ReFacto AF

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 
 
ReFacto AF 250 IU powder and solvent for solution for injection 
ReFacto AF 500 IU powder and solvent for solution for injection 
ReFacto AF 1000 IU powder and solvent for solution for injection 
ReFacto AF 2000 IU powder and solvent for solution for injection 
ReFacto AF 250 IU powder and solvent for solution for injection in pre-filled syringe 
ReFacto AF 500 IU powder and solvent for solution for injection in pre-filled syringe 
ReFacto AF 1000 IU powder and solvent for solution for injection in pre-filled syringe 
ReFacto AF 2000 IU powder and solvent for solution for injection in pre-filled syringe 
ReFacto AF 3000 IU powder and solvent for solution for injection in pre-filled syringe 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
ReFacto AF 250 IU powder and solvent for solution for injection 
Each vial contains nominally 250 IU* moroctocog alfa**. 
After reconstitution, each mL of solution contains approximately 62.5 IU moroctocog alfa. 
 
ReFacto AF 500 IU powder and solvent for solution for injection 
Each vial contains nominally 500 IU* moroctocog alfa**. 
After reconstitution, each mL of solution contains approximately 125 IU moroctocog alfa. 
 
ReFacto AF 1000 IU powder and solvent for solution for injection 
Each vial contains nominally 1000 IU* moroctocog alfa**. 
After reconstitution, each mL of solution contains approximately 250 IU moroctocog alfa. 
 
ReFacto AF 2000 IU powder and solvent for solution for injection 
Each vial contains nominally 2000 IU* moroctocog alfa**. 
After reconstitution, each mL of solution contains approximately 500 IU moroctocog alfa. 
 
ReFacto AF 250 IU powder and solvent for solution for injection in pre-filled syringe 
Each pre-filled syringe contains nominally 250 IU* moroctocog alfa**. 
After reconstitution, each mL of solution contains approximately 62.5 IU moroctocog alfa. 
 
ReFacto AF 500 IU powder and solvent for solution for injection in pre-filled syringe 
Each pre-filled syringe contains nominally 500 IU* moroctocog alfa**. 
After reconstitution, each mL of solution contains approximately 125 IU moroctocog alfa. 
 
ReFacto AF 1000 IU powder and solvent for solution for injection in pre-filled syringe 
Each pre-filled syringe contains nominally 1000 IU* moroctocog alfa**. 
After reconstitution, each mL of solution contains approximately 250 IU moroctocog alfa. 
 
ReFacto AF 2000 IU powder and solvent for solution for injection in pre-filled syringe 
Each pre-filled syringe contains nominally 2000 IU* moroctocog alfa**. 
After reconstitution, each mL of solution contains approximately 500 IU moroctocog alfa. 
 
ReFacto AF 3000 IU powder and solvent for solution for injection in pre-filled syringe 
Each pre-filled syringe contains nominally 3000 IU* moroctocog alfa**. 
After reconstitution, each mL of solution contains approximately 750 IU moroctocog alfa. 
 
* The potency (International Units) is determined using the European Pharmacopoeia chromogenic 
assay. The specific activity of ReFacto AF is 7,600-13,800 IU/mg protein. 
 
** Human coagulation factor VIII produced by recombinant DNA technology in Chinese hamster 
ovary (CHO) cells. Moroctocog alfa is a glycoprotein with 1438 amino acids with a sequence that is 



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comparable to the 90 + 80 kDa form of factor VIII (i.e. B-domain deleted) and similar 
post-translational modifications to those of the plasma-derived molecule. 
 
The manufacturing process for ReFacto was modified to eliminate any exogenous human- or 
animal-derived protein in the cell culture process, purification, or final formulation; and at the same 
time the invented name was changed to ReFacto AF. 
 
Excipient with known effect: 
 
After reconstitution, 1.23 mmol (29 mg) sodium per vial or pre-filled syringe 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
ReFacto AF 250 IU, 500 IU, 1000 IU, 2000 IU powder and solvent for solution for injection 
Powder and solvent for solution for injection 
White to off-white cake/powder  
Clear, colourless solvent 
 
ReFacto AF 250 IU, 500 IU, 1000 IU, 2000 IU, 3000 IU powder and solvent for solution for injection 
in pre-filled syringe 
Powder and solvent for solution for injection in pre-filled syringe 
White to off-white cake/powder in top chamber of the pre-filled syringe 
Clear, colourless solvent in bottom chamber of the pre-filled syringe 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII 
deficiency). 
 
ReFacto AF is appropriate for use in adults and children of all ages, including newborns. 
 
ReFacto AF does not contain von Willebrand factor, and hence is not indicated in von Willebrand’s 
disease. 
 
4.2 Posology and method of administration 
 
Treatment should be initiated under the supervision of a physician experienced in the treatment of 
haemophilia A. 
 
Treatment monitoring 
 
During the course of treatment, appropriate determination of factor VIII levels is advised to guide the 
dose to be administered and the frequency of repeated infusions. Individual patients may vary in their 
response to factor VIII, demonstrating different half-lives and recoveries. Dose based on bodyweight 
may require adjustment in underweight or overweight patients. In the case of major surgical 
interventions in particular, precise monitoring of the substitution therapy by means of coagulation 
analysis (plasma factor VIII activity) is indispensable. 
 



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When monitoring patients' factor VIII activity levels during treatment with ReFacto AF, use of the 
chromogenic assay is recommended. When using an in vitro thromboplastin time (aPTT)-based 
one-stage clotting assay for determining factor VIII activity in patients’ blood samples, plasma factor 
VIII activity results can be significantly affected by both the type of aPTT reagent and the reference 
standard used in the assay. Also there can be significant discrepancies between assay results obtained 
by aPTT-based one-stage clotting assay and the chromogenic assay. Typically, one-stage clotting 
assay results are 20-50% lower than the chromogenic substrate assay results. The ReFacto AF 
laboratory standard can be used to correct for this discrepancy (see section 5.2). This is of importance 
particularly when changing the laboratory and/or reagents used. 
 
Posology 
 
The dose and duration of the substitution therapy depend on the severity of the factor VIII deficiency, 
on the location and extent of bleeding, and on the patient’s clinical condition. Doses administered 
should be titrated to the patient's clinical response. In the presence of an inhibitor, higher doses or 
appropriate specific treatment may be required. 
 
The number of units of factor VIII administered is expressed in International Units (IUs), which are 
related to the current WHO standard for factor VIII products. Factor VIII activity in plasma is 
expressed either as a percentage (relative to normal human plasma) or in IU (relative to an 
International Standard for factor VIII in plasma). One IU of factor VIII activity is equivalent to the 
quantity of factor VIII in one mL of normal human plasma. 
 
Another moroctocog alfa product approved for use outside Europe has a different manufacturing 
potency assigned that has been calibrated to the WHO International Standard using a one-stage 
clotting assay; this product is identified by the tradename XYNTHA. Due to the difference in methods 
used to assign product potency of XYNTHA and ReFacto AF, 1 IU of the XYNTHA product 
(one-stage assay calibrated) is approximately equivalent to 1.38 IU of the ReFacto AF product 
(chromogenic assay calibrated). If a patient normally treated with XYNTHA is prescribed 
ReFacto AF, the treating physician may consider adjustment of dosing recommendations based on 
factor VIII recovery values. 
 
Based on their current regimen, individuals with haemophilia A should be advised to bring an 
adequate supply of factor VIII product for anticipated treatment when travelling. Patients should be 
advised to consult with their healthcare provider prior to travel. 
 
On demand treatment 
 
The calculation of the required dose of factor VIII is based upon the empirical finding that 1 IU of 
factor VIII per kg body weight raises the plasma factor VIII activity by 2 IU/dl. The required dose is 
determined using the following formula: 
 
Required units (IU) = body weight (kg) x desired factor VIII rise (% or IU/dl) x 0.5 (IU/kg per IU/dl), 
where 0.5 IU/kg per IU/dl represents the reciprocal of the recovery generally observed following 
infusions of factor VIII. 
 
The amount to be administered and the frequency of administration should always be oriented to the 
clinical effectiveness in the individual case. 
 



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In the case of the following haemorrhagic events, the factor VIII activity should not fall below the 
given plasma levels (in % of normal or in IU/dl) in the corresponding period. The following table can 
be used to guide dosing in bleeding episodes and surgery: 
 

Degree of haemorrhage/ 
Type of surgical procedure 

Factor VIII level 
required (% or IU/dl) 

Frequency of doses (hours)/ 
Duration of therapy (days) 

 
Haemorrhage 
 

  

Early haemarthrosis, muscle 
bleeding or oral bleeding 

20-40 Repeat every 12-24 hours. At least 1 
day until the bleeding episode as 
indicated by pain is resolved or healing 
is achieved. 

More extensive haemarthrosis, 
muscle bleeding or haematoma 

30-60 Repeat infusion every 12-24 hours for 
3-4 days or more until pain and acute 
disability are resolved. 

Life-threatening haemorrhages 
 

60-100 Repeat infusion every 8-24 hours until 
threat is resolved. 

 
Surgery 
 

  

Minor surgery 
including tooth extraction 

30-60 Every 24 hours, at least 1 day, until 
healing is achieved. 
 

Major surgery 80-100 
(pre- and 

post-operative) 

Repeat infusion every 8-24 hours until 
adequate wound healing, then therapy 
for at least another 7 days to maintain a 
factor VIII activity of 30% to 60% 
(IU/dl). 
 

 
Prophylaxis 
 
For long-term prophylaxis against bleeding in patients with severe haemophilia A, the usual doses are 
20 to 40 IU of factor VIII per kg body weight at intervals of 2 to 3 days. In some cases, especially in 
younger patients, shorter dose intervals or higher doses may be necessary. 
 
Paediatric population 
 
The need for an increased dose relative to that used for adults and older children should be anticipated 
when treating younger children (less than 6 years of age) with ReFacto AF (see section 5.2)..  
 
Elderly population 
 
Clinical studies did not include subjects aged 65 and over. In general, dose selection for an elderly 
patient should be individualised. 
 
Renal or hepatic impairment 
 
Dose adjustment for patients with renal or hepatic impairment has not been studied in clinical trials. 
 



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Method of administration 
 
Intravenous use. 
 
ReFacto AF is administered by intravenous infusion over several minutes after reconstitution of the 
lyophilised powder for injection with sodium chloride 9 mg/mL (0.9%) solution for injection 
(provided). The rate of administration should be determined by the patient’s comfort level. 
Appropriate training is recommended for non-healthcare professionals administering the product.  
 
For reconstitution instructions prior to administration, see section 6.6. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.  
 
Known allergic reaction to hamster protein. 
 
4.4 Special warnings and special precautions for use 
 
Traceability 
 
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. 
 
Hypersensitivity 
 
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. 
 
Inhibitors 
 
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. 



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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 
 
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). 
 
Cardiovascular events 
 
In patients with existing cardiovascular risk factors, substitution therapy with factor VIII may increase 
the cardiovascular risk. 
 
Catheter-related complications  
 
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). 
 
Sodium content 
 
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. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No interactions of recombinant coagulation factor VIII products with other medicinal products have 
been reported. 
 
4.6 Fertility, pregnancy and lactation 
 
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. 
 
4.7 Effects on ability to drive and use machines 
 
ReFacto AF has no influence on the ability to drive and use machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
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. 
 



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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. 
 
Tabulated list of adverse reactions 
 
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. 
 
System Organ Class Very common 

≥ 1/10 
 

Common  
≥ 1/100 

to < 1/10 

Uncommon  
≥ 1/1,000 to 

 < 1/100 
Blood and lymphatic 
system disorders 

FVIII inhibition 
(PUPs)* 

 FVIII inhibition  
(PTPs)* 

Immune system 
disorders 

  Anaphylactic reaction 

Metabolism and 
nutrition disorders 

 Decreased appetite  

Nervous system 
disorders 

Headache Dizziness Neuropathy peripheral; 
somnolence; dysgeusia 

Cardiac disorders   Angina pectoris; tachycardia; 
palpitations 

Vascular disorders  Haemorrhage; 
haematoma 

Hypotension; thrombophlebitis; 
flushing 

Respiratory, thoracic 
and mediastinal 
disorders 

Cough  Dyspnoea 

Gastrointestinal 
disorders 

 Diarrhoea; vomiting; 
abdominal pain; nausea 

 

Skin and subcutaneous 
tissue disorders 

 Urticaria; rash; pruritus Hyperhidrosis 

Musculoskeletal and 
connective tissue 
disorders 

Arthralgia Myalgia  

General disorders and 
administration site 
conditions 

Pyrexia Chills; catheter site 
related reaction 

Asthenia; injection site reaction; 
injection site pain; injection site 
inflammation 

Investigations  Antibody test positive; 
Anti-factor VIII 
antibody test positive 

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 
 
Paediatric population 
 
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 
 



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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 of suspected adverse reactions  
 
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. 
 
4.9 Overdose 
 
No symptoms of overdose have been reported with recombinant coagulation factor VIII products. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: antihaemorrhagics, blood coagulation factor VIII; ATC code: B02BD02. 
 
ReFacto AF contains B-domain deleted recombinant coagulation factor VIII (moroctocog alfa). It is a 
glycoprotein with an approximate molecular mass of 170,000 Da consisting of 1438 amino acids. 
ReFacto AF has functional characteristics comparable to those of endogenous factor VIII. Factor VIII 
activity is greatly reduced in patients with haemophilia A, and, therefore, replacement therapy is 
necessary. 
 
When infused into a haemophiliac patient, factor VIII binds to the von Willebrand factor present in the 
patient’s circulation. 
 
Activated factor VIII acts as a cofactor for activated factor IX, accelerating the conversion of factor X 
to activated factor X. Activated factor X converts prothrombin into thrombin. Thrombin then converts 
fibrinogen into fibrin, and a clot is formed. Haemophilia A is a sex-linked hereditary disorder of blood 
coagulation due to decreased levels of factor VIII:C and results in profuse bleeding into joints, muscles 
or internal organs, either spontaneously or as a result of accidental or surgical trauma. By replacement 
therapy, the plasma levels of factor VIII are increased, thereby enabling a temporary correction of the 
factor deficiency and correction of the bleeding tendencies. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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Clinical efficacy 
 
The data in the table below relates to PUP and PTP data from ReFacto AF studies in patients 
<12 years. 
 
Consumption and efficacy results in paediatric population 
 

 PTPs  
<6 years 

PTPs  
6 to <12 years 

PUPs  
<6 years 

Dose by weight (IU/kg) per 
prophylaxis infusion a  
median (min, max)  

N=14 
36 IU/kg 
(28, 51) 

N=13 
32 IU/kg 
(21, 49) 

N=22 
46 IU/kg 
(17,161) 

Total ABR all subjects b  
median (min, max) -- -- 

N=23 
3.17 

(0.0, 39.5) 
Total ABR for subjects who 
reported following an On Demand 
regimen at Baseline c 
median (min, max) 

N=5 
41.47 

(1.6, 50.6) 

N=9 
25.22 

(0.0, 46.6) 
-- 

Total ABR for subjects who 
reported following a Prophylaxis 
regimen at Baseline c  
median (min, max) 

N=13 
1.99 

(0.0, 11.2) 

N=9 
5.55 

(0.0, 13.0) 
-- 

Dose by weight (IU/kg) per 
bleeding episode for bleed 
treatment  
median (min, max) 

N=13 
35 IU/kg 
(28, 86) 

N=14 
33 IU/kg 
(17, 229) 

N=21 
55 IU/kg 
(11, 221) 

% of bleeds treated successfully 
with ≤ 2 infusions 98.7% 98.8% 96.7% 
a The dose and frequency of ReFacto AF prescribed throughout the study were at the 
investigator’s discretion as per local standard of care. 
b Subjects in the PUP study were not required to follow a regular continuous prophylaxis 
treatment; however, with the exception of one subject (with only on demand (OD) treatment) 
the majority of subjects took regular prophylaxis infusions. Several began with OD infusions 
but switched to prophylaxis treatment during their participation, and some had only sporadic 
prophylaxis infusions. 
c Subjects in the PTP study reported their FVIII treatment modality (prophylaxis or on 
demand) at baseline and were not required to maintain this modality as a condition of study 
participation. The dose and frequency of ReFacto AF prescribed throughout the study were at 
the investigator’s discretion as per local standard of care. 
Abbreviations: ABR = annualised bleeding rate 
 
Of note, annualised bleeding rate (ABR) is not comparable between different factor concentrates and 
between different clinical studies.  
 
Immune Tolerance Induction 
 
Data on immune tolerance induction (ITI) have been collected in patients with haemophilia A who had 
developed inhibitors to factor VIII. As part of the pivotal trial with ReFacto in PUPs, ITI data from 25 
patients were reviewed (15 with high titres, 10 with low titres). Of these 25 patients, 20 had a decrease 
in inhibitor titres to < 0.6 BU/mL, of whom initially 11 of 15 had high titres (≥ 5 BU/mL) and 9 of 10 
had low titres. Out of 6 patients who developed low titre inhibitors but did not receive ITI, 5 had 
similar titre decreases. No long-term outcome is available. 
 



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5.2 Pharmacokinetic properties 
 
Pharmacokinetic properties of ReFacto, derived from a cross-over study of ReFacto and a plasma-
derived FVIII concentrate, using the chromogenic substrate assay (see section 4.2), in 18 previously 
treated patients are listed in the table below. 
 

Pharmacokinetic parameter estimates for ReFacto in previously treated patients with haemophilia A 
PK parameter 
 

Mean SD Median 

AUCt (IU·h/mL) 19.9 4.9 19.9 
t1/2 (h) 14.8 5.6 12.7 
CL (mL/h·kg) 2.4 0.75 2.3 
MRT (h) 20.2 7.4 18.0 
recovery  
(IU/dl increase in FVIII:C per IU/kg FVIII given) 2.4 0.38 2.5 
Abbreviations: AUCt = area under the plasma concentration-time curve from zero to the last measurable 
concentration; t½ = half-life; CL = clearance; FVIII:C = FVIII activity; MRT = mean residence time 

 
In a study in which the potency of ReFacto AF, ReFacto and FVIII activity in patient plasma were 
measured using the chromogenic substrate assay, ReFacto AF was shown to be bioequivalent to 
ReFacto. The ratios of geometric least-square means of ReFacto AF-to-ReFacto were 100.6%, 99.5% 
and 98.1% for recovery, AUCt and AUC∞ (area under the plasma concentration curve from time zero 
to infinity), respectively. The corresponding 90% confidence intervals about the ratios of ReFacto AF 
to ReFacto geometric means were within the bioequivalence window of 80% to 125%, demonstrating 
bioequivalence of ReFacto AF to ReFacto. 
 
In a cross-over pharmacokinetic study, the pharmacokinetic parameters for ReFacto AF were 
determined at baseline and followed up in 25 previously treated patients (≥ 12 years) after repeated 
administration of ReFacto AF for six months. The ratios of geometric least-square means of month 
6-to-baseline pharmacokinetic were 107%, 100% and 104% for recovery, AUCt and AUC∞, 
respectively. The corresponding 90% confidence intervals about the ratios of month 6-to-baseline for 
the above pharmacokinetic parameters were within the equivalence window of 80% to 125%. This 
indicates no time-dependent changes in the pharmacokinetic properties of ReFacto AF.  
 
In the same study, in which the drug potency of ReFacto AF and a full-length recombinant factor VIII 
(FLrFVIII) comparator, and the FVIII activity measured in patient plasma samples were all determined 
using the same one-stage clotting assay at a central laboratory, ReFacto AF was shown to be 
pharmacokinetically equivalent to FLrFVIII in 30 previously treated patients (≥ 12 years) using the 
standard bioequivalence approach.  
 
In PUPs, pharmacokinetic parameters of ReFacto were evaluated using the chromogenic assay. These 
patients (n=59; median age 10 ± 8.3 months) had a mean recovery at Week 0 of 1.5 ± 0.6 IU/dl per 
IU/kg (range 0.2 to 2.8 IU/dl per IU/kg) which was lower than that obtained in PTPs treated with 
ReFacto at Week 0 with a mean recovery of 2.4 ± 0.4 IU/dl per IU/kg (range 1.1 to 3.8 IU/dl per 
IU/kg). In the PUPs, the mean recovery was stable over time (5 visits during a 2-year period) and 
ranged from 1.5 to 1.8 IU/dl per IU/kg. Population pharmacokinetic modeling using data from 
44 PUPs led to a mean estimated half-life of 8.0 ± 2.2 hours. 
 
In a ReFacto AF study of 19 PUPs, the recovery at the beginning of the study in the 17 children aged 
28 days to less than 2 years was 1.32 ± 0.65 IU/dl per IU/kg and in the 2 children aged 2 to <6 years 
were 1.7 and 1.8 IU/dl per IU/kg. Except in cases where inhibitors were detected, the mean recovery 
was stable over time (6 visits during a 2-year period) and individual values ranged from 0 (in presence 
of inhibitor) to 2.7 IU/dl per IU/kg. 
 
In a study of 37 paediatric PTPs, the pharmacokinetic parameters of ReFacto AF observed after a 50 
IU/kg dose are shown in the table below. 
 



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Mean ± SD FVIII Pharmacokinetic Parameters after Single 50 IU/kg Dose in Paediatric PTPs 
PK parameter Number of subjects Meana ± SD 
Recovery, IU/dl per IU/kg 

Aged <6 years 
Aged 6 to <12 years 

 
17 
19 

 
1.7 ± 0.4 
2.1 ± 0.8 

Cmax, IU/mLb 19 0.9 (45) 
AUCinf, IU∙h/mLb 14 9.9 (41) 
t½, hb 14 9.1 ± 1.9 
CL, mL/h/kgb 14 4.4 (30) 
Vss, mL/kgb 14 56.4 (15) 
a Geometric mean (geometric CV%) for all, except for arithmetic mean ±SD for incremental recovery and t½. 
b Patients aged 6 to <12 years only. 
Abbreviations: Cmax = maximum observed plasma concentration; CV = coefficient of variation; AUCinf = area 
under the plasma concentration-time profile from time zero extrapolated to infinite time; t½ = terminal half-life; 
CL = clearance; Vss = steady-state volume of distribution. 
 
5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, repeated dose toxicity, and genotoxicity. 
 
No investigations on carcinogenic potential or toxicity to reproduction have been conducted. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Powder 
Sucrose 
Calcium chloride dihydrate 
L-Histidine 
Polysorbate 80 
Sodium chloride  
 
Solvent 
Sodium chloride 
Water for injections 
 
6.2 Incompatibilities 
 
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. 
 
6.3 Shelf life 
 
3 years. 
 
The product may be removed from refrigerated storage for one single period of maximum 3 months at 
room temperature (up to 25°C). At the end of this period of room temperature storage, the product 
must not be returned to refrigerated storage, but is to be used or discarded. 
 
After reconstitution 
 



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Chemical and physical in-use stability has been demonstrated for 3 hours at temperatures up to 25°C. 
 
ReFacto AF 250 IU, 500 IU, 1000 IU, 2000 IU powder and solvent for solution for injection 
The product does not contain a preservative, and the reconstituted product should be used 
immediately, or within 3 hours after reconstitution. Other in-use storage times and conditions are the 
responsibility of the user. 
 
ReFacto AF 250 IU, 500 IU, 1000 IU, 2000 IU, 3000 IU powder and solvent for solution for injection 
in pre-filled syringe 
The product does not contain a preservative, and the reconstituted product should be used 
immediately, or within 3 hours after reconstitution or removal of the grey tip cap. Other in-use storage 
times and conditions are the responsibility of the user. 
 
6.4 Special precautions for storage 
 
ReFacto AF 250 IU, 500 IU, 1000 IU, 2000 IU powder and solvent for solution for injection 
ReFacto AF 250 IU, 500 IU, 1000 IU, 2000 IU, 3000 IU powder and solvent for solution for injection 
in pre-filled syringe 
Store and transport refrigerated (2°C - 8°C). Do not freeze. 
 
Keep the product in the outer carton in order to protect from light. 
 
For storage conditions of the reconstituted medicinal product, see section 6.3. 
 
6.5 Nature and contents of container 
 
ReFacto AF 250 IU, 500 IU, 1000 IU, 2000 IU powder and solvent for solution for injection 
250 IU, 500 IU, 1000 IU or 2000 IU powder in a 10 mL vial (type 1 glass) with a stopper (butyl) and a 
flip-off seal (aluminum) and 4 mL of solvent in a pre-filled syringe (type 1 glass) with a plunger 
stopper (butyl), a tip-cap (butyl) and a sterile vial adapter reconstitution device, a sterile infusion set, 
alcohol swabs, a plaster and a gauze pad.  
 
ReFacto AF 250 IU, 500 IU, 1000 IU, 2000 IU, 3000 IU powder and solvent for solution for injection 
in pre-filled syringe 
250 IU, 500 IU, 1000 IU, 2000 IU or 3000 IU lyophilised powder in top chamber and 4 mL of solvent 
in bottom chamber of the pre-filled syringe (type 1 glass) with butyl rubber plungers and closure, one 
plunger rod for assembly, a polypropylene vented sterile cap, a sterile infusion set, alcohol swabs, a 
plaster and a gauze pad. 
 
Pack size of 1. 
 
6.6 Special precautions for disposal and other handling 
 
ReFacto AF 250 IU, 500 IU, 1000 IU, 2000 IU powder and solvent for solution for injection 
The vial of lyophilised product powder for injection must be reconstituted with the supplied solvent 
[sodium chloride 9 mg/mL (0.9%) solution] from the pre-filled syringe using the sterile vial adapter 
reconstitution device. The vial should be gently rotated until all of the powder is dissolved. Please see 
package leaflet, section 3, for additional information on reconstitution and administration. 
 
After reconstitution, the solution is drawn back into the syringe. The solution will be clear or slightly 
opalescent and colourless. The solution is to be discarded if visible particulate matter or discolouration 
is observed. 
 
ReFacto AF 250 IU, 500 IU, 1000 IU, 2000 IU, 3000 IU powder and solvent for solution for injection 
in pre-filled syringe 
The lyophilised powder in the top chamber of the pre-filled syringe must be reconstituted with the 
solvent [sodium chloride 9 mg/mL (0.9%) solution] in the bottom chamber of the pre-filled syringe. 



14 

The pre-filled syringe should be gently rotated until all of the powder is dissolved. Please see package 
leaflet, section 3, for additional information on reconstitution and administration. 
 
After reconstitution, the solution will be clear or slightly opalescent and colourless. The solution is to 
be discarded if visible particulate matter or discolouration is observed. 
 
The product, when reconstituted, contains polysorbate-80, which is known to increase the rate of 
di-(2-ethylhexyl) phthalate (DEHP) extraction from polyvinyl chloride (PVC). This is to be considered 
during the preparation and administration of the product, including storage time elapsed in a PVC 
container following reconstitution. It is important that the recommendations in section 6.3 be followed 
closely. 
 
Any unused product or waste material is to be disposed of in accordance with local requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 
8. MARKETING AUTHORISATION NUMBER 
 
EU/1/99/103/001 
EU/1/99/103/002 
EU/1/99/103/003 
EU/1/99/103/004 
EU/1/99/103/009 
EU/1/99/103/006 
EU/1/99/103/007 
EU/1/99/103/008 
EU/1/99/103/005 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 13 April 1999 
Date of latest renewal: 15 April 2014 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu/. 

http://www.ema.europa.eu/


15 

 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
ANNEX II 

 
A. MANUFACTURER OF THE BIOLOGICAL ACTIVE 

SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR 
BATCH RELEASE  

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION 
 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 
THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 



16 

 
A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 

MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer of the biological active substance 
 
Swedish Orphan Biovitrum AB (publ)  
Strandbergsgatan 49 
SE-11276 Stockholm 
Sweden 
 
Name and address of the manufacturer responsible for batch release 
 
Wyeth Farma S.A  
Autovia del Norte A-1 Km 23  
Desvio Algete Km 1  
28700 San Sebastian de los Reyes  
Madrid  
Spain  
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2) 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic Safety Update Reports 
 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk Management Plan (RMP)  

 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP.  
 
An updated RMP should be submitted:  

• At the request of the European Medicines Agency;  
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result 
of an important (pharmacovigilance or risk minimisation) milestone being reached.  
 



17 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 



18 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
 



19 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
REFACTO AF OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ReFacto AF 250 IU powder and solvent for solution for injection 
 
ReFacto AF 500 IU powder and solvent for solution for injection 
 
ReFacto AF 1000 IU powder and solvent for solution for injection 
 
ReFacto AF 2000 IU powder and solvent for solution for injection 
 
Moroctocog alfa 
(recombinant human coagulation factor VIII) 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
1 vial: 250 IU moroctocog alfa (approx. 62.5 IU/ml after reconstitution). 
 
1 vial: 500 IU moroctocog alfa (approx. 125 IU/ml after reconstitution) 
 
1 vial: 1000 IU moroctocog alfa (approx. 250 IU/ml after reconstitution) 
 
1 vial: 2000 IU moroctocog alfa (approx. 500 IU/ml after reconstitution) 
 
 
3. LIST OF EXCIPIENTS 
 
Sucrose, 
calcium chloride dihydrate, 
L-histidine, 
polysorbate 80, 
sodium chloride 
Read the package leaflet before use. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder and solvent for solution for injection 
 
1 vial with 250 IU moroctocog alfa 
1 vial with 500 IU moroctocog alfa 
1 vial with 1000 IU moroctocog alfa 
1 vial with 2000 IU moroctocog alfa  
 
1 pre-filled syringe with 4 ml solvent 
1 vial adapter 
1 sterile infusion set 
2 alcohol swabs 
1 plaster 
1 gauze 
 



20 

 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Intravenous use, after reconstitution. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP  
Do not use after expiry date. 
 
Use immediately or within 3 hours of reconstitution. 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store and transport at 2°C – 8°C. 
Do not freeze 
 
Keep the vial in the original package in order to protect from light. 
 
ReFacto AF can be stored at room temperature (up to 25oC) for a single period up to 3 months. The 
product may not be returned to refrigerated storage after storage at room temperature. 
 
Date removed from the refrigerator: 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Discard any remaining reconstituted solution 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 



21 

 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/99/103/001  
EU/1/99/103/002  
EU/1/99/103/003  
EU/1/99/103/004  
 
 
13. MANUFACTURER’S BATCH NUMBER 
 
Lot  
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
ReFacto AF 250  
ReFacto AF 500 
ReFacto AF 1000  
ReFacto AF 2000  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN: 



22 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
REFACTO AF VIAL LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
ReFacto AF 250 IU powder for solution for injection 
 
ReFacto AF 500 IU powder for solution for injection 
 
ReFacto AF 1000 IU powder for solution for injection 
 
ReFacto AF 2000 IU powder for solution for injection 
 
Moroctocog alfa 
(recombinant human coagulation factor VIII) 
IV use 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
 
3. EXPIRY DATE 
 
EXP  
 
 
4. BATCH NUMBER 
 
Lot  
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 
6. OTHER 
 
Store in a refrigerator 
 



23 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
REFACTO AF SOLVENT PRE-FILLED SYRINGE LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Solvent for ReFacto AF 
 
 
2. METHOD OF ADMINISTRATION 
 
IV use, after reconstitution.  
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot  
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
Contains 4 ml of sodium chloride 9 mg/ml (0.9%) solution for injection 
 
 
6. OTHER 
 
Store in a refrigerator 
 



24 

 
 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
ReFacto AF 250 IU powder and solvent for solution for injection in pre-filled syringe 
 
ReFacto AF 500 IU powder and solvent for solution for injection in pre-filled syringe 
 
ReFacto AF 1000 IU powder and solvent for solution for injection in pre-filled syringe 
 
ReFacto AF 2000 IU powder and solvent for solution for injection in pre-filled syringe 
 
ReFacto AF 3000 IU powder and solvent for solution for injection in pre-filled syringe 
 
Moroctocog alfa  
(recombinant human coagulation factor VIII) 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
1 pre-filled syringe: 250 IU moroctocog alfa (approx. 62.5 IU/ml after reconstitution). 
 
1 pre-filled syringe: 500 IU moroctocog alfa (approx. 125 IU/ml after reconstitution) 
 
1 pre-filled syringe: 1000 IU moroctocog alfa (approx. 250 IU/ml after reconstitution) 
 
1 pre-filled syringe: 2000 IU moroctocog alfa (approx. 500 IU/ml after reconstitution) 
 
1 pre-filled syringe: 3000 IU moroctocog alfa (approx. 750 IU/ml after reconstitution) 
 
 
3. LIST OF EXCIPIENTS 
 
See the package leaflet for further information 
Sucrose, 
calcium chloride dihydrate, 
L-histidine, 
polysorbate 80, 
sodium chloride 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder and solvent for solution for injection in pre-filled syringe FuseNGo 
 
1 pre filled syringe (250 IU powder in top chamber and 4 ml solvent in bottom chamber) 
1 pre filled syringe (500 IU powder in top chamber and 4 ml solvent in bottom chamber) 
1 pre filled syringe (1000 IU powder in top chamber and 4 ml solvent in bottom chamber) 
1 pre filled syringe (2000 IU powder in top chamber and 4 ml solvent in bottom chamber) 
1 pre filled syringe (3000 IU powder in top chamber and 4 ml solvent in bottom chamber) 
 



25 

1 plunger rod 
1 sterile infusion set 
2 alcohol swabs 
1 plaster 
1 gauze 
1 vented sterile cap 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Intravenous use, single use administration only. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP  
 
Use immediately or within 3 hours of reconstitution or after removing the grey rubber tip cap from the 
syringe 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store and transport refrigerated (2°C – 8°C).  
Do not freeze 
 
Keep in the original package in order to protect from light. 
 
ReFacto AF can be stored at room temperature (up to 25oC) for a single period up to 3 months. The 
product may not be returned to refrigerated storage after storage at room temperature. 
 
Date removed from the refrigerator:  
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



26 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/99/103/009 
EU/1/99/103/006 
EU/1/99/103/007 
EU/1/99/103/008 
EU/1/99/103/005 
 
 
13. MANUFACTURER’S BATCH NUMBER 
 
Lot  
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
ReFacto AF 250 
ReFacto AF 500 
ReFacto AF 1000 
ReFacto AF 2000 
ReFacto AF 3000 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN: 



27 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
PRE-FILLED SYRINGE LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
ReFacto AF 250 IU powder and solvent for solution for injection 
 
ReFacto AF 500 IU powder and solvent for solution for injection 
 
ReFacto AF 1000 IU powder and solvent for solution for injection 
 
ReFacto AF 2000 IU powder and solvent for solution for injection 
 
ReFacto AF 3000 IU powder and solvent for solution for injection 
 
Moroctocog alfa 
(recombinant human coagulation factor VIII) 
IV use 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
 
3. EXPIRY DATE 
 
EXP  
 
 
4. BATCH NUMBER 
 
Lot  
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
250 IU moroctocog alfa for single IV use 
 
500 IU moroctocog alfa for single IV use 
 
1000 IU moroctocog alfa for single IV use 
 
2000 IU moroctocog alfa for single IV use 
 
3000 IU moroctocog alfa for single IV use 
 
 
6. OTHER 
 
Store in a refrigerator 



28 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 
 
 
 
 



29 

Package leaflet: Information for the user 
 

ReFacto AF 250 IU powder and solvent for solution for injection 
ReFacto AF 500 IU powder and solvent for solution for injection 
ReFacto AF 1000 IU powder and solvent for solution for injection 
ReFacto AF 2000 IU powder and solvent for solution for injection 

 
Moroctocog alfa (recombinant human coagulation factor VIII) 

 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
 
- Keep this leaflet. You may need to read it again. 
- If you have further questions, please ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor, or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet:  
 
1. What ReFacto AF is and what it is used for 
2. What you need to know before you use ReFacto AF  
3. How to use ReFacto AF  
4. Possible side effects 
5 How to store ReFacto AF 
6. Contents of the pack and other information 
 
 
1. What ReFacto AF is and what it is used for 
 
ReFacto AF contains the active substance moroctocog alfa, human coagulation factor VIII. Factor VIII 
is necessary for the blood to form clots and stop bleedings. In patients with haemophilia A (inborn 
factor VIII deficiency), it is missing or not working properly. 
 
ReFacto AF is used for the treatment and prevention of bleeding (prophylaxis) in adults and children 
of all ages (including newborns) with haemophilia A. 
 
 
2. What you need to know before you use ReFacto AF 
 
Do not use ReFacto AF  
 
- if you are allergic to moroctocog alfa or any of the other ingredients of this medicine (listed in 

section 6). 
 
- if you are allergic to hamster proteins. 
 
If you are unsure about this, ask your doctor. 
 
Warnings and precautions  
 
Talk to your doctor or pharmacist before using ReFacto AF 
- if you experience allergic reactions. Some of the signs of allergic reactions are difficulty in 

breathing, shortness of breath, swelling, hives, itching, tightness of the chest, wheezing, and low 
blood pressure. Anaphylaxis is a severe allergic reaction that can cause difficulty in swallowing 
and/or breathing, red or swollen face and/or hands. If any of these signs occur, stop the infusion 



30 

immediately and contact a doctor or seek immediate emergency care. In case of severe allergic 
reactions, alternative therapy must be considered. 

 
- the formation of inhibitors (antibodies) is a known complication that can occur during treatment 

with all factor VIII medicines. These inhibitors, especially at high levels, stop the treatment 
working properly and you or your child will be monitored carefully for the development of these 
inhibitors. If your or your child’s bleeding is not being controlled with ReFacto AF, tell your 
doctor immediately. 

 
- if your bleeding does not stop as expected and contact your doctor or seek immediate emergency 

care. 
 
Other medicines and ReFacto AF 
 
Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines. 
 
Pregnancy, breast-feeding and fertility 
 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before using this medicine. 
 
Driving and using machines 
 
ReFacto AF has no influence on the ability to drive or use machines. 
 
ReFacto AF contains sodium  
 
ReFacto AF contains 1.23 mmol (or 29 mg) sodium per vial of reconstituted powder. Inform your 
doctor if you are on a controlled sodium diet. 
 
 
3. How to use ReFacto AF 
 
Always use this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if 
you are not sure.  
 
Treatment with ReFacto AF should be started by a doctor who is experienced in the care of patients 
with haemophilia A. Your doctor will decide the dose of ReFacto AF you will receive. This dose and 
duration will depend upon your individual needs for replacement factor VIII therapy. ReFacto AF is 
given by injection into a vein lasting several minutes. Patients or their carers can give injections of 
ReFacto AF, provided that they have been trained appropriately. 
 
During your treatment, your doctor may decide to change the dose of ReFacto AF you receive. 
Consult with your health care provider before you travel. You should bring enough of your factor VIII 
product for anticipated treatment when travelling.  
 
It is recommended that every time you use ReFacto AF, you record the name on the carton and batch 
number of the product. You can use one of the peel-off labels found on the vial to document the batch 
number in your diary or for reporting any side effects. 
 
Reconstitution and administration  
 
The procedures below are provided as guidelines for the reconstitution and administration of ReFacto 
AF. Patients should follow the specific reconstitution and administration procedures provided by their 
doctors. 
 



31 

Use only the pre-filled syringe provided in the box for reconstitution. Other sterile disposable syringes 
may be used for administration. 
 
ReFacto AF is administered by intravenous (IV) infusion after reconstitution of the lyophilised powder 
for injection with the supplied solvent [sodium chloride 9 mg/ml (0.9%) solution] syringe. ReFacto AF 
should not be mixed with other infusion solutions. 
 
Always wash your hands before performing the following reconstitution and administration 
procedures. Aseptic technique (meaning clean and germ-free) should be used during the reconstitution 
procedure. 
 
Reconstitution: 
 
1. Allow the vial of lyophilised ReFacto AF and the pre-filled solvent syringe to reach room 

temperature. 
 
2. Remove the plastic flip-top cap from the ReFacto AF vial to expose the central portion of the 

rubber stopper. 
 

 
 
3. Wipe the top of the vial with the alcohol swab provided, or use another antiseptic solution and 

allow to dry. After cleaning, do not touch the rubber stopper with your hand or allow it to touch 
any surface. 

 
4. Peel back the lid from the clear plastic vial adapter package. Do not remove the adapter from the 

package.  
 
5. Place the vial on a flat surface. While holding the adapter package, place the vial adapter over 

the vial. Press down firmly on the package until the adapter snaps into place on top of the vial, 
with the adapter spike penetrating the vial stopper.  

 

 
 

6. Lift the package away from the adapter and discard the package. 
 

 
7. Attach the plunger rod to the solvent syringe by inserting the rod into the opening in the syringe 

stopper and pushing and turning the rod firmly until it is securely seated in the stopper. 
 



32 

8. Break off the tamper-resistant plastic tip cap from the solvent syringe by snapping the 
perforation of the cap. This is done by bending the cap up and down until the perforation is 
broken. Do not touch the inside of the cap or the syringe tip. The cap may need to be replaced (if 
not administering reconstituted ReFacto AF immediately), so set it aside by placing it on its top.  

 

 
 

9. Place the vial on a flat surface. Connect the solvent syringe to the vial adapter by inserting the 
tip of the syringe into the adapter opening while firmly pushing and turning the syringe 
clockwise until the connection is secured. 

 

 
 

10. Slowly depress the plunger rod to inject all the solvent into the ReFacto AF vial. 
 

 
 

11. With the syringe still connected to the adapter, gently rotate the vial until the powder is 
dissolved. 

 

 
 
12. The final solution must be inspected visually for particulate matter before administration. The 

solution will appear clear to slightly opalescent and colourless. 
 

Note: If you use more than one vial of ReFacto AF per infusion, each vial should be 
reconstituted as per the previous instructions. The solvent syringe should be removed, leaving 
the vial adapter in place, and a single large luer lock syringe may be used to draw back the 
reconstituted contents of each of the individual vials. 

 



33 

13. Ensuring that the syringe plunger rod is still fully depressed, invert the vial. Slowly draw back 
all the solution through the vial adapter into the syringe. 

 

 
 
14. Detach the syringe from the vial adapter by gently pulling and turning the syringe counter-

clockwise. Discard the vial with the adapter attached. 
 

Note: If the solution is not to be used immediately, the syringe cap is to be carefully replaced. 
Do not touch the syringe tip or the inside of the cap. 

 
ReFacto AF must be used within 3 hours of reconstitution. The reconstituted solution may be stored at 
room temperature prior to administration.  
 
Administration (Intravenous Infusion): 
 
ReFacto AF should be administered using the infusion set provided in this kit and the pre-filled solvent 
syringe provided or a single sterile disposable plastic luer lock syringe.  
 
1. Attach the syringe to the luer end of the infusion set tubing. 
 
2. Apply a tourniquet and prepare the injection site by wiping the skin well with an alcohol swab 

provided in the kit. 

 
3. Insert the needle on the infusion set tubing into the vein as instructed by your doctor, and 

remove the tourniquet. Remove any air in the infusion set tubing by drawing back on the 
syringe. The reconstituted product is to be injected intravenously over several minutes. Your 
doctor may change your recommended infusion rate to make the infusion more comfortable. 

 

 
 
Please dispose of all unused solution, the empty vial(s) and the used needles and syringes in an 
appropriate container for throwing away of medical waste as these materials may hurt others if not 
disposed of properly. 
 
If you use more ReFacto AF than you should 
 
Check with your doctor or pharmacist. 
 



34 

If you stop using ReFacto AF 
 
Do not stop using ReFacto AF without consulting your doctor. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects  
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Allergic reactions 
 
If severe, sudden allergic reactions (anaphylactic) occur, the infusion must be stopped 
immediately. You must contact your doctor immediately if you have any of the following early 
symptoms of allergic reactions: 

• rash, hives, wheals, generalised itching 
• swelling of lips and tongue 
• difficulty in breathing, wheezing, tightness in the chest 
• general feeling of being unwell 
• dizziness and loss of consciousness 

 
Severe symptoms, including difficulty in breathing and (nearly) fainting, require prompt emergency 
treatment. Severe, sudden allergic (anaphylactic) reactions are uncommon (may affect up to 1 in 100 
people). 
 
Inhibitor development 
 
For children not previously treated with factor VIII medicines, inhibitor antibodies (see section 2) may 
form very commonly (more than 1 in 10 patients); however patients who have received previous 
treatment with factor VIII (more than 150 days of treatment) the risk is uncommon (less than 1 in 100 
patients). If this happens, your or your child’s medicines may stop working properly and you or your 
child may experience persistent bleeding. If this happens, you should contact your doctor immediately. 
 
Very common side effects (may affect more than 1 in 10 people) 

• inhibitor development for patients who have never been previously treated with factor VIII 
products 

• headache 
• cough 
• joint pain 
• fever 

 
Common side effects (may affect up to 1 in 10 people) 

• bleeding  
• dizziness 
• decreased appetite, diarrhoea, vomiting, stomach pain, nausea 
• hives, rash, itching 
• muscular pain  
• chills, catheter site reaction 
• certain blood tests may show an increase in antibodies to factor VIII 

 
Uncommon side effects (may affect up to 1 in 100 people) 

• inhibitor development for patients who have been previously treated with factor VIII products 
(less than 1 in 100 patients) 



35 

• severe allergic reaction 
• numbness, sleepiness, altered taste 
• chest pain, rapid heart beat, palpitations 
• low blood pressure, pain and redness of veins associated with a blood clot, flushing 
• shortness of breath 
• excessive sweating 
• weakness, injection site reactions including pain 
• slight increase in heart enzymes 
• increased liver enzymes, increased bilirubin 

 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store ReFacto AF 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the outer carton and vial label after 
EXP. The expiry date refers to the last day of that month. 
 
Store and transport refrigerated (2°C – 8°C). Do not freeze, in order to prevent damage to the pre-filled 
solvent syringe. 
 
For your convenience, the medicine can be removed from such storage for one single period of 
maximum 3 months at room temperature (up to 25°C). At the end of this room temperature storage 
period, the product must not be put back in the refrigerator, but must be used or discarded. Record on 
the outer carton the date ReFacto AF is removed from the refrigerator and set at room temperature (up 
to 25oC). Keep the vial in the outer carton in order to protect from light. 
 
Use the reconstituted solution within 3 hours of reconstitution. 
 
The solution will be clear to slightly opalescent and colourless. Do not use this medicine if you notice 
that it is cloudy or contains visible particles. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What ReFacto AF contains 
 
- The active substance is moroctocog alfa (recombinant coagulation factor VIII). Each vial of 

ReFacto AF contains nominally 250, 500, 1000, or 2000 IU of moroctocog alfa. 
 
- The other ingredients are sucrose, calcium chloride dihydrate, L-histidine, polysorbate 80 and 

sodium chloride. A solvent [sodium chloride 9 mg/ml (0.9%) solution for injection] is also 
supplied for reconstitution. 

 
- After reconstitution with the supplied solvent [sodium chloride 9 mg/ml (0.9%) solution], each 

vial contains 62.5, 125, 250, or 500 IU, respectively (based on the strength of moroctocog alfa, 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


36 

i.e., 250, 500, 1000, or 2000 IU), of moroctocog alfa per 1 ml of the prepared solution for 
injection. 

 
What ReFacto AF looks like and contents of the pack 
 
ReFacto AF is provided as a powder for injection in a glass vial and a solvent is provided in a pre-
filled syringe. 
 
The contents of the pack are: 
- one vial of moroctocog alfa 250, 500, 1000, or 2000 IU powder 
- one pre-filled syringe of solvent, 4 ml sterile sodium chloride 9 mg/ml (0.9 %) solution for 

injection for reconstitution, with one plunger rod 
- one sterile vial adapter reconstitution device 
- one sterile infusion set 
- two alcohol swabs 
- one plaster 
- one gauze pad 
 
Marketing Authorisation Holder 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
Manufacturers 
 
Wyeth Farma S.A. 
Autovia del Norte A-1 Km 23 
Desvio Algete Km 1 
28700 San Sebastian de los Reyes 
Madrid 
Spain 
 
 
For any information about this medicinal product, please contact the local representative of the 
Marketing Authorisation Holder: 
 

België /Belgique / Belgien 
Pfizer S.A./N.V.  
Tél/Tel: +32 (0)2 554 62 11 

Lietuva 
Pfizer Luxembourg SARL filialas Lietuvoje 
Tel. +3705 2514000 

България  
Пфайзер Люксембург САРЛ, Клон 
България  
Тел.: +359 2 970 4333 

Luxembourg/Luxemburg 
Pfizer S.A. 
Tél/Tel: +32 (0)2 554 62 11 

Česká Republika 
Pfizer PFE, spol. s r.o. 
Tel: +420 283 004 111 

Magyarország 
Pfizer Kft. 
Tel.: + 36 1 488 37 00 



37 

Danmark 
Pfizer ApS 
Tlf: +45 44 20 11 00 

Malta 
Vivian Corporation Ltd. 
Tel: +35621 344610 
 

Deutschland 
Pfizer Pharma GmbH 
Tel: +49 (0)30 550055 51000 

Nederland 
Pfizer bv 
Tel: +31 (0)10 406 43 01 

Eesti 
Pfizer Luxembourg SARL Eesti filiaal 
Tel: +372 666 7500 

Norge 
Pfizer Norge AS 
Tlf: +47 67 526 100 

Ελλάδα 
PFIZER ΕΛΛΑΣ Α.Ε 
Τηλ:   +30 210 678 5800 

Österreich 
Pfizer Corporation Austria Ges.m.b.H. 
Tel: +43 (0)1 521 15-0 

España 
Pfizer S.L. 
Tel: +34 91 490 99 00 

Polska 
Pfizer Polska Sp. z o.o. 
Tel.: +48 22 335 61 00 

France 
Pfizer  
Tél: +33 (0)1 58 07 34 40 

Portugal 
Pfizer Biofarmacêutica, Sociedade Unipessoal Lda 
Tel: +351 21 423 5500 

Hrvatska 
Pfizer Croatia d.o.o. 
Tel: + 385 1 3908 777 

România 
Pfizer România S.R.L. 
Tel: +40 21 207 28 00 

Ireland 
Pfizer Healthcare Ireland 
Tel: 1800 633 363 (toll free) 
+44 (0)1304 616161 

Slovenija 
Pfizer Luxembourg SARL 
Pfizer, podružnica za svetovanje s področja 
farmacevtske dejavnosti, Ljubljana  
Tel: + 386 (0) 1 52 11 400 
 

Ísland 
Icepharma hf. 
Sími: + 354 540 8000 

Slovenská republika 
Pfizer Luxembourg SARL, organizačná zložka  
Tel: +421-2-3355 5500 

Italia 
Pfizer S.r.l. 
Tel: +39 06 33 18 21 

Suomi/Finland 
Pfizer Oy 
Puh/Tel: +358 (0)9 43 00 40 

Κύπρος 
PFIZER ΕΛΛΑΣ Α.Ε. (CYPRUS 
BRANCH) 
Τηλ: +357 22 817690 

Sverige  
Pfizer Innovations AB 
Tel:  + 46 (0)8 550 520 00 



38 

Latvija 
Pfizer Luxembourg SARL filiāle Latvijā 
Tel: +371 670 35 775 

United Kingdom 
Pfizer Limited 
Tel: +44 (0)1304 616161 

 
This leaflet was last revised in  
 
Detailed information on this medicine is available on European Medicines Agency website: 
http://www.ema.europa.eu. 
 
 

http://www.ema.europa.eu/


39 

 
Package leaflet: Information for the user 

 
 ReFacto AF 250 IU powder and solvent for solution for injection in pre-filled syringe  
 ReFacto AF 500 IU powder and solvent for solution for injection in pre-filled syringe 
 ReFacto AF 1000 IU powder and solvent for solution for injection in pre-filled syringe 
 ReFacto AF 2000 IU powder and solvent for solution for injection in pre-filled syringe 
 ReFacto AF 3000 IU powder and solvent for solution for injection in pre-filled syringe 

 
Moroctocog alfa (recombinant human coagulation factor VIII) 

 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
 
- Keep this leaflet. You may need to read it again. 
- If you have further questions, please ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet:  
 
1. What ReFacto AF is and what it is used for 
2. What you need to know before you use ReFacto AF  
3. How to use ReFacto AF  
4. Possible side effects 
5 How to store ReFacto AF 
6. Contents of the pack and other information 
 
 
1. What ReFacto AF is and what it is used for 
 
ReFacto AF contains the active substance moroctocog alfa, human coagulation factor VIII. Factor VIII 
is necessary for the blood to form clots and stop bleedings. In patients with haemophilia A (inborn 
factor VIII deficiency), it is missing or not working properly. 
 
ReFacto AF is used for the treatment and prevention of bleeding (prophylaxis) in adults and children 
of all ages (including newborns) with haemophilia A. 
 
 
2. What you need to know before you use ReFacto AF 
 
Do not use ReFacto AF  
 
- if you are allergic to moroctocog alfa or any of the other ingredients of this medicine (listed in 

section 6). 
 
- if you are allergic to hamster proteins. 
 
If you are unsure about this, ask your doctor. 
 
Warnings and precautions  
 
Talk to your doctor or pharmacist before using ReFacto AF 
- if you experience allergic reactions. Some of the signs of allergic reactions are difficulty in 

breathing, shortness of breath, swelling, hives, itching, tightness of the chest, wheezing, and low 



40 

blood pressure. Anaphylaxis is a severe allergic reaction that can cause difficulty in swallowing 
and/or breathing, red or swollen face and/or hands. If any of these signs occur, stop the infusion 
immediately and contact a doctor or seek immediate emergency care. In case of severe allergic 
reactions, alternative therapy must be considered. 

 
- the formation of inhibitors (antibodies) is a known complication that can occur during treatment 

with all factor VIII medicines. These inhibitors, especially at high levels, stop the treatment 
working properly and you or your child will be monitored carefully for the development of these 
inhibitors. If your or your child’s bleeding is not being controlled with ReFacto AF, tell your 
doctor immediately. 

 
- if your bleeding does not stop as expected and contact your doctor or seek immediate emergency 

care.  
 
Other medicines and ReFacto AF 
 
Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines. 
 
Pregnancy, breast-feeding and fertility 
 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before using this medicine. 
 
Driving and using machines 
 
ReFacto AF has no influence on the ability to drive or use machines. 
 
ReFacto AF contains sodium 
 
ReFacto AF contains 1.23 mmol (or 29 mg) sodium per pre-filled syringe of reconstituted powder. 
Inform your doctor if you are on a controlled sodium diet. 
 
 
3. How to use ReFacto AF  
 
Always use this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if 
you are not sure.  
 
Treatment with ReFacto AF should be started by a doctor who is experienced in the care of patients 
with haemophilia A. Your doctor will decide the dose of ReFacto AF you will receive. This dose and 
duration will depend upon your individual needs for replacement factor VIII therapy. ReFacto AF is 
given by injection into a vein lasting several minutes. Patients or their carers can give injections of 
ReFacto AF, provided that they have been trained appropriately. 
 
During your treatment, your doctor may decide to change the dose of ReFacto AF you receive. 
Consult with your health care provider before you travel. You should bring enough of your factor VIII 
product for anticipated treatment when travelling.  
 
It is recommended that every time you use ReFacto AF, you record the name on the carton and batch 
number of the product. You can use one of the peel-off labels found on the pre-filled syringe to 
document the batch number in your diary or for reporting any side effects. 
 
Reconstitution and administration  
 
The procedures below are provided as guidelines for the reconstitution and administration of ReFacto 
AF provided in a pre-filled syringe. Patients should follow the specific reconstitution and 
administration procedures provided by their doctors. 



41 

 
ReFacto AF is administered by intravenous (IV) infusion after reconstitution. The pre-filled syringe 
consists of 2 chambers, one chamber contains the ReFacto AF lyophilised powder and the other 
chamber contains the solvent [sodium chloride 9 mg/ml (0.9%) solution]. For the purposes of these 
instructions, this device will be referred to as a pre-filled syringe. 
 
Use only the pre-filled syringe provided in the box for reconstitution. Other sterile disposable syringes 
may be used for administration. 
 
ReFacto AF should not be mixed with other infusion solutions. 
 
Note: If you need to use more than one pre-filled syringe of ReFacto AF per infusion, each syringe 
should be reconstituted according to the specific directions. A separate 10 cc or larger luer lock syringe 
(not included in this kit) may be used to draw back the reconstituted contents of each syringe (see 
Additional Instructions) 
 
Preparation 
 

1. Always wash your hands before performing the following procedures. 
2. Aseptic technique (meaning clean and germ-free) should be used during the reconstitution 

procedure. 
3. All components used in the reconstitution and administration of this product should be used as 

soon as possible after opening their sterile containers, to minimise unnecessary exposure to the 
air. 
 

Reconstitution 
 

1. Allow the pre-filled syringe to reach room temperature.  
2. Remove the contents of the ReFacto AF pre-filled syringe kit and place on a clean surface, 

making sure you have all the supplies you will need. 
3. Grasp the plunger rod as shown in the following diagram. Screw the plunger rod firmly into 

the opening in the finger rest of the ReFacto AF pre-filled syringe by pushing and turning 
clockwise firmly until resistance is felt (approximately 2 turns). 

 

 
 

Throughout the reconstitution process, it is important to keep the ReFacto AF pre-filled syringe 
upright (with the white powder above the clear solution) to prevent possible leakage.  
 



42 

4. Holding the pre-filled syringe upright, remove the white tamper-evident seal by bending the 
seal right to left (or a gentle rocking motion) to break the perforation of the cap and expose the 
grey rubber tip cap of the ReFacto AF pre-filled syringe. 

 

 
 

5. Remove the protective blue vented sterile cap from its packaging. 
 

Whilst continuing to hold the ReFacto AF pre-filled syringe upright, remove the grey rubber tip 
cap and replace it with the protective blue vented cap. This vented cap has tiny holes that allow air 
to escape in order to prevent pressure build-up. Avoid touching the open end of the syringe or the 
protective blue vented cap.  
 

 
 
6. Gently and slowly advance the plunger rod by pushing until the two plungers inside the 

pre-filled syringe meet, and all of the solvent is transferred to the top chamber containing the 
ReFacto AF powder. 

 
Note: To prevent the escape of fluid from the tip of the syringe, do not push the plunger rod with 
excessive force. 
 

 
 



43 

7. With the ReFacto AF pre-filled syringe remaining upright, swirl gently several times until the 
powder is dissolved. 

 

 
 
Look at the final solution to check for particulate matter or discolouration. The solution should 
appear clear to slightly opalescent and colourless. Discard the pre-filled syringe if visible 
particulate matter or discolouration is observed. 
 
8. Continuing to hold the ReFacto AF pre-filled syringe in an upright position, slowly advance 

the plunger rod until most, but not all, of the air is removed from the (top) chamber. 
 

 
 
ReFacto AF should be infused within 3 hours after either reconstitution or removal of the grey tip 
cap from the pre-filled syringe.  
 

If you are not going to use the ReFacto AF solution immediately, you should store the syringe in an 
upright position, with the protective blue vented cap on the pre-filled syringe until you are ready to 
infuse. The reconstituted solution may be stored at room temperature for up to 3 hours. If you have not 
used it within 3 hours, throw it away. 
 
Administration (Intravenous Infusion) 
 
Your doctor or other healthcare professional should teach you how to infuse ReFacto AF. Once you 
learn how to self-infuse, you can follow the instructions in this Package Leaflet.  
 
ReFacto AF is administered by intravenous (IV) infusion after reconstitution of the powder with the 
solvent (0.9% sodium chloride). Once reconstituted, ReFacto AF should be inspected for particulate 
matter and discolouration prior to administration.  
 
ReFacto AF should be administered using the infusion set included in the kit, unless otherwise advised 
by your doctor or other healthcare professional. 
 



44 

1. Remove the protective blue vented cap and firmly attach the intravenous infusion set provided 
onto the ReFacto AF pre-filled syringe. 

 

 
 
2. Apply a tourniquet and prepare the injection site by wiping the skin well with an alcohol swab 

provided in the kit. 
 

 
 

3. Remove the protective needle cover and insert the butterfly needle of the infusion set tubing 
into your vein, as instructed by your doctor or other healthcare professional. Remove the 
tourniquet. The reconstituted ReFacto AF product should be injected intravenously over 
several minutes. Your doctor may change your recommended infusion rate to make the 
infusion more comfortable. Discuss your intravenous infusion procedure with your doctor or 
other healthcare professional. Do not attempt self-infusion unless properly trained. 

 

 
 
Reconstituted ReFacto AF must not be administered in the same tubing or container with other 
medicinal products. 
 



45 

4. After infusing ReFacto AF, remove the infusion set and discard. The amount of drug product 
left in the infusion set will not affect your treatment.  

 
Note: Please dispose of all unused solution, the empty pre-filled syringe, and the used medical 
supplies in an appropriate container for throwing away medical waste, as these materials may hurt 
others if not disposed of properly.  

 

 
 
It is recommended to record the lot number from the ReFacto AF pre-filled syringe label every time 
you use ReFacto AF. You can use the peel-off label found on the ReFacto AF pre-filled syringe to 
record the lot number.  
 
Additional Instructions: 
 
Multiple ReFacto AF in Pre-filled Syringe Reconstitution to a 10 cc or Larger Luer Lock 
Syringe (10 cc or larger luer lock syringes not provided) 
 
The instructions below are for the use of multiple ReFacto AF pre-filled syringe kits with a 10 cc or 
larger luer lock syringe.  

1. Reconstitute all ReFacto AF pre-filled syringes according to instructions shown above in 
the reconstitution directions (see Reconstitution and Administration). 

 
Holding the ReFacto AF pre-filled syringe in an upright position, slowly advance the 
plunger rod until most, but not all, of the air is removed from the drug product chamber. 

 

 
 

2. Remove the luer-to-luer syringe connector from its package (luer-to-luer syringe 
connectors are not provided). 

 



46 

3. Connect a sterile 10 cc or larger luer lock syringe to one opening (port) in the syringe 
connector and the ReFacto AF pre-filled syringe to the remaining open port on the 
opposite end. 

 

 
 

4. With the ReFacto AF pre-filled syringe on top, slowly depress the plunger rod until the 
contents empty into the 10 cc or larger luer lock syringe. 

 

 
 

5. Remove the empty ReFacto AF pre-filled syringe and repeat procedures 3 and 4 above for 
any additional reconstituted syringes. 

 
6. Remove the luer-to-luer syringe connector from the 10 cc or larger luer lock syringe and 

attach the infusion set, as described above in the directions for administration of the 
pre-filled syringe [see Administration (Intravenous Infusion)]. 

 
Note: Please dispose of all unused solution, the empty pre-filled syringe, and the used medical 
supplies in an appropriate container for throwing away medical waste, as these materials may 
hurt others if not disposed of properly. 

 

 
 
If you use more ReFacto AF than you should 
 
Check with your doctor or pharmacist. 
 



47 

If you stop using ReFacto AF 
 
Do not stop using ReFacto AF without consulting your doctor. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects  
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Allergic reactions 
 
If severe, sudden allergic reactions (anaphylactic) occur, the infusion must be stopped 
immediately. You must contact your doctor immediately if you have any of the following early 
symptoms of allergic reactions: 
 

• rash, hives, wheals, generalised itching 
• swelling of lips and tongue 
• difficulty in breathing, wheezing, tightness in the chest 
• general feeling of being unwell 
• dizziness and loss of consciousness 

 
Severe symptoms, including difficulty in breathing and (nearly) fainting, require prompt emergency 
treatment. Severe, sudden allergic (anaphylactic) reactions are uncommon (may affect up to 1 in 100 
people). 
 
Inhibitor development 
 
For children not previously treated with factor VIII medicines, inhibitor antibodies (see section 2) may 
form very commonly (more than 1 in 10 patients); however patients who have received previous 
treatment with factor VIII (more than 150 days of treatment) the risk is uncommon (less than 1 in 100 
patients). If this happens, your or your child’s medicines may stop working properly and you or your 
child may experience persistent bleeding. If this happens, you should contact your doctor immediately. 

 
Very common side effects (may affect more than 1 in 10 people) 

• inhibitor development for patients who have never been previously treated with factor VIII 
products 

• headache 
• cough 
• joint pain 
• fever 

 
Common side effects (may affect up to 1 in 10 people) 

• bleeding  
• dizziness 
• decreased appetite, diarrhoea, vomiting, stomach pain, nausea 
• hives, rash, itching 
• muscular pain  
• chills, catheter site reaction 
• certain blood tests may show an increase in antibodies to factor VIII 

 
Uncommon side effects (may affect up to 1 in 100 people) 

• inhibitor development for patients who have been previously treated with factor VIII products 
(less than 1 in 100 patients) 

• severe allergic reaction 



48 

• numbness, sleepiness, altered taste 
• chest pain, rapid heart beat, palpitations 
• low blood pressure, pain and redness of veins associated with a blood clot, flushing 
• shortness of breath 
• excessive sweating 
• weakness, injection site reactions including pain 
• slight increase in heart enzymes 
• increased liver enzymes, increased bilirubin 

 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store ReFacto AF  
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the outer carton and pre-filled syringe 
label after EXP. The expiry date refers to the last day of that month. 
 
Store and transport refrigerated (2°C – 8°C). Do not freeze, in order to prevent damage to the pre-filled 
syringe. 
 
For your convenience, the medicine can be removed from such storage for one single period of 
maximum 3 months at room temperature (up to 25°C). At the end of this room temperature storage 
period, the product must not be put back in the refrigerator, but must be used or discarded. Record on 
the outer carton the date ReFacto AF pre-filled syringe is removed from the refrigerator and set at 
room temperature (up to 25oC).  
 
Keep the pre-filled syringe in the outer carton in order to protect from light. 
 
Use the reconstituted solution within 3 hours of reconstitution or removal of the grey tip cap. 
 
The solution will be clear to slightly opalescent and colourless. Do not use this medicine if you notice 
that it is cloudy or contains visible particles. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


49 

 
6. Contents of the pack and other information 
 
What ReFacto AF contains 
 
- The active substance is moroctocog alfa (recombinant coagulation factor VIII). Each pre-filled 

syringe of ReFacto AF contains nominally 250, 500, 1000, 2000, or 3000 IU of moroctocog 
alfa. 

 A solvent [sodium chloride 9 mg/ml (0.9%) solution for injection] is included within the 
ReFacto AF pre-filled syringe for reconstituting moroctocog alfa. 

 
- The other ingredients are sucrose, calcium chloride dihydrate, L-histidine, polysorbate 80 and 

sodium chloride.  
 
- After reconstitution with the supplied solvent [sodium chloride 9 mg/ml (0.9%) solution], the 

prepared solution for injection contains either 62.5, 125, 250, 500 or 750 IU of moroctocog alfa 
per ml, respectively (based on the strength of moroctocog alfa, i.e., 250, 500, 1000, 2000, or 
3000 IU). 

 
What ReFacto AF looks like and contents of the pack 
 
ReFacto AF is provided as a powder and solvent for solution for injection in a pre-filled syringe that 
contains the ReFacto AF powder in the top chamber and the solvent [sodium chloride 9 mg/ml (0.9%) 
solution] in the bottom chamber. 
 
The contents of the pack are: 
- one pre-filled syringe containing moroctocog alfa 250, 500, 1000, 2000, or 3000 IU powder and 

solvent, 4 ml sterile sodium chloride 9 mg/ml (0.9 %) solution for injection for reconstitution 
- one plunger rod 
- one protective blue vented sterile cap 
- one sterile infusion set 
- two alcohol swabs 
- one plaster 
- one gauze pad 
 
Marketing Authorisation Holder 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
Manufacturer 
 
Wyeth Farma S.A. 
Autovia del Norte A-1 Km 23 
Desvio Algete Km 1 
28700 San Sebastian de los Reyes 
Madrid 
Spain 
 
 



50 

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 

België /Belgique / Belgien 
Pfizer S.A./N.V.  
Tél/Tel: +32 (0)2 554 62 11 

Lietuva 
Pfizer Luxembourg SARL filialas Lietuvoje 
Tel. +3705 2514000 

България  
Пфайзер Люксембург САРЛ, Клон 
България  
Тел.: +359 2 970 4333 

Luxembourg/Luxemburg 
Pfizer S.A. 
Tél/Tel: +32 (0)2 554 62 11 

Česká Republika 
Pfizer PFE, spol. s r.o. 
Tel: +420 283 004 111 

Magyarország 
Pfizer Kft. 
Tel.: + 36 1 488 37 00 

Danmark 
Pfizer ApS 
Tlf: +45 44 20 11 00 

Malta 
Vivian Corporation Ltd. 
Tel: +35621 344610 
 

Deutschland 
Pfizer Pharma GmbH 
Tel: +49 (0)30 550055 51000 

Nederland 
Pfizer bv 
Tel: +31 (0)10 406 43 01 

Eesti 
Pfizer Luxembourg SARL Eesti filiaal 
Tel: +372 666 7500 

Norge 
Pfizer Norge AS 
Tlf: +47 67 526 100 

Ελλάδα 
PFIZER ΕΛΛΑΣ Α.Ε.Τηλ:   +30 210 678 
5800 

Österreich 
Pfizer Corporation Austria Ges.m.b.H. 
Tel: +43 (0)1 521 15-0 

España 
Pfizer S.L. 
Tel: +34 91 490 99 00 

Polska 
Pfizer Polska Sp. z o.o., 
Tel.: +48 22 335 61 00 

France 
Pfizer  
Tél: +33 (0)1 58 07 34 40 

Portugal 
Pfizer Biofarmacêutica, Sociedade Unipessoal Lda 
Tel: +351 21 423 5500 

Hrvatska 
Pfizer Croatia d.o.o. 
Tel: + 385 1 3908 777 

România 
Pfizer România S.R.L. 
Tel: +40 21 207 28 00 

Ireland 
Pfizer Healthcare Ireland 
Tel: 1800 633 363 (toll free) 
+44 (0)1304 616161 

Slovenija 
Pfizer Luxembourg SARL 
Pfizer, podružnica za svetovanje s področja 
farmacevtske dejavnosti, Ljubljana  
Tel: + 386 (0) 1 52 11 400 



51 

 

Ísland 
Icepharma hf. 
Sími: + 354 540 8000 

Slovenská republika 
Pfizer Luxembourg SARL, organizačná zložka  
Tel: +421-2-3355 5500 

Italia 
Pfizer S.r.l. 
Tel: +39 06 33 18 21 

Suomi/Finland 
Pfizer Oy 
Puh/Tel: +358 (0)9 43 00 40 

Κύπρος 
PFIZER ΕΛΛΑΣ Α.Ε. (CYPRUS 
BRANCH) 
Τηλ: +357 22 817690 

Sverige  
Pfizer Innovations AB 
Tel:  + 46 (0)8 550 520 00 

Latvija 
Pfizer Luxembourg SARL filiāle Latvijā 
Tel: +371 670 35 775 

United Kingdom 
Pfizer Limited 
Tel: +44 (0)1304 616161 

This leaflet was last revised in  
 
Detailed information on this medicine is available on European Medicines Agency website: 
http://www.ema.europa.eu/. 
 
 
 

http://www.ema.europa.eu/

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET