Dinutuximab interacts in the following cases:
Due to their immunosuppressive activity, concomitant treatment with corticosteroids is not recommended within 2 weeks prior to the first treatment course until 1 week after the last treatment course with dinutuximab beta, except for life-threatening conditions.
There are no data in patients with renal and hepatic impairment.
Vaccinations should be avoided during administration of dinutuximab beta until 10 weeks after the last treatment course, due to immune stimulation through dinutuximab beta and possible risk for rare neurological toxicities.
Concomitant use of intravenous immunoglobulins is not recommended as they may interfere with dinutuximab beta-dependent cellular cytotoxicity.
There are no data on pregnant women. No animal data are available on teratogenicity or embryotoxicity. Dinutuximab beta target (GD2) is expressed on neuronal tissues, especially during embryofetal development, and may cross the placenta; therefore, dinutuximab may cause fetal harm when administered to pregnant women.
Dinutuximab should not be used during pregnancy.
There are no data on lactating women. It is unknown whether dinutuximab beta is excreted in human milk. Breast-feeding should be discontinued during treatment with dinutuximab and for 6 months after the last dose.
The effects of dinutuximab beta on fertility in humans are unknown. In animals, dedicated fertility studies have not been conducted, but no adverse effects on reproductive organs were observed in toxicity studies performed in Guinea pig and cynomolgous monkey.
Dinutuximab should not be used in women of childbearing potential not using contraception. It is recommended that women of childbearing potential use contraception for 6 months after discontinuation of treatment with dinutuximab beta.
Dinutuximab beta has major influence on the ability to drive and use machines. Patients should not use or drive machines during treatment with dinutuximab beta.
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%).
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 infestations | infection (including pneumonia, skin infection, herpes virus infection, myelitis, encephalomyelitis), device related infection | sepsis | |
| Blood and lymphatic system disorders | anaemia leukopenia, neutropenia, thrombocytopenia | lymphopenia | disseminated intravascular coagulation, eosinophilia |
| Immune system disorders | hypersensitivity, cytokine release syndrome | anaphylactic reaction | serum sickness |
| Metabolism and nutrition disorders | fluid retention | decreased appetite, hypoalbuminaemia, hyponatraemia, hypokalaemia, hypophosphataemia, hypomagnesaemia, hypocalcaemia, dehydration | |
| Psychiatric disorders | agitation, anxiety | ||
| Nervous system disorders | headache | peripheral neuropathy, seizure, paraesthesia, dizziness, tremor | intracranial pressure increased, posterior reversible encephalopathy syndrome |
| Eye disorders | mydriasis, pupillotonia, eye oedema (eyelid, periorbital) | ophthalmoplegia, papilloedema, accommodation disorder, blurred vision, photophobia | |
| Cardiac disorders | tachycardia | cardiac failure, left ventricular dysfunction, pericardial effusion | |
| Vascular disorders | hypotension, capillary leak syndrome | hypertension | hypovolaemic shock, veno-occlusive disease |
| Respiratory, thoracic and mediastinal disorders | hypoxia, cough | bronchospasm, dyspnoea, respiratory failure, lung infiltration, pulmonary oedema, pleural effusion, tachypnoea, laryngospasm | |
| Gastrointestinal disorders | vomiting, diarrhoea, constipation, stomatitis | nausea, lip oedema, ascites, abdominal distension, ileus, dry lips | enterocolitis |
| Hepatobiliary disorders | hepatocellular injury | ||
| Skin and subcutaneous tissue disorders | pruritus, rash, urticaria | dermatitis (including exfoliative), erythema, dry skin, hyperhidrosis, petechiae, photosensitivity reaction | |
| Musculoskeletal and connective tissue disorders | muscle spasms | ||
| Renal and urinary disorders | oliguria, urinary retention, hyperphosphaturia, haematuria, proteinuria | renal failure | |
| General disorders and administration site conditions | pyrexia, chills, pain*, peripheral oedema, face oedema | injection site reaction | |
| Investigations | increased weight, increased transaminases, increased gamma glutamyltransferase, increased blood bilirubin increased blood creatinine | decreased weight, decreased glomerular filtration rate, hypertriglyceridaemia, prolonged activated partial thromboplastin time, prolonged 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.
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 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.
Overall, 10% of CLS were severe (grade 3-4) and their frequency decreased over the treatment courses.
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.
Both motor and sensory peripheral neuropathies have been reported, overall in 9% of the patients. Most events were of grade 1-2 and resolved.
Reports of central neurotoxicity and severe neurotoxicity have been received including posterior reversible encephalopathy syndrome (0.7%) and seizures (1.7%).
The combination of dinutuximab with IL-2 increases the risk of adverse drug reactions compared to dinutuximab 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.
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