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).
Summary of adverse reactions: Adverse reactions reported during clinical trials and from spontaneous (post-marketing) reports are listed as follows. 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 frequencies of both serious and non-serious adverse drug reactions are listed by system organ classes as follows.
Blood and lymphatic system disorders: Rare (≥1/10,000, <1/1,000): Disseminated intravascular coagulation and related laboratory findings including elevated levels of D-dimer and decreased levels of AT, see Precautions; Coagulopathy.
Gastrointestinal disorders: Rare (≥1/10,000, <1/1,000): Nausea.
General disorders and administration site conditions: Uncommon (≥1/1,000, <1/100): Therapeutic response decreased*; Pyrexia.
Rare (≥1/10,000, <1/1,000): Injection site reaction including injection site pain.
Immune system disorders: Rare (≥1/10,000, <1/1,000): Hypersensitivity (see Contraindications and Precautions).
Frequency not known: Anaphylactic reaction.
Investigations: Rare (≥1/10,000, <1/1,000): Increased fibrin degradation products; Increase of alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase and prothrombin.
Nervous system disorders: Rare (≥1/10,000, <1/1,000): Headache.
Skin and subcutaneous tissue disorders: Uncommon (≥1/1,000, <1/100): Rash (including allergic dermatitis and rash erythematous); Pruritus and urticaria.
Frequency not known: Flushing; Angioedema.
Vascular disorders: Uncommon (≥1/1,000, <1/100): Venous thromboembolic events (deep vein thrombosis, thrombosis at i.v. site, pulmonary embolism, thromboembolic events of the liver including portal vein thrombosis, renal vein thrombosis, thrombophlebitis, superficial thrombophlebitis and intestinal ischaemia).
Rare (≥1/10,000, <1/1,000): Arterial thromboembolic events (myocardial infarction, cerebral infarction, cerebral ischaemia, cerebral artery occlusion, cerebrovascular accident, renal artery thrombosis, peripheral ischaemia, peripheral arterial thrombosis and intestinal ischaemia); Angina pectoris.
Frequency not known: Intracardiac thrombus.
*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 Dosage & Administration.
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 Precautions).
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 Vascular disorders previously mentioned) (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.