Adverse reactions : תופעות לוואי

4.8        Undesirable effects

Summary of the safety profile
Supportive safety data reflect exposure in 112 patients with perinatal/infantile (n=89), juvenile-onset (n = 22), adult onset (n = 1) HPP (age at enrollment from 1 day to 66.5 years) treated with asfotase alfa, with a treatment duration range from 1 day to 391.9 weeks [7.5 years]). The most common adverse reactions observed were injection site reactions (74%). A few case reports of anaphylactoid/hypersensitivity reaction have been received

Tabulated list of adverse reactions
Adverse reactions with asfotase alfa are listed by system organ class and preferred term using MedDRA frequency 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). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1: Adverse Reactions Reported in clinical trials in hypophosphatasia patients System Organ Class          Frequency                               Adverse reaction category
Infections and infestations Common                    Injection site cellulitis Blood and lymphatic system         Common                 Increased tendency to bruise disorders
Immune system disorders            Common                 Anaphylactoid reactions Hypersensitivity2
Metabolism and nutrition           Common                 Hypocalcaemia disorders
Nervous system disorders           Very common            Headache
Vascular disorders                 Common                 Hot flush
Gastrointestinal disorders         Common                 Hypoaesthesia oral Nausea
Skin and subcutaneous              Very common            Erythema tissue disorders                   Common                 Skin discolouration Skin disorder (stretched skin)


Musculoskeletal and                Very common            Pain in extremity connective tissue disorders
Common                 Myalgia
Renal and urinary disorders        Common                 Nephrolithiasis General disorders and              Very common            Injection site reactions1 administration site                                       Pyrexia conditions                                                Irritability Common                 Chills
Injury, poisoning and              Very common            Contusion procedural complications
Common                 Scar
1-
Preferred terms considered as injection site reactions are presented in section below 2-
Preferred terms considered as hypersensitivity are presented in the section below 
Description of selected adverse reactions

Injection site reactions
Injection site reactions (including injection site atrophy, abscess, erythema, discolouration, pain, pruritus, macule, swelling, contusion, bruising, lipodystrophy (lipoatrophy or lipohypertrophy), 
induration, reaction, nodule, rash, papule, haematoma, inflammation, urticarial, calcification, warmth, haemorrhage, cellulitis, scar, mass, extravasation, exfoliation and vesicles) are the most common adverse reactions observed in about 74% of the patients in clinical studies. Most injection site reactions were mild and self-limiting, and the majority (> 99%) were reported as non- serious. In the clinical trial setting, the majority of patients who experienced an injection site reaction had the first occurrence within the first 12 weeks of treatment with asfotase alfa, and some patients continued to experience injection site reactions until 1 or more years after initiating asfotase alfa dosing.
One patient withdrew from the trial due to injection site hypersensitivity.

Hypersensitivity
Hypersensitivity reactions include erythema/redness, pyrexia/fever, rash, pruritis, irritability, nausea, vomiting, pain, rigor/chills, hypoaesthesia oral, headache, flushing, tachycardia, cough, and signs and symptoms consistent with anaphylaxis (see section 4.4). A few case reports of anaphylactoid/hypersensitivity reaction have also been received and were associated with signs and symptoms of difficulty breathing, choking sensation, periorbital edema and dizziness.

Immunogenicity
There is potential for immunogenicity. Among 109 hypophosphatasia patients enrolled in the clinical studies and who have post baseline antibody data available, 97/109 (89. 0%) tested positive for anti- drug antibodies at some time point after starting Strensiq treatment. Among those 97 patients, 55 (56.7%) also showed the presence of neutralizing antibodies at some time point post-baseline. The antibody response (with or without presence of neutralizing antibodies) was time variant in nature. In clinical trials, the development of antibodies has not been shown to affect clinical efficacy or safety (see section 5.2). Data from post-marketing cases suggests that the development of antibodies may affect clinical efficacy.

No trends in adverse events based on antibody status were observed in clinical trials. Some patients confirmed positive for antidrug antibodies experienced injection site reactions (ISRs) and/or hypersensitivity, however there was no consistent trend in the frequency of these reactions over time noted between ADA ever positive and ADA always negative patients.

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