in the TREVICTA group than in the placebo group (9% vs.
3% and 5% vs. 1%, respectively). In the TREVICTA group, the mean change from double-blind baseline to double-blind end point was +2.90 ng/mL for males (vs. -10.26 ng/mL in the placebo group) and +7.48 ng/mL for females (vs. -32.93 ng/mL in the placebo group). One female (2.4%) in the TREVICTA group experienced an adverse reaction of amenorrhea, while no potentially prolactin related adverse reactions were noted among females in the placebo group. There were no potentially prolactin related adverse reactions among males in either group.

Class effects
QT prolongation, ventricular arrhythmias (ventricular fibrillation, ventricular tachycardia), sudden unexplained death, cardiac arrest, and Torsade de pointes may occur with antipsychotics.

Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis, have been reported with antipsychotic medicinal products (frequency unknown).
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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.
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