Adverse reactions : תופעות לוואי

4.8 Undesirable effects

Summary of the safety profile
Profound myelosuppression/pancytopenia is the desired therapeutic effect of conditioning therapy and occurs in all patients. Blood cell counts usually recover after HSCT.
The most commonly observed adverse reactions (adults/paediatric patients) after treosulfan-based conditioning followed by alloHSCT include overall infections (10.1% /11.6 %), gastrointestinal disorders (nausea [38.0%/26.4%], stomatitis [36.4%/66.1%], vomiting [22.5%/42.1%], diarrhoea [14.4%/33.1%], abdominal pain [9.6%/17.4%]), fatigue (14.4%/1.7%), hepatotoxicity
(0.3%/26.4%), febrile neutropenia (10.1%/1.7%), decreased appetite
(8.0%/0.8%), maculopapular rash (5.2%/7.4%), pruritus (2.8%/10.7%),
alopecia (1.5%/9.9%), pyrexia (4.1%/13.2%), oedema (6.2%/0.8%), rash
(7.2%/5.8%), and increases of alanine transaminase (ALT [4.9%/10.7%]), aspartate transaminase (AST [4.1%/6.6%]), and bilirubin (17.1%/6.6%).

Adults

Tabulated list of adverse reactions
The frequencies of adverse reactions reported in the table below are derived from 5 clinical trials (including a total of 613 patients) where treosulfan combined with fludarabine was investigated as conditioning treatment prior to alloHSCT in adult patients. Treosulfan was administered in a dose range of 10-14 g/m² BSA on 3 consecutive days.
Adverse reactions are listed below, by system organ class and by 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 group, undesirable effects are presented in order of decreasing seriousness.



System Organ Class (SOC)        All Adverse Reactions / Frequency        Grade 3-4 Adverse Reactions / Frequency
Infections and infestations*    Common                                   Common Infections (bacterial, viral, fungal),   Infections (bacterial, viral, sepsisa                                  fungal), sepsisa
Not known                                Not known
Septic shockc                            Septic shockc
Neoplasms benign, malignant      Not known                           Not known and unspecified (including cysts Treatment-related second malignancy Treatment-related second and polyps)*                                                         malignancy Blood and lymphatic system      Very common                              Very common disorders*                      Myelosuppression, pancytopenia,          Myelosuppression, febrile neutropenia                      pancytopenia, febrile neutropenia
Immune system disorders         Common
Hypersensitivity
Metabolism and nutrition        Common                                   Common disorders                       Decreased appetite                       Decreased appetite Uncommon                                 Uncommon
Glucose tolerance impaired including     Glucose tolerance impaired hyperglycaemia and hypoglycaemia         including hyperglycaemia and Not known                                hypoglycaemia
Acidosisb                                Not known
Acidosisb
Psychiatric disorders         Common                                  Not known Insomnia                                Confusional state
Uncommon
Confusional state

Nervous system disorders      Common                                  Uncommon Headache, dizziness                     Headache
Uncommon                                Not known
Intracranial haemorrhage, peripheral    Encephalopathy, intracranial sensory neuropathy                      haemorrhage, syncope,
Not known                               peripheral sensory neuropathy Encephalopathy, extrapyramidal disorder, syncope, paraesthesia
Eye disorders                 Not known
Dry eye
Ear and labyrinth disorders   Uncommon
Vertigo
Cardiac disorders*            Common                                  Uncommon Cardiac arrhythmias (e.g. atrial        Cardiac arrhythmias (e.g.
fibrillation, sinus arrhythmia)         atrial fibrillation, sinus
Not known                               arrhythmia)
Cardiac arrest, cardiac failure,        Not known myocardial infarction, pericardial      Cardiac arrest, myocardial effusion                                infarction
Vascular disorders            Common                                  Uncommon Hypertension, hypotension, flushing     Hypertension
Uncommon                                Not known
Haematoma                               Embolism
Not known
Embolism
Respiratory, thoracic and     Common                                  Uncommon mediastinal disorders         Dyspnoea, epistaxis                     Dyspnoea Uncommon                                Not known
Pneumonitis, pleural effusion,          Pneumonitis, pleural effusion, pharyngeal or laryngeal inflammation,   pharyngeal inflammation,
oropharyngeal pain, hiccups             epistaxis
Not known
Laryngeal pain, cough, dysphonia
Gastrointestinal disorders*     Very common                                Common Stomatitis/mucositis, diarrhoea,           Stomatitis/mucositis,
nausea, vomiting                           diarrhoea, nausea, abdominal Common                                     pain
Oral pain, gastritis, dyspepsia,           Uncommon constipation, dysphagia, abdominal         Vomiting, oral pain,
pain, oesophageal or gastrointestinal      dysphagia, oesophageal or pain                                       gastrointestinal pain
Uncommon                                   Not known
Mouth haemorrhage, abdominal               Gastric or mouth distension, dry mouth                      haemorrhage, neutropenic
Not known                                  colitis
Gastric haemorrhage, neutropenic colitis, oesophagitis, anal inflammation
Hepatobiliary disorders*        Uncommon                                   Not known Veno-occlusive liver disease               Veno-occlusive liver disease, Not known                                  hepatotoxicity
Hepatotoxicity, hepatomegaly

Skin and subcutaneous tissue    Common                                     Uncommon disorders                       Maculo-papular rash, purpura,              Maculo-papular rash erythema, palmar-plantar                   Not known erythrodysaesthesia syndrome,              Skin necrosis, purpura,
pruritus, alopecia                         erythema
Uncommon
Erythema multiforme, dermatitis acneiform, rash, dry skin
Not known
Skin necrosis or ulcer, dermatitis, skin hyperpigmentationd
Musculoskeletal and connective Common                                      Not known tissue disorders               Pain in extremity, back pain, bone          Pain in extremity, bone pain pain, arthralgia
Uncommon
Myalgia
Renal and urinary disorders     Common                                     Uncommon Acute kidney injury, haematuria            Acute kidney injury

Uncommon                                   Not known
Urinary tract pain                         Haematuria

Not known
Renal failure, haemorrhagic cystitisc,
dysuria
General disorders and            Very common                               Common administration site conditions   Asthenic conditions (fatigue, asthenia,   Fatigue lethargy)                                 Not known
Common                                    Non-cardiac chest pain,
Oedema, pyrexiae, chills                  pyrexiae
Uncommon
Non-cardiac chest pain, pain
Investigations                   Very common                               Common Blood bilirubin increased                 Blood bilirubin increased,
Common                                    transaminases (ALT/AST)
Transaminases (ALT/AST) increased,        increased, γGT increased
γGT increased, C-reactive protein         Uncommon increased, weight decreased, weight       C-reactive protein increased increased                                 Not known
Uncommon                                  Blood alkaline phosphatase
Blood alkaline phosphatase increased      increased


Not known
Blood lactate dehydrogenase (LDH) increased
* See detailed sections below.
a Clinically or microbiologically documented infection with grade 3 or 4  neutropenia (absolute neutrophil count [ANC] < 1.0 x 10 9/L) and sepsis.
b Acidosis might be a consequence of the release of methanesulfonic acid  through treosulfan activation/cleavage in the plasma.
c Case reports (> 2) after treosulfan-based conditioning obtained from other  sources.
d Bronze pigmentation.
e Fever in the absence of neutropenia where neutropenia is defined as ANC < 
1.0 x 109/L.


Description of selected adverse reactions
Overall infections
The overall incidence of infections was 10.1% (62/613). This includes the incidence for bacterial, viral and fungal infections (50/613; 8.1%) and for overall sepsis (12/613; 2%). The most frequent type of infection was lung infection (10/62[16.1%]). Pathogens included bacteria
(e.g. Staphylococcus, Enterococcus, Corynebacterium), viruses (e.g.
cytomegalovirus [CMV], Epstein-Barr virus [EBV]) as well as fungi (e.g.
candida). Overall sepsis includes sepsis (9/613; 1.5%), staphylococcal sepsis (2/613; 0.3%) and enterococcal sepsis (1/613; 0.2%). The infection rate was lowest in patients treated with the dose regimen of 10 g/m² of treosulfan per day, from day -4 to -2 (8.1%).

Neoplasms benign, malignant and unspecified (including cysts and polyps) One of 613 adult patients (0.2%) developed a second malignancy (breast cancer). A few further cases of second malignancies after treosulfan-based conditioning have been reported by other investigators. After long-term therapy with conventional doses of oral treosulfan in patients with solid tumours acute myeloid leukaemia was observed in 1.4% of 553 patients.

Blood and lymphatic system disorders
Blood disorders were observed in 62 of 613 adult patients (10.1%). The most frequent adverse reaction was febrile neutropenia (10.1%). The lowest incidence was noted with the dose regimen of 10 g/m²/day, day -4 to -2 ( 4.4%).
The median (25%/75% percentiles) duration of neutropenia was 14 (12, 20) days with the 10 g/m² treosulfan dose and 17.5 (14, 21) days with the 14 g/m² treosulfan dose.

Cardiac disorders
Cardiac disorders were observed in 21 patients (3.4%). The most frequent adverse reactions were cardiac arrhythmias, e.g. atrial fibrillation (1.0%), sinus tachycardia (0.8%), supraventricular tachycardia (0.3%), and ventricular extrasystole (0.3%). Isolated cases of cardiac arrest, cardiac failure, and myocardial infarction occurred. The lowest frequency of cardiac disorders was seen with the dose regimen of 10 g/m²/day, day -4 to -2 (2.6%).

Gastrointestinal disorders
Gastrointestinal disorders were observed in 379 patients (61.8%). The most frequent adverse reactions reported were nausea (38.0%), stomatitis (36.4%), vomiting (22.5%), diarrhoea (14.4%), and abdominal pain (9.6%). The lowest frequencies of these adverse reactions were seen with the dose regimen of 10 g/m² per day, day -4 to -2 (21.5%, 32.2%, 14.8%, 5.9%, and 6.7% respectively).

Hepatobiliary disorders
The overall incidence of veno-occlusive liver disease (VOD) was 0.8%
(5/613). VOD occurred only with the dose regimen of 14 g/m²/day treosulfan.
None of these cases were fatal or life-threatening.

Paediatric population
Tabulated list of adverse reactions
The adverse reactions reported in the table below are derived from two clinical trials (including a total of 121 patients; median age 7 years [range 0– 17 years]) where treosulfan combined with fludarabine (and mostly with additional thiotepa) was administered as conditioning treatment prior to alloHSCT in paediatric patients with malignant or non-malignant diseases.
Treosulfan was administered in a dose range of 10-14 g/m² BSA on three consecutive days.
Adverse reactions are listed below, by system organ class and by 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 group, undesirable effects are presented in order of decreasing seriousness.
System Organ Class (SOC)       All Adverse Reactions /            Grade 3-4 Adverse Reactions Frequency                          / Frequency
Infections and infestations*   Very common                        Common Infections (bacterial, viral,      Infections (bacterial, viral,
fungal)                            fungal)
Neoplasms benign, malignant    Not known                          Not known and unspecified (including     Treatment-related second           Treatment-related second cysts and polyps)*             malignancya                        malignancya Blood and lymphatic system     Very common                        Very common disorders*                     Myelosuppression, pancytopenia     Myelosuppression, Not known                          pancytopenia
Febrile neutropenia                Not known
Febrile neutropenia
Metabolism and nutrition       Not known                         Not known disorders                      Alkalosis, electrolyte imbalance, Alkalosis hypomagnesaemia, decreased appetite
Nervous system disorders*      Common                             Not known Headache                           Paraesthesia
Not known
Paraesthesia, seizure
Eye disorders                  Not known
Conjunctival haemorrhage, dry eye
Vascular disorders             Not known                          Not known Capillary leak syndrome,           Capillary leak syndrome,
hypertension, hypotension          hypertension, hypotension
Respiratory, thoracic and      Common                             Not known mediastinal disorders          Oropharyngeal pain, epistaxis      Hypoxia Not known
Hypoxia, cough
Gastrointestinal disorders*    Very common                        Very common Stomatitis/mucositis, diarrhoea,   Stomatitis/mucositis nausea, vomiting, abdominal        Common pain                               Dysphagia, diarrhoea, nausea,
Common                             vomiting
Dysphagia, anal inflammation,      Not known oral pain                          Neutropenic colitis, abdominal
Not known                          pain, oesophageal pain
Neutropenic colitis, dyspepsia,
proctitis, gingival pain,
oesophageal pain, constipation
Hepatobiliary disorders        Very common
Hepatotoxicity
Not known
Veno-occlusive liver disease,
hepatomegaly
Skin and subcutaneous tissue   Very common                        Common disorders                      Pruritus, alopecia                 Dermatitis exfoliative, maculo- Common                             papular rash
Dermatitis exfoliative, maculo- papular rash, rash, erythema,      Not known urticaria, pain of skin, skin      Erythema hyperpigmentationb
Not known
Skin ulcer, erythema multiforme, dermatitis bullous,
dermatitis acneiform, palmar- plantar erythrodysaesthesia syndrome, dermatitis diapera
Musculoskeletal and            Not known connective tissue disorders    Pain in extremity
Renal and urinary disorders    Not known                          Not known Acute kidney injury, renal         Acute kidney injury, renal failure, noninfective cystitis,    failure, noninfective cystitis haematuria
Reproductive system and        Not known breast disorders               Scrotal erythema, penile pain
General disorders and          Very common administration site conditions Pyrexiac
Common
Chills
Not known
Face oedema, fatigue, pain
Investigations                 Very common                        Common ALT increased                      ALT increased
Common                             blood bilirubin increased
AST increased,                     Uncommon bilirubin increased, C- reactive   Transaminases (ALT/AST) protein increased                  increase
Not known                          Not known
γGT increased                      AST increased,
γGT increased , C- reactive protein increased
* See detailed sections below.
a Case reports (> 1) after treosulfan-based conditioning obtained from other  sources.
b Bronze pigmentation.
c Fever in the absence of neutropenia where neutropenia is defined as ANC < 
1.0 x 109/L.

Description of selected adverse reactions
Infections
The overall incidence of infections in 121 paediatric patients was 11.6% (14/121) and thus comparable to that seen in adults. The frequency was higher in the paediatric age group 12–17 years (6/39 [15.4%]) compared to younger children (7/59 [11.9%]).

Neoplasms benign, malignant and unspecified (including cysts and polyps) 
One case of a second malignancy (myelodysplastic syndrome) was reported in a child about 12 months after treosulfan-based conditioning for sickle cell disease. Six cases of a second malignancy were reported by other investigators after treosulfan-based conditioning. Five paediatric patients received alloHSCT for primary immunodeficiencies, i.e. diseases with an increased risk for neoplasias per se.
They developed myelodysplastic syndrome, acute lymphoblastic leukaemia, and Ewing's sarcoma. One patient with haemophagocytic lymphohistiocytosis developed secondary juvenile chronic myeloid leukaemia.


Blood and lymphatic system disorders
The median (25%/75% percentiles) duration of neutropenia was 22 (17, 26) days in paediatric patients with malignant diseases and 20 (15, 25) days in patients with non-malignant disorders.

Nervous system disorders
Seizure in the context of an encephalitis infection was reported in one of 121 paediatric patients. A report from an investigator-initiated trial performed in children with primary immunodeficiencies lists five cases of seizures occurring after other treosulfan-based conditioning regimens (see section 4.4).

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization 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.