Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of safety profile
The data described below reflect the exposure to sebelipase alfa in 125 patients at doses ranging from 0.35 mg/kg once every other week to 7.5 mg/kg once weekly in clinical studies (see section 5.1), with a treatment duration range from 1 day to 60.5 months (5 years).

Of the 106 children and adults enrolled in clinical studies, 102 (96.2%) have received sebelipase alfa at a dosage regimen of 1 mg/kg once every other week, with a median duration of exposure of 33 months (6, 59 months). The median duration of exposure for the 19 infants enrolled in clinical studies was 35.5 months (1 day to 60 months).
The most serious adverse reactions experienced by 4% of patients in clinical studies were signs and symptoms consistent with anaphylaxis. Signs and symptoms included chest discomfort, conjunctival hyperaemia, dyspnoea, hyperaemia, eyelid oedema, rhinorrhoea, severe respiratory distress, tachycardia, tachypnoea, irritability, flushing, pruritus, urticaria, stridor, hypoxia, pallor and diarrhoea.

Tabulated list of adverse reactions

The data in Table 1 describe adverse reactions reported in infants who received sebelipase alfa in clinical studies. The data in Table 2 describe adverse reactions reported in children and adults who received sebelipase alfa in clinical studies

Adverse reactions are listed by System Organ Class (SOC) and frequency. Frequencies are defined according to the following convention: 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).

Table 1: Adverse reactions reported in infants receiving sebelipase alfa (N = 19 patients) MedDRA System organ class              MedDRA Preferred Term                         Frequency Immune system disorders                 Hypersensitivitya                            Very common Anaphylactic reactionb
Eye Disorders                          Eyelid oedema                                 Very common Cardiac disorders                      Tachycardia                                   Very common Respiratory, thoracic and              Respiratory distress
Very common mediastinal disorders
Vomiting
Gastrointestinal disorders                                                           Very common Diarrhoea
Rash
Skin and subcutaneous tissue           Rash maculo-papular                           Very common disorders
General disorders and                  Pyrexia administration site conditions         Hyperthermia                                  Very common Drug specific antibody present
Body temperature increased
Investigations                                                                       Very common Oxygen saturation decreased
Blood pressure increased
Heart rate increased
Respiratory rate increased a
May include: irritability, agitation, vomiting, urticaria, eczema, pruritus, pallor, and drug hypersensitivity b
Occurred in 3 infant patients treated in clinical studies. Based on Preferred Term ‘anaphylactic reaction’ and application of Sampson criteria to identify signs/symptoms consistent with anaphylaxis

Table 2: Adverse reactions reported in children and adults receiving sebelipase alfa (N = 106 patients)
MedDRA System organ class           MedDRA preferred term                        Frequency b
Immune system disorders             Hypersensitivity                             Very Common Anaphylactic reactiona                       Common
Nervous system disorders            Dizziness                                    Very common Cardiac disorders                   Tachycardia                                  Common Vascular disorders                  Hyperaemia                                   Common Hypotension
Respiratory, thoracic and           Dyspnoea mediastinal disorders                                                            Common Abdominal pain                               Very common
Gastrointestinal disorders          Diarrhoea

Abdominal distension                            Common
Rash
Skin and subcutaneous tissue         Rash papular                                    Common disorders
Fatigue                                       Very common
General disorders and                    Pyrexia administration site conditions           Chest discomfort
Infusion site reactionc                       Common
Investigations                           Body temperature increased                    Common a
Occurred in 2 patients treated in clinical studies. Based on Preferred Term ‘anaphylactic reaction’ and application of Sampson criteria to identify signs/symptoms consistent with anaphylaxis b
May include: chills, eczema, laryngeal oedema, nausea, pruritus, urticaria c
Includes: infusion site extravasation, infusion site pain and infusion site urticaria Description of selected adverse reactions

Hypersensitivity
Five of 125 (4%) patients treated with sebelipase alfa, including 3 of 19 (16%) infants and 2 of 106 (2%) children and adults, in clinical studies experienced serious signs and symptoms consistent with anaphylaxis to sebelipase alfa. Anaphylaxis occurred during the infusion as late as 1 year after treatment initiation.

In clinical studies, 59 of 125 (47%) sebelipase alfa-treated patients, including 13 of 19 (68%) infants and 46 of 106 (43%) children and adults, experienced at least 1 hypersensitivity reaction (selected using a validated, pre-determined set of terms grouped together to identify potential hypersensitivity reactions). Signs and symptoms either consistent with or that may be related to a hypersensitivity reaction occurring in two or more patients included but were not limited to abdominal pain, agitation, bronchospasm, chills, diarrhoea, eyelid oedema, eczema, face oedema, hypertension, irritability, laryngeal oedema, lip swelling, nausea, oedema, pallor, pruritus, pyrexia/body temperature increased, rash, tachycardia, urticaria, and vomiting. The majority of reactions occurred during or within 4 hours of the completion of the infusion.

Transient hyperlipidaemia
Consistent with its known mechanism of action, asymptomatic increases in circulating cholesterol and triglycerides have been observed following initiation of treatment. These increases have generally occurred within the first 2 to 4 weeks and improved within a further 8 weeks of treatment. See section 5.1.

Immunogenicity
There is potential for immunogenicity (see section 4.4). Patients have developed anti-drug antibodies (ADA) to sebelipase alfa. Compared to children and adults, an increased occurrence of ADA positivity was observed within the infant population (10/19 patients).

Among 125 patients with LAL Deficiency enrolled in the clinical studies, 19/125 (15.0%) patients tested positive for anti-drug antibodies (ADAs) at some timepoint after starting treatment with sebelipase alfa (9 children and adult patients and 10 infants). For children and adult patients with LAL Deficiency, ADA positivity was transient with generally low titers of ADAs reported. Persistence of ADA positivity was observed for all 10 infants and persistence of high titer ADAs was observed for 3 of the 10 infants. Among those 19 patients, 11 (58%) also showed the presence of inhibitory antibody activity (NAbs) at some postbaseline timepoint.

Reporting of suspected adverse reactions
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/ and emailed to the Registration Holder's Patient Safety Unit at: drugsafety@neopharmgroup.com