Adverse reactions : תופעות לוואי

4.8 Undesirable effects

Summary of the safety profile
Since agalsidase beta (r-hαGAL) is a recombinant protein, the development of IgG antibodies is expected in patients with little or no residual enzyme activity. Patients with antibodies to r-hαGAL have a greater potential to experience infusion-associated reactions (IARs). Reactions suggestive of immediate (Type I) hypersensitivity have been reported in a small number of patients (see section 4.4).

Very common adverse reactions included chills, pyrexia, feeling cold, nausea, vomiting, headache and paraesthesia. Sixty seven percent (67%) of the patients experienced at least one infusion-associated reaction. Anaphylactoid reactions have been reported in the postmarketing setting.

Tabulated list of adverse reactions
Adverse reactions reported from clinical trials with a total of 168 patients (154 males and 14 females) treated with Fabrazyme administered at a dose of 1 mg/kg every 2 weeks for a minimum of one infusion up to a maximum of 5 years are listed by System Organ Class and frequency (very common ≥ 1/10; common ≥ 1/100 to < 1/10 and uncommon ≥ 1/1,000 to < 1/100) in the table below. The occurrence of an adverse reaction in a single patient is defined as uncommon in light of the relatively small number of patients treated. Adverse reactions only reported during the Post Marketing period are also included in the table below at a frequency category of “not known” (cannot be estimated from the available data).
Adverse reactions were mostly mild to moderate in severity.


Incidence of adverse reactions with Fabrazyme treatment
System organ       Very common    Common                    Uncommon               Not known class
Infections and     ---            nasopharyngitis           rhinitis infestations
Immune system      ---            ---                       ---                    anaphylactoid disorders                                                                          reaction Nervous system     headache,      dizziness, somnolence, hyperaesthesia,           --- disorders          paraesthesia   hypoaesthesia, burning tremor sensation, lethargy,
syncope
Eye disorders      ---            lacrimation increased     eye pruritus, ocular   --- hyperaemia
Ear and labyrinth ---             tinnitus, vertigo         auricular swelling,    --- disorders                                                   ear pain
Cardiac Disorders ---             tachycardia,              sinus bradycardia      --- palpitations, bradycardia
Vascular disorders ---            flushing, hypertension, peripheral coldness      --- pallor, hypotension, hot flush
Respiratory,         ---                 dyspnoea, nasal            bronchospasm,        hypoxia thoracic and                             congestion, throat         pharyngolaryngeal mediastinal                              tightness, wheezing,       pain, rhinorrhoea, disorders                                cough, dyspnoea            tachypnoea, upper exacerbated                respiratory tract congestion
Gastrointestinal   nausea, vomiting abdominal pain,                 dyspepsia, dysphagia --- Disorders                           abdominal pain upper,
abdominal discomfort,
stomach discomfort,
hypoaesthesia oral,
diarrhoea
Skin and           ---              pruritus, urticaria, rash,      livedo reticularis,      leukocytoclastic subcutaneous                        erythema, pruritus              rash erythematous,       vasculitis tissue disorders                    generalised,                    rash pruritic, skin angioneurotic oedema,           discolouration, skin swelling face, rash             discomfort maculo-papular
Musculoskeletal ---                 pain in extremity,              musculoskeletal pain     --- and connective                      myalgia, back pain,
tissue disorders                    muscle spasms,
arthralgia, muscle tightness,
musculoskeletal stiffness
General disorders chills, pyrexia,  fatigue, chest                  feeling hot and cold, --- and administration feeling cold     discomfort, feeling hot,        influenza-like illness, site conditions                     oedema peripheral, pain,        infusion site pain, asthenia, chest pain, face      infusion site reaction,
oedema, hyperthermia            injection site thrombosis, malaise,
oedema
Investigations                                                                              oxygen saturation decreased
For the purpose of this table, ≥1% is defined as reactions occurring in 2 or more patients.
Adverse reaction terminology is based upon the Medical Dictionary for Regulatory Activities (MedDRA) 
Description of selected adverse reactions
Infusion associated reactions
Infusion associated reactions consisted most often of fever and chills. Additional symptoms included mild or moderate dyspnoea, hypoxia (oxygen saturation decreased), throat tightness, chest discomfort, flushing, pruritus, urticaria, face oedema, angioneurotic oedema, rhinitis, bronchospasm, tachypnoea, wheezing, hypertension, hypotension, tachycardia, palpitations, abdominal pain, nausea, vomiting, infusion-related pain including pain at the extremities, myalgia, and headache.

The infusion-associated reactions were managed by a reduction in the infusion rate together with the administration of non-steroidal anti-inflammatory medicinal products, antihistamines and/or corticosteroids. Sixty seven percent (67%) of the patients experienced at least one infusion-associated reaction. The frequency of these reactions decreased over time. The majority of these reactions can be 
attributed to the formation of IgG antibodies and/or complement activation. In a limited number of patients IgE antibodies were demonstrated (see section 4.4).

Paediatric population
Limited information from clinical trials suggests that the safety profile of Fabrazyme treatment in paediatric patients ages 5-7, treated with either 0.5 mg/kg every 2 weeks or 1.0 mg/kg every 4 weeks is similar to that of patients (above the age of 7) treated at 1.0 mg/kg every 2 weeks.

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/ .