Adverse reactions : תופעות לוואי

 4.8    Undesirable effects
Summary of the safety profile

The adverse reactions most frequently reported in clinical trials were insomnia, headache, anxiety, upper respiratory tract infection, injection site reaction, parkinsonism, weight increased, akathisia, agitation, sedation/somnolence, nausea, constipation, dizziness, musculoskeletal pain, tachycardia, tremor, abdominal pain, vomiting, diarrhoea, fatigue, and dystonia. Of these, akathisia and sedation/somnolence appeared to be dose-related.

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                                                 Adverse reactions Class                                                       Frequency Very             Common                   Uncommon                   Rare             Not knowna common
Infections and                   upper respiratory        pneumonia, bronchitis,     eye infection, infestations                     tract infection,         respiratory tract          acarodermatitis, urinary tract            infection, sinusitis,
infection, influenza     cystitis, ear infection,
tonsillitis,
onychomycosis,
cellulitis, subcutaneous abscess
Blood and                                                 white blood cell count     neutropenia,         agranulocytosis lymphatic system                                          decreased, anaemia         thrombocytopenia, disorders                                                                            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                        weight increased,        hyperinsulinaemia,         ketoacidosis, disorders                        weight decreased,        increased appetite,        hypoglycaemia, decreased appetite       anorexia, blood            polydipsia triglycerides increased,
blood cholesterol increased
Psychiatric        insomniae     agitation, depression,   sleep disorder, mania,     catatonia,           sleep-related disorders                        anxiety                  libido decreased,          confusional state,   eating disorder nervousness,               somnambulism,
nightmare                  blunted affect,
anorgasmia


Nervous system      parkinsonismc,          tardive dyskinesia,          neuroleptic            diabetic coma disorders           akathisiac,             syncope, psychomotor         malignant sedation/somnolence,    hyperactivity,               syndrome,
dystoniac, dizziness,   dizziness postural,          cerebral dyskinesiac, tremor,    disturbance in               ischaemia,
headache                attention, dysarthria,       unresponsive to dysgeusia,                   stimuli, loss of hypoaesthesia,               consciousness,
paraesthesia                 depressed level of consciousness,
convulsione,
balance disorder,
coordination abnormal, head titubation
Eye disorders                               vision blurred,              glaucoma, eye          floppy iris conjunctivitis, dry eye      movement               syndrome disorder, eye          (intraoperative) rolling,
photophobia,
lacrimation increased, ocular hyperaemia
Ear and labyrinth                           vertigo, tinnitus, ear disorders                                   pain
Cardiac disorders   tachycardia             atrioventricular block,      atrial fibrillation, conduction disorder,         sinus arrhythmia electrocardiogram QT prolonged, postural orthostatic tachycardia syndrome,
bradycardia,
electrocardiogram abnormal, palpitations
Vascular            hypertension            hypotension,                 pulmonary              ischaemia disorders                                   orthostatic hypotension      embolism, venous 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 discomfort,        pancreatitis,          ileus disorders           vomiting, nausea,       gastroenteritis,             intestinal constipation,           dysphagia, dry mouth,        obstruction,
diarrhoea, dyspepsia,   flatulence                   swollen tongue,
toothache                                            faecal incontinence,
faecaloma,
cheilitis
Hepatobiliary       transaminases           gamma-                                              jaundice disorders           increased               glutamyltransferase increased, hepatic enzyme increased
Skin and                                    urticaria, pruritus, rash,   drug eruption,         Stevens-Johnson subcutaneous                                alopecia, eczema, dry        hyperkeratosis,        syndrome/toxic tissue disorders                            skin, erythema, acne         seborrhoeic            epidermal 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 incontinence,    urinary retention urinary disorders                                                pollakiuria, dysuria Pregnancy,                                                                                                       drug withdrawal puerperium and                                                                                                   syndrome perinatal                                                                                                        neonatal (see conditions                                                                                                       section 4.6) Reproductive                           amenorrhoea               erectile dysfunction,    priapism, breast system and breast                                                ejaculation disorder,    discomfort, breast disorders                                                        menstrual disordere,     engorgement, gynaecomastia,           breast galactorrhoea, sexual    enlargement,
dysfunction, breast      vaginal discharge pain
General disorders                      pyrexia, asthenia,        face oedema, oedemae,    hypothermia,           body temperature and                                    fatigue, injection site   body temperature         chills, thirst, drug   decreased, administration                         reaction                  increased, gait          withdrawal             injection site site conditions                                                  abnormal, chest pain,    syndrome,              necrosis, chest discomfort,        injection site         injection site malaise, induration      abscess, injection     ulcer 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 Xeplion-treated subjects compared to a rate of 0.39% in placebo group. Overall incidence from all clinical trials was 0.65% in all Xeplion 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 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 Xeplion 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
The most commonly reported injection site related adverse reaction was pain. The majority of these reactions were reported to be of mild to moderate severity. Subject evaluations of injection site pain based on a visual analogue scale tended to lessen in frequency and intensity over time in all Phase 2 and 3 studies with Xeplion. Injections into the deltoid were perceived as slightly more painful than corresponding gluteal injections. Other injection site reactions were mostly mild in intensity and included induration (common), pruritus (uncommon) and nodules (rare).

Extrapyramidal symptoms (EPS)
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, glabellar reflex abnormal, and 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 the 13-week study involving the 150 mg initiation dosing, the proportion of subjects with an abnormal weight increase ≥ 7% showed a dose-related trend, with a 5% incidence rate in the placebo group compared with rates of 6%, 8% and 13% in the Xeplion 25 mg, 100 mg, and 150 mg groups, respectively.

During the 33-week open-label transition/maintenance period of the long-term recurrence prevention trial, 12% of Xeplion-treated subjects met this criterion (weight gain of ≥ 7% from double-blind phase to endpoint); the mean (SD) weight change from open-label baseline was + 0.7 (4.79) kg.

Hyperprolactinaemia
In clinical trials, median increases in serum prolactin were observed in subjects of both genders who received Xeplion. Adverse reactions that may suggest increase in prolactin levels (e.g., amenorrhoea, galactorrhoea, menstrual disturbances, gynaecomastia) were reported overall in < 1% of subjects.

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).

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/