Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050, Bruxelles, Belgium
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Known allergic reaction to hamster protein.
In order to improve traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
It is strongly recommended that every time ReFacto AF is administered to a patient, the name on the carton and batch number of the product are recorded in order to maintain a link between the patient and the batch number of the medicinal product. Patients can affix one of the peel-off labels found on the vial or pre-filled syringe to document the batch number in their diary or for reporting any side effects.
Allergic type hypersensitivity reactions have been observed with ReFacto AF. The medicinal product contains traces of hamster proteins. 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 shock, standard medical treatment for shock should be implemented.
The formation of neutralising antibodies (inhibitors) to factor VIII is a known complication in the management of individuals with haemophilia A. These inhibitors are usually IgG immunoglobulins directed against the factor VIII pro-coagulant activity, which are quantified in Bethesda Units (BU) per mL of plasma using the modified assay. The risk of developing inhibitors is correlated to the severity of the disease as well as the exposure to factor VIII, this risk being highest within the first 50 exposure days but continues throughout life although the risk is uncommon.
The clinical relevance of inhibitor development will depend on the titre of the inhibitor, with low titre posing less of a risk of insufficient clinical response than high titre inhibitors.
In general, all patients treated with coagulation factor VIII products should be carefully monitored for the development of inhibitors by appropriate clinical observations and laboratory tests. If the expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, testing for factor VIII inhibitor presence should be performed. In patients with high levels of inhibitor, factor VIII therapy may not be effective and other therapeutic options should be considered.
Management of such patients should be directed by physicians with experience in the care of haemophilia and factor VIII inhibitors.
Reports of lack of effect, mainly in prophylaxis patients, have been received in the clinical trials and in the post-marketing setting for ReFacto. The reported lack of effect with ReFacto has been described as bleeding into target joints, bleeding into new joints or a subjective feeling by the patient of new onset bleeding. When prescribing ReFacto AF it is important to individually titrate and monitor each patient’s factor level in order to ensure an adequate therapeutic response (see section 4.8).
In patients with existing cardiovascular risk factors, substitution therapy with factor VIII 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 (see section 4.8).
After reconstitution this medicinal product contains 1.23 mmol (29 mg) sodium per vial or pre-filled syringe, to be taken into consideration by patients on a controlled sodium diet.
No interactions of recombinant coagulation factor VIII products with other medicinal products have been reported.
Animal reproduction studies have not been conducted with factor VIII, therefore no data are available on fertility. Because of the rare occurrence of haemophilia A in women, experience regarding the use of factor VIII during pregnancy and breast-feeding is not available. Therefore, factor VIII should be used during pregnancy and breast-feeding only if clearly indicated.
ReFacto AF 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 infrequently for ReFacto, and may in some cases progress to severe anaphylaxis including shock (see section 4.4).
Trace amounts of hamster protein may be present in ReFacto AF. Very rarely, development of antibodies to hamster protein has been observed, but there were no clinical sequelae. In a study of ReFacto, twenty of 113 (18%) previously treated patients (PTPs) had an increase in anti-CHO antibody titre, without any apparent clinical effect.
Development of neutralising antibodies (inhibitors) may occur in patients with haemophilia A treated with factor VIII, including with ReFacto AF. If such inhibitors occur, the condition may manifest itself as an insufficient clinical response. In such cases, it is recommended that a specialised haemophilia centre be contacted.
The table 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) and uncommon (≥1/1,000 to <1/100). The table lists adverse reactions reported in the clinical trials with ReFacto or ReFacto AF. The frequencies are based on all causality treatment emergent adverse events in pooled clinical trials with 765 subjects.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Very common ≥1/10
Common ≥1/100 to <1/10
Uncommon ≥1/1,000 to <1/100
Very common: FVIII inhibition (PUPs)*
Uncommon: FVIII inhibition (PTPs)*
Uncommon: Anaphylactic reaction
Common: Decreased appetite
Very common: Headache
Common: Dizziness
Uncommon: Neuropathy peripheral; somnolence; dysgeusia
Uncommon: Angina pectoris; tachycardia; palpitations
Common: Haemorrhage; haematoma
Uncommon: Hypotension; thrombophlebitis; flushing
Very common: Cough
Uncommon: Dyspnoea
Common: Diarrhoea; vomiting; abdominal pain; nausea
Common: Urticaria; rash; pruritus
Uncommon: Hyperhidrosis
Very common: Arthralgia
Common: Myalgia
Very common: Pyrexia
Common: Chills; catheter site related reaction
Uncommon: Asthenia; injection site reaction; injection site pain; injection site inflammation
Common: Antibody test positive; Anti-factor VIII antibody test positive
Uncommon: Aspartate aminotransferase increased; alanine aminotransferase increased; blood bilirubin increased; blood creatinine phosphokinase increased
* Frequency is based on studies with all FVIII products which included patients with severe haemophilia A. PTPs = previously-treated patients, PUPs = previously-untreated patients
One event of cyst in an 11-year old patient and one event described as confusion in a 13-year old patient have been reported as possibly related to ReFacto AF treatment.
Safety of ReFacto AF was evaluated in studies that included both previously treated adults and previously treated children and adolescents (n=18, aged 12-16 years in a study and n=49, aged 7-16 years in a supporting study), with a tendency for higher frequencies of adverse reactions in children aged 7-16 years as compared to adults. Additional safety experience in children has been accrued through studies that encompassed both previously treated (n=18 aged <6 years and n=19 aged 6 to <12 years) and previously untreated (n=23 aged <6 years) patients and which supports a safety profile similar with that observed in adult patients.
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, including other infusion solutions.
Only the provided infusion set is to be used, because treatment failure can occur as a consequence of human-coagulation factor VIII adsorption to the internal surfaces of some infusion equipment.
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