Adverse reactions : תופעות לוואי

4.8    Undesirable effects
Summary of the safety profile

The adverse reactions described in this section were evaluated in 24 patients with CLN2 disease who received at least one dose of Brineura in clinical studies of up to 141 weeks or in post-marketing experience.
The most frequent (>20%) adverse reactions observed during Brineura clinical trials include pyrexia, low CSF protein, ECG abnormalities, vomiting, upper respiratory tract infections, and hypersensitivity. No patients had to have their treatment discontinued due to adverse events.

Tabulated list of adverse reactions

Adverse reactions observed are listed below, by system organ class and frequency, following the MedDRA frequency convention defined as: 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), not known (cannot be estimated from the available data).



Table 2: Frequency of adverse reactions with Brineura

MedDRA                                                     MedDRA                                              Frequency System organ class                                         Preferred term Infections and infestations                                Upper respiratory tract infection                   Very common Conjunctivitis                                      Common
Device-related infectiona                           Common
Meningitis                                          Not known
Immune system disorders                                    Hypersensitivity                                    Very common Anaphylactic reaction                               Common
Psychiatric disorders                                      Irritability                                        Very common 
Nervous system disorders                                   Convulsion eventsb                                  Very common Headache                                            Very common
CSF Pleocytosis                                     Very common
Dropped head syndrome                               Common
Cardiac disorders                                          Bradycardia                                         Common Gastrointestinal disorders                                 Vomiting                                            Very common Abdominal pain                                      Common
Oral mucosal blistering                             Common
Tongue blistering                                   Common
Gastrointestinal disorder                           Common
Skin and subcutaneous tissue disorders                     Rash                                                Common Urticaria                                           Common
General disorders and administration site                  Pyrexiac                                            Very common conditions                                                 Feeling jittery                                     Common Pain                                                Common
Investigations                                             CSF protein increased                               Very common ECG abnormalities                                   Very common
CSF protein decreased                               Very common
Product issues                                             Device issue: Device leakage                                      Common
Device occlusiond                                   Common
Device dislocatione                                 Not known
Needle issuef                                       Very common a Propionibacterium   acnes, Staphylococcus epidermis b Atonic seizures, clonic convulsion, drop attacks, epilepsy, generalised tonic-clonic seizure, myoclonic epilepsy, partial seizures, petit mal epilepsy, seizure, seizure cluster, and status epilepticus c Pyrexia includes combined preferred terms “Pyrexia” and “Increased body temperature” d Catheter flow obstruction e Device dislocation did not occur in clinical trials f Dislodgement of infusion needle



Description of selected adverse reactions

Convulsions
Convulsions are a common manifestation of CLN2 disease and are expected to occur in this population. Overall, 23 (96%) subjects who received cerliponase alfa experienced an event that mapped to the Convulsions Standardized MedDRA Query. The most commonly reported convulsion events include seizure, epilepsy and generalized tonic-clonic seizure. Total convulsion events with a temporal relationship to cerliponase alfa administration was 17% and were mild to moderate, grade 1 to 2 in severity. Overall, 6% of all convulsion events were considered related to cerliponase alfa and ranged from mild to severe, CTCAE grade 1-4. Convulsions resolved with standard anti-convulsive therapies, and did not result in discontinuation of Brineura treatment.

Hypersensitivity

Hypersensitivity reactions were reported in 14 out of 24 patients (58%) treated with Brineura. Severe (Common Terminology Criteria for Adverse Events (CTCAE) grade 3) hypersensitivity reactions occurred in three patients and no patients discontinued treatment. The most common manifestations included pyrexia with vomiting, pleocytosis, or irritability, which are inconsistent with classic immune mediated hypersensitivity. These adverse reactions were observed during or within 24 hours after completion of the Brineura infusion and did not interfere with treatment. Symptoms resolved over time or with administration of antipyretics, antihistamines and/or glucocorticosteroids.

Immunogenicity

Anti-drug antibodies (ADAs) were detected in both serum and CSF in 79% and 21%, respectively, of patients treated with cerliponase alfa for up to 107 weeks. Drug-specific neutralising antibodies (NAb) capable of inhibiting receptor-mediated cellular uptake of cerliponase alfa were not detected in the CSF.
No association was found between serum or CSF ADA titres and incidence or severity of hypersensitivity.
Patients who experienced moderate hypersensitivity adverse events were tested for drug-specific IgE and found to be negative. No correlations were found between higher ADA titres and reductions in efficacy measurements. There was no apparent effect of serum or CSF ADA on the plasma or CSF pharmacokinetics, respectively.

Paediatric population

An ongoing study provides experience with two patients aged 2 years of age treated with Brineura at 300 mg every other week (see section 5.1). Both patients have received 8 infusions and the overall safety profile of Brineura in these younger patients appears consistent with the safety profile observed in older children.
Currently no clinical experience of Brineura in children below 2 years of age is available.

Reporting of suspected adverse reaction
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/