Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
The most frequently observed adverse drug reactions (ADRs) reported in ≥ 5 % of patients in two double-blind , long-term trials of Abilify Maintena were weight increased (9.0 %), akathisia (7.9 %), insomnia (5.8 %), and injection site pain (5.1 %).

Tabulated list of adverse reactions

The incidences of the ADRs associated with aripiprazole therapy are tabulated below. The table is based on adverse reactions reported during clinical trials and/or post-marketing use.

All ADRs are listed by system organ class and frequency; 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, adverse reactions are presented in order of decreasing seriousness.

The frequency of adverse reactions reported during post-marketing use cannot be determined as they are derived from spontaneous reports. Consequently, the frequency of these adverse events is qualified as "not known".

Common           Uncommon                     Not known

Blood and                        Neutropenia                  Leukopenia lymphatic                        Anaemia system                           Thrombocytopenia disorders                        Neutrophil count decreased
White blood cell count decreased
Immune                           Hypersensitivity             Allergic reaction (e.g.
system                                                        anaphylactic reaction, disorders                                                     angioedema including swollen tongue, tongue oedema, face oedema,
pruritus, or urticaria)
Endocrine                        Blood prolactin decreased    Diabetic hyperosmolar coma disorders                        Hyperprolactinaemia          Diabetic ketoacidosis 
Metabolism      Weight           Hyperglycaemia               Anorexia and             increased        Hypercholesterolaemia        Hyponatraemia nutrition       Diabetes         Hyperinsulinaemia disorders       mellitus         Hyperlipidaemia
Weight           Hypertriglyceridaemia decreased        Appetite disorder

Psychiatric     Agitation        Suicidal ideation            Completed suicide disorders       Anxiety          Psychotic disorder           Suicide attempt Restlessness     Hallucination                Pathological gambling
Insomnia         Delusion                     Impulse-control disorders Hypersexuality               Binge eating
Panic reaction               Compulsive shopping
Depression                   Poriomania
Affect lability              Nervousness
Apathy                       Aggression
Dysphoria
Sleep disorder
Bruxism
Libido decreased
Mood altered
Nervous         Extrapyramidal   Dystonia                     Neuroleptic malignant system          disorder         Tardive dyskinesia           syndrome disorders       Akathisia        Parkinsonism                 Grand mal convulsion Tremor           Movement disorder            Serotonin syndrome
Dyskinesia       Psychomotor hyperactivity    Speech disorder
Sedation         Restless legs syndrome
Common       Uncommon                     Not known

Somnolence   Cogwheel rigidity
Dizziness    Hypertonia
Headache     Bradykinesia
Drooling
Dysgeusia
Parosmia
Eye                          Oculogyric crisis disorders                    Vision blurred
Eye pain
Diplopia
Photophobia

Cardiac                      Ventricular extrasystoles    Sudden unexplained death disorders                    Bradycardia                  Cardiac arrest Tachycardia                  Torsades de pointes
Electrocardiogram T wave     Ventricular arrhythmias amplitude decreased          QT prolongation
Electrocardiogram abnormal
Electrocardiogram T wave inversion
Vascular                     Hypertension                 Syncope disorders                    Orthostatic hypotension      Venous thromboembolism Blood pressure increased     (including pulmonary embolism and deep vein thrombosis)
Respiratory,                 Cough                        Oropharyngeal spasm thoracic and                 Hiccups                      Laryngospasm mediastinal                                               Aspiration pneumonia disorders
Gastrointesti Dry mouth      Gastrooesophageal reflux     Pancreatitis nal disorders                disease                      Dysphagia
Dyspepsia
Vomiting
Diarrhoea
Nausea
Abdominal pain upper
Abdominal discomfort
Constipation
Frequent bowel movement
Salivary hypersecretion
Hepatobiliary                Liver function test          Hepatic failure disorders                    abnormal                     Jaundice
Hepatic enzyme increased     Hepatitis
Alanine aminotransferase     Alkaline phosphatase increased                    increased
Gamma-glutamyl transferase increased
Blood bilirubin increased
Aspartate aminotransferase
Common            Uncommon                    Not known
 increased
Skin and                         Alopecia                    Rash subcutaneous                     Acne                        Photosensitivity reaction tissue                           Rosacea                     Hyperhidrosis disorders                        Eczema                      Drug Reaction with Skin induration             Eosinophilia and Systemic
Symptoms (DRESS)
Musculoskel    Musculoskeletal   Muscle rigidity             Rhabdomyolysis etal and       stiffness         Muscle spasms connective                       Muscle twitching tissue                           Muscle tightness disorders                        Myalgia
Pain in extremity
Arthralgia
Back pain
Joint range of motion decreased
Nuchal rigidity
Trismus
Renal and                        Nephrolithiasis             Urinary retention, Urinary urinary                          Glycosuria                  incontinence disorders
Pregnancy,                                                   Drug withdrawal syndrome puerperium                                                   neonatal (see section 4.6) and perinatal conditions
Reproductive   Erectile          Galactorrhoea               Priapism system and     dysfunction       Gynaecomastia breast                           Breast tenderness disorders                        Vulvovaginal dryness
General        Injection site    Pyrexia                     Temperature regulation disorders      pain              Asthenia                    disorder (e.g. hypothermia, and            Injection site    Gait disturbance            pyrexia) administrati   induration        Chest discomfort            Chest pain on site        Fatigue           Injection site reaction     Peripheral oedema conditions                       Injection site erythema
Injection site swelling
Injection site discomfort
Injection site pruritus
Thirst
Sluggishness


Common             Uncommon                        Not known

Investigations   Blood creatine     Blood glucose increased         Blood glucose fluctuation phosphokinase      Blood glucose decreased increased          Glycosylated haemoglobin increased
Waist circumference increased
Blood cholesterol decreased
Blood triglycerides decreased


Description of selected adverse reactions
Injection site reactions
During the double-blind, controlled phases of the two long-term trials, injection site reactions were observed; those seen were generally mild to moderate in severity, and resolved over time. Injection site pain (incidence 5.1 %), had a median onset on day 2 after the injection and a median duration of 4 days.

In an open label study comparing bioavailability of Abilify Maintena administered in the deltoid or gluteal muscle, injection site related reactions were slightly more frequent in the deltoid muscle. The majority were mild and improved on subsequent injections. When compared to studies where Abilify Maintena was injected in the gluteal muscle, repeated occurrence of injection site pain was more frequent in the deltoid muscle.

Leukopenia
Neutropenia has been reported in the clinical program with Abilify Maintena and typically started around day 16 after first injection, and lasted a median of 18 days.

Extrapyramidal Symptoms (EPS)
In trials in stable patients with schizophrenia, Abilify Maintena was associated with a higher frequency of EPS symptoms (18.4 %) than oral aripiprazole treatment (11.7 %). Akathisia was the most frequently observed symptom (8.2 %) and typically started around day 10 after first injection, and lasted a median of 56 days.

Subjects with akathisia typically received anti-cholinergic medicines as treatment, primarily benzatropine mesilate and trihexyphenidyl. Less often substances such as propranolol and benzodiazepines (clonazepam and diazepam) were administered to control akathisia.
Parkinsonism events followed in frequency of 6.9 % for Abilify Maintena, 4.15 % for oral aripiprazole 10-30 mg tablets and 3.0 % for placebo, respectively.


Dystonia
Class effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with 
high potency and at higher doses of first generation antipsychotic medicinal products. An elevated risk of acute dystonia is observed in males and younger age groups.

Weight
During the Double-blind, Active-controlled Phase of the 38-week long-term trial, the incidence of weight gain of ≥ 7 % from baseline to last visit was 9.5 % for Abilify Maintena and 11.7 % for the oral aripiprazole tablets 10-30 mg. The incidence of weight loss of ≥ 7 % from baseline to last visit was 10.2 % for Abilify Maintena and 4.5 % for oral aripiprazole tablets 10-30 mg.

During the Double-blind, Placebo-controlled Phase of the 52-week long-term trial, the incidence of weight gain of ≥ 7 % from baseline to last visit was 6.4 % for Abilify Maintena and 5.2 % for placebo.
The incidence of weight loss of ≥ 7 % from baseline to last visit was 6.4 % for Abilify Maintena and 6.7 % for placebo. During double-blind treatment, mean change in body weight from baseline to last visit was -0.2 kg for Abilify Maintena and -0.4 kg for placebo (p = 0.812).

Prolactin
In clinical trials for the approved indications and post-marketing, both increase and decrease in serum prolactin as compared to baseline was observed with aripiprazole (section 5.1).

Pathological gambling and other impulse control disorders

Pathological gambling, hypersexuality, compulsive shopping and binge or compulsive eating can occur in patients treated with aripiprazole (see section 4.4).


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/