| 4.4 Special warnings and precautions for use
As recombinant coagulation factor - inserted "VIIa"
4.6 Pregnancy and lactation
Inserted:
Lactation
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.
Deleted:
Use during lactation: It is not known whether rFVIIa is excreted in human milk. No effects on the breastfed newborn/infant are anticipated. NovoSeven can be used during breast-feeding.
4.8 Undesirable effects
in clinical trials The frequencies of both serious and non-serious adverse drug reactions are listed by system organ classes in the table below.
Based on post-marketing experience adverse drug reactions are rare (< 1 per 1,000 standard doses). When analysed by system organ classes, the reporting rates of adverse drug reactions during the post-marketing period, including both serious and non-serious reactions, are as indicated in the table below:
Inserted:
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Blood and the lymphatic system disorders
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Rare (> 1/10,000, < 1/1,000)
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– Disseminated intravascular coagulation and related laboratory findings including elevated levels of D-dimer and AT-III, (see Section 4.4)
– Coagulopathy.
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Immune system disorders
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Rare (> 1/10,000, < 1/1,000)
Not known
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– Hypersensitivity, (see Sections 4.3 and 4.4)
– Anaphylactic reaction.
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Nervous system disorders
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Rare (> 1/10,000, < 1/1,000)
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– Headache.
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Vascular disorders
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Rare (> 1/10,000, < 1/1,000)
Uncommon (> 1/1,000, < 1/100)
Rare (> 1/10,000, < 1/1,000)
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– 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)
– 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)
– Angina pectoris.
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Gastrointestinal disorders
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Rare (> 1/10,000, < 1/1,000)
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– Nausea.
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Skin and subcutaneous disorders
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Uncommon (> 1/1,000, < 1/100)
Not known
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– Rash (including allergic dermatitis and rash erythematous)
– Pruritus and urticaria
– Flushing
– Angioedema.
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General disorders and administration site conditions
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Uncommon (> 1/1,000, < 1/100)
Rare (> 1/10,000, < 1/1,000)
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– Therapeutic response decreased*
– Pyrexia
– Injection site reaction including injection site pain.
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Investigations
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Rare (> 1/10,000, < 1/1,000)
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– Increased fibrin degradation products
– Increase in alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase and prothrombin.
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Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Adverse drug reaction reported post-marketing only (i.e. not in clinical trials) are presented with a frequency of not known.
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* Lack of efficacy (therapeutic response decreased) has been reported. It is important that the dosage regimen of NovoSeven is compliant with the recommended dosage as stated in Section 4.2.
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 frequent (1% based on treatment episodes):
Inserted & Deleted:
Thromboembolic events
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 (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.i
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Serious adverse reactions reported during the post-marketing period include:
– Arterial thrombotic events such as myocardial infarctions or ischaemia, cerebrovascular disorders and bowel infarction. In the vast majority of cases the patients were predisposed to arterial thrombotic disorders either due to underlying disease, age, atherosclerotic or current medical conditions as described in section 4.4.
– Venous thrombotic events such as thrombophlebitis, deep vein thrombosis and hereto related pulmonary embolism. In the vast majority of cases the patients were predisposed to venous thrombotic events due to concurrent risk factors. Patients at increased risk of venous thrombotic disorders either due to concurrent conditions, previous history of thrombotic events, post surgery immobilisation or venous catheterisation should be carefully monitored.
– Thrombotic events of the liver. In the vast majority of cases the patients were predisposed due to liver disease or liver surgery.
Isolated cases of hypersensitivity reactions including anaphylactic reactions have been reported post-marketing. Patients with a history of allergic reactions should be carefully monitored.
There have been no reports of antibodies against factor VII in haemophilia A or B patients. Isolated cases of factor VII deficient patients developing antibodies against factor VII have been reported after treatment with rFVIIa. These patients have previously been treated with human plasma and/or plasma-derived factor VII. In two patients the antibodies showed inhibitory effect in vitro. Patients with factor VII deficiency treated with NovoSeven should be monitored for factor VII antibodies.
One case of angioneurotic oedema has been reported spontaneously in a patient with Glanzmann’s thrombasthenia after administration of rFVIIa.
4.9 Overdose
Dose limiting toxicities of NovoSeven have not been investigated in clinical trials.
Three cases of overdose have been reported in patients with haemophilia in 13 years. The only complication reported in connection with an overdose was a slight transient increase in blood pressure in a 16 year-old patient receiving 24 mg rFVIIa instead of 5.5 mg.
No cases of overdose have been reported in patients with acquired haemophilia or Glanzmann’s thrombasthenia.
In patients with factor VII deficiency, where the recommended dose is 15 – 30 µg/kg rFVIIa, one episode of overdose has been associated with a thrombotic event (occipital stroke) in an elderly (> 80 year) male patient treated with 10 – 20 times the recommended dose. In addition, the development of antibodies against NovoSeven and FVII has been associated with overdose in one patient with factor VII deficiency.
The dose schedule should not be intentionally increased above the recommended doses due to the absence of information on the additional risk that may be incurred.A thrombotic event has been reported in an elderly (> 80 year) male patient with factor VII deficiency treated with 10 - 20 times the recommended dose.
No other thrombotic complications from overdose have been reported, not even after treatment of a 6 year old boy with haemophilia A with inhibitors with 8 - 10 times the recommended dose.
10. date of revision of the text
08/2008 05/2009
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