Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile

The most frequently reported adverse drug reactions are decreased therapeutic response, pyrexia, rash, venous thromboembolic events, pruritus and urticaria. These reactions are reported as uncommon (≥ 1/1,000, < 1/100).

Tabulated summary of adverse reactions

Table 1 lists adverse reactions reported during clinical trials and from spontaneous (post-marketing) reports. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Adverse drug reactions reported post-marketing only (i.e. not in clinical trials) are presented with a frequency of ‘not known’.

Clinical trials conducted in 484 patients (including 4297 treatment episodes) with haemophilia A and B, acquired haemophilia, factor VII deficiency or Glanzmann’s thrombasthenia have shown that adverse drug reactions are common (≥ 1/100 to < 1/10). As the total number of treatment episodes in clinical trials is below 10,000, the lowest possible frequency of adverse drug reactions that can be assigned is rare (≥ 1/10,000 to < 1/1,000).

The most frequent adverse drug reactions are pyrexia and rash (uncommon: ≥ 1/1,000 to < 1/100), and the most serious adverse drug reactions include venous thromboembolic events (uncommon: ≥ 1/1,000 to < 1/100) and arterial thromboembolic events (rare: ≥ 1/10,000 to < 1/1,000).
The frequencies of both serious and non-serious adverse drug reactions are listed by system organ classes in the table below.

Table 1      Adverse reactions from clinical trials and spontaneous (post-marketing) reports 
MedDRA system            Uncommon                      Rare (≥1/10,000 to <1/1,000)               Frequency Not organ class        (≥1/1,000 to <1/100)                                                            Known 
Blood and                                    -     Disseminated intravascular coagulation lymphatic system                                   (see section 4.4) disorders
-     Related laboratory findings, including elevated levels of D-dimmer and decreased levels of AT (see section 4.4)

-     Coagulopathy

Gastrointestinal                             -     Nausea disorders
General disorders   -   Therapeutic          -     Injection site reaction including and                     response                   injection site pain administration          decreased* site conditions
-   Pyrexia

Immune system                                -     Hypersensitivity (see sections 4.3 and     -     Anaphylactic disorders                                          4.4)                                             reaction 
Investigations                               -     Increased fibrin degradation products 

-     Increase of alanine aminotransferase,
alkaline phosphatase, lactate dehydrogenase and prothrombin
Nervous system                               -     Headache disorders

Skin and            -   Rash (including                                                        -   Flushing subcutaneous            allergic tissue disorders        dermatitis and                                                         -   Angioedema rash erythematous)

-   Pruritus and urticaria

Vascular            -   Venous               -     Arterial thromboembolic events              -   Intracardiac disorders               thromboembolic             (myocardial infarction, cerebral                thrombus events (deep vein          infarction, cerebral ischaemia, cerebral thrombosis,                artery occlusion, cerebrovascular thrombosis at i.v.         accident, renal artery thrombosis,
site, pulmonary            peripheral ischaemia, peripheral arterial embolism,                  thrombosis and intestinal ischaemia) thromboembolic events of the        -     Angina pectoris liver including portal vein thrombosis, renal vein thrombosis,
thrombophlebitis
, superficial thrombophlebitis and intestinal ischaemia)


* Lack of efficacy (therapeutic response decreased) has been reported. It is important that the dosage regimen of NovoSeven RT is compliant with the recommended dosage as stated in section 4.2.

Description of selected adverse reactions

Inhibitory antibody formation
In post-marketing experience, there have been no reports of inhibitory antibodies against NovoSeven RT or FVII in patients with haemophilia A or B. Development of inhibitory antibodies to NovoSeven RT has been reported in a post-marketing observational registry of patients with congenital FVII deficiency.

In clinical trials of patients with factor VII deficiency, formation of antibodies against NovoSeven RT and FVII is the only adverse drug reaction reported (frequency: common (≥ 1/100 to < 1/10)). In some cases, the antibodies showed inhibitory effect in vitro. Risk factors that may have contributed to antibody development including previous treatment with human plasma and/or plasma-derived factor VII, severe mutation of FVII gene, and overdose of NovoSeven RT, were present. Patients with factor VII deficiency treated with NovoSeven RT should be monitored for factor VII antibodies (see section 4.4).

Thromboembolic events - arterial and venous

When NovoSeven RT is administered to patients outside approved indications, arterial thromboembolic events are common (≥ 1/100 to < 1/10). A higher risk of arterial thromboembolic adverse events (see table: Vascular disorders) (5.6% in patients treated with NovoSeven RT versus 3.0% in placebo-treated patients) has been shown in a meta-analysis of pooled data from placebo- controlled trials conducted outside current approved indications in various clinical settings, each of these having distinct patient characteristics and hence different underlying risk profiles.

Safety and efficacy of NovoSeven RT have not been established outside the approved indications and therefore NovoSeven RT should not be used.
Thromboembolic events may lead to cardiac arrest.

Other special populations

Patients with acquired haemophilia
Clinical trials conducted in 61 patients with acquired haemophilia with a total of 100 treatment episodes, showed that certain adverse drug reactions were reported more frequently (1% based on treatment episodes): Arterial thromboembolic events (cerebral artery occlusion, cerebrovascular accident), venous thromboembolic events (pulmonary embolism and deep vein thrombosis), angina pectoris, nausea, pyrexia, erythematous rash and investigation of increased levels of fibrin degradation products.

Women with severe postpartum haemorrhage

In an open-label randomised clinical trial, venous thromboembolic events were reported in 2 of 51 patients treated with a single dose of NovoSeven RT (median dose 58 μg/kg) and none of 33 patients not treated with NovoSeven RT; no arterial thromboembolic events were reported in either group.
In 4 non-interventional studies, venous thromboembolic events were reported in 3 of 358 (0.8%) patients treated with NovoSeven RT (median dose range 63-105 μg/kg) and arterial thromboembolic events were reported in 1 (0.3%) patient treated with NovoSeven RT.

For known contributing factors to thromboembolic risk associated with pregnancy and severe postpartum haemorrhage, see section 4.4.

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