Summary of the safety profile Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the injection site, chills, flushing, generalized urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed and may in some cases progress to severe anaphylaxis (including shock).
1). If such inhibitors occur, the condition will manifest itself as an insufficient clinical response. In such cases, it is recommended that a specialized haemophilia centre be contacted. The most frequently reported adverse reactions in clinical studies in PTPs were headache, cough and pyrexia.
Tabulated list of adverse reactions A total of 256 patients constituted the safety population from 4 pivotal Phase I and III studies (one phase I study and 3 phase III studies), 148 adolescents/adults and 108 paediatric patients < 12 years.
9 The median number of exposure days to Jivi per patient was 195 (min-max: 1-698) for all patients in the clinical studies. Overall, in all studies 75 patients, 39 of them below 12 years of age, were observed for a treatment duration of more than 5 years.
1 for additional details on the clinical studies. The table presented below is according to the MedDRA system organ classification (SOC and Preferred Term Level). Frequencies have been evaluated 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).
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 2:
Frequency of adverse drug reactions in clinical studies MedDRA Standard System Organ Class Adverse reactions Frequency Blood and lymphatic system disorders FVIII inhibition Uncommon (PTPs)a Immune system disorders Hypersensitivity common Psychiatric disorders Insomnia common Nervous system disorders Headache very common Dizziness common Dysgeusia uncommon Vascular disorders Flushing uncommon Respiratory, thoracic and mediastinal disorders Cough common Gastrointestinal disorders Abdominal pain, Nausea, Vomiting common Skin and subcutaneous tissue disorders Erythemac, Rashd common Pruritus uncommon General disorders and administration site conditions Injection site reactions b, Pyrexia common PTPs: previously treated patients a Frequency is based on studies with all factor VIII products which included patients with severe haemophilia A b Includes injection site pruritus, injection site rash, infusion site pain and vessel puncture site pruritus c Includes erythema and erythema multiforme d Includes rash and rash papular There was no change in the safety profile during the PROTECT VIII and the PROTECT Kids extension studies.
Description of selected adverse reactions Immunogenicity Immunogenicity was evaluated during clinical studies with Jivi in 159 (including surgery patients) previously treated adolescents (≥ 12 to < 18 years of age, n=14) and adults (n=145) diagnosed with severe haemophilia A (FVIII:C < 1%), and ≥ 150 previous exposure days and 108 paediatric PTPs < 12 years of age (n=60 aged 7-<12 years) and ≥ 50 previous exposure days.
10 FVIII inhibitors No de novo or confirmed cases of inhibitor against factor VIII occurred. 7 BU/mL) was reported in one adult patient undergoing surgery. Anti-PEG antibodies Immunogenicity against PEG with development of specific IgM anti-PEG antibodies was observed in 2 patients.
In one patient > 12 years of age, the immune response was accompanied by a clinical hypersensitivity reaction after 4 injections of Jivi. Antibodies to PEG disappeared after discontinuation of Jivi. One child ˃ 7 years, developed high titre neutralising anti-PEG IgM antibodies within the first 4 exposure days associated with loss of drug effect.
Antibodies disappeared after discontinuation and patient safely re-started treatment with Jivi 2 months later. Transient low titre anti-PEG antibodies of the IgM isotype were observed in some patients within the first 4 ED resulting in minor reduction of recovery.
No clinical immune response to PEG resulting in loss of drug efficacy or hypersensitivity was observed from the 5th ED through the end of the extension studies. Paediatric population in the PROTECT Kids study In the completed clinical study with 73 paediatric PTPs < 12 years (44 PTPs < 6 years, 29 PTPs 6- < 12 years), adverse reactions due to immune response to PEG were observed in children less than 6 years of age.
In 10 of 44 patients (23%) in the age group of younger than 6 years of age loss of drug effect due to neutralising anti-PEG antibodies during the first 4 exposure days was observed. 4). No triggers or predictors of the immune response to PEG could be identified.
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. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.