Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
Immune thrombocytopenia in adult and paediatric patients

The safety of Revolade was assessed in adult patients (N=763) using the pooled double-blind, placebo-controlled studies TRA100773A and B, TRA102537 (RAISE) and TRA113765, in which 403 patients were exposed to Revolade and 179 to placebo, in addition to data from the completed open-label studies (N=360) TRA108057 (REPEAT), TRA105325 (EXTEND) and TRA112940 (see section 5.1). Patients received study medication for up to 8 years (in EXTEND). The most important serious adverse reactions were hepatotoxicity and thrombotic/thromboembolic events. The most common adverse reactions occurring in at least 10% of patients included nausea, diarrhoea, increased alanine aminotransferase and back pain.

The safety of Revolade in paediatric patients (aged 1 to 17 years) with previously treated ITP has been demonstrated in two studies (N=171) (see section 5.1). PETIT2 (TRA115450) was a two-part, double- blind and open-label, randomised, placebo-controlled study. Patients were randomised 2:1 and received Revolade (n=63) or placebo (n=29) for up to 13 weeks in the randomised period of the study.
PETIT (TRA108062) was a three-part, staggered-cohort, open-label and double-blind, randomised, placebo-controlled study. Patients were randomised 2:1 and received Revolade (n=44) or placebo (n=21), for up to 7 weeks. The profile of adverse reactions was comparable to that seen in adults with some additional adverse reactions, marked ♦ in the table below. The most common adverse reactions in paediatric ITP patients 1 year and older (≥3% and greater than placebo) were upper respiratory tract infection, nasopharyngitis, cough, pyrexia, abdominal pain, oropharyngeal pain, toothache and rhinorrhoea.

Thrombocytopenia with HCV infection in adult patients

ENABLE 1 (TPL103922 n=716, 715 treated with eltrombopag)) and ENABLE 2 (TPL108390 n=805) were randomised, double-blind, placebo-controlled, multicentre studies to assess the efficacy and safety of Revolade in thrombocytopenic patients with HCV infection who were otherwise eligible to initiate antiviral therapy. In the HCV studies the safety population consisted of all randomised patients who received double-blind study medicinal product during Part 2 of ENABLE 1 (Revolade treatment n=450, placebo treatment n=232) and ENABLE 2 (Revolade treatment n=506, placebo treatment n=252). Patients are analysed according to the treatment received (total safety double-blind population, Revolade n=955 and placebo n=484). The most important serious adverse reactions identified were hepatotoxicity and thrombotic/thromboembolic events. The most common adverse reactions occurring in at least 10% of patients included headache, anaemia, decreased appetite,cough, nausea, diarrhoea, hyperbilirubinaemia, alopecia, pruritus, myalgia, pyrexia, fatigue, influenza-like illness, asthenia, chills and oedema.

Severe Aplastic Anaemia

First-line treatment of severe aplastic anaemia
The safety of eltrombopag was established based upon a single-arm trial of 153 patients with severe aplastic anaemia who had not received prior definitive immunosuppressive therapy. In this trial, eltrombopag was administered in combination with horse antithymocyte globulin (h-ATG) and cyclosporine [see section 5.1]. Among the 153 patients who were dosed in this trial, 92 patients were evaluable for safety of the concurrent use of eltrombopag, h-ATG, and cyclosporine at the recommended dose and schedule.
In this cohort, eltrombopag was administered at up to 150 mg once daily on Day 1 to Month 6 (D1- M6) in combination with h-ATG on Days 1 to 4 and cyclosporine for 6 months, followed by low dose of cyclosporine (maintenance dose) for an additional 18 months for patients who achieved a 

haematologic response at 6 months. The median duration of exposure to eltrombopag in this cohort was 183 days with 70% of patients exposed for > 24 weeks.
Table 8 presents the most common adverse reactions (experienced by greater than or equal to 5% of patients) associated with eltrombopag in the D1-M6 cohort.
Table 8.    Adverse Reactions (≥ 5%) From One Open-label Trial in First-Line Treatment of Patients With Severe Aplastic Anaemia
Eltrombopag n = 92
Adverse Reaction                                 (%)
ALT increased                                                       29 AST increased                                                       17 Blood bilirubin increased                                           17 Rash                                                                 8 Skin discoloration including hyperpigmentation                       5 In the eltrombopag D1-M6 cohort, ALT increased (29%), AST increased (17%), and blood bilirubin increased (17%) were reported more frequently than in patients with refractory severe aplastic anaemia.
New or worsening liver function laboratory abnormalities (CTCAE Grade 3 and Grade 4) in the eltrombopag D1-M6 cohort were 15% and 2% for AST, 26% and 4% for ALT, and 12% and 1% for bilirubin, respectively.
In this single-arm open-label clinical trial, ALT or AST > 3 x ULN with total bilirubin > 1.5 x ULN and ALT or AST > 3 x ULN with total bilirubin > 2 x ULN were reported in 44% and 32% of patients, respectively, in the eltrombopag D1-M6 cohort.
Paediatric Patients
A total of 34 paediatric patients (2 patients 2 to 5 years of age, 12 patients 6 to 11 years of age, and 20 patients 12 to 16 years of age) were enrolled in this single-arm trial of which 26 paediatric patients were enrolled in the eltrombopag D1-M6 cohort. In this cohort, the most frequent serious adverse reactions (experienced by ≥ 10% of patients) were upper respiratory tract infection (12% in patients age 2 to 16 years compared to 5% in patients 17 years of age and older, respectively) and rash (12% compared to 2%). The most common adverse reactions (experienced by ≥ 10% of patients) associated with eltrombopag were ALT increased (23% in patients age 2 to 16 years compared to 32% in patients 17 years of age and older, respectively), blood bilirubin increased (12% compared to 20%), AST increased (12% compared to 20%), and rash (12% compared to 6%).
Cytogenetic Abnormalities
In this trial, patients had bone marrow aspirates evaluated for cytogenetic abnormalities. Seven patients in the eltrombopag D1-M6 cohort had a new cytogenetic abnormality reported of which 4 had the loss of chromosome 7; these 4 occurred within 6.1 months. Across all cohorts, clonal cytogenetic evolution occurred in 15 out of 153 (10%) patients. Of the 15 patients who experienced a cytogenetic abnormality: 7 patients had the loss of chromosome 7, 6 of which occurred within 6.1 months; 4 patients had chromosomal aberrations which were of unclear significance; 3 patients had a deletion of chromosome 13; and 1 patient had a follow-up bone marrow assessment at 5 years with features of dysplasia with hypercellularity concerning for potential development of MDS. It is unclear whether these findings occurred due to the underlying disease, the immunosuppressive therapy, and/or treatment with eltrombopag.


Refractory severe aplastic anaemia in adult patients
The safety of eltrombopag in refractory severe aplastic anaemia was assessed in a single-arm, open- label study(N=43) in which 11 patients (26%) were treated for >6 months and 7 patients (16 %) were treated for >1 year (see section 5.1). The most common adverse reactions occurring in at least 10% of patients included headache, dizziness, cough, oropharyngeal pain, rhinorrhoea ,nausea, diarrhoea, abdominal pain, transaminases increased, arthralgia, pain in extremity, muscle spasms ,fatigue and pyrexia.


List of adverse reactions
The adverse reactions in the adult ITP studies (N = 763), paediatric ITP studies (N=171), the HCV studies (N = 1 520), the definitive immunosuppressive therapy-naïve SAA study (N=92), the refractory SAA studies (N=43) and post-marketing reports are listed below by MedDRA system organ class and by frequency. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. The corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): 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); not known (cannot be estimated from the available data).

ITP study population

System organ class             Frequency     Adverse reaction
Infections and infestations    Very          Nasopharyngitis♦, upper respiratory tract infection♦ common
Common   Pharyngitis, influenza, oral herpes, pneumonia, sinusitis, tonsillitis, respiratory tract infection, gingivitis
Uncommon Skin infection
Neoplasms benign,              Uncommon Rectosigmoid cancer malignant and unspecified
(incl cysts and polyps)
Blood and lymphatic system     Common        Anaemia, eosinophilia, leukocytosis, thrombocytopenia, disorders                                    haemoglobin decreased, white blood cell count decreased Uncommon      Anisocytosis, haemolytic anaemia, myelocytosis, band neutrophil count increased, myelocyte present, platelet count increased,
haemoglobin increased
Immune system disorders        Uncommon      Hypersensitivity
Metabolism and nutrition       Common        Hypokalaemia, decreased appetite, blood uric acid increased disorders                      Uncommon      Anorexia, gout, hypocalcaemia Psychiatric disorders          Common        Sleep disorder, depression Uncommon      Apathy, mood altered, tearfulness
Nervous system disorders       Common        Paraesthesia, hypoaesthesia, somnolence, migraine Uncommon      Tremor, balance disorder, dysaesthesia, hemiparesis, migraine with aura, neuropathy peripheral, peripheral sensory neuropathy, speech disorder, toxic neuropathy, vascular headache
Eye disorders                  Common        Dry eye, vision blurred, eye pain, visual acuity reduced Uncommon      Lenticular opacities, astigmatism, cataract cortical, lacrimation increased, retinal haemorrhage, retinal pigment epitheliopathy,
visual impairment, visual acuity tests abnormal, blepharitis,
keratoconjunctivitis sicca
Ear and labyrinth disorders    Common        Ear pain, vertigo
Cardiac disorders              Uncommon      Tachycardia, acute myocardial infarction, cardiovascular disorder, cyanosis, sinus tachycardia, electrocardiogram QT prolonged



Vascular disorders             Common       Deep vein thrombosis, haematoma, hot flush Uncommon     Embolism, thrombophlebitis superficial, flushing
Respiratory, thoracic and      Very         Cough♦ mediastinal disorders          common
Common       Oropharyngeal pain ♦, rhinorrhoea♦
Uncommon     Pulmonary embolism, pulmonary infarction, nasal discomfort, oropharyngeal blistering, sinus disorder, sleep apnoea syndrome
Gastrointestinal disorders     Very         Nausea, diarrhoea common
Common   Mouth ulceration, toothache♦, vomiting, abdominal pain*, mouth haemorrhage, flatulence
* Very common in paediatric ITP
Uncommon Dry mouth, glossodynia, abdominal tenderness, faeces discoloured, food poisoning, frequent bowel movements, haematemesis, oral discomfort
Hepatobiliary disorders        Very     Alanine aminotransferase increased† common
Common   Aspartate aminotransferase increased†, hyperbilirubinaemia, hepatic function abnormal
Uncommon Cholestasis, hepatic lesion, hepatitis, drug-induced liver injury Skin and subcutaneous tissue   Common   Rash, alopecia, hyperhidrosis, pruritus generalised, petechiae disorders                      Uncommon Urticaria, dermatosis, cold sweat, erythema, melanosis, pigmentation disorder, skin discolouration, skin exfoliation
Musculoskeletal and            Very     Back pain connective tissue disorders    common
Common   Myalgia, muscle spasm, musculoskeletal pain, bone pain,
Uncommon Muscular weakness
Renal and urinary disorders    Common   Proteinuria, blood creatinine increased, thrombotic microangiopathy with renal failure‡
Uncommon Renal failure, leukocyturia, lupus nephritis, nocturia, blood urea increased, urine protein/creatinine ratio increased
Reproductive system and        Common   Menorrhagia breast disorders
General disorders and          Common   Pyrexia*, chest pain, asthenia administration site                     *Very common in paediatric ITP conditions                     Uncommon Feeling hot, vessel puncture site haemorrhage, feeling jittery, inflammation of wound, malaise, sensation of foreign body
Investigations                 Common   Blood alkaline phosphatase increased Uncommon Blood albumin increased, protein total increased, blood albumin decreased, pH urine increased
Injury, poisoning and          Uncommon Sunburn procedural complications
♦
Additional adverse reactions observed in paediatric studies (aged 1 to 17 years).
†
Increase of alanine aminotransferase and aspartate aminotransferase may occur simultaneously, although at a lower frequency.
‡
Grouped term with preferred terms acute kidney injury and renal failure 

HCV study population (in combination with anti-viral interferon and ribavirin therapy) 


System organ class                Frequency   Adverse reaction
Infections and infestations       Common      Urinary tract infection, upper respiratory tract infection, bronchitis, nasopharyngitis, influenza, oral herpes
Uncommon    Gastroenteritis, pharyngitis
Neoplasms benign, malignant       Common      Hepatic neoplasm malignant and unspecified (incl cysts and polyps)
Blood and lymphatic system        Very        Anaemia disorders                         common
Common      Lymphopenia
Uncommon    Haemolytic anaemia
Metabolism and nutrition          Very        Decreased appetite disorders                         common
Common      Hyperglycaemia, abnormal loss of weight
Psychiatric disorders             Common      Depression, anxiety, sleep disorder Uncommon    Confusional state, agitation
Nervous system disorders          Very        Headache common
Common      Dizziness, disturbance in attention, dysgeusia, hepatic encephalopathy, lethargy, memory impairment, paraesthesia
Eye disorders                     Common      Cataract, retinal exudates, dry eye, ocular icterus, retinal haemorrhage
Ear and labyrinth disorders       Common      Vertigo
Cardiac disorders                 Common      Palpitations
Respiratory, thoracic and         Very        Cough mediastinal disorders             common
Common      Dyspnoea, oropharyngeal pain, dyspnoea exertional, productive cough
Gastrointestinal disorders        Very        Nausea, diarrhoea common
Common      Vomiting, ascites, abdominal pain, abdominal pain upper,
dyspepsia, dry mouth, constipation, abdominal distension,
toothache, stomatitis, gastrooesophagal reflux disease,
haemorrhoids, abdominal discomfort, varices oesophageal
Uncommon    Oesophageal varices haemorrhage, gastritis, aphthous stomatitis Hepatobiliary disorders           Common      Hyperbilirubinaemia, jaundice, drug-induced liver injury Uncommon    Portal vein thrombosis, hepatic failure



Skin and subcutaneous tissue      Very           Pruritus disorders                         common
Common         Rash, dry skin, eczema, rash pruritic, erythema, hyperhidrosis, pruritus generalised, alopecia
Uncommon       Skin lesion, skin discolouration, skin hyperpigmentation, night sweats
Musculoskeletal and               Very           Myalgia connective tissue disorder        common
Common         Arthralgia, muscle spasms, back pain, pain in extremity, musculoskeletal pain, bone pain
Renal and urinary disorders       Uncommon       Thrombotic microangiopathy with acute renal failure†, dysuria General disorders and             Very           Pyrexia, fatigue, influenza-like illness, asthenia, chills administration site conditions    common
Common      Irritability, pain, malaise, injection site reaction, non-cardiac chest pain, oedema, oedema peripheral
Uncommon Injection site pruritus, injection site rash, chest discomfort Investigations                  Common        Blood bilirubin increased, weight decreased, white blood cell count decreased, haemoglobin decreased, neutrophil count decreased, international normalised ratio increased, activated partial thromboplastin time prolonged, blood glucose increased,
blood albumin decreased
Uncommon Electrocardiogram QT prolonged
†
Grouped term with preferred terms oliguria, renal failure and renal impairment 
Adverse Reactions (≥ 5%) From One Open-label Trial in First-line Treatment of Patients With Severe Aplastic Anemia

Revolade

N=92
Adverse Reaction                                            (%)

ALT increased                                                                          29 
AST increased                                                                          17 
Blood bilirubin increased                                                              17 
Rash                                                                                    8 
Skin discoloration including hyperpigmentation                                          5 

Refractory SAA study population

System organ class                Frequency      Adverse reaction
Blood and lymphatic system        Common         Neutropenia, splenic infarction disorders
Metabolism and nutrition          Common         Iron overload, decreased appetite, hypoglycaemia, increased disorders                                        appetite
Psychiatric disorders             Common         Anxiety, depression



Nervous system disorders         Very           Headache, dizziness common
Common         Syncope
Eye disorders                    Common         Dry eye, cataract, ocular icterus, vision blurred, visual impairment, vitreous floaters
Respiratory, thoracic and        Very           Cough, oropharyngeal pain, rhinorrhoea mediastinal disorders            common
Common         Epistaxis
Gastrointestinal disorders       Very           Diarrhoea, nausea, gingival bleeding, abdominal pain common
Common         Oral mucosal blistering, oral pain, vomiting, abdominal discomfort, constipation, abdominal distension, dysphagia, faeces discoloured, swollen tongue, gastrointestinal motility disorder,
flatulence
Hepatobiliary disorders          Very           Transaminases increased common
Common         Blood bilirubin increased (hyperbilirubinemia), jaundice Not known      Drug-induced liver injury*
* Cases of drug-induced liver injury have been reported in patients with ITP and HCV
Skin and subcutaneous tissue     Common         Petechiae, rash, pruritus, urticaria, skin lesion, rash macular disorders                        Not known      Skin discolouration, skin hyperpigmentation Musculosketal and connective     Very           Arthralgia, pain in extremity, muscle spasms tissue disorders                 common
Common         Back pain, myalgia, bone pain
Renal and urinary disorders      Common         Chromaturia
General disorders and            Very           Fatigue, pyrexia, chills administration site conditions   common
Common         Asthenia, oedema peripheral, malaise
Investigations                   Common         Blood creatine phosphokinase increased 
Description of selected adverse reactions

Thrombotic/thromboembolic events (TEEs)
In 3 controlled and 2 uncontrolled clinical studies among adult ITP patients receiving eltrombopag (n = 446), 17 patients experienced a total of 19 TEEs, which included (in descending order of occurrence) deep vein thrombosis (n = 6), pulmonary embolism (n = 6), acute myocardial infarction (n = 2), cerebral infarction (n = 2), embolism (n = 1) (see section 4.4).

In a placebo-controlled study (n = 288, Safety population), following 2 weeks’ treatment in preparation for invasive procedures, 6 of 143 (4%) adult patients with chronic liver disease receiving eltrombopag experienced 7 TEEs of the portal venous system and 2 of 145 (1 %) patients in the placebo group experienced 3 TEEs. Five of the 6 patients treated with eltrombopag experienced the TEE at a platelet count >200 000/µl

No specific risk factors were identified in those patients who experienced a TEE with the exception of platelet counts ≥200 000/µl (see section 4.4).

In controlled studies in thrombocytopenic patients with HCV (n = 1 439), 38 out of 955 patients (4%) treated with eltrombopag experienced a TEE and 6 out of 484 patients (1%) in the placebo group experienced TEEs. Portal vein thrombosis was the most common TEE in both treatment groups (2% in patients treated with eltrombopag versus < 1% for placebo) (see section 4.4). Patients with low albumin levels (≤ 35 g/l) or MELD ≥ 10 had a 2-fold greater risk of TEEs than those with higher albumin levels; those aged ≥60 years had a 2-fold greater risk of TEEs compared to younger patients.

Hepatic decompensation (use with interferon)

Chronic HCV patients with cirrhosis may be at risk of hepatic decompensation when receiving alfa interferon therapy. In 2 controlled clinical studies in thrombocytopenic patients with HCV, hepatic decompensation (ascites, hepatic encephalopathy, variceal haemorrhage, spontaneous bacterial peritonitis) was reported more frequently in the eltrombopag arm (11 %) than in the placebo arm (6 %). In patients with low albumin levels (≤35 g/l) or MELD score ≥10 at baseline, there was a 3-fold greater risk of hepatic decompensation and an increase in the risk of a fatal adverse event compared to those with less advanced liver disease. Eltrombopag should only be administered to such patients after careful consideration of the expected benefits in comparison with the risks. Patients with these characteristics should be closely monitored for signs and symptoms of hepatic decompensation (see section 4.4).

Hepatotoxicity

In the controlled clinical studies in chronic ITP with eltrombopag, increases in serum ALT, AST and bilirubin were observed (see section 4.4).

These findings were mostly mild (Grade 1-2), reversible and not accompanied by clinically significant symptoms that would indicate an impaired liver function. Across the 3 placebo-controlled studies in adults with chronic ITP, 1 patient in the placebo group and 1 patient in the eltrombopag group experienced a Grade 4 liver test abnormality. In two placebo-controlled studies in paediatric patients (aged 1 to 17 years) with chronic ITP, ALT ≥3 x ULN was reported in 4.7% and 0% of the eltrombopag and placebo groups, respectively.

In 2 controlled clinical studies in patients with HCV, ALT or AST ≥3 x ULN was reported in 34% and 38% of the eltrombopag and placebo groups, respectively. Most patients receiving eltrombopag in combination with peginterferon / ribavirin therapy will experience indirect hyperbilirubinaemia.
Overall, total bilirubin ≥1.5 x ULN was reported in 76% and 50% of the eltrombopag and placebo groups, respectively.

In the single-arm phase II monotherapy refractory SAA study, concurrent ALT or AST >3 x ULN with total (indirect) bilirubin >1.5 x ULN were reported in 5% of patients. Total bilirubin >1.5 x ULN occurred in 14% of patients.

Thrombocytopenia following discontinuation of treatment

In the 3 controlled clinical ITP studies, transient decreases in platelet counts to levels lower than baseline were observed following discontinuation of treatment in 8 % and 8 % of the eltrombopag and placebo groups, respectively (see section 4.4).

Increased bone marrow reticulin

Across the programme, no patients had evidence of clinically relevant bone marrow abnormalities or clinical findings that would indicate bone marrow dysfunction. In a small number of ITP patients, eltrombopag treatment was discontinued due to bone marrow reticulin (see section 4.4).

Cytogenetic abnormalities

In the phase II refractory SAA clinical study with eltrombopag with a starting dose of 50 mg/day (escalated every 2 weeks to a maximum of 150 mg/day) (ELT112523), the incidence of new cytogenetic abnormalities was observed in 17.1% of adult patients [7/41 (where 4 of them had changes in chromosome 7)]. The median time on study to a cytogenetic abnormality was 2.9 months.

In the phase II refractory SAA clinical study with eltrombopag at a dose of 150 mg/day (with ethnic or age related modifications as indicated) (ELT116826), the incidence of new cytogenetic abnormalities 
was observed in 22.6% of adult patients [7/31 (where 3 of them had changes in chromosome 7)]. All 7 patients had normal cytogenetics at baseline. Six patients had cytogenetic abnormality at Month 3 of eltrombopag therapy and one patient had cytogenetic abnormality at Month 6.

Haematologic malignancies

In the single-arm, open-label study in SAA, three (7%) patients were diagnosed with MDS following treatment with eltrombopag, in the two ongoing studies (ELT116826 and ELT116643), 1/28 (4%) and 1/62 (2%) patient has been diagnosed with MDS or AML in each study.

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/.