Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
The safety of dinutuximab beta has been evaluated in 791 patients with high-risk and relapsed/refractory neuroblastoma, who received it as a continuous infusion (212) or as repeated daily infusions (416). It was combined with 13-cis retinoic in most patients and with IL-2 in 307 patients.

The most common adverse reactions were pyrexia (86%) and pain (57%) that occurred despite analgesic treatment. Other frequent adverse reactions were hypersensitivity (74.1%), vomiting (55%), diarrhoea (52%), capillary leak syndrome (36%), anaemia (49%), neutropenia (46%), thrombocytopenia (42%) and hypotension (41%).

Tabulated list of adverse reactions
Adverse reactions reported in clinical trials are listed by system organ class and by frequency and summarised in the table below. These adverse reactions are presented by MedDRA system organ class and frequency. Frequency categories are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10) and uncommon (≥ 1/1,000 to < 1/100). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. The type of adverse reactions seen in the post-marketing setting is consistent with the reactions seen in clinical trials.
System organ class      Very common                 Common                        Uncommon Infections and          infection (including        sepsis infestations            pneumonia, skin infection, herpes virus infection, myelitis,
encephalomyelitis),
device related infection
Blood and lymphatic     anaemia,                    lymphopenia                   disseminated system disorders        leukopenia,                                               intravascular neutropenia,                                              coagulation, thrombocytopenia                                          eosinophilia Immune system           hypersensitivity,           anaphylactic reaction         serum sickness disorders               cytokine release syndrome
Metabolism and          fluid retention             decreased appetite, nutrition disorders                                 hypoalbuminaemia, hyponatraemia,
hypokalaemia,
hypophosphataemia,
hypomagnesaemia,
hypocalcaemia,
dehydration
Psychiatric disorders                               agitation, anxiety Nervous system          headache                    peripheral neuropathy,        intracranial pressure disorders                                           seizure, paraesthesia,        increased, posterior dizziness, tremor             reversible encephalopathy syndrome
Eye disorders           mydriasis,                  ophthalmoplegia,
pupillotonia, eye           papilloedema,
oedema (eyelid,             accommodation disorder,
periorbital)                blurred vision,
photophobia
Cardiac disorders       tachycardia                 cardiac failure, left ventricular dysfunction,
pericardial effusion
Vascular disorders      hypotension, capillary      hypertension                  hypovolaemic shock, leak syndrome                                             veno-occlusive disease
Respiratory, thoracic   hypoxia, cough              bronchospasm,
and mediastinal                                     dyspnoea, respiratory disorders                                           failure, lung infiltration, pulmonary oedema,
pleural effusion,
tachypnoea,
laryngospasm
Gastrointestinal        vomiting, diarrhoea,        nausea, lip oedema,           enterocolitis disorders               constipation, stomatitis    ascites, abdominal distension, ileus, dry lips
Hepatobiliary                                                                     hepatocellular injury disorders
Skin and                pruritus, rash, urticaria   dermatitis (including subcutaneous tissue                                 exfoliative), erythema, disorders                                           dry skin, hyperhidrosis, System organ class      Very common                Common                      Uncommon petechiae,
photosensitivity reaction

Musculoskeletal and                                muscle spasms connective tissue disorders
Renal and urinary                                  oliguria, urinary           renal failure disorders                                          retention,
hyperphosphaturia,
haematuria, proteinuria
General disorders       pyrexia, chills, pain*,    injection site reaction and administration      peripheral oedema,
site conditions         face oedema
Investigations          increased weight,          decreased weight,
increased                  decreased glomerular transaminases,             filtration rate,
increased gamma            hypertriglyceridaemia,
glutamyltransferase,       prolonged activated increased blood            partial thromboplastin bilirubin increased        time, prolonged blood creatinine           prothrombin time,
prolonged thrombin time
* includes abdominal pain, pain in extremity, oropharyngeal pain, and Back pain reported in >10% of patients. In addition, other common pain types reported were arthralgia, injection site pain, musculoskeletal pain, bone pain, chest pain, and neck pain.

Description of selected adverse reactions
Hypersensitivity
The most frequent hypersensitivity reactions included hypotension (42.2%), urticaria (7%) and bronchospasm (1%). Cytokine release syndrome was also reported in 32% of the patients. Serious anaphylactic reactions occurred in 3.5% of the patients.

Pain
Pain typically occurs during the first infusion of dinutuximab beta and decreases over the treatment courses. Most commonly, patients reported abdominal pain, pain in the extremities, back pain, chest pain, or arthralgia.

Capillary leak syndrome (CLS)
Overall, 10% of CLS were severe (grade 3-4) and their frequency decreased over the treatment courses.

Eye problems
These included impaired visual accommodation that is correctable with eye glasses, as well as mydriasis (2%), periorbital oedema and eyelid oedema (3%), blurred vision (3%) or photophobia (3%), which were usually reversible after treatment discontinuation. Severe eye disorders were also reported including ophthalmoplegia (2%) and optic atrophy.
Peripheral neuropathy
Both motor and sensory peripheral neuropathies have been reported, overall in 9% of the patients.
Most events were of grade 1-2 and resolved.

Central Neurotoxicity
Reports of central neurotoxicity and severe neurotoxicity have been received including posterior reversible encephalopathy syndrome (0.7%) and seizures (1.7%).

Safety profile with and without IL-2
The combination of Qarziba with IL-2 increases the risk of adverse drug reactions compared to Qarziba without IL-2, especially for pyrexia (94% vs. 80%), CLS (45% vs. 20%), pain related to dinutuximab beta (70% vs. 62%), hypotension (44% vs. 27%), and peripheral neuropathy (9% vs.
5%), respectively.

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