Adverse reactions : תופעות לוואי

 4.8    Undesirable effects
The most frequently reported adverse drug reactions (ADRs) (incidence ≥ 10%) are: Parkinsonism, sedation/somnolence, headache, and insomnia.
The ADRs that appeared to be dose-related included parkinsonism and akathisia.

In a placebo-controlled acute mania trial in children and adolescents (aged 10 – 17 years), there were no significant changes in ECG parameters, other than the effect of RISPERDAL® to transiently increase pulse rate (< 6 beats per minute). In two controlled schizophrenia trials in adolescents (aged 13 – 17 years), there were no clinically meaningful changes in ECG parameters including corrected QT intervals between treatment groups or within treatment groups over time.

The following are all the ADRs that were reported in clinical trials and post-marketing experience with risperidone by frequency category estimated from RISPERDAL 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).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

System Organ                                            Adverse Drug Reaction Class
Frequency
Very Common Common                        Uncommon                                    Rare          Very Rare      Not Known Infections and             pneumonia, bronchitis,        respiratory tract infection,       infection infestations               upper respiratory tract       cystitis, eye infection, infection, sinusitis, urinary tonsillitis, onychomycosis,
tract infection, ear          cellulitis localised infection,
infection, influenza          viral infection,
acarodermatitis
Blood and                                                     neutropenia, white blood cell agranulocytosisc lymphatic                                                     count decreased, system                                                        thrombocytopenia, anaemia, disorders                                                     haematocrit decreased, eosinophil count increased

Immune                                                        hypersensitivity              anaphylactic system                                                                                      reactionc disorders

Endocrine                        hyperprolactinaemiaa                                        inappropriate disorders                                                                                    antidiuretic hormone secretion, glucose urine present
Metabolism                       weight increased,                             b diabetes mellitus ,            water  intoxicationc, diabetic and nutrition                    increased appetite,          hyperglycaemia, polydipsia, hypoglycaemia,           ketoacidosis disorders                        decreased appetite           weight decreased, anorexia, hyperinsulinaemia ,   c  blood cholesterol increased blood triglycerides increased
Psychiatric     insomniad        sleep disorder, agitation,   mania, confusional state,      catatonia, disorders                        depression, anxiety          libido decreased, nervousness, somnambulism, nightmare                      sleep- related eating disorder, blunted affect, anorgasmia


Nervous          sedation/      akathisiad, dystoniad,      tardive dyskinesia, cerebral      neuroleptic malignant system           somnolence,    dizziness, dyskinesiad,     ischaemia, unresponsive to        syndrome, disorders        parkinsonismd, tremor                      stimuli, loss of consciousness,   cerebrovascular headache                                   depressed level of                disorder, diabetic consciousness, convulsiond,       coma, head titubation syncope, psychomotor hyperactivity, balance disorder, coordination abnormal, dizziness postural,
disturbance in attention,
dysarthria, dysgeusia,
hypoaesthesia, paraesthesia
Eye disorders                    vision blurred,            photophobia, dry eye,             glaucoma, eye conjunctivitis             lacrimation increased, ocular     movement disorder, hyperaemia                        eye rolling, eyelid margin crusting,
floppy iris syndrome
(intraoperative)c
Ear and                                                     vertigo, tinnitus, ear pain labyrinth disorders

Cardiac                          tachycardia                atrial fibrillation,        sinus arrhythmia disorders                                                   atrioventricular block, conduction disorder,
electrocardiogram QT prolonged, bradycardia,
electrocardiogram abnormal,
palpitations
Vascular                         hypertension               hypotension, orthostatic    pulmonary embolism, disorders                                                   hypotension, flushing       venous thrombosis 

Respiratory,                     dyspnoea,                  pneumonia aspiration,             sleep apnoea thoracic and                     pharyngolaryngeal pain,    pulmonary congestion,             syndrome, mediastinal                      cough, epistaxis, nasal    respiratory tract congestion,     hyperventilation disorders                        congestion                 rales, wheezing, dysphonia, respiratory disorder
Gastrointestin                   abdominal pain,            faecal incontinence,              pancreatitis, intestinal ileus al disorders                     abdominal discomfort,      faecaloma, gastroenteritis,       obstruction, swollen vomiting, nausea,          dysphagia, flatulence             tongue, cheilitis constipation, diarrhoea,
dyspepsia, dry mouth,
toothache
Skin and                         rash, erythema             urticaria, pruritus, alopecia, drug eruption,             angioedema Stevens-Johnson subcutaneous                                                hyperkeratosis, eczema, dry dandruff                                 syndrome/toxic tissue                                                      skin, skin discolouration,                                           epidermal disorders                                                   acne, seborrhoeic dermatitis,                                        necrolysisc skin disorder, skin lesion
Musculoskelet                    muscle spasms,             blood creatine phosphokinase rhabdomyolysis al and                           musculoskeletal pain,      increased, posture abnormal, connective                       back pain, arthralgia      joint stiffness, joint swelling tissue                                                      muscular weakness, neck pain disorders
Renal and                        urinary incontinence       pollakiuria, urinary retention, urinary                                                     dysuria disorders


Pregnancy,                                                                                   drug withdrawal puerperium,                                                                                  syndrome neonatalc and neonatal conditions
Reproductive                                                 erectile dysfunction,           priapismc, system and                                                   ejaculation disorder,           menstruation breast                                                       amenorrhoea, menstrual          delayed, breast disorders                                                    disorderd, gynaecomastia,       engorgement, breast galactorrhoea, sexual           enlargement, breast dysfunction, breast pain,       discharge breast discomfort, vaginal discharge
General                           oedemad, pyrexia, chest    face oedema, chills, body       hypothermia, body disorders and                     pain, asthenia, fatigue,   temperature increased, gait     temperature administration                    pain                       abnormal, thirst, chest         decreased, peripheral site conditions                                              discomfort, malaise, feeling    coldness, drug abnormal, discomfort            withdrawal syndrome,
indurationc
Hepatobiliary                                                transaminases increased,        jaundice disorders                                                    gamma-glutamyltransferase increased, hepatic enzyme increased
Injury,                           fall                       procedura pain poisoning and procedural complications
 a
Hyperprolactinaemia can in some cases lead to gynaecomastia, menstrual disturbances, amenorrhoea, anovulation, galactorrhoea, fertility disorder, decreased libido, erectile dysfunction.
b
In placebo-controlled trials diabetes mellitus was reported in 0.18% in risperidone-treated subjects compared to a rate of 0.11% in placebo group. Overall incidence from all clinical trials was 0.43% in all risperidone-treated subjects.
c
Not observed in RISPERDAL clinical studies but observed in post-marketing environment with risperidone.
d
Extrapyramidal disorder may occur: Parkinsonism (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 (akathisia, restlessness, hyperkinesia, and restless leg syndrome), tremor, dyskinesia (dyskinesia, muscle twitching, choreoathetosis, athetosis, and myoclonus), dystonia. 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. It should be noted that a broader spectrum of symptoms are included, that do not necessarily have an extrapyramidal origin. Insomnia includes initial insomnia, middle insomnia.
Convulsion includes grand mal convulsion. Menstrual disorder includes menstruation irregular, oligomenorrhoea.
Oedema includes generalised oedema, oedema peripheral, pitting oedema.

Undesirable effects noted with paliperidone 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 reaction has been noted with the use of paliperidone products and can be expected to occur with RISPERDAL.

Cardiac disorders
Postural orthostatic tachycardia syndrome

Class effects
As with other antipsychotics, very rare cases of QT prolongation have been reported post-marketing with risperidone. Other class-related cardiac effects reported with antipsychotics which prolong QT interval include ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia, sudden death, cardiac arrest and Torsades de Pointes.

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

Weight gain
Weight gain has been observed in children and adolescents during treatment with RISPERDAL.
Clinical monitoring of weight is recommended during treatment.
The proportions of RISPERDAL and placebo-treated adult patients with schizophrenia meeting a weight gain criterion of ≥ 7% of body weight were compared in a pool of 6- to 8-week, placebo- controlled trials, revealing a statistically significantly greater incidence of weight gain for RISPERDAL (18%) compared to placebo (9%). In a pool of placebo-controlled 3-week studies in adult patients with acute mania, the incidence of weight increase of ≥ 7% at endpoint was comparable in the RISPERDAL (2.5%) and placebo (2.4%) groups, and was slightly higher in the active-control group (3.5%).

In a population of children and adolescents with conduct and other disruptive behaviour disorders, in long-term studies, weight increased by a mean of 7.3 kg after 12 months of treatment. The expected weight gain for normal children between 5-12 years of age is 3 to 5 kg per year. From 12-16 years of age, this magnitude of gaining 3 to 5 kg per year is maintained for girls, while boys gain approximately 5 kg per year.

Data derive from short-term placebo-controlled trials and longer-term uncontrolled studies in pediatric patients (ages 5 to 17 years) with schizophrenia, bipolar disorder, autistic disorder, or other psychiatric disorders. In the short-term trials (3 to 8 weeks), the mean weight gain for RISPERDAL-treated patients was 2 kg, compared to 0.6 kg for placebo-treated patients. In these trials, approximately 33% of the RISPERDAL group had weight gain >7%, compared to 7% in the placebo group. In longer-term, uncontrolled, open-label pediatric studies, the mean weight gain was 5.5 kg at Week 24 and 8 kg at Week 48.


Additional information on special populations
Adverse drug reactions that were reported with higher incidence in elderly patients with dementia or paediatric patients than in adult populations are described below:

Elderly patients with dementia
Transient ischaemic attack and cerebrovascular accident were ADRs reported in clinical trials with a frequency of 1.4% and 1.5%, respectively, in elderly patients with dementia. In addition, the following ADRs were reported with a frequency ≥ 5% in elderly patients with dementia and with at least twice the frequency seen in other adult populations: urinary tract infection, peripheral oedema, lethargy, and cough.

Paediatric population

In general, type of adverse reactions in children is expected to be similar to those observed in adults.
The following ADRs were reported with a frequency ≥ 5% in paediatric patients (5 to 17 years) and with at least twice the frequency seen in clinical trials in adults: somnolence/sedation, fatigue, headache, increased appetite, vomiting, upper respiratory tract infection, nasal congestion, abdominal pain, dizziness, cough, pyrexia, tremor, diarrhoea, and enuresis.
Somnolence was the most commonly observed adverse reaction in the clinical trial of bipolar disorder in children and adolescents, as well as in the schizophrenia trials in adolescents.
The effect of long-term risperidone treatment on sexual maturation and height has not been adequately studied (see section 4.4, subsection “Paediatric population”).

Hyperprolactinemia

RISPERDAL has been shown to elevate prolactin levels in children and adolescents as well as in adults In double-blind, placebo-controlled studies of up to 8 weeks duration in children and adolescents (aged 5 to 17 years) with autistic disorder or psychiatric disorders other than autistic disorder, schizophrenia, or bipolar mania, 49% of patients who received RISPERDAL had elevated prolactin levels compared to 2% of patients who received placebo. Similarly, in placebo-controlled trials in children and adolescents (aged 10 to 17 years) with bipolar disorder, or adolescents (aged 13 to 17 years) with schizophrenia, 82–87% of patients who received RISPERDAL had elevated levels of prolactin compared to 3-7% of patients on placebo. Increases were dose-dependent and generally greater in females than in males across indications.
In clinical trials in 1885 children and adolescents, galactorrhea was reported in 0.8% of RISPERDAL- treated patients and gynecomastia was reported in 2.3% of RISPERDAL-treated patients.

Pediatric Patients with Schizophrenia
The table below lists the adverse reactions reported in 5% or more of RISPERDAL®-treated pediatric patients with schizophrenia in a 6-week double-blind, placebo-controlled trial.

Table       Adverse Reactions in ≥5% of RISPERDAL-Treated Pediatric Patients (and greater than placebo) with Schizophrenia in a Double-Blind Trial
Percentage of Patients Reporting Reaction
RISPERDAL
System/Organ Class                                 1-3 mg per day       4-6 mg per day         Placebo Adverse Reaction                                      (N=55)                (N=51)            (N=54) Gastrointestinal Disorders
Salivary hypersecretion                                 0                     10                  2 Nervous System Disorders
Sedation                                                24                    12                  4 Parkinsonism*                                           16                    28                  11 Tremor                                                  11                    10                  6 Akathisia*                                              9                     10                  4 Dizziness                                               7                     14                  2 Dystonia*                                               2                     6                   0 Psychiatric Disorders
Anxiety                                                 7                     6                   0 * Parkinsonism includes extrapyramidal disorder, muscle rigidity, musculoskeletal stiffness, and hypokinesia. Akathisia includes akathisia and restlessness. Dystonia includes dystonia and oculogyration.


Growth and Sexual Maturation
The long-term effects of RISPERDAL on growth and sexual maturation have not been fully evaluated in children and adolescents.

Juvenile Animal Studies
Juvenile dogs were treated with oral risperidone from weeks 10 to 50 of age (equivalent to the period of childhood through adolescence in humans), at doses of 0.31, 1.25, or 5 mg/kg/day, which are 1.2, 3.4, and 13.5 times the MRHD of 6 mg/day for children, based on mg/m2 body surface area. Bone length and density were decreased with a no-effect dose of 0.31 mg/kg/day; this dose produced plasma AUC of risperidone plus its active metabolite paliperidone (9-hydroxyrisperidone) that were similar to those in children and adolescents receiving the MRHD of 6 mg/day. In addition, sexual maturation was delayed at all doses in both males and females. The above effects showed little or no reversibility in females after a 12 week drug-free recovery period.
Juvenile rats, treated with oral risperidone from days 12 to 50 of age (equivalent to the period of infancy through adolescence in humans) showed impaired learning and memory performance (reversible only in females), with a no-effect dose of 0.63 mg/kg/day which is 0.5 times the MRHD of 6 mg/day for children, based on mg/m2 body surface area. This dose produced plasma AUC of risperidone plus paliperidone about half the exposure observed in humans at the MRHD. No other consistent effects on neurobehavioral or reproductive development were seen up to the highest tested dose of 1.25 mg/kg/day which is 1 time the MRHD and produced plasma AUC of risperidone plus paliperidone that were about two thirds of those observed in humans at the MRHD of 6 mg/day for children.

Reporting of suspected adverse reactions

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