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% /11.4%), gastrointestinal disorders (nausea [38.0%/30.7%], stomatitis [36.4%/69.3%], vomiting [22.5%/43.2%], diarrhoea [14.4%/33.0%], abdominal pain [9.6%/17%]), fatigue (14.4%/2.3%), febrile neutropenia (10.1%/1.1%), decreased appetite (8.0%/0.8%), maculopapular rash
(5.2%/7.4%), oedema (6.2%/0%), and increases of alanine transaminase
(ALT [4.9%/9.1%]), aspartate transaminase (AST [4.1%/8.0%]), and bilirubin (17.1%/5.7%).
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 109/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 88 patients; median age 8 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
Nervous system disorders*      Not known                       Not known Headache, paraesthesia, seizure Paraesthesia
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
Gastrointestinal disorders     Very common                         Very common Stomatitis/mucositis, diarrhoea,    Stomatitis/mucositis, nausea nausea, vomiting, abdominal         Common pain                                Dysphagia, diarrhoea,
Common                              vomiting, abdominal pain
Dysphagia, oral pain                Not known
Not known                           Neutropenic colitis
Neutropenic colitis, anal inflammation, dyspepsia,
proctitis, gastrointestinal pain,
constipation
Hepatobiliary disorders        Not known                           Not known Veno-occlusive liver disease,       Veno-occlusive liver disease hepatomegaly, hepatotoxicity
Skin and subcutaneous tissue   Very common                       Common disorders                      Pruritus                          Dermatitis exfoliative, maculo- Common                            papular rash, erythema
Dermatitis exfoliative, maculo- papular rash, rash, erythema,
pain of skin, skin hyperpigmentationb, alopecia
Not known
Skin ulcer, erythema multiforme, urticaria, dermatitis bullous, dermatitis acneiform,
palmar-plantar erythrodysaesthesia syndrome,
dermatitis diapera
Musculoskeletal and            Not known connective tissue disorders    Pain in extremities
Renal and urinary disorders     Not known                        Not known Acute kidney injury, renal       Acute kidney injury, renal failure, noninfective cystitis   failure
Reproductive system and         Not known breast disorders                Scrotal erythema
General disorders and          Very common administration site conditions Pyrexiac
Not known
Chills, fatigue, pain
Investigations                  Common                           Common Transaminases (ALT/AST)          Bilirubin increased increased, bilirubin increased   Uncommon
Not known                        Transaminases (ALT/AST)
γGT increased                    increase
Not known
γGT 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 88 paediatric patients was 11.4% (10/88) and thus comparable to that seen in adults. The frequency was higher in the paediatric age group 12–17 years (6/35 [17.1%]) compared to younger children (4/53 [7.5%]).

Neoplasms benign, malignant and unspecified (including cysts and polyps) Five cases of a second malignancy (myelodysplastic syndrome, acute lymphoblastic leukaemia, Ewing's sarcoma) were reported by other investigators after treosulfan-based conditioning. All five paediatric patients received alloHSCT for primary immunodeficiencies, i.e. diseases with an increased risk for neoplasias per se.

Blood and lymphatic system disorders
The median (25%/75% percentiles) duration of neutropenia was 21 (16, 26) days in paediatric patients with malignant diseases and 24 (17, 26) days in patients with non-malignant disorders.

Nervous system disorders
Seizure in the context of an encephalitis infection was reported in one of 88 paediatric patients. A report from an investigator-initiated trial performed in children with primary immunodeficiencies lists four 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.