Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Narcolepsy with or without cataplexy
Summary of the safety profile

The most frequent adverse drug reactions (ADRs) reported with pitolisant were insomnia (8.4%), headache (7.7%), nausea (4.8%), anxiety (2.1%), irritability (1.8%), dizziness (1.4%), depression (1.3%), tremor (1.2%), sleep disorders (1.1%), fatigue (1.1%), vomiting (1.0%), vertigo (1.0%), dyspepsia (1.0%), weight increase (0.9%), abdominal pain upper (0.9%). The most serious ADRs are abnormal weight decrease (0.09%) and abortion spontaneous (0.09%).

Tabulated list of adverse reactions

The following adverse reactions have been reported with pitolisant during clinical studies in narcolepsy and other indications and are listed below as MedDRA preferred term by system organ class and frequency; frequencies are defined as: 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); within each frequency group, adverse reactions are presented in order of decreasing seriousness: 
Common                    Uncommon                       Rare
Metabolism and nutrition                                       Decreased appetite              Anorexia disorders                                                      Increased appetite            Hyperphagia Fluid retention           Appetite disorder
Psychiatric disorders                    Insomnia                   Agitation             Abnormal behaviour Anxiety                Hallucination             Confusional state
Irritability          Hallucination visual,        Depressed mood
Depression                   auditory                  Excitability
Sleep disorder             Affect lability          Obsessive thoughts Abnormal dreams                Dysphoria
Dyssomnia                Hypnopompic
Middle insomnia              hallucination
Initial insomnia          Depressive symptom
Terminal insomnia             Hypnagogic
Nervousness                hallucination
Tension              Mental impairment
Apathy
Nightmare
Restlessness
Panic Attack
Libido decreased
Libido increased

Suicidal ideation

Nervous system disorders      Headache               Dyskinesia          Loss of consciousness Dizziness          Balance disorder         Tension headache
Tremor                Cataplexy           Memory impairment
Disturbance in attention    Poor sleep quality
Dystonia
On and off phenomenon
Hypersomnia
Migraine
Psychomotor hyperactivity
Restless Legs Syndrome
Somnolence
Epilepsy
Bradykinesia
Paresthesia
Eye disorders                                  Visual acuity reduced
Blepharospasm
Ear and labyrinth disorders    Vertigo               Tinnitus
Cardiac disorders                                  Extrasystoles
Bradycardia
Vascular disorders                                 Hypertension
Hypotension
Hot flush
Respiratory, thoracic and                           Yawning mediastinal disorders
Gastrointestinal disorders     Nausea               Dry mouth            Abdominal distension Vomiting           Abdominal pain              Dysphagia
Dyspepsia             Diarrhoea                Flatulence
Abdominal discomfort          Odynophagia
Abdominal pain upper          Enterocolitis
Constipation
Gastrooesophageal reflux disease
Gastritis
Gastrointestinal pain
Hyperacidity
Paraesthesia oral
Stomach discomfort
Skin and subcutaneous                               Erythema              Toxic skin eruption tissue disorders                                     Pruritus              Photosensitivity Rash
Hyperhidrosis
Sweating
Musculoskeletal and                                 Arthralgia               Neck pain connective tissue disorders                         Back pain            Musculoskeletal chest Muscle rigidity                pain
Muscular weakness
Musculoskeletal pain
Myalgia
Pain in extremity


Renal and urinary disorders                                         Pollakiuria Pregnancy, puerperium and                                                                 Abortion spontaneous perinatal conditions
Reproductive system and                                           Metrorrhagia breast disorders
General disorders and                    Fatigue                     Asthenia                     Pain administration site                                                 Chest Pain                Night sweats conditions                                                      Feeling Abnormal           Sense of oppression Malaise
Oedema
Peripheral oedema
Investigations                                                  Weight increased                Creatine Weight decreased             phosphokinase
Hepatic enzymes                increased increased
Electrocardiogram QT          General physical prolonged             condition abnormal
Heart rate increased        Electrocardiogram
Gamma-                  repolarisation glutamyltransferase            abnormality increased             Electrocardiogram T wave inversion

Description of selected adverse reactions

Headache and insomnia
During clinical studies, episodes of headache and insomnia have been reported (7.7 % to 8.4%). Most of these adverse reactions were mild to moderate. If symptoms persist a reduced daily dose or discontinuation should be considered.

Gastric disorders
Gastric disorders caused by hyperacidity have been reported during clinical studies in 3.5% of the patients receiving pitolisant. These effects were mostly mild to moderate. If they persist a corrective treatment with proton pump inhibitor could be initiated.

Obstructive sleep apnoea (OSA)

Summary of the safety profile
The most frequent adverse reactions are headache 12.4%, insomnia (all types) 8.9%, nausea 3.3%, anxiety 2.2%, abdominal pain 2.8%, vertigo 1.7% and diarrhoea 1%.

Tabulated list of adverse reactions

The following adverse reactions have been reported with pitolisant during clinical studies are listed below as MedDRA preferred term by system organ class and frequency; frequencies are defined as: 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); within each frequency group, adverse reactions are presented in order of decreasing seriousness:

Very Common               Common                           Uncommon
Infections and infestations                                                                  Herpes zoster; Viral upper respiratory;
tract infection.

Blood and lymphatic system                                                   Alanine disorders                                                                aminotransferase increased;
Blood cholesterol increased;
Blood pressure increased
Blood triglycerides increased;
Hepatic enzyme increased;
Transaminase increased
Metabolism and nutrition                                                     Alcohol disorders                                                                  intolerance; Increased appetite;
Hypoglycaemia;
Weight decreased;
Weight increased


Psychiatric disorders                         Insomnia (all types)         Confusional Anxiety disorders              arousal;
Sleep disorders         Depressed mood disorders and disturbances;
Fear;
Irritability;
Nervousness disorders;
Libido disorders;
Panic reaction;
Withdrawal syndrome
Nervous system disorders      Headache                                  Circadian rhythm sleep disorder;
Dizziness;
Dysgeusia;
Psychomotor hyperactivity;
Migraine;
Sleep paralysis
Hypotonia

Eye disorders                                                               Dry eye; Photopsia
Ear and labyrinth disorders                         Vertigo                  Tinnitus 
Cardiac disorders                                                        Atrioventricular block first degree;
Palpitations;
Tachycardia;
Ventricular extrasystoles;
Electrocardiogram
QT prolonged;
Heart rate increased


Vascular disorders                                           Hypertension                     Hot flush 

Respiratory, thoracic and                                                                  Yawning Cough; mediastinal disorders                                                                        Nocturnal dyspnoea

Gastrointestinal disorders                                Nausea/vomiting;                Constipation; Abdominal pain and discomfort          Dry mouth;
Diarrhoea                     Enterocolitis;
Faeces discoloured
;Gastrointestinal disorders;
Breath odour;
Flatulence;
Rectal haemorrhage;
Salivary hypersecretion
Skin and subcutaneous tissue                                                                   Rash; disorders                                                                                 Hyperhidrosis, Pruritus Erythema;
Cold sweat;
Night sweats;
Solar dermatitis

Musculoskeletal and                                                                        Limb discomfort; connective tissue disorders                                                                 Muscle spasms; Myalgia;
Arthralgia;
Tendonitis


Renal and urinary disorders                                                                   Pollakiuria 

General disorders and                                     Pain and Discomfort                 Asthenia; administration site conditions                                                                 Pyrexia; Thirst

Description of selected adverse reactions

Headache and insomnia
During clinical studies in OSA indication, episodes of headache and insomnia have been reported (12.4 % and 8.9%) more frequently in women (headache and insomnia) and in elderly (insomnia) patients. Most of these adverse reactions were mild to moderate (see section 4.2). Dosing should be adjusted accordingly.

Gastric disorders
Gastric disorders presumably caused by hyperacidity have been reported during clinical studies in 3.5% of the patients receiving pitolisant. Higher rates of nausea are reported in women. These effects were mostly mild to moderate. If they persist, a corrective treatment with proton pump inhibitor could be initiated.

Patients with low/normal Body Mass Index (BMI) (<25)
Headache, insomnia, nausea and anxiety have been reported in higher rates in patients with low/normal BMI. Dosing should be adjusted accordingly.

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