Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile

The most serious adverse reactions during treatment were liver aminotransferase abnormalities (see section 4.4).

The most common adverse reactions were gastrointestinal effects. Gastrointestinal adverse reactions were reported by 27 (93%) of 29 patients in the Phase 3 clinical study. Diarrhoea occurred in 79% of patients, nausea in 65%, dyspepsia in 38%, and vomiting in 34%. Other reactions reported by at least 20% of patients include abdominal pain, abdominal discomfort, abdominal distension, constipation,
and flatulence. Gastrointestinal adverse reactions occurred more frequently during the dose escalation phase of the study and decreased once patients established the maximum tolerated dose of lomitapide.

Gastrointestinal adverse reactions of severe intensity were reported by 6 (21%) of 29 patients in the Phase 3 clinical study, with the most common being diarrhoea (4 patients, 14%); vomiting (3 patients, 10%); and abdominal pain, distension, and/or discomfort (2 patients, 7%). Gastrointestinal reactions contributed to the reasons for early discontinuation from the study for 4 (14%) patients.

The most commonly reported adverse reactions of severe intensity were diarrhoea (4 subjects, 14%), vomiting (3 patients, 10%), and abdominal distension and ALT increased (2 subjects each, 7%).

Tabulated list of adverse reactions

The adverse reactions are listed below by SOC (System Organ Class) and by frequency, most frequent reactions first. Frequency of the adverse reactions is 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), not known (cannot be estimated from the available data).

Table 3 lists all adverse reactions reported across the 35 patients treated in the Phase 2 Study UP1001 and in the Phase 3 Study UP1002/AEGR-733-005 or its extension study AEGR-733-012.



Table 3:         Frequency of adverse reactions in HoFH patients
System Organ Class                 Frequency              Adverse reaction Infections and infestations        Common                 Gastroenteritis Metabolism and nutrition           Very common            Decreased appetite disorders                          Not known              Dehydration Nervous system disorders           Common                 Dizziness
Headache
Migraine
Gastrointestinal disorders         Very common            Diarrhoea
Nausea
Vomiting
Abdominal discomfort
Dyspepsia
Abdominal pain
Abdominal pain upper
Flatulence
Abdominal distension
Constipation
Common                 Gastritis
Rectal tenesmus
Aerophagia
Defaecation urgency
Eructation
Frequent bowel movements
Gastric dilatation
Gastric disorder Gastro- oesophageal reflux disease
Haemorrhoidal haemorrhage
Regurgitation
Hepatobiliary disorders            Common                 Hepatic steatosis Hepatotoxicity
Hepatomegaly
Skin and subcutaneous tissue       Common                 Ecchymosis disorders                                                 Papule
Rash erythematous
Xanthoma
Not known              Alopecia
Musculoskeletal and connective     Not known              Myalgia tissue disorders
General disorders and              Common                 Fatigue administration site conditions
Investigations                     Very common            Alanine aminotransferase increased Aspartate aminotransferase increased
Weight decreased
Common                 International normalised ratio increased
Blood alkaline phosphatase increased
Blood potassium decreased
Carotene decreased
International normalised ratio abnormal
Liver function test abnormal
Prothrombin time prolonged
Transaminases increased
Vitamin E decreased
Vitamin K decreased

Table 4 lists all adverse reactions for subjects who received lomitapide monotherapy (N=291) treated in Phase 2 studies in subjects with elevated LDL-C (N=462).
Table 4:        Frequency of adverse reactions in elevated LDL-C patients System Organ Class                 Frequency               Adverse reaction Infections and infestations        Uncommon                Gastroenteritis Gastrointestinal infection
Influenza
Nasopharyngitis
Sinusitis
Blood and lymphatic system         Uncommon                Anaemia disorders
Metabolism and nutrition           Common                  Decreased appetite disorders                          Uncommon                Dehydration Increased appetite
Nervous system disorders           Uncommon                Paraesthesia Somnolence
Eye disorders                      Uncommon                Eye swelling Ear and labyrinth disorders        Uncommon                Vertigo
Respiratory, thoracic and          Uncommon                Pharyngeal lesion mediastinal disorders                                      Upper-airway cough syndrome Gastrointestinal disorders         Very common             Diarrhoea
Nausea
Flatulence
Common                  Abdominal pain upper
Abdominal distension
Abdominal pain
Vomiting
Abdominal discomfort
Dyspepsia
Eructation
Abdominal pain lower
Frequent bowel movements
Uncommon                Dry mouth
Faeces hard
Gastro-oeosophageal reflux disease
Abdominal tenderness
Epigastric discomfort
Gastric dilatation
Haematemesis
Lower gastrointestinal haemorrhage
Reflux oesophagitis
Hepatobiliary disorders            Uncommon                Hepatomegaly Skin and subcutaneous tissue       Uncommon                Blister disorders                                                  Dry skin
Hyperhidrosis
Musculoskeletal and connective     Common                  Muscle spasms tissue disorders                   Uncommon                Arthralgia Myalgia
Pain in extremity
Joint swelling
Muscle twitching
Renal and urinary disorders        Uncommon                Haematuria 


System Organ Class                    Frequency                 Adverse reaction General disorders and                 Common                    Fatigue administrative site conditions                                  Asthenia Uncommon                  Chest pain
Chills
Early satiety
Gait disturbance
Malaise
Pyrexia
Investigations                        Common                    Alanine aminotransferase increased Aspartate aminotransferase increased
Hepatic enzyme increased
Liver function test abnormal
Neutrophil count decreased
White blood cell count decreased
Uncommon                  Weight decreased
Blood bilirubin increased
Gamma-glutamyltransferase increased
Neutrophil percentage increased
Protein urine
Prothrombin time prolonged
Pulmonary function test abnormal
White blood cell count increased

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