Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the infusion site, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed rarely and may in some cases progress to severe anaphylaxis (including shock).

Very rarely development of antibodies to hamster protein with related hypersensitivity reactions has been observed.

Development of neutralising antibodies (inhibitors) may occur in patients with haemophilia A treated with factor VIII, including with NovoEight. If such inhibitors occur, the condition will manifest itself as an insufficient clinical response. In such cases, it is recommended that a specialised haemophilia centre is contacted.

Tabulated list of adverse reactions
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); and not known (cannot be estimated from the available data).
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.


Table 2 Frequency of adverse drug reactions in clinical trials
System Organ Class     Frequencya in      Frequencya in             Adverse reaction PTPs               PUPs
Blood and lymphatic    Uncommonb          Very commonb              FVIII inhibition system disorders
Psychiatric disorders  Uncommon                                     Insomnia Nervous system         Uncommon                                     Headache, dizziness, burning disorders                                                           sensation Cardiac disorders      Uncommon                                     Sinus tachycardia, acute myocardial infarction
Vascular disorders        Uncommon                                  Hypertension, lymphoedema, hyperaemia
Common              Flushing, Thrombophlebitis superficial
Skin and subcutaneous                           Common              Rash, rash erythematous tissue disorders      Uncommon                                      Rash, lichenoid keratosis, skin burning sensation
Musculoskeletal and       Uncommon                                  Musculoskeletal stiffness, connective tissue                                                   arthropathy, pain in extremity, disorders                                                           musculoskeletal pain Common              Haemarthrosis, Muscle haemorrhage
Respiratory, thoracic                           Common              Cough and mediastinal disorders
General disorders and     Common                                    Injection site reactionsC administration site                             Common              Pyrexia, catheter site erythema conditions                Uncommon                                  Fatigue, feeling hot, oedema peripheral, pyrexia
Investigations            Common                                    Hepatic enzymes increasedd Common              Anti factor VIII antibody positive
Uncommon                                  Heart rate increased
Gastrointestinal                                 Common             Vomiting disorders
Injury, poisoning and       Common                                   Incorrect dose administered procedural                                       Common              Infusion related reaction complications               Uncommon                                 Contusion Product issues                                   Common              Thrombosis in device a      Calculated based on total number of unique patients in all clinical trials (301), of which 242 were previously treated patients (PTPs) and 60 were previously untreated patients (PUPs).
b     Frequency is bsed on studies with all FVIII products which included patients with severe haemophilia A.
c      Injection site reactions include injection site erythema, injection site extravasation and injection site pruritus.
d      Hepatic enzymes increased include alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase and bilirubin.

Description of selected adverse reactions
During all clinical studies with NovoEight in previously treated patients, a total of 35 adverse reactions were reported in 23 of 242 patients exposed to NovoEight. The most frequently reported adverse reactions were injection site reactions, incorrect dose administered and hepatic enzymes increased. Of the 35 adverse reactions, 2 were reported in 1 out of 31 patients below 6 years of age, none in patients from 6≤12 years of age, 1 event in 1 out of 24 patients (12 to <18 years of age) and 32 were reported in 21 out of 155 adults (≥18 years).


Paediatric population
In clinical trials involving 63 previously treated paediatric patients between 0 and 12 years of age and 24 adolescents between 12 and 18 years of age with severe haemophilia A no difference in the safety profile of NovoEight was observed between paediatric patients and adults.

In the trial with previously untreated patients, between 0 and 6 years of age, a total of 46 adverse reactions were reported in 33 of 60 patients exposed to NovoEight. The most frequently reported adverse reaction was Factor VIII inhibition, see section 4.4. High risk genetic mutations were identified in 92.3% of the overall and 93.8% of the high titre confirmed inhibitors. No other factors were significantly associated with inhibitor development.

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 http://sideeffects.health.gov.il