Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Novo Nordisk A/S, Novo Allé, DK-2880, Bagsværd, Denmark
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or to mouse, hamster or bovine protein.
In pathological conditions in which tissue factor may be expressed more extensively than considered normal, there may be a potential risk of development of thrombotic events or induction of Disseminated Intravascular Coagulation (DIC) in association with NovoSeven treatment.
Such situations may include patients with advanced atherosclerotic disease, crush injury, septicaemia or DIC. Because of the risk of thromboembolic complications, caution should be exercised when administering NovoSeven to patients with a history of coronary heart disease, to patients with liver disease, to patients post-operatively, to neonates, or to patients at risk of thromboembolic phenomena or disseminated intravascular coagulation. In each of these situations, the potential benefit of treatment with NovoSeven should be weighed against the risk of these complications.
As recombinant coagulation factor VIIa NovoSeven may contain trace amounts of mouse IgG, bovine IgG and other residual culture proteins (hamster and bovine serum proteins), the remote possibility exists that patients treated with the product may develop hypersensitivity to these proteins. In such cases treatment with antihistamines i.v. should be considered.
If allergic or anaphylactic-type reactions occur, the administration should be discontinued immediately. In case of shock, standard medical treatment for shock should be implemented. Patients should be informed of the early signs of hypersensitivity reactions. If such symptoms occur, the patient should be advised to discontinue use of the product immediately and contact their physician.
In case of severe bleeds the product should be administered in hospitals preferably specialised in treatment of haemophilia patients with coagulation factor VIII or IX inhibitors, or if not possible, in close collaboration with a physician specialised in haemophilia treatment.
If bleeding is not kept under control hospital care is mandatory. Patients/carers should inform the physician/supervising hospital at the earliest possible opportunity about all usages of NovoSeven.
Factor VII deficient patients should be monitored for prothrombin time and factor VII coagulant activity before and after administration of NovoSeven. In case the factor VIIa activity fails to reach the expected level or bleeding is not controlled after treatment with the recommended doses, antibody formation may be suspected and analysis for antibodies should be performed. Thrombosis has been reported in FVII deficient patients receiving NovoSeven during surgery but the risk of thrombosis in factor VII deficient patients treated with NovoSeven is unknown (see section 5.1).
The risk of a potential interaction between NovoSeven and coagulation factor concentrates is unknown. Simultaneous use of prothrombin complex concentrates, activated or not, should be avoided.
Anti-fibrinolytics have been reported to reduce blood loss in association with surgery in haemophilia patients, especially in orthopaedic surgery and surgery in regions rich in fibrinolytic activity, such as the oral cavity. Experience with concomitant administration of anti-fibrinolytics and rFVIIa treatment is however limited.
Based on a non-clinical study (see section 5.3) it is not recommended to combine rFVIIa and rFXIII. There are no clinical data available on interaction between rFVIIa and rFXIII.
As a precautionary measure, it is preferable to avoid use of NovoSeven during pregnancy. Data on a limited number of exposed pregnancies within approved indications indicate no adverse effects of rFVIIa on pregnancy or on the health of the foetus/new-born child. To date, no other relevant epidemiological data are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3).
It is unknown whether rFVIIa is excreted in human breast milk. The excretion of rFVIIa in milk has not been studied in animals. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with NovoSeven should be made taking into account the benefit of breast-feeding to the child and the benefit of NovoSeven therapy to the woman.
Data from non-clinical studies as well as post-marketing data show no indication that rFVIIa has a harmful effect on male or female fertility.
No studies on the effect on the ability to drive and use machines have been performed.
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).
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 are thromboembolic events. 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:
Rare: Disseminated intravascular coagulation (see section 4.4), Related laboratory findings, including elevated levels of Ddimmer and decreased levels of AT (see section 4.4), Coagulopathy
Rare: Nausea
Uncommon: Therapeutic response decreased*, Pyrexia
Rare: Injection site reaction including injection site pain
Rare: Hypersensitivity (see sections 4.3 and 4.4)
Frequency Not Known: Anaphylactic reaction
Rare: Increased fibrin degradation products, Increase of alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase and prothrombin
Rare: Headache
Uncommon: Rash (including allergic dermatitis and rash erythematous), Pruritus and urticaria
Frequency Not Known: Flushing, Angioedema
Uncommon: 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: 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 NovoSevenis compliant with the recommended dosage as stated in section 4.2.
In post-marketing experience, there have been no reports of inhibitory antibodies against NovoSeven or FVII in patients with haemophilia A or B. Development of inhibitory antibodies to NovoSeven 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 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, were present. Patients with factor VII deficiency treated with NovoSeven should be monitored for factor VII antibodies (see section 4.4).
When NovoSeven 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 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 have not been established outside the approved indications and therefore NovoSeven should not be used.
Thromboembolic events may lead to cardiac arrest.
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.
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.
NovoSeven must not be mixed with infusion solutions or be given in a drip.
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