Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile

Chronic liver disease
The safety of avatrombopag was evaluated in two randomised, double-blind, placebo-controlled trials, ADAPT-1 and ADAPT-2, in which 430 patients with chronic liver disease and thrombocytopenia received either avatrombopag (n = 274) or placebo (n = 156), and had 1 post-dose safety assessment.



Chronic immune thrombocytopenia

The safety of avatrombopag was evaluated in three controlled trials and one uncontrolled trial which enrolled 161 patients with chronic immune thrombocytopenia. The pooled safety data from these four trials includes 128 patients who were exposed to avatrombopag for a median duration of 29 weeks.

Tabulated list of adverse reactions

Adverse reactions are classified by Preferred Term and System Organ Class, and by 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); not known (cannot be estimated from the available data).

Chronic liver disease study population

System organ class
Common                 Uncommon                Not known
(MedDRA terminology*)
Blood and lymphatic system                               Anaemia disorders
Immune system disorders                                                          Hypersensitivity Portal vein
Vascular disorders thrombosis
Musculoskeletal & connective                             Bone pain tissue disorders                                         Myalgia
General disorders and            Fatigue                 Pyrexia administration site conditions
*
Medical Dictionary for Regulatory Activities (MedDRA) version 19.1.

Chronic primary immune thrombocytopenia study population

System organ class               Frequency        Adverse reaction
MedDRA terminology
Infections and infestations      Uncommon         Furuncle, Thrombophlebitis septic, Upper respiratory tract infection
Neoplasms benign, malignant      Uncommon         Myelofibrosis and unspecified (including cysts and polyps)
Blood and lymphatic system       Common           Thrombocytopenia, Anaemia, Splenomegaly disorders                        Uncommon         Leukocytosis
Immune system disorders          Not known        Hypersensitivity
Metabolism and nutrition         Common           Hyperlipidaemia, Decreased appetite disorders                        Uncommon         Dehydration, Hypertriglyceridaemia, Increased appetite, Iron deficiency
Psychiatric disorders            Uncommon         Mood swings
Nervous system disorders         Very common      Headache
Common           Dizziness, Head discomfort, Migraine,
Paraesthesia
Uncommon         Cerebrovascular accident, Cognitive disorder,
Dysgeusia, Hypoaesthesia, Sensory disturbance,
Transient ischaemia attack
Eye disorders                    Uncommon         Abnormal sensation in eye, Eye irritation, Eye 
System organ class               Frequency        Adverse reaction
MedDRA terminology pruritus, Eye swelling, Lacrimation increased,
Ocular discomfort, Photophobia, Retinal artery occlusion, Vision blurred, Visual impairment
Ear and labyrinth disorders      Uncommon         Ear pain, Hyperacusis Cardiac disorders                Uncommon         Myocardial infarction Vascular disorders               Common           Hypertension
Uncommon         Deep vein thrombosis, Jugular vein thrombosis,
Vasoconstriction
Respiratory, thoracic and        Common           Epistaxis, Dyspnoea mediastinal disorders            Uncommon         Haemoptysis, Nasal congestion, Pulmonary embolism
Gastrointestinal disorders       Common           Nausea, Diarrhoea, Vomiting, Abdominal pain upper, Flatulence
Uncommon         Abdominal discomfort, Abdominal distension,
Abdominal pain lower, Anorectal varices,
Constipation, Eructation, Gastrooesophageal reflux disease, Glossodynia, Haemorrhoids,
Paraesthesia oral, Swollen tongue, Tongue disorder
Hepatobiliary disorders          Uncommon         Portal vein thrombosis Skin and subcutaneous tissue     Common           Rash, Acne, Petechiae, Pruritis disorders                        Uncommon         Alopecia, Dry skin, Ecchymosis, Hyperhidrosis, Pigmentation disorder, Rash pruritic, Skin haemorrhage, Skin irritation
Musculoskeletal and              Common           Arthralgia, Back pain, Pain in extremity, connective tissue disorders                       Myalgia, Musculoskeletal pain Uncommon         Arthropathy, Limb discomfort, Muscle spasms,
Muscular weakness, Musculoskeletal chest pain
Renal and urinary disorders      Uncommon         Haematuria
Reproductive system and          Uncommon         Menorrhagia, Nipple pain breast disorders
General disorders and            Very common      Fatigue administration site conditions   Common           Asthenia
Uncommon        Chest discomfort, Hunger, Pain, Peripheral swelling
Investigations                 Common            Blood  glucose increased, Platelet count increased, Blood glucose decreased, Blood triglycerides increased, Blood lactate dehydrogenase increased, Platelet count decreased, Alanine aminotransferase increased,
Blood gastrin increased
Uncommon          Aspartate aminotransferase increased , Blood pressure increased, Heart rate irregular, Hepatic enzyme increased
*
Medical Dictionary for Regulatory Activities (MedDRA) version 19.1.



Description of selected adverse reactions

Thromboembolic events
In the ADAPT-1 and ADAPT-2 clinical trials in patients with thrombocytopenia and chronic liver disease, there was 1 treatment-emergent event of portal vein thrombosis in a patient (n = 1/274 of patients receiving avatrombopag) which was reported 14 days after treatment with Optzuro ended.
This adverse reaction was assessed as non-serious.

In the four pooled clinical trials in patients with chronic immune thrombocytopenia, thromboembolic events were observed in 7% (9/128) of patients. The only thromboembolic event which occurred in more than 1 individual patient was cerebrovascular accident, occurring in 1.6% (2/128).

Thrombocytopenia following discontinuation of treatment in patients with chronic immune thrombocytopenia

In the 4 pooled clinical trials in patients with chronic immune thrombocytopenia, transient decreases in platelet counts to levels lower than baseline were observed following discontinuation of treatment in 8.6% (11/128) of patients treated with avatrombopag.

Hypersensitivity reactions

Hypersensitivity reactions including pruritus, rash, swelling face, and swollen tongue.
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