Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Swedish Orphan Biovitrum AB (publ), SE-112 76 Stockholm, Sweden
Hypersensitivity to the active substance (recombinant human coagulation factor IX, and/or Fc domain) or to any of the excipients listed in section 6.1.
Allergic type hypersensitivity reactions have been reported with ALPROLIX. If symptoms of hypersensitivity occur, patients should be advised to discontinue use of the medicinal product immediately and contact their physician. Patients should be informed of the early signs of hypersensitivity reactions including, hives, generalised urticaria, tightness of the chest, wheezing, hypotension and anaphylaxis.
In case of anaphylactic shock, standard medical treatment for shock should be implemented.
After repeated treatment with human coagulation factor IX products, patients should be monitored for the development of neutralising antibodies (inhibitors) that should be quantified in Bethesda Units (BU) using appropriate biological testing.
There have been reports in the literature showing a correlation between the occurrence of a factor IX inhibitor and allergic reactions. Therefore, patients experiencing allergic reactions should be evaluated for the presence of an inhibitor. It should be noted that patients with factor IX inhibitors may be at an increased risk of anaphylaxis with subsequent challenge with factor IX.
Because of the risk of allergic reactions with factor IX products, the initial administrations of factor IX should, according to the treating physician’s judgement, be performed under medical observation where proper medical care for allergic reactions could be provided.
Because of the potential risk of thrombotic complications with factor IX products, clinical surveillance for early signs of thrombotic and consumptive coagulopathy should be initiated with appropriate biological testing when administering this product to patients with liver disease, to patients post-operatively, to new- born infants, or to patients at risk of thrombotic phenomena or disseminated intravascular coagulation (DIC). The benefit of treatment with ALPROLIX in these situations should be weighed against the risk of these complications.
In patients with existing cardiovascular risk factors, substitution therapy with FIX may increase the cardiovascular risk.
If a central venous access device (CVAD) is required, risk of CVAD-related complications including local infections, bacteraemia and catheter site thrombosis should be considered.
It is strongly recommended that every time that ALPROLIX is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the medicinal product.
The listed warnings and precautions apply both to adults and children.
This medicinal product contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially “sodium-free”.
No interactions of ALPROLIX with other medicinal products have been reported. No interaction studies have been performed.
Animal reproduction studies have not been conducted with ALPROLIX. A placental transfer study in mice was conducted (see section 5.3). Based on the rare occurrence of haemophilia B in women, experience regarding the use of factor IX during pregnancy and breast-feeding is not available. Therefore, factor IX should be used during pregnancy and breast-feeding only if clearly indicated.
There are no fertility data available. No fertility studies have been conducted in animals with ALPROLIX.
ALPROLIX has no influence on the ability to drive and use machines.
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). In some cases, these reactions have progressed to severe anaphylaxis, and they have occurred in close temporal association with development of factor IX inhibitors (see also 4.4). Nephrotic syndrome has been reported following attempted immune tolerance induction in haemophilia B patients with factor IX inhibitors and a history of allergic reaction.
Patients with haemophilia B may develop neutralising antibodies (inhibitors) to factor IX. 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 be contacted.
There is a potential risk of thromboembolic episodes following the administration of factor IX products, with a higher risk for low purity preparations. The use of low purity factor IX products has been associated with instances of myocardial infarction, disseminated intravascular coagulation, venous thrombosis and pulmonary embolism. The use of high purity factor IX is rarely associated with thromboembolic complications.
The frequencies in the table below were observed in a total of 153 patients with severe haemophilia B in phase III clinical studies and an extension study. Adverse events were monitored for a total of 561 subject-years. The total number of exposure days was 26,106 with a median of 165 (range 1-528) exposure days per subject.
Table 2 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), not known (cannot be estimated from the available data).
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 2. Adverse reactions reported for ALPROLIX in clinical trials:
Uncommon: Decreased appetite
Common: Headache
Uncommon: Dizziness, Dysgeusia
Uncommon: Palpitations
Uncommon: Hypotension
Common: Paresthesia oral
Uncommon: Breath odour
Common: Obstructive uropathy
Uncommon: Haematuria, Renal colic
Uncommon: Fatigue, Infusion site pain
In post-marketing experience, FIX inhibitor development and hypersensitivity (including anaphylaxis) have been observed.
Frequency, type and severity of adverse reactions in children are expected to be similar as in adults. For extent and age characterisation of the safety database in children see section 5.1.
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.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Only the provided infusion set should be used because treatment failure can occur as a consequence of coagulation factor IX adsorption to the internal surfaces of some injection equipment.
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